Miltefosine and GM-CSF in Cutaneous Leishmaniasis

Study Overview
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Brief Summary
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Cutaneous leishmaniasis (CL) standard treatment is done with parenteral pentavalent antimony (Sbv) at the dose of 15-20mg / kg per day for 20 days. However, therapeutic failure has been described in up to 50% of patients, and the long period of 60 to 90 days required for healing of the ulcerated lesion indicate the need for alternative drugs. Currently the alternatives include other parenteral drugs such as pentamidine and amphotericin B, whose use is limited either by toxicity or because, as with Sbv, the parenteral route hinders adherence and regularity of treatment in the rural area. Recent studies by our group indicate that oral miltefosine is the most effective drug for the treatment of patients with CL caused by L. (V.) guyanensis and L. (V.) braziliensis in Brazil, with a cure rate of 71.4% and 75% respectively. CL pathogenesis is associated with intense inflammatory infiltrate and tissue damage. Previous trials associating GM-CSF to Sbv improved the cure rate of CL caused by L. (V.) braziliensis. The objective of this trial is to evaluate the therapeutic response to the use of miltefosine associated to GM-CSF in the treatment of CL caused by L. (V.) braziliensis in an endemic region in Bahia and Ceará, and by L. (V.) guyanensis in the Amazon region.

Official Title
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Miltefosine and GM-CSF in Cutaneous Leishmaniasis: a Randomized and Controlled Trial

Conditions
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Cutaneous Leishmaniasis

Intervention / Treatment
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* Drug: Sbv
* Drug: Miltefosine plus placebo
* Drug: Miltefosine plus GM-CSF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Untreated ulcerative cutaneous leishmaniasis, with laboratory diagnosis obtained through at least one of the following tests: direct examination of the lesion, positive culture or PCR for Leishmania. Age: 18 to 65 years; Sex: male and female patients; Presence of at least 1 ulcerated lesion at any location; Presence of a maximum of 3 ulcerated lesions; Diameter of lesions varying between 1 and 5 cm; Clinical evolution of the disease of not less than 1 month and not more than 3 months. Exclusion Criteria: Evidence of severe underlying disease (cardiac, renal, hepatic, pulmonary) or malignant disease; Patients with immunodeficiency or HIV carriers; Serious protein and / or caloric malnutrition; Active and uncontrolled infectious-contagious disease such as tuberculosis, leprosy, systemic fungal disease (histoplasmosis, paracoccidioidomycosis) or any other similar condition; Women who are pregnant or breastfeeding; Allergy to Sbv or miltefosine; Previous treatment for leishmaniasis; Lack of capacity or willingness to provide informed consent (patient and / or parent / legal representative); Absence of availability for the visits or to comply with the study procedures.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sbv<br>Meglumine antimoniate (Glucantime): Dosage: 20 mg / kg / day, intravenously, during 20 days. | Drug: Sbv<br>* Standard treatment for CL, parenteral drug used during 20 days.<br>* Other names: Glucantime;|
| Experimental: Miltefosine plus placebo<br>Miltefosine (28 days / 2.5mg / Kg / day at a maximum dose of 150mg / day orally) + Topical placebo (gel cream, 2 times a day for 28 days) | Drug: Miltefosine plus placebo<br>* Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. Placebo gel cream will be used topically.<br>* Other names: Impavido plus placebo;|
| Experimental: Miltefosine plus GM-CSF<br>Miltefosine (28 days / 2.5mg / kg / day at a maximum dose of 150mg / day orally) + Topical GM-CSF (0.01% gel cream, 2 times a day for 28 days) | Drug: Miltefosine plus GM-CSF<br>* Oral treatment for CL, capsules with 50mg used 3 times a day, during 28 days. GM-CSF gel cream will be used topically.<br>* Other names: Impavido plus GM-CSF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Final cure rate or complete cicatrization of the ulcer | All lesions will be categorized as either active or healed (cured) at follow-up visits. Only lesions with complete re-epithelialization, without raised borders, infiltrations or crusts will be considered healed. Evaluation of the lesions will be performed by 2 clinicians who will be unaware of the group assignment of all patients. Bidirectional measurements of ulcers will be taken of the patients' lesions at the initial visit, and at each follow-up visit with standardized caliper. The area involved will be calculated as the product of the two measurements. | 6 months after the end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Initial cure rate or initial cicatrization of the ulcer | All lesions will be categorized as either active or healed (cured) at follow-up visits. Only lesions with complete re-epithelialization, without raised borders, infiltrations or crusts will be considered healed. Evaluation of the lesions will be performed by 2 clinicians who will be unaware of the group assignment of all patients. Bidirectional measurements of ulcers will be taken of the patients' lesions at the initial visit, and at each follow-up visit with standardized caliper. The area involved will be calculated as the product of the two measurements. | 2 months after the end of treatment | 
| Healing time | Time (in days) to achieve complete cicatrization will be recorded. | Up to 2 months after the end of treatment | 
| Clinical and laboratory adverse events | Clinical and laboratory adverse events will be recorded and graded according to the Common Terminology Criteria for Adverse Event (CTCAE) of the National Cancer Institute | During treatment and through study completion, an average of 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cutaneous leishmaniasis, miltefosine, cytokines, treatment