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Study Title and Description

Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study.



Key Questions Addressed
1 What is the effect of doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis?
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Primary Publication Information
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TitleData
Title Wolbachia endobacteria depletion by doxycycline as antifilarial therapy has macrofilaricidal activity in onchocerciasis: a randomized placebo-controlled study.
Author Hoerauf A., Specht S., Büttner M., Pfarr K., Mand S., Fimmers R., Marfo-Debrekyei Y., Konadu P., Debrah AY., Bandi C., Brattig N., Albers A., Larbi J., Batsa L., Taylor MJ., Adjei O., Büttner DW.
Country Institute for Medical Microbiology, Immunology and Parasitology, University Clinic, Bonn, Sigmund-Freud-Strasse 25, Bonn, Germany. hoerauf@parasit.meb.uni-bonn.de
Year 2008
Numbers Pubmed ID: 17999080

Secondary Publication Information
There are currently no secondary publications defined for this study.


Extraction Form: Doxycycline plus ivermectin versus ivermectin alone for treatment of patients with onchocerciasis 2016
Arms
Number Title Description Comments
1 Doxycycline 6 weeks + Ivermectin 200 mg/d doxycycline for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months.
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2 Ivermectin placebo for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months.
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3 Doxycycline 4 weeks + ivermectin 200 mg/d doxycycline for 4 weeks, then placebo for 2 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months
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Design Details
Question... Follow Up Answer Follow-up Answer
Page 295-311
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Study design parallel-group randomized controlled trial
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Number randomly assigned 76 total participants; 26 in the doxycycline 4 weeks plus ivermectin group, 25 in the doxycycline 6 weeks plus ivermectin group, and 25 in the ivermectin group
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Exclusions after randomization 9 total; 4 in the doxycycline 4 weeks plus ivermectin group, 3 in the doxycycline 6 weeks plus ivermectin group, and 2 in the ivermectin group
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Losses to follow-up At 20 months: 31 total; 15 in the doxycycline 4 weeks plus ivermectin group, 9 in the doxycycline 6 weeks plus ivermectin group, and 7 in the ivermectin group; At 27 months: 48 total; 15 in the doxycycline 4 weeks plus ivermectin group, 17 in the doxycycline 6 weeks plus ivermectin group, and 16 in the ivermectin group
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Number analyzed At 20 months: 36 total; 7 in the doxycycline 4 weeks plus ivermectin group, 13 in the doxycycline 6 weeks plus ivermectin group, and 16 in the ivermectin group; At 27 months: 19 total; 7 in the doxycycline 4 weeks plus ivermectin group, 5 in the doxycycline 6 weeks plus ivermectin group, and 7 in the ivermectin group
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Unit of analysis individual
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Power calculation &";The sample size was calculated for the presence of mf in the patients' skin. Applying Fisher's exact test, the power calculation resulted in a sample size of 20 patients per treatment arm for a power of 90% at a significance level of 0.001, in order to observe a significantly higher proportion of doxycycline-treated patients without skin mf compared to placebo. Allowing a dropout rate of 20%, the calculation suggested starting treatment with 25 patients for each arm&";
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Country Ghana
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Mean age total not provided; per group: 39 years (range 23 to 58) in the doxycycline 4 weeks plus ivermectin group, 41 years (range 19 to 59) in the doxycycline 6 weeks plus ivermectin group, and 39 years (range 20 to 61) in the ivermectin group
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Gender 51 (76.1%) men, 16 (23.9%) women; per group: 18 men, 4 women in the doxycycline 4 weeks plus ivermectin group; 18 men, 4 women in the doxycycline 6 weeks plus ivermectin group; and 15 men, 8 women in the ivermectin group
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Inclusion criteria &";nodule carriers of both sexes, aged 18–62 years, with a body weight of more than 40 kg, in good health, and without any clinical condition requiring chronic medication&";
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Exclusion criteria &";palpation of less than two onchocercomas, abnormal hepatic and renal enzymes (AST [0–40 IU/l], ALT [0–45 IU/l], and creatinine [3–126 mol/l]), pregnancy, breast-feeding, intolerance to doxycycline, and alcohol or drug abuse&";
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Equivalence of baseline characteristics no, &";The mf loads of the 6-week doxycycline group were higher than those in the other two groups&";
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Intervention 1 200 mg/d doxycycline for 4 weeks, then placebo for 2 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months
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Intervention 2 200 mg/d doxycycline for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months
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Intervention 3 placebo for 6 weeks, followed by a single dose of 0.15 mg/kg ivermectin after 6 months
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Length of follow-up Planned: 27 months; Actual: 27 months
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Primary outcome, as defined in study report "The primary outcome of this study was the assessment of sustained effects of doxycycline treatment on worm fertility and worm survival. Worm fertility was measured (1) by observation of the presence or absence of normal or degenerated embryos in female worms and of mf in the human nodule tissue using histology, and (2) by analysis of the presence and quantity of skin mf. Worm survival was measured as the proportion of living and dead worms detected by histology"
