Safety, Efficacy and Pharmacokinetics (PK) Study of WR 279,396 Versus Paromomycin for Treatment of Cutaneous Leishmaniasis (Peru-PK)

The objectives of the study are to evaluate the pharmacokinetics (PK), safety, and efficacy of WR 279,396 (Paromomycin + Gentamicin Topical Cream) and Paromomycin Topical Cream in subjects with cutaneous leishmaniasis (CL).

This study is a single-site, randomized, double-blind, two group trial assessing the PK, safety and efficacy of WR 279,396 Topical Cream and Paromomycin Topical Cream in subjects with CL. Subjects will be screened over a period up to 28 days for eligibility including parasitology for confirmation of ulcerative CL. Subjects will be randomized in a targeted 1:1 ratio to receive either WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) (target n=15) or Paromomycin Topical Cream (15% paromomycin topical cream) (target n=15) by topical application to CL lesions once daily for 20 days. Because the primary objective of this trial is to determine PK in all age groups, subjects will be stratified by age: 5-11 yrs, 12-17 yrs, and ≥ 18 yrs with at least 6 PK subjects in each age stratum and no more than 18 total subjects will be randomized in any age range. A target of 30 subjects who complete the PK part of the study is the goal. Any subject who does not complete the PK portion of the study will be replaced with another subject from the same age group that will be given the same treatment assignment to maintain the balance. Safety will be assessed by monitoring adverse events (AEs), lesion site reactions, vital signs, and blood creatinine levels. The primary efficacy analysis will be by evaluation of an index lesion with secondary efficacy analyses including all lesions. Lesions will also be examined for parasite negativity by classical means (positive culture for promastigotes or microscopic identification of amastigotes in stained lesion tissue) on Day 21.

In adult subjects, on Days 1 and 20, blood will be collected prior to topical cream application and at 0.5h, 1h, 2h, 3h, and 4h ± 5 minutes and 8h, 12h, and 24h ± 15 minutes after completion of cream application to determine plasma levels of paromomycin and gentamicin to calculate PK parameters. Thus, the last blood draw in this series will occur on Day 21. In addition, blood will be collected on Days 4, 7, 12, and 17 ± 1 day before study drug application to examine trough plasma levels of paromomycin and gentamicin. A follow-up plasma sample for PK analysis will also be obtained on Day 28 ± 2 days.

Subjects under the age of 18 years will have a total of four blood samples drawn. The first will be drawn at pre-application and the second will be drawn at 4 hours ± 5 minutes after completion of application of the topical cream on Study Day 1. The third will be drawn pre-application and the fourth at 4 hours ± 5 minutes after completion of application of the topical cream on Study Day 20. Subjects who receive Paromomycin Topical Cream are not expected to have blood levels of gentamicin, but as the study is blinded, plasma specimens will be tested for both paromomycin and gentamicin.

The index lesion (primary ulcerated) and all other ulcerated lesions will be assessed for clinical response by measurement of the length and width of area of ulceration. A lesion will be considered to be completely cured if 100% re-epithelialization is observed (i.e., 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 (i.e., absence of signs of an active lesion).

Subjects will have an in-clinic follow-up weekly (Days 28, 35, 42, 49, 56, and 63 ± 2 days) after completion of treatment for safety assessments, lesion measurements, and lesion photographs. On Day 21, index lesions in adult subjects that have not completely re-epithelialized will be assessed for parasites by classical means (positive culture for promastigotes or microscopic identification of amastigotes in stained lesion tissue). An interim analysis of all of the data collected on all subjects who were randomized and completed the nominal Day 63 follow-up will be performed to make decisions about the final design of a Phase 3 trial. Subjects will continue to be followed for outcomes at Day 100 and 168 ± 14 days. A final analysis of outcomes after the longer term followup period has been completed for all subjects will be performed when the trial is closed. Follow-up evaluations include AEs, medication use, lesion measurements, and lesion photographs.

Patients who fail therapy (see definition of failure below) may be administered rescue therapy at the discretion of the patient's personal physician.

• Drug: WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream)
  topical application to CL lesions once daily for 20 days
  Other Name: Topical paromomycin/gentimicin cream
• Drug: Paromomycin Alone Cream (15% paromomycin topical cream)
  topical application to CL lesions once daily for 20 days

• Active Comparator: Paromomycin Alone Treatment
  Intervention: Drug: Paromomycin Alone Cream (15% paromomycin topical cream)
• Active Comparator: WR 279,396
  Intervention: Drug: WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream)

Inclusion Criteria:

• To be eligible for the study, the following must be answered "YES" or not applicable, as appropriate for the study subject:

  1. Is the subject a male or female at least 5 years-of-age?
  2. Is the subject or legal guardian able to give written informed consent or assent, as appropriate?
  3. Does the subject have a diagnosis of CL in at least one lesion by at least one of the following methods: 1) positive culture for promastigotes, or 2) microscopic identification of amastigotes in stained lesion tissue.
  4. Does the subject have at least one ulcerative lesion ≥ 1 cm and ≤ 5 cm, that meets the criteria for an index lesion?
  5. Is the subject willing to forego other forms of treatments for CL including other investigational treatments during the study?
  6. In the opinion of the investigator, is the subject (or their legal guardian) capable of understanding and complying with the protocol?
  7. If female and of child-bearing potential, did the subject 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?
  8. Does the subject have adequate venous access for blood draws?

Exclusion Criteria:

To be eligible for the study, the following must be answered "NO" or not applicable as appropriate for the study subject:

1. Does the subject have 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 drugs topically?
2. Does the subject have a lesion due to leishmania that involves the mucosa or palate or any signs of mucosal disease that might be due to leishmania?
3. Does the subject have signs and symptoms of disseminated disease in the opinion of the Principal Investigator?
4. Does the subject have > 10 lesions?
5. Is the subject a female who is breast-feeding?
6. Does the subject have 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?
7. Does the subject have significant organ abnormality, chronic disease such as diabetes, severe hearing loss, evidence of renal or hepatic dysfunction, or creatinine greater than 15%, or aspartate aminotransferase (AST), or alanine aminotransferase (ALT) greater than 1.5 times the above the upper limit of normal (ULN) as defined by the clinical laboratory defined normal ranges?
8. Has the subject received treatment for leishmaniasis including any medication with pentavalent antimony including sodium stibogluconate (Pentostam), meglumine antimoniate (Glucantime); amphotericin B (including liposomal amphotericin B and amphotericin B deoxycholate); or other medications containing paromomycin (administered parenterally or topically) or methylbenzethonium chloride (MBCL); gentamicin; fluconazole; ketoconazole; pentamidine; miltefosine, azithromycin or allopurinol that was completed within 8 weeks of starting study treatments?
9. Does the subject have a history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides?
10. Does the subject have any other topical disease/condition which would interfere with the objectives of this study?