Efficacy, Safety, and Dose of Pafuramidine, a New Oral Drug for Treatment of First Stage Sleeping Sickness, in a Phase 2a Clinical Study and Phase 2b Randomized Clinical Studies

Christian Burri, Patrick D Yeramian, James L Allen, Ada Merolle, Kazadi Kyanza Serge, Alain Mpanya, Pascal Lutumba, Victor Kande Betu Ku Mesu, Constantin Miaka Mia Bilenge, Jean-Pierre Fina Lubaki, Alfred Mpoo Mpoto, Mark Thompson, Blaise Fungula Munungu, Francisco Manuel, Théophilo Josenando, Sonja C Bernhard, Carol A Olson, Johannes Blum, Richard R Tidwell, Gabriele Pohlig, Christian Burri, Patrick D Yeramian, James L Allen, Ada Merolle, Kazadi Kyanza Serge, Alain Mpanya, Pascal Lutumba, Victor Kande Betu Ku Mesu, Constantin Miaka Mia Bilenge, Jean-Pierre Fina Lubaki, Alfred Mpoo Mpoto, Mark Thompson, Blaise Fungula Munungu, Francisco Manuel, Théophilo Josenando, Sonja C Bernhard, Carol A Olson, Johannes Blum, Richard R Tidwell, Gabriele Pohlig

Abstract

Background: Sleeping sickness (human African trypanosomiasis [HAT]) is caused by protozoan parasites and characterized by a chronic progressive course, which may last up to several years before death. We conducted two Phase 2 studies to determine the efficacy and safety of oral pafuramidine in African patients with first stage HAT.

Methods: The Phase 2a study was an open-label, non-controlled, proof-of-concept study where 32 patients were treated with 100 mg of pafuramidine orally twice a day (BID) for 5 days at two trypanosomiasis reference centers (Angola and the Democratic Republic of the Congo [DRC]) between August 2001 and November 2004. The Phase 2b study compared pafuramidine in 41 patients versus standard pentamidine therapy in 40 patients. The Phase 2b study was open-label, parallel-group, controlled, randomized, and conducted at two sites in the DRC between April 2003 and February 2007. The Phase 2b study was then amended to add an open-label sequence (Phase 2b-2), where 30 patients received pafuramidine for 10 days. The primary efficacy endpoint was parasitologic cure at 24 hours (Phase 2a) or 3 months (Phase 2b) after treatment completion. The primary safety outcome was the rate of occurrence of World Health Organization Toxicity Scale Grade 3 or higher adverse events. All subjects provided written informed consent.

Findings/conclusion: Pafuramidine for the treatment of first stage HAT was comparable in efficacy to pentamidine after 10 days of dosing. The cure rates 3 months post-treatment were 79% in the 5-day pafuramidine, 100% in the 7-day pentamidine, and 93% in the 10-day pafuramidine groups. In Phase 2b, the percentage of patients with at least 1 treatment-emergent adverse event was notably higher after pentamidine treatment (93%) than pafuramidine treatment for 5 days (25%) and 10 days (57%). These results support continuation of the development program for pafuramidine into Phase 3.

Trial registration: ClinicalTrials.gov NCT00802594 NCT00803933.

Conflict of interest statement

The Swiss Tropical and Public Health Institute (STPH) planned, managed, and monitored the trial and is a member of the Consortium for Parasitic Drug Development, which developed pafuramidine maleate with a grant from the Bill and Melinda Gates Foundation. In addition, the STPH is an academic contract research organization, which develops therapies against human African trypanosomiasis (nifurtimox-eflornithine combination and fexinidazole) and are supported on behalf of the Drugs for Neglected Diseases initiative. Carol A. Olson is now employed my Sapphire Oak Consultants. Richard R. Tidwell had stock options with Immtech Pharmaceuticals, Inc. They are a publicly help, for profit business. He no longer holds these stock options. These competing interests do not alter our adherence to all PLOS NTDs policies on sharing data and materials.

Figures

Fig 1. CONSORT flowchart for pafuramidine phase…
Fig 1. CONSORT flowchart for pafuramidine phase 2 studies.
Fig 2. Schematic representation of the clinical…
Fig 2. Schematic representation of the clinical development program.

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