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Ivermectin for onchocercal eye disease (river blindness)

  1. Henry OD Ejere1,*,
  2. Ellen Schwartz2,
  3. Richard Wormald3,
  4. Jennifer R Evans3

Editorial Group: Cochrane Eyes and Vision Group

Published Online: 15 AUG 2012

Assessed as up-to-date: 2 APR 2012

DOI: 10.1002/14651858.CD002219.pub2


How to Cite

Ejere HOD, Schwartz E, Wormald R, Evans JR. Ivermectin for onchocercal eye disease (river blindness). Cochrane Database of Systematic Reviews 2012, Issue 8. Art. No.: CD002219. DOI: 10.1002/14651858.CD002219.pub2.

Author Information

  1. 1

    Hode Internal Medicine, Texas, USA

  2. 2

    Institute of Ophthalmology, London, UK

  3. 3

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

*Henry OD Ejere, Hode Internal Medicine, 125 South Park Drive, Suite F, Brownwood, Texas, 76801, USA. hodejere2000@yahoo.com.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 15 AUG 2012

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Characteristics of included studies [ordered by study ID]
Abiose 1993

MethodsMethod of allocation: individual randomisation with a blocked design. Sequential administration of pre-coded containers.
Masking: participants, provider and outcome assessors masked.


ParticipantsCountry: Northern Nigeria.
Type of river blindness: savannah type.
Number randomised: 8136*.
Age: 5 years and above.
Sex: male and female.
Inclusion criteria: Individuals above 5 years normally resident in communities in which the prevalence of positive skin snip for microfilariae among residents 20 years and over was 30% or more.
Exclusion criteria: pregnant or lactating women; children < 5 years or weighing < 15 kg; Individuals with disorders of the central nervous system or other debilitating disease.
Number of participants analysed for incidence of optic nerve disease after exclusion of children < 15 years and individuals with optic nerve disease at baseline: 3045.


InterventionsTreatment: single dose ivermectin tablets taken orally and given annually for 3 years.
Dose: 150 ug/kg.
Control: placebo tablets taken orally and given once annually for 3 years.
Duration of follow-up: 17 to 39 months.


OutcomesIncidence of optic nerve disease, visual field deterioration.


NotesIndividuals who were 5 years or older were randomised but only individuals 15 years and above were re-examined for outcome measures and included for analyses.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Randomisation to the ivermectin or placebo group was done at the individual level with a blocked design." Abiose 1993, page 131, first paragraph.

Allocation concealment (selection bias)Low risk"At registration a master card was completed for each individual. It carried identification information, including a photograph, a unique pre-printed identification number, and a pre-printed sequential treatment group number between 1 and 30. Merck, Sharp and Dohme donated 30 identical containers, numbered 1-30, to which ivermectin (6 mg per tablet) or a visually indistinguishable placebo tablet had been randomly allocated. Each participant received tablets from the container with the same number as his or her card.
Staff conducting the trial were unaware which containers held ivermectin." Abiose 1993, page 131, first paragraph.

Blinding (performance bias and detection bias)
All outcomes
Low riskSee above

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"....3522 individuals examined at the first examination were re-examined at least once-an overall follow-up rate of 82%. The mean duration of follow-up for these individuals was 2-54 (range 1.41-3.25) years. There were no differences between the ivermectin and placebo groups in the mean duration of follow-up or in the proportions of participants re-examined at each examination." Abiose 1993, page 131, results, first paragraph.

Communities endemic for onchocerciasis were treated i.e. everyone aged 5 years and above received ivermectin or placebo. However, as very few people aged less than 15 years will experience significant onchocercal eye disease children under the age of 15 years were not examined at follow-up. Although this means that not everyone treated was examined, as this was an a priori decision at study design stage, and intervention/control groups were treated the same it is unlikely to have lead to any bias in estimating the effect of the intervention.

Selective reporting (reporting bias)High riskNo information on pre-specified outcomes and only optic nerve disease and visual field loss reported.

