Topical Treatment of Cutaneous Leishmaniasis With WR 279,396: A Phase 2 Study in the Old World

Topical Treatment of Cutaneous Leishmaniasis With WR 279,396: a Phase 2 Study in the Old World

This study is to determine the effectiveness and safety of WR 279,396, a topical cream for the treatment of cutaneous leishmaniasis. This study is to be conducted with a placebo control under double-blind conditions in a local population group in Tunisia where leishmaniasis is endemic.

Study Overview

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

Detailed Description

WR 279,396 is a paromomycin-based topical cream that has shown some suggestion of being effective for the treatment of non-serious, non-complicated cutaneous leishmaniasis in previous clinical studies. The goal of this study is to expand those observations in a larger, more rigorous study to clearly define the efficacy of this product and collect information about adverse effects. Subjects will be randomized to receive either WR 279,396 or vehicle placebo; applied twice a day for 20 days.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Paris, France, 75015
    • Medical Center Institut Pasteur
• Tunisia
  • Tunis, Tunisia
    • Institue Pasteur

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 5-75 years
• Lesions must measure at least 1 cm and be primarily ulcerative
• Have cutaneous leishmaniasis proven parasitologically in the lesion selected for study
• Must have given written informed consent to participate in the study

Exclusion Criteria:

• Known drug intolerance to aminoglycosides in the patient or immediate family
• Previous use of antileishmanial drugs (within 3 months) or present use of routinely nephrotoxic or ototoxic drugs
• Patients with tuberculosis under treatment
• Potential for follow-up: have less than 7 months time remaining in present address and/or plan to leave the area for more than 30 days
• Extent of disease: more than 5 lesions or lesion equal to or greater than 5 cm or a lesion less than 5 cm from the eye, 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 greater than 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:
• Hearing abnormality
• Ongoing pregnancy or have plans to become pregnant
• Females of child bearing age (Tunisia Only)
• Signs or symptoms of peripheral neuropathy

Kidney: clinically significant abnormalities of urine analysis, serum levels of creatinine, BUN, total proteins greater than the upper limit of normal for the laboratory.

Liver: AST or ALT greater than the upper limit of normal for the laboratory General: glucose, Na+, or K+ greater than the upper limit of normal for the laboratory

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WR 279,396; WR 279,396 is a topical antibiotic cream containing paromomycin and gentamicin	Drug: WR 279,396; A topical cream containing 15% paromomycin and 0.5% gentamicin. Approximately 0.0005 mL per mm2 of skin lesion; Other Names: Paromomycin topical cream
Placebo Comparator: Placebo; Topical cream vehicle containing all of the components in WR 279,396 except the active ingredients.	Drug: Placebo; Topical cream vehicle. Approximately 0.0005 mL per mm2 of skin lesion; Other Names: Topical vehicle placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Clinical Response (CCR) of Lesion at Days 50, 100 and 180 (+7 Days)	CCR is defined as at least 50% reduction, from baseline, in index lesion area of ulceration at study days 50, 100 and 180 (+ 7 days). Randomized subjects were compared using the uncorrected Fisher's exact test. Confidence intervals (95%) were constructed on the difference between the two group proportions. The log-rank test was used to compare the time to complete re-epithelialization of the index lesion without relapse. Cure of all subjects lesions was also compared using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable. The Breslow-Day test was used to examine whether the effect of WR 279,396 varied between subgroups	180 days
Safety of WR 279,396 (AEs and SAEs)	Safety was evaluated on each day during daily administration of the topical products. Subjects were observed and questioned for the occurrence of solicited local side effects (eg, pain, erythema, edema) and solicited systemic side effects (eg, vertigo, tinnitus, diminished hearing). Non-solicited AE evaluations included spontaneous reports from subjects and clinical observations.	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Complete Re-epithelialization of the Index Lesion Ulcer Without Relapse	100% re-epithelialization of the index lesion without having had a relapse. The log-rank test was used to compare the time to complete re-epithelialization.	180 days
Final Cure Rate by Subject of All Lesions	Final cure rate by subject was determined using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable.	180 days
Rate of Relapse	Relapse is defined as enlargement of the index lesion compared to previous measurement at any time after day 50 (+ 7 days) or not demonstrating CCR by study day 180. CCR was compared using uncorrected Fisher's exact test. Confidence intervals (95%) were constructed on the difference between the two group proportions. The log-rank test was used to compare the time to complete re-epithelialization of the index lesion without relapse. Cure of all subjects lesions was also compared using the Fisher's exact test. To adjust for baseline differences in the treatment groups, a linear model for the proportion of subjects achieving CCR was fit for each baseline variable of interest with covariates for treatment group and the baseline variable.	180 days

Collaborators and Investigators

• Sponsor: U.S. Army Medical Research and Development Command
• Collaborators: Walter Reed Army Institute of Research (WRAIR)
• Investigators: Principal Investigator: Afif Ben Salah, M.D., Ph.D., Institute Pasteur Tunisia

Publications and helpful links

General Publications

• Ben Salah A, Buffet PA, Morizot G, Ben Massoud N, Zaatour A, Ben Alaya N, Haj Hamida NB, El Ahmadi Z, Downs MT, Smith PL, Dellagi K, Grogl M. WR279,396, a third generation aminoglycoside ointment for the treatment of Leishmania major cutaneous leishmaniasis: a phase 2, randomized, double blind, placebo controlled study. PLoS Negl Trop Dis. 2009;3(5):e432. doi: 10.1371/journal.pntd.0000432. Epub 2009 May 5.

Study record dates

Study Major Dates

• Study Start: March 1, 2003
• Primary Completion (Actual): November 1, 2004
• Study Completion (Actual): November 1, 2005

Study Registration Dates

• First Submitted: June 20, 2008
• First Submitted That Met QC Criteria: June 23, 2008
• First Posted (Estimate): June 24, 2008

Study Record Updates

• Last Update Posted (Actual): May 30, 2017
• Last Update Submitted That Met QC Criteria: April 25, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: cutaneous leishmaniasis topical treatment safety efficacy
• 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; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Paromomycin
• Other Study ID Numbers: A-9768.1; IND 50098 (Other Identifier: FDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be shared with WRAIR