Safety, Efficacy, and PK of Topical Paromomycin/Gentamicin Cream for Treatment of Cutaneous Leishmaniasis

Study Overview
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Brief Summary
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The objectives of the study are to evaluate the safety, pharmacokinetics (PK), and efficacy of open label treatment with WR 279,396 (Topical Paromomycin/Gentamicin Cream)in subjects with cutaneous leishmaniasis (CL).

Detailed Description
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Subjects will be screened over a period of up to 14 days prior to first treatment, and will receive treatment once daily for 20 days. Safety will be assessed by monitoring AEs, lesion site reactions, vital signs, hematology, and blood chemistry parameters. Complete cure of ulcerated lesions is defined as 100% re-epithelialization or a measurement of ulceration of 0 x 0 mm. non-ulcerated treated lesions will also be measured to monitor total area of exposure of lesions to study drug and will be evaluated for cure (the absence of raised area on the skin). Follow-up evaluations will be at 28 +2 days, 60 +7 days and 100 +14 days.

Official Title
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An Open-Label Clinical Study to Examine the Safety, Efficacy, and Pharmacokinetics of WR 279,396 (Paromomycin + Gentamicin Topical Cream) for the Treatment of Cutaneous Leishmaniasis at Walter Reed National Military Medical Center (WRNMMC)

Conditions
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Leishmaniasis, Cutaneous

Intervention / Treatment
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* Drug: WR 279,396


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be male or female military health care beneficiary of any race or ethnicity and at least 18 years of age Subjects must give written informed consent. Subjects must have a diagnosis of CL in at least one lesion by at least one of the following methods: 1) positive culture for promastigotes; 2) microscopic identification of amastigotes in stained lesion tissue; 3) positive polymerase chain reaction (PCR) assay; and/or 4) prior diagnosis of CL within 14 days of the start of treatment. Subjects must have at least one ulcerative lesion ≥ 1 cm and < 5 cm, that meets the criteria for an index lesion (Larger lesions will be accepted for treatment, but these will not be included in the primary evaluation of efficacy). Subjects must be willing to forego other forms of treatments for CL including other investigational treatment during the study. Subjects must be capable of understanding and complying with the protocol (in the opinion of the investigator). Subjects must expect to be located in the Washington DC metropolitan area for at least the duration of the screening, 20-day treatment period, and Day 28 +/- 2 days follow-up visit. Subjects who are female and of child-bearing potential, must have a negative pregnancy test during screening and agree to use an acceptable method of birth control during the treatment phase and for 1 month after treatment is completed. Subject has adequate venous access for blood draws, if consented to the PK part of study. Exclusion Criteria: Subject has had a prior diagnosis of leishmaniasis where all lesions had healed. Subject has only a single lesion whose characteristics include any of the following: verrucous or nodular lesion (non-ulcerative), lesion <1 cm in its greatest diameter, lesion in a location that in the opinion of the Investigator is difficult to maintain application of study drug topically. Subject has a lesion due to Leishmania that involves the mucosa or palate. Subject has signs and symptoms of disseminated disease. Subject is a female who is breast-feeding. Subject has an active malignancy or history of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed. Subject has significant organ abnormality, chronic disease such as diabetes, severe hearing loss, evidence of renal or hepatic dysfunction, or creatinine, AST, or ALT greater than the upper limit of normal as defined by the clinical laboratory normal ranges. Subject has received treatment for leishmaniasis including thermosurgery (ThermoMed™) or any medication with pentavalent antimony including sodium stibogluconate (Pentostam), meglumine antimoniate (Glucantime); amphotericin B (including liposomal amphotericin B and amphotericin B deoxycholate); WR 279,396; or other medications containing paromomycin (administered parenterally or topically) or methylbenzethonium chloride (MBCL); gentamicin; fluconazole; ketoconazole; pentamidine; or allopurinol within 4 weeks of starting study treatment. Subject has a history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides. Subject has any other topical disease/condition which interferes with the objectives of this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: WR 279,396<br>All subjects in this one-arm study will receive topical WR 279,396 | Drug: WR 279,396<br>* Topical application of WR 279,396 cream (15% paromomycin + 0.5% gentamicin)once daily for 20 days<br>* Other names: Topical Paromomycin/Gentamicin Cream;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events | Application site reactions including elicited question about pain, and clinician examination for erythema/redness and swelling/edema Blood chemistries and hematology Vital signs | 3 months | 
| 100% Re-epithelialization of Index Lesion by Nominal Day 60 | Number of participants with 100% re-epithelialization of index lesion by nominal Day 60 | Day 60 | 
| Number of Participants Demonstrating Initial Clinical Improvements | Number of participants with > 50% re-epithelialization of index lesion by Day 60 followed by complete re-epithelialization of index lesion on or before nominal Day 100; | 60-100 days | 
| Number of Participants With No Relapse of Index Lesion Between Nominal Day 60 and 100 | Number of participants with no relapses of lesion between 60 and 100 days. Relapse is defined as a 10% or greater increase in the area of ulceration of the index lesion or a shift from 100% re-epithelialization to < 100% re-epithelialization of the index lesion at Day 100 for those subjects that had 100% re-epithelialization of the index lesion at nominal Day 60 or before | 60-100 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cures of All Other Lesions | Number of participants with 100% re-epithelialization of all ulcerated lesions and resolution of all other types of lesions | 100 days | 
| Complete Cure of Index Lesion by Day 100 | Number of participants with complete cure of index lesion by day 100. Cure rate is defined as 100% re-epithelialization of an ulcerated lesion | 100 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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leishmaniasis, cutaneous, WR 279,396, paromomycin, gentamicin, pharmacokinetics, safety, efficacy, military