Intervention Review

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Antibiotics for trachoma

  1. Jennifer R Evans*,
  2. Anthony W Solomon

Editorial Group: Cochrane Eyes and Vision Group

Published Online: 16 MAR 2011

Assessed as up-to-date: 11 DEC 2010

DOI: 10.1002/14651858.CD001860.pub3


How to Cite

Evans JR, Solomon AW. Antibiotics for trachoma. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD001860. DOI: 10.1002/14651858.CD001860.pub3.

Author Information

  1. London School of Hygiene & Tropical Medicine, Cochrane Eyes and Vision Group, ICEH, London, UK

*Jennifer R Evans, Cochrane Eyes and Vision Group, ICEH, London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, UK. jennifer.evans@lshtm.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 16 MAR 2011

SEARCH

 
Characteristics of included studies [ordered by study ID]
ACT 1999 Egypt

MethodsAllocation: random within one matched pair.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no.

Exclusions after randomisation: no.
Losses to follow up: yes, temporary absence.


ParticipantsCountry: Egypt.

Number randomised: 2238.
Age (ave.): all ages.
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: LCR.

Inclusion criteria: all villagers present.
Exclusion criteria: none, but alternative treatment for azithromycin-allocated women at childbearing age.


InterventionsTREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg up to 1 g.
Duration: once a week for 3 weeks. Women of childbearing age erythromycin for 14 days, 500 mg twice daily or 250 mg four times daily (amoxicillin in case of intolerance).

COMPARISON: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: once daily for 6 weeks.


OutcomesPrimary: active trachoma.
Secondary: infection.


Notes“Compliance was good for all groups, except the tetracycline treatment village in Egypt (table 2)." (page 633). From table 2, the percentage receiving at least 1 dose of azithromycin was 95% and the percentage receiving 28 applications of tetracycline was 59.5%.

Only one pair of villages randomised.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
High riskThe treatments were quite different - oral versus topical. No measures were reported to mask study participants and personnel from knowledge of which intervention a participant received.

Blinding?
Ocular Chlamydia trachomatis infection
Low risk“Laboratory staff were not aware of the clinical and treatment status of study participants” and “Identification numbers for laboratory samples differed from those used on the ocular examination forms to conceal village and treatment status from the laboratory staff” (page 632).

Incomplete outcome data addressed?
Active trachoma
High risk"Some individuals or families could not be reached at scheduled treatment times (they worked out of town, had moved away on a temporary or permanent basis, or were working in the fields when the teams were present). There were some refusals at all sites.” Egypt: "little movement was documented" (page 633).

From table 6 (page 633): 92% of azithromycin group and 86% of tetracycline group had assessment of active trachoma at baseline. At one year, 87% of azithromycin group and 75% of tetracycline group had data on active trachoma.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
High riskFrom table 4 (page 632): 81% of azithromycin group and 58% of tetracycline group had assessment of ocular infection after treatment. At one year, 80% of azithromycin group and 69% of tetracycline group had data on ocular infection.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Recruitment bias addressed?Unclear riskRecruitment bias was not specifically addressed in the report however the following statement was made “At all study sites we attempted to treat every individual present in each village” (Schachter page 631).

The following data were available in the report which suggests that recruitment bias may have been a possibility.

A=Azithromycin group T=tetracycline group, numbers expressed as % of pre-study census.

Pre-study census: A: 1179 T: 1212

At time of treatment: A: 1139 (97%) T: 1099 (91%)

Baseline clinical trachoma status: A: 1080 (92%) T: 1044 (86%)

Compliance (at least 1 dose azithromycin or 28 applications of tetracycline) A: 95% T:60%

Baseline imbalances addressed?Low risk"In each of the endemic areas, pairs of villages were matched on the basis of an initial rapid assessment of the trachoma rate among children aged between 1 and 10 years. One member of each village pair was randomly assigned mass treatment with oral azithromycin, with the other receiving the topical tetracycline regimen; in each village we generated a random number for each and took the number closest to one to be assigned azithromycin". (Schachter page 631). However, note in Egypt only 2 clusters were randomised.

Baseline comparability of clusters not reported in Schachter but “[...], we have done multivariate analyses, which adjust for clustering of individual within households and for co-variates that may affect an individuals’ risk of being infected with chlamydia (LCR positive) at 1 year. The assumption underlying these models is that after adjustment for covariates there are no village characteristics, other than treatment type, that affect the risk of positivity at 1 year after treatment" (Schachter page 632).

ACT 1999 Tanzania

MethodsAllocation: random within one matched pair.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no.

Exclusions after randomisation: none
Losses to follow up: yes, temporary absence.


ParticipantsCountry: Tanzania.

Number randomised: 3261.
Age (ave.): all ages.
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: LCR.

Inclusion criteria: all villagers present.
Exclusion criteria: none, but alternative treatment for azithromycin-allocated women at childbearing age.


InterventionsTREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg up to 1 g.
Duration: once a week for 3 weeks. Women of childbearing age erythromycin for 14 days, 500 mg twice daily or 250 mg four times daily (amoxicillin in case of intolerance).

COMPARISON: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: once daily for 6 weeks.


OutcomesPrimary: active trachoma.
Secondary: infection.


NotesOnly one pair of villages randomly allocated to treatment.

High population movement.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
High riskThe treatments were quite different - oral versus topical. No measures were reported to mask study participants and personnel from knowledge of which intervention a participant received.

Blinding?
Ocular Chlamydia trachomatis infection
Low risk“Laboratory staff were not aware of the clinical and treatment status of study participants” and “Identification numbers for laboratory samples differed from those used on the ocular examination forms to conceal village and treatment status from the laboratory staff” (page 632).

Incomplete outcome data addressed?
Active trachoma
High riskSome individuals or families could not be reached at scheduled treatment times (they worked out of town, had moved away on a temporary or permanent basis, or were working in the fields when the teams were present). There were some refusals at all sites (page 633).

From table 6 ( page 633): 78% of azithromycin group and 88% of tetracycline group had assessment of active trachoma at baseline. At one year, 60% of azithromycin group and 77% of tetracycline group had data on active trachoma.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
High riskFrom table 4 ( page 632): 58% of azithromycin group and 78% of tetracycline group had assessment of ocular infection after treatment. At one year, 45% of azithromycin group and 61% of tetracycline group had data on ocular infection.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Recruitment bias addressed?Unclear riskRecruitment bias was not specifically addressed in the report however the following statement was made “At all study sites we attempted to treat every individual present in each village” (Schachter page 631).

The following data were available in the report which suggests that recruitment bias may have been a possibility.

A=Azithromycin group T=tetracycline group, numbers expressed as % of pre-study census.

Pre-study census: A: 2167 T: 1179

At time of treatment: A: 2161 (100%) T: 1100 (93%)

Baseline clinical trachoma status: A: 1696 (78%) T: 1036 (88%)

Compliance (at least 1 dose azithromycin or 28 applications of tetracycline) A: 89% T: 90%

Baseline imbalances addressed?Low riskBaseline comparability of clusters not reported in Schachter but “[...], we have done multivariate analyses, which adjust for clustering of individual within households and for co-variates that may affect an individuals’ risk of being infected with chlamydia (LCR positive) at 1 year. The assumption underlying these models is that after adjustment for covariates there are no village characteristics, other than treatment type, that affect the risk of positivity at 1 year after treatment." (Schachter page 632).

ACT 1999 The Gambia

MethodsAllocation: random within four matched pairs.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no.

Exclusions after randomisation: no.
Losses to follow up: yes, temporary absence.


ParticipantsCountry: The Gambia.

Number randomised: 1753.
Age (ave.): all ages.
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: LCR.

Inclusion criteria: all villagers present.
Exclusion criteria: none, but alternative treatment for azithromycin-allocated women at childbearing age.


InterventionsTREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg up to 1 g.
Duration: once a week for 3 weeks. Women of childbearing age erythromycin for 14 days, 500 mg twice daily or 250 mg four times daily (amoxicillin in case of intolerance).

COMPARISON: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: once daily for 6 weeks.


OutcomesPrimary: active trachoma.
Secondary: infection.


NotesVery high migration rate.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
High riskThe treatments were quite different - oral versus topical. No measures were reported to mask study participants and personnel from knowledge of which intervention a participant received.

Blinding?
Ocular Chlamydia trachomatis infection
Low risk“Laboratory staff were not aware of the clinical and treatment status of study participants” and “Identification numbers for laboratory samples differed from those used on the ocular examination forms to conceal village and treatment status from the laboratory staff” (Schachter page 632).

Incomplete outcome data addressed?
Active trachoma
High riskAll clusters completed the trial in theory although one cluster allocated to azithromycin had very poor follow-up (0% at 12 months). 

Some individuals or families could not be reached at scheduled treatment times (they worked out of town, had moved away on a temporary or permanent basis, or were working in the fields when the teams were present). There were some refusals at all sites (Schachter page 633).

From table 6 (Schachter page 633): 91% of azithromycin group and 82% of tetracycline group had assessment of active trachoma at baseline. At one year, 65% of azithromycin group and 50% of tetracycline group had data on active trachoma.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
High riskFrom table 4 (Schachter page 632): 61% of azithromycin group and 54% of tetracycline group had assessment of ocular infection after treatment. At one year, 47% of azithromycin group and 36% of tetracycline group had data on ocular infection.

Fraser-Hurt: Individual factors statistically associated with attendance at none or only one of the three post-treatment surveys were increasing age (P = 0.02), Wolof ethnicity (P < 0.001), absence of active trachoma at baseline (P = 0.001), and non-compliance with treatment (P = 0.06).

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Recruitment bias addressed?Unclear risk“All residents who were present at the pre-treatment survey were eligible for participation in the trial.” (Fraser-Hurt).

“At all study sites we attempted to treat every individual present in each village” (Schachter page 631).

Baseline imbalances addressed?Low risk“In each of the endemic areas, pairs of villages were matched on the basis of an initial rapid assessment of the trachoma rate among children aged between 1 and 10 years. One member of each village pair was randomly assigned mass treatment with oral azithromycin, with the other receiving the topical tetracycline regimen; in each village we generated a random number for each and took the number closest to one to be assigned azithromycin” (Schachter page 631).  

