Phase 3 Study of Walter Reed (WR) 279,396 and Paromomycin Alone for the Treatment of Cutaneous Leishmaniasis in Panama

A Randomized, Double-blind, Pivotal Phase 3 Study of WR 279,396 (Paromomycin + Gentamicin Topical Cream) and Paromomycin Alone Topical Cream for the Treatment of Cutaneous Leishmaniasis in Panama

This study is a pivotal Phase 3, randomized, double-blind, 3-site, two-group trial assessing the efficacy and safety of WR 279,396 Topical Cream and Paromomycin Alone Topical Cream in subjects with CL in Panama. The primary objective of this study is to determine if WR 279,396 results in statistically superior final clinical cure rates of an index lesion when compared with Paromomycin Alone for the treatment of CL in Panama expected to be caused by L panamensis.

Study Overview

• Status: Completed
• Conditions: Cutaneous Leishmaniasis
• Intervention / Treatment: Drug: WR 279,396; Drug: Paromomycin

Detailed Description

Subjects will be recruited from three regions in Panama known to be endemic for L panamensis CL. Subjects will be screened over a period up to 28 days for eligibility including medical history, physical examination, leishmaniasis history, vital signs, clinical chemistry, prior medications, and parasitology for confirmation of ulcerative CL. If eligible, subjects will be randomized in a targeted 1:1 ratio (200 subjects per group) using site as a stratification variable to receive either WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) or Paromomycin Alone (15% paromomycin topical cream) by topical application to CL lesions once daily for 20 days. Efficacy will be assessed by measuring the size of the index lesion ulcer, non-index lesions ulcers, and overall size of other non-ulcerated lesions at baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days. A notation will be made if clinical evidence of parasite persistence is observed at the Day 63 and beyond visits including significant erythema and induration when a lesion has otherwise completely re-epithelialized to document any subjects removed from the study early if the investigator judges them to be in need of rescue treatment. A photograph will be taken of all lesions at baseline, Day 20 and each of the follow-up visits. Safety will be assessed by monitoring adverse events (AEs) from the start of treatment until study completion, lesion site reactions during treatment, physical examination of the nasal and oral mucosa for appearance of mucosal leishmaniasis on Days 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days, concomitant medication use for the duration of the study, blood creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on Study Day 20. After the sponsor's approval, biochemistry can be repeated in the case of abnormal results and if the causes of these results could not be determined. A repeat pregnancy test on Day 35. Recent infection with leishmaniasis prior to the start of the study may result in the development of lesions that were not present at the start of the study that did not receive treatment. New lesions may be treated at the discretion of the investigator with the topical cream to which the subject was assigned any time during the conduct of the study except that treatment must be completed by the Day 168 visit. If a new lesion is discovered at the final study visit, the subject will be referred to their primary physician for treatment.

Subjects who fail therapy (see definition of failure below) will be taken off study and may be administered rescue therapy at the discretion of the subject's personal physician. If the subject met the criteria for therapy failure but was undergoing treatment for new lesions, the subject can continue in the study (by signing a consent addendum) if the investigator decides it is in the best interest of the subject to do so.

• Study Type: Interventional
• Enrollment (Actual): 399
• Phase: Phase 3

Contacts and Locations

Study Locations

• Panama
  • Panama City, Panama
    • Instituto Conmemorativo Gorgas de Estudios de la Salud,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female at least 2 years-of-age
• Subject or legal guardian able to give written informed consent or assent, as appropriate
• 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
• At least one ulcerative lesion ≥ 1 cm and ≤ 5 cm that has a diagnosis of CL
• Willing to forego other forms of treatments for CL including other investigational treatments during the study
• In the opinion of the investigator, subject (or their legal guardian), subject is capable of understanding and complying with the protocol
• If female and of child-bearing potential, must have a negative serum pregnancy test during screening and agree to use an acceptable method of birth control during the treatment phase and for 1 week after treatment is completed

