title: 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.
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.
  
  
  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.
authors.affiliation: Swiss Tropical and Public Health Institute, Pharmaceutical Medicine Unit, Swiss Centre for International Health, Basel, Switzerland.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pohlig
authors.affiliation: Swiss Tropical and Public Health Institute, Pharmaceutical Medicine Unit, Swiss Centre for International Health, Basel, Switzerland.|Pharmacy & Clinical Pharmacology at the Division of Clinical Pharmacology, University of Basel, Basel, Switzerland.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Bernhard
authors.affiliation: Swiss Tropical and Public Health Institute, Medical Services and Diagnostic, Basel, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Blum
authors.affiliation: Pharmacy & Clinical Pharmacology at the Division of Clinical Pharmacology, University of Basel, Basel, Switzerland.|Swiss Tropical and Public Health Institute, Department of Medicines Research, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Burri
authors.affiliation: Programme Nationale de Lutte contre la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the Congo.
authors.forename: Alain
authors.initials: A
authors.lastname: Mpanya
authors.affiliation: Hôpital Evangélique de Vanga, Vanga, Province of Bandundu, Democratic Republic of the Congo.
authors.forename: Jean-Pierre Fina
authors.initials: JP
authors.lastname: Lubaki
authors.affiliation: Mission Hospital of Vanga, Vanga, Democratic Republic of Congo.
authors.forename: Alfred Mpoo
authors.initials: AM
authors.lastname: Mpoto
authors.affiliation: Centre Hospitalier Lisungi BDOM, Kinshasa, Democratic Republic of the Congo.
authors.forename: Blaise Fungula
authors.initials: BF
authors.lastname: Munungu
authors.affiliation: Mission Hospital of Vanga, Vanga, Democratic Republic of Congo.
authors.forename: Patrick Mangoni
authors.initials: PM
authors.lastname: N'tombe
authors.affiliation: Clinique Damas Aleka, Libreville, Gabon.
authors.forename: Gratias Kambau Manesa
authors.initials: GK
authors.lastname: Deo
authors.affiliation: Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of the Congo.
authors.forename: Pierre Nsele
authors.initials: PN
authors.lastname: Mutantu
authors.affiliation: Programme Nationale de Lutte contre la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the Congo.
authors.forename: Florent Mbo
authors.initials: FM
authors.lastname: Kuikumbi
authors.affiliation: Zone de Santé de Djuma, Djuma, Democratic Republic of the Congo.
authors.forename: Alain Fukinsia
authors.initials: AF
authors.lastname: Mintwo
authors.affiliation: Zone de Santé de Mpayi, Mpay, Democratic Republic of Congo.
authors.forename: Augustin Kayeye
authors.initials: AK
authors.lastname: Munungi
authors.affiliation: Instituto de Combate e de Controlo das Tripanossomíases, Luanda, Angola.
authors.forename: Amadeu
authors.initials: A
authors.lastname: Dala
authors.affiliation: Management Sciences for Health, Juba, South Sudan.
authors.forename: Stephen
authors.initials: S
authors.lastname: Macharia
authors.affiliation: Ministry of Health, Kinshasa, Democratic Republic of the Congo.
authors.forename: Constantin Miaka Mia
authors.initials: CM
authors.lastname: Bilenge
authors.affiliation: Programme des Maladies Tropicales Négligées, Ministère de la Santé Publique Kinshasa, Democratic Republic of the Congo.
authors.forename: Victor Kande Betu Ku
authors.initials: VK
authors.lastname: Mesu
authors.affiliation: World Health Organisation Geneva, Department of Control of Neglected Diseases, Geneva, Switzerland.
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Franco
authors.affiliation: World Health Organization, Luanda, Angola.
authors.forename: Ndinga Dieyi
authors.initials: ND
authors.lastname: Dituvanga
authors.affiliation: University of North Carolina, Department of Pathology and Lab Medicine, School of Medicine, Chapel Hill, North Carolina, United States of America.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Tidwell
authors.affiliation: Sapphire Oak Consultants, LLC, Lindenhurst, Illinois, United States of America.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Olson
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000810:Angola; D001550:Benzamidines / Q000008:administration & dosage* / Q000009:adverse effects*; D002648:Child; D015023:Democratic Republic of the Congo; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000473:pathology; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010419:Pentamidine / Q000008:administration & dosage* / Q000009:adverse effects*; D011247:Pregnancy; D013397:Sudan; D016896:Treatment Outcome; D014347:Trypanosoma brucei gambiense; D014353:Trypanosomiasis, African / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D001550:Benzamidines; D010419:Pentamidine; C458513:pafuramidine