Clinical trial NCT00606580: Phase 3 Study to Evaluate WR 279,396 vs. Paromomycin Alone to Treat Cutaneous Leishmaniasis (in Tunisia)
Official title: A Pivotal, Randomized, Double-blind, Vehicle-controlled Study to Evaluate WR 279,396 and Paromomycin Alone to Treat Cutaneous Leishmaniasis (in Tunisia)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cutaneous Leishmaniasis
Keywords: cutaneous leishmaniasis, topical treatment, Tunisia
Lead sponsor: U.S. Army Medical Research and Development Command
Sponsor class: FED
First posted: 2008-02-04
Enrollment: 375
Sex: ALL
Minimum age (years): 5
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will test the ability of the topical cream WR 279,396 to treat the skin lesions caused by the parasite called leishmania. WR 279,396 is an antibiotic preparation that contains paromomycin + gentamicin. This cream will be compared to the effect of a topical cream containing paromomycin alone and to a placebo cream that contains no antibiotics. Therefore, this study will have three groups of patients, and they will be assigned to one of these treatments randomly. The study will be carried out without the patient or the physician knowing which cream is being used for which patient. The goal is to determine if WR 279,396 cream or the paromomycin cream is better than placebo, and if WR 279,396 is better than paromomycin alone.

Detailed description: This is an efficacy study to test the ability of WR 279,396 topical cream to treat uncomplicated cutaneous leishmaniasis caused primarily by Leishmania major in adults and children in Tunisia where the disease in endemic. A total of 375 volunteers will be randomized to the three arms described above to determine product efficacy. Safety data in all three arms will also be collected.

Eligibility criteria: Inclusion Criteria:

* The subject was age 5 years or older, but less than 65 years.
* The subject was able to understand the information provided to him/her and give written informed consent. Consent was obtained from the parent/guardian of subjects who were \< 18 years old. Children 12 to \< 18 years old were asked to sign the written assent form. Witnessed verbal assent was obtained from subjects 5 to 11 years old.
* The subject was a male or female who was generally healthy.
* The subject had cutaneous lesions diagnosed as leishmaniasis in the index lesion by: (1) the identification of promastigotes in a culture of an aspirated lesion, or (2) the microscopic identification of Leishmania amastigotes on a DifQuik or Giemsa stained smear obtained from a lesion scraping.
* The subject had five or fewer cutaneous lesions.
* The subject had one lesion, which would be designated as the index lesion, that was ≥ 1 and \< 5 cm in its greatest diameter and primarily ulcerative, ie, not purely verrucous or nodular.
* The subject was willing to forego other forms of treatment for CL, including other investigational treatment during the study.
* In the opinion of the principal investigator, the subject or subject's parent/guardian was capable of understanding and complying with the protocol

Exclusion Criteria

* The subject received previous treatment for leishmaniasis (including WR 279,396) within the last 6-months, with the exception of mercurochrome.
* The subject had difficulty complying with instructions on maintaining the dressing, eg, due to life style activities or age.
* The subject had only a single lesion whose characteristics included any of the following: verrucous or nodular lesion, ≥ 5 cm in its greatest diameter, \< 1 cm or located on the ear, or other location that in the opinion of the principal investigator would be difficult to maintain application of study drug topically.
* The subject had a lesion due to Leishmania that involved the mucosa.
* The subject had signs or symptoms of disseminated disease, ie, clinically significant lymphadenitis with nodules that were painful and \> 1 cm in the lymphatic drainage of the ulcer.
* The subject was a female with a positive urine pregnancy test, or who was breast feeding or lactating.
* The subject had an active malignancy or had a history of a solid, metastatic or hematologic malignancy, with the exception of a basal or squamous cell carcinoma of the skin that had been removed.
* The subject had a significant organ abnormality or chronic disease that, in the opinion of the investigator, would warrant exclusion of the subject from the study or would prevent the subject from completing the study.
* The subject was receiving any of the following medications: any medication containing pentavalent antimony, including stibogluconate sodium (Pentostam®) and meglumine antimoniate (Glucantime®); amphotericin B, including liposomal amphotericin B and amphotericin B deoxycholate; other medications containing paromomycin (administered IV or topically); methylbenzethonium chloride, fluconazole, ketoconazole, itraconazole; pentamidine; or allopurinol.
* The subject or the subject's parent/guardian was unable to understand verbal and/or written Arabic, English, or French (languages in which certified translations of the informed consent were available).
* The subject presented with an immuno-compromising condition, including recidivant leishmaniasis (during the past 2 years), or diabetes.
* The subject had a history of known or suspected idiosyncratic reactions or hypersensitivity to aminoglycosides.

Primary outcomes:
measure: Final Clinical Cure Rate
timeFrame: Day 42, 98, and 168
Secondary outcomes:
measure: Final Clinical Cure Rate (Per Protocol Dataset)
timeFrame: Day 42, 98, and 168
measure: Estimated Percentage Subjects With Re-epithelialization of the Index Lesion Without Relapse
timeFrame: Day 42
measure: Estimated Percentage of Subjects With Re-epithelialization of the Index Lesion Without Relapse at Various Times of Follow-up
timeFrame: Days 42, 49, and 98
measure: Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 42
timeFrame: Days 42
measure: Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 49
timeFrame: Days 49
measure: Estimated Percentage of All Treated Ulcerated Lesions Without Relapse at Day 98
timeFrame: Days 98
measure: Number of Subjects Achieving Initial Clinical Improvement of the Index Lesion
timeFrame: Day 42
measure: Number of Subjects Achieving Re-epithelialization of the Index Lesion Without Relapse
timeFrame: Day 168
measure: Number of Subjects Achieving Re-epithelialization of All Treated Ulcerated Lesions Without Subsequent Relapse
timeFrame: Day 168
measure: Number of All Ulcerated Lesions Achieving 100% Re-epithelialization by Day 42
timeFrame: Day 42
measure: Number of Subjects With a Relapse on or After Day 42
timeFrame: Day 168
Other outcomes:
Locations:
city: Tunis
country: Tunisia
facility: Central Clinic-Sidi Bouzid
Study officials:
affiliation: Institute Pasteur Tunisia
name: Afif Ben Salah, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ben Salah A, Ben Messaoud N, Guedri E, Zaatour A, Ben Alaya N, Bettaieb J, Gharbi A, Belhadj Hamida N, Boukthir A, Chlif S, Abdelhamid K, El Ahmadi Z, Louzir H, Mokni M, Morizot G, Buffet P, Smith PL, Kopydlowski KM, Kreishman-Deitrick M, Smith KS, Nielsen CJ, Ullman DR, Norwood JA, Thorne GD, McCarthy WF, Adams RC, Rice RM, Tang D, Berman J, Ransom J, Magill AJ, Grogl M. Topical paromomycin with or without gentamicin for cutaneous leishmaniasis. N Engl J Med. 2013 Feb 7;368(6):524-32. doi: 10.1056/NEJMoa1202657.