Safety and Efficacy of Novel Combination Regimens for Treatment of Onchocerciasis

Study Overview
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Brief Summary
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This study will investigate the safety and effectiveness of combination regimens 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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The open label, randomized clinical trial studies the safety and efficacy of combination regimens for the treatment of onchocerciasis. Around 300 participants from Bong Mines, Liberia will be randomly assigned to one of four treatment groups after receiving Ivermectin pre-treatment: Ivermectin plus Albendazole (IA0, Ivermectin plus DEC plus Albendazole (IDA), Moxidectin plus albendazole (MoxA), or Moxidectin plus DEC plus Albendazole (MoxDA). Participants will be treated at baseline and 6 months after initial treatment. Safety will be measured through extensive adverse event monitoring from baseline to 6 months. Efficacy of the treatment will be measured at 24 months after the initial treatment by the proportion of all adult female worms that are fertile in the Onchocerca nodules and the percentage of participants without microfilaremia at 6, 18, and 24 months after the first treatment.

Official Title
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Safety and Efficacy of Novel Combination Regimens for Treatment of Onchocerciasis

Conditions
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Onchocercal Subcutaneous Nodule, Onchocerciasis, Onchocerciasis, Ocular, Onchocerca Infection, Tropical Disease

Intervention / Treatment
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* Drug: Ivermectin w/ Albendazole
* Drug: Ivermectin + Diethylcarbamazine + Albendazole
* Drug: Moxidectin + Albendazole
* Drug: Moxidectin + Diethylcarbamazine + Albendazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men and women, 18 years to 75 years old Participants must have at least 1 palpable subcutaneous nodule (onchocercoma) Participants with mean skin Mf counts ≥ 1 Mf/mg at the time of enrollment (prior to pretreatment) Exclusion Criteria: History of treatment with IVM or Mox less than six months prior to pretreatment with IVM. Treatment with IVM or Mox outside of the study after the pre-treatment clearing dose before treatment with one of the four study treatments. Pregnant or breastfeeding mothers. Severe ocular disease at baseline (assessed just prior to the first study treatment, approximately 6-12 months after IVM pretreatment). Briefly, these conditions include severe uveitis, severe glaucoma, severe keratitis, and/or cataracts that interfere with visualization of the posterior segment of the eye. Details regarding ocular exclusion criteria are provided below. Individuals who are excluded with significant ocular disease will be referred for appropriate All ocular disease exclusion criteria apply to either eye. That is to say, participants will be excluded if any of the ocular exclusion criteria listed below are met for either eye. These exclusions are needed to reduce the risk of study treatments worsening severe pre-existing ocular disease. They also are needed to ensure that study staff will be able to adequately evaluate the posterior segment before and after treatment. Any cataract that prevents clear visualization of fundus or imaging by OCT. Severe retinal nerve fiber layer thinning of the optic nerve in the superior and inferior quadrant analysis by OCT with a corresponding visual field defect in the superior and inferior hemifield, and/or visual field loss within 5 degrees of fixation in at least one hemifield. Note: If OCT is not available, the following exclusion criteria will apply: vertical cup/disc ratio by fundoscopy greater than or equal to 0.80 with a corresponding visual field defect in the superior and inferior hemifield, and/or visual field loss within 5 degrees of fixation in at least one hemifield. Intraocular pressure (IOP) greater than or equal to 25 by Goldmann tonometry. Retinal detachment or retinal break. Acute ocular infection (i.e., viral conjunctivitis, corneal ulcer, endophthalmitis). Optic atrophy with a reproducible visual field defect detected by confrontation visual field testing. Exam consistent with Herpes simplex virus eye infection. Homonymous hemianopsia, quadrantopsia, 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 participant. Severe tremor, blepharospasm, or other voluntary or involuntary motor condition that limits careful slit lamp examinations, OCT, gonioscopy, IOP measurement, fundus photography, and automated perimetry. Cognitive impairment that limits participant's ability to understand and perform a Visual Acuity Test with a 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. A history of uveitis not associated with onchocerciasis. 