Research Article: 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

Date Published: February 16, 2016

Publisher: Public Library of Science

Author(s): 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, Carlos Franco-Paredes.

Abstract: BackgroundSleeping 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.MethodsThe 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/ConclusionPafuramidine 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.

Partial Text: Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently requires parenteral administration. It is caused by the protozoan parasites Trypanosoma brucei (T.b.) gambiense (the West African form of the disease) and Trypanosoma brucei rhodesiense (the East African form of the disease). T.b. gambiense is found in 24 countries in west and central Africa and currently accounts for over 98% of reported cases of sleeping sickness [1]. Sleeping sickness due to T.b. gambiense is characterized by a chronic progressive course, which may last from several months to several years before death occurs. The disease has two defined stages. The first stage is characterized by trypanosomes in the hemolymphatic system, which multiply in subcutaneous tissues, blood, and lymph. First stage symptoms entail bouts of fever, headaches, joint pains and itching. In the first stage, a person can be infected for months or even years without major signs or symptoms of the disease. When more evident symptoms emerge, the patient is often already in an advanced disease stage where the central nervous system is affected (second stage). The second (or neurological) stage begins once parasites penetrate the central nervous system, where their presence initiates deterioration in neurological function, including disruption of sleep/wake patterns that lend the name “sleeping sickness” to this stage of the disease [1].



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