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INTRODUCTION The parasitic disease visceral leishmaniasis (VL) is most commonly caused by Leishmania donovani in eastern Africa, currently the region with highest burden worldwide. Current treatment for VL comprises the combination of sodium stibogluconate and paromomycin, SSG/PM; this is toxic, painful, and requires hospitalisation and daily injections. Treatments are urgently needed that are safe, effective, and appropriate for use in remote areas. METHODS We conducted a phase III open-label randomised non-inferiority trial in Ethiopia, Kenya, Sudan, and Uganda. The trial used a parallel-arm design with two arms, comparing the combination regimen of 20 mg/kg/day paromomycin and allometric miltefosine (MF) for 14 days with the current 17-day standard of care, 20 mg/kg/day SSG and 15 mg/kg/day PM. We enrolled adults and children aged 4-50 years with primary VL, without HIV or severe concomitant disease co-infection. The primary endpoint was definitive cure at 6 months’ follow-up. ETHICS This study was approved by the MSF Ethics Review Board and by ethics committees at the Institute of Endemic Diseases, Khartoum, Sudan; Kenya Medical Research Institute, Nairobi, Kenya; Makerere University, Uganda; and the University of Gondar, Ethiopia. Clinicaltrials.gov registry number, NCT03129646. RESULTS 439 predominantly male (80%) patients aged 4 to 50 years were recruited over a period of 29 months. A similar proportion of patients in the PM/MF and the SSG/PM arms achieved definitive cure at 6-month follow-up in primary efficacy analysis using modified intention-to-treat; mITT; 91.2% cure for PM/MF (97.5% confidence interval, CI, 85-98.6) and 91.8% for SSG/PM (97.5% CI, 85.6-99.2). Non-inferiority was not demonstrated in the mITT population, with the upper limit of the 97.5% CI, 7.4%, slightly exceeding the non-inferiority margin of 7%. However, the per protocol analysis did show non-inferiority, with 92% (97.5% CI, 85-98.5) cure in the PM/MF arm, as compared to 91.7% (97.5% CI, 84.7-98.2) in the SSG/PM arm. Most adverse drug reactions (ADR’s) were mild to moderate. The most common expected ADR’s were MF-related vomiting, and PM-related injection site pain and hypoacusis. ADR’s suggesting SSG-related cardiac toxicity were reported in 6.5% (11/170) of patients in the SSG/PM arm. Eighteen serious adverse events were reported in 13 patients, four of which were considered related to study drugs. Fatality rate in the trial was 0.9% (4/439), with one death judged due to SSG-related cardiotoxicity. CONCLUSION The results of this study demonstrate that the 14-day PM/MF regimen achieved a clinically meaningful rate of cure with very similar efficacy to the standard of care, SSG/PM. It was generally well tolerated, with ADR’s as expected, based on the known safety profiles of study drugs. The PM/MF regimen has one fewer painful injection per day, a 3-day shorter treatment duration, and with no risk of SSG-associated life threating cardiotoxicity, as compared to SSG/PM. This regimen may therefore provide a more patient-friendly alternative for adults and children with VL in eastern Africa. CONFLICTS OF INTEREST None declared |
