Drugs for treating urinary schistosomiasis

  • Review
  • Intervention

Authors


Abstract

Background

Urinary schistosomiasis is caused by an intravascular infection with parasitic Schistosoma haematobium worms. The adult worms typically migrate to the venous plexus of the human bladder and excrete eggs which the infected person passes in their urine. Chronic infection can cause substantial morbidity and long-term complications as the eggs become trapped in human tissues causing inflammation and fibrosis. We summarised evidence of drugs active against the infection. This is new edition of a review first published in 1997.

Objectives

To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis.

Search methods

We searched the Cochrane Infectious Diseases Group Specialized Register, MEDLINE, CENTRAL, EMBASE and LILACS and reference lists of articles up to 23 May 2014.

Selection criteria

Randomized controlled trials (RCTs) of antischistosomal drugs and drug combinations compared to placebo, no intervention, or each other.

Data collection and analysis

Two researchers independently screened the records, extracted the data and assessed risk of bias. The primary efficacy outcomes were parasitological failure (defined as the continued presence of S. haematobium eggs in the urine at time points greater than one month after treatment), and percent reduction of egg counts from baseline. We presented dichotomous data as risk ratios (RR), and continuous data as mean difference (MD), alongside their 95% confidence intervals (CIs). Where appropriate we combined trials in meta analyses or tables. We assessed the quality of evidence using the GRADE approach.

Main results

We included 30 RCTs enrolling 8165 participants in this review. Twenty-four trials were conducted in children in sub-Saharan Africa, and 21 trials were over 20 years old. Many studies were assessed as being at unclear risk of bias due to inadequate descriptions of study methods.

Praziquantel

On average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting eggs in their urine by around 60% compared to placebo at one to two months after treatment (treatment failure: RR 0.42, 95% CI 0.29 to 0.59, 864 participants, seven trials, high quality evidence). The proportion of people cured with praziquantel varied substantially between trials, from 22.5% to 83.3%, but was higher than 60% in five of the seven trials. At one to two months following praziquantel treatment at 40 mg/kg, the mean number of schistosome eggs in the urine was reduced by over 95% in five out of six trials (678 participants, six trials, high quality evidence).

Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose, and in a single trial of 220 participants the split dose caused more vomiting (RR 0.5, 95% CI 0.29 to 0.86) and dizziness (RR 0.39, 95% CI 0.16 to 0.94).

Metrifonate

A single dose of metrifonate 10 mg/kg reduced egg excretion (210 participants, one trial, at eight months), but was only marginally better than placebo at achieving cure at one month (RR 0.83, 95% CI 0.74 to 0.94, 142 participants, one trial). In a single trial comparing one, two and three doses, the absolute number of participants cured improved from 47% after one dose to 81% after three doses (93 participants, one trial, low quality evidence).

Two small trials compared 40 mg/kg single dose praziquantel with two or three doses of 10 mg/kg metrifonate and found no clear evidence of differences in cure (metrifonate 2 x 10 mg/kg at one month: RR 1.03, 95% CI 0.8 to 1.34, 72 participants, one trial; metrifonate 3 x 10 mg/kg at three months: RR 0.33, 95% CI 0.07 to 1.57, 100 participants, one trial. In one trial both drugs performed badly and in one trial both performed well.

Other drugs

Three trials have evaluated the antimalarial artesunate; with inconsistent results. Substantial antischistosomal effects were only seen in one of the three trials, which was at unclear risk of bias due to poor reporting of the trial methods. Similarly, another anti-malarial mefloquine has been evaluated in two small trials with inconsistent effects.

Adverse events were described as mild for all evaluated drugs, but adverse event monitoring and reporting was generally of low quality.

Authors' conclusions

Praziquantel 40 mg/kg is the most studied drug for treating urinary schistosomiasis, and has the strongest evidence base.

Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarial drugs with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous, adequately powered trials using standardized outcome measures.

Plain language summary

Drugs for treating urinary schistosomiasis

What is urinary schistosomiasis and how is it treated?

Urinary schistosomiasis is a disease caused by infection of people with the parasitic worm Schistosoma haematobium. These worms live in blood vessels around the infected person's bladder and the worm releases eggs which are released in the person's urine. If the urine is passed into ponds or lakes, the eggs can hatch and infect people that are washing or swimming there. Infection can cause blood in the urine and if left untreated can eventually lead to anaemia, malnutrition, kidney failure, or bladder cancer. Urinary schistosomiasis is diagnosed by looking for worm eggs in the urine.

The disease occurs mainly in school-aged children and young adults in sub-Saharan Africa. The drug currently recommended for treatment is praziquantel, which can be given as a single dose, but other drugs such as metrifonate, artesunate, and mefloquine have also been evaluated.

After examining the research published up to 23th May 2014, we included 30 randomized controlled trials, enrolling 8165 children and adults.

What does the research say?

On average, the standard dose of praziquantel cures around 60% of people at one to two months after treatment (high quality evidence), and reduces the number of schistosome eggs in the urine by over 95% (high quality evidence).

Metrifonate, an older drug no longer in use, had little effect when given as a single dose but an improved effect when given as multiple doses two weeks apart. Two trials compared three doses of metrifonate with the single dose of praziquantel and found similar effects.

Two more recent trials evaluated a combination of artesunate and praziquantel compared to praziquantel alone. In one trial artesunate improved cure and in one it made no difference.

Authors conclusions

Future treatments for schistosomiasis could include combining praziquantel with metrifonate, or with artesunate, but these need to be evaluated in high quality trials.

Резюме на простом языке

Лекарства для лечения мочеполового шистосомоза

Что такое мочеполовой шистосомоз и как он лечится?

Мочеполовой шистосомоз - это инфекционное заболевание людей, вызываемое паразитическим червем Schistosoma haematobium. Эти черви живут в кровеносных сосудах вокруг мочевого пузыря инфицированного человека и откладывают яйца, которые выделяются в мочу человека. Если такая моча попадет в водоемы, яйца могут вылупиться и заразить тех, кто там плавает или купается. Инфекция может вызвать появление крови в моче, и если оставить ее без лечения, может привести к анемии, недостаточному питанию (потере веса), почечной недостаточности или раку мочевого пузыря. Мочеполовой шистосомоз диагностируют по наличию личинок червей в моче.

Заболевание встречается преимущественно у детей школьного возраста и молодых людей в странах Африки к югу от Сахары. В настоящее время рекомендуемый препарат для лечения - празиквантел, который дается как однократная доза. Но и другие лекарства, такие как метрифонат, артесунат и мефлохин также изучаются.

Изучив исследования, опубликованные по 23 мая 2014 года, мы отобрали и включили 30 рандомизированных контролируемых испытаний с участием 8165 детей и взрослых.

О чем говорит это исследование?

Стандартная доза празиквантела излечивает в среднем около 60% людей в течение одного-двух месяцев после начала лечения (высокое качество доказательств), и уменьшает число личинок шистосом в моче более чем на 95% (высокое качество доказательств).

Метрифонат, более старый препарат, который сейчас не используется, имел незначительный эффект при введении однократной дозы, но показал хороший результат при введении нескольких доз с промежутком в две недели. В двух испытаниях сравнили метрифонат (три дозы) с однократным введением празиквантела (одна доза) и выявили схожие результаты по эффективности.

В еще двух последних испытаниях оценили эффективность артесуната в сочетании с празиквантелом по сравнению с празиквантелом отдельно. В одном испытании артесунат улучшил излечение, в другом - не было различий.

Выводы авторов

Будущие методы лечения шистосомоза могут включать комбинацию празиквантела с метрифонатом или с артесунатом, но эти методы должны быть оценены в испытаниях высокого качества.

Заметки по переводу

Перевод: Махмутова Джамиля Маратовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Praziquantel 40 mg/kg versus placebo for treating urinary schistosomiasis
  1. 1 No serious risk of bias: Several trials were at unclear or low risk of selection bias. However, a sensitivity analysis excluding these trials still found a strong effect.
    2 No serious inconsistency: Six of the seven trials found large consistent effects. The seventh trial found no difference, this may be explained by the different diagnostic criteria used in this trial.
    3 No serious indirectness: These seven trials are all conducted in children in endemic areas of sub-Saharan Africa.
    4 No serious imprecision: The result is statistically significant and the 95% CI is narrow around a clinically important effect.
    5 No serious imprecision: The trials are small and most did not report tests of statistical significance, however the differences are large.
    6 No serious risk of bias: This trial was well conducted.
    7 Downgraded by 1 for serious indirectness: Only a single trial reports this outcome. Further trials from different settings would be needed to be confident in this effect.
    8 Downgraded by 1 for serious imprecision: This trial is underpowered.
    9 Downgraded by 1 for serious risk of bias: both trials had inadequate sequence generation and allocation concealment.
    10 No serious inconsistency: Low statistical heterogeneity.
    11 No serious imprecision: only two trials reported this outcome. CIs are narrow. The effect is not statistically significant and does not appear to be clinically important, when compared to the baseline data.
    12 Downgraded by 2 for serious risk of bias: Three trials do not comment on adverse events. Six trials made comments that praziquantel was generally well tolerated and no statistically significant differences were noted. However, adverse events were poorly reported in all six trials such that meta-analysis, and assessment of other quality criteria was not possible.

Praziquantel 40 mg/kg versus placebo for treating urinary schistosomiasis
Patient or population: People with urinary schistosomiasis
Settings: Endemic areas in sub-Saharan Africa
Intervention: Praziquantel 40 mg/kg (single dose) versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
Placebo Praziquantel 40 mg/kg

Parasitological failure

At 1 to 2 months

91 per 100 38 per 100
(26 to 54)
RR 0.42
(0.29 to 0.59)
864
(7 trials)
⊕⊕⊕⊕
high 1,2,3,4
Percentage egg reduction
At 1 to 2 months
Mean change in egg excretion in the control groups ranged from a 53.2% reduction to a 138% increase.Mean egg excretion in the intervention groups was reduced by > 98% in all trialsNot pooled

678

(6 trials)

⊕⊕⊕⊕
high 1,2,3,5

Microhaematuria

At 8 weeks

53 per 100 28 per 100
(17 to 45)
RR 0.53
(0.33 to 0.84)
119
(1 trial)
⊕⊕⊝⊝
low 6,7,8

Haemoglobin

At 6 to 8 months

The mean haemoglobin ranged across control groups from
11.3 to 11.9 G/dL
The mean haemoglobin in the intervention groups was 0.08 G/dL lower
(0.24 lower to 0.09 higher)
727
(2 trials)
⊕⊕⊕⊝
moderate 3, 9,10 11
Adverse events1591
(9 trials)
⊕⊕⊝⊝
low 12
The basis for the assumed risk is the mean risk in the control groups across trials. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Praziquantel 40 mg/kg single dose versus 30 mg/kg single dose

Summary of findings 2. Praziquantel 40 mg/kg single dose versus 30 mg/kg single dose
  1. 1 Downgraded by 1 for serious risk of bias: None of the trials described a method of allocations concealment or blinding outcome assessors.
    2 No serious inconsistency: No statistical heterogeneity in the relative effect of the two praziquantel doses. However, treatment failure with praziquantel 40 mg/kg ranged from 0% to than more than 50%.
    3 No serious indirectness: All trials were conducted in sub-Saharan Africa, in patients aged from seven to 20 years.
    4 Downgraded by 1 for serious imprecision: None of the individual studies found statistical significant differences, and overall, the meta-analysis remains underpowered to confidently detect an effect.
    5 No serious inconsistency: Three of the four trials report the difference was not statistically significant. The fourth trial did not report significance but effects were similar.
    6 Downgraded by 1 for serious imprecision: We were unable to pool the data, and as such cannot exclude a small difference in effect between the two doses in a pooled analysis.
    7 No serious inconsistency. Low statistical heterogeneity.
    8 No serious imprecision. The effect is of no clinically important difference between the two doses, and the 95% CIs are narrow.
    9 Downgraded by 1 for serious inconsistency: In one trial praziquantel 40 mg/kg had a very low percent egg reduction of 46%. The reasons for this are unclear.
    10 Unable to assess precision as the data were not pooled.
    11 Downgraded by 1 for serious risk of bias: This trial did not adequately describe allocation concealment. Participants and clinicians were not blinded.
    12 Downgraded by 1 for serious indirectness: Only one trial from one setting.
    13 Downgraded by 1 for serious imprecision. This trial is underpowered to detect an effect. The 95% CI is wide and includes clinically important benefits and no effect.
    14 Downgraded by 2 for serious risk of bias. Six out of ten trials comparing praziquantel 40 mg/kg to lower doses did not comment on adverse events, and of the remaining only two used prospective active surveillance to monitor adverse events. Only two trials out of ten described blinding for clinicians or participants.

Praziquantel 40 mg/kg compared to praziquantel 30 mg/kg for treating urinary schistosomiasis
Patient or population: people with urinary schistosomiasis
Settings: endemic areas in Sub-Saharan Africa
Intervention: praziquantel 40 mg/kg (single dose)
Comparison: praziquantel 30 mg/kg (single dose)
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
Praziquantel 30 mg/kg single dose Praziquantel 40 mg/kg single dose
Parasitological failure
At 1 month
32 per 100 24 per 100
(19 to 32)
RR 0.76
(0.59 to 0.99)
401
(4 trials)
⊕⊕⊝⊝
low 1,2,3,4
Mean percent egg reduction
At 1 month
The mean reduction in control groups ranged from an 85% reduction to a 99% reduction.The mean reduction in the intervention groups was > 95% in all trialsNot pooled

362

(4 trials)

⊕⊕⊝⊝
low 1,3,5,6
Parasitological failure
At 6 months
29 per 100

28 per 100

(22 to 36)

RR 0.97

(0.76 to 1.23)

669

(6 trials)

⊕⊕⊕⊝

moderate

1,3,7,8

Mean percent egg reduction
At 6 months
The mean reduction in control groups ranged from an 97% reduction to a 99% reduction.The mean reduction in the intervention groups ranged from a 46% reduction15 to a 99% reductionNot pooled

362

(4 trials)

⊕⊕⊝⊝
low 1,3,9,10
Haematuria 26 per 100 23 per 1000
(12 to 44)
RR 0.89
(0.47 to 1.67)
117
(1 trial)
⊕⊝⊝⊝
very low 11,12,13
Proteinuria 15 per 100 13 per 100
(5 to 31)
RR 0.85
(0.34 to 2.12)
117
(1 trial)
⊕⊝⊝⊝
very low 11,12,13
Adverse eventsNot estimable992
(8 trials)
⊕⊕⊝⊝
low 14
*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Praziquantel 40 mg/kg multiple doses versus single dose

Summary of findings 3. Praziquantel 40 mg/kg multiple doses versus single dose
  1. 1 Downgraded by 2 for serious risk of bias. The one trial reporting the outcome did not report adequately on sequence generation and blinding. Allocation was not concealed, and loss to follow up was very high.
    2 No serious inconsistency: only one trial.
    3 No serious indirectness: only one trial.
    4 Downgraded by 1 for serious imprecision: This single trial is small and underpowered to reliably detect an effect.
    5 This trial did not report on adverse events.

Praziquantel 40 mg/kg multiple doses compared to single dose for treating urinary schistosomiasis
Patient or population: patients with treating urinary schistosomiasis
Settings: endemic settings
Intervention: Praziquantel 40 mg/kg multiple doses (every three months for two years)
Comparison: Praziquantel 40 mg/kg single dose
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Praziquantel 40 mg/kg single dosePraziquantel 40 mg/kg multiple doses

Parasitological failure

At 2 years

90 per 100 244 per 100
(132 to 450)
RR 2.71
(1.47 to 5.00)
62
(1 trial)
⊕⊝⊝⊝
very low 1,2,3,4
 

Mean percent egg reduction

At 2 years

This study reports a81% reduction after a single dose of praziquantelThis study reports a96% reduction after multiple doses of praziquantel

62

(1 trial)

⊕⊝⊝⊝
very low 1,2,3,4
 

Parasitological failure

At 3 years

63 per 100 56 per 100
(37 to 89)
RR 0.92
(0.59 to 1.42)
43
(1 trial)
⊕⊝⊝⊝
very low 1,2,3,4
 

Haematuria

At 3 years

48 per 100 34 per 100
(20 to 56)
RR 0.7
(0.42 to 1.17)
43
(1 trial)
⊕⊝⊝⊝
very low 1,2,3,4
 
Adverse eventsThis study reports a96% reduction after multiple doses of praziquantel

43

(1 trial)

⊕⊝⊝⊝
very low 5
 
*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 4 Metrifonate 3 x 7.5 mg/kg given two weeks apart versus placebo

Summary of findings 4. Metrifonate 3 x 7.5 mg/kg given two weeks apart versus placebo
  1. 1 Downgraded by 1 for serious risk of bias; the single trial reporting this outcome did not adequately describe sequence generation, allocation concealment and blinding of participants, clinicians or outcome assessors.
    2 No serious inconsistency. Only one trial.

    3 No serious indirectness. This single trial was conducted in children in rural sub-Saharan Africa.
    4 Downgraded by 1 for serious imprecision. The trial was underpowered.

    5 Downgraded by 1 for serious risk of bias. The trial did not report on sequence generation and allocation concealment. The study described blinding of participants, clinicians and outcome assessors.

    6 No serious imprecision. CIs are narrow and both CI limits have clinically important effects. The trial is adequately powered for this outcome.

    7 No serious imprecision. The difference in effect between metrifonate and placebo group is large.

    8 None of the trials reported on adverse events.

Metrifonate compared to placebo for treating urinary schistosomiasis
Patient or population: patients with treating urinary schistosomiasis
Settings: endemic settings
Intervention: metrifonate 3 x 7.5 mg/kg given two weeks apart
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
Placebo Metrifonate 3 x 7.5 mg/kg given two weeks apart

Parasitological failure

At 2 to 2.5 months

40 per 100

16 per 100

(12 to 22)

RR 0.41

(0.3 to 0.56)

93

(1 trial)

⊕⊕⊝⊝

low 1,2,3,4

Mean percent egg reduction

At 2 to 2.5 months

Egg excretion increased by 131% in the placebo group in this studyEgg excretion was reduced by 100% in this trial-

93

(1 trial)

⊕⊕⊝⊝

low 1,2,3,4

Parasitological failure

At 6 months

96 per 100

29 per 100

(23 to 36)

RR 0.3

(0.24 to 0.37)

400
(1 trial)
⊕⊕⊕⊝
moderate 2,3,5,6

Mean percent egg reduction

At 6 months

13% increase 94% reduction

400

(1 trial)

⊕⊕⊕⊝

moderate 2,3,5,7

Adverse events

493

(2 trials)

8
*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 5 Artesunate versus placebo

Summary of findings 5. Artesunate versus placebo
  1. 1 Downgraded by 1 for serious risk of bias. One trial described sequence generation, allocation concealment and blinding adequately, whereas the second study did not.

    2 Downgraded by 1 for serious inconsistency. One of the trials (at high risk of bias) reported a large effect, while the other trial (at low risk of bias) detected no effect.

    3 No serious indirectness. The trials were conducted in Gabon and Nigeria in patients of a similar age range.

    4 Downgraded by 1 for serious imprecision. The CI is very wide and reaches from no benefit to a significant benefit after treatment.

    5 No for serious inconsistency. Percent egg reductions the studies reported were similar.

    6 Downgraded by 1 for serious imprecision. The meta analysis is underpowered.

    7 No serious risk of bias. The one trial reporting the outcome reported adequately on sequence generation, allocation concealment and blinding.

    8 No serious inconsistency: only one trial.

    9 No serious indirectness: This trial was conducted in school children in Gabon.

    10 Downgraded by 2 for very serious imprecision: only one trial reporting 74 events in 119 participants evaluated this outcome.

    11Downgraded by 1 for serious risk of bias: only one trial was blinded. Both trials reported on adverse events, but the methods are unclear.

    12 Downgraded by 1 for imprecision. One study reported on clinically diagnosed outcomes per treatment group, but was underpowered to confidently detect a difference.

Artesunate compared to placebo for treating urinary schistosomiasis
Patient or population: patients with treating urinary schistosomiasis
Settings: endemic settings
Intervention: artesunate 4 mg/kg for three days
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
Placebo Artesunate

Parasitological failure

At 8 weeks

87 per 100 46 per 100
(14 to 148)
RR 0.53
(0.16 to 1.71)
251
(2 trials)
⊕⊕⊝⊝
very low 1,2,3,4

Mean percent egg reduction

At 8 weeks

Mean change in egg excretion ranged from range from 47.1% reduction to 111.5% increase.Reduction in egg excretion ranged from 52.1% to a 69.3%

276

(2 trials)

⊕⊝⊝⊝
low 1,3,5,6

Microhaematuria

At 8 weeks

53 per 100 65 per 100
(45 to 94)
RR 1.22
(0.85 to 1.76)
119
(1 trial)
⊕⊕⊝⊝
low 7,8,9,10
Adverse events

276

(2 trials)

⊕⊕⊝⊝

low 11,12

*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 6 Praziquantel and artesunate versus praziquantel

Summary of findings 6. Praziquantel and artesunate versus praziquantel
  1. 1 Downgraded by 1 for serious risk of bias: only one out of two studies did report adequate random sequence generation, allocation concealment and blinding or participants and clinicians, while the other study did not provide enough information to allow a judgement.
    2 No serious inconsistency. Both studies favour the combination of Praziquantel and ARS over Praziquantel alone.
    3 No serious indirectness. The trials were conducted in rural communities in Gabon and Nigeria, in children (6 to 15 years) and young adults (4 to 20 years)
    4 Downgraded by 1 for serious imprecision: Only two studies were included in this comparison. The effect size, described by the 95% CI ranged from a very small, clinically non-important effect to a clinically important effect.
    5 Downgraded by 1 for serious inconsistency: egg reduction varied widely between the two trials.
    6 Downgraded by 1 for serious imprecision: Only two studies reported this outcome.
    7 No serious risk of bias. The one study that reporting this outcome described adequate random sequence generation, allocation concealment and blinding.
    8 Downgraded by 2 for serious imprecision: only one small study reported this outcome, the outcome is not statistically significant with wide 95% CI.
    9 Downgraded by 2 for serious risk of bias. This study did not provide enough information to allow a judgement regarding sequence generation, allocation concealment and blinding.
    10Downgraded by 1 for serious imprecision. Only one study reported on adverse events. The study was underpowered, and no difference in adverse events was detected between treatment groups.

Praziquantel plus artesunate compared to praziquantel alone for treating urinary schistosomiasis
Patient or population: patients with urinary schistosomiasis
Settings: Countries endemic for urinary schistosomiasis
Intervention: Praziquantel plus artesunate
Comparison: Praziquantel alone
Outcomes Illustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(trials)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
Praziquantel 40 mg/kg single dose alone Praziquantel 40 mg/kg single dose plus artesunate 4 mg/kg/d for 3 days
Parasitological failure at 8 weeks 27 per 100

17 per 100

(10 to 27)

RR 0.62 (0.38 to 0.99)265
(2 trials)
⊕⊕⊝⊝
low 1,2,3,4
Percent egg reductionEgg reduction in the Praziquantel groups ranged from 52.1% reduction to a 97.11% reduction.Egg reduction in the Praziquantel and ARS groups ranged from 93.5% to 98.8%

265

(2 trials)

⊕⊝⊝⊝
very low 1,2,5,6
Microhaematuria 28 per 100

19 per 100

(11 to 33)

RR 0.69
(0.4 to 1.18)
177
(1 trial)
⊕⊕⊝⊝
low 7,8
Adverse events

156

(1 trial)

⊕⊝⊝⊝

very low 9,10

*The basis for the assumed risk (for example, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Urinary schistosomiasis, also called bilharzia or snail fever, is an intravascular infection caused by parasitic Schistosoma haematobium worms. It is endemic in sub-Saharan Africa, the Arabian peninsula and the Middle East. According to the World Health Organization (WHO), at least 243 million people required treatment for schistosomiasis in 2011 (WHO 2013), and more than 700 million people live in endemic areas (WHO 2014).

The WHO currently recommends regular chemoprophylaxis with praziquantel for populations at risk to prevent the long term consequences of infection. These programmes usually target school children (Table 1), but may be extended to the whole community in high risk settings (King 2011).

Table 1. Population based treatment according to prevalence among schoolchildren (WHO)

 

Category

Prevalence among school-aged childrenAction to be taken Comment
High-risk community

50% by parasitological methods (intestinal or urinary schistosomiasis;

or

30% by questionnaire for visible haematuria

(urinary schistosomiasis)

Treat all school-age children (enrolled and not enrolled) once a year

Also treat adults considered to be at risk (from special groups to entire communities living in endemic areas)

 

Moderate-risk community

> 10 to < 50% by parasitological methods (intestinal and urinary schistosomiasis); or

30% by questionnaire for visible haematuria (urinary schistosomiasis)

Treat all school-age children (enrolled or not enrolled) once every two yearsAlso treat adults considered to be at risk (special groups only)
Low–risk community< 10% by parasitological methods (intestinal and urinary schistosomiasis)

Treat all school-age children

(enrolled and not enrolled) twice during their primary schooling age

(for example, once on of suspected cases

entry and once on exit)

Praziquantel should be available in dispensaries and clinics for treatment of suspected cases.

Description of the condition

Human infection with S. haematobium is acquired through contact with water bodies containing cercariae, the larval form of the parasite. The cercariae are able to penetrate human skin and migrate via blood vessels to the liver, where they mature into male and female forms for reproduction. Typically, they then migrate further to the venous plexus of the urinary bladder, and begin to produce eggs which the infected person excretes in their urine (Gryseels 2006). If these eggs reach water, they hatch into miracidia, infect specific freshwater snails which act as intermediate hosts, before emerging as cercariae that can infect humans (Gray 2011; Ross 2002).

Any illness associated with acute infection is typically mild, but chronic schistosomiasis can cause considerable morbidity with chronic pain, anaemia, fatigue, under nutrition and reduced exercise tolerance (King 2005). A review of 124 observational studies and 11 randomized controlled trials (RCTs) in 2005 estimated that up to 15% of people infected with any form of schistosomiasis suffer disabling long-term complications (King 2005). The main pathological process occurs when schistosome eggs become trapped in the tissue around the bladder and ureters causing chronic inflammation, which may obstruct the ureters, damage the kidneys, and lead to bladder cancer. Occasionally, eggs can become trapped in other tissues such as the brain and spinal cord (WHO 1985).

Two-thirds of all infected persons are schoolchildren (aged five to 14 years), and the intensity of infection with S. haematobium is highest in children aged ten to 14 years (WHO 1985).

The standard test for urinary schistosomiasis is urine filtration and microscopic examination of the urine sample (WHO 1991). The urine sample is passed through a filter paper and the eggs retained on the filter are counted either with or without staining. Sedimentation and centrifugation is less commonly used for urine concentration (Cook 2003). High urine egg counts are related to high infection intensity.

Parasitologists define cure when eggs can no longer be detected in one or more urine samples using standard methods. Besides parasitological cure, researchers also record the relative reduction in egg output after treatment compared to pre-treatment levels. This outcome, expressed as % egg reduction, is an indirect estimate of a reduction of the worm burden (Cook 2003).

Blood and protein excretion in the urine is usually elevated in urinary schistosomiasis and decreases when the infection resolves. The most commonly used test is a dipstick test. Ultrasound can demonstrate organ involvement of the urinary tract as well as its resolution.  

Description of the intervention

Praziquantel is the current treatment for urinary schistosomiasis recommended by the WHO (WHO 2006). Historically, metrifonate was also used but this fell out of favour due to the need for multiple doses (Feldmeier 1999; WHO 1998). More recently, there has been interest in the antischistosomal properties of artemisinin derivates and mefloquine, more commonly used for treating malaria (Utzinger 2004).

Praziquantel is an pyrazinoisoquinoline derivative with activity against adult worms of all schistosome species (S. mansoni, S. intercalatum and S. japonicum), but not against maturing worms. Praziquantel has a rapid onset of action. It is well-tolerated, can be given as a single dose (Utzinger 2004) and paediatric formulations are available (Stothard 2013).

Metrifonate, an organophosphorous cholinesterase inhibitor, is active against S. haematobium but not against other schistosome species (Utzinger 2004).

Artemisinin, extensively used as potent antimalarial, has highest activity against immature schistosomes. Artemsinins are safe and well-tolerated (Utzinger 2004).

