Phase III Clinical Trial for Mucosal or Mucocutaneous Leishmaniasis. Comparison Between the Standard and Alternative Antimonial Schemes

1. Introduction. Pentavalent antimonials are first line drugs for the treatment of leishmaniasis. WHO and Brazilian Ministry of Health recommend treating patients with mucosal (ML) or mucocutaneous leishmaniasis (MCL) with doses of 20mg/kg/day, intramuscularly or intravenously, for a period of three to four weeks. In the Reference Centre on Leishmaniasis - IPEC - FIOCRUZ, the dose of 5mg/kg/day IM has been effective and well tolerated in the treatment. ML is treated for 30 continuous or intermittent days, in series of 10 days interspersed with periods of 10 days without medication, up to 12 series of treatment (120 medication days), with a lower incidence of adverse effects and lower treatment dropout rates. The evolution of the lesions is usually similar to that observed with continuous treatment. In all cases patients should be monitored with clinical examination, electrocardiogram, blood count, liver function, renal and pancreatic tests. Some side effects can be observed, although they not necessarily lead to discontinuation of treatment: arthralgia, myalgia, anorexia, abdominal pain, rash, fever, headache, edema, and herpes zoster. Electrocardiographic abnormalities most frequent are heart rhythm and ventricular repolarization disturbances: flattening or inversion of T wave and corrected QT space widening.
2. Background: Ideally, the most appropriate antimoniate therapeutic regimens should be established for each endemic area, based on their efficacy and toxicity, without ignoring the difficulties of administration and cost. The treatment of ML or MCL must achieve the healing of mucosal lesions and prevention of severe scarring of mucosal tissues and consequent disabilities. The recognition, recommendation and acceptance of new regimens should be preceded by demonstration of their superiority to currently recommended treatments. We aim to compare the effectiveness and safety among treatment schemes with meglumine antimoniate currently recommended in Brazil for the treatment of ATL and an alternative scheme with low doses of antimony.
3. Objectives. 3.1. General Objective. To compare the effectiveness and safety of meglumine antimoniate at a dose of 20 mg/kg/day for 30 days or 5 mg continuous up to 120 days, in the treatment of patients with ML or MCL.

3.2. Specific Objectives. 1. To compare the frequencies of epithelialization and reduction of mucosal infiltration (assessed on days 30, 120, 150 from the beginning of the treatment) between the two groups. 2. To compare the frequencies of good late therapeutic response (maintenance of epithelialization, with total regression of infiltration and no re-emergence of a skin lesion) between the two groups, up to two years. 3. To compare the frequency and severity of adverse clinical, laboratory and electrocardiogram effects between the two groups, controlling for age above or below 60 years. 4. To compare the time in days until the epithelialization and reduction of infiltration of the lesions between the two groups, according to the nasal, oropharyngeal or laryngeal location. 4. Subjects and methods.

4. 1. Study design: Controlled clinical trial with standard and alternative treatment, randomized, double-blind, phase III.

4.2. Description of interventions: Meglumine antimoniate (Aventis, São Paulo, Brazil) is stored and ministered under actual conditions employed by the health services in Brazil. A single lot of medication will be used in all patients. Each patient will be included in one of two treatment groups with meglumine antimoniate IM: 1) 20mg / kg / day for 30 continuous days. Patients with remaining active lesions in the day 120 from the beginning of the treatment will be re-treated with the same regimen. 2) 5mg / kg / day continuous until the epithelization and resolution of mucosal infiltration, respecting the limit of 120 days of treatment.

There will be no cross-over between the groups for the purpose of this study. The data from those patients who require permanent discontinuation of a scheme will be assessed in the group that were randomized, ie, by intention to treat.