Dadzie 1989

MethodsMethod of allocation: individual randomisation with sequential administration of pre-packed, precoded envelopes which were labelled with allocation numbers.
Masking:


ParticipantsCountry: Northern Ghana.
Type of river blindness: savannah type.
Area under concomitant vector control.
Number randomised: 198.
Age: 15 to 64 years.
Sex: male and female.
Inclusion criteria: not available.
Exclusion criteria: not available.


InterventionsTreatment: single dose ivermectin tablets taken orally and given annually.
Dose: 100 ug/kg or 150 ug/kg or 200 ug/kg.
Control: placebo tablet given as single dose.
Duration of follow-up: 1 year.


OutcomesSystemic reactions to treatment; Visual function: improvement or deterioration; Skin microfilariae load (geometric mean); Cornea, anterior chamber microfilarial load (geometric mean)**; Punctate opacity load; Sclerosing keratitis; Iridocyclitis; Fundus changes.


Notes


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskNot reported

Allocation concealment (selection bias)Low risk"The doses of ivermectin or placebo were formulated as identical capsules and presented in pre-packed, precoded envelopes, each containing five capsules, and labelled with weight ranges and allocation numbers. On admission into hospital, the patients were given the allocation numbers sequentially and the contents of the envelopes with three weight ranges into which their body weights fitted. This procedure generated four groups of patients: the first with 49 patients who took 100 mcg/kg; the second with 50 patients who had 150 mcg/kg, the third with 50 patients who received 200 mcg/kg body weight of ivermectin and fourth with 49 patients who were given placebo consisting of 185 mg corn starch (STA-RX L500)."Dadzie 1989, page 356.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskSee above for allocation concealment which would also suggest that blinding was adequate. However, "The code of the study was broken after the month 6 review" Dadzie 1989, page 356. The significance of this for subsequent examinations (at 12 months) is unclear.

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk"Only 154 of the 198 patients who were ophthalmologically examined on all occasions were considered in the analysis of the results.

Selective reporting (reporting bias)Unclear riskSee  Table 3

Taylor 1988

MethodsMethod of allocation: Individual randomisation using computer generated random numbers. Drug administered in coded packages.
Masking: provider, participants and outcome assessors masked.


ParticipantsCountry: Grand Bassa County - Liberia.
Type of river blindness: forest type.
Number randomised: 200.
Age: 12 to 60 years.
Sex: male and female.
Inclusion criteria: heavy skin microfilarial count greater than 15 microfilariae/mg skin.
Exclusion criteria: pregnant and lactating women; people who had received anti-filaricidal drug within 1 year.


InterventionsTreatment: single dose ivermectin tablets taken orally and given annually.
Dose: 100 ug/kg or 150 ug/kg or 200 ug/kg.
Control: placebo tablet given as single dose.
Duration of follow-up: 1 year.


OutcomesVisual acuity; Visual field; Skin, cornea, anterior chamber microfilarial count (geometric mean)**; Punctate opacity load (geometric mean)**; Ocular reaction index; Sclerosing keratitis; Anterior uveitis; Retinal pigment epithelial atrophy; Optic nerve changes.


NotesNumber analysed in treatment groups not reported, therefore number randomised to treatment groups used for analyses.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low risk"Subjects were randomly assigned by using computer-generated random numbers to receive 100, 150, or 200 μg/kg of ivermectin/kg or placebo" White et al 1987, page 464, treatment protocol, first paragraph

Allocation concealment (selection bias)Low risk"The drug was provided in coded packages containing five identical capsules; each patient was treated individually and closely observed to ensure compliance." Newland 1988, page 562, treatment protocol, first paragraph

Also see below for "blinding".

Blinding (performance bias and detection bias)
All outcomes
Low risk"Data were gathered in a double-masked fashion and entered for computer analysis prior to breaking the treatment code at six months. The patients were examined at 12 months without reference to the treatment code." Newland 1988, page 562, treatment protocol, first paragraph

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information on follow-up given.