How the intervention might work

After treatment with praziquantel, the worms appear to die quickly but egg excretion continues for several weeks. There are several possible reasons for this:

  • Firstly, some worms might not have been mature at the time of praziquantel treatment and therefore not killed by praziquantel (Cioli 2003). Maturation of the worms after infection takes four to six weeks, and after two months eggs can be detected in the urine.

  • Secondly, the patient might have been re-infected (Cioli 2003).

  • Thirdly, dead eggs still wander out of the tissue into the urine several weeks after clearing adult worms (Taylor 1988 ZWE). Therefore, a follow-up four to six weeks after treatment is useful (Renganathan 1998). There is also considerable variation in daily urinary egg output (Cook 2003).

Although there is concern that S. haematobium might develop resistance against praziquantel (Fenwick 2006), there is no clinically relevant evidence for resistance up to now (Doenhoff 2008).

In endemic settings, reinfection with S. haematobium is likely, and cure (often defined as complete cessation of egg excretion) is not a sustainable long term goal. However, reduction of infection intensity results in clinical improvement, low morbidity and prevention of long term complications. Therefore, WHO promotes morbidity control rather than cure as an objective for schistosomiasis control programmes (WHO 2002).

Why it is important to do this review

At present, praziquantel as the only drug in use that is exposed to resistance development. It is therefore important to monitor its performance and to assess the effects of other drugs against urinary schistosomiasis.  

Dosing regimens for subgroups such as highly infected patient groups, incremental benefits of drug combinations, double dosing and optimal interval between doses have to be determined to inform control programmes for urinary schistosomiasis.

Paediatric schistosomiasis has gained attention as a public health problem, and evaluation of existing treatment studies is indicated.

Objectives

To evaluate the efficacy and safety of drugs for treating urinary schistosomiasis.

Methods

Criteria for considering studies for this review

Types of studies

Randomized controlled trials.

Types of participants

Patients diagnosed with urinary schistosomiasis by: 

  • detection of macro or microhaematuria;

  • identification of schistosome eggs by urine microscopy;

  • detection of parasite antigens in blood or urine.

Types of interventions

Intervention

Drugs used to treat urinary schistosomiasis.  Drugs considered as obsolete (such as ambilhar, oltipraz and niridazole) were not included. Metrifonate was included.

Control

Placebo, no intervention, an alternative regimen of the same drug, or an alternative drug used to treat urinary schistosomiasis.

Types of outcome measures

Primary outcomes
  • Parasitological failure at one month post-treatment (as defined by the trial authors);

  • Percent egg reduction at one month.

Secondary outcomes
  • Parasitological failure at time-points > one month;

  • Percent egg reduction from baseline at > one month;

  • Clinical outcomes: resolutions of signs and symptoms (for example, haematuria and proteinuria);

  • Anaemia (decrease of the number of red blood cells or the quantity of haemoglobin in the blood);

  • Growth outcomes (gain in body weight, body length).

Adverse events
  • Serious adverse events;

  • Other adverse events

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language and publication status (published, unpublished, in press, under review and in progress).

Electronic searches

We searched the following databases using the search terms outlined in Appendix 1: The Cochrane Infectious Diseases Group Specialized Register (23 May 2014); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2014, Issue 4); MEDLINE (1966 to 23 May 2014); EMBASE (1974 to 23 May 2014); and LILACS (1982 to 23 May 2014). We also searched the metaRegister of Controlled Trials (mRCT) using 'Schistosoma haematobium' as the search term (23 May 2014).

Searching other resources

We checked the reference lists of all studies identified by the above methods for additional studies relevant to this review.

Data collection and analysis

Selection of studies

Vittoria Lutje, the Cochrane Infectious Diseases Group (CIDG) Information Retrieval Specialist, searched the literature and retrieved trial titles and abstracts.

VK and FZ independently screened the results of the search and retrieved full trial reports of all potentially relevant trials. Then, VK and FZ independently assessed each trial for inclusion using an eligibility form based on the inclusion criteria. We resolved any discrepancies by discussion with PG.

Data extraction and management

VK and FZ independently extracted data using pre-tested standardized forms. We resolved any differences through discussion with PG. For each trial we extracted details of the trial methods, participants, interventions and outcomes.

VK and FZ extracted the number of participants randomized and number of participants followed up in each treatment arm. For dichotomous outcomes, we extracted the number of participants experiencing the event in each group. For continuous outcomes summarized as geometric means, we extracted means and their standard error, if reported. If the data were presented as arithmetic means, we extracted arithmetic means and their standard deviations (SD), if reported, for each treatment group. Where continuous data were summarized as medians and ranges, these were extracted and entered into tables.  

VK and FZ double-entered the data and cross-checked to minimise errors. VK tried to contact trial authors for clarification or insufficient of missing data when necessary and summarised data reported in multiple publications as one single data set.

Assessment of risk of bias in included studies

VK and FZ independently assessed the risk of bias of each trial using an assessment form based on the Cochrane Collaboration's 'Risk of bias' tool (Higgins 2008). DS verified the assessment results.

We assessed the risk of bias for six domains: sequence generation; allocation concealment; blinding (of participants, personnel, and outcome assessors); incomplete outcome data; selective outcome reporting; and other sources of bias. We categorized these judgments as low, high or unclear risk of bias.

For sequence generation, allocation concealment and blinding, we quoted the method as described in the trial in the Characteristics of included studies tables. For blinding, we stated the blinding method and who was blinded separately for different outcomes. For incomplete outcome data, we assigned a judgement for different outcomes (for example, loss to follow-up at different time points).

We resolved disagreements by discussion or consultation. Where risk of bias was unclear, we attempted to contact the trial authors for clarification.

Measures of treatment effect

We presented dichotomous outcomes as risk ratios (RR), and continuous outcomes as mean differences or geometric mean ratios. All results are shown with a 95% confidence interval (CI).

Unit of analysis issues

For trials including more than two comparison groups, we split and analysed as individual pair-wise comparisons. When conducting meta-analysis we ensured that participants and cases in the placebo group were not counted more than once, by dividing the placebo cases and participants evenly between the intervention groups.

Dealing with missing data

The primary analysis is a complete case analysis where the number of evaluable participants at each time point is used as the denominator.

Assessment of heterogeneity

We assessed heterogeneity by inspecting forest plots for overlapping CIs and outlying data. We applied the Chi2 test with a P value < 0.10 to indicate statistically significant heterogeneity, and the I2 statistic with a value of greater than 50% to indicate moderate heterogeneity. 

Assessment of reporting biases

We planned to evaluate the possibility of publication bias by constructing funnel plots, but there were too few trials within each comparison to make this meaningful.

Data synthesis

We analysed the data in pair-wise comparisons using Review Manager (RevMan). We stratified the primary analysis by drug dose and the time point after treatment. Data were combined in meta-analyses using a fixed-effect model. If we detected moderate heterogeneity but still considered combination of the trials to be appropriate we used a random-effects model. We presented data which could not be presented in forest plots in tables (medians, means without measure of variance, ranges).

We assessed quality of evidence using the GRADE approach, and displayed the results in 'Summary of Findings' tables. The GRADE approach defines quality as a measure of 'our confidence in the effect estimates' and defines four levels of quality; high, moderate, low and very low. The evidence from RCTs is rated as 'high quality' but can be downgraded where there are major concerns about: 1) the risk of bias of the trials; 2) inconsistency between the trial results; 3) a mismatch between the question being asked and the trial setting, population, intervention or control; 4) the trial being underpowered; or 5) evidence of publication bias.

Subgroup analysis and investigation of heterogeneity

We planned to conduct the following subgroup analyses to explore the potential causes of heterogeneity. However, there were too few trials within each comparison to make this meaningful: patient age (children versus adults), intensity of infection, endemicity.

Sensitivity analysis

Data were insufficient to assess the robustness of results by sensitivity analyses to evaluate risk of bias components and the effects of missing data.

Results

Description of studies

Results of the search

Following database searches, we identified 116 individual citations, and a further 40 potential studies after we checked trial abstracts. Following abstract screening, we assessed 71 full text articles for inclusion. Figure 1 shows the flow diagram of these trials.

Figure 1.

Study flow diagram

Included studies

We included 30 RCTs, enrolling 8965 participants, and reported in 39 publications. Twenty trials were over 20 years old, and only eight were published since the year 2000.

Settings

All but one trial were conducted in sub Saharan Africa; 13 trials from East Africa: Somalia (one) Sudan (three), Tanzania (two), Kenya (six), Malawi (one); 13 trials from West Africa: Cameroon (two), Gabon (three), Niger (two), Mali (one), Nigeria (two), Cote d' Ivoire (one), Ghana (one), Gambia (one); and three trials from southern Africa: Zimbabwe (two), and Zambia (one). Most trials were based in rural settings, but two were conducted in peri-urban or semi-rural settings, three were from urban settings, and in one trial the setting was not described. The remaining trial was conducted in an urban setting in Saudi Arabia.

Twenty trials were based in schools and one in a college, seven in villages, farms or settlements, one in antenatal clinics and two in referral hospitals.

Participants

Twenty-four trials enrolled school-age children and young adults, although the exact age-range varied; age six to 20 years (16 trials), age five to 18 years (three trials), age two to 23 years (five trials). Two trials enrolled adults only, and four trials didn't clearly state the age range.

All trials diagnosed S. haematobium infection by detection of eggs or miracidia on urine microscopy. Sixteen trials reported egg counts as geometric mean egg counts, four trials as arithmetic mean egg counts, three trials reported both. One study reported geometric mean miracidial counts. Six trials used ranges or medians.

Interventions

Eight trials compared praziquantel with placebo, and 14 trials published between 1981 and 2009 compared different doses or regimens of praziquantel.

Five trials compared metrifonate with placebo, and seven trials published between 1983 and 1990 directly compared the efficacy of praziquantel and metrifonate.

More recently, three trials published between 2001 and 2009 evaluated artesunate as single agent or in combination with praziquantel, and two trials published in 2009 and 2011 evaluated mefloquine.

Excluded studies

We excluded 65 studies for the reasons given in the 'Characteristics of excluded studies' table.

Risk of bias in included studies

Many trials lacked adequate descriptions of methods to allow judgements on risk of bias, and so have been classified as unclear (see Figure 2).

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included trial.

Allocation

Fourteen trials adequately described a random method of sequence generation, but only six described a method of allocation concealment and could be considered at low risk of selection bias (Abden Abdi 1989 SOM; Basra 2012 GAB; Borrmann 2001 GAB; Olds 1999 KEN; Pugh 1983 MWI; Sacko 2009 MLI).

Blinding

Ten trials reported adequate attempts to blind participants and trial staff to treatment allocation, six trials were unblinded and blinding was unclear in the remaining trials. Seven trials reported adequate blinding of outcome assessors.

Incomplete outcome data

Many trials had high levels of attrition, particularly at later time points. When trials presented cure or failure rates as percentages, we were unable to assess attrition. We considered the risk of attrition bias to be unclear in 13 trials and high in nine trials.

Selective reporting

We found evidence of reporting bias in one trial, as trial authors did not present pre-specified outcomes. In three trials, selective reporting was at unclear risk of bias.

Other potential sources of bias

Trial authors reported baseline imbalances in two trials, which we identified as sources of other bias.

The trials were mostly funded by funds, trusts or international agencies (see Characteristics of included studies tables). Eight trials did not declare funding, four received drug donations and only two trials declared funding by pharmaceutical companies (both Dafra Pharma).

Effects of interventions

See: Summary of findings for the main comparison Praziquantel 40 mg/kg versus placebo for treating urinary schistosomiasis; Summary of findings 2 Praziquantel 40 mg/kg single dose versus 30 mg/kg single dose; Summary of findings 3 Praziquantel 40 mg/kg multiple doses versus single dose; Summary of findings 4 Metrifonate 3 x 7.5 mg/kg given two weeks apart versus placebo; Summary of findings 5 Artesunate versus placebo; Summary of findings 6 Praziquantel and artesunate versus praziquantel

Section A: Praziquantel

Praziquantel 40 mg/kg single dose versus placebo (comparison 1)

On average, a single 40 mg/kg dose of praziquantel reduces the proportion of people still excreting eggs at one to two months after treatment by around 60% compared to placebo, and reduces the mean number of eggs excreted by over 95%.

Eight trials compared a single 40 mg/kg dose of praziquantel with placebo or no treatment in schoolchildren in sub-Saharan Africa. We have listed the definitions of parasitological failure in Table 2.

Table 2. Definion of cure, reporting and calculation of egg counts
Study IDDefinition cureReporting of egg counts/10 mL urineMethods to calculate egg countsComment
Abden Abdi 1989 SOMPatients without schistosome eggs in their urine after treatmentMean (SD), % ERNot reportedNo hatching test employed, cured might be underestimated because of dead eggs
Al Aska 1990 SAU

Clinical improvement

Disappearance of ova from the urine on three successive examinations

Mean, rangeNot reported
Basra 2012 GABThree consecutive urine samples without presence of eggsMedian, interquartile rangeNot reported
Befidi Mengue 1992 CMRCure not reportedGMECNot reportedHb and weight as outcomes
Borrmann 2001 GABTwo negative egg counts on two consecutive daysGMECArithmetric mean of two egg counts per participant before and after treatment including 0 egg counts (cured patients). Geometric means of these arithmetic means.

We received the data file from the study author

Day to day variation in egg counts explains 10% cure rate with placebo.

Davis 1981 ZMBDefined as three negative urine defined as the absence of hatched miracidia, although recently dead or black eggs might be present.Geometric mean miracidial countAt follow-up: If the first urine specimen contained hatched miracidia, then random 10 mL samples were taken from further bladder collections, the miracidial count was recorded, and the geometric mean of the counts was compared directly with the geometric mean of the pretreatment counts.

Quantitaive hatching test.

if the first sedimented urine specimen was negative, then two further urine specimens taken on consecutive days were sedimented and examined.

de Jonge 1990 SDNNo definition of cure given, presumably absence of urinary egg excretionMinimum and maximum value, median, 90%valueNot reportedExcretion of eggs following treatment
Inyang Etoh 2009 NGANo definition of cure given, cure rates and egg reduction rates as end pointsMean ± SD"Treatment-related changes
in egg counts were investigated using paired Student’s t
test."
Jewsbury 1976 ZWENo definition of cure given"median urine egg count"Not reported
Kardaman 1985 SDNNo definition of cure given, "negative"GMECNot reported"It would appear that the cure rate determined in any trial is dependent on the pretreatment egg count and on the ...urine examination techniques used."
Keiser 2010 CIV

Absence of urinary egg excretion

Cure rate (CR, defined as the percentage of children excreting no S. haematobium eggs 26 days after treatment among children with confirmed parasites at baseline)

GMEC

S. haematobium egg counts before and after treatment were averaged for every child (arithmetic mean) and the GM egg count for each treatment group was calculated. Because egg counts are over dispersed, they were logarithmically transformed log [count+1], and the GM was expressed as the antilogarithm of the mean.

Egg reduction rate (ERR) defined as reduction of geometric mean (GM) egg count among S. haematobium positive children after treatment, compared with the respective GM pretreatment.

The ERR was calculated as (1 - [GM egg count after treatment/GM egg counts at enrolment] x 100

(ERR; defined as reduction of geometric mean egg count
among S. haematobium–positive children after treatment, compared
with the respective geometric mean pretreatment)
King 1989 KENNo definition of cure given

AMEC

GMEC

Not reportedInfection was identified and quantified by Nucleopore filtration
King 1990 KENNo definition of cure given

AMEC

GMEC

Not reportedInfection was identified and quantified by Nucleopore filtration
King 2002 KENCure defined as egg-negativeGMECNot reported
McMahon 1979 TZAProbable cure rate: excretion of no or only non viable eggs in the urineGMEC, 95%confidence limit of the meanNot reported
McMahon 1983 TZAPeople were considered cured when no eggs or non-viable eggs were excreted in the urine

Screening: GMEC of miracidia/10 mL urine

reduction in egg excretion

"In non cured cases the reduction of egg excretion was calculated."
Mott 1985 GHAAbsence of S. haematobium eggs in two random 5 mL samples of urine from the same specimen

GMEC 5 mL urine samples

reduction in GMEC

Not reported
Olds 1999 KENNo definition givenGMEC"Egg counts are geometric means in subjects who remained
infected. Reduction in egg no. after treatment in infected children was significant in all infections at 45 days."
Omer 1981 SDN

100% reduction of egg excretion (absence of egg excretion in the urine)

or 98% egg reduction and neg miracidial hatching test

GMECNot reportedOnly children with GMEC > 60/10 mL (in three egg counts) included
Oyediran 1981 NGANo definition of cure givenGMEC mean ± SDNot reportedOnly children with GMEC > 60/10 mL (in three egg counts) included
Pugh 1983 MWINo definition of cure given

AMEC

% egg count reduction

Percentage reduction in egg output was determined by comparing the arithmetic and geometric means of pooled egg counts before and after treatment. The geometric mean was obtained by recording the logarithm of egg counts and using the n +1 transformation for a series of counts after treatment that included zeros.We did not use a hatching test to determine the viability of excreted ova since percentage reduction in egg output rather than parasitological cure was our main criterion of efficacy.
Rey 1983 NERNo definition of cure given

AMEC

"nombre moyenne"

average number

Not reportedIf possible, a hatching test was that at the last control (6 months)
Rey 1984 NERNo definition of cure given, "negativation"

AMEC

moyenne des nombres d'oeufs/10 mL urine

Number average

Not reported
Sacko 2009 MLIThe
cure rate was calculated as the proportion of infected individuals who became parasitologically negative (0 egg/10 mL urine based on three urine samples) at three months post treatment
GMECIndividual egg counts were
calculated as the mean number of eggs per 10 mL of urine in the three urine samples. To compare the effect of the treatment on the intensity of the infection at 3,
6 and 18 months geometric mean egg/10 mL for all urine samples examined for S. haematobium eggs were calculated as log10(x+1) to allow egg count of
0 to be included in the analysis.
Stephenson 1985 KENno definition of cure givenAMECNot reported
Stephenson 1989 KEN

AMEC

GMEC

Not reported
Taylor 1988 ZWE

Cure defined as negative egg counts

"infections as were cured by a negative GMEC at 1,3 and 6 months"

GMECNot reported"in cases were only one egg was found in three (urine) examinations the egg count was always taken as positive."
Tchuente 2004 CMRThe parasitologic cure rates were calculated as the proportion
of children excreting eggs at the first survey before treatment
and who were not excreting eggs in their urine after treatment.
GMEC

Geometric mean (GM) values of all
individuals were used to assess average egg counts of each group. The GM was calculated as the antilogarithm of the
mean of all log transformed egg counts + 1.

The intensity reduction rate was calculated as [1 − (GM egg counts per 10
mL of urine after treatment/GM egg counts per 10 mL before treatment)] × 100

The parasitological cure rates were calculated as the proportion of children excreting eggs at the first survey before treatment and who were not excreting eggs in their urine after treatment.
van den Biggelaar 02 GAB

Negative for both eggs and circulating antigen

failure: pos. for eggs or circulating antigen

GMEC interquartile rangeNot reported
Wilkins 1987 GMBNo definition of cure givenGMECWhen appropriate a log10 transformation was used in statistical analysis to make their skewed distribution approximate to normal. This was reversed for the presentation of results to give a geometric mean which included zero values.
Parasitological failure

Praziquantel 40 mg/kg as a single dose reduced parasitological treatment failure by around 60% at one to two months compared to placebo (RR 0.42, 95% CI 0.29 to 0.59; 864 participants, seven trials, Analysis 1.1). The absolute level of treatment failure with praziquantel ranged from 16.6% (McMahon 1979 TZA) to 77.5% (de Jonge 1990 SDN). Treatment failure with placebo was greater than 80% in all seven trials and over 90% in four trials.

Four trials reported follow-up beyond two months (Analysis 1.1). Failure rate increased over time in two trials, as might be expected in areas of schistosomiasis transmission as people become re-infected (McMahon 1979 TZA; Pugh 1983 MWI). However, treatment outcomes improved in Taylor 1988 ZWE over time, with moderate reductions in treatment failure at one month and three months and a 70% reduction at six months. The trial authors stated that this improvement might have been due to excretion of remaining eggs from the urinary tract over time.

The fourth trial, de Jonge 1990 SDN, found no difference in treatment failure between praziquantel and placebo at any time point. The trial authors used a more sensitive diagnostic method (three urine samples, filtration of the whole volume up to 350 mL when the 10 mL urine sample contained fewer than 10 eggs) and a strict definition of cure (no excretion of eggs, no viability testing of eggs). This may explain the high failure rates observed despite high percent egg reductions comparable to other trials.

Stephenson 1989 KEN reported treatment failure at eight months, its only time point. A single dose of praziquantel reduced treatment failure by 86% compared to placebo (RR 0.14, 95% CI 0.08 to 0.22; 209 participants, one trial, Analysis 1.1).

Six trials reported parasitological failure stratified by intensity of infection; the categorisation of strata varied between trials (642 participants, see Appendix 2). At the first follow-up at four to six weeks, three out of four trials had a tendency to higher failure in participants with higher infection intensity. The pattern attenuated at later time points.

Percent egg reduction

Seven trials reported mean urine egg counts per 10 mL urine at baseline, and at one to two months after a single dose of praziquantel 40 mg/kg or placebo (867 participants, seven trials, see Table 3), although we were only able to reliably interpret this data for six trials (678 participants).

Table 3. Praziquantel 40 mg/kg single dose versus placebo: % egg reduction at one and two months
  1. 1P for therapeutic efficacy (not defined) Praziquantel versus placebo

    2 Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.

Study IDSubgroupTimepointMeasurePraziquantel 40 mg/kg single dosePlaceboP value difference between groups

Egg count/10 mL

(Range/95% CI)

N

% egg reduction

Egg count/10 mL

(Range/95% CI)

N

% egg reduction
BaselineFollow-upBaselineFollow-up
de Jonge 1990 SDN1 monthMedian

66

N = 48

1

N = 40

98.5

124

N = 21

58

N = 18

53.2

P = 0.29

not significant

McMahon 1979 TZA1 month

Miracidial count

(95% CI)

288.4 (33.2 to 2508.9)

N = 32

1.1 (0 to 8.3) N = 3099.6

324.9

(22.1 to 4783.3)

N = 37

187.5

(6.3 to 5601.3)

N = 29

42.3Not reported
Pugh 1983 MWI1 month

GMEC

AMEC

385.5

780.9

N = 97

1.8/

1.8

99.5

99.7

136.8

188.8

N = 52

119.9

437.2

12.35 (GMEC)

- 131.5 (AMEC) (increase)

Not reported
Taylor 1988 ZWE

light infections

< 50/10 mL

1 month

GMEC

N = (both light and heavy)

15.1

N = 77

(both groups)

0.499.7

15.7

N = 90

(both groups)

37.5

-138

(increase)

Not reported

heavy infections

< 100/10 mL

1 month

GMEC

N = (both light and heavy)

204.7

N = 77

(both groups)

4.098.1

191.9

N = 90

(both groups)

147.023.39Not reported
Olds 1999 KEN45 daysGMEC

Not reported

N = 95

1.4N = 9429.8Not reported
Borrmann 2001 GAB8 weeks

GMEC

(range)

38.51

(1 to 3313)

N = 90

1.11

N = 89

97.11

21.57

(1 to 778)

N = 30

11.41

N = 30

47.1Significant
Inyang Etoh 2009 NGA 2without placebo8 weeks

42.0 ± 1.7

N = 52

9.8 ± 0.5

N = 42

76.7

34.1 ± 0.8

N = 52

72.0 ± 2.3

N = 44

- 111.5

(increase)

P < 0.0012

The mean egg count was reduced by more than 95% at one to two months following praziquantel in five trials, and by 75% in one trial. In the placebo groups the change in mean egg count ranged from a 53% decrease to a 115% increase.

Percent egg reduction in the praziquantel group remained high (> 95%) in all three trials reporting at three months, and in all four trials at six months. Percent egg reduction was variable in the placebo group, ranging from 26% increase to 54% reduction at three months and from 5% to 64% reduction at six months (see Table 4). One additional trial, Stephenson 1989 KEN, reported percent egg reduction at eight months as its only time point (209 participants, see Table 4). Percent egg reduction after praziquantel was 99% compared to 5% with placebo.

Table 4. Praziquantel 40 mg/kg single dose versus placebo: % egg reduction at later time points
  1. 1Praziquantel 40 mg/kg single dose: significant egg reduction in praziquantel group (before, after treatment) P < 0.0002. no significant reduction in the placebo group (before, after treatment).

Study IDSubgroupTime pointMeasurePraziquantel 40 mg/kg single dosePlaceboP value for difference between groups
Egg count /10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
McMahon 1979 TZA3 months

miracidial count

(95% CI)

288.4 (33.2 to 2508.9)

N = 32

1.1 (0 to 16.3)99.6

324.9

(22.1 to 4783.3)

N = 37

149.4

(6.3 to 3556.6)

54Not reported
Pugh 1983 MWI3 months

GMEC

AMEC

385.5

780.9

N = 97

1.9

1.9

99.5 (GMEC)

99.75(AMEC)

136.8

188.8

N = 52

85.9

270.3

37.2 (GMEC)

43.16

(AMEC)

Not reported
Taylor 1988 ZWE

light infections

< 50/10 mL

3 monthsGMEC

15.1

N = 77

(for both groups)

0.497.35

15.7

N = 90

19.8

-26.11

(increase)

Not reported

heavy infections

< 100/10 mL

GMEC

204.7

N = 77

(for both groups)

2.099.02

191.9

N = 90

94.750.65Not reported
de Jonge 1990 SDN5 monthsmedian

66

N = 48

0100

124

N = 21

9523.38

P = 0.27

not significant

McMahon 1979 TZA6 months

miracidial count

(95% CI)

288.4 (33.2 to 2508.9)

N = 32

1.1

(0-20.3)

99.6

324.9

(22.1 to 4783.3)

N = 37

188.6 (13.9 to 2563.5)41.95Not reported
Pugh 1983 MWI6 months

GMEC

AMEC

385.5

780.9

N = 97

2.4

20.1

99.3 (GMEC)

97.4

(AMEC)

136.8

188.8

N = 52

69.7

261.8

49.0

GMEC

-38.7

(increase)

AMEC

Not reported
Befidi Mengue 1992 CMR6 monthsGMEC

41/10 mL

N = 238

2/10 mL95.1

39/10 mL

N = 198

14/10 mL64.1 
Taylor 1988 ZWE

light infections

< 50/10 mL

6 monthsGMEC

15.1

N = 77

(for both groups)

0.298.67

15.7

N = 90

11.725.5Not reported

heavy infections

< 100/10 mL

204.7

N = 77

(for both groups)

0.699.7

191.9

N = 90

75.560Not reported
Stephenson 1989 KEN8 months

GMEC

AMEC

57/

112

N = 105

0.2/

1

99.64 (GMEC)

99.1 (AMEC)

38/

85

N = 104

36/

102

5.26

(GMEC)

-20

(increase)

(AMEC)

Not reported1

Five trials reported percent egg reduction stratified by intensity of infection (764 participants, Appendix 2). At four to six weeks, all trials reported percent egg reductions over 90% across the strata. Percent egg reduction as a relative measure was at least as high in heavy infections as in mild infections, but post-treatment egg counts as an absolute measure tended to be higher in people with high intensity infections. This pattern persisted at later time points.

Clinical resolution

At eight weeks the proportion of patients with persistent haematuria (defined as > 5 erythrocytes/mL) was lower in those given praziquantel than placebo in one small trial which reported this (RR 0.53, 95% CI 0.33 to 0.84; 119 participants, one trial, Analysis 1.2). There were substantial reductions in the mean number of erythrocytes in the urine in three trials at one to two months, but we could not combine these data in a meta-analysis (357 participants, three trials, see Appendix 3).

Proteinuria was reduced by 65% to 84% at one to two months after praziquantel compared to increases in the placebo groups (238 participants, two trials, see Appendix 3).

Two trials reported mean haemoglobin at baseline and at six to eight months after treatment with no difference between groups (mean difference -0.08, 95% CI -0.24 to 0.09; 727 participants, two trials, Analysis 1.3).

