WR 279, 396 Open Label Treatment Protocol in Tunisia

• Final clinical cure rate for the index lesion [ Time Frame: Final clincial cure is measured at day 98 ] [ Designated as safety issue: No ]
  Number of index lesions with 100% reepithelialization at Day 98 divided by the total number of index lesions that received any treatment.
• Number of participants with adverse events as a measure of safety and tolerability [ Time Frame: Adverse events graded 1-4 captured during treatment day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 ,19 and 20; also on follow up day 28 +/-, 42+/- 4 and 98 +/- 8 days ] [ Designated as safety issue: Yes ]
  Safety endpoints include all AEs including application site reactions graded 1-4 as per the predefined toxicity grading scale in the protocol.

• Lesion healing characteristics [ Time Frame: Measured at day 28, 42, and 98 ] [ Designated as safety issue: No ]
  Area of index lesion at each measurement time point.
• Lesion healing characteristics-early reepithelialization [ Time Frame: Measured at day 28, 42 ] [ Designated as safety issue: No ]
  Proportion of index lesions with 100% reepithelialization at Days 28 and 42.
• Lesion Healing Characteristics [ Time Frame: Measured at day 28, 42 and 98 ] [ Designated as safety issue: No ]
  Area of all ulcerated lesions at each measurement time point.
• Lesion Healing characteristics [ Time Frame: Measured at day 98 ] [ Designated as safety issue: No ]
  Final cure rate for all ulcerated lesions (100% reepithelialization for ulcerative lesions) at Day 98
• Lesion healing characteristics [ Time Frame: Measured at day 98 ] [ Designated as safety issue: No ]
  Loss of all lesion activity for non-ulcerative lesions at Day 98

The U.S. Army has recently completed a Phase 3 clinical trial in Tunisia. This is an open-label single site trial designed to expand our safety database and capture additional efficacy (final clinical cure rate of an index lesion) of WR 279,396 Topical Cream in Tunisian subjects with non-complicated, non-severe Cutaneous Leishmaniasis (CL). Subjects will be patients who visit Ministry of Health sponsored clinics in Tunisia who present with at least one CL lesion that is ulcerated and amenable to topical treatment. Potential trial subjects will be consented and screened for eligibility including medical history, physical exam, lesion parasitology, and renal and liver function tests. If eligible for the study, subjects will receive WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) (target n = 110). The cream will be applied topically to all CL lesions once daily for 20 days by an investigator or study nurse. If a subject develops a new lesion during the study, the new lesion may also be treated with the topical cream.

Subjects will have an in-clinic follow-up on Days 28 +/- 2 days, 42 +/- 4 days and 98 +/- 8 days to assess safety and cure rates. Safety variables including adverse events (AEs) and serious adverse events (SAEs) will be collected through Day 98. For the primary efficacy evaluation, the index ulcerative lesion will be assessed for clinical response by measurement of the length and width of area of ulceration. All other treated lesions will also be assessed for cure as secondary efficacy endpoints with ulcerated and non-ulcerated lesions being evaluated independently. An ulcerated lesion will be considered to be completely cured if 100% reepithelialization is observed. The length and width of non-ulcerated lesions (nodules, plaques) will also be measured and evaluated for cure (ie, absence of signs of an active lesion). The primary efficacy endpoint is the final clinical cure rate calculated by the number of index lesions that had 100% reepithelialization at Day 98 divided by the total number of index lesions that received at least one topical treatment of WR 279,396.

Inclusion Criteria:

• At least 18 years of age
• Subject has a diagnosis of CL in at least one lesion by at least one of the following methods: 1) microscopic identification of amastigotes in stained lesion tissue, or 2) positive culture for promastigotes.

• Subject has a parasitologically confirmed lesion that satisfies the following criteria for an Index lesion:

  • ulcerative in character
  • lesion size ≥ 1 cm and ≤5 cm (including the area of induration surrounding the lesion)
  • not located on the ear, or on a location that in the opinion of the PI is difficult to maintain application of study drug topically.
• Subject has < 7 leishmaniasis total lesions.
• Subject is willing to forego other forms of treatments for CL including other investigational treatments during the study.
• In the opinion of the investigator, the subject (or their legal guardian) is capable of understanding and complying with the protocol.

Exclusion Criteria:

• Female with a positive serum pregnancy test or who is breast feeding.
• History of clinically significant medical problems in the investigator's judgment that might interact, either negatively or positively, with topical treatment of leishmaniasis including any immunocompromising condition.
• Age adjusted blood creatinine or blood urea nitrogen (BUN) levels indicative of clinically significant renal disease or aspartate amino transferase (AST), alanine amino transferase (ALT), or total bilirubin that suggest clinically significant hepatic impairment as judged by the PI or subinvestigator. Note: This study is designed to evaluate populations who may have some renal or hepatic dysfunction as the drug has not been shown to have serum levels that would be expected to show renal or hepatic toxicity and treatment of the general population presenting with CL is highly desired based on its safety profile compared to other leishmanial drugs.
• Evidence of disseminated leishmaniasis.
• Received treatment for leishmaniasis with antimonials or any medication likely, in the opinion of the PI, to modify the course of the Leishmania infection within 56 days of starting study treatments.
• History of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides.