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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

Primary Purpose

Leishmaniasis, Cutaneous

Status
Completed
Phase
Phase 2
Locations
Panama
Study Type
Interventional
Intervention
WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream)
Paromomycin Alone Cream (15% paromomycin topical cream)
Sponsored by
U.S. Army Medical Research and Development Command
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leishmaniasis, Cutaneous focused on measuring leishmaniasis, cutaneous, WR 279,396, paromomycin, gentamicin, pharmacokinetics, safety, efficacy

Eligibility Criteria

5 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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?

Sites / Locations

  • Gorgas Memorial Institute Clinical Research Unit

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Paromomycin Alone Treatment

WR 279,396

Arm Description

Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated cutaneous leishmaniasis (CL) lesions once daily for 20 days

WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days

Outcomes

Primary Outcome Measures

Number of Participants Who Obtained Final Clinical Cure of Index Lesion
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
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
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
Paromomycin plasma concentrations following administration of paromomycin alone or WR 279,396 in adults
Paromomycin Plasma Concentrations in Children
Paromomycin plasma concentrations 4 hours following administration of paromomycin alone or WR 279,396 in children
Pharmacokinetic Parameter: Cmax
Cmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
Pharmacokinetic Parameter: Tmax
Tmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
Pharmacokinetic Parameter: Area Under the Curve (AUC)
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)
t(1/2) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
Pharmacokinetic Parameter: Cmax/D
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
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

Full Information

First Posted
March 8, 2010
Last Updated
June 23, 2015
Sponsor
U.S. Army Medical Research and Development Command
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1. Study Identification

Unique Protocol Identification Number
NCT01083576
Brief Title
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
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2014
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
June 2011 (Actual)
Study Completion Date
July 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
U.S. Army Medical Research and Development Command

4. Oversight

Data Monitoring Committee
No

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leishmaniasis, Cutaneous
Keywords
leishmaniasis, cutaneous, WR 279,396, paromomycin, gentamicin, pharmacokinetics, safety, efficacy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Non-Randomized
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Paromomycin Alone Treatment
Arm Type
Active Comparator
Arm Description
Paromomycin Alone Cream (15% paromomycin topical cream): topical application to uncomplicated cutaneous leishmaniasis (CL) lesions once daily for 20 days
Arm Title
WR 279,396
Arm Type
Active Comparator
Arm Description
WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream): topical application to uncomplicated CL lesions once daily for 20 days
Intervention Type
Drug
Intervention Name(s)
WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream)
Other Intervention Name(s)
Topical paromomycin/gentimicin cream
Intervention Description
topical application to CL lesions once daily for 20 days
Intervention Type
Drug
Intervention Name(s)
Paromomycin Alone Cream (15% paromomycin topical cream)
Intervention Description
topical application to CL lesions once daily for 20 days
Primary Outcome Measure Information:
Title
Number of Participants Who Obtained Final Clinical Cure of Index Lesion
Description
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.
Time Frame
168 days
Secondary Outcome Measure Information:
Title
Number of Participants Who Obtained a Modified Final Clinical Cure of All Lesions
Description
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)
Time Frame
168 days
Title
Detectable Paromomycin or Gentamicin Plasma Levels
Description
Proportion of subjects with any detectable Paromomycin or Gentamicin plasma levels on a study day when blood for PK was collected
Time Frame
20 days
Title
Paromomycin Plasma Concentrations in Adults
Description
Paromomycin plasma concentrations following administration of paromomycin alone or WR 279,396 in adults
Time Frame
Day 4 to Day 28
Title
Paromomycin Plasma Concentrations in Children
Description
Paromomycin plasma concentrations 4 hours following administration of paromomycin alone or WR 279,396 in children
Time Frame
Days 1 and 20
Title
Pharmacokinetic Parameter: Cmax
Description
Cmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
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
Title
Pharmacokinetic Parameter: Tmax
Description
Tmax of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
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
Title
Pharmacokinetic Parameter: Area Under the Curve (AUC)
Description
Area under the curve (AUC) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
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
Title
Pharmacokinetic Parameter: t(1/2)
Description
t(1/2) of paromomycin following administration of paromomycin alone or WR 279,396 to adults in Panama
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
Title
Pharmacokinetic Parameter: Cmax/D
Description
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
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
Title
Pharmacokinetic Parameter: AUC/D
Description
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
Time Frame
Days 1 and 20
Other Pre-specified Outcome Measures:
Title
Serum Creatinine Levels
Description
Blood creatinine was measured to assess possible nephrotoxicity associated with aminoglycosides
Time Frame
Day 1 and Day 20

10. Eligibility

Sex
All
Minimum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: To be eligible for the study, the following must be answered "YES" or not applicable, as appropriate for the study subject: Is the subject a male or female at least 5 years-of-age? Is the subject or legal guardian able to give written informed consent or assent, as appropriate? 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. Does the subject have at least one ulcerative lesion ≥ 1 cm and ≤ 5 cm, that meets the criteria for an index lesion? Is the subject willing to forego other forms of treatments for CL including other investigational treatments during the study? In the opinion of the investigator, is the subject (or their legal guardian) capable of understanding and complying with the protocol? 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? 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: 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? 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? Does the subject have signs and symptoms of disseminated disease in the opinion of the Principal Investigator? Does the subject have > 10 lesions? Is the subject a female who is breast-feeding? 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? 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? 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? Does the subject have a history of known or suspected hypersensitivity or idiosyncratic reactions to aminoglycosides? Does the subject have any other topical disease/condition which would interfere with the objectives of this study?
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nestor Sosa, M.D. FACP
Organizational Affiliation
Instituto Conmemorativo Gorgas de Estudios de la Salud
Official's Role
Principal Investigator
Facility Information:
Facility Name
Gorgas Memorial Institute Clinical Research Unit
City
Panama City
Country
Panama

12. IPD Sharing Statement

Citations:
PubMed Identifier
23877689
Citation
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.
Results Reference
derived

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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

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