“The villages were matched in pairs of similar size, and azithromycin and tetracycline were allocated randomly within these pairs.” (Fraser-Hurt page 633). Baseline comparability of clusters reported (Fraser-Hurt table 1 page 635). There were some baseline imbalances but these were controlled for in the analysis: “Point estimates of the odds ratio for the comparison of azithromycin with tetracycline, adjusted for age, latrine ownership and, where appropriate, trachoma status at baseline, were obtained using logistic regression with individual records.” (Fraser-Hurt page 634).

Baseline comparability of clusters not reported in Schachter but “[...], we have done multivariate analyses, which adjust for clustering of individual within households and for co-variates that may affect an individuals’ risk of being infected with chlamydia (LCR positive) at 1 year. The assumption underlying these models is that after adjustment for covariates there are no village characteristics, other than treatment type, that affect the risk of positivity at 1 year after treatment." (Schachter page 632).

Atik 2006

MethodsAllocation: random allocation of surgery or surgery plus antibiotics.

Unit of randomisation: commune.

Masking:
participant - no,
provider - no,
outcome - unclear.

Exclusions after randomisation: no.
Losses to follow up: unclear.


ParticipantsCountry: Vietnam.

Number randomised: 2 communes randomised; 1851 people enrolled in the study.

Age: 6 months and older.
Sex: approximately 60% female.

Clinical grading: Thylefors 1987.
Lab tests:Amplicor-PCR (polymerase chain reaction) assay (Roche Diagnostics, Branchburg, NJ) of conjunctival samples.

Inclusion criteria: all ages 6 months and older.
Exclusion criteria: none, but pregnant women received erythromycin.


InterventionsAzithromycin 20 mg/kg for children; 1 g for adults. Pregnant women received erythromycin.

All commune residents older than 6 months were included in the study. There were 2 components to the assessment and intervention. The first component involved examination of all schoolchildren aged 5 through 15 years; children who had active trachoma defined as follicular inflammation, intense inflammation, or both were considered index cases. The second component included examination of the remaining individuals either at a central commune or village site.

Index cases and their household members were treated with a single oral dose of azithromycin at baseline and 12 months. Non–index cases and non-household members who had active trachoma (follicular inflammation, intense inflammation, or both) received topical tetracycline.

In the control community trachomatous trichiasis cases were identified and informed of the availability of surgery. All patients who had active trachoma (follicular inflammation, intense inflammation, or both) received topical tetracycline.


OutcomesActive trachoma and C. trachomatis infection.


NotesOnly two communes compared.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
Unclear riskThe interventions were not masked but the communes were “geographically isolated from one another” (page 1489).  It was not clear if the participants were aware of the existence of other potential interventions.

"At each time point of the study, all participants were examined by an ophthalmologist and graded for trachoma in a masked fashion using a modified grading scale" (page 1489).

However, the extent to which the ophthalmologist might be aware of what treatment the community had received was not discussed.

Blinding?
Ocular Chlamydia trachomatis infection
Low risk"Samples were labelled with date and a unique identification number to maintain confidentiality and to process samples in a masked fashion" (page 1489).

Incomplete outcome data addressed?
Active trachoma
High riskBoth clusters completed the trial. Response rates were not reported explicitly.

The following gives the total population and the percentage graded for trachoma at baseline, 6 months, 12 months and 24 months (from table 1 and figure 2).

Azithromycin community: total = 659: 100%; 86%;79%;56%.

Untreated community: total=1192; 100%; 89%; 83%; 72%.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
High riskThe following gives the total population and the percentage graded for ocular infection at baseline, 6 months, 12 months and 24 months (from table 1 and figure 2).

Azithromycin community: total = 659: 98%;79%;100%;52%.

Untreated community: total=1192; 95%; 76%; 100%; 71%.

A response rate of 100% at one year is unusual and might suggest that some of the people assessed at one year were not present at census. it is also surprising that both communities had 100% follow-up at the same time point.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Recruitment bias addressed?Unclear risk“selected communes were geographically isolated from one another” (page 1489) and “All commune residents older than 6 months were included in the study” (page 1489) however no information on response rates were given so it is not clear how many of the residents actually took part in the study.

Baseline imbalances addressed?High riskOnly two clusters included in the trial so no pair-matching. Baseline comparability of clusters was reported with respect to sex and trachoma only (table 1 page 1491). There was a higher baseline prevalence of active trachoma in people aged > 15 in the control cluster (10.6% versus 3.6% P < 0.001) and higher baseline prevalence of active trachoma in children 5-15 years in the intervention cluster (9.2% versus 4.7% P = 0.033). Statistical adjustment was made for sex, age, and having at least one person with chlamydial infection in the household.

Attiah 1973

MethodsAllocation: stratified random.
Unit of randomisation: individual.

Masking:
participant - no,
provider - yes,
outcome - yes.

Exclusions after randomisation: no.
Losses to follow-up: 0.
Unusual study design: follow up right after treatment termination, over two weeks.


ParticipantsCountry: Egypt

Number randomised: 228.
Age (ave.): 6 to 12 years.
Sex: not reported.

Clinical grading: WHO.
Lab tests: none.

Inclusion criteria: active trachoma or 'undetermined case'.
Exclusion criteria: none.


InterventionsTREATMENT 1: tetracycline derivative GS2989.
Administration: topical.
Dose: 0.25%.
duration: once every school day for 11 weeks.

TREATMENT 2: terramycin.
Administration: topical.
Dose: not reported.
Duration: once every school day for 11 weeks.

COMPARISON: no treatment.
Administration: not applicable.
Dose: not applicable.
Duration: not applicable.


OutcomesPrimary: active trachoma.
Secondary: -
Adverse effects: n.a.


NotesTreatment irregular, although intended for every school day.

One village - no description of why it was chosen. Only school children. 228 subjects divided into 11 clinical groups, each of which randomised into three intervention groups. Unclear why 10 weeks and 6 days was felt to be the optimal duration of therapy.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskNot reported

Blinding?
Active trachoma
Unclear risk"the principle of double blindness ensured in the experiment" (page 11).

"The examiner had no knowledge of the treatment assignment to the groups or of the randomisation process used in the trial" (page 12).

"After three months treatment, the results were checked using WHO criteria without investigators knowing what treatment applied" (page 16).

However, the report gave no indication as to how the groups were masked and whether the control group received any placebo treatment.

Incomplete outcome data addressed?
Active trachoma
Unclear riskReported 100% follow up. This is unusual and could indicate that children who were not followed-up were not reported. However, 100% may be feasible in a school situation. We have left this as "unclear" because we cannot tell which of the two options apply.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskNo data on ocular infection reported.

Free of selective reporting?Low riskClinical examination only and no suggestion that any assessment of ocular infection made.

Free of other bias?Low risk

Bailey 1993

MethodsAllocation: not reported.
Unit of randomisation: unclear "randomisation was by room, all active cases within a room receiving the same treatment" (page 454).

Masking:
participant - no,
provider - no,
outcome - unclear.

Exclusions after randomisation: none.
Losses to follow up: none.


ParticipantsCountry: The Gambia.

Number randomised: 194.
Age: 9 months to 60 years.
Sex: 51% male.

Clinical grading: Dawson 1981.
Lab tests: IDEIA amplified enzyme-linked immunosorbent assay (Dako) for genus-specific lypopolysaccharide antigen.

Inclusion criteria: active trachoma.
Exclusion criteria: pregnant or lactating.


InterventionsOral azithromycin single-dose 20 mg/kg.

Topical tetracycline 1% eye ointment twice daily for six weeks. Those with 'severe disease' also received oral erythromycin stearate 250 mg four times daily for two weeks.


Outcomes"resolution of disease".


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskNo information on how the sequence was generated or allocated "Randomisation was by room, all active cases within a room receiving the same treatment" (page 454).

Blinding?
Active trachoma
Unclear riskNo placebos used for either tablets or ointment.  "Subjects were examined [...] by a trained observer (RLB) unaware of treatment allocation" (page 454).

Blinding?
Ocular Chlamydia trachomatis infection
Unclear riskNo specific information on this but as clinical examinations masked it is likely that the laboratory analyses were as well.

Incomplete outcome data addressed?
Active trachoma
Low riskOf 194 subjects randomised, 194 examined at 4 weeks, 194 examined at 8 weeks, 191 examined at 16 weeks, and 193 examined at 26 weeks (one subject had died by that point).

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Low riskOf 194 subjects randomised, 194 examined at 4 weeks, 194 examined at 8 weeks, 191 examined at 16 weeks, and 193 examined at 26 weeks (one subject had died by that point).

Free of selective reporting?Low riskBoth outcomes - infection and clinical disease - reported

Free of other bias?Low risk

Bowman 2000

MethodsAllocation: randomisation by block.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome - yes.

Exclusions after randomisation: no.
Losses to follow up: numbers recorded.


ParticipantsCountry: The Gambia.

Number randomised: 314.
Age: 6 months to 10 years.
Sex: Boys 50%.

Clinical grading: simplified WHO scale 1987.
No lab tests.


InterventionsTREATMENT: single-dose azithromycin 20 mg/kg.

COMPARISON: topical tetracycline applied once by a nurse in front of the care-giver and then twice daily by care-giver for 6 weeks.


OutcomesPrimary: active trachoma.
No secondary outcome.


NotesTrial aim to compare treatments under operational and not best possible conditions.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Low risk“Codes in numbered sealed envelopes were used by the nurse administering treatment to allocate treatment to the subject. The clinical assessors had no knowledge of the randomisation sequence or of the treatment received by previous subjects. Similarly the nurse had no knowledge of the block randomisation procedure and did not examine the children but administered treatment according to the allocation in the envelope.” (page 4075).  

Blinding?
Active trachoma
Low riskInterventions were different - oral dose of azithromycin syrup versus topical tetracycline -so not possible to prevent knowledge to caregivers and participants.  However, eyes were graded by “a clinical assessor blind to the treatment allocation.” (page 4075). 

“Patients were aware of their treatments, and therefore inadvertent unmasking of the clinical assessors at follow-up by the patients was possible. There were no reports of the occurring, however, and the similar cure rate ratios for both clinical and photographic outcome suggest that unmasking and bias were not a significant problem.“ (page 4077).

Incomplete outcome data addressed?
Active trachoma
Low riskFigure 1 (page 4076).

Analysis was not by intention to treat as 4 participants received the wrong allocation and were analysed according to their received treatment not according to their random allocation. However as this number was low it is unlikely to have biased the outcome.

