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

Primary Purpose

Chagas Disease, Trypanosomiasis, Heart Disease

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Benznidazole
Placebo
Sponsored by
Population Health Research Institute
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chagas Disease focused on measuring Chagas Disease, Trypanosomiasis, Benznidazole, Chronic Heart disease, Trypanosoma Cruzi

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesAccepts 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

Sites / Locations

  • BENEFIT Ivestigational Site
  • BENEFIT Investigational Site
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  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
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  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Investigational Site
  • BENEFIT Ivestigational Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Benznidazole

Placebo

Arm Description

40 - 80 days (according to body weight) treatment with benznidazol

40 - 80 days (according to body weight) treatment with matching placebo

Outcomes

Primary Outcome Measures

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.
Composite cardiovascular outcome,

Secondary Outcome Measures

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.
New 12 lead ECG alterations (complete bundle branch block, fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc).
Progression of NYHA functional class by at least one category
New 12 lead electrocardiogram (ECG) alterations (complete bundle branch block; fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc.)
Progression of New York Heart Association (NYHA) functional class by at least one category
Evaluation of safety (adverse events: dermatitis, peripheral neuropathy, gastro-intestinal intolerance, leucopenia [2500 x 10^9 L]), tolerance and adherence to treatment
Determination of the efficacy of benznidazole in patients with Chronic Chagas heart disease based on a 50% reduction in both qualitative and quantitative PCR.
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

Full Information

First Posted
July 21, 2005
Last Updated
February 27, 2020
Sponsor
Population Health Research Institute
Collaborators
Canadian Institutes of Health Research (CIHR), World Health Organization, Instituto Dante Pazzanese de Cardiologia, University of Sao Paulo
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1. Study Identification

Unique Protocol Identification Number
NCT00123916
Brief Title
BENEFIT: Evaluation of the Use of Antiparasital Drug (Benznidazole) in the Treatment of Chronic Chagas' Disease
Acronym
BENEFIT
Official Title
Benznidazole Evaluation for Interrupting Trypanosomiasis - The BENEFIT Trial
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Completed
Study Start Date
November 2004 (undefined)
Primary Completion Date
July 2015 (Actual)
Study Completion Date
August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Population Health Research Institute
Collaborators
Canadian Institutes of Health Research (CIHR), World Health Organization, Instituto Dante Pazzanese de Cardiologia, University of Sao Paulo

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chagas Disease, Trypanosomiasis, Heart Disease
Keywords
Chagas Disease, Trypanosomiasis, Benznidazole, Chronic Heart disease, Trypanosoma Cruzi

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
2854 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Benznidazole
Arm Type
Experimental
Arm Description
40 - 80 days (according to body weight) treatment with benznidazol
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
40 - 80 days (according to body weight) treatment with matching placebo
Intervention Type
Drug
Intervention Name(s)
Benznidazole
Other Intervention Name(s)
Rochagan/LaFepe
Intervention Description
Daily po Benznidazole or placebo (weight based) during 40 - 80 days (depending on body weight)
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
Rochagan/LaFepe
Intervention Description
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 Outcome Measure Information:
Title
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.
Description
Composite cardiovascular outcome,
Time Frame
through study completion, an average of 5 years
Secondary Outcome Measure Information:
Title
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.
Time Frame
through study completion, an average of 5 years
Title
New 12 lead ECG alterations (complete bundle branch block, fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc).
Time Frame
through study completion, an average of 5 years
Title
Progression of NYHA functional class by at least one category
Time Frame
through study completion, an average of 5 years
Title
New 12 lead electrocardiogram (ECG) alterations (complete bundle branch block; fascicular block, advanced atrio-ventricular block, atrial fibrillation, etc.)
Time Frame
through study completion, an average of 5 years
Title
Progression of New York Heart Association (NYHA) functional class by at least one category
Time Frame
through study completion, an average of 5 years
Title
Evaluation of safety (adverse events: dermatitis, peripheral neuropathy, gastro-intestinal intolerance, leucopenia [2500 x 10^9 L]), tolerance and adherence to treatment
Time Frame
through study completion, an average of 5 years
Title
Determination of the efficacy of benznidazole in patients with Chronic Chagas heart disease based on a 50% reduction in both qualitative and quantitative PCR.
Description
Polymerase Chain Reaction study on patient's blood samples and report negativization at the end of treatment, 2Y and final visit.
Time Frame
through study completion, an average of 5 years
Title
Safety and tolerability of benznidazole
Time Frame
through study completion, an average of 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlos Morillo, MD
Organizational Affiliation
Population Health Research Institute - McMaster University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Jose Antonio Marin-Neto, MD, PhD
Organizational Affiliation
University of Sao Paulo
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Salim Yusuf, MD, DPh
Organizational Affiliation
Population Health Research Institute - McMaster University
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Sergio Sosa-Estani, MD, PhD
Organizational Affiliation
Argentina National Coordinator - CenDIE, Argentina
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fernando Rosas, M.D.
Organizational Affiliation
Fundacion Clinica Shaio, Bogota, Colombia
Official's Role
Principal Investigator
Facility Information:
Facility Name
BENEFIT Ivestigational Site
City
Ciudad Autónoma de Buenos Aires
State/Province
Apital Federal
ZIP/Postal Code
3556
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Belén De Escobar
State/Province
Buenos Aires
ZIP/Postal Code
1753
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Isidro Casanova
State/Province
Buenos Aires
ZIP/Postal Code
1282
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
San Juan
State/Province
Buenos Aires
ZIP/Postal Code
1625
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Santiago del Estero
State/Province
Buenos Aires
ZIP/Postal Code
4200
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Santiago del Estero
State/Province
Buenos Aires
ZIP/Postal Code
5400
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Ciudad Autónoma de Buenos Aires
State/Province
Capital Federal
ZIP/Postal Code
1063
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
San Fernando del Valle de Catamarca
State/Province
Catamarca
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Charata
State/Province
Chaco
ZIP/Postal Code
H3730AVI
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Paraná
State/Province
Entre Rios
ZIP/Postal Code
3100
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Buenos Aires
State/Province
General Rodríguez Partido
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
San Salvador de Jujuy
State/Province
Jujuy
ZIP/Postal Code
4600
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Corrientes
State/Province
Rosario, Santa Fe
ZIP/Postal Code
3400
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Rosario
State/Province
Santa Fe
ZIP/Postal Code
2000
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Añatuya
State/Province
Santiago Del Estero
ZIP/Postal Code
3760
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Santiago Del Estero
State/Province
Sgo. Del Estero
ZIP/Postal Code
4200
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Buenos Aires
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Salta
ZIP/Postal Code
A4406CLA
Country
Argentina
Facility Name
BENEFIT Investigational Site
City
Tupiza
State/Province
Potosi
Country
Bolivia
Facility Name
BENEFIT Investigational Site
City
Salvador
State/Province
Bahaia
ZIP/Postal Code
40050-410
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Salvador
State/Province
Bahaia
ZIP/Postal Code
40110-909
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Salvador
State/Province
Bahaia
ZIP/Postal Code
40425-060
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Carmo
State/Province
Belo Horizonte
ZIP/Postal Code
30130-690
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Brasília
State/Province
Brazilian Federal District
ZIP/Postal Code
70658-700
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Goiânia
State/Province
GO
ZIP/Postal Code
74110-010
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Goiânia
State/Province
GO
ZIP/Postal Code
74110-020
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Goiânia
State/Province
GO
ZIP/Postal Code
74605-050
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Uberlandia
State/Province
MG
ZIP/Postal Code
38025-440
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Uberlândia
State/Province
MG
ZIP/Postal Code
38400-299
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Uberaba
State/Province
Minas Gerais
ZIP/Postal Code
38010-160
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Curitiba
State/Province
Parana
ZIP/Postal Code
80060-900
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Recife
State/Province
Pernambuco
ZIP/Postal Code
50100-130
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Pelotas
State/Province
Rio Grande Do Sul
ZIP/Postal Code
96015-290
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Campinas
State/Province
São Paulo
ZIP/Postal Code
13059-740
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Ribeirão Preto
State/Province
São Paulo
ZIP/Postal Code
14048-900
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
São José do Rio Preto
State/Province
São Paulo
ZIP/Postal Code
15015-210
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
São José do Rio Preto
State/Province
São Paulo
ZIP/Postal Code
15090-000
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Votuporanga
State/Province
São Paulo
ZIP/Postal Code
15500-003
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Rio de Janeiro
ZIP/Postal Code
21040-360
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Rio de Janeiro
ZIP/Postal Code
21941-913
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
São Paulo
ZIP/Postal Code
01417 010
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
São Paulo
ZIP/Postal Code
04012-909
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
São Paulo
ZIP/Postal Code
05403-000
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
São Paulo
ZIP/Postal Code
05403-901
Country
Brazil
Facility Name
BENEFIT Investigational Site
City
Bogota
State/Province
Bogotá
Country
Colombia
Facility Name
BENEFIT Investigational Site
City
San Gil
State/Province
Santander
Country
Colombia
Facility Name
BENEFIT Ivestigational Site
City
San Salvador
Country
El Salvador

12. IPD Sharing Statement

Citations:
PubMed Identifier
18585495
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.
Results Reference
background
PubMed Identifier
26323937
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.
Results Reference
derived
PubMed Identifier
19753491
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. Erratum In: Mem Inst Oswaldo Cruz. 2009 Sep;104(6):937. Morillo, Carlos A [added]; Sosa-Estani, Sergio [added]; Yusuf, Salim [added]; BENEFIT Investigators [added].
Results Reference
derived
Links:
URL
http://www.phri.ca
Description
Population Health Research Institute
URL
http://www.idpc.org.br/pesquisa/
Description
Instituto Dante Pazzanese de Cardiologia

Learn more about this trial

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

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