Efficacy and Safety Study of Drugs for Treatment of Visceral Leishmaniasis in Brazil

Study Overview
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Brief Summary
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This study is aimed to compare the efficacy and safety of medications currently used in Brazil for treatment of visceral leishmaniasis. The investigators will compare the effects of meglumine antimoniate, two formulations of amphotericin B: deoxycholate and liposomal, and a combination of meglumine plus the liposomal amphotericin B formulation. The study is designed to demonstrate the difference in efficacy measured as cure rate at six months after treatment and the safety profile based on the adverse event rate observed with each intervention.

Detailed Description
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Visceral leishmaniasis is a relevant public health problem in Brazil with approximately 3500 cases registered every year. Eight percent lethality rate has been observed during the past decade in spite of free of charge availability of antileishmanial drugs supplied by the public health system. The present study was designed as a phase IV, multicentric, open label, active controlled clinical trial targeted to visceral leishmaniasis adult and pediatric cases. The current drugs approved for visceral leishmaniasis treatment in Brazil will be compared in four treatment groups: meglumine antimoniate, amphotericin B deoxycholate, liposomal amphotericin B and a combination of single dose of liposomal amphotericin B plus meglumine antimoniate. Meglumine antimoniate treated patients will constitute the active control group. Drugs will be compared based on the cure rate observed after six months follow-up. The study arm submitted to treatment with Amphotericin B deoxycholate was suspended in September 2012.

Official Title
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Multicentric Efficacy and Safety Study of Antileishmanial Drugs for Treatment of Visceral Leishmaniasis in Brazil

Conditions
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Visceral Leishmaniasis

Intervention / Treatment
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* Drug: Antimoniate of N-methylglucamine
* Drug: amphotericin B deoxycholate
* Drug: Liposomal amphotericin B
* Drug: Liposomal amphotericin B
* Drug: Antimoniate of N-methylglucamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients with visceral leishmaniasis characterized by fever plus hepatomegaly or splenomegaly with at least one positive result in the following laboratory tests: direct observation of leishmania amastigotes in bone marrow smear leishmania in vitro culture from bone marrow aspirates leishmania kDNA amplification by PCR in bone marrow or peripheral blood samples rK39 immunochromatographic rapid test performed on serum sample Exclusion Criteria: pregnancy HIV infection chronic diseases such as diabetes mellitus,kidney, liver or cardiac diseases, schistosomiasis, malaria or tuberculosis immune disorders or use of drugs which interferes with the immune response treatment with drugs with increased risk for toxicity associated with the study drugs exposure to antileishmanial drugs during the past six months I.V. drug users episodes of visceral leishmaniasis relapse hypersensibility to the study drugs difficulties for accomplishing the follow-up schedule any of the following clinical signs of laboratory abnormalities: hepatic encephalopathy, generalized edema, toxemic individuals, severe malnutrition, jaundice, abnormal serum creatinine, bilirubin, INR > 2,0, platelet count < 20000/mm3

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 50 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Meglumine antimoniate<br>Antimoniate of N-methylglucamine 20mg/kg/d, I.V. for 20 consecutive days. | Drug: Antimoniate of N-methylglucamine<br>* Antimoniate of N-methyl glucamine 20mg/kg/d of pentavalent antimonial, I.V. for 20 consecutive days.<br>* Other names: Glucantime;|
| Experimental: Liposomal Amphotericin B<br>Liposomal amphotericin B 3mg/kg/d I.V. for 7 consecutive days. | Drug: Liposomal amphotericin B<br>* 3mg/kg/d, I.V. for 7 consecutive days.<br>* Other names: AmBisome;|
| Experimental: Amphotericin B<br>Amphotericin B deoxycholate 1mg/kg/d I.V. for 14 consecutive days. This arm was suspended in September 19th, 2012, because of a relevant excess of adverse events and serious adverse events associated with this experimental intervention in comparison with the active comparator and the other two experimental arms. The suspension of this study arm was supported by a DSMB statement. | Drug: amphotericin B deoxycholate<br>* 1mg/kg/d, I.V. for 14 consecutive days.<br>* Other names: Anforicin B;|
| Experimental: Combination therapy<br>Liposomal amphotericin B 10mg/kg/d, I.V. single dose on day 0 plus Antimoniate of N-methylglucamine 20mg/kg/d for 10 consecutive days on days 1 to 10. | Drug: Liposomal amphotericin B<br>* 10mg/kg/d, I.V. single dose.<br>* Other names: AmBisome;Drug: Antimoniate of N-methylglucamine<br>* 20mg/kg/d of pentavalent antimonial I.V. for 10 days<br>* Other names: Glucantime;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cure rate | Complete remission of clinical signs and symptoms, three months after treatment plus normal hematological lab evaluation and no relapse at sixth month follow-up. | 6 month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement rate | Fever disappearing, stable or improving hematological lab abnormalities plus any spleen size reduction. | 30 days | 
| Relapse rate | Reappearing of signs and symptoms after any improvement observed after treatment, during the six months follow-up period. | (6 months post treatment) After treatment until the sixth month of follow-up | 
| Serious adverse events rate | Rate of adverse events defined as conditions which fulfilled any of the following: results in death, is life threatening, requires inpatient hospitalization or prolongs hospitalization, results in persistent or significant disability/incapacity, causes a congenital anomaly or birth defect or it is considered as a important medical event for the responsible clinician. | During (day one) and within the six months follow-up | 
| Adverse event rate and intensity | Cumulative rate of any adverse event, including clinical, laboratory and electrocardiographic abnormalities observed within the treatment and follow-up periods. All adverse events will be graded using an adapted ACTG 0-4 scale. | During (day one) treatment and within the six months follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Visceral leishmaniasis, Leishmania infantum, Leishmania chagasi