Etiologic Treatment With Benznidazole in Adult Patients With Chronic Chagas Disease. A Randomized Clinical Trial

Study Overview
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Brief Summary
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The purpose of this study is: -to determine whether benznidazole (BZN) will be able to modify the natural evolution of chronic Chagas disease in adult patients by means of a randomized, double-blind clinical trial (RCT). Also: -to validate therapeutic efficacy with new methods, such as recombinant antigen F29 of Trypanosoma cruzi visualized by conventional ELISA, in the context of the RCT compared with conventional serology (CS) -to develop the real-time polymerase chain-reaction (RT-PCR) to quantify the parasite load as an early therapeutic effect. to determine the potential of such serological and parasitological methods as predictors of therapeutic effect or failure.

Detailed Description
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Patients and Methods. Patients selected to be enrolled were born in Chagas disease endemic areas of Argentina and bordering countries such as Bolivia and Paraguay, whose current residence is in urban non endemic areas of Argentina. They were sorted by clinical stage: stage 0, 1, 2 and 3 according to a modified Kuschnir classification.1 Briefly, Stage 0 corresponds to patients only with reactive serology for Chagas disease; stage 1, patients with reactive serology plus electrocardiographic abnormalities; stage 2, patients with the abovementioned characteristics plus dilatation of left ventricle by echocardiography, and stage 3, patients with the abovementioned characteristics, plus cardiac failure. The follow-up was performed every 4 months during the first 2 years, every 6 months in the 3rd and 4th year, and annually from then on until the end of the study in 2012. The safety of TRAENA was controlled at days 25 and 45 intra-treatment by means of laboratory tests and clinical evaluation, and at any time that an adverse event was apparent in patients. Adherence to medication administration was verified by means of a booklet where the patient recorded the daily intake of medication and any physical abnormality that appeared during the time they were taking of medicine. Adherence was controlled by a surveillance and recovery system which consisted of telephone calls, telegrams, letters or home visits that was termed active monitoring, which was immediately applied to the control visit when the patient did not attend the corresponding schedule control. Telephone calls were the most useful tool to recover adherence to monitoring. Patients were assigned to BZN or Placebo treatment by an investigator independent from the research group. Prior to randomization, a pre randomization stratification was performed according to prognostic factors based on clinical stages of Chagas disease. A database was designed to be used as the registry for the whole study. Demographic, epidemiologic, serologic, parasitological and clinical variables were used in its design, and were registered pre treatment, intra treatment and post treatment throughout the monitoring. Medical records were the primary documents for the registry, where all the variables were recorded manually. Based on the data, variables were registered on a daily basis and a random weekly check was conducted on the data against the medical records. Our Standard Operating Procedure was based on the following procedures: patient screening, selection and coding, sample collection, serum bank, DNA sample storage, monitoring systematization, surveillance systems to recover patients who had discontinued monitoring, etc. In October 2011 the Base Data Monitoring Board for the last Interim Analysis, recommended an addendum modifying the secondary outcomes, adding simple and combined events. These events were characterized only by electrocardiographic abnormalities or associated to echocardiographic ones. These events were evaluated up April 2013.

Official Title
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Etiologic Treatment With Benznidazole in Adult Patients With Chronic Chagas Disease. A Randomized Double Blind Clinical Trial