Exclusion Criteria:

• Lesion due to leishmania that involves the nasal or oral mucosa or any signs of mucosal disease that might be due to Leishmania
• Only a single lesion on the ear with erosive cartilage
• Signs and symptoms of disseminated disease in the opinion of the investigator
• More than 10 lesions
• Female who is breast-feeding
• Significant organ abnormality, chronic disease such as diabetes, severe hearing loss, evidence of renal or hepatic dysfunction, or creatinine, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) greater than 15% above the upper limit of normal (ULN) as defined by the clinical laboratory defined normal ranges
• 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 56 days of starting study treatments
• History of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: WR 279,396; (Paromomycin and Gentamicin Topical Cream)	Drug: WR 279,396; WR 279,396 is a topical cream of paromomycin 15% and gentamicin 0.5%; Other Names: Paromomycin/Gentamicin topical cream
EXPERIMENTAL: Paromomycin; Paromomycin alone	Drug: Paromomycin; Paromomycin alone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Participants With Final Clinical Cure	The primary efficacy endpoint is percent of subjects with final clinical cure. Final clinical cure is defined as follows: Subject has initial clinical cure (100% re-epithelialization of index lesion by nominal Day 63); OR,; Subject has initial clinical improvement (> 50% re-epithelialization of index lesion by nominal Day 63) followed by 100% re-epithelialization of the index lesion on or before nominal Day 100; AND,; Subject has no relapse of index lesion.	baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With All Lesions Cured	• Percentage of subjects with all lesions cured, defined as: Final clinical cure as defined in primary objective (which is based solely on the index lesion); AND, Cure of all other lesions by nominal Day 100 (100% re-epithelialization of all ulcerated lesions and resolution of all other types of lesions)	100 ± 14 days
Percentage of All Lesions Cured at Day 168 (Ignores Per Subject Cure Rate)	Percentage of all lesions meeting criteria for clinical cure during the study at 168 day mark for mITT subjects	Day 168
Area of Ulceration (mm^2) of the Index Lesion at Each Measurement Time Point	Area of ulceration (mm^2) of the index lesion at each measurement time point for mITT subjects	baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days
Area of Ulceration (mm^2) All Treated Lesions at Each Measurement Time Point	Area of ulceration (mm^2) of all treated lesions from baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days for mITT subjects. Data presented is as presented in the Final Clinical Study Report; any inconsistencies can't be changed.	baseline (before the start of treatment), and on Study Days 20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days
Median Time to Initial Clinical Cure for Index Lesions	Median time to initial clinical cure for index lesions (100% re-epithelialization of the index lesion)	When 100% re-epithelialization of the index lesion is observed at any visit Study Days (20, 35 ± 2 days, 49 ± 4 days, 63 ± 7 days, 100 ± 14 days, and 168 ± 14 days

Collaborators and Investigators

• Sponsor: U.S. Army Medical Research and Development Command
• Investigators: Principal Investigator: Nestor Sosa, MD, FACP, Instituto Conmemorativo Gorgas de Estudios de la Salud

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (ACTUAL): January 1, 2016
• Study Completion (ACTUAL): January 1, 2016

Study Registration Dates

• First Submitted: February 5, 2013
• First Submitted That Met QC Criteria: February 11, 2013
• First Posted (ESTIMATE): February 13, 2013

Study Record Updates

• Last Update Posted (ACTUAL): February 14, 2018
• Last Update Submitted That Met QC Criteria: January 17, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Paromomycin; leishmaniasis; cutaneous leishmaniasis; Leishmania panamensis; L panamensis; Paromomycin/Gentamicin
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Skin Diseases, Parasitic; Skin Diseases, Infectious; Euglenozoa Infections; Leishmaniasis; Leishmaniasis, Cutaneous; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Anti-Bacterial Agents; Protein Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Gentamicins; Paromomycin
• Other Study ID Numbers: S-12-21

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO