Paromomycin and Miltefosine Combination as an Alternative to Treat Patients With Visceral Leishmaniasis in Eastern Africa: A Randomized, Controlled, Multicountry Trial

Abstract

Background: This study aimed to determine whether paromomycin plus miltefosine (PM/MF) is noninferior to sodium stibogluconate plus paromomycin (SSG/PM) for treatment of primary visceral leishmaniasis in eastern Africa.

Methods: An open-label, phase 3, randomized, controlled trial was conducted in adult and pediatric patients at 7 sites in eastern Africa. Patients were randomly assigned to either 20 mg/kg paromomycin plus allometric dose of miltefosine (14 days), or 20 mg/kg sodium stibogluconate plus 15 mg/kg paromomycin (17 days). The primary endpoint was definitive cure after 6 months.

Results: Of 439 randomized patients, 424 completed the trial. Definitive cure at 6 months was 91.2% (155 of 170) and 91.8% (156 of 170) in the PM/MF and SSG/PM arms in primary efficacy modified intention-to-treat analysis (difference, 0.6%; 97.5% confidence interval [CI], -6.2 to 7.4), narrowly missing the noninferiority margin of 7%. In the per-protocol analysis, efficacy was 92% (149 of 162) and 91.7% (155 of 169) in the PM/MF and SSG/PM arms (difference, -0.3%; 97.5% CI, -7.0 to 6.5), demonstrating noninferiority. Treatments were well tolerated. Four of 18 serious adverse events were study drug-related, and 1 death was SSG-related. Allometric dosing ensured similar MF exposure in children (<12 years) and adults.

Conclusions: PM/MF and SSG/PM efficacies were similar, and adverse drug reactions were as expected given the drugs safety profiles. With 1 less injection each day, reduced treatment duration, and no risk of SSG-associated life-threatening cardiotoxicity, PM/MF is a more patient-friendly alternative for children and adults with primary visceral leishmaniasis in eastern Africa.

Clinical trials registration: NCT03129646.

Keywords: eastern Africa; miltefosine; paromomycin; phase 3 trial; visceral leishmaniasis.

Conflict of interest statement

Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Figures

Figure 1.

Patient disposition. aThe most common reasons for screening failure were negative parasitology (746 patients, 22.6%), laboratory abnormalities (338 patients, 13%), age <4 years or >50 years (329 patients, 12.7%), severe malnourishment (230 patients, 8.9%), or other reasons (245 patients, 9.4%). One patient died during screening. bOne additional patient discontinued the study treatment due to AEs but did not receive rescue medication and completed the study. cThree patients missed the EOT (day 28) visit but were included at later visits. Abbreviations: AE, adverse event; D, day; EOT, end of treatment; MF, miltefosine; PM, paromomycin; SSG, sodium stibogluconate.