Safety and efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial

Raymond Omollo, Neal Alexander, Tansy Edwards, Eltahir A G Khalil, Brima M Younis, Abuzaid A Abuzaid, Monique Wasunna, Njenga Njoroge, Dedan Kinoti, George Kirigi, Thomas P C Dorlo, Sally Ellis, Manica Balasegaram, Ahmed M Musa, Raymond Omollo, Neal Alexander, Tansy Edwards, Eltahir A G Khalil, Brima M Younis, Abuzaid A Abuzaid, Monique Wasunna, Njenga Njoroge, Dedan Kinoti, George Kirigi, Thomas P C Dorlo, Sally Ellis, Manica Balasegaram, Ahmed M Musa

Abstract

Background: Treatment options for visceral leishmaniasis (VL) in East Africa are far from satisfactory due to cost, toxicity, prolonged treatment duration or emergence of parasite resistance. Hence there is a need to explore alternative treatment protocols such as miltefosine alone or in combinations including miltefosine, sodium stibogluconate (SSG) or liposomal amphotericin B. The aim of this trial is to identify regimen(s) which are sufficiently promising for future trials in East Africa.

Methods/design: A phase II randomized, parallel arm, open-labelled trial is being conducted to assess the efficacy of each of the three regimens: liposomal amphotericin B with SSG, Liposomal amphotericin B with miltefosine and miltefosine alone. The primary endpoint is cure at day 28 with secondary endpoint at day 210 (6 months). Initial cure is a single composite measure based on parasitologic evaluation (bone marrow, spleen or lymph node aspirate) and clinical assessment. Repeated interim analyses have been planned after recruitment of 15 patients in each arm with a maximum sample size of 63 for each. These will follow group-sequential methods (the triangular test) to identify when a regimen is inadequate (<75% efficacy) or adequate (>90% efficacy). We describe a method to ensure consistency of the sequential analysis of day 28 cure with the non-sequential analysis of day 210 cure.

Discussion: A regimen with adequate efficacy would be a candidate for treatment of VL with reasonable costs. The design allows repeated testing throughout the trial recruitment period while maintaining good statistical properties (Type I & II error rates) and reducing the expected sample sizes.

Trial registration: ClinicalTrials.gov: NCT01067443.

Figures

Figure 1
Figure 1
Consort Trial Diagram.
Figure 2
Figure 2
Triangular region for study arms. Showing the boundaries for analyzing the sequential trial using the Triangular test with the following parameters (p0 = 0.75, pa = 0.9, α = 0.05, β = 0.05, and n = 10). The vertical line at n = 30 indicates that, for the PK component of the trial, a minimum of 30 patients per arm will be recruited, unless the lower boundary has been crossed before then.

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