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Few therapies for cutaneous leishmaniasis are available. In this phase 3 trial involving 375 patients with cutaneous leishmaniasis in Tunisia, paromomycin-based topical creams, as compared with a control agent, improved healing of lesions caused by Leishmania major . Leishmania, a genus of trypanosomatid protozoa, is endemic in 98 countries or territories worldwide, with infection transmitted by the bite of a female sand fly. The estimated yearly incidence of leishmania infection is 1.5 million cases of cutaneous leishmaniasis and 500,000 cases of visceral leishmaniasis. 1 Cutaneous leishmaniasis results from the parasitization of skin macrophages and generally is manifested as a papule that enlarges to a nodule that often ulcerates during a period of 1 to 3 months. Diverse leishmania species cause cutaneous leishmaniasis. There are at least five species, including Leishmania major, on the Eurasian and African continents and seven . . .

Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the standard monotherapy in India. Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5–60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer-generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00696969. Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93·0%; CI 87·5–96·3) for amphotericin B, 156 (97·5%; 93·3–99·2) for liposomal amphotericin B and miltefosine, 154 (97·5%; 93·24–99·2) for liposomal amphotericin B and paromomycin, and 157 (98·7%; 95·1–99·8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment. Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. Drugs for Neglected Diseases initiative and the Indian Council of Medical Research.

Abstract Background Cutaneous leishmaniasis (CL) presents as 1 or more skin lesions, which makes local therapy inherently attractive compared to systemic therapy that exposes the whole body to a drug. For 30 years, 15% paromomycin topical formulations have been in clinical experimentation. Recently, 15% paromomycin in Aquaphilic, a complex base to facilitate adsorption into the lesion, was found superior to aquaphilic vehicle for Old World Leishmania major disease. Methods We performed a randomized trial of 15% paromomycin in Aquaphilic (40 patients) vs Aquaphilic vehicle (20 patients) vs a positive control (intralesional pentamidine; 20 patients) against L. braziliensis CL in Bolivia Results Cure rates after 6 months of follow-up were 31 of 40 (77.5%, 95% confidence interval [CI] 62.5–88%) for paromomycin-Aquaphilic, 2 of 20 (10%, 95% CI 3–30%) for Aquaphilic vehicle (P < .0001 vs paromomycin-Aquaphilic), and 14 of 20 (70%, 95% CI 48–85.5%) for intralesional pentamidine. Both paromomycin-Aquaphilic and the Aquaphilic vehicle were very well tolerated, with only grade 1 adverse reactions in 5–10% of patients. Conclusions Against L. braziliensis CL, a prevalent, aggressive form of New World CL, 15% paromomycin-aquaphilic was vastly superior to a negative vehicle control and was comparable in efficacy to a positive control. This study enlarges the potential use of 15% paromomycin-Aquaphilic from one form of Old World CL to CL more generally. Clinical Trials Registration NCT03096457. Topical application of 15% paromomycin in Aquaphilic cured 77.5% of 40 patients with Bolivian Leishmania braziliensis cutaneous leishmaniasis, compared to 10% of 20 patients randomized to placebo (Aquaphilic). This suggests that paromomycin-Aquaphilic has a role for New World cutaneous leishmaniasis.

Visceral leishmaniasis (kala-azar) disproportionately affects the rural poor, with approximately 500,000 cases worldwide. Treatment options are limited, especially in resource-poor settings. In this open label, comparator-controlled trial, intramuscular paromomycin was found to be noninferior to intravenous amphotericin B in the treatment of visceral leishmaniasis, with cure rates of 94.6% and 98.8%, respectively. Intramuscular paromomycin was found to be noninferior to intravenous amphotericin B in the treatment of visceral leishmaniasis, with cure rates of 94.6% and 98.8%, respectively. Visceral leishmaniasis (kala-azar) is primarily a fatal vectorborne parasitic disease characterized by fever, hepatosplenomegaly, and pancytopenia. Most of the approximately 500,000 cases of visceral leishmaniasis reported worldwide affect the rural poor in India, Nepal, Bangladesh, Sudan, and Brazil. 1 Treatment options for visceral leishmaniasis are limited. Sodium stibogluconate, a historically effective and affordable pentavalent antimonial compound, is associated with fatal toxic effects, 2 – 4 and in some regions its use has led to the development of resistant strains of Leishmania donovani, 5 with the result that fewer than 50% of treated patients are cured. 2 , 6 – 8 In regions where antimony resistance is prevalent, . . .

