Clinical Trial: Pharmacokinetics, Safety, and Efficacy Trial of WR 279,396 (Paromomycin + Gentamicin Topical Cream) and Paromomycin Topical Cream for the Treatment of Cutaneous Leishmaniasis in Panama

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: Double-blind, Randomized, Pharmacokinetics, Safety, and Efficacy Trial of WR 279,396 (Paromomycin + Gentamicin Topical Cream) and Paromomycin Topical Cream for the Treatment of C

Brief Summary: 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).

Detailed Summary:

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,
Sponsor: U.S. Army Medical Research and Materiel Command

Current Primary Outcome: Number of Participants Who Obtained Final Clinical Cure of Index Lesion [ Time Frame: 168 days ]

Number of participants who had initial clinical cure (100% re-epithelialization of index lesion by Day 63) OR initial clinical improvements (> 50% re-epithelialization of index lesion followed by Day 63 by 100% re-epithelialization of the index lesion on or before Day 100), AND no relapse of index lesion.


Original Primary Outcome: Proportion of subjects with any detectable paromomycin or gentamicin plasma levels on a study day when blood for PK is collected • Determination of PK parameters in adults where data permits [ Time Frame: On Study Days 1 and 20, blood will be drawn from adult subjects pre-drug application and at 0.5h, 1h, 2h, 3h, and 4h ± 5 minutes and 8h, 12h, and 24h ± 15 minutes after application of cream to all lesions is completed. ]

Current Secondary Outcome:

  • Number of Participants Who Obtained a Modified Final Clinical Cure of All Lesions [ Time Frame: 168 days ]
    Final cure as defined by the primary outcome measure AND and cure of all other lesions by Day 168. (100% re-epithelialization of all ulcerated lesions and resolution of all other type of lesions)
  • Detectable Paromomycin or Gentamicin Plasma Levels [ Time Frame: 20 days ]
    Proportion of subjects with any detectable Paromomycin or Gentamicin plasma levels on a study day when blood for PK was collected
  • Paromomycin Plasma Concentrations in Adults [ Time Frame: Day 4 to Day 28 ]
    Paromomycin plasma concentrations following administration of paromomycin alone or WR 279,396 in adults
  • Paromomycin Plasma Concentrations in Children [ Time Frame: Days 1 and 20 ]
    Paromomycin plasma concentrations 4 hours following administration of paromomycin alone or WR 279,396 in children
  • Pharmacokinetic Parameter: Cmax [ Time Frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20 ]
    Cmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
  • Pharmacokinetic Parameter: Tmax [ Time Frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20 ]
    Tmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
  • Pharmacokinetic Parameter: Area Under the Curve (AUC) [ Time Frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20 ]
    Area under the curve (AUC) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
  • Pharmacokinetic Parameter: t(1/2) [ Time Frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20 ]
    t(1/2) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
  • Pharmacokinetic Parameter: Cmax/D [ Time Frame: 0, 0.5, 1.0, 2.0, 3.0, 4.0, 8.0, 12.0, 24.0 hours on both Days 1 and 20 ]
    Maximum observed plasma concentration divide by topical dose (Cmax/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
  • Pharmacokinetic Parameter: AUC/D [ Time Frame: Days 1 and 20 ]
    Area under the plasma concentration-time curve over 24 hrs divided by topical dose (AUC/D) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama


Original Secondary Outcome: Safety: AEs and vital signs; local site reactions, including solicited exam for pain and clinician exam for erythema/redness and swelling/edema; Blood creatinine Efficacy: final clinical cure [ Time Frame: Safety:AEs assessed at each visit, days 1 to 168; Any ongoing AEs at Day 168 ± 14 followed to resolution. Efficacy: >50% re-epithelialization of index lesion by Day 63; or 100% re-epithelialization of index lesion by Day 100 ]

Information By: U.S. Army Medical Research and Materiel Command

Dates:
Date Received: March 8, 2010
Date Started: March 2010
Date Completion:
Last Updated: June 23, 2015
Last Verified: May 2014