Sodium stibogluconate (SSG) & paromomycin combination compared to SSG for visceral leishmaniasis in East Africa: a randomised controlled trial

Abstract

Background: Alternative treatments for visceral leishmaniasis (VL) are required in East Africa. Paromomycin sulphate (PM) has been shown to be efficacious for VL treatment in India.

Methods: A multi-centre randomized-controlled trial (RCT) to compare efficacy and safety of PM (20 mg/kg/day for 21 days) and PM plus sodium stibogluconate (SSG) combination (PM, 15 mg/kg/day and SSG, 20 mg/kg/day for 17 days) with SSG (20 mg/kg/day for 30 days) for treatment of VL in East Africa. Patients aged 4-60 years with parasitologically confirmed VL were enrolled, excluding patients with contraindications. Primary and secondary efficacy outcomes were parasite clearance at 6-months follow-up and end of treatment, respectively. Safety was assessed mainly using adverse event (AE) data.

Findings: The PM versus SSG comparison enrolled 205 patients per arm with primary efficacy data available for 198 and 200 patients respectively. The SSG & PM versus SSG comparison enrolled 381 and 386 patients per arm respectively, with primary efficacy data available for 359 patients per arm. In Intention-to-Treat complete-case analyses, the efficacy of PM was significantly lower than SSG (84.3% versus 94.1%, difference = 9.7%, 95% confidence interval, CI: 3.6 to 15.7%, p = 0.002). The efficacy of SSG & PM was comparable to SSG (91.4% versus 93.9%, difference = 2.5%, 95% CI: -1.3 to 6.3%, p = 0.198). End of treatment efficacy results were very similar. There were no apparent differences in the safety profile of the three treatment regimens.

Conclusion: The 17 day SSG & PM combination treatment had a good safety profile and was similar in efficacy to the standard 30 day SSG treatment, suggesting suitability for VL treatment in East Africa.

Clinical trials registration: www.clinicaltrials.govNCT00255567.

Conflict of interest statement

The authors have read the journal's policy and have the following conflicts: Manica Balasegaram is employed by DNDi as Head of VL Clinical Program. Sally Ellis is employed by DNDi as Clinical Manager (VL). Robert Kimutai is employed by DNDi as a Clinical Trial Manager. Raymond Omollo works for DNDi. Marius Mueller works for MSF.

Figures

Figure 1. CONSORT Patient Flowchart – SSG vs. PM.

SSG, sodium stibogluconate; PM, paromomycin sulphate; SAE, serious adverse event; LTFU, loss to follow-up; ITT, intention-to-treat; PP, per protocol. Patients included in the SSG (20 mg/kg/day for 30 days) vs. PM (20 mg/kg/day for 21 days) arms; a data from these patients were previously reported .

Figure 2. CONSORT Patient Flowchart – SSG vs. SSG&PM.

SSG, sodium stibogluconate; PM, paromomycin sulphate; SAE, serious adverse event; LTFU, loss to follow-up; ITT, intention-to-treat; PP, per protocol. Patients included in the SSG (SSG at 20 mg/kg/day for 30 days) vs. SSG & PM combination (SSG at 20 mg/kg/day & PM at 15 mg/kg/day for 17 days) arms; a patient was diagnosed with tuberculosis and was removed from the study before the end of treatment; b patient died from non-VL causes; c patient with deviation also had a missing outcome value and was already excluded from the ITT analysis.