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Secondary outcomes, as defined in study report median and range of microfilarial loads for skin snips
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Adverse events reported yes
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Intervals at which outcomes assessed 6, 20, and 27 months
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Subgroup analyses none reported
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Study period September 2003 to November 2006
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Trial registration ISRCTN 71141922
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Funding sources &";This study received major funding by the European Commission (ICA4-2002-10051). AYD received a PhD scholarship from the German Academic Exchange Service (DAAD). PWzer Inc., Karlsruhe, donated Vibramycin® capsules and matching placebos. Technical assistance by Daniel Tagoe, Kumasi, Ingeborg Albrecht, Frank Geisinger, Hamburg, and Karin Lemke, Bonn, is gratefully acknowledged&";
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Disclosures of interest not reported
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Main outcomes, as reported in study
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Study design issues
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Random sequence generation (selection bias):Authors' judgement Low risk
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Random sequence generation (selection bias):Support for judgement &";The random allocation sequence was computer-generated by AH (StatView® version 4.5. for Macintosh)&";
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Allocation concealment (selection bias):Authors' judgement Low risk
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Allocation concealment (selection bias):Support for judgement &";The random allocation sequence was implemented by packing tablet containers according to the consecutive running numbers to which the mode of treatment had been allocated and which had been assigned to the patients&";
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Masking of participants and personnel (performance bias):Authors' judgement Low risk
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Masking of participants and personnel (performance bias):Support for judgement &";Blinding was assured by the exclusion of persons involved in randomisation or tablet packaging in any clinical or laboratory assessments as described. At the beginning of the study and during drug treatment, all members of the team and the patients were blinded. Patients were blinded to group allocation. A few nodules were excised from patients with many onchocercomas at 6 months after the beginning of the study to confirm the depletion of Wolbachia. These patients had been selected by AH without giving information on treatment to other members of the team (only a list with patient identification numbers was provided)&";
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Masking of outcome assessment (detection bias):Authors' judgement Low risk
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Masking of outcome assessment (detection bias):Support for judgement &";All persons involved with the assessment of nodules and skin biopsies in the laboratory were kept blinded until the end of the analysis&";
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Incomplete outcome data (attrition bias):Authors' judgement High risk
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Incomplete outcome data (attrition bias):Support for judgement At 20 months, 40 (52.6%) of 76 participants who were randomly assigned were excluded or lost to follow-up, and they were not included in the analysis At 27 months, 57 (75.0%) of 76 participants who were randomly assigned were excluded or lost to follow-up, and they were not included in the analysis
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Selective reporting (reporting bias):Authors' judgement High risk
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Selective reporting (reporting bias):Support for judgement &";New information based on the results of the studies that we had performed in 2000–2003 led to some deviations from the original study protocol&"; &";Since skin snipping without the prospect of nodulectomy would have led to reduced compliance at later follow-up times, we omitted mf analysis at 6 months in the 4-week doxycycline group&"; &";Since no difference between placebo and doxycycline was seen, we do not report this topic here&"; &";All patients who were available for follow-up underwent skin snipping regardless of their IVM uptake. However, IVM itself affects skin mf. Therefore, for the analysis of skin mf in Table 5, only patients who had taken IVM at 6 months were included. The data from patients without IVM were measured but were not considered, although inclusion of these patients did not alter the significance of the data (not shown)&";
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Other bias:Authors' judgement High risk
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Other bias:Support for judgement Difference at baseline: &";The mf loads of the 6-week doxycycline group were higher than those in the other two groups&"; Vibramycin and placebo capsules were donated by a pharmaceutical company
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Results & Comparisons


Results Data
Outcome: Parasitological      Population: All Participants
Time Point Measure Doxycycline 6 weeks + Ivermectin Ivermectin Doxycycline 4 weeks + ivermectin


20 months

N Analyzed 14 18 10
Mean 15% 94% 60%
SD
SE


27 months

N Analyzed 10 15 10
Mean 70% 80% 50%
SD
SE

Adverse Events
Arm or Total Title Description Number of events Comments
Doxycycline 6 weeks + Ivermectin Bloody diarrhea on day 3 of treatment
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Ivermectin
Doxycycline 4 weeks + ivermectin 1
Total
Doxycycline 6 weeks + Ivermectin Death died eight months after receiving doxycycline treatment
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Ivermectin
Doxycycline 4 weeks + ivermectin 1
Total