Randomized Trial of Benznidazole Randomized Trial of Benznidazole for Chronic Chagas Cardiomyopathyfor Chronic Chagas Cardiomyopathy

BENBENznidazole EEvaluation FFor IInterrupting TTrypanosomiasis (BENEFIT Trial)

Carlos A. Morillo and Jose Antonio Marin-NetoCo-Principal Investigators

on behalf of the BENEFIT Investigators

DisclosuresFunded 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 da Faculdade de Medicina de RibeirãoPreto da Universidade de São Paulo•Ministerio de Salud and Fundacion Bunge y Born, Argentina

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

BENEFIT Objectives

Primary•To evaluate whether the use of trypanocidal therapy with benznidazole (BNZ) reduces mortality and progression in Chagas cardiomyopathy.

Secondary•Determine effects of BNZ on parasite detection rates by conventional PCR.•Evaluate safety and tolerability of BNZ.

Study Design

PlaceboBNZ 300 mg daily

Follow-up: 11, 21 days, end of treatment, 6-mos, annually until study end(mean 5.4 yrs)

R

Chronic Chagas Cardiomyopathy

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

Primary Outcome: Composite: death, resuscitated cardiac arrest, sustained VT, pacemaker/ICD, cardiac transplant, new or hospitalized HF, stroke/TIA and systemic or pulmonary embolism

Study Procedures• BNZ or matching placebo for 40-80 days

• Adverse events, liver function tests during treatment period and 12-lead ECGs annually.

• Blood samples for qualitative conventional PCR to detect circulating T. cruzi kinetoplast DNA (kDNA)* at end of treatment, 2 years and final follow-up (> 5 yrs).

*Schijman AG, et al. PLoS Negl Trop Dis 2011, 5:e931.

BENEFIT: 49 sites, 5 countries2854 patients randomized (2004 to 2011)

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

CANADA

Global Coordinating Center:Population Health Research Institute

BENEFIT Trial Flow and Adherence

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

1431 BNZ84% took ≥75% of target dose

1423 Placebo90% took ≥75% of target dose

99.5% Complete Follow-up1423 analyzed

99.5% Complete Follow-up1431 analyzed

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

2854 randomized

Mean FU 5.4 yrs.

Baseline CharacteristicsBenznidazole

N=1431PlaceboN=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 NegativizationNo. of

PatientsPlacebo Interaction

P value

0.5 1.0 2.0 4.0 6.08.0

Placebo Benznidazole

Odds Ratio

<0.001

Benznidazole

Overall E.O.T.

Year 2

>5 Years

918

673

647

33.5

35.3

33.1

66.2

55.4

46.7

Colombia, El Salvador E.O.T. Year 2 >5 Years

317245230

45.638.540.2

43.942.635.4

Brazil E.O.T. Year 2 >5 Years

21396141

24.331.127.4

86.360.835.3

Argentina, Bolivia E.O.T. Year 2 >5 Years

388332276

28.634.130.2

73.062.961.4

(Pts with Events%)

Primary Outcome

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

0.2

0.3

0.4

0 1 2 3 4 5 6 7

BNZPlacebo

Log-Rank p-value=0.31

Primary Outcome ComponentsBenznidazole(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)

0.2 0.5 1.0 2.0 4.0

Colombia, El Salvador Brazil

Argentina, Bolivia

Baseline PCR Positive Baseline PCR Negative

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

Female Male

Low Intermediate

<40% ≥40%

Country Presumed DTU

PCR

Age

Sex

Disease Severity Score

LV Ejection Fraction

5801358916

1148748

14281426

14451409

1309890

3892465

0.16

0.96

0.56

0.81

0.45

25.637.618.5

26.925.3

25.632.7

25.133.4

16.233.3

63.023.9

Benznidazole PlaceboHazard Ratio

No. ofPatients

Placebo(Rate %)

InteractionP value

24.133.221.4

24.623.7

22.832.1

24.130.8

16.829.9

62.521.8

Benznidazole(Rate %)

High 655 0.5550.045.1

Primary Outcome: Subgroups (2)

0.2 0.5 1.0 2.0 4.0

Benznidazole PlaceboHazard Ratio

No. ofPatients

Placebo(Rate %)

InteractionP value

<50 mm ≥50 mm

No Yes

No Yes

No Yes

No Yes

No

LV End Diastolic Diameter

Amiodarone

Spironolactone

Regional Wall Motion Abnormality

Low QRS Voltage

RBBB and Left Anterior Fascicular Block

6741548

2302551

2375478

1397853

2342341

1946

0.41

0.008

0.49

0.92

0.88

17.936.6

24.150.9

23.557.0

22.443.6

29.928.2

29.2 Yes 907 0.4629.0

Benznidazole(Rate %)

13.734.6

24.739.1

21.656.8

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% <0.001

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 than previously reported.

Available Online at www.NEJM.org

AcknowledgementsData Safety Monitoring Board

P. Sleight (Chair)

H. Acquatella

J. Lazzari

R. Roberts

D. Sackett

J. Pogue (DSMB statistician)

Coordinating Centers

Population Health Research InstituteHamilton, ON, Canada

L.R. Bonilla Ruz, B. Meeks, M. Lawrence,R. Tuhy, J. Pogue, P. RaoMelacini,H. Jung, L. Dyal, K. Balasubramanian

Instituto Dante PazzaneseSão Paulo, Brazil

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

Steering Committee

C.A. Morillo (Co-PI)

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

S. Yusuf (Chair)

A. Avezum

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

ARGENTINANC: S. Sosa EstaniT. OrdunaF. Silva NietoM.P. BernacheaR. Carrizo PaezR.E. ManzurC.A. CuneoG. Perez PradosJ. Beloscar E. Oshiro

M. del Carmen BangherL. GomezV.I. VolvergM.H. MallagrayG. MazoM.A. AuteriO.A. ReyesM. LeguizamònR.J. Fernandez

*NC=National Coordinator

BRAZILNC: A. Rassi JrA. LuquettiA. SchmidtA. Fragata FilhoL. Nigro MaiaA. Menezes LorgaA. Silvestre de SousaR. Coury PedrosaR. Morais TorresW. AlvesR. Aras JuniorG. Soares Feitosa

D. CorreiaT. Luíz da Silva JúniorA. Avelino SteffensC. Pereira da CunhaL.F. Avezum OliveiraA.C. Alves de SouzaJ.F. Kerr SaraivaC. MadyM. HernandesC. BastosL. Amaganijan

BOLIVIANC: E. Villena

COLOMBIANC: F. RosasF.R. Quiroz S. NavarreteR. Onate J.G. Pérez

EL SALVADORNC: R. de BonillaV. RodriguezR. Bonilla