Safety and Efficacy of IDA for Onchocerciasis

Study Overview
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Brief Summary
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This DOLF study will investigate the safety and effectiveness of IDA treatment in persons with onchocerciasis when it is administered after pre-treatment with ivermectin to clear or greatly reduce microfilariae from the skin and eyes.

Detailed Description
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This study will provide preliminary data on the safety of IDA treatment in persons with onchocerciasis when it is administered after pre-treatment with IVM to clear or greatly reduce microfilariae from the skin and eyes. Widespread use of IDA following IVM pretreatment (I/IDA) has the potential to greatly accelerate elimination of lymphatic filariasis (LF) in African countries that are co-endemic for LF and onchocerciasis. study later. This study will also assess the efficacy of IDA for killing and sterilizing adult filarial worms. An improved macrofilaricidal treatment would be a major advance for the global program to eliminate onchocerciasis. Since the safety and efficacy objectives are both very important, we have included dual primary objectives for the study. Primary objectives: Safety: To compare rates and types of severe adverse events (grade 3 or higher) that occur within 7 days following 1 day or 3 days of treatment with triple drug treatment (IDA = diethylcarbamazine (DEC) with ivermectin (IVM) and albendazole (ALB)) with the comparator regimen of 1 day of treatment with ivermectin and albendazole (IA) in persons with active Onchocerca volvulus infections after pretreatment with ivermectin alone. Efficacy: To compare the effect of three treatment regimens (1 day of IDA, 3 days of IDA, or IA) for killing or sterilizing adult female O. volvulus worms based on the percentage of all adult female worms in nodules that are alive with embryos in the uterus 18 months after treatment. This is an open label, randomized clinical trial.

Official Title
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Safety and Efficacy of Combination Therapy With Ivermectin, Diethylcarbamazine, and Albendazole (IDA) for Individuals With Onchocerciasis