Conditions
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Chagas Disease

Intervention / Treatment
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* Drug: Benznidazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients living in urban areas Reactive to at least 2 for serological test performed in Fatala Chaben Institute (ELISA and IFI) , Patients who agreed to be part of this protocol through informed consent form signed Exclusion Criteria: Patients with chronic Chagas disease who have received prior treatment with benznidazole Other cardiomyopathies : idiopathic , alcoholic , peripartum myocarditis, secondary to coronary artery disease, valve disease, hypertension, restrictive, hypertrophic or congenital Chronic renal disease Bleeding disorders History of liver disease or current liver disease , Any other severe clinical disease that decreases their life expectancy History of severe allergies Pregnant patients Patients who have not signed the informed consent.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 55 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Benznidazole<br>Benznidazole pills of 100 mg, dose 5 mg/Kg/day, twice a day during 60 days | Drug: Benznidazole<br>* Benznidazole at a dose 5 mg/Kg/day until 60 days have been completed or development of non-acceptable toxicity-<br>* Other names: Radanil (Roche Laboratory);|
| Placebo Comparator: Placebo<br>Placebo pills 100 mg, dose 5mg/Kg/day, twice a day, during 60 days | Drug: Placebo<br>* Placebo at a dose 5 m/Kg/day until 60 days<br>* Other names: Placebo pills;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular Mortality | Sudden death, unexpectedly in time and in its presentation,preceded by the abrupt loss of consciousness within a maximum of one hour of the onset of symptoms,when it happened during sleep or unexpectedly in a patient was stable until then. Related Death, when presented in a patient with signs of progressive heart failure.Ischemic or Hemorrhagic Stroke | Time to event: from date of randomization until the date of first documented progression or date of death from any cause up to 10 years of follow-up | 
| Development of heart failure | Dyspnea is evaluated according to the classification of the New York Heart Association (NYHA),gallop rhythm, jugular venous distension, crackles in the lungs, edema or pleural effusion,hepatomegaly | Time to event: from date of randomization until the date of first documented progression of heart failure up to 10 years of follow-up | 
| Severe arrhythmias with hemodynamic compromise or pacemaker implant or Implantable cardiac defibrillator | Sustained ventricular tachycardia, atrioventricular block, trifascicular block, Atrial fibrillation | Time to event: from date of randomization until the date of first documented progression up to 10 years of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Electrocardiographic endpoints. New development of permanent changes in the electrocardiographic | Stable sinus bradycardia (<50 beats / min) Auriculoventricular blocks of 2nd and 3rd degree Left anterior hemi-block Complete right bundle branch block Atrial flutter or fibrillation Sustained ventricular tachycardia | Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up | 
| Changes in clinical stage in chronic Chagas disease | Clinical progression | Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up | 
| Enlargement of the left ventricle (LV) detected by echocardiography. | Clinical Progression | Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up | 
| New Heart Failure | Clinical Progression | Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up | 
| Stroke | Clinical progression | Time to event: from date of randomization until the date of first documented as defined in the secondary outcome up to 10 years of follow-up | 
| Serological negativization | by ELISA F29 vs. conventional serology as a late indicator of efficacy or therapeutic failure. | time to event: from the date of randomization to the date of the first documented serological negativization that persists until 10 years of follow-up | 
| Development and validation of RT-PCR | Demonstration of RT-PCR as an early indicator of efficacy or therapeutic failure. | time to event: from the date of randomization to the date of the first documented no detectable RT-PCR that persists until 10 years of follow-up | 
| Changes of the secondary objectives during RCT development. New single endpoints | Any change in clinical stage 0 to II due to left ventricular enlargement demonstrated by echocardiogram, or I to III stage due to development of heart failure. Complete left branch block 3. Atrial fibrillation 4. Repetitive ventricular extrasystoles: doublets, triplets, bigemina, trigeminus, ventricular tachycardia | Since October 2011 during 18 months | 
| Combined clinical endpoints: | Right bundle branch block associated with left anterior hemi-block. Parietal motility disorders of left ventricle by echocardiography (akinesia, hypokinesia, and dyskinesia) associated with impaired left ventricular systolic function. Parietal motility disorders of left ventricle by echocardiogram (Akinesia, Hypokinesia, dyskinesia) and /or impaired LV systolic function associated with new electrocardiographic changes (complete left branch block, right bundle branch block, left anterior hemi-block, ventricular extrasystoles. Occurrence of left ventricle aneurysm point by echocardiogram associated to ventricular arrhythmia (section 2.4.1.4.). Occurrence of left ventricle aneurysm point by echocardiogram associated with depression of LV systolic function by echocardiography. | Since October 2011 during 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Chagas Disease, Randomized Clinical Trial double blind, Benznidazole vs Placebo, Adult patients