Efficacy and Safety of AmBisome in Combination with Sodium Stibogluconate or Miltefosine and Miltefosine Monotherapy for African Visceral Leishmaniasis: Phase II Randomized Trial

Background: SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. Methods: A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments. Results: In sequential analyses with 49–51 patients per arm, initial cure was 85% (95% CI: 73–92) in all arms. At D210, definitive cure was 87% (95% CI: 77–97) for AmBisome + SSG, 77% (95% CI 64–90) for AmBisome + miltefosine and 72% (95% CI 60–85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. Conclusion: No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated. Trial Registration: The study was registered with ClinicalTrials.gov, number NCT01067443 Author Summary: Visceral leishmaniasis, or kala-azar, is a parasitic disease which is fatal without treatment. A 17-day treatment of sodium stibogluconate (SSG) with paromomycin (PM) is the recommended treatment in eastern Africa, but requires painful injections, causes adverse events, and patients need to stay in the hospital during treatment. An affordable, safe and effective oral treatment would be preferable. Whilst research to identify entirely new drugs is underway, existing treatments are being optimized as a short-term solution. Combination regimens based on AmBisome and miltefosine have been shown to be safe and effective in treating Indian patients, but there are no published data from use of these drugs in combination regimens from Africa, where efficacy of treatments can be different from India. Three regimens were evaluated for treating VL in eastern Africa, using AmBisome in combination with SSG or miltefosine, or miltefosine alone. Once again, drugs which are effective in India were found to be less so in African patients, and none of the regimes tested showed sufficiently high definitive cure rates to evaluate in Phase III trials. The results also suggest miltefosine was under-dosed in children and so allometric dosing, which takes into account the differences in drug metabolism seen in children compared to adults, needs to be studied.