Moxidectin for LF, Cote d'Ivoire (DOLF)

A Clinical Trial to Assess the Safety and Efficacy of Moxidectin Combination Treatments vs. Ivermectin Combination Treatments for Bancroftian Filariasis

The purpose of this study is to determine whether moxidectin (Mox) will be more effective than ivermectin (IVM) when used in single-dose combination therapies for lymphatic filariasis (LF).

This study will test the hypothesis that Moxidectin combination therapies are superior to ivermectin combination therapies for achieving sustained clearance of W. bancrofti microfilaremia. This trial is designed as single-site, Phase III, randomized, open-label, masked-observer superiority trial with four treatment arms: ivermectin + albendazole (IA), moxidectin + albendazole (MoxA), ivermectin + diethylcarbamazine + albendazole (IDA), and moxidectin + diethylcarbamazine + albendazole (MoxDA). The primary endpoint is the proportion of participants achieving complete clearance of microfilaremia at 12 months (IA vs. MoxA comparison) or 24 months (IDA vs. MoxDA comparison). Block randomization by gender will be used to assign treatment arms. The first 48 participants (12 each arm) will be treated at Agboville Hospital in Cote d'Ivoire at the Centre de Recherche de Filariose with inpatient AE monitoring and collection of post-treatment plasma drug levels (Part 1). For Part 1, active AE surveillance will be conducted in the hospital on days 1, 2, and 3, post-treatment, and in the participant's village of residence on day 7 post-treatment and passive surveillance will be conducted by trained village health workers on days 4-6. An interim safety analysis will take place after Part 1. If no safety concerns are identified, the remainder of the participants will be treated in their home villages, with active AE monitoring on days 1 and 2 post-treatment (Part 2) with passive surveillance by trained village health workers on days 3-7. Any participant in either Part 1 or Part 2 experiencing AEs of grade 2 or higher will be followed until adverse event (AE) severity falls below grade 2. Follow-up assessments for efficacy of treatments for all participants (Parts 1 and 2) will be conducted at 6, 12, 24, and 36 months. The study includes both safety and efficacy analyses. The safety assessment (Part 1 only) ends 7 days after treatment (unless AEs remain grade 2 or higher). The efficacy assessment (Parts 1 and 2 combined) ends when participants are retested for filarial infection 36 months post-treatment. Participants in the IA arm will receive IA annually (standard of care). Participants in the other arms will receive the assigned treatment at baseline; those found to be microfilaremic at 24 months post-treatment will be retreated with the same treatment received at baseline. If clearance of microfilariae (Mf) at 12 months in the IA arm is superior to Mf clearance in the MoxA arm, the MoxA group will be switched to annual IA treatment. The study design does not currently include stratification, nor do any sub-studies. However, the study may stratify based on pre-treatment Mf levels if high variability among pre-screening Mf counts is observed.

This trial is a single-site, Phase III, randomized, open-label, masked-observer superiority trial with four treatment arms (IA, MoxA, IDA, and MoxDA). Block randomization by gender will be used to assign treatment arms.

Recognizing that number and appearance of tablets received in each study arm will be noticeably different, this study will not be completely masked to participants or care providers. To minimize bias, administration of study medications will be performed by a staff member with no role in assessing AEs. AE assessments and all other outcome measures will be assessed by observers masked to the treatment assignment as best as possible.

Participants will receive one oral dose of Ivermectin (IVM) 200 µg/kg + Albendazole (ABZ) 400 mg (IA) annually for 24 months.

Participants will receive one oral dose of Mox 8 mg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with MoxA at the same dosage.

Participants will receive one oral dose of IVM 200 µg/kg + Diethylcarbamazine (DEC) 6mg/kg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with IDA at the same dosage.

Participants will receive one oral dose of Mox 8 mg + DEC 6mg/kg + ABZ 400 mg. Participants who are Mf positive at 24 months will be retreated with MoxDA at the same dosage.

The proportion of participants in IA and MoxA study arms with complete clearance of W. bancrofti microfilaremia at 12 months after treatment.

The proportion of participants in IDA and MoxDA study arms with complete clearance of W. bancrofti microfilaremia at 24 months after treatment.

The proportion of participants in each study arm with complete clearance of W. bancrofti microfilaremia at 6, 12, 24, & 36 months after treatment.

Inactivation of adult worm nests as assessed by scrotal ultrasound at 6, 12, and 24 months after treatment

Noncompartmental pharmacokinetic analyses of DEC, ABZ, ABZSO, ABZSO2, IVM and Mox concentrations will be conducted using WinNonlin (Pharsight Corporation; Cary, North Carolina, USA). Drug plasma concentrations and computed pharmacokinetic parameters will be listed by subject and summarized by drug or metabolite (geometric mean with coefficient of variation, arithmetic mean with standard deviation, minimum, maximum, number of observations). Individual and geometric mean (by time) concentrations versus time will be plotted for each treatment group on both linear and natural logarithm scales.

Inclusion Criteria: Provision of signed and dated informed consent form Male or female, aged 18-70 years In good general health as evidenced by medical history Peripheral night blood W. bancrofti Mf levels ≥40 Mf/mL No history of taking antifilarial medications in past 12 months Resident of the study area with no plans to change residence in the next 36 months For women of childbearing potential, willing to use appropriate method of contraception for one month following each treatment Exclusion Criteria: Pregnancy or currently breastfeeding Known allergic reactions to any of the study medications Evidence of severe or systemic comorbidities (aside from features of filarial disease), as judged by the principal investigator Baseline biochemical abnormalities, as indicated by AST, ALT, or creatinine > 2 times the upper limit of normal Evidence of urinary tract infection as indicated by 3+ nitrites on dipstick (individuals with 1+ or 2+ nitrites will not be excluded) or underlying chronic kidney disease as indicated by 3+ protein or 3+ blood on urine dipstick exam Hgb < 7 gm/dL (any such individuals will be referred to the local health center for evaluation and treatment) Positive skin snip for onchocerciasis

De-identified datasets used for published results will be shared publically through a journal or other open source data repository so that the broader scientific community can access it. Datasets used for published results will be shared publically through a journal or other open source data repository so that the broader scientific community can access it. Only de-identified data will be shared outside of the study team.

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