Three trials measured a variety of growth parameters (Befidi Mengue 1992 CMR; Olds 1999 KEN; Stephenson 1989 KEN). Two trials reported little or no effect on the outcomes measured (Befidi Mengue 1992 CMR; Olds 1999 KEN). The third trial (Stephenson 1989 KEN) reports 14 measures, some of which are reported as statistically significant, but all appear to be of no or only borderline clinical importance (see Appendix 4). Most notably, there is a reported increase in children's physical fitness as measured by the Harvard Step test. The difference in mean improvement between groups was 6.8% at five weeks (mean end scores 81.2% praziquantel versus 75.5% placebo). Scores between 68% and 82% are considered average. Children that took praziquantel also gained 1.2 kg more weight than those in the control group, however baseline differences between groups were of a similar magnitude to this effect.

Adverse events

Of nine trials, six (with 1286 participants) commented on adverse events. Only four described the methods used for data collection, but rarely reported them in detail (see Appendix 5). Adverse events were usually monitored in the first days after medication. Only two trials actually reported numbers of adverse events, and only abdominal pain was reported by both trials. The absolute number of adverse events was low and none were more common with praziquantel than placebo (see Analysis 1.4). The other trials summarized narratively with comments such as "both treatments were well tolerated" (see Appendix 5).

Praziquantel 40 mg/kg versus lower doses (comparison 2)

Praziquantel doses of 20 to 40 mg/kg result in similar reductions in mean egg excretion, but 40 mg/kg is marginally superior at achieving cure.

Ten trials compared praziquantel 40 mg/kg with lower doses: 30 mg/kg (seven trials), 20 mg/kg (three trials), and 10 mg/kg (three trials). All trials were conducted in sub-Saharan Africa in schoolchildren, apart from one trial, which recruited college students and army recruits.

Treatment with praziquantel 40 mg/kg had fewer treatment failures than lower doses when measured at four to six weeks after treatment (versus 30 mg/kg; RR 0.76, 95% CI 0.59 to 0.99; 401 participants, four trials, Analysis 2.1, versus 20 mg/kg; RR 0.74, 95% CI 0.59 to 0.93; 338 participants, two trials, Analysis 2.1). However, there was no difference between 40 mg/kg and 30 mg/kg at two to three months (517 participants, five trials, Analysis 2.2), or six months after treatment (699 participants, six trials, Analysis 2.3).

In the five trials comparing praziquantel 40 mg/kg and 30 mg/kg, the mean number of eggs excreted was reduced by greater than 90% with both doses and without significant differences between groups (495 participants, five trials, see Table 5).

Table 5. Praziquantel 40 mg/kg single dose versus 30 mg/kg single dose: % egg reduction
  1. 1Baseline data not reported separately per group.

    2A reduction as low as 46% after praziquantel 40 mg/kg was not observed by any other study that reported this outcome. At six months, five other studies reported % egg reduction above 90% (see Table 4 and Table 5)

    3Heavy and light infections together; N = 77 for Praziquantel 40 mg/kg and N = 72 for Praziquantel 30 mg/kg.

    4 GMEC/10 mL urine, stratum 1: 60 to 250, stratum 2: 251 to 500, stratum 3 > 500.

Study IDSubgroupTime pointMeasurePraziquantel 40 mg/kg (SD)Praziquantel 30 mg/kg (SD)P value difference between groups
Egg count/10 mL urine% reductionEgg count/10 mL urine% reduction
BaselineFollow-upBaselineFollow-up
McMahon 1979 TZA1 month

GMEC

(95 Confidence limits of mean)

N

288.4 (33.2 to 2508.9)

N = 33

1.1 (0-8.3)

N = 30

99.61

308.5 (31.2 to 3034.7)

N = 32

1.2 (0 to 15.4)

N = 31

99.6

Not significant

P value not reported

Rey 1983 NER 11 month

AMEC

N

7.5 ± 1.7

N = 57

0.24

N = 54

96.8

7.5 ± 1.7

N = 46

0.74

N = 39

90.13Not significant
Taylor 1988 ZWE 2

heavy infection

< 100/10 mL

1 month

GMEC

N

204.7

N = 77 for both groups

4.098.04

185.4

N = 72 for both groups

3.198.32Not reported

light infection

> 50/10 mL

1 monthGMEC15.10.497.3515.90.696.23
Oyediran 1981 NGA 31 month

GMEC

mean ± SE,

N =

Stratum 1

87.4 ± 23.46

N = 15

Stratum 2

339.4 ± 32.61

N = 5

Stratum 3

518.00 ± 0.71

N = 2

N = 22

N = 2197.69 ± 0.98

Stratum 1:

111.67 ± 47.14

N = 15

Stratum 2:

306.83 ± 54.29

(N = 6)

Stratum 3:

1507.00 ± 1400.07

N = 2

N = 23

N = 1985.65 ± 13.08

Not significant

Not reported

King 1989 KEN 2-3 months

AMEC (± SD)

GMEC

N =

377

255

N = 64

31 (± 21)

2

N = 54

91.7

(AMEC)

99.2

(GMEC)

327

204

N = 69

22 ± 17

2

N = 60

93.27

(AMEC)

99

(GMEC)

Not significant

Not reported

McMahon 1979 TZA 3 months

GMEC

(95 Confidence limits of mean)

N

288.4 (33.2 to 2508.9)

N = 33

1.1 (0-16.3)

N = 29

99.61

308.5 (31.2 to 3034.7)

N = 31

0.9 (0 to 13.4)

N = 31

97.08

Not significant

Not reported

Rey 1983 NER 3 months

AMEC

N =

7.5 ± 1.7

N = 57

0.42

N = 52

94.4

7.5 ± 1.7

N = 46

1.21

N = 42

83.86Not reported
Taylor 1988 ZWE 3heavy infections < 100/10 mL3 months

GMEC

N =

204.7

N = 77 for both groups

2.099.02

185.4

N = 72 for both groups

1.199.4Not reported
light infections > 50/10 mL3 monthsGMEC15.10.497.3515.90.497.48
Oyediran 1981 NGA 33 months

GMEC

mean ± SE,

N =

Stratum 1

87.4 ± 23.46

N = 15

Stratum 2

339.4 ± 32.61

N = 5

Stratum 3

518.00 ± 0.71

N = 2

N = 22

 97.55 ± 0.85 (N = 18)

Stratum 1

111.67 ± 47.14

N = 15

Stratum 2

306.83 ± 54.29

N = 6

Stratum 3

1507.00 ± 1400.07

N = 2

N = 23

 99.01 ± 0.47 (N = 19)

Not significant

Not reported

McMahon 1979 TZA6 months

GMEC

(95 Confidence limits of mean)

288.4 (33.2 to 2508.9)

N = 33

1.1 (0 to 20.3)

N = 28

99.6

308.5 (31.2 to 3034.7)

N = 32

1.4 (0 to 39.5)

N = 28

99.46

Not significant

Not reported

Rey 1983 NER6 monthsAMEC

7.5 ± 1.7

N = 57

4

N = 34

46.6

7.5 ± 1.7

N = 462

0.18

N = 28

97.6Not reported
Taylor 1988 ZWE 3heavy infections < 100/10 mL6 months

GMEC

N =

204.7 (N = 77)0.699.7185.4 (N = 72)0.799.62

Not significant

Not reported

light infections > 50/10 mL6 monthsGMEC N =15.1 (N = 77)0.298.6715.9 (N = 72)0.199.37
Oyediran 1981 NGA 46 months

GMEC

mean ± SE,

(N =)

Stratum 1

87.4 ± 23.46

(N = 15)

Stratum 2

339.4 ± 32.61

(N = 5)

Stratum 3

518.00 ± 0.71

(N = 2)

(N = 22)

(N = 15)93.09 ± 0.12

Stratum 1

111.67 ± 47.14

(N = 15)

Stratum 2

306.83 ± 54.29

(N = 6)

Stratum 3

1507.00 ± 1400.07

(N = 2)

(N = 23)

(N = 17)98.72 ± 0.28

Not significant

Not reported

9 months(N = 6)92.4 ± 5.92(N = 8)96.49 ± 1.59
12 months(N = 3)99.3 ± 0.26(N = 4)99.28 ± 0.46

In trials comparing 40 mg/kg and 20 mg/kg, again the mean number of eggs excreted was reduced by more than 95% for both doses and differences in percent egg reduction appeared small (636 participants, four trials, see Appendix 2). Treatment with praziquantel 40 mg/kg appeared to result in greater percent egg reductions than 10 mg/kg (357 participants, three trials, see Appendix 2).

One small trial from Kenya (King 1989 KEN) reported similar numbers of participants with persistent haematuria or proteinuria at three months with praziquantel 40 mg/kg, 30 mg/kg and 20 mg/kg, but 40 mg/kg was superior to 10 mg/kg (haematuria at three months: RR 0.35, 95% CI 0.21 to 0.58, 119 participants, one trial, Analysis 2.4; proteinuria at three months: RR 0.25, 95% CI 0.12 to 0.51; 119 participants, one trial, Analysis 2.5). A larger trial by the same authors comparing 40 mg/kg and 20 mg/kg (King 2002 KEN) detected fewer participants with haematuria at six weeks following praziquantel 40 mg/kg (RR 0.63, 95% CI 0.47 to 0.86; 245 participants, one trial, Analysis 2.6), and fewer participants with proteinuria (RR 0.66, 95% CI 0.46 to 0.96; 245 participants, one trial, Analysis 2.7). These differences were still observed at nine months (haematuria: RR 0.59, 95% CI 0.44 to 0.78; 215 participants, one trial, Analysis 2.8; proteinuria RR 0.67, 95% CI 0.5 to 0.9; 214 participants, one trial, Analysis 2.9). King 2002 KEN also reported ultrasound findings (bladder thickening, bladder irregularity and hydronephrosis) before and after treatment with praziquantel 40 mg/kg and 20 mg/kg respectively, but the results were inconclusive (264 participants, see Appendix 6).

Six of these trials did not comment on adverse events. Four trials described the methods of data collection, but often in insufficient detail; two out of four trials used active, prospective surveillance for adverse events (Appendix 5). Two trials stated for all treatment arms collectively that adverse events after praziquantel treatment were mild and transient. Two trials reported numbers of adverse events with no differences between groups (163 participants, Analysis 3.2).

Praziquantel 40 mg/kg single dose versus split dose (comparison 3)

Splitting the dose of praziquantel 40 mg/kg into two 20 mg/kg doses over 24 hours has not been shown to improve tolerability and may actually cause more vomiting and dizziness.

Three trials compared the single 40 mg/kg dose with a split dose regimen giving two doses of 20 mg/kg over 24 hours. There was no statistically significant difference in treatment failure at one month (RR 0.75, 95% CI 0.51 to 1.11; 374 participants, three trials), three months (RR 0.74, 95% CI 0.45 to 1.2; 361 participants, three trials), or six months (RR 0.83, 95% CI 0.51 to 1.35; 234 participants, three trials, Analysis 3.1). Similarly percent egg reduction was over 90% for both groups (332 participants, three trials, see Appendix 2).

These trials enrolled 191 participants for a single dose of praziquantel 40 mg/kg and 195 participants for a split dose of 2 x 20 mg/kg. All trials used active surveillance for adverse events (see Appendix 5). Adverse events were generally reported to be mild and transient. However one trial reports significantly more vomiting and dizziness with the split dose compared to the single dose (vomiting: RR 0.5, 95% CI 0.29 to 0.86; dizziness: RR 0.39, 95% CI 0.16 to 0.94; 373 participants, three trials, Analysis 3.2).

Praziquantel 40 mg/kg single dose versus multiple doses (comparison 4 and 5)

There are too few trials to determine the optimal frequency and timing of repeated praziquantel dosing.

Two trials compared the standard single dose of praziquantel (40 mg/kg) with two or three doses given at two or three week intervals, and found no statistically significant differences in parasitological failure (Analysis 4.1, Analysis 4.2), percentage egg reduction (Appendix 2), or clinical resolution (Appendix 3; Analysis 4.3).

One additional very small trial from a high transmission setting in Gabon (van den Biggelaar 02 GAB), compared praziquantel 40 mg/kg every three months for two years to a single dose of praziquantel 40 mg/kg given at the beginning of the trial. At two years, patients who received only one dose of praziquantel had almost three times the risk of treatment failure compared to multiple doses (RR 2.71, 95% CI 1.47 to 5.00; 62 participants, one trial, Analysis 5.1). Percent egg reduction was 96% after multiple doses and 80% after a single dose of praziquantel at two years (90 participants, see Table 6). These effects were no longer apparent one year after the last praziquantel dose.

Table 6. Praziquantel 40 mg/kg multiple doses versus single dose: % egg reduction
  1. 1Baseline egg counts not reported separately per treatment group; no difference at baseline stated. Praziquantel 40 mg/kg given every 3 months over 2 years. Location: Gabon, endemic area.

Study IDTime pointMeasurePraziquantel 40 mg/kg single dose% egg reductionPraziquantel 40 mg/kg multiple doses% egg reductionComments
Egg count/10 mLEgg count/10 mL
BaselineFollow-upBaselineFollow-up
van den Biggelaar 02 GAB 12 years

GMEC

(IQR)

47

N = 45

9 (2-45)80.85

47

N = 45

2 (1-3)95.74

Significant

P = 0.002

These trials did not report on adverse events.

Section B: Metrifonate

Metrifonate single dose versus placebo (comparison 6)

A single dose of metrifonate 10 mg/kg probably reduces egg excretion but is only marginally better than placebo at achieving cure.

Two trials compared a single dose of metrifonate to placebo, although one trial only reported outcomes at a single time point eight months after treatment (Stephenson 1989 KEN).

In the first trial (Pugh 1983 MWI), 80% of those treated with metrifonate continued to excrete eggs one month after treatment which was only marginally better than placebo (RR 0.83, 95% CI 0.74 to 0.94; 142 participants, one trial, Analysis 6.1), and no difference was seen at six months (RR 0.94, 95% CI 0.87 to 1.02; 102 participants, one trial, Analysis 6.1).

In the second trial (Stephenson 1989 KEN), 61% of those treated with metrifonate continued to excrete eggs eight months after treatment compared with almost 100% who received placebo (RR 0.63, 95% CI 0.54 to 0.73, 210 participants, one trial, Analysis 6.1). Egg excretion was also reduced by more than 90% eight months after treatment compared to just 5% with placebo (210 participants, see Appendix 2).

The second trial also reported mean haemoglobin at baseline and eight months (with no difference between groups, Analysis 6.2), and various measures of nutrition and growth (see Appendix 4). However, this trial had three arms and the nutritional measures are reported for the metrifonate and praziquantel groups combined. Consequently, we were unable to evaluate the effect of metrifonate. Trial authors did not report adverse events.

Metrifonate multiple doses versus placebo (comparison 7)

Subsequently trials evaluated multiple doses of metrifonate given two weeks apart, which improved the proportion of patients being cured.

Two trials evaluated three doses of metrifonate 7.5 mg/kg given two weeks apart (Jewsbury 1976 ZWE; Stephenson 1985 KEN), and reported much reduced treatment failures compared to placebo at 11 weeks (RR 0.41, 95% CI 0.30 to 0.56; 93 participants, one trial, Analysis 7.1) and six months respectively (RR 0.30, 95% CI 0.24 to 0.37; 400 participants, one trial, Analysis 7.1).

A third small trial (de Jonge 1990 SDN) comparing two 10 mg/kg doses given two weeks apart with placebo found very low levels of cure and no difference compared to placebo at one month or five months (51 participants, one trial, Analysis 7.1). However, this is the same trial that found very high levels of treatment failure with praziquantel, which may be a result of the highly sensitive method used for detecting low level egg excretion and the strict definition of cure.

All three trials found substantial reductions in the number of eggs being excreted at their various time points (> 90% reductions in all three trials, see Table 7).

Table 7. Metrifonate 20 mg/kg given as divided dose versus placebo: % egg reduction
  1. 1Metrifonate 2 x 10 mg/kg, dose interval two weeks. Placebo: multivitamins.

    2Reports two groups with metrifonate 7.5 mg x 3, dose interval two weeks. Control group: nil.

    3 Metrifonate 3 x 7.5 mg/kg, dose interval one to two weeks.

Study IDTime pointMeasureMetrifonate 21.5 mg, 20 mg/kg given as divided dosePlacebo or no treatmentP value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
de Jonge 1990 SDN 11 month

median

N =

(reports min, max, 90th percentile

and median

of egg counts/10 mL)

95

N = 38

1

N = 32

98.94

124

N = 21

58

N = 18

53.22

Not significant

P = 0.29

Jewsbury 1976 ZWE 211 weeks

median

N =

101

N = 32

0100

26

N = 38

60

-130.77

(increase)

Not reported
11 weeks

median

N =

40

N = 23

0100
de Jonge 1990 SDN 15 months

median

N =

(reports min, max, 90th percentile

and median

of egg counts/10 mL)

124

N = 38

1

N = 32

99.19

124

N = 21

95

N = 19

23.38

Not significant

P = 0.27

Stephenson 1985 KEN 36 months

AMEC

N =

109

N = 202

794

110

N = 198

124

-12.7

(increase)

Not reported

Stephenson 1985 KEN also reported mean haemoglobin, with slightly higher values at six months after metrifonate compared to placebo (mean difference 0.3 G/dL, 95% CI 0.14 to 0.46; 400 participants, one trial, Analysis 7.2). The authors noted that hookworm endemicity was high, and metrifonate also has an effect on hookworm which could account for this finding.

None of the trials reported on adverse events.

Direct comparisons of different metrifonate regimens (comparisons 8 and 9)

In one trial, multiple doses of 10 mg/kg were superior to a single dose.

One three-arm trial directly compared a single dose of 10 mg/kg with two or three doses given two weeks apart. Parasitological failure at one month was 53% with a single dose, 40% with two doses, and 19% with three doses. The difference was statistically significant for three doses versus one dose (RR 0.36, 95% CI 0.17 to 0.77; 93 participants, one trial, Analysis 8.1), but not two doses versus one dose (RR 0.75, 95% CI 0.5 to 1.13; 112 participants, one trial, Analysis 8.1). Results were similar at four months (Analysis 8.2).

The percent egg reduction was also improved from 37% after a single dose to 88% after three doses, although this was not maintained at the four months' follow-up (see Appendix 2). This trial did not report on adverse events.

One additional trial (Abden Abdi 1989 SOM) compared three doses of 7.5 mg/kg given two weeks apart with three doses of 5 mg/kg given in one day. The trial detected no difference for parasitological failure at one month, three months or six months (201 participants, one trial, Analysis 9.1). Egg reduction at one month was above 90% after both metrifonate doses and was sustained (> 90%) at two, three and six months (201 participants, see Appendix 2). This trial recorded adverse events by active surveillance (Appendix 5). It did not detect a significant difference for any of the symptoms between treatment groups (201 participants, one trial, Analysis 9.2) The adverse events were mild and transient.Headache and abdominal pain were most common.

Section C: Praziquantel versus metrifonate

Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose (comparison 10)

Single dose praziquantel 40 mg/kg was more effective than single dose metrifonate 10 mg/kg in curing patients and reducing egg excretion.

Three trials compared the standard dose of praziquantel 40 mg/kg with a single dose of metrifonate 10 mg/kg, although one trial only reported outcomes at eight months after treatment (Stephenson 1989 KEN).

In the first trial (Pugh 1983 MWI), parasitological failure at one month was halved with praziquantel 40 mg/kg compared to metrifonate 10 mg/kg (RR 0.46, 95% CI 0.34 to 0.61; 183 participants, one trial, Analysis 10.1). Treatment failure increased in both groups over the following five months which the authors suspect was due to egg excretion by maturing worms, as transmission and re-infection were low in the trial setting (Analysis 10.1). The second trial (Wilkins 1987 GMB), also found praziquantel to be superior to metrifonate at two to three months as its only time point (RR 0.45, 95% CI 0.27 to 0.75; 72 participants, one trial, Analysis 10.1).

The third trial (Stephenson 1989 KEN), found substantial reductions in both treatment failure (RR 0.21, 95% CI 0.13 to 0.36; 208 participants, one trial, Analysis 10.1) and egg excretion (see Appendix 2), with praziquantel compared to metrifonate. Haemoglobin levels measured in this trial were higher in the praziquantel treatment arm both at baseline and at follow-up (208 participants, one trial, Analysis 10.2). The trial did not detect a difference in growth parameters between groups but does not report them separately (see Appendix 4).

None of the trials reported on adverse events.

Praziquantel 40 mg/kg single dose versus multiple doses of metrifonate 10 mg/kg

Two small trials found no difference in parasitological treatment failure or egg excretion between single dose praziquantel 40 mg/kg and two or three doses of metrifonate 10 mg/kg.

Two small trials compared praziquantel 40 mg/kg single dose to two and three doses of metrifonate 10 mg/kg given two weeks apart. The trials detected no difference in parasitological treatment failure at different time points and with different metrifonate regimens. However, in one trial both drugs performed poorly (de Jonge 1990 SDN), and in one trial both performed well (Al Aska 1990 SAU) (see Analysis 10.3). The trial where both drugs performed poorly for parasitological failure has been discussed above and this is likely to be due to the very sensitive method for detecting eggs. In this trial, both drugs reduced mean egg excretion by over 98% at one month and five months (see Appendix 2), and a decrease in haematuria by over 90% at one month. Reduction in proteinuria was almost 80% in both groups (see Appendix 3).

Only Al Aska 1990 SAU reported adverse events; dizziness was more common after praziquantel (RR 2.9, 95% CI 1.59 to 5.3; 100 participants, one trial, Analysis 10.4). Dizziness (20% in the praziquantel group and 10% in the metrifonate group) and abdominal pain (12% both in the praziquantel and metrifonate group) were the most common side effects (Appendix 5).

Additional comparisons of praziquantel and metrifonate

One small trial compared a single dose of praziquantel 30 mg/kg to three doses of metrifonate 10 mg/kg given two weeks apart and found no difference in parasitological failure at two months, but a statistically significant difference in favour of praziquantel at four months (RR 0.24, 95% CI 0.07 to 0.8; 52 participants, one trial, Analysis 10.5). Egg reduction at four months was above 98% in both treatment groups (Appendix 2). In this trial, abdominal pain was more common in the metrifonate group (RR 0.33, 95% CI 0.12 to 0.92; 60 participants, one trial, Analysis 10.6), while no difference was detected for the eight other clinically diagnosed symptoms reported.

One large population-based trial from Kenya compared praziquantel 40 mg/kg given once a year to metrifonate 10 mg/kg given three times a year. After one year, this trial detected no difference in treatment failure, haematuria or proteinuria (1400 participants, one trial, Analysis 10.7), but mean egg excretion was reduced by over 80% in both groups at one year (Appendix 2). There continued to be no difference in parasitological failure at two years, but praziquantel was superior in the third year (RR 0.62, 95% CI 0.42 to 0.93; 827 participants one trial, Analysis 10.8). Ultrasound findings, recorded in a sub-sample of children, were inconclusive (373 participants, Appendix 6).

One further small trial compared a single dose of praziquantel 40 mg/kg with a combination of praziquantel 10 mg/kg and metrifonate 10 mg/kg. At two to three months there was no difference in treatment failure (72 participants, one trial, Analysis 10.9). Percent egg reduction was 99.4% after praziquantel alone and 92.9% after the combination treatment (see Appendix 2).

Section D: Artesunate

Artesunate versus placebo (comparison 11)

The two placebo controlled trials of artesunate had inconsistent results, and the single trial at low risk of bias found only a modest effect on egg excretion compared to placebo.

Two trials compared artesunate 4 mg/kg once daily for three days with placebo. The two trials had inconsistent results on parasitological failure, with one trial finding no difference between artesunate and placebo, and one finding lower treatment failures with artesunate at eight weeks (251 participants, two trials, Analysis 11.1). The trial finding an effect was at unclear risk of both selection and detection bias due to an inadequate description of trial methods (Inyang Etoh 2009 NGA).

Both trials found that artesunate reduced egg excretion compared to placebo (Table 8), but the percent reduction was low compared to that seen in placebo controlled trials of praziquantel (percent egg reductions of between 52% and 69%).

Table 8. Artesunate versus placebo: % egg reduction
  1. 1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.

Study IDTime pointMeasureArtesunate 4 mg/kg/d for 3 daysPlaceboP value difference between groups
Egg count/10 mL urine

% egg

reduction

Egg count/10 mL

% egg

reduction

BaselineFollow-upBaselineFollow-up
Borrmann 2001 GAB8 weeks

GMEC (range)

95% CI N =

35.22 (1-4360)

N = 90

10.8

N = 89

69.34

21.56

(1-778)

N = 30

11.41

N = 30

47.1Not significant
Inyang Etoh 2009 NGA 18 weeks

Mean ova count ± SD

N =

39.8 ± 1.1

N = 52

19.1 ± 1.0

N = 44

52.1

34.1 ± 0.8

N = 52

72.0 ± 2.3

N = 44

111.5

(increase)

P for "therapeutic efficacy" < 0.001

The trial at unclear risk of bias also reported improved reductions in haematuria and proteinuria compared to placebo, while the trial at low risk of bias (Borrmann 2001 GAB) found no effect on proteinuria (see Appendix 3). No differences in adverse events were reported (see Appendix 5, Analysis 11.3).

Praziquantel versus artesunate (comparison 12)

The results of the three trials are inconsistent, with the single trial at low risk of bias finding only a modest reduction in egg excretion with artesunate.

Three trials (Borrmann 2001 GAB; Inyang Etoh 2009 NGA; Keiser 2010 CIV) compared artesunate 4 mg/kg/d for three days with praziquantel 40 mg/kg single dose.

The three trials had mixed results. In two trials artesunate performed poorly, with parasitological treatment failures of over 70% at one month and two months respectively (Borrmann 2001 GAB; Keiser 2010 CIV). In these trials praziquantel was clearly superior (Analysis 12.1). In the third trial (Inyang Etoh 2009 NGA), at unclear risk of bias due to inadequate description of trial methods, artesunate performed similarly to praziquantel with 28% treatment failures at two months (Analysis 12.1).

The percent egg reduction with artesunate varied across the three trials from 52% to 85% (see Appendix 2). In the single trial where both praziquantel and artesunate performed well at reducing treatment failures, both drugs had fairly modest effects on egg excretion (Inyang Etoh 2009 NGA).

Only the trial at unclear risk of bias (Inyang Etoh 2009 NGA) reported substantial effects of artesunate on haematuria and proteinuria (see Appendix 3). In the trial at low risk of bias (Borrmann 2001 GAB) praziquantel was clearly superior at reducing microhematuria (RR 0.43, 95% CI 0.3 to 0.62; 178 participants, one trial, Analysis 12.2).

All trials reported on adverse events with no significant differences noted between groups (see Appendix 5, Analysis 12.3).

Praziquantel versus praziquantel plus artesunate (comparison 13)

The results of the two trials were inconsistent but the trial at low risk of bias found no benefit with adding artesunate to praziquantel.

Two of the trials comparing artesunate with praziquantel also had a treatment arm where patients received both drugs (Borrmann 2001 GAB; Inyang Etoh 2009 NGA). Again, in the trial at low risk of bias (Borrmann 2001 GAB) adding artesunate to praziquantel did not substantially reduce treatment failures or percent egg reduction at eight weeks compared to praziquantel alone, whereas in the trial at unclear risk of bias (Inyang Etoh 2009 NGA), adding artesunate improved outcomes (Analysis 13.1; Table 9; Appendix 2). No differences in adverse events were reported (see Appendix 5).

Table 9. Praziquantel and Artesunate versus Praziquantel: % egg reduction
  1. 1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.