Of 154 children who received tetracycline 15 (10%) were not followed at 6 months; of 160 who received azithromycin 11 (7%) missed follow up. No reason was given for loss to follow up but as this was low and not substantially different between the groups it is unlikely to have caused bias.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskNot enough information provided

Free of selective reporting?Low riskThis study reported one of the primary outcomes for this review - active trachoma. There was no indication that the other outcome C. trachomatis infection was collected but not reported.

Free of other bias?Low risk

Chidambaram 2006

MethodsLongitudinal cohort study conducted March 2003 to March 2005 in the Gurage Zone of Ethiopia. Eight randomly selected villages were assessed for ocular chlamydial infection. Twelve months after treatment, an additional 2 untreated villages were randomly selected from each of the original 8 peasant associations.


ParticipantsAll residents aged 1 year or older.


InterventionsSingle-dose oral azithromycin (1 g in adults/20 mg/kg in children) directly observed treatment. Pregnant
women, children younger than 1 year, and those allergic to macrolides were offered a 6-week course of topical 1% tetracycline ointment (applied twice daily to both eyes, not directly observed).


OutcomesPresence of ocular chlamydial infection in children aged 1 to 5. A random sample of adults were tested at 18 months.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
High riskUnclear whether this outcome was collected.

Blinding?
Ocular Chlamydia trachomatis infection
Unclear riskMasking not reported.

Incomplete outcome data addressed?
Active trachoma
Unclear riskNot applicable - prevalence surveys in selected communities at 12 months.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskNot applicable - prevalence surveys in selected communities at 12 months.

Free of selective reporting?Unclear riskOnly ocular infection reported - data on active trachoma were collected but not reported.

Free of other bias?Low risk

Recruitment bias addressed?Unclear riskNo information on recruitment bias in the report.

Baseline imbalances addressed?Unclear riskDifficult to assess as no data reported and study design is such that information on baseline infection status in control villages not available.

Cochereau 2007

MethodsAllocation: randomisation by block.
Unit of randomisation: individual.

Masking:
participant - yes,
provider - yes,
outcome - yes.

Exclusions after randomisation: yes.
Losses to follow up: numbers recorded


ParticipantsCountry: Guinea-Conakry (comunity) and Pakistan (boys schools only)

Number randomised: 670
Age: 1-10 years.
Sex: 49.8% male

Clinical grading: simplified WHO scale 1987.
No lab tests.


InterventionsAzithromycin 1.5% eye drops 2x daily for 2 days (n=224) and 2x daily for 3 days (n=225) compared to oral azithromycin 20 mg/kg single dose (n=221)


Outcomes% clinical cure in children with clinically active trachoma 2 months after treatment


NotesIn Pakistan only children from boys schools recruited.

Last observation carried forward for missing data.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear risk“The randomisation list used random permuted blocks of six (SAS v 8.2). Within each village, patient numbers were allocated in ascending order using the next available number. Study drugs were identified by patient number using the randomisation list. (Randomisation procedures and treatments p668).

Blinding?
Active trachoma
Low risk“We used a double-dummy design with placebo eye drops and placebo paediatric suspension” (Randomisation procedures and treatments p668).

Incomplete outcome data addressed?
Active trachoma
Low riskFollow-up data reported as follows (figure 1, page 669). Some patients may have more than one reason for not being followed up.

2-day eye drops group (n=224):

·        Did not receive allocated treatment (lost to follow-up) (1)

·        moved to another region (2)

·        probably did not fit inclusion criteria (22)

·        use of other medications (1)

·        non-compliance (2)

·        no follow-up at 2 months (1)

·        number available for analysis (199, 88.8%)

3-day eye drops group (n=225):

·        moved to another region (9)

·        probably did not fit inclusion criteria (23)

·        use of other medications (1)

·        non-compliance (1)

·        no follow-up at 2 months (7)

·        patient request (1)

·        adverse event (1)

·        family member illness (1)

·        number available for analysis (190, 84.4%)

 Oral azithromycin (n=221)

·        moved to another region (9)

·        probably did not fit inclusion criteria (33)

·        non-compliance (2)

·        no follow-up at 2 months (4)

·        patient request (1)

·        adverse event (1)

·        family member illness (1)

·        number available for analysis (179, 81.0%)

Free of selective reporting?High risk“A conjunctival swabbing was taken on days 0, 30 and 60 under strictly sterile conditions and analyzed for Chlamydia trachomatis using a polymerase chain reaction.” Study assessments p668. The PCR used (name of product used if a commercial assay, or details of method if an in-house assay) are not specified, and no data on PCR positivity are provided, other than the statement “Positivity to Chlamydia was not confirmed to be a prognostic factor by the stepwise logistic regression analysis.” (First paragraph, page 669).

Free of other bias?High risk“In order to limit the confounding factors for assessing the outcome of the initial trachoma episode, reinfection risks were strictly controlled. Person coming to the investigation centre with the affected children were to be treated with oral azithromcin. Soap was provided and villagers were informed about well-known environmental risk factors for trachoma” (Randomisation procedures and treatments p668).

However, no information was provided on the numbers of people offered and accepting this treatment and the potential efficacy of this additional intervention. Any imbalance between the two groups in the extent to which this was taken up.

Darougar 1980

MethodsAllocation: randomisation schedule, stratification by age, sex, trachoma intensity, diseased children in family.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome: unclear.

Exclusions after randomisation: yes, poor compliers.
Losses to follow up: not given by group.
Unusual study design: family-based treatment (family members treated but not analysed).


ParticipantsCountry: Iran.

Number randomised: 147.
Age (ave.): pre-school (5.5 years).
Sex: 38% male.
Clinical grading: Darougar 1980, 1981.
Lab tests: culture (Darougar 1970).
Inclusion criteria: active trachoma, residence in study village.
Exclusion criteria: none


InterventionsTREATMENT 1: oxytetracycline.
Administration: topical.
Dose: 1%.
Duration: twice daily for 7 consecutive days every month for 12 months.

TREATMENT 2: doxycycline.
Administration: oral.
Dose: 5 mg/kg.
Duration: one dose per month for 12 months.

COMPARISON: vitamin pills
Administration: oral.
Dose: not reported.
Duration: 1 dose per month for 12 months.


OutcomesPrimary: active trachoma.
Secondary: culture (McCoy cells).
Adverse effects: n.a.


NotesSome data only in graphical form. Data on whole conjunctiva and upper conjunctiva given. Patients with "active trachoma in their whole conjunctiva" were included. Patients with active disease may have been excluded.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskNo information about allocation concealment although the study is described as “double-blind” (abstract page 291).

Blinding?
Active trachoma
Unclear riskNo information about the masking although study is described as “double blind” (see above). Treatments are different - topical versus oral antibiotics versus vitamin tablets - so the participants will not have been masked. 

Blinding?
Ocular Chlamydia trachomatis infection
Unclear riskSee above.

Incomplete outcome data addressed?
Active trachoma
High risk147 patients included; 18 excluded because of inadequate treatment or follow-up; it was not reported to which groups these 18 patients were originally allocated.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
High riskSee above.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Dawson 1969 Sherman

MethodsAllocation: random.
Unit of randomisation: individual.

Masking:
participant: yes,
provider: yes,
outcome: yes.

Exclusions after randomisation: no.
Losses to follow up: -
Unusual study design: two similar studies with few participants each.


ParticipantsCountry: USA.

Number randomised: 29.
Age (ave.): 12 to 21 years.
Sex: not reported.

Clinical grading: MacCallan 1936
Lab tests: IFAT on conjunctival smears.

Inclusion criteria: active disease, boarding at Sherman Institute.
Exclusion criteria: none


InterventionsTREATMENT: trisulphapyrimidines.
Administration: oral.
Dose: 3 daily doses to total 3.5 g/day
Duration: 21 consecutive days

COMPARISON: lactose-placebo.
Administration: oral.
Dose: not reported.
Duration: 3 daily for 3 consecutive weeks.


OutcomesPrimary: active trachoma.
Secondary: positive IFAT (1 - 5 identifiable inclusions per 100 - 1000 cells).


NotesParticipants from Indian reservations.
Numbers need to be read from figures, some not very clear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear risk"At each school, a full-time nurse personally administered all drugs and placebos. All materials were coded, and the identify of drug or placebo remained unknown to subjects, nurse, and physicians throughout the trials until all examination results had been recorded” (page 582). This statement suggests that allocation was concealed however it does not tell us who allocated the treatment.

Blinding?
Active trachoma
Low risk“At each school, a full-time nurse personally administered all drugs and placebos. All materials were coded, and the identify of drug or placebo remained unknown to subjects, nurse, and physicians throughout the trials until all examination results had been recorded” (page 582).

Blinding?
Ocular Chlamydia trachomatis infection
Low riskThe statement above implies that all outcome assessments were masked including laboratory analyses.

Incomplete outcome data addressed?
Active trachoma
Unclear risk36 children took part in one school, 29 in the other. All (100%) were followed up. Theoretically they could have recruited more and had some lost to follow-up which they did not report but it is also possible that in a boarding school environment loss to follow-up would be nil. As we cannot distinguish between these two possibilities we have put unclear.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskSee above

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Dawson 1969 Stewart

MethodsAllocation: random.
Unit of randomisation: individual.

Masking:
participant - yes,
provider - yes,
outcome - yes.

Exclusions after randomisation: no
Losses to follow up: -
Unusual study design: two similar studies with few participants each.


ParticipantsCountry: USA.

Number randomised: 36.
Age (ave.): 12 to 21 years.
Sex: not reported.

Clinical grading: Dawson 1966.
Lab tests: IFAT on conjunctival smears.

Inclusion criteria: active disease, boarding at Stewart School.
Exclusion criteria: none.


InterventionsTREATMENT: trisulphapyrimidines.
Administration: oral.
Dose: 3.5 g/day.
Duration: 3 daily during 3 consecutive weeks.

COMPARISON: lactose-placebo.
Administration: oral.
Dose: not reported.
Duration: 3 daily for 3 consecutive weeks.


OutcomesPrimary: active trachoma.
Secondary: positive IFAT (1 - 5 identifiable inclusions per 100 - 1000 cells).


