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.
- Pohlig G Swiss Tropical and Public Health Institute, Pharmaceutical Medicine Unit, Swiss Centre for International Health, Basel, Switzerland.
- Bernhard SC Swiss Tropical and Public Health Institute, Pharmaceutical Medicine Unit, Swiss Centre for International Health, Basel, Switzerland.
- Blum J Swiss Tropical and Public Health Institute, Medical Services and Diagnostic, Basel, Switzerland.
- Burri C Pharmacy & Clinical Pharmacology at the Division of Clinical Pharmacology, University of Basel, Basel, Switzerland.
- Mpanya A Programme Nationale de Lutte contre la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the Congo.
- Lubaki JP Hôpital Evangélique de Vanga, Vanga, Province of Bandundu, Democratic Republic of the Congo.
- Mpoto AM Mission Hospital of Vanga, Vanga, Democratic Republic of Congo.
- Munungu BF Centre Hospitalier Lisungi BDOM, Kinshasa, Democratic Republic of the Congo.
- N'tombe PM Mission Hospital of Vanga, Vanga, Democratic Republic of Congo.
- Deo GK Clinique Damas Aleka, Libreville, Gabon.
- Mutantu PN Institut National de Recherche Biomédicale, Kinshasa, Democratic Republic of the Congo.
- Kuikumbi FM Programme Nationale de Lutte contre la Trypanosomiase Humaine Africaine, Kinshasa, Democratic Republic of the Congo.
- Mintwo AF Zone de Santé de Djuma, Djuma, Democratic Republic of the Congo.
- Munungi AK Zone de Santé de Mpayi, Mpay, Democratic Republic of Congo.
- Dala A Instituto de Combate e de Controlo das Tripanossomíases, Luanda, Angola.
- Macharia S Management Sciences for Health, Juba, South Sudan.
- Bilenge CM Ministry of Health, Kinshasa, Democratic Republic of the Congo.
- Mesu VK Programme des Maladies Tropicales Négligées, Ministère de la Santé Publique Kinshasa, Democratic Republic of the Congo.
- Franco JR World Health Organisation Geneva, Department of Control of Neglected Diseases, Geneva, Switzerland.
- Dituvanga ND World Health Organization, Luanda, Angola.
- Tidwell RR University of North Carolina, Department of Pathology and Lab Medicine, School of Medicine, Chapel Hill, North Carolina, United States of America.
- Olson CA Sapphire Oak Consultants, LLC, Lindenhurst, Illinois, United States of America.
- 2016-02-17
Published in:
- PLoS neglected tropical diseases. - 2016
Administration, Oral
Adolescent
Adult
Aged
Angola
Benzamidines
Child
Democratic Republic of the Congo
Drug-Related Side Effects and Adverse Reactions
Female
Humans
Injections, Intramuscular
Kidney Diseases
Male
Middle Aged
Pentamidine
Pregnancy
Sudan
Treatment Outcome
Trypanosoma brucei gambiense
Trypanosomiasis, African
Young Adult
English
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.
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.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1371/journal.pntd.0004363
- PMID 26882015
- Persistent URL
- https://folia.unifr.ch/global/documents/270280
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