Study IDTime pointMeasurePraziquantel 40 mg/kg single dose and artesunate 4 mg/kg/d for 3 daysPraziquantel 40 mg/kg single doseP value difference between groups
Egg count/10 mL% egg reductionEgg count/10 mL% egg reduction
BaselineFollow-upBaselineFollow-up
Borrmann 2001 GAB8 weeks

GMEC (range),

(95% CI)

N =

31.5

(1 to 3225)

N = 90

0.36

N = 88

98.8

38.51

(1 to 3313)

N = 90

1.11 (0.7 to 1.7)

N = 89

97.11Not significant
Inyang Etoh 2009 NGA 18 weeks

mean ± SD

N =

62.2 ± 2.1

N = 52

4.0 (± 15.2) N = 4493.6

39.8 (± 1.1)

N = 52

19.1 (± 1.0)

N = 44

52.1Not reported

Section E: Others

Mefloquine versus sulfadoxine-pyrimethamine (comparison 14)

In a single trial comparing the use of mefloquine and sulfadoxine-pyrimethamine as intermittent preventive treatment for malaria in pregnancy, a re-analysis of the small number of mothers infected with S. haematobium found more women were cured at one month after mefloquine compared to sulfadoxine-pyrimethamine (RR 0.57, 95% CI 0.4 to 0.83; 44 participants, one trial, Analysis 14.1), and an egg reduction of 80% four weeks after treatment and 98% ten weeks after treatment (see Appendix 2).

Praziquantel versus mefloquine alone or mefloquine in combination with artesunate (comparison 15 and 16)

A single small trial (Keiser 2010 CIV) reported lower treatment failures with praziquantel 40 mg/kg alone than with mefloquine 25 mg/kg (RR 0.15, 95% CI 0.05 to 0.43; 45 participants, one trial, Analysis 15.1) or with mefloquine in combination with artesunate 4 mg/kg/d for three days (RR 0.23, 95% CI 0.07 to 0.74; 44 participants, one trial, Analysis 16.1). At four weeks, this trial reports a percent egg reduction of 74% at four weeks with mefloquine alone (19 participants), 96% with mefloquine and artesunate combined, and 97% with praziquantel (Appendix 2).

Keiser 2010 CIV recorded adverse events by active, prospective surveillance. Adverse events were mild to moderate and common in all groups. There were no statistically significant differences in any individual adverse event (Appendix 5).

Praziquantel versus praziquantel and albendazole (comparison 17)

One trial (Olds 1999 KEN) compared a single dose of praziquantel 40 mg/kg with a combination of single dose praziquantel 40 mg/kg plus albendazole 400 mg at day 45 (RR 0.9, 95% CI 0.62 to 1.3; 193 participants, one trial, Analysis 17.1). The authors concluded that albendazole does not influence the effect of praziquantel.

Adverse events were monitored by active, prospective surveillance and described as mild and transient. Diarrhoea, headache and abdominal pain were observed most frequently, but adverse events were reported for participants treated for S. haematobium and S. mansoni together (Appendix 5).

Discussion

For a summary of the main results of the review and GRADE assessment of the quality of evidence see: Summary of findings for the main comparison; Summary of findings table 2; Summary of findings 2; Summary of findings 3; Summary of findings 4; Summary of findings 5; and Summary of findings 6.

Summary of main results

On average, a single 40 mg/kg dose of praziquantel reduced the proportion of people still excreting S. haematobium eggs in their urine by around 60% compared to placebo at one to two months after treatment (high quality evidence), and reduced the mean number of schistosome eggs in the urine by over 95% in five out of six trials (high quality evidence). Splitting praziquantel 40 mg/kg into two doses over 12 hours probably has no benefits over a single dose.

Two small trials compared a single 40 mg/kg dose of praziquantel with two or three doses of 10 mg/kg metrifonate and found no differences in cure. In one trial both drugs performed badly and in one trial both performed well.

Three trials evaluated the antimalarial artesunate, and two trials evaluated mefloquine, with inconsistent results.

Overall completeness and applicability of evidence

The WHO currently recommend that schistosomiasis is treated with a single dose of praziquantel of at least 40 mg/kg (WHO 2006). In this review we found no trials evaluating doses higher than 40 mg in urinary schistosomiasis, but doses of 40 mg/kg or even 30 mg/kg are effective at reducing egg excretion and achieving cure.

Of all the drugs that have been evaluated for treating urinary schistosomiasis, praziquantel has by far the strongest evidence base. It has been evaluated across a wide range of endemic countries, and most trials were conducted in children who bear the highest burden of disease. However, few trials included children younger than five years of age, and Stothard 2013 suggested that higher doses of praziquantel might be required for this group. We would have liked to explore this possibility through an analysis stratified by age, but the data did not allow this and no firm conclusions can be made. In addition, most trials concentrated on parasitological efficacy, and few reported clinical outcomes such as improvement in haematuria or anaemia. Data on resolution of long-term morbidity after treatment, as nutritional outcomes and sonographic findings are very rare, and follow-up is limited to less than one year.

The absolute proportion of people cured by praziquantel varied between trials while percent egg reduction was relatively homogenous. This may be explained by low sensitivity and negative predictive value of the diagnostic test, compounded with the fact that egg yield varies during the day and with physical activity. This means that patients with few eggs in their urine may be variably declared as positive or negative in different settings. The proportional reduction in the mean egg counts from before to after treatment is less prone to this error. It also appears that some trials based post-treatment egg reduction on the whole trial population (including cured patients with zero egg counts), while other trials based the post-treatment calculations on those patients still excreting eggs. We were unable to combine egg reduction values in meta-analysis, and assess statistical significance, due to the poor reporting of standard deviations and methods for calculating the mean (Table 2).

None of the included trials suggested drug resistance as a possible cause of high parasitological failure, or of recurrent schistosomiasis over prolonged follow-up. In high transmission areas two mechanisms could explain rising parasitological failure over time: maturation of immature worms (which escape the action of praziquantel) to egg producing adults, and reinfection.

Previously the WHO also recommended metrifonate at 7.5 mg/kg for three doses (given two weeks apart), but this drug is now largely unavailable (Danso-Appiah 2008). We found some evidence that repeated doses of metrifonate had reasonable antischistosomal effects but we found no trials directly comparing this dose with the standard dose of praziquantel. Combining praziquantel with metrifonate is one possible strategy for improving parasitological cure as they attack S. haematobium by different mechanisms (Utzinger 2004). However, we only found one small trial evaluating a combination approach and this used a low dose of praziquantel rather than the standard 40 mg/kg (Wilkins 1987 GMB).

Antimalarials (such as artesunate and mefloquine) given alone or in combination with praziquantel are another potential future treatment option, but the current evidence base is limited to a few trials with inconsistent results. As many locations in sub-Saharan Africa are co-endemic for schistosomiasis and malaria, there are also concerns about development of Plasmodium parasite resistance to artemisinins, especially as they would be used in a single dose and without a companion antimalarial drug (Utzinger 2004). Any change in policy would need to fully consider this potential public health harm.

Quality of the evidence

We used the GRADE approach to assess the quality for the evidence.

We consider the evidence for substantial benefits with praziquantel compared to placebo to be of high quality, meaning we have confidence in this result. Many of the included trials are old, but reassuringly the findings of the most recent trial conducted in 2005/2006 are consistent with the older studies.

However, we consider most of the evidence for other comparisons in this review to be of low or even very low quality. Most of the trials evaluating metrifonate are old and precede guidelines on transparent reporting of clinical trials. As such, many trials lacked adequate descriptions of methods to allow judgements on risk of bias, and so risk of bias has been classified as unclear. Trials were also generally small and underpowered to reliably detect or exclude effects.

Of the three trials reporting on the antischistosomal effects of artesunate, only one was at low risk of bias and this trial found little effect with artesunate compared to placebo (Borrmann 2001 GAB). Although the metanalysis suggests artesunate may improve cure when added to praziquantel, this evidence was of low quality due to inconsistency between trials, and the single trial showing a large effect being at unclear risk of bias for all domains.

Potential biases in the review process

Our information specialist followed a detailed, reproducible search strategy, and we searched reference lists of included trials. However, some trials might not be available online, and therefore an electronic search will not identify them.

In many cases, clarification of information with authors was not possible as no contact e-mail addresses were available as the trials were very old.

Agreements and disagreements with other studies or reviews

Two recent systematic reviews evaluated the use of artemisinins in treating urinary schistosomiasis (Liu 2011; Pérez del Villar 2012), and both concluded that the combination of artesunate plus praziquantel is superior to praziquantel alone, While we find some evidence to support this we conclude that this evidence is only of low quality and encourage further high quality and adequately powered trials before any change in treatment policy. Of note, the trial at lowest risk of bias (Borrmann 2001 GAB), found no significant difference in cure between artesunate alone and placebo, or between praziquantel plus artesunate and praziquantel alone.

One further systematic review evaluated single or repeated doses of praziquantel, and found no evidence of benefit with repeated dosing compared to a single dose in people with S. haematobium infection (King 2011). We would agree that repeating doses two or three weeks apart does not seem to provide benefit over a single dose based on two trials with 686 participants. However, repeating doses at three monthly intervals over two years did seem to provide some additional benefits in a single small trial and further trials could evaluate this.

Authors' conclusions

Implications for practice

Praziquantel is the most studied drug for treating urinary schistosomiasis and has the strongest evidence base. Although there is some evidence that 30 mg/kg may be sufficient, operationally this would prove difficult as 40 mg/kg is used to treat people with intestinal schistosomiasis, and the two diseases often overlap.

Implications for research

Potential strategies to improve future treatments for schistosomiasis include the combination of praziquantel with metrifonate, or with antimalarials with antischistosomal properties such as artesunate and mefloquine. Evaluation of these combinations requires rigorous. adequately powered trials using standardized outcome measures. It is both important and urgent that these parameters be agreed upon and applied. Trial protocols with standardised diagnostic methods, time points of follow-up and efficacy outcomes would enable us to combine trials in meta-analysis and to reduce heterogeneity between trials.

Acknowledgements

We would like to thank the authors of the previous version of this review Anthony Danso-Appiah, Jürg Utzinger, and Jianping Liu, who stood down for this update.

We thank the trial authors for their research, which enabled us to conduct a systematic review and particularly trial authors that responded to our requests for further information. We acknowledge Paul Garner for his expertise, experience and encouragement; Anne Marie Stephani, whose ready technical assistance with Review Manager (RevMan) was most helpful; and to Vittoria Lutje for her approachability and support. The editorial base of the Cochrane Infectious Diseases Group is funded by the UK Department for International Development for the benefit of developing countries.

Data and analyses

Download statistical data

Comparison 1. Praziquantel 40 mg/kg single dose versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 at one month to two months7864Risk Ratio (M-H, Random, 95% CI)0.42 [0.29, 0.59]
1.2 at three months3354Risk Ratio (M-H, Random, 95% CI)0.51 [0.34, 0.77]
1.3 at five months154Risk Ratio (M-H, Random, 95% CI)0.73 [0.58, 0.91]
1.4 at six months3332Risk Ratio (M-H, Random, 95% CI)0.42 [0.10, 1.84]
1.5 at eight months1209Risk Ratio (M-H, Random, 95% CI)0.14 [0.08, 0.22]
2 Haematuria at eight weeks1119Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.33, 0.84]
3 Haemoglobin2 Mean Difference (IV, Random, 95% CI)Subtotals only
3.1 at baseline2727Mean Difference (IV, Random, 95% CI)-0.17 [-0.35, 0.02]
3.2 at six to eight months2727Mean Difference (IV, Random, 95% CI)-0.08 [-0.24, 0.09]
4 Adverse events2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Diarrhoea1156Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Vomiting2226Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.15, 2.87]
4.3 Dizziness2226Risk Ratio (M-H, Fixed, 95% CI)0.37 [0.11, 1.27]
4.4 Anorexia170Risk Ratio (M-H, Fixed, 95% CI)0.20 [0.05, 0.85]
4.5 Abdominal pain2226Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.22, 1.14]
4.6 Tiredness170Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.14, 1.71]
4.7 Weakness170Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.36, 2.57]
4.8 Headache2226Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.02, 1.47]
4.9 Fever2226Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.07, 17.22]
4.10 Pain in limbs170Risk Ratio (M-H, Fixed, 95% CI)5.59 [0.28, 112.34]
4.11 Itching1156Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.19, 5.28]
4.12 Cough1156Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.09, 10.78]
4.13 Chills1156Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.16, 14.07]
4.14 Nausea1156Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.09, 10.78]
4.15 Constipation1156Risk Ratio (M-H, Fixed, 95% CI)1.51 [0.06, 36.54]
Analysis 1.1.

Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 1 Parasitological failure.

Analysis 1.2.

Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 2 Haematuria at eight weeks.

Analysis 1.3.

Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 3 Haemoglobin.

Analysis 1.4.

Comparison 1 Praziquantel 40 mg/kg single dose versus placebo, Outcome 4 Adverse events.

Comparison 2. Praziquantel 40 mg/kg single dose versus lower doses
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at four to six weeks5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 versus 30 mg/kg4401Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.59, 0.99]
1.2 versus 20 mg/kg2338Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.59, 0.93]
1.3 versus 10 mg/kg1150Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.53, 0.84]
2 Parasitological failure at two to three months6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 versus 30 mg/kg5517Risk Ratio (M-H, Fixed, 95% CI)0.95 [0.72, 1.24]
2.2 versus 20 mg/kg3330Risk Ratio (M-H, Fixed, 95% CI)0.72 [0.56, 0.92]
2.3 versus 10 mg/kg3339Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.39, 0.60]
3 Parasitological failure at six to seven months6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 versus 30 mg/kg6669Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.76, 1.23]
3.2 versus 20 mg/kg1138Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.53, 1.44]
3.3 versus 10 mg/kg1150Risk Ratio (M-H, Fixed, 95% CI)0.43 [0.29, 0.64]
4 Haematuria at three months1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 versus 30 mg/kg1117Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.47, 1.67]
4.2 versus 20 mg/kg1122Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.60, 2.33]
4.3 versus 10 mg/kg1119Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.21, 0.58]
5 Proteinuria at three months1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 versus 30 mg/kg1117Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.34, 2.12]
5.2 versus 20 mg/kg1122Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.36, 2.30]
5.3 versus 10 mg/kg1119Risk Ratio (M-H, Fixed, 95% CI)0.25 [0.12, 0.51]
6 Haematuria at six weeks1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 versus 20 mg/kg1245Risk Ratio (M-H, Fixed, 95% CI)0.63 [0.47, 0.86]
7 Proteinuria at six weeks1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 versus 20 mg/kg1245Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.46, 0.96]
8 Haematuria at nine months1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 versus 20 mg/kg1215Risk Ratio (M-H, Fixed, 95% CI)0.59 [0.44, 0.78]
9 Proteinuria at nine months1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
9.1 versus 20 mg/kg1214Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.50, 0.90]
10 Adverse events2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
10.1 Vomiting2163Risk Ratio (M-H, Random, 95% CI)0.79 [0.05, 13.51]
10.2 Dizziness2163Risk Ratio (M-H, Random, 95% CI)0.73 [0.11, 4.62]
10.3 Anorexia165Risk Ratio (M-H, Random, 95% CI)4.85 [0.24, 97.31]
10.4 Abdominal pain2163Risk Ratio (M-H, Random, 95% CI)1.14 [0.23, 5.56]
10.5 Tiredness165Risk Ratio (M-H, Random, 95% CI)0.32 [0.10, 1.09]
10.6 Weakness165Risk Ratio (M-H, Random, 95% CI)1.16 [0.39, 3.44]
10.7 Headache2163Risk Ratio (M-H, Random, 95% CI)0.49 [0.08, 2.85]
10.8 Fever165Risk Ratio (M-H, Random, 95% CI)2.91 [0.12, 68.95]
10.9 Pain in limbs165Risk Ratio (M-H, Random, 95% CI)0.39 [0.08, 1.86]
Analysis 2.1.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 1 Parasitological failure at four to six weeks.

Analysis 2.2.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 2 Parasitological failure at two to three months.

Analysis 2.3.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 3 Parasitological failure at six to seven months.

Analysis 2.4.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 4 Haematuria at three months.

Analysis 2.5.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 5 Proteinuria at three months.

Analysis 2.6.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 6 Haematuria at six weeks.

Analysis 2.7.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 7 Proteinuria at six weeks.

Analysis 2.8.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 8 Haematuria at nine months.

Analysis 2.9.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 9 Proteinuria at nine months.

Analysis 2.10.

Comparison 2 Praziquantel 40 mg/kg single dose versus lower doses, Outcome 10 Adverse events.

Comparison 3. Praziquantel 40 mg/kg single dose versus 2 x 20 mg/kg split dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure4 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 at one month3374Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.51, 1.11]
1.2 at three months3361Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.45, 1.20]
1.3 at six to seven months3234Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.51, 1.35]
2 Adverse events3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Blood in stool1215Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2.2 Vomiting3373Risk Ratio (M-H, Fixed, 95% CI)0.50 [0.29, 0.86]
2.3 Dizziness3373Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.16, 0.94]
2.4 Anorexia169Risk Ratio (M-H, Fixed, 95% CI)2.18 [0.21, 22.96]
2.5 Abdominal pain3373Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.83, 1.25]
2.6 Tiredness169Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.12, 1.41]
2.7 Weakness169Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.35, 2.50]
2.8 Headache2158Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.20, 1.33]
2.9 Fever2284Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.23, 1.23]
2.10 Pain in limbs169Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.09, 2.10]
2.11 Diarrhoea1215Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.67, 1.73]
2.12 Skin reaction1215Risk Ratio (M-H, Fixed, 95% CI)1.84 [0.34, 9.83]
Analysis 3.1.

Comparison 3 Praziquantel 40 mg/kg single dose versus 2 x 20 mg/kg split dose, Outcome 1 Parasitological failure.

Analysis 3.2.

Comparison 3 Praziquantel 40 mg/kg single dose versus 2 x 20 mg/kg split dose, Outcome 2 Adverse events.

Comparison 4. Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or 3 x 40 mg/kg
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: parasitological failure2 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 at six weeks1269Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.50, 1.34]
1.2 at nine weeks to three months2686Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.91, 1.25]
1.3 at six months1556Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.95, 1.31]
2 Praziquantel 40 mg/kg single dose versus praziquantel 3 x 40 mg/kg: parasitological failure1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 at nine weeks1185Risk Ratio (M-H, Fixed, 95% CI)0.94 [0.42, 2.12]
3 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: microhaematuria at six months1300Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.88, 1.56]
Analysis 4.1.

Comparison 4 Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or 3 x 40 mg/kg, Outcome 1 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: parasitological failure.

Analysis 4.2.

Comparison 4 Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or 3 x 40 mg/kg, Outcome 2 Praziquantel 40 mg/kg single dose versus praziquantel 3 x 40 mg/kg: parasitological failure.

Analysis 4.3.

Comparison 4 Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or 3 x 40 mg/kg, Outcome 3 Praziquantel 40 mg/single dose versus praziquantel 2 x 40 mg/kg: microhaematuria at six months.

Comparison 5. Praziquantel 40 mg/kg single dose versus multiple doses
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 at two years162Risk Ratio (M-H, Fixed, 95% CI)2.71 [1.47, 5.00]
1.2 at three years143Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.59, 1.42]
2 Haematuria143Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.42, 1.17]
Analysis 5.1.

Comparison 5 Praziquantel 40 mg/kg single dose versus multiple doses, Outcome 1 Parasitological failure.

Analysis 5.2.

Comparison 5 Praziquantel 40 mg/kg single dose versus multiple doses, Outcome 2 Haematuria.

Comparison 6. Metrifonate single dose (10 mg/kg) versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 at one month1142Risk Ratio (M-H, Random, 95% CI)0.83 [0.74, 0.94]
1.2 at two and a half to three months1122Risk Ratio (M-H, Random, 95% CI)0.92 [0.85, 0.99]
1.3 at six months1102Risk Ratio (M-H, Random, 95% CI)0.94 [0.87, 1.02]
1.4 at eight months1210Risk Ratio (M-H, Random, 95% CI)0.63 [0.54, 0.73]
2 Haemoglobin1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 at baseline1207Mean Difference (IV, Fixed, 95% CI)0.0 [-0.33, 0.33]
2.2 at eight months1207Mean Difference (IV, Fixed, 95% CI)0.30 [-0.05, 0.65]
Analysis 6.1.

Comparison 6 Metrifonate single dose (10 mg/kg) versus placebo, Outcome 1 Parasitological failure.

Analysis 6.2.

Comparison 6 Metrifonate single dose (10 mg/kg) versus placebo, Outcome 2 Haemoglobin.

Comparison 7. Metrifonate multiple doses versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 at one month150Risk Ratio (M-H, Random, 95% CI)0.84 [0.65, 1.09]
1.2 at 11 weeks193Risk Ratio (M-H, Random, 95% CI)0.41 [0.30, 0.56]
1.3 at five months151Risk Ratio (M-H, Random, 95% CI)0.89 [0.76, 1.03]
1.4 at six months1400Risk Ratio (M-H, Random, 95% CI)0.30 [0.24, 0.37]
2 Haemoglobin1 Mean Difference (IV, Random, 95% CI)Subtotals only
2.1 at baseline1400Mean Difference (IV, Random, 95% CI)-0.17 [-0.45, 0.11]
2.2 at six months1391Mean Difference (IV, Random, 95% CI)0.30 [0.14, 0.46]
Analysis 7.1.

Comparison 7 Metrifonate multiple doses versus placebo, Outcome 1 Parasitological failure.

Analysis 7.2.

Comparison 7 Metrifonate multiple doses versus placebo, Outcome 2 Haemoglobin.

Comparison 8. Metrifonate multiple doses versus single dose
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at one month1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 20 mg/kg versus 10 mg/kg1112Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.50, 1.13]
1.2 30 mg/kg versus 10 mg/kg193Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.17, 0.77]
2 Parasitological failure at four months1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 20 mg/kg versus 10 mg/kg1133Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.58, 1.06]
2.2 30 mg/kg versus 10 mg/kg1111Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.45, 0.99]
Analysis 8.1.

Comparison 8 Metrifonate multiple doses versus single dose, Outcome 1 Parasitological failure at one month.

Analysis 8.2.

Comparison 8 Metrifonate multiple doses versus single dose, Outcome 2 Parasitological failure at four months.

Comparison 9. Metrifonate 3 doses 2 weeks apart: 7.5 mg/kg versus 5 mg/kg
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 at one month1201Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.69, 1.21]
1.2 at two months1165Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.72, 1.30]
1.3 at three months1133Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.67, 1.26]
1.4 at six months1139Risk Ratio (M-H, Fixed, 95% CI)1.43 [0.99, 2.05]
2 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Nausea1201Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.05, 5.48]
2.2 Vomiting1201Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.06, 15.93]
2.3 Dizziness1201Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.06, 15.93]
2.4 Abdominal pain1201Risk Ratio (M-H, Fixed, 95% CI)3.03 [0.32, 28.64]
2.5 Headache1201Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.04, 3.18]
2.6 Heaviness of the tongue1201Risk Ratio (M-H, Fixed, 95% CI)2.02 [0.19, 21.92]
Analysis 9.1.

Comparison 9 Metrifonate 3 doses 2 weeks apart: 7.5 mg/kg versus 5 mg/kg, Outcome 1 Parasitological failure.

Analysis 9.2.

Comparison 9 Metrifonate 3 doses 2 weeks apart: 7.5 mg/kg versus 5 mg/kg, Outcome 2 Adverse events.

Comparison 10. Praziquantel versus metrifonate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: parasitological failure3 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 at one month1183Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.34, 0.61]
1.2 at two to three months2243Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.57, 0.79]
1.3 at six months1149Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.79, 1.01]
1.4 at eight months1208Risk Ratio (M-H, Fixed, 95% CI)0.21 [0.13, 0.36]
2 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: haemoglobin1 Mean Difference (IV, Fixed, 95% CI)Subtotals only
2.1 at baseline1208Mean Difference (IV, Fixed, 95% CI)-0.30 [-0.52, -0.08]
2.2 at eight months1208Mean Difference (IV, Fixed, 95% CI)-0.40 [-0.66, -0.14]
3 Praziquantel 40 mg/kg single dose versus metrifonate 20 and 30 mg/kg given as split doses: parasitological failure2 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 2 x 10 mg/kg Metrifonate at one month172Risk Ratio (M-H, Random, 95% CI)1.03 [0.80, 1.34]
3.2 2 x 10 mg/kg Metrifonate at five months167Risk Ratio (M-H, Random, 95% CI)0.82 [0.64, 1.05]
3.3 3 x 10 mg/kg Metrifonate at three months1100Risk Ratio (M-H, Random, 95% CI)0.33 [0.07, 1.57]
3.4 3 x 10 mg/kg Metrifonate at six months1100Risk Ratio (M-H, Random, 95% CI)0.2 [0.02, 1.65]
4 Praziquantel 40 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4.1 Dizziness1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Abdominal pain1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 Joint pain1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.4 Nausea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.5 Rash1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.6 Vomiting1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.7 Itching1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.8 Fatigue1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.9 Hair loss1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.10 Change in taste1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.11 Diarrhoea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.12 Convulsion1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: parasitological failure1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 at two months154Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.17, 1.68]
5.2 at four months152Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.07, 0.80]
6 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
6.1 Nausea160Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.13, 70.83]
6.2 Vomiting160Risk Ratio (M-H, Fixed, 95% CI)0.2 [0.01, 4.00]
6.3 Abdominal pain160Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.12, 0.92]
6.4 Headache160Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.87]
6.5 Fever160Risk Ratio (M-H, Fixed, 95% CI)0.33 [0.01, 7.87]
6.6 Loose bowel motions160Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 15.26]
6.7 Dizziness160Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 15.26]
6.8 Itching160Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 15.26]
6.9 Body pain160Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.07, 15.26]
7 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
7.1 Parasitological failure at one year11436Risk Ratio (M-H, Fixed, 95% CI)1.05 [1.00, 1.11]
7.2 Haematuria at one year11400Risk Ratio (M-H, Fixed, 95% CI)1.08 [0.85, 1.36]
7.3 Proteinuria at one year11400Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.79, 1.11]
8 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months: parasitological failure1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
8.1 at one year11018Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.61, 1.00]
8.2 at two years11025Risk Ratio (M-H, Fixed, 95% CI)0.77 [0.53, 1.11]
8.3 at three years1827Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.42, 0.93]
9 Praziquantel 40 mg/kg versus praziquantel 10 mg/kg and metrifonate 10 mg/kg172Risk Ratio (M-H, Random, 95% CI)0.59 [0.34, 1.03]
Analysis 10.1.

Comparison 10 Praziquantel versus metrifonate, Outcome 1 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: parasitological failure.

Analysis 10.2.

Comparison 10 Praziquantel versus metrifonate, Outcome 2 Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: haemoglobin.

Analysis 10.3.

Comparison 10 Praziquantel versus metrifonate, Outcome 3 Praziquantel 40 mg/kg single dose versus metrifonate 20 and 30 mg/kg given as split doses: parasitological failure.

Analysis 10.4.

Comparison 10 Praziquantel versus metrifonate, Outcome 4 Praziquantel 40 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events.

Analysis 10.5.

Comparison 10 Praziquantel versus metrifonate, Outcome 5 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: parasitological failure.

Analysis 10.6.

Comparison 10 Praziquantel versus metrifonate, Outcome 6 Praziquantel 30 mg/kg single dose versus metrifonate 30 mg/kg given as split dose: adverse events.

Analysis 10.7.

Comparison 10 Praziquantel versus metrifonate, Outcome 7 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months.

Analysis 10.8.

Comparison 10 Praziquantel versus metrifonate, Outcome 8 Praziquantel 40 mg/kg once a year versus metrifonate 10 mg/kg every 4 months: parasitological failure.

Analysis 10.9.

Comparison 10 Praziquantel versus metrifonate, Outcome 9 Praziquantel 40 mg/kg versus praziquantel 10 mg/kg and metrifonate 10 mg/kg.

Comparison 11. Artesunate versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at eight weeks2251Risk Ratio (M-H, Random, 95% CI)0.53 [0.16, 1.71]
2 Haematuria1119Risk Ratio (M-H, Fixed, 95% CI)1.22 [0.85, 1.76]
3 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Headache1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Vomiting1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Fever1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.4 Itching1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.5 Cough1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.6 Diarrhoea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.7 Chills1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.8 Nausea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.9 Dizziness1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.10 Abdominal pain1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.11 Constipation1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 11.1.

Comparison 11 Artesunate versus placebo, Outcome 1 Parasitological failure at eight weeks.

Analysis 11.2.

Comparison 11 Artesunate versus placebo, Outcome 2 Haematuria.

Analysis 11.3.

Comparison 11 Artesunate versus placebo, Outcome 3 Adverse events.

