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Pre-referral rectal artesunate for severe malaria

  1. Joseph Okebe1,*,
  2. Michael Eisenhut2

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 29 MAY 2014

Assessed as up-to-date: 21 MAY 2014

DOI: 10.1002/14651858.CD009964.pub2


How to Cite

Okebe J, Eisenhut M. Pre-referral rectal artesunate for severe malaria. Cochrane Database of Systematic Reviews 2014, Issue 5. Art. No.: CD009964. DOI: 10.1002/14651858.CD009964.pub2.

Author Information

  1. 1

    Medical Research Council Unit, Banjul, Gambia

  2. 2

    Luton & Dunstable University Hospital NHS Foundation Trust, Paediatric Department, Luton, UK

*Joseph Okebe, Medical Research Council Unit, P.O. Box 273, Banjul, Gambia. jokebe@mrc.gm.

Publication History

  1. Publication Status: New
  2. Published Online: 29 MAY 2014

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Characteristics of included studies [ordered by study ID]
Gomes 2009

MethodsCommunity-based individually randomized placebo-controlled

Length of follow-up: 7 to 30 days

Mortality was assessed at the clinic and during home visits carried out 7 to 30 days after randomization (median 14 days).


Participants17,826 participants recruited from 291 rural villages in Africa (Ghana, Tanzania; 142) and Asia (Bangladesh; 149)

Intervention group (rectal artesunate)=8954, control group (placebo)= 8872

Number analyzed and reported in trial result: 12,068 (intervention= 6072, control= 5996)

46% of participants (n = 5504) were female and information on gender was missing for two participants; (one in each group).

Age range: 6 to 72 months (African and Asian trial sites); participants > 72 months recruited only from sites in Bangladesh (Asia)

Inclusion criteria: suspected malaria determined by trained resident recruiters, and participants unable to swallow

Exclusion criteria at screening: not stated

Reported baseline characteristics did not show any differences between the trial groups


InterventionsArtesunate (100 mg and 400 mg for the younger children and older children and adults respectively) versus placebo.

Participant received either artesunate or placebo suppository of identical appearance, sealed in a waterproof sachet. After insertion, the buttocks held together for about 10 min to prevent expulsion. Participants were considered included in trial on successful insertion even if the suppository was later expelled


OutcomesMortality at 7 to 30 days after randomization

Permanent disability 7 to 30 days after randomization

Eight participants (0·07%), all in the placebo group, were lost to follow- up.


NotesDifferent malaria transmission characteristics: high (Ghana, Tanzania); low and unstable (Bangladesh)

The trial was conducted between August 2000 and July 2006.

Treatment administered by resident village recruiters with little previous medical knowledge and no research experience; they got monitored by field supervisors

Data for participants > 72 months old were from one site

Access to and quality of available care at referral hospital was notably different between African and Asian sites

Determination of alternative diagnosis was ruled out by expert opinion

Trial Registration: http://www.controlled-trials.com/ISRCTN83979018; http://www.controlled-trials.com/ISRCTN46343627; http://www.controlled-trials.com/ISRCTN76987662


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskused computer generated block-balanced boxes of 4 or 8 random allocations

Allocation concealment (selection bias)Low riskConsecutively numbered treatment boxes

Blinding of participants and personnel (performance bias)
All outcomes
Low riskAll trial staff were blinded until after the endpoints were finalized

Blinding of outcome assessment (detection bias)
All outcomes
Low riskAlthough some participants initially randomized were excluded from analysis, this was done before unblinding.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk5758 (32%) of participants were excluded from the analysis after randomization. This was documented as a pre-unblinding decision in trial publication.

Selective reporting (reporting bias)Low riskThe protocol is available and the trial authors addressed all of the important and pre-specified outcomes

Other biasUnclear riskDifference in age distribution of recruited participants and in proportion of participants without blood slide at recruitment between the African and Asian regions,

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Aceng 2005Rectal artesunate given in hospital

Barnes 2004Rectal artesunate given in hospital and patients with moderate malaria included

Gomes 2010Rectal artesunate given in hospital

Karunajeewa 2006Rectal artesunate given in hospital

Kitua 2010Discussion of Gomes 2009

Krishna 2001Excluded patients with severe malaria

 
Comparison 1. Pre-referral artesunate vs Placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 All cause mortality (all enrolled)117826Risk Ratio (M-H, Fixed, 95% CI)0.89 [0.75, 1.05]

