Safety, Efficacy, and PK of Topical Paromomycin/Gentamicin Cream for Treatment of Cutaneous Leishmaniasis (WRNMMC)
The objectives of the study are to evaluate the safety, pharmacokinetics (PK), and efficacy of open label treatment with WR 279,396 (Topical Paromomycin/Gentamicin Cream)in subjects with cutaneous leishmaniasis (CL).
|Study Design:||Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Open-Label Clinical Study to Examine the Safety, Efficacy, and Pharmacokinetics of WR 279,396 (Paromomycin + Gentamicin Topical Cream) for the Treatment of Cutaneous Leishmaniasis at Walter Reed National Military Medical Center (WRNMMC)|
- PK: Proportion of subjects with any detectable paromomycin or gentamicin plasma levels on a study day when blood for PK is collected. [ Time Frame: Days 1, 20 and 28+/-2 days for day 28 only (Trough levels on days 2, 4, 7, 12,17, and 21, all with +/- 1 day, except day 28, which is +/-2 days) ] [ Designated as safety issue: Yes ]
Determination of PK parameters where data permits including:
- Cmax: Maximum observed plasma concentration
- Tmax: Observed time to reach maximum plasma concentration
- AUC: Area under the plasma-concentration time curve over a specified time period
- t1/2: Apparent terminal exponential half-life
- λz: Terminal-phase exponential rate constant
- Absolute paromomycin and gentamicin bioavailability (based on historical data) if feasible.
The trough blood draws on Days 2 and 21 will be used for the determination of PK parameters along with the blood collected on Days 1 and 20.
- Safety: Proportion of subjects with adverse events by type [ Time Frame: Days 1-28 +/- 2 days ] [ Designated as safety issue: Yes ]AEs will be coded using MedDRA terms and grouped by system, organ, and class (SOC). The severity, frequency, and relationship of AEs to study drug will be presented by preferred term by SOC grouping. Laboratory data and vital signs will be presented as summary statistics by Study Day including changes from baseline, and by-subject data listings. The severity and frequency of application site reactions will be presented as summary statistics by Study Day. Clinically significant AEs that are ongoing at the end of the study will be followed until stabilization or resolution.
- Efficacy: Final Clinical Cure (index lesion) [ Time Frame: Days 1-100 ] [ Designated as safety issue: No ]
- Subject has initial clinical cure (100% re-epithelialization of index lesion by nominal Day 60); OR,
- Subject has initial clinical improvement (>50% re-epithelialization of index lesion by Day 60 followed by complete re-epithelialization of index lesion on or before nominal Day 100; AND
- Subject has no relapse of index lesion between nominal Day 60 and nominal Day 100
- Efficacy: All lesions cured [ Time Frame: Days 1-100 ] [ Designated as safety issue: No ]
All lesions cured, defined as:
- Final clinical cure as defined above; 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).
Area of ulceration of the index lesion at each measurement time point.
Area of ulceration all treated lesions at each measurement time point.
Ulcerated lesion complete cure rate at each measurement time point (complete cure is defined as 100% re-epithelialization of an ulcerated lesion).
|Study Start Date:||July 2010|
|Estimated Study Completion Date:||October 2014|
|Estimated Primary Completion Date:||June 2014 (Final data collection date for primary outcome measure)|
Experimental: WR 279,396
All subjects in this one-arm study will receive topical WR 279,396
Drug: WR 279,396
Topical application of WR 279,396 cream (15% paromomycin + 0.5% gentamicin)once daily for 20 days
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:
- Subjects living in close proximity to WRNMMC will be asked to return to the study site for the follow-up visits.
- 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.
- 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.
- At the discretion of the Principal Investigator, subjects may be brought back to WRNMMC for lesion evaluations.
|United States, Maryland|
|Walter Reed National Military Medical Center (WRNMMC)|
|Bethesda, Maryland, United States, 20889|
|Principal Investigator:||COL Glenn W. Wortman, M.D.||Walter Reed Army Medical Center|