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 the participant rates as 9 or 10 out of 10. Best corrected or pinhole visual acuity worse than 6/60 (20/200). Age-related macular degeneration (AMD). >5 motile Mf in the anterior chamber in either eye at the time of secondary screening (6 months after pre-treatment with IVM).* The presence of one or more Mf in the posterior segment of the eye (detected by any opthalmological test performed) at the time of treatment (at least six months after pre-treatment with IVM). *Note regarding exclusion criteria t and u: The cut-off of 5 Mf in either anterior chamber was suggested by external reviewers of our proposal to the Gates Foundation. These were experts in onchocerciasis selected by the Foundation. The reviews were anonymous, so we do not know their names. They also suggested that we exclude persons with any Mf in the posterior segment of the eye, and we have added that exclusion criterion to the protocol. Significant comorbidities such as renal insufficiency (creatinine > 2 times the upper limit of normal), liver disease (jaundice or either AST or ALT greater than 2.5 times the upper limit of normal), 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 or hypersensitivity reactions or intolerance to IVM, Mox, ALB, or DEC. Evidence of severe or systemic comorbidities (aside from features of onchocerciasis), as judged by a study physician. Persons with baseline medical conditions that correspond to adverse event severity scores of grade 3 or higher will also be excluded. Evidence of urinary tract infection as indicated by 3+ nitrites by dipstick (individuals with 1+ or 2+ nitrites will not be excluded) or underlying chronic kidney disease as indicated by 3+ protein or 3+ blood by dipstick. Persons with urinary tract infections can be enrolled after their infections are treated and cured. Hgb <7 gm/dL; any such individuals will be referred to a local health center for evaluation and treatment).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: IVM + ALB (IA) - Dose of oral IVM (150 µg/kg) plus ALB (400 mg) Mox + ALB (MoxA) - Dose of oral Mox (8mg tablets) plus ALB (400mg) IVM + DEC + ALB (IDA) - Dose of oral IVM (150 µg/kg), DEC (6 mg/kg) and ALB (400 mg) MOX + DEC + IVM (MoxDA) - Dose of oral Mox (8 mg), DEC (6 mg/kg) and ALB (400 mg)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ivermectin + Albendazole (IA)<br>Dose of oral Ivermectin (150 µg/kg) plus Albendazole (400 mg) | Drug: Ivermectin w/ Albendazole<br>* Participants will be given a dose of oral Ivermectin (IVM) (150 µg/kg) plus Albendazole (ALB) (400 mg)<br>* Other names: IA;|
| Experimental: Ivermectin + Diethylcarbamazine + Albendazole (IDA)<br>Dose of oral Ivermectin (150 µg/kg), Diethylcarbamazine (6 mg/kg) and Albendazole (400 mg) | Drug: Ivermectin + Diethylcarbamazine + Albendazole<br>* Participants will be given a dose of oral Ivermectin (IVM) (150 µg/kg), Diethylcarbamazine (DEC) (6 mg/kg) and Albendazole (ALB) (400 mg)<br>* Other names: IDA;|
| Experimental: Moxidectin + Albendazole (MoxA)<br>Dose of oral Moxidectin (8mg) plus Albendazole (400 mg) | Drug: Moxidectin + Albendazole<br>* Participants will be given a dose of oral Moxidectin (Mox) (8 mg) plus Albendazole (ALB) (400 mg)<br>* Other names: MoxA;|
| Experimental: Moxidectin+ Diethylcarbamazine + Albendazole (MoxDA)<br>Dose of oral Moxidectin (8mg), Diethylcarbamazine (6 mg/kg) and Albendazole (400 mg) | Drug: Moxidectin + Diethylcarbamazine + Albendazole<br>* Participants will be given a dose of oral Moxidectin (Mox) (8 mg), Diethylcarbamazine (DEC) (6 mg/kg) and Albendazole (ALB) (400 mg)<br>* Other names: MoxDA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates and types of severe or serious adverse events within 6 months following Ivermectin treatments | Rates and types of severe or serious adverse events (grade 3 or higher) occurring within 6 months following combination treatment with DEC, ivermectin, and albendazole (IDA) vs. the comparator regimen of ivermectin plus albendazole (IA). | Baseline to 6 months | 
