Randomized Trial of Randomized Trial of Benznidazole Benznidazole

for for Chronic Chagas CardiomyopathyChronic Chagas Cardiomyopathy

BENBENznidazole EEvaluation FFor IInterrupting TTrypanosomiasis

(BENEFIT Trial)(BENEFIT Trial)

Carlos A. Morillo and Jose Antonio Marin-Neto

Co-Principal Investigators

on behalf of the BENEFIT Investigators

Disclosures

Funded by:

• Population Health Research Institute - HHSC, McMaster University, Canada

• Canadian Institutes of Health Research

• UNICEF/UDNP/World Bank/WHO-TDR

• Fundação de Amparo à Pesquisa, Ensino e Assistência, Hospital das Clínicas• Fundação de Amparo à Pesquisa, Ensino e Assistência, Hospital das Clínicas

da Faculdade de Medicina de RibeirãoPreto da Universidade de São Paulo

• Ministerio de Salud and Fundacion Bunge y Born, Argentina

Rassi A.Jr., et al.Lancet 2010

Rationale

• Chagas disease

– Third most common parasitic disease globally

– Most common form of non-ischemic cardiomyopathy in Latin America

– 5-7 million infected, 1.4-2.1 million develop cardiomyopathy within 20-30 yrs.

• T. cruzi low level parasitemia may directly or through an autoimmune

mechanism cause cardiomyopathy

• Role of trypanocidal therapy in Chagas cardiomyopathy is unknown

Rassi A.Jr., et al.Lancet 2010

BENEFIT Objectives

Primary

• To evaluate whether the use of trypanocidal therapy with benznidazole

(BNZ) reduces mortality and progression in Chagas cardiomyopathy.

SecondarySecondary

• Determine effects of BNZ on parasite detection rates by conventional PCR.

• Evaluate safety and tolerability of BNZ.

Study Design

PlaceboBNZ 300 mg daily

R

Chronic Chagas Cardiomyopathy

Aged 18 to 75 years, ≥2 positive serological tests for T. cruzi, ECG Abnormalities

Follow-up: 11, 21 days, end of treatment, 6-mos, annually until study end

(mean 5.4 yrs)

Primary Outcome:

Composite: death, resuscitated cardiac arrest, sustained VT, pacemaker/ICD, cardiac

transplant, new or hospitalized HF, stroke/TIA and systemic or pulmonary embolism

BENEFIT: 49 sites, 5 countries

2854 patients randomized (2004 to 2011)

*PCR Core labs:

CANADA

Global Coordinating Center:Population Health Research Institute

El Salvador (78)

Brazil (1359)

Colombia (502)

Bolivia (357)

Argentina (559)

*PCR Core labs: Argentina, Brazil & Colombia**BENEFIT Echo Core lab:Riberao Preto, Brazil

LA Coordinating Center:Instituto Dante Pazzanese

BENEFIT Trial Flow and Adherence

1431 BNZ84% took ≥75% of target dose

1423 Placebo90% took ≥75% of target dose

2854 randomized

Discontinuation 51 (3.6%)Discontinuation 192 (13.4%)

84% took ≥75% of target dose 90% took ≥75% of target dose

99.5% Complete Follow-up

1423 analyzed

99.5% Complete Follow-up

1431 analyzed

Lost to follow-up (n=8) Lost to follow-up (n=7)

Mean FU 5.4 yrs.

Baseline CharacteristicsBenznidazole

N=1431

Placebo

N=1423

Mean Age 55.4 years 55.2 years

Abnormal ECG 93.3% 94.8%

Previous Heart Failure 9.9% 9.0%

NYHA Class I 74.4% 73.5%

Mean LVEF 54.4% 54.6%

Wall-motion Abnormality 38.3% 37.6%

Diuretics 30.4% 29.9%

ACE-Inhibitor or ARB 49.6% 49.2%

Beta-blocker 31.0% 30.3%

Amiodarone 19.9% 18.8%

PCR ConversionNo. of

PatientsPlacebo Interaction

P value

<0.001

Benznidazole

OverallE.O.T.Year 2

>5 Years

918673

647

33.535.3

33.1

66.255.4

46.7

BrazilE.O.T.Year 2>5 Years

21396141

24.331.127.4

86.360.835.3

Argentina, Bolivia

(Pts with Events%)

