Improved melarsoprol therapy for "Trypanosoma brucei rhodesiense" sleeping sickness

Human African Trypanosomiasis (HAT) is a parasitic disease that occurs in a chronic form caused \nby Trypanosoma brucei gambiense in Western and Central Africa, and an acute form caused by \nTrypanosoma brucei rhodesiense in Eastern and Southern Africa. \nThe treatment of HAT is unsatisfactory; for over 50 years melarsoprol (Arsobal®) has been the only \ndrug active against both forms of the disease and the only drug available to treat second stage T.b. \nrhodesiense infections. However, its use is hampered by high toxicity and lengthy and \ncomplicated treatment schedules. \nMelarsoprol therapy was substantially improved by the introduction of an abridged 10‐day \nmelarsoprol schedule in T.b. gambiense affected areas in 2003. The new schedule was based on \npharmacological investigations and was shown to be non‐inferior compared to the standard \nregimens in the framework of the clinical trial programs IMPAMEL I & II (1997‐2004). A significant \nreduction in overall hospitalization time from about 25 – 35 days to 13 days and a more economic \nuse of the drug made it favorable to the patients and the health system. Subsequently, the \nconduct of the IMPAMEL III program in T.b. rhodesiense affected areas was declared a high priority \nby the WHO. \nThe presented thesis aimed at a) the assessment of the safety and efficacy of the 10‐day \nmelarsoprol schedule in T.b. rhodesiense patients and b) the rationalization of the suramin pretreatment \nprior to melarsoprol which is proposed to control adverse drug reactions, but which is \nonly partially implemented in East Africa. \nThe IMPAMEL III program consisted of the sequential conduct of a proof‐of‐concept trial and a \nutilization study using historic controls as comparator. The trials were conducted in two \ntreatment centers in Tanzania and Uganda. Consenting patients with confirmed second stage T.b. \nrhodesiense HAT and a minimum age of 6 years were eligible for participation. Pregnant as well as \nunconscious or moribund patients were excluded from the trial. The primary outcome measures \nwere safety and efficacy at end of treatment. The secondary outcome measure was efficacy during \nfollow‐up after 3, 6 and 12 months. The studies were approved by the ethics committees in \nTanzania (National Institute for Medical Research/NIMR) and Uganda (Ministry of Health) and \nthe ethics committee of both cantons of Basel (EKBB), Switzerland. \nIn the proof‐of‐concept trial a total of 60 patients were enrolled into two consecutive subgroups (2x15 in each center) of which only the first subgroup received the suramin pre‐treatment. \nSuramin as well as steroids were administered according centre‐specific guidelines. In this trial, \nthe incidence of the encephalopathic syndrome (ES) was significantly higher in Uganda (20%) than in Tanzania (3.3%, p=0.0444). Adverse events were more frequent in patients that received \nsuramin (63.3%) than in patients that were directly treated with melarsoprol (23.3%, p=0.0018). \nBased on these results, the utilization study was designed as an extension to the arm of the proofof‐ \nconcept trial without suramin. An additional 77 patients were enrolled and directly treated \nwith melarsoprol. \nFinal data analysis was performed on the pooled data set of all patients that were directly treated \nwith the 10‐day melarsoprol schedule (i.e. without suramin, n=107). These results were compared \nto historic controls of patients treated during past two years in the same centers. The incidence of \nES in the trial population was 11.2% (CI 5‐17%) and 13% (CI 9‐17%) in the historic data. The \nrespective case fatality rates were 8.4% (CI 3‐13.8%) and 9.3% (CI 6‐12.6%). The historic data did \nnot allow any elucidation of the efficacy of the standard treatment regimens since systematic \nfollow‐up of patients was not routine. However, the efficacy of the 10‐day melarsoprol schedule \nwas highly satisfactory: all patients were free of parasites the day after treatment. 99% of the \npatients eligible for follow‐up were considered clinically cured 6 months after discharge. The 12 \nmonths follow up is currently ongoing. Based on the follow‐up results of the proof‐of‐concept \ntrial no issues regarding treatment efficacy are expected. \nOur results show that T.b. rhodesiense patients treated with the 10‐day melarsoprol schedule were \nnot subject to a higher incidence of serious adverse events (ES or death) than the historic controls \ntreated with the national regimens. The hospitalization time was reduced from an average of 29 \ndays to 13 days (p<0.0001). \nIn a separate analysis we compared the clinical presentation of the disease in Ugandan and \nTanzanian patients as a wide spectrum of disease severity has been described for T.b. rhodesiense \nHAT. \nIn an ancillary study, the molecular characterization of the trypanosomes confirmed that all \npatients were infected with T.b. rhodesiense. The fear of an overlap in the T.b. gambiense and T.b. \nrhodesiense disease distribution areas could not be confirmed in our study area. \nOn the basis of our trial experience we were able to write a review on clinical research in resource \nlimited settings. Minimal standards for sponsors and host countries were suggested in order to \nensure a trial conduct in compliance with international standards.