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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier:
NCT01083576
First received: March 8, 2010
Last updated: May 16, 2014
Last verified: May 2014
  Purpose

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).


Condition Intervention Phase
Leishmaniasis, Cutaneous
Drug: WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream)
Drug: Paromomycin Alone Cream (15% paromomycin topical cream)
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
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 Cutaneous Leishmaniasis in Panama

Resource links provided by NLM:


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

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • Number of Participants Who Obtained a Modified Final Clinical Cure of All Lesions [ Time Frame: 168 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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


Other Outcome Measures:
  • 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


Enrollment: 30
Study Start Date: March 2010
Study Completion Date: July 2011
Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Paromomycin Alone Treatment
Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated cutaneous leishmaniasis (CL) lesions once daily for 20 days
Drug: Paromomycin Alone Cream (15% paromomycin topical cream)
topical application to CL lesions once daily for 20 days
Active Comparator: WR 279,396
WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Drug: WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream)
topical application to CL lesions once daily for 20 days
Other Name: Topical paromomycin/gentimicin cream

  Hide Detailed Description

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   5 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • To be eligible for the study, the following must be answered "YES" or not applicable, as appropriate for the study subject:

    1. Is the subject a male or female at least 5 years-of-age?
    2. Is the subject or legal guardian able to give written informed consent or assent, as appropriate?
    3. Does the subject have a diagnosis of CL in at least one lesion by at least one of the following methods: 1) positive culture for promastigotes, or 2) microscopic identification of amastigotes in stained lesion tissue.
    4. Does the subject have at least one ulcerative lesion ≥ 1 cm and ≤ 5 cm, that meets the criteria for an index lesion?
    5. Is the subject willing to forego other forms of treatments for CL including other investigational treatments during the study?
    6. In the opinion of the investigator, is the subject (or their legal guardian) capable of understanding and complying with the protocol?
    7. If female and of child-bearing potential, did the subject 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?
    8. Does the subject have adequate venous access for blood draws?

Exclusion Criteria:

To be eligible for the study, the following must be answered "NO" or not applicable as appropriate for the study subject:

  1. Does the subject have 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 drugs topically?
  2. Does the subject have a lesion due to leishmania that involves the mucosa or palate or any signs of mucosal disease that might be due to leishmania?
  3. Does the subject have signs and symptoms of disseminated disease in the opinion of the Principal Investigator?
  4. Does the subject have > 10 lesions?
  5. Is the subject a female who is breast-feeding?
  6. Does the subject have 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?
  7. Does the subject have significant organ abnormality, chronic disease such as diabetes, severe hearing loss, evidence of renal or hepatic dysfunction, or creatinine, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) greater than 15% above the upper limit of normal (ULN) as defined by the clinical laboratory defined normal ranges?
  8. Has the subject received treatment for leishmaniasis including any medication with pentavalent antimony including sodium stibogluconate (Pentostam), meglumine antimoniate (Glucantime); amphotericin B (including liposomal amphotericin B and amphotericin B deoxycholate); or other medications containing paromomycin (administered parenterally or topically) or methylbenzethonium chloride (MBCL); gentamicin; fluconazole; ketoconazole; pentamidine; miltefosine, azithromycin or allopurinol that was completed within 8 weeks of starting study treatments?
  9. Does the subject have a history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides?
  10. Does the subject have any other topical disease/condition which would interfere 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: NCT01083576

Locations
Panama
Gorgas Memorial Institute Clinical Research Unit
Panama City, Panama
Sponsors and Collaborators
U.S. Army Medical Research and Materiel Command
Investigators
Principal Investigator: Nestor Sosa, M.D. FACP Instituto Conmemorativo Gorgas de Estudios de la Salud
  More Information

No publications provided by U.S. Army Medical Research and Materiel Command

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: U.S. Army Medical Research and Materiel Command
ClinicalTrials.gov Identifier: NCT01083576     History of Changes
Other Study ID Numbers: PG-PANAMA-08-04; A-15810
Study First Received: March 8, 2010
Results First Received: November 20, 2013
Last Updated: May 16, 2014
Health Authority: United States: Food and Drug Administration
Panama: Commemorative Institute GORGAS of Studies of Health
Panama: Ministry of Health

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

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

ClinicalTrials.gov processed this record on October 20, 2014