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

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  • Pohlig, Gabriele
    • Other Affiliation: Swiss Tropical and Public Health Institute; Pharmaceutical Medicine Unit; Swiss Centre for International Health
  • Bernhard, Sonja C.
    • Other Affiliation: Swiss Tropical and Public Health Institute; Pharmaceutical Medicine Unit; Swiss Centre for International Health
  • Blum, Johannes
    • Other Affiliation: Swiss Tropical and Public Health Institute; Medical Services and Diagnostic
  • Burri, Christian
    • Other Affiliation: Pharmacy & Clinical Pharmacology at the Division of Clinical Pharmacology; University of Basel
  • Mpanya, Alain
    • Other Affiliation: Programme Nationale de Lutte contre la Trypanosomiase Humaine Africaine
  • Lubaki, Jean-Pierre Fina
  • Mpoto, Alfred Mpoo
    • Other Affiliation: Mission Hospital of Vanga
  • Munungu, Blaise Fungula
    • Other Affiliation: Centre Hospitalier Lisungi BDOM
  • N’tombe, Patrick Mangoni
    • Other Affiliation: Mission Hospital of Vanga
  • Deo, Gratias Kambau Manesa
    • Other Affiliation: Clinique Damas Aleka
  • Mutantu, Pierre Nsele
    • Other Affiliation: Institut National de Recherche Biomédicale
  • Kuikumbi, Florent Mbo
    • Other Affiliation: Programme Nationale de Lutte contre la Trypanosomiase Humaine Africaine
  • Mintwo, Alain Fukinsia
  • Munungi, Augustin Kayeye
  • Dala, Amadeu
    • Other Affiliation: Instituto de Combate e de Controlo das Tripanossomíases
  • Macharia, Stephen
  • Bilenge, Constantin Miaka Mia
    • Other Affiliation: Ministry of Health
  • Mesu, Victor Kande Betu Ku
    • Other Affiliation: Programme des Maladies Tropicales Négligées; Ministère de la Santé Publique Kinshasa
  • Franco, Jose Ramon
    • Other Affiliation: World Health Organisation Geneva; Department of Control of Neglected Diseases
  • Dituvanga, Ndinga Dieyi
    • Other Affiliation: World Health Organization
  • Tidwell, Richard R.
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
  • Olson, Carol A.
    • Other Affiliation: Sapphire Oak Consultants; LLC
Abstract
  • BackgroundSleeping 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.MethodsThis 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/ConclusionsThe 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.Author SummarySleeping sickness, or human African trypanosomiasis (HAT), is a neglected tropical disease. Because only 2 treatment options are available to treat persons with stage 1 disease, and both require parenteral administration, oral drugs would be of great benefit to the affected population. In this Phase 3, multi-center, randomized, open-label, parallel-group study, we compared oral pafuramidine with intramuscular pentamidine in persons in sub-Sahara Africa with first stage HAT. At 12 months, the overall cure rates (combined clinical and parasitological cure) were similar: 89% in the pafuramidine group and 95% in the pentamidine group. At 24 months, the cure rates continued to be high: 84% and 89%, respectively. Pafuramidine’s safety profile was superior to the comparator drug, and it was consistent with the overall safety profile seen in previous Phase 2 studies. Upon further analysis, however, a renal safety issue was identified as being possibly related to pafuramidine and further clinical development was halted. Nevertheless, the clinical studies conducted in the pafuramidine development program provide a model for future studies in rural Africa.
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  • Article
Rights statement
  • In Copyright
Journal title
  • PLoS Neglected Tropical Diseases
Journal volume
  • 10
Journal issue
  • 2
Page start
  • e0004363
Language
  • English
ISSN
  • 1935-2735
  • 1935-2727

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