BENEFIT: Evaluation of the Use of Antiparasital Drug (Benznidazole) in the Treatment of Chronic Chagas' Disease

A randomized double-blind controlled clinical trial investigating the role of benznidazole in patients with chronic Chagas' heart disease.

Chagas disease has 3 phases: acute, undetermined and chronic phases. There are no clinical trials up to date that have investigated the use of antiparasitic drugs in patients that are in the chronic phase.

This study will evaluate the efficacy and safety of benznidazole (an antiparasitic drug) in patients with chronic Chagas' heart disease. Evaluate if benznidazole, an antiparasite drug, given at a dose calculated as 5mg/kg/day for 60 days, now administered as a fixed daily dose of 300mg during 40 to 80 days of treatment - period adjusted according to the patient's body weight to a total minimum dose of 12g (corresponding to 40kg) and a total maximum dose of 24g (corresponding to 80kg) - reduces morbidity and mortality in patients with Chronic Chagas' Cardiomyopathy (CCC). It will be developed in 49 study centres in Argentina, Bolivia,Brazil,Colombia, and El Salvador - countries with high incidence of Chagas Disease.

The Pilot study is evaluating if benznidazole is effective in producing parasitic cure (PCR negativization or reducing parasitic load) in chronic Chagas Disease as well as assessing the feasibility of conducting a large trial in chronic Chagas Disease in South America.

• Benznidazole (Drug), also known as Rochagan/LaFepe: Daily po Benznidazole or placebo (weight based) during 40 - 80 days (depending on body weight)
• Placebo (Drug), also known as Rochagan/LaFepe: a dose calculated as 5mg/kg/day for 60 days, now administered as a fixed daily dose of 300mg during 40 - 80 days of treatment - period adjusted according to the patient's body weight to a total minimum dose of 12g (corresponding to 40kg) and a total maximum dose of 24g (corresponding to 80kg)

Primary outcomes

• Composite of First of cardiovascular events: Death, Resuscitated Cardiac Arrest, Sustained VentricularTachycardia, New/worsening Heart Failure, New Pacemaker/ICD, Stroke/TIA or other Embolic Events, Cardiac Transplant. [through study completion, an average of 5 years]: Composite cardiovascular outcome,

Secondary outcomes

• New development of any of the following echo changes, segmental wall motion abnormalities, ventricular aneurysm, reduction in LV ejection fraction >5%, increase in LVDD> 5 mm compared to baseline. [through study completion, an average of 5 years]
• New 12 lead ECG alterations (complete bundle branch block, fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc). [through study completion, an average of 5 years]
• Progression of NYHA functional class by at least one category [through study completion, an average of 5 years]
• New 12 lead electrocardiogram (ECG) alterations (complete bundle branch block; fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc.) [through study completion, an average of 5 years]
• Progression of New York Heart Association (NYHA) functional class by at least one category [through study completion, an average of 5 years]
• Evaluation of safety (adverse events: dermatitis, peripheral neuropathy, gastro-intestinal intolerance, leucopenia [2500 x 10^9 L]), tolerance and adherence to treatment [through study completion, an average of 5 years]
• Determination of the efficacy of benznidazole in patients with Chronic Chagas heart disease based on a 50% reduction in both qualitative and quantitative PCR. [through study completion, an average of 5 years]: Polymerase Chain Reaction study on patient's blood samples and report negativization at the end of treatment, 2Y and final visit.
• Safety and tolerability of benznidazole [through study completion, an average of 5 years]

Sex: All, ages: 18 Years to 75 Years, accepts healthy volunteers

Inclusion Criteria:

* Consenting patients (between 18 and 75 years of age) with serological evidence of Chagas infection (any combination of 2 positive tests) and that have one or more of the following:
* Abnormal electrocardiogram with at least two components (complete RBBB or LBBB; left anterior or posterior fascicular block; ventricular premature beat; first degree atrioventricular \[AV\] block; Mobitz type I AV block; sinus bradycardia; primary ST-T changes; abnormal Q waves; low voltage QRS; or atrial fibrillation);
* Abnormal ECG (Mobitz type II, advanced or third degree AV block);
* Increased cardiothoracic ratio (> 0.50);
* Complex ventricular arrythmias on 24 hour ambulatory ECG monitoring;
* Evidence of regional wall motion abnormality or reduced global left ventricular systolic function or increased left ventricular and diastolic diameter on 2D-Echo.

Exclusion Criteria:

Patients will be excluded if having:

* NYHA heart failure class IV or decompensated heart failure
* Evidence of concomitant coronary artery disease (CAD) or other etiology of dilated cardiomyopathy
* Previous treatment with antitrypanosomal agents or an accepted indication for antiparasitic therapy
* Inability to comply with follow-up visits
* History of severe alcohol abuse within 2 years
* Known chronic renal or hepatic insufficiency or hepatic insufficiency
* Pregnancy or breast feeding
* Megaesophagus with swallowing impairment
* Other severe disease significantly curtailing life expectancy

• Marin-Neto JA, Rassi A Jr, Morillo CA, Avezum A, Connolly SJ, Sosa-Estani S, Rosas F, Yusuf S; BENEFIT Investigators. Rationale and design of a randomized placebo-controlled trial assessing the effects of etiologic treatment in Chagas' cardiomyopathy: the BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT). Am Heart J. 2008 Jul;156(1):37-43. doi: 10.1016/j.ahj.2008.04.001. PMID 18585495
• Results publication: Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi A Jr, Rosas F, Villena E, Quiroz R, Bonilla R, Britto C, Guhl F, Velazquez E, Bonilla L, Meeks B, Rao-Melacini P, Pogue J, Mattos A, Lazdins J, Rassi A, Connolly SJ, Yusuf S; BENEFIT Investigators. Randomized Trial of Benznidazole for Chronic Chagas' Cardiomyopathy. N Engl J Med. 2015 Oct;373(14):1295-306. doi: 10.1056/NEJMoa1507574. Epub 2015 Sep 1. PMID 26323937
• Results publication: Marin-Neto JA, Rassi A Jr, Avezum A Jr, Mattos AC, Rassi A, Morillo CA, Sosa-Estani S, Yusuf S; BENEFIT Investigators. The BENEFIT trial: testing the hypothesis that trypanocidal therapy is beneficial for patients with chronic Chagas heart disease. Mem Inst Oswaldo Cruz. 2009 Jul;104 Suppl 1:319-24. doi: 10.1590/s0074-02762009000900042. PMID 19753491

• Carlos Morillo, MD, Study chair, Population Health Research Institute - McMaster University
• Jose Antonio Marin-Neto, MD, PhD, Study chair, University of Sao Paulo
• Salim Yusuf, MD, DPh, Study chair, Population Health Research Institute - McMaster University
• Sergio Sosa-Estani, MD, PhD, Principal investigator, Argentina National Coordinator - CenDIE, Argentina
• Fernando Rosas, M.D., Principal investigator, Fundacion Clinica Shaio, Bogota, Colombia