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

Abstract

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Participant Flow.

Fig 2. Sequential stopping for the three arms.

The horizontal axis (V) is proportional to sample size. The vertical axis (Z) is the observed minus expected number of cures, so higher values are more favourable. Each arm is shown by a line with three points representing, from left to right, the first interim analysis (decision: continue for all arms), the second interim analysis (decision: continue for all arms) and the final analysis. The final analysis (shown here) includes patients whose follow-up was still in progress at the time of the third interim analysis, and confirmed the ‘stop’ decisions. Having all stopped at the same analysis, the point estimates of proportion cured are the same for all arms (85%), as are the 95% confidence intervals (77–97%). Based on the probability tree method, the point estimate at day 210 for AmBisome + SSG is 87% (95% CI 77–97%); for AmBisome + Miltefosine it is 77% (64–90%) and for Miltefosine 72% (60–85%).

Fig 3. Comparison of the end-of-treatment miltefosine plasma concentrations between body weight categories.

The left plot shows the AmBisome + miltefosine arm (10 days of miltefosine), the right plot the miltefosine alone arm (28 days of miltefosine).

Fig 4. Parasite clearance from the blood in the first week of treatment.

All parasite blood loads are relative to the individual parasite load at baseline. The full lines indicate the mean and the error bars its 95% confidence interval, stratified per treatment arm.