Safety, Efficacy, and PK of Topical Paromomycin/Gentamicin Cream for Treatment of Cutaneous Leishmaniasis (WRNMMC)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborators:
Walter Reed National Military Medical Center
Walter Reed Army Institute of Research (WRAIR)
Information provided by (Responsible Party):
U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier:
NCT01140191
First received: June 7, 2010
Last updated: March 3, 2014
Last verified: March 2014
  Purpose

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).


Condition Intervention Phase
Leishmaniasis, Cutaneous
Drug: WR 279,396
Phase 2

Study Type: Interventional
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)

Resource links provided by NLM:


Further study details as provided by U.S. Army Medical Research and Materiel Command:

Primary Outcome Measures:
  • 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 ]
    1. Subject has initial clinical cure (100% re-epithelialization of index lesion by nominal Day 60); OR,
    2. 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
    3. Subject has no relapse of index lesion between nominal Day 60 and nominal Day 100


Secondary Outcome Measures:
  • Efficacy: All lesions cured [ Time Frame: Days 1-100 ] [ Designated as safety issue: No ]

    All lesions cured, defined as:

    1. Final clinical cure as defined above; AND,
    2. 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).



Estimated Enrollment: 30
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)
Arms Assigned Interventions
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
Other Names:
  • WR 279,396
  • Topical Paromomycin/Gentamicin Cream

Detailed Description:

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:

  1. Subjects living in close proximity to WRNMMC will be asked to return to the study site for the follow-up visits.
  2. 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.
  3. 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.
  4. At the discretion of the Principal Investigator, subjects may be brought back to WRNMMC for lesion evaluations.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subjects must be male or female military health care beneficiary of any race or ethnicity and at least 18 years of age
  • Subjects must give written informed consent.
  • Subjects must have a diagnosis of CL in at least one lesion by at least one of the following methods: 1) positive culture for promastigotes; 2) microscopic identification of amastigotes in stained lesion tissue; 3) positive polymerase chain reaction (PCR) assay; and/or 4) prior diagnosis of CL within 14 days of the start of treatment.
  • Subjects must have at least one ulcerative lesion ≥ 1 cm and < 5 cm, that meets the criteria for an index lesion (Larger lesions will be accepted for treatment, but these will not be included in the primary evaluation of efficacy).
  • Subjects must be willing to forego other forms of treatments for CL including other investigational treatment during the study.
  • Subjects must be capable of understanding and complying with the protocol (in the opinion of the investigator).
  • Subjects must expect to be located in the Washington DC metropolitan area for at least the duration of the screening, 20-day treatment period, and Day 28 +/- 2 days follow-up visit.
  • Subjects who are female and of child-bearing potential, must have a negative pregnancy test during screening and agree to use an acceptable method of birth control during the treatment phase and for 1 month after treatment is completed.
  • Subject has adequate venous access for blood draws, if consented to the PK part of study.

Exclusion Criteria:

  • Subject has had a prior diagnosis of leishmaniasis where all lesions had healed.
  • Subject has only a single lesion whose characteristics include any of the following: verrucous or nodular lesion (non-ulcerative), lesion <1 cm in its greatest diameter, lesion in a location that in the opinion of the Investigator is difficult to maintain application of study drug topically.
  • Subject has a lesion due to Leishmania that involves the mucosa or palate.
  • Subject has signs and symptoms of disseminated disease.
  • Subject is a female who is breast-feeding.
  • Subject has an active malignancy or history of solid, metastatic or hematologic malignancy with the exception of basal or squamous cell carcinoma of the skin that has been removed.
  • Subject has significant organ abnormality, chronic disease such as diabetes, severe hearing loss, evidence of renal or hepatic dysfunction, or creatinine, AST, or ALT greater than the upper limit of normal as defined by the clinical laboratory normal ranges.
  • Subject has received treatment for leishmaniasis including thermosurgery (ThermoMed™) or any medication with pentavalent antimony including sodium stibogluconate (Pentostam), meglumine antimoniate (Glucantime); amphotericin B (including liposomal amphotericin B and amphotericin B deoxycholate); WR 279,396; or other medications containing paromomycin (administered parenterally or topically) or methylbenzethonium chloride (MBCL); gentamicin; fluconazole; ketoconazole; pentamidine; or allopurinol within 4 weeks of starting study treatment.
  • Subject has a history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides.
  • Subject has any other topical disease/condition which interferes with the objectives of this study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01140191

Locations
United States, Maryland
Walter Reed National Military Medical Center (WRNMMC)
Bethesda, Maryland, United States, 20889
Sponsors and Collaborators
U.S. Army Medical Research and Materiel Command
Walter Reed National Military Medical Center
Walter Reed Army Institute of Research (WRAIR)
Investigators
Principal Investigator: COL Glenn W. Wortman, M.D. Walter Reed Army Medical Center
  More Information

No publications provided

Responsible Party: U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier: NCT01140191     History of Changes
Other Study ID Numbers: A-16049; S-10-0007, USAMMDA Protocol Number
Study First Received: June 7, 2010
Last Updated: March 3, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by U.S. Army Medical Research and Materiel Command:
leishmaniasis
cutaneous
WR 279,396
paromomycin
gentamicin
pharmacokinetics
safety
efficacy
military

Additional relevant MeSH terms:
Leishmaniasis
Leishmaniasis, Cutaneous
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Skin Diseases, Parasitic
Skin Diseases, Infectious
Skin Diseases
Gentamicins
Paromomycin
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Amebicides
Antiprotozoal Agents
Antiparasitic Agents

ClinicalTrials.gov processed this record on October 16, 2014