NotesParticipants from Indian reservations.
Numbers need to be read from figures, some not very clear.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear risk"At each school, a full-time nurse personally administered all drugs and placebos. All materials were coded, and the identify of drug or placebo remained unknown to subjects, nurse, and physicians throughout the trials until all examination results had been recorded” (page 582). This statement suggests that allocation was concealed however it does not tell us who allocated the treatment.

Blinding?
Active trachoma
Low risk“At each school, a full-time nurse personally administered all drugs and placebos. All materials were coded, and the identify of drug or placebo remained unknown to subjects, nurse, and physicians throughout the trials until all examination results had been recorded” (page 582).

Blinding?
Ocular Chlamydia trachomatis infection
Low riskThe statement above implies that all outcome assessments were masked including laboratory analyses.

Incomplete outcome data addressed?
Active trachoma
Unclear risk36 children took part in one school, 29 in the other. All (100%) were followed up. Theoretically they could have recruited more and had some lost to follow up which they did not report but it is also possible that in a boarding school environment loss to follow up would be nil. As we cannot distinguish between these two possibilities we have put unclear.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskSee above.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Dawson 1997

MethodsAllocation: random.
Unit of randomisation: blocks of eight.

Masking:
participant: for azithromycin,
provider: no,
outcome: yes.

Exclusions after randomisation: no.
Losses to follow up: absence in village/not found.
Unusual study design: oral placebo for different azithromycin regimens, no placebo for topical treatment.


ParticipantsCountry: Egypt.

Number randomised: 168.
Age (ave.): 2 to 10 years (4).
Sex: 59.5% male.

Clinical grading: Thylefors 1987.
Lab tests: Thylefors 1987; Dawson 1981.

Inclusion criteria: active trachoma, two to 10 years, resident in a study village.
Exclusion criteria: missing baseline record.


InterventionsTREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg
Duration: single dose; or single dose weekly for 3 weeks; or single dose monthly for six months

COMPARISON: Oxytetracycline/polymyxin + oral placebo.
Administration: topical.
Dose: oxytetracycline 1%/polymyxin 10,000 units/g.
Duration: once daily for 5 consecutive days every 28 days for 6 times.


OutcomesPrimary: active trachoma.
Secondary: elementary bodies ≤ 200 or > 200 on conjunctival smears.
Adverse effects: -


NotesEpidemic of purulent conjunctivitis at 8/12 years; cut-off for positivity not justified.
Three azithromycin regimens analysed together.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear risk"This clinical trial was double-masked, placebo-controlled, and randomized” (page 364). However, no information about allocation concealment given. Treatment groups were different, for example, no  ointment placebo and different dosing schedules for oral antibiotic.

Blinding?
Active trachoma
Unclear risk“Ophthalmologists experienced in the diagnosis of trachoma performed all examinations and were masked as to the treatment used” (page 365). However, no details of the masking were given and theoretically, as the treatments were different, the examiners could have been unmasked by their patients.

Blinding?
Ocular Chlamydia trachomatis infection
Low riskAssessment of conjunctival specimens will have been easier to mask.

Incomplete outcome data addressed?
Active trachoma
Low riskFollow-up rates at 12 months were good from 91% to 98%. Ointment group 42/43, one oral dose 39/40, 3 oral doses 39/43, 6 oral doses 39/42. The groups with larger number of oral doses had lower follow-up rates but these were only 4 and 3 children respectively.

“In most cases, children were lost to follow-up at specific examinations because they and their family were not in the village or because the child could not be found on the day of the examination.” (page 365). 

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Low riskSee above.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Foster 1966

MethodsAllocation: random.
Unit of randomisation: individuals.

Masking:
participant: no,
provider: no,
outcome: yes.

Exclusions after randomisation: not reported.
Losses to follow-up: yes.


ParticipantsCountry: USA.

Number randomised: approx. 305.
Age (ave.): 8 to 20 years.
Sex: not reported.

Clinical grading: Thygeson 1960.
Lab tests: -

Inclusion criteria: active trachoma, studying in a study school.
Exclusion criteria: none.


InterventionsTREATMENT 1: sulphamethoxypyridazine.
Administration: oral.
Dose: 0.5 g.
Duration: once daily for 5 consecutive days every week for 3 weeks.

TREATMENT 2: tetracycline.
Administration: topical.
Dose: 1%.
Duration: 3 times daily on 5 consecutive days every week for 6 weeks.

COMPARISON: no treatment.


OutcomesPrimary: active trachoma.
Secondary: none.
Adverse effects: not recorded.


NotesParticipants boarding.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskNot reported.

Blinding?
Active trachoma
Unclear riskThe treatments were different so the students will have known which treatment they received (oral versus topical antibiotic).

Clinical outcome: “The examiner had no knowledge of the earlier findings or of the nature of the treatment of the students being examined, and the order of the examinations was randomised” (page 452). 

Potential for the examiners being told by students which treatment they received.

Incomplete outcome data addressed?
Active trachoma
High riskA total of 457 active cases were identified but only results reported for 325 (71%) “For the purpose of analysis, only the 325 students who were examined on all three occasions are included in Tables 3,4 and 5.” (page 452 and 453).

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskNo data on ocular infection reported.

Free of selective reporting?Low riskOnly clinical outcomes recorded but no indication of any assessment of ocular infection.

Free of other bias?Low risk

Hoshiwara 1973

MethodsAllocation: random.
Unit of randomisation: individual.

Masking:
participant - yes,
provider - yes,
outcome - yes.

Exclusions after randomisation: no.
Losses to follow up: poor compliance, lack of sample.


ParticipantsCountry: USA.

Number randomised: 120.
Age (ave.): 7 to 13 years (9.9).
Sex: not reported.

Clinical grading: Dawson 1969.
Lab tests: IFAT on scrapings of upper tarsal conjunctival epithelium.

Inclusion criteria: active disease, boarding at study school.
Exclusion criteria: none


InterventionsTREATMENT: doxycycline.
Administration: oral.
Dose: 2.5-4.0 mg/kg.
Duration: once daily for 5 consecutive days every week up to 28 doses in 40 days.

COMPARISON: placebo.
Administration: oral.
Duration: once daily for 5 consecutive days every week up to 28 doses in 40 days.


OutcomesPrimary: active trachoma.
Secondary: TRIC-positive immunofluorescent inclusions.

Adverse effects: anorexia, nausea, vomiting or diarrhoea.


NotesParticipants boarding.
Placebo with 'strong beneficial effect'.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskAlthough the drugs were identical appearance and taste and coded A/B (see below) it was not clear how they were allocated, for example, whether they were sequentially numbered.

Blinding?
Active trachoma
Unclear risk“Doxycycline capsules (50 mg) and a placebo of identical appearance and taste were used. Medications were coded as Drug A or Drug B, and the identity remained unknown to subjects, physicians and nursing personnel until the results of all examination had been recorded.“ (page 221).

However, since there was a marked improvement in the doxycycline-treated group and the drugs were only labelled A or B, the identity of the active drugs may well have been obvious well before the end of the trial.

Blinding?
Ocular Chlamydia trachomatis infection
Low risk“Doxycycline capsules (50 mg) and a placebo of identical appearance and taste were used. Medications were coded as Drug A or Drug B, and the identity remained unknown to subjects, physicians and nursing personnel until the results of all examination had been recorded.“ (page 221).

Laboratory analyses will have been easier to mask effectively,

Incomplete outcome data addressed?
Active trachoma
High risk120 students randomised and 103 (86%) followed up: 54 placebo and 49 active treatment. However, not clear what the original random allocations were.

“The others had to be eliminated because of definite gaps in intake of medication, because serum levels or drug could not be documented, or because they were unavailable for one or more follow-up examinations“ (page 222).

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
High riskSee above.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

Lee 2007

MethodsAllocation: random.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no (active trachoma), yes (C.trachomatis infection).

Exclusions after randomisation: no.
Losses to follow up: no information.


ParticipantsCountry: Ethiopia.

Number randomised: 3 villages in each group; 170 children examined in treated villages and 185 in control villages.
Age: 1 to 5 years.
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: Amplicor polymerase chain reaction (PCR; Roche Diagnostics, Branchburg, NJ).

Inclusion criteria:
Exclusion criteria:


InterventionsTREATMENT: azithromycin "mass treatment" so presumably whole community treated not just the children.
Administration: oral.
Dose: not stated.
Duration: two doses per year.

COMPARISON: no treatment.


OutcomesPrimary: ocular chlamydial infection.


Notes3 villages randomly selected for treatment as part of national control programme. 3 villages randomly selected out of villages not yet enrolled in national programme for examination as controls.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
High riskIn treated villages children were given oral antibiotic. In control villages, treatment was planned for a later date. So children would have known whether or not they had been treated and probably the person conducting the clinical examinations would also have known which villages had been treated.

Blinding?
Ocular Chlamydia trachomatis infection
Low risk“All samples were processed in a masked manner” (page 129).

“Samples and controls were labelled with random numbers for processing by masked laboratory personnel.” (page 130).

Incomplete outcome data addressed?
Active trachoma
Unclear riskStudy design - random selection of 3 treated villages and 3 as yet untreated villages in a trachoma control program for survey - meant that all clusters by definition completed the trial.

No information on numbers of children in villages and percentage seen in survey given so difficult to tell.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskSee above.

Free of selective reporting?Unclear riskBoth microbiological and clinical outcomes collected but only microbiological outcomes reported. However, this appeared to be the main purpose of the trial so it is not clear that this was selective outcome reporting as such.

Free of other bias?Low risk

Recruitment bias addressed?Unclear risk“All children 1-5 years of age were identified through the census and requested to come to a central location with a guardian.” (page 129).

No information given on response rates to this request for participation.

Baseline imbalances addressed?Unclear riskStratified or pair-matched randomisation of clusters was not employed.  No baseline characteristics other than prevalence of infection (1) in the conjunctivae of children and (2) in flies caught from children’s eyes were reported.

Peach 1986

MethodsAllocation: stratified randomisation.
Unit of randomisation: community but analysed as individuals.

Masking:
participant - no,
provider - no,
outcome: no.

Exclusions after randomisation: no.
Losses to follow up: yes.


ParticipantsCountry: Australia.

Number randomised: 641.
Age: children 5 to 14 years (plus 5% under 5 and 5% over 14).
Sex: not reported.
Grading: local version with at least one follicle or some papillary hypertrophy being positive.
No lab tests.


InterventionsTREATMENT: oily tetracycline daily for 5 days once a month for 3 months.