AmBisome therapy for VL has an excellent efficacy and safety profile and has been adopted as a first-line regimen in Bangladesh. Second-line treatment options are limited and should preferably be given in short course combinations in order to prevent the development of resistant strains. Combination regimens including AmBisome, paromomycin and miltefosine have proved to be safe and effective in the treatment of VL in India. In the present study, the safety and efficacy of these same combinations were assessed in field conditions in Bangladesh. The safety and efficacy of three combination regimens: a 5 mg/kg single dose of AmBisome + 7 subsequent days of miltefosine (2.5 mg/kg/day), a 5 mg/kg single dose of AmBisome + 10 subsequent days of paromomycin (15 mg/kg/day) and 10 days of paromomycin (15 mg/kg/day) + miltefosine (2.5 mg/kg/day), were compared with a standard regimen of AmBisome 15 mg/kg given in 5 mg/kg doses on days 1, 3 and 5. This was a phase III open label, individually randomized clinical trial. Patients from 5 to 60 years with uncomplicated primary VL were recruited from the Community Based Medical College Bangladesh (CBMC,B) and the Upazila Health Complexes of Trishal, Bhaluka and Fulbaria (all located in Mymensingh district), and randomly assigned to one of the treatments. The objective was to assess safety and definitive cure at 6 months after treatment. 601 patients recruited between July 2010 and September 2013 received either AmBisome monotherapy (n = 158), AmBisome + paromomycin (n = 159), AmBisome + miltefosine (n = 142) or paromomycin + miltefosine (n = 142). At 6 months post- treatment, final cure rates for the intention-to-treat population were 98.1% (95%CI 96.0-100) for AmBisome monotherapy, 99.4% (95%CI 98.2-100) for the AmBisome + paromomycin arm, 94.4% (95%CI 90.6-98.2) for the AmBisome + miltefosine arm, and 97.9% (95%CI 95.5-100) for paromomycin + miltefosine arm. There were 12 serious adverse events in the study in 11 patients that included 3 non-study drug related deaths. There were no relapses or PKDL up to 6 months follow-up. All treatments were well tolerated with no unexpected side effects. Adverse events were most frequent during treatment with miltefosine + paromomycin, three serious adverse events related to the treatment occurred in this arm, all of which resolved. None of the combinations were inferior to AmBisome in both the intention-to-treat and per-protocol populations. All the combinations demonstrated excellent overall efficacy, were well tolerated and safe, and could be deployed under field conditions in Bangladesh. The trial was conducted by the International Centre for Diarrhoeal Disease Research (ICDDR,B) and the Shaheed Suhrawardy Medical College (ShSMC), Dhaka, in collaboration with the trial sites and sponsored by the Drugs for Neglected Diseases initiative (DNDi). ClinicalTrials.gov NCT01122771.

Paromomycin-based topical treatments were shown to be effective in curing cutaneous leishmaniasis (CL) lesions caused by Leishmania major in Tunisia. Cure rates of an index lesion were approximately 80%. As a follow on, we conducted a similar Phase 3 trial in Panama to demonstrate the efficacy of these treatments against New World species. The primary objective was to determine if a combination topical cream (paromomycin-gentamicin) resulted in statistically superior final clinical cure rates of an index lesion compared to a paromomycin alone topical cream for the treatment of CL, primarily caused by Leishmania panamensis. We conducted a randomized, double blind, Phase 3 trial of topical creams for the treatment of CL caused by Leishmania spp. Three hundred ninety nine patients with one to ten CL lesions were treated by topical application once daily for 20 days. The primary efficacy endpoint was percentage of subjects with clinical cure of an index lesion confirmed to contain Leishmania with no relapse. The clinical cure of the index lesion for paromomycin-gentamicin was 79% (95% CI; 72 to 84) and for paromomycin alone was 78% (95% CI; 74 to 87) (p = 0.84). The most common adverse events considered related to study cream application were mild to moderate dermatitis, pain, and pruritus. Superiority of paromomycin-gentamicin was not demonstrated. However, the approximately 80% cure rates for both topical creams were similar to those demonstrated in Tunisia and previously reported with parenteral antimonials.

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. 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. 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. 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. www.clinicaltrials.govNCT00255567.