0.5 1.0 2.0 4.0 6.08.0

Placebo Benznidazole

Odds Ratio

Colombia, El SalvadorE.O.T.Year 2>5 Years

317245230

45.638.540.2

43.942.635.4

Argentina, BoliviaE.O.T.Year 2>5 Years

388332276

28.634.130.2

73.062.961.4

Primary OutcomeP

ropo

rtio

n w

ith E

vent

s

0.2

0.3

0.4

BNZPlacebo

Log-Rank p-value=0.31

Years of Follow-up

Pro

port

ion

with

Eve

nts

# at RiskBNZ

Pl1431 1312 1246 1178 936 695 484 3231423 1316 1233 1155 881 649 459 294

0.0

0.1

0 1 2 3 4 5 6 7

Primary Outcome Components

Benznidazole

(N=1431) (%)

Placebo

(N=1423) (%)HR 95% CI p

Primary composite outcome 394 (27.5%) 414 (29.1%) 0.93 0.81-1.07 0.31

Death 246 (17.2%) 257 (18.1%) 0.95 0.79-1.13

Resuscitated Cardiac Arrest 10 (0.7%) 17 (1.2%) 0.58 0.27-1.28

Sustained VT 33 (2.3%) 41 (2.9%) 0.80 0.50-1.26

Pacemaker/ICD 109 (7.6%) 125 (8.8%) 0.86 0.66-1.11

New/Worsening HF 109 (7.6%) 122 (8.6%) 0.88 0.68-1.15

Cardiac Transplant 3 (0.2%) 9 (0.6%) 0.33 0.09-1.22

Stroke/TIA, SE or PE 54 (3.8%) 61 (4.3%) 0.88 0.61-1.27

Primary Outcome: Subgroups (1)

Colombia, El SalvadorBrazilArgentina, Bolivia

Baseline PCR PositiveBaseline PCR Negative

Age ≤56 yrs (median)Age >56 yrs (median)

Country Presumed DTU

PCR

Age

5801358916

1148748

14281426

0.16

0.96

0.56

25.637.618.5

26.925.3

25.632.7

No. ofPatients

Placebo(Rate %)

InteractionP value

24.133.221.4

24.623.7

22.832.1

Benznidazole(Rate %)

0.2 0.5 1.0 2.0 4.0

FemaleMale

LowIntermediate

<40%≥40%

Sex

Disease Severity Score

LV Ejection Fraction

14451409

1309890

3892465

0.81

0.45

25.133.4

16.233.3

63.023.9

Benznidazole PlaceboHazard Ratio

24.130.8

16.829.9

62.521.8

High 655 0.5550.045.1

Primary Outcome: Subgroups (2)No. of

PatientsPlacebo(Rate %)

InteractionP value

<50 mm≥50 mm

NoYes

NoYes

LV End Diastolic Diameter

Amiodarone

Spironolactone

Regional Wall Motion Abnormality

6741548

2302551

2375478

0.41

0.008

0.49

17.936.6

24.150.9

23.557.0

Benznidazole(Rate %)

13.734.6

24.739.1

21.656.8

0.2 0.5 1.0 2.0 4.0

Benznidazole PlaceboHazard Ratio

NoYes

NoYes

No

Regional Wall Motion Abnormality

Low QRS Voltage

RBBB and Left Anterior Fascicular Block

1397853

2342341

1946

0.92

0.88

22.443.6

29.928.2

29.2Yes 907 0.4629.0

21.241.1

28.725.8

28.625.4

Safety: Adverse Events

Leading to Drug Interruption

BNZ Placebo P

Any adverse event 23.9% 9.5% <0.001

Permanent treatment discontinuation 13.4% 3.6% < 0.001

Cutaneous rash 9.6% 1.3% <0.001Cutaneous rash 9.6% 1.3% <0.001

Gastrointestinal 7.8% 2.9% <0.001

Nervous system 3.6% 1.3% <0.001

Leukopenia < 1.9 103/mm3 neutrophil 0.1% 0.1% 1

Alanine aminotransferase >2X ULN 4.9% 1.6% <0.001

Conclusions

• BNZ with a 40-80 day course in established Chagas cardiomyopathy

did not significantly reduce clinical progression, despite significantly

reducing PCR blood T. cruzi detection.

