Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
MCT-79704
Study information
Scientific title
BENznidazole Evaluation For Interrupting Trypanosomiasis pilot trial
Acronym
BENEFIT Pilot
Study hypothesis
Benznidazole is effective in producing parasitic cure in patients with Chronic Chagas Cardiomyopathy. 60 days of therapy with Benznidazole will:
1. Increase negativization of Trypanosomiasis cruzi as detected by Polymerase Chain Reaction (PCR) by at least 30%, and
2. Reduce t. cruzi parasite load by at least 50%
Ethics approval
1. Research Ethics Board of Hamilton Health Sciences Corporation & McMaster University (Canada), 21/09/2006, ref: NREC # 05-348
2. Comité de Ethica em Pesquisa de l'Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto da Universidade de Sao Paulo (Brazil), 04/02/2004, ref: NREC# 213/2004
3. Ministerio de Salud y Ambiente (Argentina), 11/03/2005, ref: NREC 1-0047-0000-00733-05-1
4. Comite Investigaciones de Fundacion ABBOD SHAIO (Columbia), 19/04/2004
Study design
Multicentre multinational two-arm randomised parallel controlled placebo trial with study participant, study investigator, caregiver, outcome assessor, and data analyst blinding
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
Chagas disease; American trypanosomiasis
Intervention
1. Benznidazole: 60 days of treatment at 5 mg/kg/day given twice a day (at maximum dose of 400 mg/day)
2. Matching placebo: 60 days of treatment at 5 mg/kg/day given twice a day (at maximum dose of 400 mg/day)
Intervention type
Drug
Phase
Not Applicable
Drug names
Benznidazole
Primary outcome measures
There are two related co-primary outcomes:
1. Negativisation and reduction of t. cruzi detected by PCR at the end of treatment which lasted 60 days, and at a two-year follow-up
2. Reduction in the mean burden of t. cruzi (parasite load) as detected by the concentration of t. cruzi/ml of blood by PCR in the treated group, at the end of treatment which lasted 60 days, and at a two-year follow-up
Secondary outcome measures
1. Safety and tolerability of benznidazole in chronic Chagas cardiomyopathy, 11 ± 2 days after initial randomisation, three weeks ± 3 days after randomisation, end of therapy (60 days) and two years later
2. Long-term feasibility of conducting a Randomised Controlled Trial (RCT) in patients with Chagas disease measured by patient enrolment and completion of follow-up, recruitment rate measured at baseline, completion measured at the end of therapy (60 days later), and two years later
3. Cardiovascular events:
3.1. Composite of major cardiovascular outcomes defined as the first occurrence of: death, cardiac arrest, sustained ventricular tachycardia, symptomatic heart failure, pacemaker or implantable cardiac defibrillator insertion, ischemic stroke or other systemic thromboembolic event, 11 days, 21 days, 60 days, 6 months, 1 year and 2 year after randomisation
3.2. New development of any of the following echo changes: segmental wall motion abnormalities, ventricular aneurysm, reduction in LV ejection fraction greater than 5%, increase in Left Ventricular end-Diastolic Dimension [LVDD] greater than 5.0 mm compared with baseline, 11 days, 21 days, 60 days, 6 months, 1 year and 2 year after randomisation
3.3. New 12 lead ECG alterations (complete bundle branch block, fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc); 1st Degree AV Block PR greater than 280 ms, 11 days, 21 days, 60 days, 6 months, 1 year and 2 year after randomisation
3.4. Progression of NYHA functional class by at least one category, 11 days, 21 days, 60 days, 6 months, 1 year and 2 year after randomisation
Overall trial start date
01/03/2006
Overall trial end date
30/04/2009
Reason abandoned
Eligibility
Participant inclusion criteria
1. Either sex, aged greater than or equal to 18 and less than or equal to 70 years
2. At least two positive serological tests for Chagas disease (indirect immunofluorescence, indirect hemagglutination, OR Enzyme-Linked Immunosorbent Assay [ELISA]) and at least ONE of the following markers of cardiac involvement (which identify individuals at high risk of progression):
2.1. Abnormal 12 lead Electrocardiogram (ECG): One-major criteria (second or third degree AV block) OR at least two minor criteria:
2.1.1. Any bundle branch block
2.1.2. Any fascicular block
2.1.3. Ventricular premature beats (greater than one)
2.1.4. First degree AV block greater than 220 ms, in the absence of drugs that slow AV node conduction
2.1.5. Mobitz type I AV block, in the absence of drugs that slow AV
2.1.6. Sinus bradycardia less than 50 bpm or sinus pauses greater than 3.0s, in the absence of sinus node blocking drugs
2.1.7. Low voltage of QRS in the frontal plane
2.1.8. Atrial fibrillation
2.2. Increased cardiothoracic ratio greater than 0.50 at baseline on upright chest X ray
2.3. Evidence of regional wall motion abnormality (hypokinesis, akinesis or dyskinesis) or reduced global Left Ventricular Systolic Function (LVEF) less than 50% (2D-Echo Radionuclide Angiography [RNA] LV ventriculography) or increased left ventricular diastolic diameter (greater than 55 mm) on 2D-Echo
2.4. Complex ventricular arrhythmias (multiform greater than 10/hour, couplets or non-sustained Ventricular Tachycardia [NSVT]) on 24 hour ambulatory ECG monitoring
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
600
Participant exclusion criteria
1. New York Heart Association (NYHA) heart failure class IV or decompensated heart failure
2. Evidence of concomitant Coronary Artery Disease (CAD) or other etiology of dilated cardiomyopathy
3. Previous treatment with antitrypanosomal agents or an accepted indication for antiparasitic therapy (e.g. reactivation of Chagas infection due to immunosuppression by several diseases or treatment with steroids)
4. Patients living in inadequate housing conditions that may predispose to t. cruzi re-infection will not be excluded; instead this condition will be appropriately documented
5. Inability to comply with follow-up
6. History of severe alcohol abuse within two years
7. Known chronic renal insufficiency (serum creatinine greater than 2.5 mg/dl or 200 umol) or hepatic insufficiency (Aspartate Aminotransferase [AST]/Alanine Aminotransferase [ALT] greater than 3 x normal)
8. Pregnancy or breast feeding
9. Megaesophagus with swallowing impairment
10. Other severe disease significantly curtailing life expectancy
Recruitment start date
01/03/2006
Recruitment end date
30/04/2009
Locations
Countries of recruitment
Argentina, Brazil, Canada, Colombia
Trial participating centre
McMaster University
Ontario
L8L 2X2
Canada
Sponsor information
Organisation
Hamilton Health Science Corporation (HHSC) (Canada)
Sponsor details
c/o Beena Cracknell
Population Health Research Institute
CEBA McMaster University
1200 Main Street West
Hamilton
Ontario
L8N 3Z5
Canada
+1 (0)905 527 4322 ext. 44555
beena@cardio.on.ca
Sponsor type
Government
Website
Funders
Funder type
Research organisation
Funder name
The Canadian Institutes of Health Research (CIHR) (Canada) - http://www.cihr-irsc.gc.ca (ref: MCT-79704)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Results - basic reporting
Publication summary
2008 protocol in: http://www.ncbi.nlm.nih.gov/pubmed/18585495
2015 results in: http://www.ncbi.nlm.nih.gov/pubmed/26323937
Publication citations
-
Protocol
Marin-Neto JA, Rassi A, Morillo CA, Avezum A, Connolly SJ, Sosa-Estani S, Rosas F, Yusuf S, , 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, 156, 1, 37-43, doi: 10.1016/j.ahj.2008.04.001.
-
Results
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 .