A Phase-II, Randomised, Double-blind, Parallel-group Trial to Investigate Emodepside (BAY 44-4400) in Subjects With Onchocerca Volvulus Infection, Comprising: Part 1 to Investigate Safety, Tolerability, Pharmacodynamics, Pharmacokinetics and Dose-Response Relationship for Efficacy (Proof-of-Concept); Part 2 to Investigate Efficacy of Selected Doses, Safety, Tolerability and Pharmacokinetics
Overview
- Phase
- Phase 2
- Intervention
- emodepside
- Conditions
- Onchocerciasis
- Sponsor
- Drugs for Neglected Diseases
- Enrollment
- 578
- Locations
- 3
- Primary Endpoint
- Part 2 - absence (or presence) of skin microfilariae
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
The trial evaluates safety, tolerability, pharmacodynamics, pharmacokinetics, dose-response, and efficacy of emodepside tablets, administrated as a range of dose regimens, in adults infected with Onchocerca Volvulus.
Detailed Description
There is an urgent need for a macrofilaricidal drug targeting the adult stage of Onchocerca volvulus, which could be used in individual case management and, after appropriate testing, as an alternative drug to ivermectin in Mass Drug Administration (MDA) programs. Emodepside is a promising drug candidate to kill the adult and sexually mature Onchocerca volvulus. Emodepside was shown to be macrofilaricidal and microfilaricidal against a variety of filarial nematodes in non-clinical studies, and is a registered drug for animal health, commercialized by Bayer AG under the name of Profender® (in combination with praziquantel) or Procox® (in combination with toltrazuril). Three Phase I trials of emodepside with single or multiple doses of emodepside have been conducted in healthy Caucasian men. The results are encouraging and support continuation of the clinical development programme of emodepside as treatment for onchocerciasis. One of these trials also enabled the selection of a field-adapted tablet formulation, suitable for use in countries endemic for onchocerciasis. The present trial is designed in a stepwise approach starting with a proof of concept part, which is further subdivided in steps to investigate the safety, tolerability and pharmacokinetics of emodepside in the target population - Part 0 (pilot group), followed by investigations of the safety of emodepside in low and high-microfilaria carriers - Part 1a, and the dose-response relationship for efficacy of emodepside compared to placebo in microfilaria-positive patients - Part 1b. This approach allows to maximize the information regarding the safety of emodepside in the target population and to establish a dose range, in which emodepside is efficacious. Based on the information obtained from Parts 0 and 1, up to two efficacious dose regimens will be selected to carry forward into the confirmatory, active-controlled Part 2 of the trial, which will investigate the superiority of emodepside over ivermectin assessed using a clinically relevant endpoint, i.e. long-term absence of microfilariae at month 24.
Investigators
Eligibility Criteria
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Part 0 Pilot group emodepside 15mg Once a day (OD) 1 day
emodepside tablets 15 milligrams once a day for 1 day
Intervention: emodepside
Part 1 emodepside 30mg OD 1 day
emodepside tablets 30 milligrams once a day for 1 day
Intervention: emodepside
Part 1 emodepside 15mg OD 7 days
emodepside tablets 15 milligrams once a day for 7 days
Intervention: emodepside
Part 1 emodepside 15mg OD 14 days
emodepside tablets 15 milligrams once a day for 14 days
Intervention: emodepside
Part 1 emodepside 15mg twice a day (BID) 10 days
emodepside tablets 15 milligrams twice a day for 10 days
Intervention: emodepside
Part 1 placebo
matching placebo of emodepside tablets
Intervention: matching placebo of emodepside
Part 2 emodepside dose regimen A
emodepside tablets, dose regimen A selected from regimens tested in Part 1
Intervention: emodepside
Part 2 emodepside dose regimen A
emodepside tablets, dose regimen A selected from regimens tested in Part 1
Intervention: matching placebo of ivermectin
Part 2 emodepside dose regimen B
emodepside tablets, dose regimen B selected from regimens tested in Part 1
Intervention: emodepside
Part 2 emodepside dose regimen B
emodepside tablets, dose regimen B selected from regimens tested in Part 1
Intervention: matching placebo of ivermectin
Part 2 ivermectin
ivermectin, single oral dose of 150 micrograms per kilogram by weight
Intervention: matching placebo of emodepside
Part 2 ivermectin
ivermectin, single oral dose of 150 micrograms per kilogram by weight
Intervention: ivermectin
Outcomes
Primary Outcomes
Part 2 - absence (or presence) of skin microfilariae
Time Frame: 24 months
Absence (or presence) of skin microfilariae, assessed across all skin snips in a participant
Part 1 - absence (or presence) of skin microfilariae (co-primary outcome)
Time Frame: 12 months
Absence (or presence) of skin microfilariae across four skin snips
Part 1 - absence (or presence) of live female adult worms with normal embryogenesis
Time Frame: 12 months
Absence (or presence) of live female adult worms with normal embryogenesis, assessed by histological examination of nodules collected on nodulectomy
Secondary Outcomes
- Part 1- absence (or presence) of live female adult worms(12 months)
- Part 1 - Absence (or presence) of microfilariae in nodular tissue(12 months)
- Part 2 - Presence (or absence) of dead female adult worms(24 months)
- Part 1 - presence (or absence) of dead female adult worms(12 months)
- Part 1 - reduction in skin microfilarial density(up to 12 months)
- Part 2 - The reduction in skin microfilarial density(up to 24 months)
- Part 1 - Absence (or presence) of skin microfilariae(up to 12 months)
- Part 2 - Absence (or presence) of live female adult worms with normal embryogenesis(24 months)
- Part 2 - Absence (or presence) of live female adult worms(24 months)
- Part 2 - Absence (or presence) of skin microfilariae(up to 24 months)
- Part 2 - Absence (or presence) of microfilariae in nodular tissue(24 months)