Selective reporting (reporting bias)Unclear riskSee  Table 3

Whitworth 1991a

MethodsMethod of allocation: individual randomisation with a blocked design. Computer generated random numbers. Concealed allocation using coded containers.
Masking: provider, participants and outcome assessors masked.


ParticipantsCountry: Southern Sierra-Leone.
Type of river blindness: forest type.
Number randomised: 1625.
Age: 1 year and above.
Sex: male and female.
Inclusion criteria: individuals normally resident in the study villages.
Exclusion criteria (after randomisation): children under five years; pregnant and one month postpartum women; those with neurological disease including epilepsy; individuals with severe intercurrent infection.


InterventionsTreatment: single dose ivermectin tablets taken orally and given 6 monthly.
Dose: 150 ug/kg body weight.
Control: placebo tablet given 6 monthly.
Duration of follow-up: 2 years.


OutcomesIncidence of blindness; Incidence of visual impairment; Skin microfilarial load (mf/mg) (geometric mean)**; Prevalence of microfilariae in cornea, anterior chamber; Prevalence of punctate keratitis, sclerosing keratitis, iritis, Chorioretinitis, retinal pigment epithelial atrophy, adverse drug reactions.


NotesAdverse reactions reported include: cutaneous reactions; musculoskeletal reactions; fever; swellings of the face, joints or limbs; headache; dizziness; lymphadenopathy; eye reactions; nodule pain.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear risk"All inhabitants of 6 study villages in southern Sierra-Leone were allocated at random to receive either ivermectin (150μg/kg) or placebo throughout the trial." Whitworth et al Transactions of the Royal Society of Tropical Medicine and Hygiene 1991, page 501 materials and methods.

Allocation concealment (selection bias)Unclear riskControl group received placebo but no information about allocation and how it was concealed.

Blinding (performance bias and detection bias)
All outcomes
Low riskThe control group received placebo and even though there was no information about allocation and how it was concealed we have assumed that people were unaware to which group they had been allocated.

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe eye study aimed to examine 312 people who had received four doses of placebo and 331 who had received four doses of ivermectin. 272 (87%) of the placebo cohort and 296 (89%) of the ivermectin cohort were examined. However original numbers treated were much higher ranging from 812 to 870 in the ivermectin group and 813 to 875 in the placebo group.

Selective reporting (reporting bias)Unclear riskUnclear see  Table 3

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Gardon 2002All groups received ivermectin. No placebo group.

 
Summary of findings for the main comparison. Ivermectin to prevent and treat onchocercal eye disease in people infected with O.volvulus

ivermectin to prevent and treat onchocercal eye disease in people infected with O.volvulus

Patient or population: people infected with O.volvulus
Settings: community
Intervention: ivermectin

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

Assumed riskCorresponding risk

Controlivermectin

Visual impairment
Follow-up: 12 months
See commentSee commentNot estimable354
(2 studies)
See commentNo events seen in either treatment or control groups

Visual field loss
Follow-up: 12 months
See commentSee commentNot estimable0
(0)
See commentNot reported

Punctate keratitis
Follow-up: 12 months
See commentSee commentNot estimable0
(2 studies)
See commentData could not be pooled however both studies reported significant reduction in number of punctate opacities

Sclerosing keratitis
Follow-up: 12 months
222 per 100013 per 1000
(0 to 273)
RR 0.06
(0 to 1.23)
39
(1 study)
⊕⊕⊝⊝
low1,2

Iridocyclitis
Follow-up: 12 months
See commentSee commentNot estimable0
(2 studies)
See commentData not pooled. See footnote for more details. 3

Chorioretinitis
Follow-up: 12 months
146 per 10003 per 1000
(0 to 47)
RR 0.02
(0 to 0.32)
200
(1 study)
⊕⊕⊕⊝
moderate4

Optic nerve disease
Follow-up: 12 months
See commentSee commentNot estimable354
(2 studies)
See commentNo events seen in either treatment or control groups

*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 Serious indirectness: Only one trial reported this finding on a subset of people with severe ocular onchocerciasis
2 Serious imprecision: One small study (total participants 39): wide confidence intervals including 1.
3 Dadzie 1989: 7/116 in ivermectin group and 0/38 placebo group had mild iridocyclitis that resolved by 3 months after treatment and left no sequelae.Taylor 1988 "no ivermectin-treated patients had uveitis at the three year examination".(NOTE: placebo group given ivermectin at 12 months)
4 Serious indirectness: Actual outcome reported was new or progression of retinal pigment epithelium atrophy which is an early manifestation of chorioretinal change.
 