• BNZ was well tolerated and permanent discontinuation was lower • BNZ was well tolerated and permanent discontinuation was lower

than previously reported.

• BENEFIT included 2,854 patients from 5 countries in Central and South

America”. It is the largest study in Chagas disease and the most

comprehensive program ever conducted and will inform research into

the field for some time to come”

• “The trial took 13 years from its inception and built a large network of

clinical investigators interested in this neglected disease. It has

furthered our knowledge of the disease and response to trypanocidal furthered our knowledge of the disease and response to trypanocidal

therapy. Approximately 7 million people world wide are infected by T.

cruzi and, given the favorable risk/benefit ratio observed in BENEFIT,

treatment during the early stages of chronic Chagas infection should be

strongly encouraged. We need further research to determine whether

different dosing and duration schemes as well as geographic

susceptibility may improve results”

Available Online at www.NEJM.org

Acknowledgements

Data Safety Monitoring Board

P. Sleight (Chair)

H. Acquatella

J. Lazzari

R. Roberts

D. Sackett

J. Pogue (DSMB statistician)

Coordinating Centers

Population Health Research Institute

Hamilton, ON, Canada

L.R. Bonilla Ruz, B. Meeks, M. Lawrence,

R. Tuhy, J. Pogue, P. RaoMelacini,

H. Jung, L. Dyal, K. Balasubramanian

Steering Committee

C.A. Morillo (Co-PI)

J.A. Marin-Neto (Co-PI)

S. Yusuf (Chair)

A. Avezum

S. Sosa-Estani E. Velazquez J. Pogue (DSMB statistician)Instituto Dante Pazzanese

São Paulo, Brazil

A. Avezum, A. Mattos, J.R. Zappiello Mendes

S. Sosa-Estani E. Velazquez

C. Britto A. Mattos

F. Guhl L.R. Bonilla Ruz

S. Connolly R. Figueroa de Bonilla

J. Lazdins J. Pogue

A. Rassi Jr. A. Rassi Sr.

F. Rosas E. Villena

BENEFIT Investigators

ARGENTINA

NC: S. Sosa Estani

T. Orduna

F. Silva Nieto

M.P. Bernachea

R. Carrizo Paez

R.E. Manzur

M. del Carmen Bangher

L. Gomez

V.I. Volverg

M.H. Mallagray

G. Mazo

M.A. Auteri

BRAZIL

NC: A. Rassi Jr

A. Luquetti

A. Schmidt

A. Fragata Filho

L. Nigro Maia

A. Menezes Lorga

D. Correia

T. Luíz da Silva Júnior

A. Avelino Steffens

C. Pereira da Cunha

L.F. Avezum Oliveira

A.C. Alves de Souza

BOLIVIA

NC: E. Villena

COLOMBIA

NC: F. Rosas

F.R. Quiroz

S. NavarreteR.E. Manzur

C.A. Cuneo

G. Perez Prados

J. Beloscar

E. Oshiro

M.A. Auteri

O.A. Reyes

M. Leguizamòn

R.J. Fernandez

*NC=National Coordinator

A. Menezes Lorga

A. Silvestre de Sousa

R. Coury Pedrosa

R. Morais Torres

W. Alves

R. Aras Junior

G. Soares Feitosa

A.C. Alves de Souza

J.F. Kerr Saraiva

C. Mady

M. Hernandes

C. Bastos

L. Amaganijan

S. Navarrete

R. Onate

J.G. Pérez

EL SALVADOR

NC: R. de Bonilla

V. Rodriguez

R. Bonilla