COMPARISON: no treatment.


OutcomesPrimary: active trachoma.


NotesOne arm of a larger trial with components face washing and face washing plus antibiotics.


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
Unclear riskTopical antibiotics versus observation. Communities will have known which treatment group.

“The trachoma workers did not know what treatment program, if any, had been allocated to a particular community and communities were visited in the same order in which they had initially been screened.“ (page 76).

Incomplete outcome data addressed?
Active trachoma
Low riskNo information on the clusters.

“Children lost to follow-up were assumed to have follicles and were included in the analysis on that basis” (page 76).

22/211 (10%) were lost to follow-up in control communities. 34/374 (9%) lost to follow-up in treated communities. These were not large losses to follow up and the assumption that they all have active trachoma is a conservative one which is why we have put yes here.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskNo data on ocular infection reported.

Free of selective reporting?Low riskOnly clinical outcomes reported but no indication of any collection of data on microbiological outcomes.

Free of other bias?Low risk

Resnikoff 1995

MethodsAllocation: random.
Unit of randomisation: village.

Masking:
participant - no,
provider - no,
outcome - no.

Exclusions after randomisation: no information.
Losses to follow-up: no information.


ParticipantsCountry: Mali.

Number randomised: 4 villages randomly allocated to four different interventions. 2 villages only eligible for inclusion in this review.
Age: 1 to 5 years.
Sex: not reported.

Clinical grading: Thylefors 1987.
Lab tests: none.

Inclusion criteria: all inhabitants.
Exclusion criteria: none.


InterventionsTREATMENT: 1% oxytetracycline eye drop solution (Innolyre). 1 drop 4 times daily for 7 days a month for 6 months. Directly supervised by village workers.

COMPARISON: no treatment.


OutcomesPrimary: active trachoma.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Blinding?
Active trachoma
High riskThis was not reported so we have assumed that it did not happen as treatment was compared to no treatment.  The study was described as “open controlled clinical trial” (page 103).

Incomplete outcome data addressed?
Active trachoma
High risk“At the initial examination, 1810 subjects were enrolled and examined” (page 104).  Of these, 424 were from the community treated with topical antibiotics (village 2) and 476 were from the control community (village 4) (table 2 page 109).

“A total of 347 subjects with active trachoma were included in the clinical trial. Two hundred and sixty five (76%) of these subjects were successfully followed for 6 months and were included in the analysis of the results.” (page 105).

However, the distribution of these cases by village is not reported. Using figure 1 (page 109) we can estimate that there were 89 cases of active trachoma in treatment community and 90 cases in control community. The “cure rate” in treatment village was 82% (estimated 73 people cured) and 36% in control community (estimated 33 people cured). 

No information was given on possible reasons for loss to follow up.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskNo data on ocular infection reported.

Free of selective reporting?Low riskOnly clinical outcomes reported but no indication that microbiological data collected.

Free of other bias?Low risk

Recruitment bias addressed?Unclear risk“With the permission of administrative and traditional authorities, all inhabitants of these four villages were surveyed” (page 102). 

No other information on recruitment in particular no indication as to response rates of the survey in the villages concerned.

Baseline imbalances addressed?High risk“Four villages, matched for size and epidemiological, economic and social conditions, were included in the study. All villages were situated the same distance from the health centre and each village possessed a school and was equipped with boreholes.” (page 102) (NB: two of these villages concerned health education and data from these not included in this review).

“The age and sex distribution was identical in all four villages” (page 103). Table 2 (page 109) shows the sex distribution (46% male in treatment community and 51% male in control community). No data on age distribution.

Baseline prevalence of active trachoma (figure 1, page 109) just over 20% in treatment community and just under 20% in control community.

Shukla 1966

MethodsType of trial: clinical.

Allocation: random.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome: - unclear.

Exclusions after randomisation: no.
Losses to follow up: none.
Unusual study design: four-armed trial with factorial design.


ParticipantsCountry: India.

Number randomised: 349.
Age (ave.): 5 to 13 years.
Sex: not reported.

Clinical grading: WHO 1962.
Lab tests: none.

Inclusion criteria: active trachoma, schooling at a study school.
Exclusion criteria: none.


InterventionsTREATMENT 1: sulphafurazole + sulphadimethoxine.
Administration: topical + oral.
Dose: 15%/100 mg/kg.
Duration: twice daily for 5 consecutive days every month for 5 months/bi-weekly for 5 months.

TREATMENT 2: sulphadimethoxine.
Administration: oral.
Dose: 100 mg/kg.
Duration: biweekly or weekly dose for 5 months.

TREATMENT 3: sulphafurazole.
Administration: topical.
Dose: 15%.
Duration: twice daily for 5 consecutive days every month for 5 months.

COMPARISON: no treatment.


OutcomesPrimary: active trachoma.
Secondary: -


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskNo information given .

Blinding?
Active trachoma
High riskNo information given and treatments different in the different groups so study unlikely to have been blinded.  However, study is described as “double-blind study”.

Incomplete outcome data addressed?
Active trachoma
Unclear riskApparently 100% follow up with exception of one group B1 at five months where 35/41 seen.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskNo data on ocular infection reported.

Free of selective reporting?Low riskOnly clinical outcomes reported but no indication that microbiological data collected.

Free of other bias?Unclear riskReport too brief to assess.

Tabbara 1996

MethodsType of trial: clinical.

Allocation: random.
Unit of randomisation: individual.

Masking:
participant - no,
provider - no,
outcome - yes.

Exclusions after randomisation: no.
Losses to follow up: absence.


ParticipantsCountry: Saudi Arabia.

Number randomised: 64.
Age (ave.): 6 to 14 years (11.1).
Sex: not reported.

Clinical grading: Dawson 1981.
Lab tests: conjunctival scrapings for inclusion bodies/cells/organisms/mucus; IFAT for free elementary bodies.

Inclusion criteria: active trachoma, schooling in study village.
Exclusion criteria: none.


InterventionsTREATMENT: azithromycin.
Administration: oral.
Dose: 20 mg/kg.
Duration: 1 dose.

COMPARISON: tetracycline.
Administration: topical.
Dose: 1%.
Duration: twice daily for 5 consecutive days per week over 6 weeks.


OutcomesPrimary: active trachoma.
Secondary: intraepithelial cell inclusion bodies, free elementary bodies.
Adverse effects: none.


NotesCase definition not clear (probable diagnosis of trachoma based on cytology, definitive diagnosis of trachoma based on microscopical assessment of scrapings).


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskNot reported.

Blinding?
Active trachoma
Unclear riskStudy was described as “single-masked” (page 843). Patients were aware of therapy because oral versus topical treatment.

“The examiner was unaware of the treatment allocation at the time of the examination” (page 843).

No information on whether the masking was effective - for example, did the patients tell the examiners which treatment they had received?

Blinding?
Ocular Chlamydia trachomatis infection
Low risk“Conjunctival scrapings were obtained from each patient before initiation of therapy" “The slides were coded and masked to the reader” (page 843).

Incomplete outcome data addressed?
Active trachoma
Unclear riskIt was not clear how many randomised to treatment/control but reported percentages suggest that it was 32 in each group.

8 weeks: treatment 2/32 (6.3%) and control 5/32 (15.6%) lost to follow up.

12 weeks: treatment 1/32 (3.1%) and control 3/32 (9.4%) lost to follow up.

24 weeks: treatment 2/32 (6.3%) and control 6/32 (18.8%) lost to follow up.

Higher loss to follow up in control group but actual numbers not very large. No indication as to reason for not being seen. We have put “unclear” here because not sure what the effect of these missing data will be.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskSee above.

Free of selective reporting?Low riskBoth outcomes of relevance to this review reported.

Free of other bias?Low risk

TANA 2009

MethodsCluster-randomised trial. 72 subkebeles (government defined units) randomised to treatment or delayed treatment. Six treatment groups of 12 subkebeles each.


ParticipantsPeople resident in these communities. Different members of the population were treated according to the treatment schedule being tested (see interventions below).


Interventions(1) Children aged 1-10 were offered oral azithromycin 4 times per year. Height based dosing equivalent to roughly 20 mg/Kg. Treatment directly observed. Children younger than 1 year were offered a 6-week course of topical tetracycline 1% (not directly observed). Children and adults aged 11 years and above were assessed for ocular chlamydial infection at 12 months.

(2) Treatment was delayed and delivered at 12 months. Children and adults aged 11 years and above were assessed for ocular chlamydial infection at 12 months.

(3) Annual mass treatment. All individuals aged 1 year and older were offered oral azithromycin as for (1). Women self-reporting as pregnant or children under 1 year offered topical tetracycline.

(4) Biannual mass treatment as for (3).

[Treatment groups (5) and (6) refer to evaluation of benefits of added Intensive latrine construction and are outwith the remit of this review).]

The following information about the overall study aims was obtained from the trial registration information on ClinicalTrials.gov.

"The proposed study is a group-randomized trial to determine the frequency and treatment target of community-wide mass antibiotic treatment to eliminate trachoma. We will also study the impact of community-wide antibiotic distribution on antibiotic-resistance in pneumococcus. Communities in Goncha Siso Enese district of East Gojam Zone, Ethiopia will be randomly assigned to different treatment schemes and monitored to study the following research questions:

Specific Aim 1. To determine whether biannual mass treatments is more likely to eliminate ocular chlamydia from hyper-endemic communities than annual mass treatments.

Specific Aim 2. To determine whether children form a core group for the transmission of trachoma.

Specific Aim 3. To determine whether latrine construction prevents the return of infection into a community after mass treatment.

Specific Aim 4. To determine the effect of mass azithromycin treatments on antibiotic resistance in pneumococcus and the reduction in mortality."

As at April 2010, there are two publications available from this study. House et al addresses study aim 2 but has a slightly different emphasis - "Assessment of herd protection against trachoma due to repeated mass antibiotic distributions: a cluster-randomised trial". Porco et al address part of aim 4 looking at mortality in Ethiopian children. "Effect of Mass Distribution of Azithromycin for Trachoma Control on Overall Mortality in Ethiopian Children".


OutcomesThe following information about outcomes was obtained from the trial registration information on ClinicalTrials.gov.