Conditions
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Onchocerciasis

Intervention / Treatment
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* Drug: IVM w/ ALB
* Drug: Single dose of IDA
* Drug: Three daily doses of IDA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women who were previously enrolled in the preceding Part I study (Protocol ID#201804116) and residing in the study area Must have at least palpable subcutaneous nodule (onchocercoma) Participants with baseline skin Mf counts less than or equal to 3 Mf/mg at the time of enrollment into the Part I study (Protocol ID#201804116) Exclusion Criteria: Pregnant and breastfeeding mothers within 1 month of giving birth Severe eye disease at baseline including uveitis, severe glaucoma, severe keratitis, and/or cataracts that interfere with visualization of the posterior segment of the eye as well as the list of ocular diseases as outlined below. All ocular disease exclusion criteria apply to either eye. Bilateral disease is not necessary to exclude a participant. A participant will be excluded if any of the criteria are met for one eye. Any cataract of any type preventing clear visualization of fundus or imaging on Optical Coherence Tomography (OCT). Severe retinal nerve fiber layer thinning in the superior and inferior quadrant analysis on Ocular Coherence Tomography of the optic nerve with a corresponding visual field defect of grade 2 or worse on the same eye.If Ocular Coherence Tomography is not available, the following exclusion criteria will apply: vertical Cup/disc ratio on fundoscopy (not by OCT reading) greater than or equal to 0.80. Intraocular pressure (IOP) greater than or equal to 25 by Goldmann tonometry .12 Retinal Detachment or Retinal Break Acute ocular infection (i.e., Viral conjunctivitis, corneal ulcer, endophthalmitis) Optic Atrophy with visual field defect reproducible on confrontation visual field testing.. Exam consistent with Herpes Simplex Virus eye infection Homonymous hemianopsia, quadrantanopsia, bitemporal hemianopsia, or central scotoma related to cerebral vascular disease by Automated Visual Field testing and confrontation visual field testing. Acute Angle Closure Glaucoma Gonioscopy grade 0 (slit) limiting ability to safely dilate patient Severe Tremor, blepharospasm, or other voluntary or involuntary motor condition that prevents ability to examine patient with slit lamp, OCT, gonioscopy, IOP measurement, fundus photography, and Frequency doubling technology perimetry. Cognitive impairment sufficient to prevent ability to understand and perform Visual Acuity Test with Tumbling E chart, confrontation visual field, slit lamp exam, or any other ocular exam component. Optic nerve edema Active retinopathy or retinitis not attributable to onchocercal disease History of uveitis not associated with onchocercal disease Any pre-existing chorioretinal scar or retinal degeneration and other significant retinal pathologies (foveomacular schisis, dystrophies, arterial macroaneurysms etc) involving the macula. Severe ocular pain, that patient rates as 9 or 10 out of 10 pain. Best corrected or pinhole visual acuity worse than 6/60 (20/200) Age related macular degeneration (AMD) Significant comorbidities such as renal insufficiency, liver failure, or any other acute or chronic illness identified by study clinicians and investigators that interferes with the participant's ability to go to school or work or perform routine household chores. Prior allergic / hypersensitivity reactions or intolerance to IVM, ALB, or DEC. Treatment with IVM outside of the study after the pre-treatment clearing dose provided in the Part I study. >5 motile Mf in the anterior chamber in either eye at the time of enrollment (after pre-treatment with IVM). Any Mf identified in the posterior segment of the eye at the time of enrollment (six months after pre-treatment with IVM). Any other condition identified by study clinicians or investigators that may preclude participation in the study.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be split into two strata - those without ocular Mf detected six months after ivermectin pretreatment in the Part I preceding study AND without ocular Mf detected at baseline in the part II study will be in stratum 1. Those participants with ocular Mf detected 6 months after ivermectin pretreatment in the preceding study OR with ocular Mf detected at the baseline exam for this study will be in stratum 2. Stratum 1 will be enrolled first, followed by stratum 2. Members of each stratum will be evenly randomized into one of three treatment arms: IVM + ALB - Single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB) IDA x 1 dose - Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) IDA x 3 doses -Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: IVM + ALB<br>Single dose of oral IVM (150 µg/kg) plus ALB (400 mg) | Drug: IVM w/ ALB<br>* Participants will be given a single dose of oral IVM (150 µg/kg) plus ALB (400 mg) (IVM/ALB)<br>* Other names: IA;|
| Experimental: IDA x 1 dose<br>Single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) | Drug: Single dose of IDA<br>* Participants will be given a single dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)<br>* Other names: IVM/DEC/ALB (x1);|
| Experimental: IDA x 3 doses<br>Once daily for 3 days oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) | Drug: Three daily doses of IDA<br>* Participants will be given one daily dose for 3 days of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg)<br>* Other names: IVM/DEC/ALB (x3);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of Severe Adverse Events (SAEs) Across Study Arms | Rates of severe adverse events (grade 3 or higher) following 1-day or 3-day triple drug treatment will be compared against those of the comparator regimen of 1 day of IVM/ALB. | Within 7 days following end of treatment | 
| Percentage of Worms Killed Across Study Arms | The effect of three treatment regimens for killing adult female O. volvulus worms will be compared based on the percentage of all adult female worms in nodules that are alive with embryos in the uterus 18 months after treatment. | 18 months following treatment. | 
| Percentage of Worms Sterilized Across Study Arms | The effect of three treatment regimens for sterilizing adult female O. volvulus worms will be compared based on the percentage of all adult female worms that are fertile in the nodules 18 months after treatment. | 18 months following treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of SAEs by Treatment Group in Those With Intraocular Microfilariae Just Prior to Treatment With IDA | Rates of adverse events grade 3 or higher that occur within 7 days of treatment in the subset of participants who have intraocular microfilariae just prior to treatment with IDA will be compared by treatment group. | within 7 days following end of treatment | 
| Rates of Ocular Adverse Events (Any Grade) by Treatment Group | Rates of ocular adverse events of any grade within 3 months will be compared by treatment group. | within 3 months of treatment with IDA | 
| Effectiveness of Killing Adult Female Worms | The effectiveness of three treatment regimens for killing adult female O. volvulus worms based on the percentage of all adult female worms in nodules that are alive 18 months after treatment. | 18 months following treatment | 
| Effectiveness of Clearing Microfilariae From Skin by Skin Snips | The effectiveness of three treatment regimens for complete clearance of microfilariae from the skin as determined by skin snips at 3, 12, and 18 months after treatment with IDA will be compared by treatment arm. | Baseline, 3 months, 12 months, & 18 months following treatment. | 
| Effectiveness for Preventing Reappearance of Microfilariae in the Skin by Skin Snips | The effectiveness of three treatment regimens for preventing reappearance of microfilariae in the skin as determined by skin snips at 12 and 18 months after treatment will be compared by treatment arm. Measured by the presence of microfilariae in skin snips. | Baseline, 12 months, and 18 months following treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ophthalmology