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
|First Received Date ICMJE||March 8, 2010|
|Last Updated Date||June 23, 2015|
|Start Date ICMJE||March 2010|
|Primary Completion Date||June 2011 (final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Number of Participants Who Obtained Final Clinical Cure of Index Lesion [ Time Frame: 168 days ] [ Designated as safety issue: No ]
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 Measures ICMJE
||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. ] [ Designated as safety issue: No ]|
|Change History||Complete list of historical versions of study NCT01083576 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
||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 ] [ Designated as safety issue: No ]|
|Current Other Outcome Measures ICMJE
||Serum Creatinine Levels [ Time Frame: Day 1 and Day 20 ] [ Designated as safety issue: Yes ]
Blood creatinine was measured to assess possible nephrotoxicity associated with aminoglycosides
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||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|
|Official Title ICMJE||Double-blind, Randomized, 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|
|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).|
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, the last blood draw in this series will occur on Day 21. In addition, blood will be collected on Days 4, 7, 12, and 17 ± 1 day before study drug application to examine trough plasma levels of paromomycin and gentamicin. A follow-up plasma sample for PK analysis will also be obtained on Day 28 ± 2 days.
Subjects under the age of 18 years will have a total of four blood samples drawn. The first will be drawn at pre-application and the second will be drawn at 4 hours ± 5 minutes after completion of application of the topical cream on Study Day 1. The third will be drawn pre-application and the fourth at 4 hours ± 5 minutes after completion of application of the topical cream on Study Day 20. Subjects who receive Paromomycin Topical Cream are not expected to have blood levels of gentamicin, but as the study is blinded, plasma specimens will be tested for both paromomycin and gentamicin.
The index lesion (primary ulcerated) and all other ulcerated lesions will be assessed for clinical response by measurement of the length and width of area of ulceration. A lesion will be considered to be completely cured if 100% re-epithelialization is observed (i.e., 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 (i.e., absence of signs of an active lesion).
Subjects will have an in-clinic follow-up weekly (Days 28, 35, 42, 49, 56, and 63 ± 2 days) after completion of treatment for safety assessments, lesion measurements, and lesion photographs. On Day 21, index lesions in adult subjects that have not completely re-epithelialized will be assessed for parasites by classical means (positive culture for promastigotes or microscopic identification of amastigotes in stained lesion tissue). An interim analysis of all of the data collected on all subjects who were randomized and completed the nominal Day 63 follow-up will be performed to make decisions about the final design of a Phase 3 trial. Subjects will continue to be followed for outcomes at Day 100 and 168 ± 14 days. A final analysis of outcomes after the longer term followup period has been completed for all subjects will be performed when the trial is closed. Follow-up evaluations include AEs, medication use, lesion measurements, and lesion photographs.
Patients who fail therapy (see definition of failure below) may be administered rescue therapy at the discretion of the patient's personal physician.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2|
|Study Design ICMJE||Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
|Condition ICMJE||Leishmaniasis, Cutaneous|
|Study Arm (s)||
|Publications *||Ravis WR, Llanos-Cuentas A, Sosa N, Kreishman-Deitrick M, Kopydlowski KM, Nielsen C, Smith KS, Smith PL, Ransom JH, Lin YJ, Grogl M. Pharmacokinetics and absorption of paromomycin and gentamicin from topical creams used to treat cutaneous leishmaniasis. Antimicrob Agents Chemother. 2013 Oct;57(10):4809-15. doi: 10.1128/AAC.00628-13. Epub 2013 Jul 22.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||July 2011|
|Primary Completion Date||June 2011 (final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
To be eligible for the study, the following must be answered "NO" or not applicable as appropriate for the study subject:
|Ages||5 Years and older (Child, Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Panama|
|Removed Location Countries|
|NCT Number ICMJE||NCT01083576|
|Other Study ID Numbers ICMJE||PG-PANAMA-08-04; A-15810|
|Has Data Monitoring Committee||No|
|Plan to Share Data||Not Provided|
|IPD Description||Not Provided|
|Responsible Party||U.S. Army Medical Research and Materiel Command|
|Study Sponsor ICMJE||U.S. Army Medical Research and Materiel Command|
|Collaborators ICMJE||Not Provided|
|Information Provided By||U.S. Army Medical Research and Materiel Command|
|Verification Date||May 2014|
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