"Primary Outcome Measures:

  • The average prevalence of ocular chlamydia infection in communities in an arm as determined by pooled NAAT (Nucleic Acid Amplification Test)(at 42 months for Aim 1, at 12 months for Aim 2, post-treatment relative to pre-treatment for Aim 3) [ Time Frame: 42 months ] [ Designated as safety issue: No ]


Secondary Outcome Measures:

  • Clinical active trachoma in community, as determined by the WHO simplified grading system [ Time Frame: 42 months ] [ Designated as safety issue: No ]


  • Childhood (>= 1 year of age) mortality, analyzed as 1-5, 6-10 years of age, and total [ Time Frame: 42 months ] [ Designated as safety issue: No ]


  • Macrolide resistance in pneumococcus (% resistance over time, clustered by randomization unit) [ Time Frame: 42 months ] [ Designated as safety issue: No ]"


NotesClnicalTrials.gov identifier: NCT00322972

TANA: Trachoma Amelioration in Northern Amhara


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Low risk"The 72 subkebeles were randomly assigned to one of six groups of 12 subkebeles each, forming three separate trachoma-specific comparisons (generation by KJR with RANDOM() and SORT() in Excel [version 2003], implementation by BA, concealed until assignment)." (House et al Lancet 2009, page 1112).

Blinding?
Active trachoma
Unclear risk"Censuses for all study communities were undertaken by trained health-care personnel who were blinded to study group and to the prevalence of ocular chlamydial infection".House et al Lancet 2009, page 1112. However, no mention of masking of clinical observers.

Blinding?
Ocular Chlamydia trachomatis infection
Low risk"Laboratory personnel were blinded to individual, community, and treatment-group identifications. Since dilution effects and underestimation due to pooling could theoretically occur, all communities had to be processed in an identical way, and complete masking of laboratory personnel had to be maintained." (House et al Lancet 2009, page 1114).

Incomplete outcome data addressed?
Active trachoma
Unclear riskData not reported.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Low riskRandom sample selected for measurement of ocular infection. 637/720 (88%) children seen in "children-treated" group, 618/720 (86%) children seen in control group (delayed treatment) and 600/720 (83%) children seen in mass treatment group. Equivalent measures for children>=11 and adults: 561/720 (78%); 550/720 (76%); 599/720 (83%).

Free of selective reporting?Low riskCurrently data available for aim 2 of original study. Outcomes reported match those specified at trial registration.

Free of other bias?Low risk

Recruitment bias addressed?Low riskNo information reported however we believe that this is unlikely because in all arms treatment was offered at the same time as assessment.

Baseline imbalances addressed?Low riskPre-treatment age, sex, ocular and clinical infection in children reported at baseline for treated communities and 12 months for untreated communities. No major imbalances reported. (House et al 2009. Table 1).

Woolridge 1967

MethodsAllocation: random.
Unit of randomisation: individual.

Masking:
participant: no,
provider: no,
outcome: yes.

Exclusions after randomisation: unclear.
Losses to follow up: unclear.
Unusual study design: combined vaccine and therapy trial. Review considers groups with placebo-vaccine.


ParticipantsCountry: Taiwan.

Number randomised: 322.
Age (ave.): primary school age.
Sex: not reported.

Clinical grading: Modified McCallan classification.

Lab tests: none.

Inclusion criteria: active trachoma.
Exclusion criteria: none.


InterventionsTREATMENT: tetracycline.
Administration: topical.
Dose: 1%.
Duration: twice daily for 6 consecutive days per week for 6 weeks.

COMPARISON: no treatment.


OutcomesPrimary: active trachoma.
Secondary: none.

Adverse effects: not assessed.


NotesOnly trachoma-positives included, but table does not show this. Numbers for analysis calculated from percentages given.


Risk of bias

BiasAuthors' judgementSupport for judgement

Allocation concealment?Unclear riskNot reported.

Blinding?
Active trachoma
Unclear risk“The ophthalmologists making the eye examinations at no time knew to which vaccine or treatment group the subject belonged nor what his previous diagnosis had been” (page 1578).

“Placebo therapy was not employed” (page 1578).

No discussion as to whether the ophthalmologists might have been unmasked because the patients knew their treatment group.

Incomplete outcome data addressed?
Active trachoma
Unclear riskNo information on completeness of follow up.

Incomplete outcome data addressed?
Ocular Chlamydia trachomatis infection
Unclear riskData on ocular infection not reported.

Free of selective reporting?Low riskActive trachoma only reported but no indication any data collected on C. trachomatis infection.

Free of other bias?Low risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abdou 2007Prevalence study only.

Assaad 1968Concealment of allocation: C (twice randomisation among two groups).

Astle 2006Prevalence study only.

Babbar 1982No comparison group receiving placebo or no treatment.

Biebesheimer 2009No comparator villages.

Bietti 1967Review only.

Broman 2006Not randomised controlled trial.

Cerulli 1983No evidence of randomisation.

Chumbley 1988No comparison group receiving placebo or no treatment.

Daghfous 1974No evidence of randomisation.

Daghfous 1985No comparison group receiving placebo or no treatment.
No evidence of randomisation.

Darougar 1980aNo comparison group receiving placebo or no treatment.

Darougar 1981No comparison group.

Dawson 1967aAllocation concealment inadequate (alternation).

Dawson 1967bAllocation concealment inadequate (alternation).

Dawson 1968No evidence of randomisation.

Dawson 1971Allocation concealment inadequate (alternation).

Dawson 1972aNo evidence of randomisation.

Dawson 1972bNo evidence of randomisation.

Dawson 1974aNo evidence of randomisation.

Dawson 1974bAllocation concealment inadequate.

Dawson 1975aAllocation concealment inadequate.

Dawson 1981aNo proper control group (previously treated children who did not receive treatment during actual trial).

Dawson 1982No comparison group receiving placebo or no treatment.

Edwards 2006Health education intervention.

Gower 2006Not randomised controlled trial.

Gupta 1966No evidence of randomisation.

Gupta 1968No comparison group receiving placebo or no treatment.

Guzey 2000Inclusion criteria of participants non-specific. They had bilateral trachoma or showed symptoms (not described).

Hasan 1976No comparison group receiving placebo or no treatment.

Humet 1989No eye outcome.

Isenberg 2002Study not carried out in a trachoma endemic area.

Ji 1986No trial report.

Kamiya 1956Lack of comparison villages.

Khandekar 2006Prevalence study.

Lakew 2009No comparator villages

Litricin 1968No comparison group.

Mesfin 2006Prevalence study

Mohan 1982No evidence of randomisation.

Nabli 1988No comparison group.

Ngondi 2006aPrevalence study.

Ngondi 2006bNo antibiotic/no antibiotic comparison.

Nisbet 1979Placebo invalid.

Obikili 1988No comparison group.

Putschky 2006No eye outcome.

Reinhards 1959No comparison group.

Resnikoff 1994No comparison group.

Schemann 2007Comparison of different treatment targeting strategies therefore does not meet inclusion criteria for review.

Tabbara 1988Randomisation was by eye and not patient. It was not possible to determine the individual patient outcome.

Toufic 1968Report of control campaigns not trials.

Wadia 1980No comparison group.

Werner 1977No comparison group.
No evidence of randomisation.

West 2006Test efficacy of insecticide.

Whitcher 1974No evidence of randomisation.

Zhang 2006No appropriate control group.

 
Comparison 1. Any antibiotic versus control (individuals)

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

 1 Active trachoma at three months91961Risk Ratio (M-H, Random, 95% CI)0.78 [0.69, 0.89]

 2 Ocular C.trachomatis infection at three months4297Risk Ratio (M-H, Random, 95% CI)0.81 [0.63, 1.04]

 3 Active trachoma at 12 months41035Risk Ratio (M-H, Random, 95% CI)0.74 [0.55, 1.00]

 4 Ocular C. trachomatis infection at 12 months1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

 
Comparison 2. Subgroup analysis: oral and topical antibiotics versus control (individuals)

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

 1 Active trachoma at three months9Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Oral antibiotic
6599Risk Ratio (M-H, Random, 95% CI)0.81 [0.67, 0.97]

    1.2 Topical antibiotic
61478Risk Ratio (M-H, Random, 95% CI)0.82 [0.72, 0.92]

 2 Ocular C. trachomatis infection at three months4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Oral antibiotic
4259Risk Ratio (M-H, Fixed, 95% CI)0.85 [0.66, 1.11]

    2.2 Topical antibiotic
185Risk Ratio (M-H, Fixed, 95% CI)0.18 [0.02, 1.37]

 3 Active trachoma at 12 months4Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    3.1 Oral antibiotic
3429Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.76, 1.00]

    3.2 Topical antibiotic
4724Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.71, 0.88]

 4 Ocular C. trachomatis infection at 12 months1Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    4.1 Oral antibiotic
191Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.10, 1.23]

    4.2 Topical antibiotic
185Risk Ratio (M-H, Fixed, 95% CI)0.14 [0.02, 1.04]

 
Comparison 3. Oral versus topical antibiotics (individuals)

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

 1 Active trachoma at three months6953Risk Ratio (M-H, Random, 95% CI)0.98 [0.82, 1.18]

 2 Ocular C. trachomatis infection at three months3Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 3 Active trachoma at 12 months5886Risk Ratio (M-H, Random, 95% CI)0.93 [0.75, 1.15]

 4 Ocular C. trachomatis infection at 12 months2Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 4. Oral azithromycin versus topical tetracycline (individuals)

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

 1 Active trachoma at three months3Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 2 Ocular C. trachomatis infection at three months2Risk Ratio (M-H, Random, 95% CI)Totals not selected

 3 Active trachoma at 12 months2447Risk Ratio (M-H, Fixed, 95% CI)0.76 [0.59, 0.99]

 4 Ocular C. trachomatis infection at 12 months1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

 
Comparison 5. Oral azithromycin versus control (communities)

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

 1 Active trachoma at 12 months2Risk Ratio (M-H, Random, 95% CI)Totals not selected

 2 Ocular C. trachomatis infection at 12 months44345Risk Ratio (M-H, Random, 95% CI)0.35 [0.21, 0.60]

 
Comparison 6. Oral azithromycin versus topical tetracycline (communities)

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

 1 Active trachoma at 3 months3Risk Ratio (M-H, Random, 95% CI)Totals not selected

 2 Ocular C. trachomatis infection at 3 months3Risk Ratio (M-H, Random, 95% CI)Totals not selected

 3 Active trachoma at 12 months3Risk Ratio (M-H, Random, 95% CI)Totals not selected

 4 Ocular C. trachomatis infection at 12 months3Risk Ratio (M-H, Random, 95% CI)Totals not selected

 
Summary of findings for the main comparison. Antibiotic versus control for trachoma: individuals

Antibiotic versus control for trachoma

Patient or population: patients with trachoma
Settings: individuals
Intervention: antibiotic
Comparison: control

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

Assumed riskCorresponding risk

controlantibiotic

Active trachoma
Follow-up: 3 months
Medium risk population1RR 0.78
(0.69 to 0.89)
1961
(9 studies)
⊕⊕⊝⊝
low2,3

800 per 1000624 per 1000
(552 to 712)

Ocular chlamydia trachomatis infection
Follow-up: 3 months
Medium risk population1RR 0.81
(0.63 to 1.04)
297
(4 studies)
⊕⊕⊝⊝
low4,5

600 per 1000486 per 1000
(378 to 624)

Active trachoma
Follow-up: 12 months
Medium risk population1RR 0.74
(0.55 to 1)
1035
(4 studies)
⊕⊕⊝⊝
low6,7,8

750 per 1000555 per 1000
(413 to 750)

Ocular chlamydial trachomatis infection
Follow-up: 12 months
Medium risk populationRR 0.25
(0.08 to 0.78)
129
(1 study)
⊕⊕⊝⊝
low9

190 per 100048 per 1000
(15 to 148)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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.