Visceral leishmaniasis (VL) is a major health problem in developing countries. The untreated disease is fatal, available treatment is expensive and often toxic, and drug resistance is increasing. Improved treatment options are needed. Paromomycin was shown to be an efficacious first-line treatment with low toxicity in India. This was a 3-arm multicentre, open-label, randomized, controlled clinical trial to compare three treatment regimens for VL in East Africa: paromomycin sulphate (PM) at 15 mg/kg/day for 21 days versus sodium stibogluconate (SSG) at 20 mg/kg/day for 30 days; and the combination of both dose regimens for 17 days. The primary efficacy endpoint was cure based on parasite-free tissue aspirates taken 6 months after treatment. Overall, 135 patients per arm were enrolled at five centres in Sudan (2 sites), Kenya (1) and Ethiopia (2), when the PM arm had to be discontinued due to poor efficacy. The trial has continued with the higher dose of PM as well as the combination of PM and SSG arms. These results will be reported later. Baseline patient characteristics were similar among treatment arms. The overall cure with PM was significantly inferior to that with SSG (63.8% versus 92.2%; difference 28.5%, 95%CI 18.8% to 38.8%, p<0.001). The efficacy of PM varied among centres and was significantly lower in Sudan (14.3% and 46.7%) than in Kenya (80.0%) and Ethiopia (75.0% and 96.6%). No major safety issues with PM were identified. The efficacy of PM at 15 mg/kg/day for 21 days was inadequate, particularly in Sudan. The efficacy of higher doses and the combination treatment warrant further studies.

A recent study has shown that treatment of visceral leishmaniasis (VL) with the standard dose of 15 mg/kg/day of paromomycin sulphate (PM) for 21 days was not efficacious in patients in Sudan. We therefore decided to test the efficacy of paramomycin for a longer treatment duration (15 mg/kg/day for 28 days) and at the higher dose of 20 mg/kg/day for 21 days. This randomized, open-label, dose-finding, phase II study assessed the two above high-dose PM treatment regimens. Patients with clinical features and positive bone-marrow aspirates for VL were enrolled. All patients received their assigned courses of PM intramuscularly and adverse events were monitored. Parasite clearance in bone-marrow aspirates was tested by microscopy at end of treatment (EOT, primary efficacy endpoint), 3 months (in patients who were not clinically well) and 6 months after EOT (secondary efficacy endpoint). Pharmacokinetic data were obtained from a subset of patients weighing over 30 kg. 42 patients (21 per group) aged between 4 and 60 years were enrolled. At EOT, 85% of patients (95% confidence interval [CI]: 63.7% to 97.0%) in the 20 mg/kg/day group and 90% of patients (95% CI: 69.6% to 98.8%) in the 15 mg/kg/day group had parasite clearance. Six months after treatment, efficacy was 80.0% (95% CI: 56.3% to 94.3%) and 81.0% (95% CI: 58.1% to 94.6%) in the 20 mg/kg/day and 15 mg/kg/day groups, respectively. There were no serious adverse events. Pharmacokinetic profiles suggested a difference between the two doses, although numbers of patients recruited were too few to make it significant (n = 3 and n = 6 in the 20 mg/kg/day and 15 mg/kg/day groups, respectively). Data suggest that both high dose regimens were more efficacious than the standard 15 mg/kg/day PM for 21 days and could be further evaluated in phase III studies in East Africa.

This study was conducted in Bangladeshi patients in an outpatient setting to support registration of Paromomycin Intramuscular Injection (PMIM) as a low-cost treatment option in Bangladesh. This Phase IIIb, open-label, multi-center, single-arm trial assessed the efficacy and safety of PMIM administered at 11 mg/kg (paromomycin base) intramuscularly once daily for 21 consecutive days to children and adults with VL in a rural outpatient setting in Bangladesh. Patients ≥5 and ≤55 years were eligible if they had signs and symptoms of VL (intermittent fever, weight loss/decreased appetite, and enlarged spleen), positive rK39 test, and were living in VL-endemic areas. Compliance was the percentage of enrolled patients who received 21 daily injections over no more than 22 days. Efficacy was evaluated by initial clinical response, defined as resolution of fever and reduction of splenomegaly at end of treatment, and final clinical response, defined as the absence of new clinical signs and symptoms of VL 6 months after end of treatment. Safety was assessed by evaluation of adverse events. A total of 120 subjects (49% pediatric) were enrolled. Treatment compliance was 98.3%. Initial clinical response in the Intent-to-Treat population was 98.3%, and final clinical response 6 months after end of treatment was 94.2%. Of the 119 subjects who received ≥1 dose of PMIM, 28.6% reported at least one adverse event. Injection site pain was the most commonly reported adverse event. Reversible renal impairment and/or hearing loss were reported in 2 subjects. PMIM was an effective and safe treatment for VL in Bangladesh. The short treatment duration and lower cost of PMIM compared with other treatment options may make this drug a preferred treatment to be investigated as part of a combination therapy regimen. This study supports the registration of PMIM for use in government health facilities in Bangladesh. ClinicalTrials.gov identifier: NCT01328457.