Clinical trial NCT00123916: BENEFIT: Evaluation of the Use of Antiparasital Drug (Benznidazole) in the Treatment of Chronic Chagas' Disease
Official title: Benznidazole Evaluation for Interrupting Trypanosomiasis - The BENEFIT Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chagas Disease
Trypanosomiasis
Heart Disease
Keywords: Chagas Disease
Trypanosomiasis
Benznidazole
Chronic Heart disease
Trypanosoma Cruzi
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: World Health Organization
name: Instituto Dante Pazzanese de Cardiologia
name: University of Sao Paulo
First posted: 2005-07-26
Enrollment: 2854
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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).

The BENEFIT study is being conducted by the Population Health Research Institute (in Hamilton, Canada) and the Institute Dante Pazzanese de Cardiologia (Sao Paulo, Brazil) together with a Steering Committee, and an independent Safety Monitoring Board.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: through study completion, an average of 5 years
Secondary outcomes:
measure: 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.
timeFrame: through study completion, an average of 5 years
measure: New 12 lead ECG alterations (complete bundle branch block, fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc).
timeFrame: through study completion, an average of 5 years
measure: Progression of NYHA functional class by at least one category
timeFrame: through study completion, an average of 5 years
measure: New 12 lead electrocardiogram (ECG) alterations (complete bundle branch block; fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc.)
timeFrame: through study completion, an average of 5 years
measure: Progression of New York Heart Association (NYHA) functional class by at least one category
timeFrame: through study completion, an average of 5 years
measure: Evaluation of safety (adverse events: dermatitis, peripheral neuropathy, gastro-intestinal intolerance, leucopenia [2500 x 10^9 L]), tolerance and adherence to treatment
timeFrame: through study completion, an average of 5 years
measure: Determination of the efficacy of benznidazole in patients with Chronic Chagas heart disease based on a 50% reduction in both qualitative and quantitative PCR.
timeFrame: through study completion, an average of 5 years
measure: Safety and tolerability of benznidazole
timeFrame: through study completion, an average of 5 years
Other outcomes:
Locations:
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: BENEFIT Ivestigational Site
state: Apital Federal
city: Belén De Escobar
country: Argentina
facility: BENEFIT Investigational Site
state: Buenos Aires
city: Isidro Casanova
country: Argentina
facility: BENEFIT Investigational Site
state: Buenos Aires
city: San Juan
country: Argentina
facility: BENEFIT Investigational Site
state: Buenos Aires
city: Santiago del Estero
country: Argentina
facility: BENEFIT Investigational Site
state: Buenos Aires
city: Santiago del Estero
country: Argentina
facility: BENEFIT Investigational Site
state: Buenos Aires
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: BENEFIT Investigational Site
state: Capital Federal
city: San Fernando del Valle de Catamarca
country: Argentina
facility: BENEFIT Investigational Site
state: Catamarca
city: Charata
country: Argentina
facility: BENEFIT Investigational Site
state: Chaco
city: Paraná
country: Argentina
facility: BENEFIT Investigational Site
state: Entre Rios
city: Buenos Aires
country: Argentina
facility: BENEFIT Investigational Site
state: General Rodríguez Partido
city: San Salvador de Jujuy
country: Argentina
facility: BENEFIT Investigational Site
state: Jujuy
city: Corrientes
country: Argentina
facility: BENEFIT Investigational Site
state: Rosario, Santa Fe
city: Rosario
country: Argentina
facility: BENEFIT Investigational Site
state: Santa Fe
city: Añatuya
country: Argentina
facility: BENEFIT Investigational Site
state: Santiago Del Estero
city: Santiago Del Estero
country: Argentina
facility: BENEFIT Investigational Site
state: Sgo. Del Estero
city: Buenos Aires
country: Argentina
facility: BENEFIT Investigational Site
city: Salta
country: Argentina
facility: BENEFIT Investigational Site
city: Tupiza
country: Bolivia
facility: BENEFIT Investigational Site
state: Potosi
city: Salvador
country: Brazil
facility: BENEFIT Investigational Site
state: Bahaia
city: Salvador
country: Brazil
facility: BENEFIT Investigational Site
state: Bahaia
city: Salvador
country: Brazil
facility: BENEFIT Investigational Site
state: Bahaia
city: Carmo
country: Brazil
facility: BENEFIT Investigational Site
state: Belo Horizonte
city: Brasília
country: Brazil
facility: BENEFIT Investigational Site
state: Brazilian Federal District
city: Goiânia
country: Brazil
facility: BENEFIT Investigational Site
state: GO
city: Goiânia
country: Brazil
facility: BENEFIT Investigational Site
state: GO
city: Goiânia
country: Brazil
facility: BENEFIT Investigational Site
state: GO
city: Uberlandia
country: Brazil
facility: BENEFIT Investigational Site
state: MG
city: Uberlândia
country: Brazil
facility: BENEFIT Investigational Site
state: MG
city: Uberaba
country: Brazil
facility: BENEFIT Investigational Site
state: Minas Gerais
city: Curitiba
country: Brazil
facility: BENEFIT Investigational Site
state: Parana
city: Recife
country: Brazil
facility: BENEFIT Investigational Site
state: Pernambuco
city: Pelotas
country: Brazil
facility: BENEFIT Investigational Site
state: Rio Grande Do Sul
city: Campinas
country: Brazil
facility: BENEFIT Investigational Site
state: São Paulo
city: Ribeirão Preto
country: Brazil
facility: BENEFIT Investigational Site
state: São Paulo
city: São José do Rio Preto
country: Brazil
facility: BENEFIT Investigational Site
state: São Paulo
city: São José do Rio Preto
country: Brazil
facility: BENEFIT Investigational Site
state: São Paulo
city: Votuporanga
country: Brazil
facility: BENEFIT Investigational Site
state: São Paulo
city: Rio de Janeiro
country: Brazil
facility: BENEFIT Investigational Site
city: Rio de Janeiro
country: Brazil
facility: BENEFIT Investigational Site
city: São Paulo
country: Brazil
facility: BENEFIT Investigational Site
city: São Paulo
country: Brazil
facility: BENEFIT Investigational Site
city: São Paulo
country: Brazil
facility: BENEFIT Investigational Site
city: São Paulo
country: Brazil
facility: BENEFIT Investigational Site
city: Bogota
country: Colombia
facility: BENEFIT Investigational Site
state: Bogotá
city: San Gil
country: Colombia
facility: BENEFIT Investigational Site
state: Santander
city: San Salvador
country: El Salvador
facility: BENEFIT Ivestigational Site
Study officials:
affiliation: Population Health Research Institute - McMaster University
name: Carlos Morillo, MD
role: STUDY_CHAIR
affiliation: University of Sao Paulo
name: Jose Antonio Marin-Neto, MD, PhD
role: STUDY_CHAIR
affiliation: Population Health Research Institute - McMaster University
name: Salim Yusuf, MD, DPh
role: STUDY_CHAIR
affiliation: Argentina National Coordinator - CenDIE, Argentina
name: Sergio Sosa-Estani, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundacion Clinica Shaio, Bogota, Colombia
name: Fernando Rosas, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.