 1 Median risk in control groups in included studies (rounded to nearest 10 per 1000)
2 Serious limitations in design: None of the trials reported methods to conceal the allocation. Two trials only attempted to mask the assessment of active trachoma.
3 Serious inconsistency: Risk ratios ranged from 0.40 to 1.02.
4 Serious limitations in study design: None of the trials reported adequate allocation concealment. Three out of four trials masked outcome assessment.
5 Serious imprecision: 95% confidence intervals include 1 (0.63 to 1.04)
6 Serious limitations in design: None of the trials reported allocation concealment or masking of outcome assessment.
7 Serious inconsistency: Risk ratios ranged from 0.50 to 1.05.
8 No downgrading for imprecision: The pooled estimate of effect is imprecise (confidence intervals 0.55 to 1). However, we felt that this inconsistency probably arises due to limitation in study design and inconsistency and therefore did not additionally downgrade the quality of evidence on the basis of this criteria.
9 Very serious limitations in study design: Only one small trial which did not report adequate methods of allocation concealment and did not mask outcome assessment.
 
Summary of findings 2. Oral versus topical antibiotic for trachoma: individuals

Oral versus topical antibiotic for trachoma

Patient or population: patients with trachoma
Settings: individuals
Intervention: oral antibiotic
Comparison: topical antibiotic

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

Assumed riskCorresponding risk

topical antibioticoral antibiotic

Active trachoma
Follow-up: 3 months
Medium risk population1RR 0.98
(0.82 to 1.18)
953
(6 studies)
⊕⊕⊕⊝
moderate2
Pooled RR excluding Bowman 2000 RR 1.04 (95% CI 0.94, 1.16). 3

578 per 1000566 per 1000
(474 to 682)

Ocular chlamydia trachomatis infection
Follow-up: 3 months
See commentSee commentNot estimable298
(3 studies)
⊕⊝⊝⊝
very low4,5
Darougar 1980 RR 6.05 (95% CI 0.78, 46.95); Dawson 1997 RR 0.57 (0.14, 2.30); Tabbara 1996 RR 1.30 (0.41,4.11).

Active trachoma
Follow-up: 12 months
Medium risk population1RR 0.93
(0.75 to 1.15)
886
(5 studies)
⊕⊝⊝⊝
very low6,7
Pooled RR excluding Bowman 2000 RR 1.01 (95% CI 0.85, 1.20). 3

565 per 1000525 per 1000
(424 to 650)

Ocular chlamydia trachomatis infection
Follow-up: 12 months
See commentSee commentNot estimable220
(2 studies)
⊕⊝⊝⊝
very low
Darougar 1980 RR 2.59 (95% CI 0.28, 23.88); Dawson 1997 RR 0.50 (0.18, 1.43).

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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.

 1 Median risk in control groups in included studies (rounded to nearest 10 per 1000)
2 Serious limitations in design: none of the trials reported adequate methods for allocation concealment and masking of outcome assessment.
3 In contrast to the other trials here Bowman 2000 aimed to compare azithromycin and tetracycline "under practical operational conditions - i.e. without supervision of the administration of the ointment". The results of this study were quite different from the other trials and excluding it from the pooled estimated reduced the I2 value from 63% to 0% for 3 months follow-up and from 56% to 29% for 12 months follow-up.
4 Serious limitations in design: no trial reported adequate allocation concealment. Two out of the three trials reported masking outcome assessment.
5 Very serious inconsistency: Effect estimates ranged from 0.57 in favour of oral antibiotics to 6.05 in favour of topical antibiotics, although confidence intervals for all studies overlapped with each other. Only 8 events in total in the control groups of these three studies.
6 Serious limitations in design: no trial reported adequate allocation concealment. One out of the two trials reported masking outcome assessment.
7 Very serious inconsistency: One trial found in favour of oral antibiotics with a RR of 0.5, the other found in favour of topical antibiotics with a RR of 2.59. Neither trial was statistically significant and their confidence intervals overlapped.
 
Summary of findings 3. Oral azithromycin compared to control for trachoma: communities

Oral azithromycin compared to control for trachoma

Patient or population: patients with trachoma
Settings: communities
Intervention: oral azithromycin
Comparison: control

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

Assumed riskCorresponding risk

controloral azithromycin

Active trachoma
Follow-up: 12 months
See commentSee commentNot estimable2764
(2 studies)
⊕⊕⊕⊝
moderate1,2
Best estimate of effect is likely to come from TANA 2009 RR 0.58 (95% CI from individual analysis 0.52 to 0.65, 95% CI adjusted for clustering 0.47 to 0.72).3

Ocular chlamydia trachomatis infection
Follow-up: 12 months
Medium risk population4RR 0.35
(0.21 to 0.60)5
4345
(4 studies)
⊕⊕⊕⊝
moderate1,6

100 per 100035 per 1000
(21 to 60)

High risk population4

500 per 1000175 per 1000
(105 to 300)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) 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.

 1 Trials were of variable quality but the majority of evidence was from TANA 2009 which was judged to be at low risk of bias so we did not downgrade for limitations in design.
2 Serious inconsistency: TANA 2009 and Atik 2006 provided different estimates of effect. RR 0.58, (95% CI 0.67, 1.94) in TANA 2009 compared to RR 1.14, (0.67, 1.94) in Atik 2006.
3 TANA 2009 randomised 24 communities and was judged to be at low risk of bias. Atik 2006 randomised 2 communities and was judged to be at a greater risk of bias. For that reason, we judge that the estimate of effect from TANA 2009 is likely to provide a better estimate of the true effect.
4 Populations with medium (10%) prevalence and high (50%) prevalence of trachoma.
5 These confidence intervals do not take into account the cluster design of the study. Adjusting for cluster design of the study did not affect the conclusions. Adjusting for an ICC of 0.2 gave a confidence interval for the pooled risk ratio of 0.20 to 0.63.
6 Serious inconsistency: Estimates of effect in the four studies range from 0.04 to 0.61.
 
Summary of findings 4. Oral azithromycin compared to topical tetracycline for trachoma: communities

Oral azithromycin compared to topical tetracycline for trachoma

Patient or population: patients with trachoma
Settings: communities
Intervention: oral azithromycin
Comparison: topical tetracycline

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

Assumed riskCorresponding risk

topical tetracyclineoral azithromycin

Active trachoma
Follow-up: 3 months
See commentSee commentNot estimable6002
(3 studies)
⊕⊕⊝⊝
low1,2
ACT 1999 Egypt: RR 0.52 (95% CI 0.43,0.64); ACT 1999 Tanzania RR 1.16 (1.00,1.36); ACT 1999 The Gambia RR 0.76 (0.50,1.15)

Ocular C. trachomatis infection
Follow-up: 3 months
See commentSee commentNot estimable5773
(3 studies)
⊕⊕⊝⊝
low1,2
ACT 1999 Egypt: RR 0.22 (95% CI 0.11,0.44); ACT 1999 Tanzania RR 0.68 (0.49,0.95); ACT 1999 The Gambia RR 0.51 (0.37,0.70)

Active trachoma
Follow-up: 12 months
See commentSee commentNot estimable5414
(3 studies)
⊕⊕⊝⊝
low1,2
ACT 1999 Egypt: RR 0.74 (95% CI 0.61,0.90); ACT 1999 Tanzania RR 1.19 (1.02,1.40); ACT 1999 The Gambia RR 0.55 (0.40,0.75)

Ocular C. trachomatis infection
Follow-up: 12 months
See commentSee commentNot estimable5276
(3 studies)
⊕⊕⊝⊝
low1,2
ACT 1999 Egypt: RR 0.48 (95% CI 0.31,0.74); ACT 1999 Tanzania RR 1.01 (0.76,1.35); ACT 1999 The Gambia RR 0.62 (0.44,0.87)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval;

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 Serious limitations in design: Three cluster-randomised trials, two of the trials only randomised two communities to oral/topical antibiotic. Assessment of trachoma was not masked but assessment of ocular infection was. Recruitment bias not addressed and problems with incomplete outcome data. Some attempt made to adjust for baseline imbalances.
2 Serious inconsistency:
 
Table 1. Antibiotics: trial in individuals

StudyOral antibioticOral antibiotic doseOral antibiotic scheduleOral antibiotic commentsTopical antibioticTopical antibiotic doseTopical antibiotic scheduleTopical antibiotic comments

1Attiah 1973Tetracycline0.25%1x daily for 11 weeksSchool days only

2Bailey 1993Azithromycin20 mg/kgsingle doseNot given to pregnant or lactating womenTetracycline1%2x daily for six weeksPeople with "severe disease" were also given erythromycin 250mg 4x daily for two weeks

3Bowman 2000*Azithromycin20 mg/kgsingle doseTetracyclinenot reported2x daily for six weeksUnsupervised administration

4Cochereau 2007Azithromycin20 mg/Kgsingle dosePersons accompanying children enrolled in the trial were treated with oral azithromycin; soap and health education providedAzithromycin1.5%2x daily for 2 days and 3 daysPersons accompanying children enrolled in the trial were treated with oral azithromycin; soap and health education provided

5Darougar 1980Doxycycline5 mg/kg1x monthly for 12 monthsOxytetracycline1%2x daily for 7 days, every month for 12 monthsconsecutive days

6& 7Dawson 1969 (Sherman and Sterwart)Trisulphapyrimidines3.5 g3x daily for 21 days3 daily doses to total 3.5g/dayOxytetracycline1%1 drop 4x daily for 7 days, every months for 6 monthsconsecutive days

8Dawson 1997*Azithromycin20 mg/kgsingle dose; single dose weekly for 3 weeks; single dose monthly for six monthsthree different dosing schedulesOxytetracycline/polymyxin1% / 10,000 units per g1x daily for 5 days, every month for 6 months

9Foster 1966Sulphamethoxypyridazine500 mg/day1x daily for 5 days, every week for 3 weeks.Tetracycline1%3x daily for 5 days, every week for 6 weeks

10Hoshiwara 1973Doxycycline2.5-4.0 mg/kg1x daily for 5 days, every week up to 28 doses in 40 days.