    1.1 Blood smear negative
14648Risk Ratio (M-H, Fixed, 95% CI)0.88 [0.64, 1.21]

    1.2 Antimalarial injection just before randomization
11110Risk Ratio (M-H, Fixed, 95% CI)1.07 [0.68, 1.70]

    1.3 Analyzed in trial report
112068Risk Ratio (M-H, Fixed, 95% CI)0.86 [0.69, 1.06]

 2 All cause mortality (young children)18050Risk Ratio (M-H, Fixed, 95% CI)0.74 [0.59, 0.93]

    2.1 Africa
16040Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.63, 1.04]

    2.2 Asia
12010Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.24, 0.85]

 3 All cause mortality (older children/adults)14018Risk Ratio (M-H, Fixed, 95% CI)2.21 [1.18, 4.15]

 4 Neurodisability (all participants)117280Risk Ratio (M-H, Fixed, 95% CI)0.68 [0.35, 1.30]

    4.1 Excluded in trial analysis
15543Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.62, 3.36]

    4.2 Analyzed in trial report
111737Risk Ratio (M-H, Fixed, 95% CI)0.15 [0.03, 0.67]

 5 Severe malaria on admission (coma, repeated convulsions or prostration)112068Risk Ratio (M-H, Fixed, 95% CI)1.01 [0.90, 1.14]

    5.1 Asia (6 to 72 months)
12010Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.74, 1.30]

    5.2 Asia (older child/adult)
14018Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.81, 1.33]

    5.3 Africa (6 to 72 months)
16040Risk Ratio (M-H, Fixed, 95% CI)1.02 [0.87, 1.19]

 6 Proportion with parasitaemia on admission117826Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.98, 1.02]

 7 Proportion reaching a hospital within 6 hours112068Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.98, 1.01]

    7.1 Africa
16040Risk Ratio (M-H, Fixed, 95% CI)1.00 [0.95, 1.04]

    7.2 Asia
16028Risk Ratio (M-H, Fixed, 95% CI)0.99 [0.98, 1.01]

 
Summary of findings for the main comparison. Pre-referral rectal artesunate compared to placebo for severe malaria

Pre-referral rectal artesunate compared to placebo for preventing deaths from severe malaria

Patient or population: Children and adults with severe malaria
Settings: Rural settings in Africa and Asia
Intervention: Rectal artesunate and referral for further care
Comparison: Placebo and referral for further care

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

PlaceboRectal Artesunate

All cause mortality Children aged 6 to 72 monthsRR 0.74
(0.59 to 0.93)
8050
(1 study)
⊕⊕⊕⊝
moderate1,2,3,4

41 per 100030 per 1000
(24 to 38)

Older children and adultsRR 2.21
(1.18 to 4.15)
4018
(1 study)
⊕⊕⊝⊝
low1,5,6

7 per 100015 per 1000
(8 to 29)

NeurodisabilityAll age groupsRR 0.68
(0.35 to 1.30)
17,280
(1 study)
⊕⊕⊝⊝
low1,7

3 per 10002 per 1000
(1 to 4)

*The assumed risk is the control group risk from the single included study. The corresponding risk (and its 95% CI) is based on the assumed risk in the control 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.

 1 No serious risk of bias: Allocation was concealed and trial participants and staff were blinded to treatment allocation.
2 Downgraded by 1 for serious inconsistency: In both Africa and Asia there was a trend towards benefit with rectal artesunate in this age group. However in Africa, where most of the deaths occurred, and where almost half of participants failed to reach secondary care within six hours, the magnitude of the effect was smaller and did not reach statistical significance (RR 0.81; 95% CI 0.63 to 1.04).
3 No serious indirectness: Children aged 6 to 72 months were recruited from community settings in Tanzania, Ghana and Bangladesh.
4 No serious imprecision: The overall result reached statistical significance and was adequately powered to detect this effect.
5 Downgraded by 1 for serious indirectness: Older children and adults were only recruited from community settings in Bangladesh. This result may not easily be generalized to elsewhere.
6 Downgraded by 1 for serious imprecision: There were very few deaths in this group, and the trial was underpowered to detect this effect.
7 Downgraded by 1 for serious imprecision: Too few events, wide confidence interval, single site.
 
Table 1. Differences Between African and Asian sites

FeatureAfricaAsia

Number analyzed in trial report60406028

Participants aged 6 to 72 months60402010

Participants above 72 months04018

Number without a blood slide10208

Death within 6 hours after enrolment8127

Not reached a hospital within 6 hours after randomization2686399