Comparison 12. Praziquantel versus artesunate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 at day 28146Risk Ratio (M-H, Random, 95% CI)0.15 [0.05, 0.46]
1.2 at day 562352Risk Ratio (M-H, Random, 95% CI)0.58 [0.23, 1.44]
2 Haematuria1178Risk Ratio (M-H, Random, 95% CI)0.43 [0.30, 0.62]
3 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Abdominal pain1208Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Dizziness1208Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Headache1208Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.43, 2.30]
3.4 Vomiting1208Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.26, 3.89]
3.5 Fever1208Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.41, 3.35]
3.6 Itching1208Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.26, 3.89]
3.7 Cough1208Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.14, 6.97]
3.8 Diarrhoea1208Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.9 Chills1208Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.26, 8.79]
3.10 Nausea1208Risk Ratio (M-H, Fixed, 95% CI)1.0 [0.14, 6.97]
3.11 Constipation1208Risk Ratio (M-H, Fixed, 95% CI)3.0 [0.12, 72.80]
Analysis 12.1.

Comparison 12 Praziquantel versus artesunate, Outcome 1 Parasitological failure.

Analysis 12.2.

Comparison 12 Praziquantel versus artesunate, Outcome 2 Haematuria.

Analysis 12.3.

Comparison 12 Praziquantel versus artesunate, Outcome 3 Adverse events.

Comparison 13. Praziquantel and artesunate versus praziquantel
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at eight weeks2265Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.38, 0.99]
2 Haematuria at eight weeks1177Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.40, 1.18]
3 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Abdominal pain1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Dizziness1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Headache1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.4 Vomiting1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.5 Fever1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.6 Itching1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.7 Cough1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.8 Diarrhoea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.9 Chills1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.10 Nausea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.11 Constipation1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 13.1.

Comparison 13 Praziquantel and artesunate versus praziquantel, Outcome 1 Parasitological failure at eight weeks.

Analysis 13.2.

Comparison 13 Praziquantel and artesunate versus praziquantel, Outcome 2 Haematuria at eight weeks.

Analysis 13.3.

Comparison 13 Praziquantel and artesunate versus praziquantel, Outcome 3 Adverse events.

Comparison 14. Mefloquine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at six weeks144Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.40, 0.83]
Analysis 14.1.

Comparison 14 Mefloquine versus placebo, Outcome 1 Parasitological failure at six weeks.

Comparison 15. Praziquantel versus mefloquine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at one month145Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.05, 0.43]
Analysis 15.1.

Comparison 15 Praziquantel versus mefloquine, Outcome 1 Parasitological failure at one month.

Comparison 16. Praziquantel versus artesunate and mefloquine
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at one month144Risk Ratio (M-H, Fixed, 95% CI)0.23 [0.07, 0.74]
Analysis 16.1.

Comparison 16 Praziquantel versus artesunate and mefloquine, Outcome 1 Parasitological failure at one month.

Comparison 17. Praziquantel versus praziquantel and albendazole
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure1193Risk Ratio (M-H, Random, 95% CI)0.90 [0.62, 1.30]
Analysis 17.1.

Comparison 17 Praziquantel versus praziquantel and albendazole, Outcome 1 Parasitological failure.

Comparison 18. Praziquantel versus praziquantel and artesunate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Parasitological failure at eight weeks2265Risk Ratio (M-H, Fixed, 95% CI)1.62 [1.01, 2.60]
2 Haematuria at eight weeks1177Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.85, 2.50]
3 Adverse events1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
3.1 Abdominal pain1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.2 Dizziness1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.3 Headache1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.4 Vomiting1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.5 Fever1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.6 Itching1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.7 Cough1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.8 Diarrhoea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.9 Chills1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.10 Nausea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
3.11 Constipation1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 18.1.

Comparison 18 Praziquantel versus praziquantel and artesunate, Outcome 1 Parasitological failure at eight weeks.

Analysis 18.2.

Comparison 18 Praziquantel versus praziquantel and artesunate, Outcome 2 Haematuria at eight weeks.

Analysis 18.3.

Comparison 18 Praziquantel versus praziquantel and artesunate, Outcome 3 Adverse events.

Appendices

Appendix 1. Search strategy

Search setCIDG SR*CENTRALMEDLINE**EMBASE**LILACS**
1Schistosoma haematobiumSCHISTOSOMIASIS HAEMATOBIASCHISTOSOMA HAEMATOBIASCHISTOSOMA-HAEMATOBIASchistosoma haematobium
2praziquantelurinary schistosomiasisurinary schistosomiasisurinary schistosomiasisurinary schistosomiasis
3metrifonate1 OR 21 OR 21 OR 21 or 2
4albendazolepraziquantelpraziquantelpraziquantelpraziquantel
5artesunatemetrifonatemetrifonatemetrifonatemetrifonate
6artemetheralbendazolealbendazolealbendazolealbendazole
72-6/ORartesunateartesunateartesunateartesunate
81 AND 7artemetherartemetherartemetherartemether
9--4-8/OR4-8/OR4-8/OR4-8/OR
10--3 AND 93 AND 93 AND 93 AND 9
11----Limit 10 to humanLimit 10 to human--

 *Cochrane Infectious Diseases Group Specialized Register.

 **Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Lefebvre 2008); upper case: MeSH or EMTREE heading; lower case: free text term.

Appendix 2. Appendix: Additional tables for egg reduction data

Praziquantel 40 mg/kg single dose versus placebo: parasitological failure stratified by severity of infection

Trial IDTime pointStratificationGMEC or miracidial count/10 mL urinePraziquantel 40 mg/kg single dosePlaceboP value difference between groups
Parasitological failureParasitological failure
Taylor 1988 ZWE1 monthlight

< 100

N = 77 for all strata

37.7%100%Not reported
heavy> 10091.7%100%
McMahon 1979 TZA1 monthlight

60 to 250

N = 101 for all strata

13.6%
moderate251 to 50012.1%
heavy≥ 50034.5%
King 2002 KEN6 weekslight

0 to 99

N = 48

6/48

12%

moderate

100 to 399

N = 27

13/27

50%

heavy

≥ 400

N = 26

15/26

59%

McMahon 1983 TZA2 monthslight

250 to 500 miracidia

N = 10

1/10
moderate

501 to 1000 miracidia

N = 10

2/10
heavy

> 1000 miracidia

N = 10

1/10
McMahon 1979 TZA3 monthslight

60 to 250

N = 101 for all strata

15.9%
moderate251 to 5008.1%
heavy≥ 50046.4%
King 1989 KEN3 monthslight

1 to 99

N = 9

0%
moderate

100 to 399

N = 29

10%
heavy

≥ 400

N = 18

33%
Taylor 1988 ZWE3 monthslight

< 100

N = 77 for all strata

43.1%

N = 90 for all strata

98.3%Not reported
heavy> 10079.2%95.5%
McMahon 1983 TZA4 monthslight

250 to 500 miracidia

N = 10

1/10
moderate

501 to 1000 miracidia

N = 10

1/10
heavy

> 1000 miracidia

N = 10

1/10
McMahon 1979 TZA6 monthslight

60 to 250

N = 101 for all strata

18.6%
moderate251 to 50026.3%
heavy≥ 50028%
Taylor 1988 ZWE6 monthslight

< 100

N = 77 for all strata

25%96.1%Not reported
heavy> 10036.8%100%
Omer 1981 SDN6 monthslight

60 to 249

N = 11

1/11
moderate

250 to 499

N = 11

3/11
heavy

> 500

N = 14

2/14

Praziquantel 40 mg/kg single dose versus placebo: % egg reduction stratified by severity of infection

Trial IDTime pointStratumBy GMEC/10 mL/urine or by "egg count"Praziquantel 40 mg/kg single dosePlaceboP value difference between groups
GMEC/10 mL urine% egg reductionGMEC/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Pugh 1983 MWI1 monthlight20 to 124

51.7

N = 21

2.195.93

52.7

N = 20

35.632.45Not reported
moderate125 to 499

234.7

N = 30

1.599.36

248.0

N = 32

256.2- 3.2 % (increase)
heavy500 to 1999

907.6

N = 38

1.799.86
very heavy> 2000

3433.3

N = 8

2.899.9
Taylor 1988 ZWE 11 monthlight< 50

15.1

N = n.r.

0.497.3515.737.5138.85 (increase)
heavy> 100

204.7

N = n.r.

4.098191.9147.023.4
King 2002 KEN6 weekslight0 to 99N = 482.0793
moderate100 to 399N = 272.6799
heavy≥ 400N = 263.4999.6
Pugh 1983 MWI 23 monthslight20 to 124

51.7

N = 21

1.996.32

52.7

N = 20

36.830.17Not reported
moderate125 to 499

234.7

N = 30

1.999.19

248.0

N = 32

145.741.25
heavy500 to 1999

907.6

N = 38

1.899.8
very heavy> 2000

3433.3

N = 8

2.299.93
Tchuente 2004 CMR3 monthslight< 50

8.22

N = 183

0.8689.53%
heavy> 50

115.59

N = 63

4.1196.4%
Taylor 1988 ZWE3 monthslight< 50

15.1

N = n.r.

0.497.3515.719.826.1 increase
heavy> 100

204.7

N = n.r.

2.099191.994.750.65
Pugh 1983 MWI6 monthslight20 to 124

51.7

N = 21

2.395.5
moderate125 to 499

234.7

N = 30

2.099.14
heavy500 to 1999

907.6

N = 38

2.699.7
very heavy> 2000

3433.3

N = 8

2.899.9
Taylor 1988 ZWE6 monthslight< 50

15.1

N = n.r.

0.298.6715.711.725.5
heavy> 100

204.7

N = n.r.

0.699.7191.975.560.6

1Stratum I: light infections < 50 eggs/10 mL, praziquantel (N = 77), placebo (N = 90). "Pretreatment light infections exhibited better cure rates for S. haematobium than pretreatment heavy infections". Praziquantel (N = 77), placebo (N = 90).

2Baseline imbalance in terms of intensity of infection "In accordance with local ethical guidelines the placebo group consisted only of children with light (20 to 124 ova/10 mL or moderate (125 to 4999 ova/10 mL) infections before treatment."

Praziquantel 40 mg/kg single dose versus 20 mg/kg single dose: % egg reduction

Trial IDSubgroupTime pointMeasurePraziquantel 40 mg/kg single dosePraziquantel 20 mg/kg single doseP value difference between groups
Egg count/10 mL urine

% egg

reduction

Egg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Taylor 1988 ZWE

light infections

< 50/10 mL

1 monthGMEC

15.1

N = 77

(in both groups)

0.497.35

15.5

N = 61

0.596.77Not reported

heavy infections

> 100/10 mL

1 monthGMEC

204.7

N = 77

(in both groups)

4.098.04

177.3

N = 61

3.498.08
King 2002 KEN6 weeks

GMEC (± CI)

N =

Not reported

2.54

(1.84 to 3.5)

N = 145

98Not reported

4.42 (3.1 to 6.3)

N = 146

95Not reported
Wilkins 1987 GMB2 to 3 months

GMEC

median

AMEC

N =

54/63/298

N = 33

0.3/0/1

99.4

100

99.6

53/87/313/

N = 35

0.8/0.3/7

98.4

99.7

97.6

0.31
King 1989 KEN3 months

GMEC

AMEC ± SD

GMEC

N =

255

377/

N = 64

2

31(± 21)

N = 56

99.2 (GMEC)

91.7 (AMEC)

210

327/

N = 75

2

13 ± 9/

N = 68

99.04 (GMEC)

96

(AMEC)

Not significant
Taylor 1988 ZWE

light infections

< 50/10 mL

3 monthsGMEC

15.1

N = 77

(in both groups)

0.497.35

15.5

N = 61

0.696.12Not reported

heavy infections

> 100/10 mL

3 monthsGMEC

204.7

N = 77

(in both groups)

2.099.02

177.3

N = 61

3.697.97
Taylor 1988 ZWE

light infections

< 50/10 mL

6 monthsGMEC

15.1

N = 77

(in both groups)

0.298.67

15.5

N = 61

0.298.7Not significant

heavy infections

> 100/10 mL

6 monthsGMEC

204.7

N = 77

(in both groups)

0.699.7

177.3

N = 61

2.798.5

Praziquantel 40 mg/kg single dose versus 10 mg/kg single dose: % egg reduction

Trial IDSubgroupTime pointMeasurePraziquantel 40 mg/kg single dosePraziquantel 10 mg/kg single doseP value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Taylor 1988 ZWE

light infections

< 50/10 mL

1 monthGMEC

15.1

N = 77

0.497.35

14.8

N = 73

2.384.46Not reported

heavy infections

> 100/10 mL

1 monthGMEC

204.7

N = 77

4.098.04

197.5

N = 73

34.782.43Not reported
King 1989 KEN 2 to 3 months

GMEC

AMEC ± SE

N =

245

378

N = 64

2/

31 ± 21

N = 56

99.183 (GMEC)

91.79 (AMEC)

255

377

N = 72

20/

102 ± 22

N = 62

92.156

(GMEC)

72.94 (AMEC)

0.001
Wilkins 1987 GMB 2 to 3 months

GMEC

median

AMEC

N =

54

63

298

N = 33

0.3/

0/

1/

99.4

(GMEC)

100

(median)

99.6

(AMEC)

61/82/297N = 38

7.9/

5.9/

33/

87.0

(GMEC)

92.8

(median)

88.8

(AMEC)

Not reported
Taylor 1988 ZWE

light infections

< 50/10 mL

3 monthsGMEC15.10.497.3514.82.285.14Not reported

heavy infections

> 100/10 mL

3 monthsGMEC204.72.099.02197.527.686.02Not reported
Taylor 1988 ZWE

light infections

< 50/10 mL

6 monthsGMEC15.10.298.6714.81.291.89Not reported

heavy infections

> 100/10 mL

6 monthsGMEC204.70.697.07197.514.492.7Not reported

Praziquantel 40 mg/kg single dose versus split dose: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg single dosePraziquantel 40 mg/kg split dose (2 x 20 mg/kg in one day)P value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Kardaman 1985 SDN5 weeks

GMEC

N =

Not reported

N = 114

28

Not reported

N = 106

26

No significant difference,

P value not reported

McMahon 1979 TZA1 month

GMEC+ 95

range

288.4 (33.2 to 2508.9)

N = 33

1.1 (0 to 8.3)99.61

352.8 (37.0 to 3361.8)

N =36

0.8 (0 to 62)99.7P value not reported
Oyediran 1981 NGA 11 month

GMEC

mean + SD

(N = )

Stratum 1

87.4 ± 23.46

(N = 15)

Stratum 2

339.4 ± 32.61

(N = 5)

Stratum 3

518.00 ± 0.71

(N = 2)

N = 22

97.69 ± 0.98

(N = 21)

Stratum 1

84.93 ± 34.71 (N = 15)

Stratum 2

296.00 ± 26.19

(N = 5)

Stratum 3

526.00

(N = 1)

N = 21

 

98.69 ± 0.39

(N = 19)

No significant difference,

P value not reported

Kardaman 1985 SDN3 monthsGMEC

-

N = 114

15

-

N =106

9

No significant difference,

P value not reported

McMahon 1979 TZA3 monthsGMEC+ 95% CIs

288.4 (33.2 to 2508.9)

N = 33

1.1 (0-16.3)99.61

352.8 (37.0 to 3361.8)

N = 36

0.5 (0 to 3.9)99.85P value not reported
Oyediran 1981 NGA 13 months

GMEC

mean + SD

(N = )

Stratum 1

87.4 ± 23.46

(N = 15)

Stratum 2

339.4 ± 32.61

(N = 5)

Stratum 3

518.00 ± 0.71

(N = 2)

N = 22

97.55 ± 0.85 (N = 18)

Stratum 1

84.93 ± 34.71 (N = 15)

Stratum 2

296.00 ± 26.19

(N = 5)

Stratum 3

526.00

(N = 1)

N = 21

99.48 ± 0.3

(N = 16)

N

o significant difference,

P value not reported

McMahon 1979 TZA6 monthsGMEC+ 95 % CIs

288.4 (33.2 to 2508.9)

N =33

1.1 (0 to 20.3)99.61

352.8 (37.0 to 3361.8)

N =36

0.6 (0 to 11.3)99.82P value not reported
Oyediran 1981 NGA 16 months

GMEC

mean + SD

(N = )

Stratum 1

87.4 ± 23.46

(N = 15)

Stratum 2

339.4 ± 32.61

(N = 5)

Stratum 3

518.00 ± 0.71

(N = 2)

N = 22

93.09 ± 0.12 (N = 15)

Stratum 1

84.93 ± 34.71 (N = 15)

Stratum 2

296.00 ± 26.19

(N = 5)

Stratum 3

526.00

(N = 1)

N = 21

99.52 ± 0.21

(N = 13)

No significant difference in egg counts between treatment groups,

P value not reported.

9 months92.4 ± 5.92 (N = 6)

98.12 ± 1.13

(N = 6)

12 months99.3 ± 0.26 (N = 3)

98.68 ± 0.51

(N = 5)

1GMEC/10 mL urine, Stratum 1: 60 to 250 GMEC/10 mL urine; Stratum 2: 251 to 500 GMEC/10 mL; Stratum 3 > 500 GMEC/10 mL.

Praziquantel 40 mg/kg single dose versus praziquantel 2 x 40 mg/kg or praziquantel 3 x 40 mg/kg given three weeks apart: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg (single dose)Praziquantel 2 x 40 mg/kgP value for differences between groups
Egg count /10 mL urineEgg count/10 mL urine
BaselineFollow-up% egg reductionBaselineFollow-up% egg reduction
Tchuente 2004 CMR6 weeksGMEC

All classes 15.83

Light infection 8.22

Heavy infection 115.59

N = 135

0.29/

0.2/

0.64

98.18/

97.63/

99.44

All classes

19.00/

Light infection

9.5/

Heavy infection

129.05

N = 246

0.25/

0.19/

0.43/

98.69/

97.99/

99.67

Follow-up at 6 weeks, 6 weeks after a single dose (cohort 3)

Follow-up at 6 weeks, 3 weeks after the second dose (cohort 1)

6 weeksGMEC

All classes 15.83

Light infection 8.22

Heavy infection 115.59

N = 135

0.29/

0.2/

0.64/

98.18/

97.63/

99.44/

All classes 16.96

Light infection 7.3

Heavy infection 173.02

N = 134

0.27/

0.17/

0.64/

98.39/

97.7/

99.63

F

ollow-up at 6 weeks, 6 weeks after a single dose (cohort 3)

P > 0.066

Follow-up at 6 weeks, 3 weeks after the second dose (cohort 2)

9 weeksGMEC

All classes 15.83

Light infection 8.22

Heavy infection 115.59

N = 135

0.17/

0.15/

0.23

N = 70

99.06/

98.29/

99.80

All classes

16.96

Light infection

7.3

Heavy infection 173.02

N = 134

0.43/

0.2/

1.23

N = 60

97.88/

97.59/

99.29

Follow-up at 9 weeks, 9 weeks after a single dose (cohort 3)

Follow-up at 9 weeks, 6 weeks after the second dose (cohort 2)

  Praziquantel 40 mg/kg (single dose)Praziquantel 3 x 40 mg/kgComments
9 weeksGMEC

All classes 15.83

Light infection 8.22

Heavy infection 115.59

N = 135

0.17/

0.15/

0.23

N = 70

99.06/

98.29/

99.80

All classes

0.19

Light infection

0.06

Heavy infection

0.51

N = 246

99.18/

99.61/

99.36

Follow-up at 9 weeks, 9 weeks after a single dose (cohort 3)

Follow-up at 9 weeks: 3 weeks after the last (third) dose (cohort 1)

Praziquantel 40 mg/kg single dose x 2, interval three weeks: one arm received praziquantel single at baseline, one arm received a second dose at three weeks, one arm received the second dose at three weeks and a third dose at six weeks. Follow-up for all groups at six weeks and nine weeks.

Strata: light infection < 50/10 mL, heavy infection > 50/10 mL.

Metrifonate 10 mg/kg single dose versus placebo: % egg reduction

Trial IDTime pointMeasureMetrifonate 10 mg/kg single dosePlacebo
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Stephenson 1989 KEN8 months

GMEC

AMEC

N =

47/

94

N = 105

4/

23

N = 103

91.48/

76

38/

85/

N = 105

36/

102

N = 104

5.26/

-20 (increase)

Metrifonate 2 x 10 and 3 x 10 mg/kg given two weeks apart versus 10 mg/kg single dose: % egg reduction

Trial IDTime pointMeasureMetrifonate 2 x 10 mg/kgMetrifonate 10 mg/kg single dose
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Rey 1984 NER1 month

AMEC

N =

93.2

N = 99

16.9

N = 49

81.9

N = 50

30.4

N = 125

19.1

N = 62

37.2
4 months

AMEC

N =

93.2

N = 99

58.4

N = 35

37.34

30.4

N = 125

22.8

N = 69

25
Trial IDTime pointMeasureMetrifonate 3 x 10 mg/kgMetrifonate 10 mg/kg single dose
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Rey 1984 NER1 month

AMEC

N =

17.8

N = 62

2.0

N = 31

88.7

30.4

N = 125

19.1

N = 62

37.2
4 months

AMEC

N =

17.8

N = 62

10.8

N = 42

39.32

30.4

N = 125

22.8

N = 69

25

Metrifonate 3 doses two weeks apart: 7.5 mg/kg versus 5 mg/kg: % egg reduction

Trial IDTime pointMeasureMetrifonate 7.5 mg/kg x 3Metrifonate 5 mg/kg x 3P value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Abden Abdi 1989 SOM1 month

Egg count/10 mL urine mean

(SD)

% egg reduction mean (SD)

1010 (1550)97 (5)997 (1700)96 (6)

P > 0.7

(difference in egg counts at 1 and 6 months)

2 months1010 (1550)97 (6)997 (1700)96 (7)
3 months1010 (1550)95 (8)997 (1700)94 (8)
6 months1010 (1550)93 (11)997 (1700)92 (11)

1N = 101 for both groups together

Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg single doseMetrifonate 10 mg/kg single doseP value differences between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Stephenson 1989 KEN8 months

AMEC

GMEC

112/

57

N = 105

1/

0.2

99

94/

47

N = 103

23/

4

76

Significant

P < 0.0001

Praziquantel 40 mg/kg single dose versus metrifonate 2 x 10 mg/kg given two weeks apart: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg single doseMetrifonate 2 x 10 mg/kgP value differences between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
de Jonge 1990 SDN1 month

median

N =

66

N = 48

1

N = 40

98.48

95

N = 38

1

N = 32

98.94Not reported
5 months

median

N =

66

N = 48

0

N = 35

100

95

N = 38

1

N = 32

98.94

Praziquantel 30 mg/kg single dose versus metrifonate 3 x 10 mg/kg given two weeks apart: % egg reduction

Trial IDTime pointMeasurePraziquantel 30 mg/kg single doseMetrifonate 3 x 10 mgP value difference between groups
N% egg reductionN% egg reduction
McMahon 1983 TZA4 monthsGMEC of miracidia/10 mL urine30993098Not reported

Praziquantel 40 mg/kg 1x/year versus metrifonate 10 mg/kg 3x/year: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg 1x/yearMetrifonate 10 mg/kg 3x/yearP value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
King 1990 KEN 112 months

AMEC (± SD)

GMEC

Light

33

19

6 ± 281.81

Light

33

19

4 ± 3

87.87Not significant

Moderate

193

86

3 ± 298.44

Moderate

193

86

5 ± 2

97.4

Heavy

597

581

8 ± 498.65

Heavy

597

581

9 ± 3

89.49

1Baseline data reported for both treatment groups together.

Praziquantel 40 mg/kg single dose versus praziquantel 10 mg/kg and metrifonate 10 mg/kg: % egg reduction

Trial IDTime pointPraziquantel 40 mg/kg single dosePraziquantel 10 mg/kg and Metrifonate 10 mg/kgP value difference between groups
GMEC/10 mL% egg reductionGMEC/10 mL% egg reduction
BaselineFollow-upBaselineFollow-up
Wilkins 1987 GMB 12 to 3 months

54

N = 33

70.399.4

67

N = 39

4.892.9Not reported

1AMEC and median also reported.

Praziquantel versus artesunate: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg single doseArtesunate 4 mg/kg/d for 3 daysP value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Keiser 2010 CIV26 days

GMEC (range)

N =

32.0 (1 to 457)

N = 26

1.1 (1 to 5)97

40.2 (2 to 562)

N = 20

6.2 (1 to 267)85

Significant

P < 0.001

Borrmann 2001 GAB8 weeksGMEC (range)

38.51

(1 to 3313)

N = 90

1.11

N = 89

97.11

35.22

(1 to 4360)

N = 90

10.8

N = 89

69.34Significant, P value not reported
Inyang Etoh 2009 NGA18 weeks

mean ± SD

N =

42.0 ± 1.7

N = 52

9.8 ± 0.5

N = 42

76.7

39.8 ± 1.1

N = 52

19.1 ± 1.0

N = 44

52.1Not reported

1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.

Mefloquine versus placebo: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg single doseMefloquine 25 mg/kg single doseP value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Keiser 2010 CIV28 days

GMEC

range

N =

32.0 (1 to 457)

N = 26

1.1 (1 to 5)

N = 26

97

30.1

(1 to 2039)

N = 19

1.7 (1 to 73)

N = 19

74

Significant

P < 0.001

Praziquantel versus mefloquine: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg single doseMefloquine 25 mg/kg single doseP value difference between groups
Egg count/10 mL urine% egg reductionEgg count/10 mL urine% egg reduction
BaselineFollow-upBaselineFollow-up
Keiser 2010 CIV28 days

GMEC

range

N =

32.0 (1 to 457)

N = 26

1.1 (1 to 5)

N = 26

97

30.1

(1 to 2039)

N = 19

1.7 (1 to 73)

N = 19

74

Significant

P < 0.001

Praziquantel versus mefloquine and artesunate: % egg reduction

Trial IDTime pointMeasurePraziquantel 40 mg/kg single doseArtesunate 100 mg plus Mefloquine 250 mg fixed dose combination (FDC) x 3 in one dayP value difference between groups
Egg count/10 mL urinepercent egg reductionEgg count/10 mL urinePercent egg reduction
BaselineFollow-upBaselineFollow-up
Keiser 2010 CIV28 days

GMEC

range

N =

32.0 (1 to 457)

N = 26

1.1 (1 to 5)

N = 26

97

42.0

(1 to 688)

N = 18

1.7 (1 to 73)

N = 18

96%

Not significant

P = 0.13

Appendix 3. Appendix: Additional tables for haematuria and proteinuria

Praziquantel 40 mg/kg single dose versus placebo: haematuria and proteinuria

OutcomeTrial IDTime pointMeasurePraziquantel 40 mg/kg single dosePlaceboP value difference between groups
BaselineFollow-upMean % changeBaselineFollow-upMean % change
Haematuria de Jonge 1990 SDN1 monthmedian erythrocytes/mykrol (95% CI)159 (34 to 627) N = 56

1(0 to 2)

N = 56

-99.37

290 (54 to 1224)

N = 26

323 (51 to 864)+11.37Not reported
Borrmann 2001 GAB 18 weekserythrocytes/mL (95% CI)

NR

N = 89

- 1101
(-137 to -84)

NR

N = 30

-391
(-86 to -8)

Significant

P < 0.001

Inyang Etoh 2009 NGA8 weeksunits unclear mean (± SD)47.6(± 2.0) N = 52

7.6(± 0.9)

N = 42

-84.033

38.0 (±1.6)

N = 52

59.6 (± 2.2) N = 44+56.84P < 0.001
Proteinuria de Jonge 1990 SDN1 month

median, g/L

(95% CI)

0.42 (0.22 to 0.62) N = 560.09 (0.05 to 0.12)-78

0.24 (0.09 to 0.59)

N = 26

0.32 (0.14 to 0.35)+33.3Not reported
Inyang Etoh 2009 NGA 28 weeks

mean (± SD)

units unclear

160.2 (± 5.2) N = 52

24.8 ± 1.9

N = 42

-84

185.2 ± 5.0

N = 52

213.9 ± 5.3 N = 44+15.49P < 0.001
Footnotes

1Mean change from baseline in erythrocytes/mL urine (95% CI).

2Data shown here are for the treatment group praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a treatment group for praziquantel with placebo, (data not shown).

Praziquantel 40 mg/kg single dose versus Praziquantel 2 x 40 mg/kg: haematuria

OutcomeTrial IDTime pointMeasurePraziquantel 40 mg/kg single dosePraziquantel 2 x 40 mg (one additional dose)P value difference between groups
BaselineFollow-up% changeBaselineFollow-up% change
Prevalence of haematuria1

Sacko 2009 MLI

Koulikoro

12 weeksN = 310

81.3 %

(N = ?)

