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

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...

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Published in:PLoS neglected tropical diseases 2016-02, Vol.10 (2), p.e0004362-e0004362
Main Authors: Burri, Christian, Yeramian, Patrick D, Allen, James L, Merolle, Ada, Serge, Kazadi Kyanza, Mpanya, Alain, Lutumba, Pascal, Mesu, Victor Kande Betu Ku, Bilenge, Constantin Miaka Mia, Lubaki, Jean-Pierre Fina, Mpoto, Alfred Mpoo, Thompson, Mark, Munungu, Blaise Fungula, Manuel, Francisco, Josenando, Théophilo, Bernhard, Sonja C, Olson, Carol A, Blum, Johannes, Tidwell, Richard R, Pohlig, Gabriele
Format: Article
Language:English
Subjects:
Administration, Oral
Adolescent
Adult
Analysis
Angola
Antiprotozoal Agents - administration & dosage
Antiprotozoal Agents - adverse effects
Benzamidines - administration & dosage
Benzamidines - adverse effects
Biology and Life Sciences
Clinical trials
Democratic Republic of the Congo - epidemiology
Disease
Dosage and administration
Drug dosages
Drug therapy
Drug-Related Side Effects and Adverse Reactions - epidemiology
Drug-Related Side Effects and Adverse Reactions - pathology
Female
Funding
Humans
Laboratories
Male
Medicine and Health Sciences
Middle Aged
Nervous system
Orphan drugs
Parasites
Pentamidine - administration & dosage
Pentamidine - adverse effects
Pharmaceutical industry
Public health
Research and Analysis Methods
Stock options
Studies
Technical communication
Treatment Outcome
Trypanosomiasis
Trypanosomiasis, African - drug therapy
Young Adult
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Description
Summary: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. 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. 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.
ISSN:1935-2735
1935-2727
1935-2735
DOI:10.1371/journal.pntd.0004362