Journal Article

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

Wasunna, Monique, Kip, Anke E., Ali, Mohammed Hassan Sharaf, Olobo, Joseph, Musa, Ahmed, Balasegaram, Manica, Musa, Brima, Njenga, Simon, Khalil, Eltahir Awad Gasim, Kirigi, George, Alves, Fabiana, Omollo, Raymond, Wells, Susan, Juma, Rashid, Strub Wourgaft, Nathalie, Alexander, Neal, Ellis, Sally, Dorlo, Thomas P. C., Edwards, Tansy, Hailu, Asrat, Schoone, Gerard J., Elamin, Mohammed Yasein, Kimutai, Robert

2016

Overview

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. 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. 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. 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. The study was registered with ClinicalTrials.gov, number NCT01067443.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adolescent / Adult / Amphotericin B - administration & dosage / Amphotericin B - adverse effects / Antimony Sodium Gluconate - administration & dosage / Antimony Sodium Gluconate - adverse effects / Antiprotozoal Agents - administration & dosage / Antiprotozoal Agents - pharmacokinetics / Biology and Life Sciences / Care and treatment / Child / Clinical trials / Dosage and administration / Drug dosages / Drug Therapy, Combination / Epidemiology / Female / Health sciences / Hospitalization / Hospitals / Humans / Kenya / Leishmania donovani / Leishmaniasis, Visceral - drug therapy / Male / Medical research / Medicine and Health Sciences / Middle Aged / Miltefosine / Parasite Load / Parasitic diseases / Pharmaceutical industry / Pharmaceutical sciences / Pharmacokinetics / Pharmacology / Phosphorylcholine - administration & dosage / Phosphorylcholine - adverse effects / Phosphorylcholine - analogs & derivatives / Phosphorylcholine - pharmacokinetics / Research and Analysis Methods / Safety / Safety and security measures / Sodium / Studies / Sudan / Treatment Outcome / Tropical diseases / Vector-borne diseases / Visceral leishmaniasis / Young Adult