2. Academic Validation
  3. Efficacy and Safety of Pafuramidine versus Pentamidine Maleate for Treatment of First Stage Sleeping Sickness in a Randomized, Comparator-Controlled, International Phase 3 Clinical Trial

Efficacy and Safety of Pafuramidine versus Pentamidine Maleate for Treatment of First Stage Sleeping Sickness in a Randomized, Comparator-Controlled, International Phase 3 Clinical Trial

  • PLoS Negl Trop Dis. 2016 Feb 16;10(2):e0004363. doi: 10.1371/journal.pntd.0004363.
Gabriele Pohlig 1,  Sonja C Bernhard 1 2,  Johannes Blum 3,  Christian Burri 2 4,  Alain Mpanya 5,  Jean-Pierre Fina Lubaki 6,  Alfred Mpoo Mpoto 7,  Blaise Fungula Munungu 8,  Patrick Mangoni N'tombe 7,  Gratias Kambau Manesa Deo 9,  Pierre Nsele Mutantu 10,  Florent Mbo Kuikumbi 5,  Alain Fukinsia Mintwo 11,  Augustin Kayeye Munungi 12,  Amadeu Dala 13,  Stephen Macharia 14,  Constantin Miaka Mia Bilenge 15,  Victor Kande Betu Ku Mesu 16,  Jose Ramon Franco 17,  Ndinga Dieyi Dituvanga 18,  Richard R Tidwell 19,  Carol A Olson 20
Affiliations

Affiliations

  • 1 Swiss Tropical and Public Health Institute, Pharmaceutical Medicine Unit, Swiss Centre for International Health, Basel, Switzerland.
  • 2 Pharmacy & Clinical Pharmacology at the Division of Clinical Pharmacology, University of Basel, Basel, Switzerland.
  • 3 Swiss Tropical and Public Health Institute, Medical Services and Diagnostic, Basel, Switzerland.
  • 4 Swiss Tropical and Public Health Institute, Department of Medicines Research, Basel, Switzerland.
  • 5 Programme Nationale de Lutte contre la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the Congo.
  • 6 Hôpital Evangélique de Vanga, Vanga, Province of Bandundu, Democratic Republic of the Congo.
  • 7 Mission Hospital of Vanga, Vanga, Democratic Republic of Congo.
  • 8 Centre Hospitalier Lisungi BDOM, Kinshasa, Democratic Republic of the Congo.
  • 9 Clinique Damas Aleka, Libreville, Gabon.
  • 10 Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of the Congo.
  • 11 Zone de Santé de Djuma, Djuma, Democratic Republic of the Congo.
  • 12 Zone de Santé de Mpayi, Mpay, Democratic Republic of Congo.
  • 13 Instituto de Combate e de Controlo das Tripanossomíases, Luanda, Angola.
  • 14 Management Sciences for Health, Juba, South Sudan.
  • 15 Ministry of Health, Kinshasa, Democratic Republic of the Congo.
  • 16 Programme des Maladies Tropicales Négligées, Ministère de la Santé Publique Kinshasa, Democratic Republic of the Congo.
  • 17 World Health Organisation Geneva, Department of Control of Neglected Diseases, Geneva, Switzerland.
  • 18 World Health Organization, Luanda, Angola.
  • 19 University of North Carolina, Department of Pathology and Lab Medicine, School of Medicine, Chapel Hill, North Carolina, United States of America.
  • 20 Sapphire Oak Consultants, LLC, Lindenhurst, Illinois, United States of America.
PMID: 26882015 DOI: 10.1371/journal.pntd.0004363
Abstract

Background: Sleeping sickness (human African trypanosomiasis [HAT]) is a neglected tropical disease with limited treatment options that currently require parenteral administration. In previous studies, orally administered pafuramidine was well tolerated in healthy patients (for up to 21 days) and stage 1 HAT patients (for up to 10 days), and demonstrated efficacy comparable to pentamidine.

Methods: This was a Phase 3, multi-center, randomized, open-label, parallel-group, active control study where 273 male and female patients with first stage Trypanosoma brucei gambiense HAT were treated at six sites: one trypanosomiasis reference center in Angola, one hospital in South Sudan, and four hospitals in the Democratic Republic of the Congo between August 2005 and September 2009 to support the registration of pafuramidine for treatment of first stage HAT in collaboration with the United States Food and Drug Administration. Patients were treated with either 100 mg of pafuramidine orally twice a day for 10 days or 4 mg/kg pentamidine intramuscularly once daily for 7 days to assess the efficacy and safety of pafuramidine versus pentamidine. Pregnant and lactating women as well as adolescents were included. The primary efficacy endpoint was the combined rate of clinical and parasitological cure at 12 months. The primary safety outcome was the frequency and severity of adverse events. The study was registered on the International Clinical Trials Registry Platform at www.clinicaltrials.gov with the number ISRCTN85534673.

Findings/conclusions: The overall cure rate at 12 months was 89% in the pafuramidine group and 95% in the pentamidine group; pafuramidine was non-inferior to pentamidine as the upper bound of the 95% confidence interval did not exceed 15%. The safety profile of pafuramidine was superior to pentamidine; however, 3 patients in the pafuramidine group had glomerulonephritis or nephropathy approximately 8 weeks post-treatment. Two of these events were judged as possibly related to pafuramidine. Despite good tolerability observed in preceding studies, the development program for pafuramidine was discontinued due to delayed post-treatment toxicity.

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