11Peach 1986Tetracyclinenot reporteddaily for 5 days, every month for 3 months

12Shukla 1966Sulphadimethoxine100 mg/kg2x weekly or 1x weekly, for 5 monthsSulphafurazole15%2x daily for 5 days, every month for 5 months

13Tabbara* 1996Azithromycin20 mg/kgsingle doseTetracycline1%2x daily for 5 days, every week for 6 weeks

14Woolridge 1967Tetracycline1%2x daily for 6 days, every week for 6 weeks

 * No untreated or placebo control group
 
Table 2. Antibiotics: trials in communities

StudyOral antibioticOral antibiotic doseOral antibiotic scheduleOral antibiotic commentsTopical antibioticTopical antibiotic doseTopical antibiotic scheduleTopical antibiotic comments

1,2& 3ACT (Egypt, Tanzania and The Gambia)Azithromycin20 mg/kg up to 1gonce a week for three weeksPregnant women given erythromycinoxytetracycline1%once daily for 6 weeks

4Atik 2006Azithromycin20 mg/kg for children; 1g for adultssingle doseChildren with active trachoma and household members treated; Pregnant women given erythromycintetracyclinenot reportednot reportedPeople with active trachoma treated

5Chidambaram 2006Azithromycin20 mg/kg for children; 1g for adults

directly observed treatment.
single dosePregnant
women, children younger than 1 year, and those allergic to macrolides were offered a 6-week course of topical 1% tetracycline ointment (applied twice daily to both eyes, not directly observed).

6Lee 2007Azithromycinnot reportednot reported"Biannual mass azithromycin treatment of all individuals" aged 1 year or more

7Resnikoff 1995oxytetracycline1%1 drop 4x/day7 consecutive days per month for six months

8TANA 2009AzithromycinHeight-based dosing to roughly 20 mg/kgsingle doseWomen self-reporting as pregnant and children aged less than 1 year offered topical tetracycline

 
Table 3. Outcome reporting: trials in individuals

Study3 months3 months12 months12 months24 months24 months

Active trachomaOcular infectionActive trachomaOcular infectionActive trachomaOcular infection

1Attiah 1973H 1H2H2H2H2

2Bailey 1993✓ (26 weeks)✓ (26 weeks)H2H2

3Bowman 2000H3H3H2H2

4Cochereau 2007EH2H2H2H2

5Darougar 1980H2H2

6Dawson 1969 ShermanH2H2H2H2H2

7Dawson 1969 StewartH2H2H2H2H2

8Dawson 1997H2H2

9Foster 1966H 1H 1H2H2

10Hoshiwara 1973H2H2H2H2

11Peach 1986H 1H2H2H2H2

12Shukla 1966H2H2H2H2

13Tabbara 1996H2H2H2H2

14Woolridge 1967H 1H 1H2H2

 ORBIT CLASSIFICATION (Kirkham 2010)
E: Clear that the outcome was measured but not necessarily analysed.
H: Outcome not mentioned but clinical judgement says unlikely to have been measured.
1. No mention of collection of laboratory samples in the paper.
2. No evidence of any data collection at this time point.
3. Study conducted on low budget therefore may not have been able to afford to collect lab specimens
 
 
Table 4. Outcome reporting: trials in communities

Study3 months3 months12 months12 months24 months24 months

Active trachomaOcular infectionActive trachomaOcular infectionActive trachomaOcular infection

1ACT 1999 EgyptH2H2

2ACT 1999 TanzaniaH2H2

3ACT 1999 The GambiaH2H2

4Atik 2006

5Chidambaram 2006Request to authors for information✓ (treatment group only)Request to authors for information✓ (treatment group only and control group treated at 12 months)

6Lee 2007H3H3H4H2H2

7Resnikoff 1995H 1H 1H2H2

8TANA 2009Request to authors for informationFRequest to authors for informationH5H5

 ORBIT CLASSIFICATION (Kirkham 2010)
F: Clear that outcome was measured but not necessarily analysed.
H: Outcome not mentioned but clinical judgement says unlikely to have been measured.
1. No mention of collection of laboratory samples in the paper.
2. No suggestion that study went on longer than 12 months.
3. Only 12 month examination appeared to have been conducted.
4. Paper did not report any clinical examination whilst this is unusual the focus of the study was “chlamydia on flies and children” so it is possible that only laboratory samples were collected.
5. Control group treated at 12 months
 
Table 5. Adverse effects

StudyAntibiotic (number treated)Report

1, 2 & 3ACT 1999 (Egypt/Tanzania/The Gambia)Azithromycin (approx 3800)

Tetracycline (approx 2400)
No comment on adverse effects in report

4Atik 2006Azithromycin and tetracycline (numbers treated difficult to work out exactly but probably in the order of 100)No comment on adverse effects in report

5Attiah 1973Oxytetracycline (77)

Tetracycline derivative GS2989 (75)
No comment on adverse effects in report

6Bailey 1993Azithromycin (97)

Topical tetracycline with oral erythromycin in severe cases (97)
Table 2 on page 454 reports adverse effects. Abdominal pain reported more often in azithromycin group (26% versus 16%, P = 0.09). Other effects: diarrhoea, vomiting, fever, headache, body pain, other similar between two study groups.

"There were no serious adverse reactions and both treatments were well tolerated. All symptoms resolved spontaneously and none required treatment." One study subject died, probably due to malaria. He had received topical tetracycline.

7Bowman 2000Azithromycin (160)

Tetracycline (154)
No comment on adverse effects in report

8Chidambaram 2006Azithromycin (approx 500 children)No comment on adverse effects in report

9Cochereau 2007Azithromycin topical 2-day regimen (222) 3-day (220 and oral azithromycin (214)"Ocular adverse events were reported in 10.8%, 8.9% and 13.1% of patients in the 2-day, 3-day and oral treatment groups respectively. Systemic adverse events were reported in 2.6%, 10.2% and 9.0% of patients. None of the adveres events were treatment-related events. On epatient (3-day group) had a serious unrelated adverse events (death due to head injury)." Page 670

10Darougar 1980Doxycycline (44)

Oxytetracycline (38)
No comment on adverse effects in report

11 & 12Dawson 1969 (Sherman/Stewart)Trisulfapyrimidines (33)"No untoward reactions to sulfonamides were noted" (page 587)

13Dawson 1997Oxytetracycline/polymyxin (43)

Azithromycin (125)
"In this trial, azithromycin was well tolerated and only two children (of 125 treated) complained of nausea" (page 367)

14Foster 1966Sulfamethoxypyridazine (112)

Tetracycline (106)
"3/155 students who received sulfamethoxypyridazine had adverse reactions to the drug. One girl developed a severe purpura associated with marked thrombocytopenia. She recovered following withdrawal of the drug and administration of corticosteroids. Two cases of diagnosed drug rash necessitated discontinuance of the drug. The nephrotic syndrome developed in one boy three months after completion of sulphonamide therapy, but the relationship of this development to therapy was not determined. No reactions or rashes occurred in the other two treatment groups" (page 453) (note: Table 3/table 4 report 112 children treated with sulphamethoxypyridazine).

15Hoshiwara 1973Doxycycline (49)"Anorexia, nausea, vomiting or diarrhea occurred in three children between the 15th and 25th days of medication. Two of these children were receiving doxycycline, and the disturbances lasted only a single day in each child, in spite of continuing medication. Between day 21 and 28 of medication, transient macular rashes and one-day illness with low-grade fever and anorexia occurred in four children. Two of them had received drug, and two placebo. It is likely that an intercurrent, unrelated illness was responsible. Gross enamel dysplasia or tooth discoloration was not observed on examination 20 weeks after the end of medication." (page 222)

16Lee 2007Azithromycin (8 villages treated, number individuals treated not reported)No comment on adverse effects in report

17Peach 1986Tetracycline (932)No comment on adverse effects in report

18Resnikoff 1995Oxytetracycline (346)No comment on adverse effects in report

19Shukla 1966Sulphafurazole (140)

Sulphadimethoxine (161)
No comment on adverse effects in report

20Tabbara 1996Azithromycin (31)

Tetracycline (29)
"No adverse effects were noted" (page 844) and "The safety of a single oral dose of azithromycin has been demonstrated in this study. Similar to other clinical studies, no adverse effects developed in any of the patients in the azithromycin group" (page 845).

21TANA 2009Azithromycin (over 16,000 people treated at baseline)"We recorded no reported serious adverse events attributed to study medication. 96 deaths were recorded in subkebeles in the children-treated group and 126 deaths recorded in those in the control group. At 12 months a survey was undertaken to assess adverse effects in the treated population (n=671, 96 side-effects reported). [.. ] 56 (11.3%) patients reported abdominal pain, vomiting, and nausea, whereas diarrhoea, constipation and related issues accounted for 16 (2.4%) of complaints. Four (0.6%) patients reported haemorrhoid or other as side effects" (House et al page 1115). "In a trachoma-endemic area, mass distribution of oral azithromycin was associated with reduced mortality in children" (Porco et al, conclusion of abstract).

22Woolridge 1967Tetracycline (726)

Sulfonamide (526)
"No more than trivial reactions were observed in any of these three studies, to vaccine, to oil adjuvant , to eye ointment or to sulfa drug." (page 1581)