PLoS Neglected Tropical Diseases (Feb 2016)

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

DOI
https://doi.org/10.1371/journal.pntd.0004362
Journal volume & issue
Vol. 10, no. 2
p. e0004362

Abstract

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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.