Summary of findings 2. Ivermectin to prevent and treat onchocercal eye disease in people living in communities affected by O.volvulus

ivermectin to prevent and treat onchocercal eye disease in people living in communities affected by O.volvulus

Patient or population: people living in communities affected by O.volvulus
Settings: community
Intervention: ivermectin

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

Assumed riskCorresponding risk

Controlivermectin

Visual impairment
Follow-up: 24 months
22 per 100024 per 1000
(7 to 77)
RR 1.08
(0.33 to 3.5)
485
(1 study)
⊕⊝⊝⊝
very low1,2,3

Visual field loss
Follow-up: mean 24 months
180 per 1000108 per 1000
(74 to 160)
RR 0.60
(0.41 to 0.89)
636
(1 study)
⊕⊕⊕⊕
high

Punctate keratitis
Follow-up: 24 months
285 per 100094 per 1000
(63 to 140)
RR 0.33
(0.22 to 0.49)
551
(1 study)
⊕⊕⊕⊝
moderate1

Sclerosing keratitis
Follow-up: 24 months
348 per 1000258 per 1000
(181 to 369)
RR 0.74
(0.52 to 1.06)
560
(1 study)
⊕⊕⊝⊝
low1,3

Iridocyclitis
Follow-up: 24 months
217 per 1000135 per 1000
(93 to 195)
RR 0.62
(0.43 to 0.9)
554
(1 study)
⊕⊕⊕⊝
moderate1

Chorioretinitis
Follow-up: 24 months
60 per 1000105 per 1000
(55 to 202)
RR 1.75
(0.91 to 3.37)
528
(1 study)
⊕⊕⊝⊝
low1,3

Optic nerve disease
Follow-up: 24 months
48 per 100037 per 1000
(27 to 51)
RR 0.78
(0.57 to 1.06)
3577
(2 studies)
⊕⊕⊝⊝
low1,4

*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 Serious limitations in design: participants and outcome assessors adequately masked but other aspects of trial design such as sequence generation, allocation concealment and incomplete outcome data not clearly reported.
2 Serious indirectness: Some of the visual impairment reported may have been attributed to other causes of visual loss. .
3 Serious imprecision: wide confidence intervals include 1.
4 Serious inconsistency: I2 = 76%. Abiose 1993 found beneficial effect of ivermectin on new cases of optic nerve disease (risk ratio 0.65, 95% CI 0.45 to 0.93) and Whitworth 1991a found no difference in optic atrophy between ivermectin and placebo groups at 24 months follow-up (risk ratio 1.40, 95% CI 0.73 to 2.68).
 
Table 1. Characteristics of included studies

StudyLocationType of O.volvulus in localityCharacteristics of participantsIntervention


Total number randomisedMean age (range)% onchocercal infectionIvermectinPlacebo

Abiose 1993*Nigeriasavannah4298(15 to ?)49% (age 5+)

72% (age 20+)
Approx 150 µg/kg

Four doses over three years
Four doses over three years

Dadzie 1989Ghanasavannah19832.5 (12 to 55)100%100, 150 and 200 µg/kg

One dose
185 mg corn starch (STA-RX L500)

One dose

Taylor 1988**Liberiaforest20029.8 (12 to 60)100%100, 150 and 200 µg/kg

One dose
One dose

Whitworth 1991aSierra-Leoneforest643 people who had received 4 doses ivermectin or placeboEstimated from grouped data at 41 years (5 to ?).73%150 µg/kg at 0,6,12,18 months. Everyone received ivermectin at 24 months.0,6,12,18 months. All ivermectin at 24 months.

