A Study to Evaluate the Efficacy and Tolerance of WR279,396 for Old World Cutaneous Leishmaniasis

Topical Treatment of Old World Cutaneous Leishmaniasis With WR279396 (Paromomycin/Gentamicin Ointment): Efficacy and Tolerance of a Regimen Using an Occlusive Polyurethane Dressing

This Phase 2 study is to determine whether WR279396 with occlusion (a polyurethane dressing) is more effective than WR279396 without occlusion for once daily treatment.

Extensive objective and subjective local tolerance data will also be captured during this trial, as well as surrogate markers (parasite loads and aminoglycosides concentration in the deep dermis) that may help to determine the optimal number and duration of treatments.

The results from this study will help determine the most practical treatment schedule and will answer questions that are crucial to improve the present treatment regimen with WR279396 which is twice a day for 20 days.

Forty-eight patients (48) with Old World cutaneous leishmaniasis will be randomly allocated to WR279396 treatment once a day for 20 days with an optimized polyurethane dressing (occlusion) (24 patients), or without occlusion (24 patients). All patients will be rescued with the standard of care accepted in Tunisia, if the patient is not cured. The active ingredients of WR279396 are two aminoglycosides - paromomycin sulphate (15%) and gentamicin sulphate (0.5%) - in a base (AQIC).

Each subject will be followed for clinical cure for 90 days after the initiation of treatment. Cure is defined as 100% reepithelialization without relapse by 3 months.

Tolerance will be evaluated by local adverse reactions and by laboratory signs of systemic events.

In addition to the clinical evaluation of the CL lesions, the following parameters/clinical healing surrogates will be investigated:

1. parasite load will be determined in superficial and deep lesional dermis samples at D0 and D10. The mean parasite reduction ratio (parasite load at D10/parasite load at D0) in each group will be compared;
2. aminoglycoside concentrations in superficial and deep infiltrated dermis in each group will be compared.

Inclusion Criteria: The study population will be selected from adults (18y) patients and children above 15y in Tunisia (Old World)

• Age: 15 - 75 years old
• Lesion character: each diameter (horizontal and vertical) of the lesion test must measure 7 mm, the lesion must be primarily ulcerative (i.e., not verrucous or nodular) and located in a biopsy friendly site of the body
• Parasitological diagnosis: have cutaneous leishmaniasis proven parasitologically in lesion selected for inclusion in study (lesion test).
• Informed consent: have given written informed consent to participate in the study: (i.e. patient or legal representative).

Exclusion Criteria:

• Drug intolerance: history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides in the patient or immediate family members.
• Previous use of antileishmanial drugs (within 2 months) or present use of routinely nephrotoxic or ototoxic drugs.
• Potential for follow up: Have less than 4 months time remaining in present address and/or plans to leave the area for more than 30 days.
• Extent of disease: More than 10 lesions or lesion ³ 5 cm or a lesion less than 2 cm from eye, in the ear, or a lesion in the face, that in the opinion of the attending dermatologist could potentially cause significant disfigurement.
• Location of disease: mucosal involvement.
• Disseminated disease: clinically significant lymphadenitis with nodules that are painful and > 1 cm in size in the lymphatic drainage of the ulcer.
• Concomitant medical problems: significant medical problems of the kidney or liver as determined by history and by the following laboratory studies:
• Kidney: clinically significant abnormalities of urine analysis, serum levels of Creatinine, BUN, total proteins > upper limit of normal for the laboratory.
• Liver: AST or ALT > upper limit of normal for the laboratory.
• General: glucose, Na, K, > upper limit of normal or < lower limit of normal for the laboratory. Volunteers in whom these normal laboratory values are exceeded by less than 25% will not be automatically excluded. These volunteers will be evaluated on the basis of history, physical, as well as laboratory values.
• Scheduled or ongoing pregnancy as determined clinical and biological criteria.
• Presence of signs or symptoms of peripheral neuropathy, myasthenia gravis or neuromuscular block