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

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.

Gambiense Human African Trypanosomiasis Sequelae after Treatment: A Follow-Up Study 12 Years after Treatment

“…In the region of Vanga, 96 first stage and 29 second stage HAT patients were recruited into several studies and trials between 2004 and 2005 [12][13][14][15][16]. The recruitment of participants for the present study took place during three visits to the following villages: (i) Kikongo Tango-Milundu, (ii) Nsalu, and (iii) Mayoko-Nkai.…”

“…Additionally, in the framework of clinical trials carried out between 2004 and 2005, clinical parameters were documented before and after treatment (but without a follow-up of three months) in 96 first stage HAT patients (parasitology confirmed) in Vanga. In these trials, the safety and efficacy of the newly developed drug pafuramidine was compared to the standard treatment with pentamidine for first stage HAT [15,16].…”

New Drugs for Human African Trypanosomiasis: A Twenty First Century Success Story

“…Small companies too, such as Immtech Pharmaceuticals Inc., Scynexis and Anacor Pharmaceuticals Inc. in the USA, also raised investment to develop new drugs against HAT. The first twenty years of the twenty first century have now seen the clinical trials and ultimate failure of a new orally available diamidine prodrug [23], the registration of the first all-orally available therapy against stage 2 disease [24], and the entry into clinical trials of a compound that may cure stage 2 HAT with a single oral administration [25]. This article outlines the successes seen in the development of new drugs for HAT in the twenty first century.…”

The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History

“…The reason that pentamidine is not active against cerebral trypanosomiasis, then, is because it is actively extruded again from the CNS to the blood, by P-glycoproteins (P-gp), Multidrug Resistance-Associated Proteins (MRPs) or other extrusion transporters [37]; Yang et al (2014) later reported that pentamidine and the furamidines are not substrates for P-gps [38]. Other diamidines such as diminazene and furamidine are equally ineffective against cerebral trypanosomiasis [39][40][41], and the distribution of DB75, although readily detectable in-whole brain extracts, was limited to the cells lining the BBB and blood-cerebrospinal fluid (CSF) barriers as it did not penetrate the brain parenchyma [36].…”