| Rates and types of severe or serious adverse events within 6 months following Moxidectin treatments | Rates and types of severe or serious adverse events (grade 3 or higher) occurring within 6 months following combination treatment with DEC, moxidectin, and albendazole (MoxDA) vs. the comparator regimen of moxidectin plus albendazole (MoxA). | Baseline to 6 months | 
| Proportion of all adult female worms that are fertile 24 months after first treatment | Proportion of all adult female worms in nodules that are fertile (i.e. with morulae or later developmental stages in the uterus) 24 months after the first treatment dose. The primary objective efficacy analysis will be restricted to comparisons between IA vs IDA and between MoxA vs. MoxDA, respectively. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of adverse events grade 3 or higher by Ivermectin treatment group, that occur within 7 days of treatment | Rates of adverse events grade 3 or higher by treatment group, that occur within 7 days of treatment. Comparison is made between IA vs IDA. | Baseline to 7 days after first treatment. | 
| Rates of adverse events grade 3 or higher by Moxidectin treatment group, that occur within 7 days of treatment | Rates of adverse events grade 3 or higher by treatment group, that occur within 7 days of treatment. Comparison is made between MoxA vs MoxDA. | Baseline to 7 days after first treatment. | 
| Rates of adverse events grade 3 or higher in participants with ocular MF in Ivermectin treatment groups. | Rates of adverse events grade 3 or higher that occur within 7 days of treatment in participants with detectable intraocular microfilariae just before the study treatment. | Baseline to 7 days after first treatment. | 
| Rates of adverse events grade 3 or higher in participants with ocular MF in Moxidectin treatment groups. | Rates of adverse events grade 3 or higher that occur within 7 days of treatment in participants with detectable intraocular microfilariae just before the study treatment. | Baseline to 7 days after first treatment. | 
| Rates of ocular adverse events (any grade) by Ivermectin treatment group | To compare rates of ocular adverse events (any grade) by treatment group that occur within 7 days of treatment. Comparison is between IA vs IDA. | Baseline to 7 days after first treatment. | 
| Rates of ocular adverse events (any grade) by Moxidectin treatment groups | To compare rates of ocular adverse events (any grade) by treatment group that occur within 7 days of treatment. Comparison is between MoxA vs MoxDA. | Baseline to 7 days after first treatment. | 
| Percentage of adult female worms in nodules that are alive | Percentage of adult female worms in nodules that are alive 24 months after the first round of study treatment. | 24 Months | 
| Percentage of nodules with microfilaria in tissue | The percentage of nodules with microfilariae in nodule tissue (outside of worms) | 24 Months | 
| Percentage of nodules that do not contain living adult worms | The percentage of nodules that do not contain any living adult female worms | 24 Months | 
| Percentage of participants without microfiladermia after the first study treatment. | Percentage of participants without microfiladermia at 6, 18 and 24 months after the first study treatment. | 6, 18, and 24 Months | 
| Percentage of participants with recurrence of microfilariae in the skin across treatment groups | Percentage of participants with recurrence of microfilariae in the skin at 18 and 24 months after the first study treatment (among persons who had complete Mf clearance 6 months after the first study treatment). | 18 and 24 Months | 
| Microfilariae density in the skin across treatment groups | Mf density in the skin at 6, 18, and 24 months after the first study treatment. | 6, 8, and 24 Months | 
| Percentage of nodules with fully or partially calcified worms | Percentage of nodules with fully or partially calcified worms 24 months after the first round of study treatment. | 24 Months |