Safety and efficacy of paromomycin/miltefosine/liposomal amphotericin B combinations for the treatment of post-kala-azar dermal leishmaniasis in Sudan: A phase II, open label, randomized, parallel arm study

BackgroundTreatment for post-kala-azar dermal leishmaniasis (PKDL) in Sudan is currently recommended only for patients with persistent or severe disease, mainly because of the limitations of current therapies, namely toxicity and long hospitalization. We assessed the safety and efficacy of miltefosine combined with paromomycin and liposomal amphotericin B (LAmB) for the treatment of PKDL in Sudan.Methodology/principal findingsAn open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with persistent (stable or progressive disease for >= 6 months) or grade 3 PKDL, aged 6 to <= 60 years in Sudan. The median age was 9.0 years (IQR 7.0-10.0y) and 64% of patients were <= 12 years old. Patients were randomly assigned to either daily intra-muscular paromomycin (20mg/kg, 14 days) plus oral miltefosine (allometric dose, 42 days)-PM/MF-or LAmB (total dose of 20mg/kg, administered in four injections in week one) and oral miltefosine (allometric dose, 28 days)-AmB/MF. The primary endpoint was a definitive cure at 12 months after treatment onset, defined as clinical cure (100% lesion resolution) and no additional PKDL treatment between end of therapy and 12-month follow-up assessment. 104/110 patients completed the trial. Definitive cure at 12 months was achieved in 54/55 (98.2%, 95% CI 90.3-100) and 44/55 (80.0%, 95% CI 70.2-91.9) of patients in the PM/MF and AmB/MF arms, respectively, in the mITT set (all randomized patients receiving at least one dose of treatment; in case of error of treatment allocation, the actual treatment received was used in the analysis). No SAEs or deaths were reported, and most AEs were mild or moderate. At least one adverse drug reaction (ADR) was reported in 13/55 (23.6%) patients in arm 1 and 28/55 (50.9%) in arm 2, the most frequent being miltefosine-related vomiting and nausea, and LAmB-related hypokalaemia; no ocular or auditory ADRs were reported.Conclusions/significanceThe PM/MF regimen requires shorter hospitalization than the currently recommended 60-90-day treatment, and is safe and highly efficacious, even for patients with moderate and severe PKDL. It can be administered at primary health care facilities, with LAmB/MF as a good alternative. For future VL elimination, we need new, safe oral therapies for all patients with PKDL.Trial registrationClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955ClinicalTrials.gov ClinicalTrials.govTrial registrationClinicalTrials.gov NCT03399955, https://clinicaltrials.gov/study/NCT03399955ClinicalTrials.gov ClinicalTrials.gov Post-kala-azar dermal leishmaniasis (PKDL) is a skin rash which appears months or years after successful treatment of visceral leishmaniasis (VL) caused by Leishmania donovani. It is not life-threatening, and since patients with PKDL are otherwise well and may self-heal, they rarely seek treatment. Sandflies (the parasite vector) become infected with L. donovani after feeding on patients with PKDL, and so, from a public health perspective, ideally all patients, regardless of severity, would be treated to control VL, even those with mild disease. However, current therapies are toxic and/or require long hospitalization. Therefore, treatment is recommended only for patients with persistent disease or severe PKDL. We conducted a phase II trial in 110 patients with PKDL to assess two antimony-free combination therapies and demonstrated that a paromomycin/miltefosine regimen was suitably safe and highly efficacious even for moderate and severe PKDL, and could be administered at primary health centres. This makes it more patient-friendly, which is important since most people with PKDL are children. A liposomal amphotericin B/miltefosine regimen is a good alternative for implementation in hospitals for a shorter period. To support VL elimination in East Africa, new, safe, oral therapies for all patients with PKDL are still needed, including mild cases and women of reproductive potential unwilling or unable to use contraception.