 *Everyone aged 5 years and above was treated with ivermectin or placebo, however, only people aged 15 years and above were examined as part of the trial.
**800 people screened; of which 200 people with highest skin microfilarial counts were given ivermectin or placebo.
 
Table 2. Follow-up

StudyFollow-upIvermectinPlacebo


Number randomisedNumber seen% seenNumber randomisedNumber seen% seen

Abiose 1993*Mean duration of follow-up 2.54 years (range 1.41 to 3.25)?175082?177282

Dadzie 1989**3, 6 and 12 months14911677.9493877.9

Taylor 19883, 6 and 12 months15211173.0483164.6

Whitworth 1991a***24 months33129689.431227287.2

 *The trialists aimed to dose all trial participants aged 5 years or more with either ivermectin or placebo once a year for three years. 5021 individuals were registered in the trial and aged 15 years and older. Of these, 3522 (82%) were re-examined at least once during the course of the trial. "There were no differences between the ivermectin and placebo groups in the mean duration of follow-up or in the proportions of participants re-examined at each examination."
** Data reported (number seen) for participants who had data for all three examinations.
*** From a larger study of 1745 people, 643 (331 ivermectin; 312 placebo) people who had received 4 doses of either ivermectin or placebo were selected for the eye study.
 
Table 3. Outcome reporting grid

OutcomeTypeAbiose 1993Dadzie 1989Taylor 1988Whitworth 1991a

Visual acuityContinuousEAEE

Visual acuity: % with new visual impairment (< 6/18)DichotomousEE

Visual acuity: % with new blindness (< 3/60)DichotomousEE

Visual field: % with deteriorationDichotomousHF

Microfilariae in skinContinuousEBCH (stated measured pretreatment)

Microfilariae in skinDichotomous / CategoricalEAEH (stated measured pretreatment)

Microfilariae in corneaContinuousEBCE

Microfilariae in corneaDichotomous / CategoricalEEE

Microfilariae in anterior chamberContinuousEBCE

Microfilariae in anterior chamberDichotomous /CategoricalEEE

Punctate keratitis % new casesDichotomousEBD (geometric mean punctate corneal opacities reported)

Sclerosing keratitis % new casesDichotomousEHE

Iridocyclitis % new casesDichotomousEE

Chorioretinitis % new casesDichotomousE

Optic nerve disease % new casesDichotomous

Adverse outcomesDichotomous E✓(postural hypotension)B  (Mazotti reaction)

Outcomes not prespecified in the review

Improvement in visual acuity 2+ lines Dichotomous EAEE

Deterioration in visual acuity 2+ lines Dichotomous EAEE

Glaucoma Dichotomous E E EReported

Proportion visually impaired or blind at end of study Dichotomous E E EReported

 Adapted from list provided by Paula Williamson at a Cochrane training workshop on selective outcome reporting bias, Edinburgh March 2009.
✓ Data included in the review
A: States outcome analysed but only reported the P value > 0.05 i.e. NS
B: States outcome analysed but only reported that P value < 0.05
C: Clear that outcome was analysed but insufficient data presented to be included in meta-analysis or full tabulation
D: Clear that outcome was analysed but no results reported
E: Clear that outcome was measured (for example, includes structurally related outcomes) but not necessarily analysed
F: States that outcome was not measured
G: Not mentioned but clinical judgement says likely to have been measured
H: Not mentioned but clinical judgement says unlikely to have been measured
I: Other give details
 
Table 4. Effect of missing data

Outcome: visual field loss

Assumption regarding missing dataRisk ratio95% confidence interval

Missing at random (available case analysis)0.600.41 to 0.89

Odds outcome in non-observed twice that in observed in ivermectin and control groups0.610.42 to 0.90

Odds outcome in non-observed half that in observed in ivermectin and control groups0.600.40 to 0.89

Odds outcome in non-observed twice that in observed in ivermectin and half in control groups0.750.51 to 1.11

Odds outcome in non-observed twice that in observed in ivermectin and half in control groups0.490.33 to 0.72