In-Hospital Safety in Field Conditions of Nifurtimox Eflornithine Combination Therapy (NECT) for T. b. gambiense Sleeping Sickness

Background: Trypanosoma brucei (T.b.) gambiense Human African trypanosomiasis (HAT; sleeping sickness) is a fatal disease. Until 2009, available treatments for 2nd stage HAT were complicated to use, expensive (eflornithine monotherapy), or toxic, and insufficiently effective in certain areas (melarsoprol). Recently, nifurtimox-eflornithine combination therapy (NECT) demonstrated good safety and efficacy in a randomised controlled trial (RCT) and was added to the World Health Organisation (WHO) essential medicines list (EML). Documentation of its safety profile in field conditions will support its wider use. Methodology: In a multicentre, open label, single arm, phase IIIb study of the use of NECT for 2nd stage T.b. gambiense HAT, all patients admitted to the trial centres who fulfilled inclusion criteria were treated with NECT. The primary outcome was the proportion of patients discharged alive from hospital. Safety was further assessed based on treatment emergent adverse events (AEs) occurring during hospitalisation. Principal Findings: 629 patients were treated in six HAT treatment facilities in the Democratic Republic of the Congo (DRC), including 100 children under 12, 14 pregnant and 33 breastfeeding women. The proportion of patients discharged alive after treatment completion was 98.4% (619/629; 95%CI [97.1%; 99.1%]). Of the 10 patients who died during hospitalisation, 8 presented in a bad or very bad health condition at baseline; one death was assessed as unlikely related to treatment. No major or unexpected safety concerns arose in any patient group. Most common AEs were gastro-intestinal (61%), general (46%), nervous system (mostly central; 34%) and metabolic disorders (26%). The overall safety profile was similar to previously published findings. Conclusions/Significance: In field conditions and in a wider population, including children, NECT displayed a similar tolerability profile to that described in more stringent clinical trial conditions. The in-hospital safety was comparable to published results, and long term efficacy will be confirmed after 24 months follow-up. Registration: The trial is registered at ClinicalTrials.gov, number NCT00906880. Author Summary: Sleeping sickness is a neglected tropical disease affecting people in Sub-Saharan Africa, most of them in poor, rural settings. If not treated, the disease usually progresses into a serious stage affecting the central nervous system, causing severe sleep disturbances, as well as other neurological and psychiatric disorders, coma, and death. Until recently, the only ways to treat 2nd stage gambiense sleeping sickness involved drugs that were either toxic (such as the arsenic derivative melarsoprol) or difficult to administer in resource-constrained settings (e.g. eflornithine). A new treatment, nifurtimox-eflornithine combination therapy (NECT), was developed and tested in clinical trials, and is now recommended as the treatment of choice for 2nd stage sleeping sickness. NECT is easier to administer than eflornithine, but more information needs to be gathered for its use in the field: logistical barriers must be overcome, health care staff must be well trained, and, importantly, the safety profile of the treatment in real-life conditions needs to be better evaluated. We report here the results of a study designed to gain better understanding of the clinical tolerability, feasibility and effectiveness of NECT in field conditions, and to gather data on its use in specific populations, such as children and pregnant women.