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

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: Final Clinical Cure for Index Lesions [ Time Frame: Initial clinical cure by day 63 and no relapse by day 168 ]

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:

• Detectable Paromomycin Plasma Levels [ Time Frame: Day 4, 7, 12, 17, 20, 28 ]
  Paromomycin plasma concentrations following administration of paromomycin alone or WR 279,396 in adults
• Paromomycin Plasma Concentrations in Children [ Time Frame: 0 and 4 hours on 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 ]
  Pharmacokinetic Parameter: Tmax
• 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
• Final Clinical Cure on All Lesions Independent of Subjects [ Time Frame: Initial clinical cure by day 63 and no relapse by day 168 ]

  Final clinical cure was defined as follows:

  1. Subject has initial clinical cure (100% re-epithelialization of lesion by nominal Day 63); OR,
  2. Subject has initial clinical improvement (> 50% re-epithelialization of lesion by nominal Day 63 followed by 100% re-epithelialization of the lesion on or before nominal Day 100; AND,
  3. Subject has no relapse of lesion by Day 168. Relapse was defined as a lesion meeting the criteria for initial clinical cure that had any new ulceration/nodule (> 0 x 0 mm measurement) by nominal day 168, or a lesion meeting the criteria for initial clinical improvement that subsequently enlarged by nominal Day 168.
• Number of Index Lesions Meeting Criteria for Clinical Cure During the Study [ Time Frame: Day 1, 4, 7, 12, 17, 20, 28, 35, 42, 49, 56, 63, 100, 168 ]
  Number of study participants who meet the criteria for clinical cure (100% re-epithelialization) at specified timepoints during the study.

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: December 14, 2009
Date Started: January 2010
Date Completion:
Last Updated: June 23, 2015
Last Verified: August 2014