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

Military health care beneficiaries referred to WRNMMC for treatment of CL will be screened
over a period of up to 14 days for eligibility including parasitologic confirmation of
ulcerative CL. Recruitment will primarily be from a group of Department of Defense (DoD)
health care beneficiaries returning from Middle Eastern countries, thus they will have been
exposed to Old World leishmaniasis and likely have a diagnosis of Leishmania major (L.
major) but may have any diagnosis of leishmaniasis. A target enrollment of 30 eligible
subjects will receive WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) once
daily for 20 days. Safety will be assessed by monitoring adverse events (AEs), lesion site
reactions, vital signs, hematology, and blood chemistries. The primary efficacy analysis
will be by evaluation of an index lesion with secondary efficacy analyses including all
lesions.

In subjects who consent to the PK portion of the study, on Days 1 and 20, blood will be
collected prior to and after study drug application. Starting on Day 1 collections will be
prior to and at approximately 1, 2, 3, 4, 8, and 24 hours after completion of study drug
application. Starting on Day 20, collections will be prior to and at approximately 0.5, 1,
2, 3, 4, 8, 12, 24, 48, and 72 hours after completion of study drug application. Plasma
levels of paromomycin and gentamicin will be determined and used to calculate PK parameters.
In addition to the collections during the first 24 hours, blood will be collected on Days 4,
7, 12, and 17 +/- 1 day just prior to study drug application to examine trough plasma levels
of paromomycin and gentamicin. Blood levels on Days 21, 22, and 23 will also be used in the
trough level analysis. A follow-up plasma sample for PK analysis will also be obtained on
Day 28 +/- 2 days.

The index lesion and all other ulcerated lesions will be assessed for clinical response by
measurement of the length and width to determine the approximate area of ulceration. A
lesion will be considered to be completely cured if 100% re-epithelialization is observed
(this is a measurement of ulceration of 0 x 0 mm). Non-ulcerated lesions will also be
measured to monitor the total area of exposure of lesions to study drug and will be
evaluated for cure (absence of signs of an active lesion or induration).

Subjects will have an in-clinic follow-up at Day 28 +/- 2 days for a final PK blood draw,
safety assessments, lesion measurements, and lesion photographs.

Follow-up evaluations including lesion measurements, and lesion photographs at Days 60 +/- 7
days and 100 +/- 14 days will be accomplished in one of several ways:

1. Subjects living in close proximity to WRNMMC will be asked to return to the study site
for the follow-up visits.

2. Subjects outside the WRNMMC area who live close to a military medical treatment
facility (MTF) will be asked to go to the MTF where the Principal Investigator will
make arrangements with local medical staff to measure and photograph lesions.

3. Subjects outside the WRNMMC area who do not live near a MTF or who otherwise cannot or
will not return to WRNMMC will be provided with a ruler, a form to record lesion
measurements, a disposable camera to photograph lesions, and will be asked to mail the
camera and assessment forms to the Principal Investigator.

4. At the discretion of the Principal Investigator, subjects may be brought back to WRNMMC
for lesion evaluations.

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.