15.5 %-80.9

75.5 %

(N = ?)

12.9 %-82.90.51

Sacko 2009 MLI

Selingue

12 weeksN = 29341.4 %-44.4

75.5%

(N = ?)

35.6 %-52.80.03

Sacko 2009 MLI

Koulikoro

6 monthsN = 300

67.7%

(N = 150)

7.6%-88.8

71.1%

(N = 150)

2.2 %-96.90.32

Sacko 2009 MLI

Selingue

6 monthsN = 275N = ?19.7%-70.9

71.1%

(N = ?)

16.4 %-76.90.47

1Microhaematuria as diagnosed by dipstick (Haemastix)

Praziquantel 40 mg/kg single dose versus Metrifonate 20 mg/kg given as split dose: haematuria and proteinuria

OutcomeTrial IDTime pointMeasurePraziquantel 40 mg/kg single doseMetrifonate 10 mg/kg two dosesP value difference between groups
BaselineFollow-up% changeBaselineFollow-up% change
Haematuria de Jonge 1990 SDN1 month

median (95% CI)

Erythrocytes/µl

159
(34 to 627)

N = 56

1
(0 to 2)
-99.37

503
(72 to 930)

N = 42

31
(1 to 112)
-93.93Not reported
Proteinuria de Jonge 1990 SDN1 month

median (95% CI)

Proteinuria g/L

0.42
(0.22 to 0.62)

N = 56

0.09
(0.05 to 0.12)
-78.57

0.44
(0.2 to 0.73)

N = 42

0.09
(0.07 to 0.15)
-79.54Not reported

ARS versus placebo: haematuria and proteinuria

OutcomeTrial IDTime pointMeasureArtesunate 4mg/kg/day for 3 daysPlaceboP value difference between groups
BaselineFollow-up% changeBaselineFollow-up% change
Haematuria Borrmann 2001 GAB8 weeks

mean change from baseline

Ery/mL

(95% CI)

-34

(-59 to -9)

-39

(-86 to +8)

Not reported
Inyang Etoh 2009 NGA 18 weeksmean haematuria + SD

61.8 ± 2.2

N = 52

25.7 ± 1.6

N = 44

-58.41

38.0 ± 1.6

N = 52

59.6

± 2.2

N = 44

-36.24Not reported
Proteinuria Inyang Etoh 2009 NGA 18 weeks

mean ± SD

unit unclear (mg/dL)

191.1 ± 5.2

N = 52

102.1 ± 4.4

N = 44

-46.57

185.2 ± 5.0

N = 52

213.9 ± 5.3

N = 44

-13.41Not reported
Footnotes

1Treatment group: Praziquantel 40 mg/kg without placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg with placebo), data not shown.

Praziquantel versus ARS: haematuria and proteinuria

OutcomeTrial IDSubgroupTime pointMeasurePraziquantel 40 mg/kg single doseArtesunate 4 mg/kg/day for 3 daysP value difference between groups
BaselineFollow-up% changeBaselineFollow-up% change
Haematuria Borrmann 2001 GAB8 weeks

Mean change from baseline

Ery/mL

(95% CI)

N = 90N = 89

- 110

(-137-84)

N = 90N = 89

- 34

(-59 to -9)

Significant

P < 0.001

Inyang Etoh 2009 NGAwith placebo8 weeksMean haematuria ± SD

55.9 ± 2

N = 52

13.6 ± 1.2

N = 44

-75.6

50.9 ± 1.9

N = 52

11.1 ± 0.9

N = 44

-78.19Not reported
without placebo

47.6 ± 2

N = 52

7.6 ± 0.9

N = 42

-84

61.8 ± 2.2

N = 52

25.7 ± 1.6

N = 44

-58.41
Proteinuria Inyang Etoh 2009 NGAwith placebo8 weeksMean proteinuria ± SD

190.9 ± 5.2

N = 52

65.7 ± 3.3

N = 44

-65

177.3 ± 5.1

N = 52

85.5 ± 3.9

N = 44

-51.7Not reported
without placebo

160.2 ± 5.2

N = 52

24.8 ± 1.9

N = 42

-84.5

191.1 ± 5.2

N = 52

102.1 ± 4.4

N = 44

-46.5Not reported

Praziquantel versus Praziquantel and ARS: haematuria and proteinuria

OutcomeTrial IDTime pointMeasurePraziquantel 40 mg/kg single dose

Artesunate 4 mg/kg/d for 3 days

Praziquantel 40 mg/kg single dose

P value difference between groups
BaselineFollow-up% changeBaselineFollow-up% change
Haematuria Borrmann 2001 GAB8 weeks

Mean change from baseline

Ery/mL

(95% CI)

-110

(-137 to -84)

-102 (-128 to -77)Not reported
Inyang Etoh 2009 NGA 18 weeksMean haematuria ± SD

55.9 (± 2)

N = 44

13.6 (± 1.2)-75.65

73.0 (± 2.3)

N = 44

8.8 (± 8.7)-87.94Not reported
Proteinuria Inyang Etoh 2009 NGA8 weeksMean proteinuria ± SD

190.9 ± 5.2

N = 52

65.7 ± 3.3

N = 44

-65.58

267.5 ± 5.4

N = 52

4.0 ± 15.2

N = 44

- 98.5Not reported

1Treatment group: Praziquantel 40 mg/kg with placebo. Inyang Etoh 2009 NGA also reports a second treatment group (Praziquantel 40 mg/kg without placebo), data not shown.

Appendix 4. Appendix: Additional tables for growth outcomes

Praziquantel 40 mg/kg single dose versus placebo: growth outcomes

Trial IDTime pointMeasure Praziquantel 40 mg/kg single dosePlaceboP value difference between praziquantel 40 mg/kg and placebo after treatment
BaselineFollow-up growth greater than placeboP value difference before and after treatmentBaselineFollow-upDifference before and after treatment
Stephenson 1989 KEN 15 weeks

Harvard step test score

mean ± SEM

76 ± +-1.4181.2 ± 16.8% pointsP = 0.000277.1 ± +-1.5175.5 ± 1.95Not significant

P < 0.05

significant

resting heart rate beats/min

mean ± SEM

81.1+- ± 1.6677.9 ± 1.1

4.3 beats/min

(decrease)

P = 0.00485.8+- ± 1.786.9 ± 1.96Not significant

P = 0.003

significant

appetite

mean ± SEM

709+- ± 58841± 65.2139 mLP = 0.014811+- ± 93.4803 ± 78Not significantNnot significant
Befidi Mengue 1992 CMR 26 months

height

median cm (SD)

134.1 (12.3)135.8 (12.5) 1.6132.8 (12.0)134.5 (12.3)1.7Not significant

weight

median kg (SD)

29.2 (7.4)31.3 (8.2) 2.128.3 (7.2)30.2 (7.9)1.9Not significant

middle upper arm circumference (MUAC)

median cm (SD)

18.4 (2.0)19.0 (2.2) 0.618.3 (2.1)18.7 (2.2)0.4Significant

triceps skinfold

median

unit not specified

(SD)

6.7 (1.5)7.1 (1.9) 0.46.6 (1.9)6.9 (2.1)0.3Not significant

mean muscle mass median

unit not specified

(SD)

16.3 (1.8)16.8 (2.0) 0.4716.2 (1.9)16.6 (1.9)0.36Not significant
ht for age (%)93.692.7 -0.7294.193.3-0.75Not significant
wt for age (%)81.382.2 0.9282.583.10.65Not significant
wt for ht (%)97.49100.78 3.2896.8799.442.57Not significant
Stephenson 1989 KEN 38 months

height (cm)

mean ± SEM

134.8 ± 1.12138.2 ± 1.100.1 cm0.0002135.9 ± 1.23139.3 ± 1.220.0002Not significant

weight (kg)

mean ± SEM

27.3 ± 0.7230.4 ± 0.761.2kg0.000228.4 ± 0.7830.3 ± 0.830.0002

P = 0.0001

significant

triceps skinfold thickness

mean ± SEM

7.4 ± 0.218.8 ± 0.251.4 mm0.00028.2 ± 0.278.1 ± 0.27Not significant

P = 0.0001

significant

subscapular skinfold

thickness

mean ± SEM

5.6 ± 0.166.9 ± 0.21.4 mm0.00026.0 ± 0.25.9 ± 0.2Not significant

P = 0.0001

significant

mid upper arm circumference (MUAC)

mean ± SEM

17.5 ± 0.2218.5 ± 0.240.7 cm0.000217.8 ± 0.2118.0 ± 0.220.0002

P = 0.0001

significant

ht for age (%)

mean ± SEM

93.0 ± 0.4492.8 ± 0.430.1% points0.0292.9 ± 0.4492.6 ± 0.440.001Not significant

wt for age (%)

mean ± SEM

72.7 ± 0.9874.9 ± 1.003.3% points0.000273.8 ± 1.0472.5 ± 1.030.0002Not significant

wt for ht (%)

mean ± SEM

89.5 ± 0.7793.0 ± 0.843.7% points0.000290.6 ± 0.7290.4 ± 0.74Not significant

P = 0.0001

significant

MUAC/age (%)

mean ± SEM

81.6 ± 0.783.1 ± 0.730.7% points0.000282.2 ± 0.780.5 ± 0.690.0002

P = 0.0001

significant

triceps skinfold/age

mean ± SEM

68.5 ± 1.6780.0 ± 1.8213.2% points0.000275.6 ± 1.8973.9 ± 1.880.014

P = 0.0001

significant

subscapular skinfold/age

mean ± SEM

86.8 ± 1.79102.7 ± 2.2421.4% points0.000291.3 ± 1.9685.7 ± 1.780.0002

P = 0.0001

significant

Olds 1999 KENReports that anthropometric data were measured at baseline and day 45, no significant difference was found before and after treatment with albendazole and praziquantel. Data not shown in the publication.

1 Stephenson 1989 KEN reports growth greater than placebo. Sixteenparticipants per group are followed up at 5 weeks. Appetite measured by mL of porridge intake. No significant difference between metrifonate and praziquantel groups for the outcomes resting heart rate, Harvard step test and appetite.

2 Befidi Mengue 1992 CMR has 238 participants in the praziquantel group and 198 in the placebogroup. "MUAC was the only anthropometric measure with a significant difference between Praziquantel and Placebo group.". Nno significant differences (before and after interventions) between the groups for height, weight, TSS; TSS:triceps skinfold thickness, MUAC: middle upper arm circumference.

3 Stephenson 1989 KEN At follow up at eight months, there are 105 participants in the praziquantel group and 104 in the placebo group.

Praziquantel 40 mg/kg or metrifonate 10 mg/kg single dose versus placebo: growth outcomes

Trial IDTime pointMeasure

Praziquantel 40 mg/kg or

Metrifonate 10 mg/kg single dose

PlaceboP value for difference between treatment and placebo group
BaselineFollow upgrowth greater than placeboP value for difference before and after treatmentbaselinefollow upP value p for difference before and after treatment
Stephenson 1989 KEN 15 weeks

height (cm)

mean ± SEM

133.8 ± 2.02134.4 ± 2.050.2cm0.0002135 ± 3.14134.4 ± 3.140.0002

P=0.056

not significant

weight (kg)

mean ± SEM

25.9 ± 1.1827 ± 1.220.2kg0.000226.8 ± 1.9927.7 ± 1.980.0002

P=0.11

not significant

triceps skinfold/age (%)

mean ± SEM

70.8 ± 371 ± 3.112.9% pointsNot significant75 ± 6.5972.3 ± 6.470.052

P=0.048

significant

wt for ht (%)

mean ± SEM

87 ± 1.38-89.7 ± 1.320.9% points0.000287.5 ± 1.4789.3 ± 1.170.004

P=0.084

not significant

1 Stephenson 1989 KEN reports growth greater than placebo for the treatment group (praziquantel 40 mg/kg group (N = 16) and metrifonate 10 mg/kg group (N = 16) together). THe treatment group has 32 participants, the placebo group 16.

Metrifonate 10 mg/kg single dose versus placebo: growth outcomes

Trial IDTime pointMeasure Metrifonate 10 mg/kgPlaceboP value difference treatment and placebo
BaselineFollow-upgrowth greater than placeboP value difference between baseline and follow-upBaselineFollow-upP value difference between baseline and follow-up
Stephenson 1989 KEN 15 weeks

Harvard step test score

mean ± SEM

76.2 ± 1.683.8 ± 1.229.2%points0.000277.1 ± 1.5175.5 ± 1.95Not significantSignificant

resting heart rate

beats/min

mean ± SEM

82 ± 2.4480.2 ± 1.652.9beats/min0.00485.8 ± 1.786.9 ± 1.96Not significantNot significant

appetite

mean ± SEM

797 ± 78.2917 ± 68.4128mL0.051811 ± 93.4803 ± 78P = 0.014

P = 0.051

Not significant.

Stephenson 1989 KEN8 months

height (cm)

mean ± SEM

139.0 ± 1.27142.6 ± 1.250.2cm0.0002135.9 ± 1.23139.3 ± 1.220.0002Not significant

weight (kg)

mean ± SEM

30.1 ± 0.8333.4 ± 0.871.4kg0.000228.4 ± 0.7830.3 ± 0.830.0002

P < 0.05

significant

triceps skinfold thickness

mean ± SEM

8.2 ± 0.289.7 ± 0.321.5mm0.00028.2 ± 0.278.1 ± 0.27Not significant

P < 0.05

significant

subscapular skinfold

thickness

mean ± SEM

6.1 ± 0.27.4 ± 0.251.4mm0.00026.0 ± 0.25.9 ± 0.2Not significant

P < 0.05

significant

middle upper arm circumference (MUAC)

mean ± SEM

18.3 ± 0.2219.2 ± 0.240.7cm0.000217.8 ± 0.2118.0 ± 0.220.0002

P < 0.05

significant

ht for age (%)

mean ± SEM

93.2 ± 0.4393.3 ± 0.430.1% pointsNot significant92.9 ± 0.4492.6 ± 0.440.001Significant

wt for age (%)

mean ± SEM

73.8 ± 1.0476.2 ± 1.083.7% points0.000273.8 ± 1.0472.5 ± 1.030.0002Significant

wt for ht

mean ± SEM

89.9 ± 0.7893.3 ± 0.783.6% points0.000290.6 ± 0.7290.4 ± 0.74Not significant.Significant

MUAC/age

mean ± SEM

82.5 ± 0.783.9 ± 0.763%points0.000282.2 ± 0.780.5 ± 0.690.0002Significant

triceps skinfold/age

mean ± SEM

74.4 ± 1.8385.7 ± 1.9313.1% points0.000275.6 ± 1.8973.9 ± 1.880.014Significant

subscapular skinfold/age

mean ± SEM

6.1 ± 0.27.4 ± 0.251.4 mm0.000291.3 ± 1.9685.7 ± 1.780.0002Significant

1 Stephenson 1989 KEN 16 participants both in the Metrifonate 10 mg group is and placebo group

2 Stephenson 1989 KEN 103 particpants in the Metrifonate 10 mg group, 104 participants in the placebogroup

Praziquantel 40 mg/kg single dose versus metrifonate 10 mg/kg single dose: growth outcomes

Trial IDTime pointMeasurePraziquantel 40 mg/kg single doseMetrifonate 10 mg/kg single doseP value (difference between praziquantel and metrifonate)
BaselineFollow-up Growth greater than placeboP valuesBaselineFollow-upGrowth greater than placeboP value
Stephenson 1 1989 KEN5 weeks

HST score

mean ± SEM

76 ± 1.4181.2 ± 16.8% points0.000276.2 ± 1.683.8 ± 1.229.2% points0.0002Significant

resting heart rate beats/min

mean ± SEM

81.1 ± 1.6677.9 ± 1.1

- 4.3 beats/min

(decrease)

0.00482 ± 2.4480.2 ± 1.652.9 beats/min0.004Significant

appetite

mean ± SEM

709 ± 58841 ± 65.2139 mL0.014797 ± 78.2917 ± 68.4128 mLl0.051Not significant
Stephenson 1 1989 KEN8 months

height (cm)

mean ± SEM

134.8 ± 1.12138.2 ± 1.100.1 cm0.0002139.0 ± 1.27142.6 ± 1.250.2 cm0.00020.0002

weight (kg)

mean ± SEM

27.3 ± 0.7230.4 ±0.761.2 kg0.000230.1 ± 0.8333.4 ± 0.871.4 kg0.00020.0002

triceps skinfold thickness

mean ±SEM

7.4 ± 0.218.8 ± 0.251.4 mm0.00028.2 ± 0.289.7 ± 0.321.5 mm0.00020.0002

subscapular skinfold

thickness

mean ± SEM

5.6 ± 0.166.9 ± 0.21.4 mm0.00026.1 ± 0.27.4 ± 0.251.4 mm0.00020.0002

Middle upper arm circumference (MUAC)

mean ± SEM

17.5 ± 0.2218.5 ± 0.240.7 cm0.000218.3 ± 0.2219.2 ± 0.240.7 cm0.00020.0002

ht for age (%)

mean ± SEM

93.0 ± 0.4492.8 ± 0.430.1% points0.0293.2 ± 0.4393.3 ± 0.430.1% pointsNot significantNot significant

wt for age (%)

mean ± SEM

72.7 ± 0.9874.9 ± 1.003.3% points0.000273.8 ± 1.0476.2 ± 1.083.7% points0.00020.0002

wt for ht (%)

mean ± SEM

89.5 ± 0.7793.0 ± 0.843.7% points0.000289.9 ± 0.7893.3 ± 0.783.6% points0.00020.0002

MUAC/age (%)

mean ± SEM

81.6 ± 0.783.1 ± 0.730.7% points0.000282.5 ± 0.783.9 ± 0.763% points0.00020.0002

triceps skinfold/age

mean ± SEM

68.5 ± 1.6780.0 ± 1.8213.2% points0.000274.4 ± 1.8385.7 ± 1.9313.1% points0.00020.0002

subscapular skinfold/age

mean ± SEM

86.8 ± 1.79102.7 ± 2.2421.4% points0.00026.1 ± 0.27.4 ± 0.2519.7% points0.00020.0002

Stephenson 1989 KEN at 5 weeks, there were 16 participants in the praziquantel group and 16 in the metrifonate group. At 8 months, there were 105 participants in the praziquantel group and 103 in the metrifonate group.

Appendix 5. Appendix: Additional tables for adverse events

Praziquantel 40 mg/kg single dose versus placebo: adverse events

Trial IDN (praziquantel treatment arm)Adverse event monitoringBlindingSummary of adverse events findings
Pugh 1983 MWIN = 97 (Praziquantel 40 mg/kg)No commentBlinded for participants and clinicians"Treatment was well tolerated".
Borrmann 2001 GAB

N = 300

90 (Praziquantel 40 mg/kg)

90 (ARS 4 mg/kg for 3 days)

90 (Praziquantel 40 mg/kg and

ARS 4 mg/kg for 3 days)

30 (placebo)

Adverse events recorded on day 1, 3 and 7

(changes in the participants condition, compared with baseline)

Blinded for participants and clinicians

No difference between treatment groups regarding the number of adverse events, or distribution of particular adverse events.

All treatment regimens well tolerated.

Six moderate and 127 mild adverse events reported.

Most common adverse events:abdominal pain (overall 14%) and headache (12%).

Inyang Etoh 2009 NGA

N = 312

104 (Praziquantel; 52 with placebo, 52 without placebo)

104 (ARS 4 mg/kg for 3 days; 52 with placebo, 52 without placebo

52 (Praziquantel

40 mg/kg and

ARS 4 mg/kg for 3 days)

52 (placebo)

Careful monitoring for adverse events by trial physician, any potential adverse events were noted and monitored for up to 72 hours post treatment. Final assessment on day 56 for 2 consecutive days.Unclear

No difference between treatment groups.

No severe adverse events reported within one hour of medication, no child required immediate medical care.

Good tolerance of all treatment regimens.

97 incidences of adverse events reported.

33 cases of headache.

McMahon 1979 TZA

N = 101

32 (Praziquantel 40 mg/kg)

33 (Praziquantel 30 mg/kg)

36 (Praziquantel 2 x 20 mg/kg)

All children examined clinically before and four and 24 hours after treatment.

Symptoms recorded after both general and specific queries (anorexia, nausea, vomiting, abdominal pain, diarrhoea, giddiness, tiredness, weakness, body pain, headache and fever)

Unclear

No difference between treatment groups and placebo group, no side effects related to the drug or to infection intensity

common side effects equally frequent before and after treatment

Olds 1999 KEN

N = 193

98 (Praziquantel and albendazole)

95 (Praziquantel)

Surveillance for 48 hours for specific side effects

(drug-related side effect compared with parasite egg counts, symptoms over the past two weeks, physical examination and treatment group).

Participants asked for overall rating of side effects and limitations of activity

recording of request for medication for symptoms and hospitalisation.

Blinded for clinicians, participants

not blinded for outcome assessors

Data not reported for S. haematobium separately.

Vomiting, abdominal pain, headache, interference with normal activity, diarrhoea, bloody diarrhoea, request for additional medication for symptoms, and total side effects were all higher in children with documented schistosomiasis.

Taylor 1988 ZWE

N = 283

77 (Praziquantel 40 mg/kg)

72 (Praziquantel 30 mg/kg)

61 (Praziquantel 20 mg/kg)

73 (Praziquantel 10 mg/kg)

No comment

Blinded for clinicians, participants

not blinded for outcome assessors

"Side effects were not monitored but it appeared that those receiving smaller doses received less abdominal discomfort."
Footnotes

Befidi Mengue 1992 CMRand Stephenson 1989 KEN did not comment on adverse events.

Praziquantel 40 mg/kg single dose versus 30 mg/kg single dose: adverse events

Trial IDNAdverse event monitoringBlindingSummary of adverse event finding
Rey 1983 NER

N = 103

57 (Praziquantel 40 mg/kg)

46 (Praziquantel 30 mg/kg)

Not describedUnclear6% had mild adverse events, no difference between groups.
Davis 1981 ZMB

N = 98

N = 45 (Praziquantel 40 mg/kg),

N = 53 (Praziquantel 30 mg/kg)

Active surveillance of frequency and severity of side effects after treatment by direct questioning.

Prospective: paired examinations of pre and post treatment measurements and haematological and clinical chemical variables before and after treatment

Single blind

no blinding out outcome assessors

Very good tolerance and patient acceptability for praziquantel; low incidence and severity of side effects.
McMahon 1979 TZA

N = 65

N = 32 (Praziquantel 40 mg/kg)

33 (Praziquantel 30 mg/kg)

All children examined clinically before and four and 24 hours after treatment. Symptoms recorded after both general and specific queries.

Active surveillance, likely to be prospective.

Unclear

No difference between groups.

Common side effects equally frequent before and after treatment and in treated and placebo groups.

No side effects related to the drug or to infection intensity.

Omer 1981 SDN

N = 100

N = 50 (Praziquantel 40 mg/kg),

N = 50 (Praziquantel 30 mg/kg)

Side effects recorded before and after treatment.

Method of monitoring not described.

Monitoring of vital signs (pulse rate, respiratory rate, blood pressure) at 24 and 48 hours.

Unclear

for participants, clinicians and outcome assessors

Difference between groups not reported.

Mild diarrhoea on day one following treatment in 31% of patients.

All other symptoms mild and transient.

Oyediran 1981 NGA

N = 22 Praziquantel 40 mg/kg

N = 23 (Praziquantel 30 mg/kg)

N = 21 (Praziquantel 2 x 20 mg/kg)

N = 24 (placebo)

Clinical examination pre-treatment and 18 to 24 hours post treatment to detect any unwanted side effects of praziquantel (pulse rate, systolic and diastolic blood pressure).

Haematological and biochemical blood tests before (standard blood count, Hb electrophoresis, Bilirubin, SGPT, SGOT) and 18 to 24 hours after treatment (packed cell volume, total and differential white blood count, Bilirubin, SGOT, SGPT).

Therapeutic doses of chloroquine (for Malaria) and levo-tetramisole (ascariasis) given to all subjects.

Unclear

Difference in clinically diagnosed side effects not reported.

No difference between groups in post treatment haematological and biochemical findings (within normal limits).

Very good tolerance of praziquantel, very few side effects (two cases of moderate abdominal pain).

Taylor 1988 ZWE 1

283

77 (Praziquantel 40 mg/kg),

72 (Praziquantel 30 mg/kg)

No comment

Blinded for clinicians, participants.

Not blinded for outcome assessors.

"Side effects were not monitored but it appeared that those receiving smaller doses received less abdominal discomfort."
Footnotes

King 2002 KEN, Mott 1985 GHA, King 2002 KEN and Wilkins 1987 GMB did not report adverse events.

1 Taylor 1988 ZWE also reported a treatment arm of 61 participants who received Praziquantel 20 mg/kg and a treatment arm of 73 participants who received Praziquantel 10 mg/kg.

Praziquantel single dose versus split doses: adverse events

Trial IDN (praziquantel treatment arm)Adverse event monitoringBlindingSummary of adverse events findings
Kardaman 1985 SDN

N = 220

114 (Praziquantel 40 mg/kg)

106 (Praziquantel 2 x 20 mg/kg)

Monitoring

Pre-treatment clinical examination and interview of all patients by a clinician at the school on the day prior to treatment. recording of pre-treatment symptoms per group.

Post-treatment interview of patients the morning after treatment by clinicians. recording or post-treatment drug-induced side-effects

per group.

Second check seven days after treatment.

Prospective, active surveillance.

Unclear

80% of children with some mild, transitory drug-induced side-effects.

Most common complaint abdominal pain (63%) (further complaints diarrhoea, nausea, vomiting).

Vomiting and dizziness significantly less common with a single dose than a split dose (resolved within 24 hours).

McMahon 1979 TZA

N = 68

32 (Praziquantel 40 mg/kg)

36 (Praziquantel 2 x 20 mg/kg)

All children examined clinically before, and four and 24 hours after treatment. Symptoms recorded after both general and specific queries (anorexia, nausea, vomiting, abdominal pain, diarrhoea, giddiness, tiredness, weakness, body pain, headache and fever).

Prospective, active surveillance, likely to be prospective.

Unclear

No side effects related to the drug or to infection intensity.

Common side effects equally frequent before and after treatment and in treated and placebo groups.

Davis 1981 ZMB

N = 98

45 (Praziquantel 40 mg/kg),

53 (Praziquantel 2 x 20 mg/kg)

Active surveillance of frequency and severity of side effects after treatment direct questioning.

Prospective monitoring: paired examinations of pre and post treatment measurements and haematological and clinical chemical variables before and after treatment.

Single blind

No blinding of outcome assessors

Very good tolerance and patient acceptability for praziquantel. Low incidence and severity of side effects.

Metrifonate 3 doses two weeks apart: 7.5 mg/kg versus 5 mg/kg: adverse events

Trial IDN (metrifonate treatment arm)Adverse event monitoringBlindingSummary of adverse events findings
Abden Abdi 1989 SOM

N = 201

100 (3 x 7.5 mg/kg)

101 (3 x 5 mg/kg)

Patients left as soon as they had received the drug; good monitoring during the first day (3 x 5 mg/kg given in one day)

Questioning about side effects when patient returned for the next treatment with a check list; spontaneous reports were also noted (active and passive surveillance).

Double blindedSide effects in 7% of patients in the 3 x 7.5 mg/kg treatment group and 9% patients in the 3 x 5 mg/kg treatment group; mostly mild and transient, headache and abdominal pain were most frequently noted (Analysis 9.2).

Praziquantel 40 mg/kg single dose versus 3 x metrifonate 10 mg/kg: adverse events

Trial IDN (metrifonate treatment arm)Adverse event monitoringBlindingSummary of adverse events findings
Al Aska 1990 SAU

N = 100

50 (metrifonate 3 x 10 mg/kg)

50 (praziquantel 1 x 40 mg/kg)

Recording of drug side effects at the second visit (time point unclear)UnclearDizziness was more common in the praziquantel group (20%) than in the metrifonate group (10%). No difference between groups for abdominal pain (12% in both groups ).

de Jonge 1990 SDN did not comment on adverse events.

Praziquantel 30 mg/kg single dose versus 3 x metrifonate 10 mg/kg: adverse events

Trial IDN (metrifonate treatment arm)Adverse event monitoringBlindingSummary of adverse events findings
McMahon 1983 TZA

N = 60

30 (metrifonate 3 x 10 mg/kg)

30 (praziquantel 1 x 30 mg/kg)

No

No major side effects.

"Abdominal pain was more common and more severe after metrifonate."

Artesunate versus placebo, praziquantel and artesunate versus praziquantel: adverse events

Trial IDN (treatment arms)Adverse event monitoringBlinding of participants and staffSummary of adverse events findings
Borrmann 2001 GAB

N = 300

90 (praziquantel 40 mg/kg)

90 (artesunate 4 mg/kg for 3 days)

90 (praziquantel 40 mg/kg and

artesunate 4 mg/kg for 3 days)

30 (placebo)

Adverse events recorded on day 1, 3 and 7

(changes in the participants condition, compared with baseline).

Prospective surveillance.

Unclear if active or passive monitoring.

Blinded for participants and clinicians

All treatment regimens well tolerated. Six moderate and 127 mild adverse events reported.

No difference between treatment groups regarding the number of adverse events, or distribution of particular adverse events, most common adverse events: abdominal pain (overall 14%) and headache (12%).

Inyang Etoh 2009 NGA

N = 312

104 (praziquantel; 52 with placebo, 52 without placebo)

104 (artesunate 4 mg/kg for 3 days; 52 with placebo, 52 without placebo)

52 (praziquantel 40 mg/kg and artesunate 4 mg/kg for 3 days)

52 (placebo)

Careful monitoring for adverse events by trial physician, any potential adverse events were noted and monitored for up to 72 hours post treatment, excellent compliance for reporting.

Final assessment on day 56 for 2 consecutive days.

Unclear if active or passive monitoring.

Unclear

No difference between treatment groups.

No severe adverse events reported within one hour of medication, no child required immediate medical care.

97 incidences of adverse events reported

33 cases of headache

Good tolerance of all treatment regimens

Praziquantel versus artesunate: adverse events

Trial IDN (treatment arms)Adverse event monitoringBlinding of participants and staffSummary of adverse events findings
Keiser 2010 CIV

N = 83

19 (mefloquine 25 mg/kg)

18 (artesunate 3 x 100 mg and mefloquine 250 mg FDC)

20 (artesunate 4 mg/kg for 3 days)

26 (praziquantel 40 mg/kg)

No placebo arm

Observation for AE for 3 hours after the first dose AE monitoring until 96 hours after the first dosing.

Interview with standardized questionnaire at 24, 48, 72 and 96 hours.

Clinical examination in case AE occurred.

Classification of AE as mild, moderate, severe or life threatening.

Not blinded

No difference between the four treatment groups (headache, coughing, vomiting, vertigo or chills).

Abdominal pain more frequent in the mefloquine group (98%, P < 0.001), mefloquine-artesunate (83%, P = 0.008, artesunate (60%, P = 0.37) than in the praziquantel group (46%).

More participants had at least one AE in any of the assessments in the mefloquine group (100%), in the mefloquine-artesunate group (94%) and in the artesunate group (80%) than in the praziquantel group (61%),

No serious or life-threatening adverse events, no hospital admissions due to AE

no neuropsychological AE, no trial discontinuation due to AE.

Borrmann 2001 GAB

N = 300

90 (praziquantel 40 mg/kg)

90 (artesunate 4 mg/kg for 3 days)

90 (praziquantel 40 mg/kg and artesunate 4 mg/kg for 3 days)

30 (placebo)

Adverse events recorded on day 1, 3 and 7

(changes in the participants condition, compared with baseline).

Prospective surveillance.

Blinded for participants and clinicians

All treatment regimens well tolerated. Six moderate and 127 mild adverse events were reported.

No difference between treatment groups regarding the number of adverse events, or distribution of particular adverse events, most common adverse events: abdominal pain (overall 14%) and headache (12%).

Inyang Etoh 2009 NGA

N = 312

104 (praziquantel; 52 with placebo, 52 without placebo)

104 (artesunate 4 mg/kg for 3 days; 52 with placebo, 52 without placebo.

52 (praziquantel 40 mg/kg and

artesunate 4 mg/kg for 3 days)

52 (placebo)

Careful monitoring for adverse events by trial physician, any potential adverse events were noted and monitored for up to 72 hours post treatment.

Final assessment on day 56 for two consecutive days.

Unclear if active or passive surveillance

Unclear

No difference between treatment groups

No severe adverse events reported within one hour of medication, no child required immediate medical care.

97 incidences of adverse events reported

33 cases of headache

Good tolerance of all treatment regimens

Praziquantel versus mefloquine: adverse events

Trial IDN (treatment arms)Adverse event monitoringBlinding of participants and staffSummary of adverse events findings
Keiser 2010 CIV

N = 83

19 (mefloquine 25 mg/kg)

18 (artesunate 3 x 100 mg and mefloquine 250 mg FDC)

20 (artesunate 4 mg/kg for 3 days)

26 (praziquantel 40 mg/kg)

No placebo arm

Observation for AE for 3 hours after the first dose AE monitoring until 96 hours after the first dosing

interview with standardized questionnaire at 24, 48, 72 and 96 hours.

Clinical examination in case AE occurred.

Classification of AEs as mild, moderate, severe or life threatening.

Not blinded

No difference between the four treatment groups (headache, coughing, vomiting, vertigo or chills),

abdominal pain more frequent in the mefloquine group (98%, P < 0.001), mefloquine-artesunate (83%, P = 0.008, artesunate (60%, P = 0.37) than in the praziquantel group (46%).

More participants had at least one AE in any of the assessments in the mefloquine group (100%), in the mefloquine-artesunate group (94%) and in the artesunate group (80%) than in the praziquantel group (61%).

No serious or life-threatening adverse events, no hospital admissions due to AE,

no neuropsychological AE, no trial discontinuation due to AE.

Praziquantel versus Praziquantel and ALB: adverse events

Trial IDParticipantsAdverse events monitoringBlindingSummary of adverse events findings
Olds 1999 KEN

N = 193

98 (Praziquantel and albendazole)

95 (Praziquantel)

AE monitoring for 48 hours for pre-defined AEDouble blind

65% of side effects for S. haematobium reported within four to six hours. Symptoms usually resolved within two hours with or without relief medication.

Data not reported for S. haematobium separately.

Appendix 6. Appendix: Ultrasound findings

Praziquantel 40 mg/kg single dose versus 20 mg/kg single dose: ultrasound findings

Trial IDTime pointMeasurePraziquantel 40 mg/kg (SD)Praziquantel 20 mg/kg (SD)
BaselineFollow-upBaselineFollow-up
King 2002 KEN 19 months

Number of participants with haematuria/total

N = 264 for both groups

22/32 (69%)16/32 (50%)20/32 (62%)17/32 (53%)
Mild hydronephrosis (%)25%15%21%18%
Moderate hydronephrosis (%)5%4%11%0%
Severe hydronephrosis (%)5%2%3%2%
Mild bladder abnormalities (%)11%4%17%6%
Severe bladder abnormalities (%)8%0%6%0%

1Haematuria measured by urine dipstick, "no statistical difference", "study might be underpowered, for ultrasound findings" all severe bladder abnormalities were eliminated.

Praziquantel 40 mg/kg 1x/year versus metrifonate 10 mg/kg 3x/year: ultrasound findings

Trial IDTime pointMeasure

Praziquantel 40 mg/kg

1x/year

Metrifonate 10 mg/kg

3x/year

Comments
King 1990 KEN12 monthsBladder wall thickness

35% improvement

8% deterioration

29% improvement

9% deterioration

Subsample N = 373

Praziquantel N = 141

Metrifonate N = 126

Bladder deformity (granulomata)

21% improvement

6% deterioration

15% improvement

2% deterioration

Hydronephrosis

12% improvement

13% deterioration

9% improvement

7% deterioration

What's new

DateEventDescription
7 July 2014New search has been performedThe review has been updated and revised with a new author team.
7 July 2014New citation required but conclusions have not changedA new author team was put in place for this review update.

Contributions of authors

VK developed the protocol with input from PG and DS. VK and FZ assessed eligibility and extracted the data. We resolved any disagreements through discussion with DS and PG. VK entered the data and drafted the manuscript with input from DS, PG and PO. DS, PG and PO assisted in interpretation of the results and revisions of the text.

Declarations of interest

We have no known conflicts of interest.

Sources of support

Internal sources

  • Liverpool School of Tropical Medicine, UK.

External sources

  • This review was supported by the Department for I nternational Development , UK.

Differences between protocol and review

While inclusion criteria of the first protocol included all RCTs which studied antischistosomal drugs, we decided to change the protocol. We excluded trials which evaluated obsolete drugs as ambilhar, oltipraz and niridazole. We also excluded studies which compared a combination of praziquantel and albendazole to placebo only, as this comparison is not of interest for this review. We included trials evaluating metronidazole.

We did not contact researchers or organizations looking for unpublished studies, as stated in the protocol. We did not report parasitological outcomes at three months as primary outcomes.

The older version of this review concluded that both metrifonate and praziquantel were effective in treating urinary schistosomiasis, even if metrifonate had operational disadvantages. As implications for further research, evaluation of different metrifonate doses and regimens and of evaluation of artemisinin drugs and of combination therapy is recommended.

While we agree with these conclusions, the data on egg reduction allow some further recommendations. We have newly included three trials evaluating artemisinin drugs, and one recent trial using mefloquine, and present this new evidence here.

Additional analysis carried out in this edition of the review, which was not in the previous edition (Danso-Appiah 2008), is the presentation of egg reduction rates in summary tables.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abden Abdi 1989 SOM

Methods

RCT

Diagnostics: egg excretion in a single, mid-day urine sample, mixing an aliquot of 10 mL urine, filtration (nucleopore)

Follow-up at 1, 2, 3 and 6 months

Participants

Children aged 11 to 12 years on average

Number randomized 300

Number analysed for primary outcome at one month 201, at six months 139

Inclusion criteria: excreting 20 or more S. haematobium eggs per 10 mL urine

Exclusion criteria: concomitant disease

Interventions

1. Metrifonate 3 x 7.5 mg/kg dose interval two weeks

2. Metrifonate 3 x 5 mg/kg within one day

3. Placebo

Outcomes

Cure rate

Percentage egg reduction

Adverse events

Notes

Location: Somalia, southern part

Setting: rural, five villages

Endemicity: high

Dates: not stated

Source of funding: SAREC (Swedish agency for research cooperation with developing countries)

Authors' conclusion: Both metrifonate regimens have similar efficacy

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized, randomly assigned, table of random numbers.
Allocation concealment (selection bias)Low riskAll doses were kept in coded envelopes.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind, placebo controlled "and the distributor of the drug and the participants were all blind to the type of treatment."
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of the lab technician.
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh loss to follow-up, 33% at one month, 53% at six months, balanced between treatment arms
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias.

Al Aska 1990 SAU

Methods

RCT

Diagnostics: ova excretion in 10 mL midday urine after sedimentation

Follow-up: three and six months

Participants

Adult patients referred to hospital, age not stated. Saudi and Jemeni

Number randomized: not reported

Number analysed: 100

Inclusion criteria: S. haematobium infection

Exclusion criteria: none stated

Co-infection with S. mansoni

Interventions

1. Praziquantel 40 mg/kg single dose

2. Metrifonate 10 mg/kg three doses in intervals of two weeks

Outcomes

Cure rates

Failure rates

Notes

Location: Saudi Arabia

Setting: King Abdul Aziz University hospital, Riyadh. Patient referral

Endemicity: not reported

Dates: not stated

Funding: not stated

Authors' conclusion: Metrifonate and praziquantel in the stated dosage are effective against S. haematobium, side effectives are minor and transient

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"allocated randomly".
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot mentioned, no placebo mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up not reported.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskFew baseline characteristics reported.

Basra 2012 GAB

Methods

RCT

Diagnostics: Ova excretion, microscopy in 10 mL urine after filtration, AMEC

Follow-up: six weeks

Participants

Pregnant women attending ANC clinics, aged 19 to 25 years

Number randomized 65

Number analysed 44

Inclusion criteria: S. haematobium infection, pregnancy

Exclusion criteria: intake of antihelminthic and antimalarial drug within the previous two months, HIV pos

Interventions

1. Praziquantel 40 mg/kg single dose

2. Metrifonate 10 mg/kg two doses, dose interval two weeks

Outcomes

Cure rates

Failure rates

Egg counts at baseline, four and six weeks

Notes

Location: Gabon

Setting: two ANC health care centres

Endemicity: highly endemic for S. haematobium and malaria

Dates: Sept 2009 to Dec 2011

Funding: European and Developing Countries Clinical Trial Partnership (EDCCTP), Malaria in Prengnancy consortium, Karl Landsteiner Gesellschaft

Authors' conclusion: Mefloquine IPTp is effective against S. haematobium in pregnant women.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe randomizations list was computer-generated and provided by the independent MIPPAD trial management team.
Allocation concealment (selection bias)Low riskTrial assignment was concealed via sealed opaque envelopes which were opened only after enrolment of a patient by a trial investigator.
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinding of outcome assessors.
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh loss to follow-up, unbalanced (in the intervention group 18/48 = 37.5%, in the control group 3/48 = 6.25%) reasons partly stated.
Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting.
Other biasLow riskNo risk of other bias.

Befidi Mengue 1992 CMR

Methods

RCT

Diagnostics: urine sample preserved with 5 mg sodium azide, sedimentation for one hour, examination of sediment, egg count

Follow-up: six months (as only time point)

Participants

Male primary school students, aged six to 15 years

Number randomized 653, 436 in groups of interest for this review

Exclusion: heavy S. haematobium infections (> 499 eggs/10 mL)

Inclusion: positive for S. haematobium

Interventions

1. Praziquantel 40 mg/kg single dose

2. Placebo

Outcomes

Geometric mean egg counts

Weight

Height

Height for age

Weigth for age

Weight for height

MUAC

Triceps skinfold thickness

Mean muscle mass

Hb (reported in a separate publication Befidi Mengue 1993, see reference Befidi Mengue 1992 CMR) with slightly higher numbers of participants: 771 randomized, 518 in treatment groups of interest of this review).

Notes

Location: Cameron, Eastern Province, Bertuoa

Setting: urban (capital city of Eastern province), primary school

Endemicity: polyparasitism is common

Dates: not reported

Funding: USAID Cameroon health constraints to rural production project 1608 - 1408

Authors' conclusion: only demonstrable effect of a single praziquantel treatment on MUAC

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomly assigned, method not stated.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskThe placebo tablets were physically identical to the praziquantel tablets.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up unclear, as numbers followed up not reported.
Selective reporting (reporting bias)Low riskNo evidence for selective reporting.
Other biasLow riskNo evidence for other bias.

Borrmann 2001 GAB

Methods

RCT

Diagnostics: two urine samples. filtration of 10 mL of urine through polycarbonate filters (Millipore), staining with Trypan blue

Follow-up at day 56 (as only time point)

Participants

School children aged six to 15 years

Participants randomized: 300

Inclusion: S. haematobium positive, asymptomatic S. haematobium infection

Exclusion: symptomatic schistosomiasis, recent schistosomiasis treatment, serious underlying disease, pregnancy or lactation, anaemia (Hb < 7 G/dL)

Interventions

1. Praziquantel 40 mg/kg single dose

2. Artesunate 4 mg/kg once daily for three days

3. Artesunate 4 mg/kg once daily for three days and praziquantel 40 mg/kg single dose

4. Placebo

Outcomes

Cure rates

Failure rates

Egg reduction rates

Microhaematuria

(Adverse events day seven)

Notes

Location: Gabon, province Moyen Ogone

Setting: rural villages

Endemicity: high (prevalence 80% in school children)

Dates: Oct. 2000 to Feb 2001

Funding: tablet donation Sanofi (Artesunate), Medochemie (Praziquantel)

Authors' conclusions: Efficacy of artesunate for S. haematobium treatment as single medication or in combination is low.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskThe randomization code was generated by computer.
Allocation concealment (selection bias)Low riskThe trial drugs were prepared in plastic bags, which were labelled sequentially with treatment numbers according to the randomization code.
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Double blind.

Praziquantel placebo and artesunate placebo were identical in appearance to the respective active substance tablets.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow loss to follow-up (7.6%).
Selective reporting (reporting bias)Unclear riskHaemoglobin measurements, proteinuria and leucocyturia at day 56 not reported.
Other biasLow riskNo evidence for other bias.

Davis 1981 ZMB

Methods

RCT

Diagnostics: three successive daily schistosome egg counts made on a random 10 mL urine sub sample of the total bladder content by a filtration staining technique; quantitative hatching technique (enumeration of miracidia, recently dead eggs and black eggs)

Follow-up: three consecutive daily urine samples, quantitative hatching test

Follow-up: at 1, 3, 7, 12 and 24 months

Participants

School children aged seven to 17 years

Number followed up after one month 151, number randomized not reported

Inclusion: S. haematobium positive

Exclusion: pregnant or lactating women, no serious acute coexistent diseases or complications, no other treatment during the past six months, older than six years

Interventions

1. Praziquantel 30 mg/kg single dose

2. Praziquantel 40 mg/kg single dose

3. Praziquantel 20 mg/kg 2 x daily

Outcomes

Cure rate

Failure rate

Notes

Location: Zambia, Ndola

Setting: eight rural schools

Dates: not reported

Endemicity: high

Funding: Parasitic Disease Programme for Research and Training in Tropical diseases

Authors' conclusion: treatment groups clinically and statistically comparable

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomly assigned, random number table.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskSingle blind technique.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow loss to follow-up (3.7% to 6%) at 1, 3 and 7 months.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting (some investigations at baseline not reported).
Other biasLow riskNo evidence of other bias.

de Jonge 1990 SDN

Methods

RCT

Diagnostics: urine collection after 250 mL soda drink at midday. Trypan blue staining technique (if the egg concentration was less than 10 eggs per 10 mL urine, the whole volume (up to 350 mL) was filtered).

Follow-up one and five months

Participants

Male primary school children aged six to 11 years

Patients randomized 160, participants randomized into treatment groups of interest for this review: 107

Inclusion: co-infection with S. haematobium and S. mansoni

Exclusion: not reported

Interventions

1. Praziquantel 40 mg/kg single dose

2. Metrifonate 2 x 10 mg/kg, dose interval 14 weeks

3. Oxaminique 60 mg/kg single dose

4. Multivitamin single dose

Outcomes

Failure

Egg count

Notes

Location: Sudan Gezira

Setting: rural, village primary schools

Funding: Science and Technology for Development, EC, WHO, UNDP, World bank, Special Programme for Training & Research. Gesellschaft für technische Zusammenarbeit

Dates: not reported

Endemicity: high for both S. mansoni and S. haematobium

Authors' conclusion: discussion of correlation of parasitological outcomes and CAA titres

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomly divided".
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskMultivitamin as placebo, but blinding not mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up high, at one months up to 23%, at five months up to 28%.
Selective reporting (reporting bias)Low riskNo evidence for selective reporting.
Other biasLow riskNo evidence for other bias.

Inyang Etoh 2009 NGA

Methods

RCT

Diagnostics: collection of two urine samples at midday (12.00 to 14.00) after exercise on two consecutive days, agitation of urine sample, preservation of eggs, staining (1% aqueous solution, carbol fuchsin), filtration, egg counts

Follow-up at eight weeks (as only time point)

Participants

School children aged four to 20 years (nursery school, primary and junior secondary schools, students)

Number randomized 260 children into five groups

Inclusion: healthy, able to swallow the medication

Exclusion: serious underlying disease, recent treatment for schistosomiasis, > 20 yrs, < 4 yrs old

Interventions

1. Praziquantel 40 mg/kg single dose and placebo

2. Praziquantel 40 mg/kg single dose only

3. Artesunate 4 mg/kg 1 x daily for three days and placebo

4. Artesunate 4 mg/kg 1 x daily for three days only

5. Praziquantel 40 mg/kg single dose and artesunate 4 mg/kg 1 x daily for three days

6. Placebo and placebo

Outcomes

Cure

Egg counts and egg reduction rate

Haematuria

Proteinuria

Notes

Location: Nigeria, Adim community, Cross RIver State

Setting: school students

Dates: August 2005 to June 2006

Endemicity: seasonal transmission

Funding: partly funded by the management of the University of Calabar

Authors' conclusion: both praziquantel and artesunate in the stated doses are safe, well-tolerated and effective in the trial area. Combined treatment is more effective and single treatment with any of the drugs.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomised".
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Placebo not identical in appearance.

Blinding not mentioned.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up of 15.4% and 19.2% at day 56.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias.

Jewsbury 1976 ZWE

Methods

RCT

Diagnostics: three urine samples on three consecutive days, determination of egg counts and cure rates

Follow-up at week 11 and week 36

Participants

Children, aged three to 15 years (and older)

Number of children randomized: 179

Number of children analysed 114 (complete case analysis)

Inclusion: S. haematobium positive

Exclusion: not reported

Interventions

1. Metrifonate 7.5 mg x 3, dose interval two weeks

2. Control: no intervention

Outcomes

Cure rate

Failure rate

Median urine egg counts

Notes

Location: Zimbabwe near Salibury

Setting: rural, four farms

Dates: not reported

Endemicity: high (pre-infection rate with S. haematobium 80%)

Funding: Drug donation by Bayer

Authors' conclusion: Metrifonate is safe and effective for the treatment of S. haematobium

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"randomised".
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
High riskParticipant numbers not reported at week 11, high loss to follow-up of 46% at week 36.
Selective reporting (reporting bias)Unclear riskData of week 11 not reported.
Other biasHigh riskBaseline imbalance; for the infected, untreated control group, an infection rate of 89.4% is given at baseline.

Kardaman 1985 SDN

Methods

RCT

Diagnostics: centrifugation, sediment taken for egg counts

Follow-up at five weeks and three months

Participants

School children aged seven to 11 years

Number of children included: 237

Inclusion: co-infection S. haematobium and S. mansoni

Exclusion: receiving medication for any other infection, treatment for schistosomiasis during the preceding 6 months.

Interventions

1. Praziquantel 40 mg/kg single dose

2. Praziquantel 2 x 20 mg/kg in one day, dose interval four to six hours

Outcomes

Cure

Failure

Adverse events

Notes

Location: Sudan, Galaga Village

Setting: rural, primary schools

Dates: not reported

Endemicity: high (mixed infections common)

Funding: Parasitic disease programme, WHO

Authors' conclusion: Results of two regimens not significantly different. Treatment for this setting has to be repeated every six months.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomly assigned.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up at five weeks up to 4.7%, at three months up to 8.4%.
Selective reporting (reporting bias)Low riskNo evidence for selective reporting.
Other biasLow riskNo evidence for other bias.

Keiser 2010 CIV

Methods

RCT

Diagnostics: collection of two urine specimen at midday (10.00 to 14.00), samples were rigorously shaken, filtration of 10 mL through a 13 mL filter with 25 µm diameter

Follow-up at 26 days

Participants

School children aged eight to 12 years

Participants randomized 83

Inclusion: confirmed S. haematobium infection

Exclusion: not reported

Interventions

1. Praziquantel 40 mg/kg single dose

2. Mefloquine 25 mg/kg single dose

3. Artesunate 4 mg/kg 1 x daily for three days

4. Artesunate 3 x 100 mg and mefloquine 250 mg

Outcomes

Cure rates

Failure rate

Egg count

Egg reduction rate

Adverse effects

Notes

Location: Cote d' Ivoire, district Agboville

Setting: rural, school children

Dates: November to December 2009

Funding: support Dafra Pharma, Mepha for drug donations

Endemicity: highly endemic, 40% among school children

Authors' conclusion: High cure rates with praziquantel, promising results for mefloquine - artesunate (in the standard dose for malaria)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"using a computer generated randomisation code". Seven children were added to one treatment group in a non-randomized manner.
Allocation concealment (selection bias)High riskNot implemented (email correspondence with author).
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up during the trial (day 26).
Selective reporting (reporting bias)Low riskUrinary findings day 26 not reported (not available, email correspondence with author).
Other biasLow riskNo evidence of other sources of bias.

King 1989 KEN

Methods

RCT

Diagnostics: collection of midday urine sample (10.00 to 13.00), urine filtration technique with nucleopore filters, egg count

Follow-up at two to three months

Participants

Primary school students aged five to 17 years and adult participants over 20 years

Number of patients randomized 280 (34 adults, 246 children)

Inclusion: egg count > 50 eggs/10 mL urine

Exclusion: not reported

Interventions

1. Praziquantel 10 mg/kg single dose

2. Praziquantel 20 mg/kg single dose

3. Praziquantel 30 mg/kg single dose

4. Praziquantel 40 mg/kg single dose

Outcomes

Cure

Egg counts

Severity of infection

Proteinuria

Haematuria

Notes

Location: Kenya, Kwale district

Setting: rural, primary schools

Dates: not reported

Endemicity: high

Funding: Edna McConnell Clark Foundation

Authors' conclusion: low dose (20 mg/kg) is as effective as standard dose (40 mg/kg) of praziquantel (reductions in parasite burden and morbidity) for population based control programmes

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation, pre-randomized cards.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
High riskClinicians not blinded to the intervention.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskOutcome assessors and laboratory staff blinded to the intervention.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up at two to three months 9% to 14%, balanced between groups.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence for other sources of bias.

King 1990 KEN

Methods

RCT

Diagnostics: sample collection of midday urine (10.00 to 13.00), nucleopore filtration, egg counts

Follow-up at one, two and three years

Participants

Primary school children aged four to 21 years

Number randomized 1813

Inclusion: S. haematobium positive

Exclusion: not reported

Interventions

1. Praziquantel 40 mg/kg single dose once a year

2. Metrifonate 10 mg/kg single dose three times a year, dose interval four months

Outcomes

Haematuria

Proteinuria

Ultrasound (hydronephrosis, bladder thickening, bladder deformity)

Notes

Location: Kenya, Coast Province, Kwale Province, Msambweni Area

Setting: rural, primary schools, nine villages

Dates: 1984

Endemicity: high (prevalence in school children 60% to 85%)

Funding: Edna McConnell Clark Foundation, WHO, Rockefeller Foundation

Authors' conclusion: Both regimens had significant effects on the prevalence of hematuria, proteinuria, and bladder abnormalities. no significant differences between the two drugs. No effect on hydronephrosis at twelve months.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom allocation with pre-randomized cards.
Allocation concealment (selection bias)High risk"Treatment allocation was not concealed to the investigators" (email correspondence with author).
Blinding of participants and personnel (performance bias)
All outcomes
High risk

Blinding of participants (different taste and appearance of commercially purchased drugs) email response).

no blinding of clinicians

Blinding of outcome assessment (detection bias)
All outcomes
Low riskEvaluators were effectively blinded to the treatment status of the children they were testing (email correspondence with author).
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias.

King 2002 KEN

Methods

RCT

Diagnostics: Collection of two mid-day (10:00 to 14:00) on different days, filtration, Nucleopore) Intensity of infection assigned according to the highest one day egg count in the repeated daily testing.

Follow-up at six weeks and nine months

Participants

School children and adults, aged four to 23 years

Number of participants randomized 291

Inclusion: S. haematobium positive

Exclusion: not reported

Interventions

1. Praziquantel 40 mg/kg single dose

2. Praziquantel 20 mg/kg single dose

Outcomes

Cure

Egg count

Ultrasound findings (Hydronephrosis, bladder thickening and bladder irregularity)

Notes

Location: Kenya, Coastal Province, Kwale District

Setting: rural, village schools

Dates: 1992 to 1993

Endemicity: high

Funding: WHO, TDR, Rockefeller Foundation Joint Funding Venture and National Institutes of Health

Authors' conclusion: Praziquantel 20 mg and praziquantel 40 mg are equally effective in reducing structural urinary tract morbidity over nine months. A praziquantel dose of 20 mg/kg may be sufficient for practical control of renal and bladder morbidity due to S. haematobium in certain settings: not reported

(trial might be underpowered for ultrasound findings).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Infected students were then individually randomised to therapy...by computer random number generation."
Allocation concealment (selection bias)High riskAllocation was not concealed.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNo blinding of personnel: "Dosing assignment lists were transmitted to clinical staff responsible for treatment".
Blinding of outcome assessment (detection bias)
All outcomes
Low risk

Blinding of outcome assessors (clinicians, parasitologists).

