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
Information source: U.S. Army Medical Research and Materiel Command
Information obtained from ClinicalTrials.gov on October 04, 2010
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Leishmaniasis, Cutaneous
Intervention: WR 279,396 (15% paromomycin + 0.5% gentamicin topical cream) (Drug); Paromomycin Alone Cream (15% paromomycin topical cream) (Drug)
Phase: Phase 2
Sponsored by: U.S. Army Office of the Surgeon General
Official(s) and/or principal investigator(s):
Nestor Sosa, M.D. FACP, Principal Investigator, Affiliation: Instituto Conmemorativo Gorgas de Estudios de la Salud
Nestor Sosa, M.D. FACP, Phone: 507-527-4815, Email: firstname.lastname@example.org
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).
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 design: Allocation: Non-Randomized, Control: Active Control, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
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
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
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.
Minimum age: 5 Years.
Maximum age: N/A.
- 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?
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?
Locations and Contacts
Nestor Sosa, M.D. FACP, Phone: 507-527-4815, Email: email@example.com
Gorgas Memorial Institute Clinical Research Unit, Panama City, Panama; Recruiting
Starting date: March 2010
Last updated: May 26, 2010