"Assignments were masked form staff parasitologists and physicians responsible for follow-up until the end of the study."

Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up 31% at six weeks.
Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting.
Other biasLow riskImportant baseline characteristics (egg counts) not reported at baseline.

McMahon 1979 TZA

Methods

RCT

Diagnostics: Collection of three midday (10.00 to 13.00) urine samples on three consecutive days, sedimentation in a conical flask for 30 mins, taking of a 10 mL sample of the bottom of the flask, centrifugation and processing of the deposit 5 mL boiled, cooled water added to deposit, miracidia hatching test, fixing and staining of miracidia (alcohol and eosin), microscopy and count.

Follow-up at one, three and six months.

Participants

School children aged seven to 15 years

No. of children randomized: 138

Inclusion: S. haematobium positive

Exclusion: not reported

Interventions

1. Praziquantel 30 mg/kg single dose

2. Praziquantel 40 mg/kg single dose

3. Praziquantel 2 x 20 mg in one day, dose interval four hours

4. Placebo

Outcomes

Cure

Egg counts

Adverse effects

Notes

Location: Tanzania, Tanga region

Setting: school, rural area

Endemicity: high, transmission may vary greatly form year to year and season to season.

Dates: not reported

Funding: MRC/WHO/Tanzania Helminthiasis Research Unit, Tanga

Authors' conclusion: Praziquantel in the given doses is not toxic. Praziquantel 40 mg did not affect the therapeutic response in children with large egg loads.

As cure rates are influenced by pre-treatment egg loads, trials of higher doses in patients with high egg loads needed.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomly sub-divided into four groups according to previously arranged blocks.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up 10% to 15% at 1, 3 and 6 months.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskBaseline characteristics not reported.

McMahon 1983 TZA

Methods

RCT

Diagnostics: collection of two midday (10.00 to 14.00) samples on two consecutive days for initial diagnosis, of three samples for follow-up), quantitative hatching technique, sedimentation of 10 mL urine

Follow-up at two and four months

Participants

School children and adults

Number of participants randomized: 90

Inclusion: 250 miracidia/10 mL urine

Exclusion: not reported

Interventions

1. Praziquantel 30 mg/kg single dose

2. Metrifonate 10 mg/kg 1 x daily, dose interval 14 days

3. Niridazole 25 mg/kg 1 x daily for six days, dose interval one day

Outcomes

Cure rates

Egg reduction rates

Adverse effects

Notes

Location: Tanzania, Tanga region

Setting: not stated

Endemicity: high

Dates: not reported

Funding: MRC/WHO/Tazania Helminthiasis Research unit, Tanga, Biltricide (Praziqantel) was supplied by Bayer.

Authors conclusion: Praziquantel was more effective than metrifonate and niridazole. Side effects were minor.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomly allocated.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot mentioned; use of different regimens, no use of placebo.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up partly high, not balanced (at four months 0% in the praziquantel group, 26% in the metrifonate and 30% in the niridazole group.
Selective reporting (reporting bias)Unclear riskNo evidence of selective reporting.
Other biasLow riskFew baseline characteristics reported.

Mott 1985 GHA

Methods

RCT

Diagnostics: collection or one urine sample, two random samples out of this urine sample were processed. quantitative urine filtration technique

Follow-up at three and six months

Participants

Residents "entire population of five settlements", aged six years or older

Number of people randomized 266

Inclusion: S. haematobium infected

Exclusion: pregnancy, alcoholism, severe debilitating disease

Interventions

1. Praziquantel 30 mg/kg single dose

2. Praziquantel 40 mg/kg single dose

Outcomes

Cure rate

Egg count, egg reduction rate

(Urinary results not reported by treatment group)

Notes

Location: Ghana, Lake Volta

Setting: rural, five settlements

Dates: not reported

Endemicity: not reported

Funding: Parasitic Diseases Programme WHO/UNDP/Wold bank/ WHO Special Programme for Research and Training in Tropical diseases

Authors' conclusions: Similar efficacy of Praziquantel 30 mg and 40 mg in this trial. Praziquantel reduces clinical signs (macrohaematuria) and morbidity in urinary schistosomiasis

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomly assigned.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up at six months 11.6%.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskBaseline characteristics not reported per group.

Olds 1999 KEN

Methods

RCT

Diagnostics: Eggs from 2 x 10 mL samples were filtered on membranes (Nucleopore)

Follow at 45 days, 90 days, six months and one year

Participants

School children aged four to 18 years

Number of participants pos for S. haematobium: 380

Inclusion: S. haematobium positive

Exclusion: pregnancy or marriage, failure to submit two stool specimens prior to initial therapy, known allergy to praziquantel or albendazole, treatment within the past six months

Interventions

1. Praziquantel 40 mg/kg single dose and albendazole 400 mg single dose

2. Praziquantel 40 mg/kg single dose and placebo

3. Albendazole 400 mg single dose and placebo

4. Placebo and placebo

Outcomes

Cure

Egg count

Ultrasound

Weight, height, skinfold thickness, MUAC

Hb

Adverse effects

Notes

Location: Kenya, Kwale District, Coast province for S. haematobium (multi centre trial for different Schistosoma species, conducted in different countries)

Setting: rural

Endemicity: endemic ascariasis, hookworm, trichuris, S. haematobium

Dates: not reported

Funding: WHO/TDR Tropical disease research

Authors' conclusion: Combined mass treatment of children with albendazole and praziquantel produced not more side effects than treatment with praziquantel alone.

Combined mass treatment should have an important impact on schistosoma and hookworm prevalence and intensity and improves Hb levels.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized in one of four treatment groups, block design with block size of 80.
Allocation concealment (selection bias)Low riskRandomization lists were prepared by WHO/TDR using a randomized block design.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble blind, placebo controlled; physically identical placebo.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up 10% at six months, loss to follow-up 17% at one year (for all groups).
Selective reporting (reporting bias)High riskHb values, proteinuria, hematuria, ultrasound findings not reported.
Other biasLow riskNo evidence for other bias.

Omer 1981 SDN

Methods

RCT

Diagnosis: sedimentation concentration technique, miracidial hatching

Follow-up at seven days, one month, three to four months, six months

Participants

Patients presenting to the Hospital of Tropical diseases, Karthoum, aged eight to 16 years

Number of patients randomized: 152

Inclusion: mixed S. haematobium and S. mansoni infections

Exclusion: under eight years of age, advanced stage of disease, severe anaemia, poor general health

Interventions

1. Praziquantel 30 mg/kg single dose

2. Praziquantel 40 mg/kg single dose

3. Praziquantel 2 x 20 mg/kg within one day

Outcomes

Cure rates

Egg counts

Adverse events

Laboratory parameters at day 0 or 1 and at day 1 or 2, not of interest for this review

Notes

Location: Sudan, Karthoum

Setting: Hospital of Tropical Diseases, Karthoum

Endemicity: not reported

Dates: 1978 to 1979

Funding: not reported

Authors' conclusion: Praziquantel is easily applicable, safe and effective in the treatment of mixed (S. haematobium and S. mansoni) infections

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskSingle blind.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up at six months 17% to 22%, balanced.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias.

Oyediran 1981 NGA

Methods

RCT

Diagnostics: collection of a midday urine sample (12.00 to 2.00), taking a 10 mL sub sample, filtration of the urine, staining with Ninhydrin, counting of the eggs retained on the filter paper

Follow-up at one, three and six months

Participants

Primary school children aged nine to 16 years

Participants randomized: 90

Inclusion criteria: mean egg count 80 eggs/10 mL, viable eggs, aged over six years

Exclusion criteria: under six years, concurrent acute or serious illness, antischistosomal treatment within the past six months

Interventions

Praziquantel 30 mg/kg single dose

Praziquantel 40 mg/kg single dose

Praziquantel 2 x 20 mg/kg, dose interval three to four hours

Placebo

OutcomesEgg counts
Notes

Nigeria, Oyo State

Setting: Primary Schools

Dates: not reported

Funding: not reported

Authors' conclusion: No significant difference in efficacy between the three dosage regimens, trials on the effects of lower doses required.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear risk

Placebo single dose

The treatment group received a split dose of praziquantel, blinding not mentioned.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh loss to follow-up, not balanced (at one month 4 to 17%, at three months 17 to 23%, at six month 26 to38%, at twelve months 76% to 87%).
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias.

Pugh 1983 MWI

Methods

RCT

Diagnostics: collection of two midday urine samples on two consecutive days filtration, staining and egg count

Follow-up at one, three and six months. Further follow-up reported at nine, 12, 15 and 24 months in a separate publication (Pugh 1983 MWI)

Participants

School children aged five to 18 years

Number of participants randomized: 499

Inclusion: mean egg count (S. haematobium) > 19/10 mL

Exclusion: malaise, febrile illness, treatment with schistosomacidal drugs in the past six months

Interventions

1. Praziquantel 40 mg/kg single dose

2. Niridazole 25 mg/kg single dose and metrifonate 10 mg/kg single dose

3. Metrifonate 10 mg/kg single dose

4. Niridazole 25 mg/kg single dose

5. Placebo

Outcomes

Cure

Geometric mean egg counts

Egg reduction rates

Notes

Location: Malawi, Pirimiti Area, Phalombe plain

Setting: rural

Endemicity: seasonal

Funding: Overseas Development Administration, U.K. MoH Malawi. Praziquatel supplied by Bayer

Authors' conclusion: Praziquantel is superior to the other drugs studied in this trial, it is the most efficient and convenient drug available. Maintained low egg output at 24 months was presumably influenced by low levels of transmission during the second year of the trial, which was very dry.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUse of a randomized x-y list.
Allocation concealment (selection bias)Low risk"An independent worker had sole and confidential access to a randomised x-y list."
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDescribed as double blind.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up low at one months: 0% to 4.1%, at three months 8% to 11% in treatment groups, up to 23% in the placebo group; at six months 20% in the treatment group. Loss to follow-up high at 24 months, about 40% to 70 %.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasHigh risk

Baseline imbalance in terms of intensity of infection.

"In accordance to with local ethical guidelines the placebo group consisted only of children with light (20-124 ova/10mL or moderate (125 to 4999 ova/10 mL) infections before treatment. Important baseline characteristics not reported (age, weight).

Rey 1983 NER

Methods

RCT

Diagnostics: collection of two urine samples, filtration (Swinex 13 Filter Millipore, 13 mm diameter), fixation and staining (Lugol), egg counts

Length of follow-up: one, three and six months

Participants

Participants: recruits aged 18 to 20 years and college students aged 15 to 19 years

Number of participants randomized: 207

(co-infection with S. mansoni likely, but not investigated)

Inclusion: S. haematobium positive

Exclusion: not reported

Interventions

1. Praziquantel 30 mg/kg daily dose

2. Praziquantel 40 mg/kg daily dose

3. Oltipraz 17.5 mg/kg 2 x daily in one day

Outcomes

Failure

Egg reduction rates

Notes

Location: Niger

Setting: not reported

Endemicity: not reported

Dates: not reported

Funding: not reported

Authors' conclusion: No significant difference found between praziquantel 30 mg/kg and praziquantel 40 mg/kg.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized, tirage au sort.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot mentioned, no use of placebo.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up acceptable at one month (9% to 15%) and three months 9% to 11%, high at six months (39% to 47%).
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskBaseline characteristics not reported.

Rey 1984 NER

Methods

RCT

Diagnostics: urine filtration, normal filtration paper, egg counts (no further details given)

Follow-up for children (aged five to 15 years) at 1, 5 and 6 months, for adults (> 15 years) at six months only

Participants

Children older than five years and adults

Participants treated and controlled: 268 randomized, 143 participants at one month, randomized

Inclusion: not reported

Exclusion: not reported

Interventions

1. Metrifonate 10 mg/kg single dose

2. Metrifonate 10 mg/kg two doses with a dose interval of two weeks

3. Metrifonate 10 mg/kg three doses with a dose interval of two weeks

Outcomes

Cure rate

Egg reduction

Notes

Location: Niger, near Niamey

Setting: not reported

Endemicity: high, the trial was conducted in the season of low transmission

Dates: not reported

Funding: not reported

Authors' conclusions: Recommendation against the combined metrifonate niridazole treatment.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"au hasard ", random number table.
Allocation concealment (selection bias)Unclear riskNo comment.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo comment.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo comment.
Incomplete outcome data (attrition bias)
All outcomes
High riskLoss to follow-up high: at one month 50%, at four months 39%.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias, funding not stated.

Sacko 2009 MLI

Methods

RCT

Diagnostics: Collection of three urine samples between 10 am and 2 PM on three consecutive days. 10 mL of urine passed through a nucleopore filter, Swinnex filter support. Egg counts.

Follow-up at 3, 6 and 18 months

Participants

School children aged seven to 14 years

Number of participants randomized: 603

Inclusion: not reported

Exclusion: not reported

Interventions

Praziquantel 40 mg/kg single dose

Praziquantel 40 mg/kg two doses, interval two weeks

Outcomes

Cure rate

Egg reduction

Haematuria

Notes

Location: Mali, Niger River Basin

Setting: rural, primary schools

Endemicity: not reported

Dates: not reported

Funding: not reported

Authors' conclusion: Significantly reduced prevalence of microhematuria with praziquantel x 2, this could indicate reduction of morbidity

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomized (SPSS generated random number tables).
Allocation concealment (selection bias)Low riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Double blind, placebo-controlled.

Placebo tablets were of the same form and colour as praziquantel.

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up unclear, as number randomized were not reported, only the numbers at first follow-up at three months.
Selective reporting (reporting bias)Low riskFollow-up data at six and 18 months reported in graphs, not in numbers.
Other biasLow riskNo evidence for other bias.

Stephenson 1985 KEN

Methods

RCT

Diagnostics: nucleopore filter method of Peters and others

collection of a midday urine sample (complete bladder content, 11.00 to 12.00) after 200 mL of fruit drink, nucleopore filter method of Peters and others, staining with 0.5 trypan blue, egg counts in 10 mL of urine adjusted for the total volume of each urine specimen

Follow-up for six months

Participants

Primary school children aged six to 16 years

Number of participants randomized: 400

Inclusion: light to moderate S. haematobium infections at exam 1

Exclusion: not reported

Interventions

1. Metrifonate 7.5 mg/kg three doses, dose interval one to two weeks

2. Placebo: gelatin capsules

Outcomes

Parasitological failure and cure

Egg counts

Egg reduction rate

Haemoglobin

Anthropometric measures weight, height, weight for height, middle upper arm circumference, triceps and subscapular skinfold thickness

Liver size

Spleen size

Notes

Location: Kenya, Kwale District, Coast Province

Setting: rural, four primary schools

Endemicity: highly endemic

Dates: not reported

Funding: not reported

Authors' conclusion: S. haematobium infections can precipitate or aggravate anaemia in vulnerable children (poor iron intake, high endemicity of other parasites). S. haematobium treatment improves Hb levels.

S. haematobium treatment may improve child growth (in populations were hookworm infections and Protein Energy Malnutrition is common). S. haematobium treatment may be associated with regression of splenomegaly and hepatomegaly in children treated for S. haematobium infection. Population-based treatment is recommended.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAllocated at random.
Allocation concealment (selection bias)Unclear riskNot described.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskUse of placebo.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskExaminations 1 and 2 were carried out in a blind fashion with the same team of workers.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up unclear, as results were reported as proportions.
Selective reporting (reporting bias)Low riskNo evidence of selective outcome reporting.
Other biasLow riskNo evidence of other sources of bias.

Stephenson 1989 KEN

Methods

RCT

Diagnostics: collection of a midday urine sample (complete bladder content, 11.00 to 12.00) after 200 mL of fruit drink, nucleotome filter method of Peters and others, staining with 0.5 trypan blue, egg counts in 10 mL of urine adjusted for the total volume of each urine specimen

Follow-up at eight months (as only time point)

Latham 1990, a sub-study nested within Stephenson 1989 KEN, followed up patients at five weeks (as only time point)

Participants

Primary school children, 98% Muslim of the Wadigo tribe, aged eight to 13 years

Number of participants randomized: not reported

Number of participants analysed: 312

Inclusion: light to moderate infections

Exclusion: anaemia (Hb < 8 G/dL, severe infections)

Latham 1990 included 48 boys aged seven to 15 years with no sign of puberty, high egg counts, Hb > 8 G/dL, cooperation for physical fitness test

Interventions

1. Praziquantel 40 mg/kg single dose

2. Metrifonate 10 mg/kg single dose

3. Placebo

As a nested study, Latham had the same study arms.

Outcomes

Parasitological failure

Egg counts (geometric and arithmetic)

Anthropometric measurements: weight, height, MUAC, triceps skinfold thickness, subscapular skinfold thickness,

Haemoglobin

Liver size

Spleen size

Latham 1990 (reference see Stephenson 1989 KEN) reports parasitological failure, egg reduction rate and anthropometric measures: weight, height, skinfold thickness, MUAC at five weeks at five weeks, and additionally reports on

Physical fitness: Harvard Step test,

Appetite (quantity of porridge consumed)

Questionnaire of clinical symptoms

Notes

Location: Kenya, Kwale district, Coast Province

Setting: rural, primary schools

Endemicity: endemic for S. haematobium, hookworm and malaria

Dates: March 1986 to April 1986

Funding: Edna McConnell Clark Foundation, grant 284-0120

Authors' conclusion: Both metrifonate and praziquantel are effective in reducing egg excretion and are both recommended for population based treatment. Praziquantel is more effective. S. haematobium treatment with a single dose of either metrifonate or praziquantel may improve child growth in areas were hookworms and malnutrition are common and appears to have a beneficial effect on hepatomegaly and splenomegaly.

Treatment of moderate to heavy S. haematobium infections with metrifonate or praziquantel in undernourished schoolboys can improve physical fitness, growth rates and appetite within approximately one month.

Recommendation for widespread population based chemotherapy in highly endemic areas as Kwale district.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAllocated at random.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskUse of placebo.
Blinding of outcome assessment (detection bias)
All outcomes
Low riskExaminations carried out in a blind fashion.
Incomplete outcome data (attrition bias)
All outcomes
Low riskLoss to follow-up 10%, 3 participants not accounted for.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence for other source of bias.

Taylor 1988 ZWE

Methods

RCT

Diagnostics: urine sample collection; three midday urine samples (10.00 to 14.00), filtration (13 mm nytrl filter), staining with Lugol

Follow-up at 1, 3 and 6 months

Participants

School children aged ten to 15 years, mixed infection with S. haematobium and S. mansoni

Number of participants randomized: 373

Inclusion: mixed S. haematobium and S. mansoni infection

Exclusion: not reported

Interventions

1. Praziquantel 10 mg/kg single dose

2. Praziquantel 20 mg/kg single dose

3. Praziquantel 30 mg/kg single dose

4. Praziquantel 40 mg/kg single dose

4. Control: Nil

Outcomes

Parasitological cure

Egg count

Notes

Location: Zimbabwe

Setting rural, primary school

Endemicity: seasonal transmission

Date: not reported

Funding: Rockefeller Foundation (financial support)

Authors' conclusion: Doses of 20 to 40 mg praziquantel may be equally effective in S. haematobium infection

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomly assigned.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskSingle blind manner "only the principal investigator knew which children had been assigned to which treatment group."
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up unclear, as only means and percentages of cure are reported.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence for other source of bias.

Tchuente 2004 CMR

Methods

RCT

Diagnostics: collection of two urine samples on two consecutive days in 50 mL plastic screw cap vials, processing in field laboratory, agitation of urine (from dispersal of eggs) filtration of 10 mL (Nucleopore filter), egg counts

Length of follow-up 3, 6 and 9 weeks

Participants

School children, age not reported

Number of participants randomized: 592

Inclusion: S. haematobium positive

Exclusion: not reported

Interventions

1. Praziquantel 40 mg/kg single dose

2. Praziquantel 40 mg/kg two single doses, dose interval three weeks

3. Praziquantel 40 mg/kg three single doses, dose interval three weeks

Outcomes

Cure rates

Egg counts, egg reduction rates

Proteinuria

Notes

Location: Cameroon, Loum

Setting: urban, schools

Date: April to June 2002

Endemicity: endemic all year, prevalence amongst school children 41.8%, trial carried out during high transmission period

Funding: European Commission INCO-DC (ICA-4-CT-2001-10079)

Authors' conclusion: No significant differences between the three dosing regimens, persistent high cure rates with a single dose of Praziquantel. Findings suggest efficacy of praziquantel against immature schistosoma stages.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAssigned to random groups.
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNo use of placebo mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh loss to follow-up of 13% at six weeks, very high loss to follow-up of 58.6% at nine weeks (change in schools schedules).
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias.

van den Biggelaar 02 GAB

Methods

RCT

Diagnostics: collection of urine samples on three different days, filtration of 10 mL urine, nucleopore pore size 13 µm), staining with ninhydrin, eggs count

Follow-up at two and three years, length of follow-up three years

Participants

School children aged five to 14 years

Participants randomized: 135

Inclusion: positive for S. haematobium eggs

Exclusion: not reported

Interventions

Praziquantel 40 mg/kg single dose

Praziquantel 40 mg/kg in repeated doses, dose interval three months, over two years

Outcomes

Cure rates, failure rates

Egg counts

Microhaematuria

Notes

Location: Gaboon, near Lambarene

Setting: rural, village schools

Endemicity: high

Funding: not reported

Dates: not reported

Authors' conclusion: relate to immunologic outcomes also measured by this trial, but not of interest for this review

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAllocated randomly.
Allocation concealment (selection bias)High risk"The allocation of children to the treatment group was open."
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskUse of placebo (given every three months) not mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
High risk

High loss to follow-up (not balanced, reasons not given):

at 24 months 8%, 23%, 44% in different treatment groups;

at 36 months 40%, 64%, 77%.

Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskNo evidence of other bias.

Wilkins 1987 GMB

Methods

RCT

Diagnostics:

Follow-up at two to three months

Participants

Residents aged two to 19 years, median age 9.5 years

Participants randomized: not reported

Interventions

1. Praziquantel 10 mg/kg

2. Praziquantel 20 mg/kg

3. Praziquantel 40 mg/kg

4. Metrifonate 10 mg/kg

5. Praziquantel 10 mg/kg and metrifonate 10 mg/kg

Outcomes

Egg counts

Side effects

Notes

Location: Gambia Upper River Division, Nyanamari

Setting: rural

Endemicity: seasonal, trial conducted during season of low transmission

Dates: not reported

Funding: not reported

Authors' conclusion: Mass treatment of intensely infected groups should be based on the standard dose of praziquantel, with metrifonate as second choice.

Note: only one of the two trials reported in this publication, the Nyanamari trial, fulfilled the inclusion criteria.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Subjects...were stratified into four age groups and within each age stratum were ordered by intensity of egg counts. They were then placed sequentially into groups of five. Computer generated random sets of the numbers one to five were used to allocated on subject in each group of five to each of the five regimens used."
Allocation concealment (selection bias)Unclear riskNot mentioned.
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskPlacebo and blinding not mentioned.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot mentioned.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLoss to follow-up unclear, as cure rates are reported as percentages.
Selective reporting (reporting bias)Low riskNo evidence of selective reporting.
Other biasLow riskBaseline characteristics not reported.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Aryeetey 1999Study of health education and community participation.
Ayoya 2007No comparison group (treatment groups receive praziquantel with or without iron supplements and multivitamins).
Bausch 1995Not a RCT.
Beasley 1999This study compares a combination of praziquantel and albendazole with placebo. This outcome is not of interest for this review.
Bejon 2008Study of gastrointestinal helminths, not urinary schistosomiasis.
Bhargava 2003This study does not report baseline criteria for control group, as the control group was not screened at baseline.
Boulanger 2007No comparison group (both groups receive artesunate).
Burchard 1984This study compares praziquantel 2 x 30 mg/kg to oltipraz, which is obsolete. Details of this trial can be seen in earlier versions of this review.
Clarke 1969Not a RCT.
Clarke 1973Not a RCT, allotted to groups, "for practical reasons, the infected children in the two senior grades were set aside for treatment with i.m. hycanthone".
Creasey 1986This study compares different doses of praziquantel (8 mg/kg, 15 mg/kg and 20 mg/kg) combined with oxaminique in patients with S. haematobium and S. mansoni co-infections. A comparison of the praziquantel dosages used is not of interest for this review.
Danso-Appiah 2009Systematic review.
Davis 1966This study evaluates different doses of ambilhar which is now obsolete. Details of this trial can be seen in earlier versions of this review.
Davis 1979Outcomes are not reported per treatment group, only for the total number of participants randomized.
De Clercq 2002Not a RCT, "systematically allocated".
Druilhe 1981Not a RCT.
el Hawey 1990No comparison group.
el Tayeb 1988This study compares praziquantel 2 x 20 mg/kg to oltipraz 2 x 15 mg/kg, which is now obsolete. Details of this trial can be seen in earlier versions of this review.
el-Zayadi 1985No outcome of interest reported.
Erikstrup 2008This is a study of HIV and S. haematobium or S. mansoni co-infection, no outcomes of interest for this review are reported.
Fontanilles 1964Conference speech.
Forsyth 1964Not a RCT. "At three of the schools, every sixth injected child received "curative" treatment..."
Garba 2001Study of health education.
Garba 2004This study evaluates mass treatment with praziquantel without comparison group.
Hammad 1997This cross-sectional study evaluates the diagnosis of urinary schistosomiasis by reagent strip and parasitological methods.
Jewsbury 1977No comparison group (sequence of treatment, then prophylaxis within one group).
Jinabhai 2001This study compares a combination of praziquantel and albendazole with placebo. This outcome is not of interest for this review.
Jordan 1966Quasi-RCT. "children were allocated to Groups 1-4 corresponding to different regimens of treatment, in rotation down the list (pre-treatment results in descending order), thus ensuring four groups matched for egg output."
Kardaman 1983No comparison group.
Kern 1984Study of intestinal manifestations of schistosomiasis, very low number for S. haematobium positive patients, outcome data not reported separately.
King 1989Review article.
King 1992Data reported in other publications.
Kurz 1986This study evaluates metrifonate in hookworm infections.
Latham 1983No comparison group.
Lucas 1969This study reports ultrasound findings in patients with urinary schistosomiasis after treatment with Niridazole to a untreated control. Niridazole is now obsolete.
Mwanakasale 2009Study of iron supplementation in S. haematobium treatment with no outcomes of interest for this review.
N'Goran 2003Study of S. haematobium prevention.
Nagaty 1962This trial studies the therapy of drug side effects in urinary schistosomiasis treatment.
Odongo-Aginya 1996Not a RCT, study of S. mansoni.
Olsen 2007Review article.
Pitchford 1978No comparison group.
Podgore 1994Study of S. haematobium prevention.
Rabarijaona 2001Epidemiological survey.
Rey 1984This study compares oltipraz 30 mg/kg to a combination of metrifonate 10 mg/kg and niridazole 25 mg/kg. Niridazole and oltipraz are now obsolete.
Rugemalila 1984Study of S. mansoni.
Schutte 1983No comparison group.
Sellin 1986This study compares metrifonate 10 mg/kg to oltipraz 30 mg/kg, which is now obsolete.
Sissoko 2009 MLIThis study compared praziquantel to a combination of artesunate with sulfamethoxypyrazine pyrimethamine; it is therefore not possible to attribute observed effects to artesunate alone.
Snyman 1997Study of calcitriol as experimental antischistosomal treatment.
Snyman 1998Study of levimasole as experimental antischistosomal treatment.
Squires 2000Review article.
Stephenson 1985No comparison group (compares children of moderate and severe infection intensity with uninfected children, using the same treatment regimen for infected children).
Taylor 2001This study compares a combination of praziquantel and albendazole with placebo. This outcome is not of interest for this review, whereas a comparison the combination of praziquantel and albendazole versus praziquantel would be of interest.
Teesdale 1980Not a RCT.
Thigpen 2011Not a RCT.
Urbani 1997Epidemiological survey.
Utzinger 2001Review article.
van Lieshout 1994Study of S. mansoni.
Wilkins 1987 Simoto trialNot a RCT, alternate allocation.
Wolfe 1967Not a RCT.
Xiao 2002Review article.
Zwingenberger 1990Case study.