Randomized Trial of Benznidazole Benznidazole Randomized Trial of - PowerPoint PPT Presentation

Randomized Trial of Benznidazole Benznidazole Randomized Trial of for Chronic Chagas Cardiomyopathy Chronic Chagas Cardiomyopathy for BEN znidazole E E valuation F F or I I nterrupting T T rypanosomiasis BEN (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 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 Chronic Chagas Cardiomyopathy Aged 18 to 75 years, ≥2 positive serological tests for T. cruzi , ECG Abnormalities R BNZ 300 mg daily Placebo 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

Study Procedures • BNZ or matching placebo for 40-80 days • Adverse events, liver function tests during treatment period and 12- lead ECGs annually, 2-D Echo at baseline, 2 yrs and final visit. • 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 countries 2854 patients randomized (2004 to 2011) CANADA Global Coordinating Center: Population Health Research Institute *PCR Core labs: El Salvador (78) Argentina, Brazil & Colombia Brazil (1359) **BENEFIT Echo Core lab: Colombia (502) Riberao Preto, Brazil Bolivia (357) LA Coordinating Center: Argentina (559) Instituto Dante Pazzanese Sao Paulo, Brazil

BENEFIT Trial Flow and Adherence 2854 randomized 1431 BNZ 1423 Placebo 84% took ≥75% of target dose 90% took ≥75% of target dose Discontinuation 51 (3.6%) Discontinuation 192 (13.4%) Mean FU 5.4 yrs. Lost to follow-up (n=8) Lost to follow-up (n=7) 99.5% Complete Follow-up 99.5% Complete Follow-up 1423 analyzed 1431 analyzed

Baseline Characteristics Benznidazole Placebo N=1431 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 Negativization No. of Placebo Benznidazole Interaction Patients P value (Pts with Events%) Overall E.O.T. 918 33.5 66.2 Year 2 673 35.3 55.4 <0.001 >5 Years 647 33.1 46.7 Brazil E.O.T. 213 24.3 86.3 Year 2 96 31.1 60.8 >5 Years 141 27.4 35.3 Argentina, Bolivia E.O.T. 388 28.6 73.0 Year 2 332 34.1 62.9 >5 Years 276 30.2 61.4 Colombia, El Salvador E.O.T. 317 45.6 43.9 Year 2 245 38.5 42.6 >5 Years 230 40.2 35.4 0.5 1.0 2.0 4.0 6.08.0 Benznidazole Placebo Odds Ratio

Primary Outcome 0.4 Proportion with Events 0.3 Log-Rank p-value=0.31 BNZ Placebo 0.2 0.1 0.0 0 1 2 3 4 5 6 7 Years of Follow-up # at Risk BNZ 1431 1312 1246 1178 936 695 484 323 Pl 1423 1316 1233 1155 881 649 459 294

Primary Outcome Components Benznidazole Placebo HR 95% CI p (N=1431) (%) (N=1423) (%) 394 (27.5%) 414 (29.1%) 0.93 0.81-1.07 0.31 Primary composite outcome 246 (17.2%) 257 (18.1%) 0.95 0.79-1.13 Death 10 (0.7%) 17 (1.2%) 0.58 0.27-1.28 Resuscitated Cardiac Arrest 33 (2.3%) 41 (2.9%) 0.80 0.50-1.26 Sustained VT 109 (7.6%) 125 (8.8%) 0.86 0.66-1.11 Pacemaker/ICD 109 (7.6%) 122 (8.6%) 0.88 0.68-1.15 New/Worsening HF 3 (0.2%) 9 (0.6%) 0.33 0.09-1.22 Cardiac Transplant 54 (3.8%) 61 (4.3%) 0.88 0.61-1.27 Stroke/TIA, SE or PE

Primary Outcome: Subgroups (1) No. of Benznidazole Placebo Interaction (Rate %) Patients (Rate %) P value Country Presumed DTU Colombia, El Salvador 24.1 580 25.6 Brazil 1358 33.2 37.6 916 21.4 18.5 0.16 Argentina, Bolivia PCR 24.6 Baseline PCR Positive 1148 26.9 Baseline PCR Negative 748 23.7 25.3 0.96 Age Age ≤56 yrs (median) 1428 22.8 25.6 0.56 Age >56 yrs (median) 1426 32.1 32.7 Sex Female 1445 24.1 25.1 0.81 Male 1409 30.8 33.4 Disease Severity Score Low 1309 16.8 16.2 Intermediate 890 29.9 33.3 0.55 High 655 45.1 50.0 LV Ejection Fraction <40% 389 62.5 63.0 0.45 ≥40% 2465 21.8 23.9 0.2 0.5 1.0 2.0 4.0 Placebo Benznidazole Hazard Ratio

Primary Outcome: Subgroups (2) No. of Placebo Interaction Benznidazole Patients (Rate %) (Rate %) P value LV End Diastolic Diameter <50 mm 674 13.7 17.9 0.41 ≥50 mm 1548 36.6 34.6 Amiodarone No 2302 24.1 24.7 Yes 551 39.1 50.9 0.008 Spironolactone No 2375 21.6 23.5 Yes 478 56.8 57.0 0.49 Regional Wall Motion Abnormality No 1397 22.4 21.2 Yes 853 43.6 41.1 0.92 Low QRS Voltage No 2342 29.9 28.7 Yes 341 25.8 28.2 0.88 RBBB and Left Anterior Fascicular Block No 1946 29.2 28.6 Yes 29.0 0.46 907 25.4 0.2 0.5 1.0 2.0 4.0 Placebo Benznidazole Hazard Ratio

Safety: Adverse Events Leading to Drug Interruption BNZ Placebo P Any adverse event 23.9% 9.5% <0.001 Permanent treatment 13.4% 3.6% < 0.001 discontinuation Hypersensitivity 10.9% 1.5% <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 10 3 /mm 3 0.1% 0.1% 1 neutrophil 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

Acknowledgements Coordinating Centers Data Safety Monitoring Board Steering Committee P. Sleight (Chair) C.A. Morillo (Co-PI) Population Health Research Institute H. Acquatella Hamilton, ON, Canada J.A. Marin-Neto (Co-PI) J. Lazzari L.R. Bonilla Ruz, B. Meeks, M. Lawrence, S. Yusuf (Chair) R. Tuhy, J. Pogue, P. RaoMelacini, R. Roberts A. Avezum H. Jung, L. Dyal D. Sackett S. Sosa-Estani E. Velazquez J. Pogue (DSMB statistician) Instituto Dante Pazzanese C. Britto A. Mattos São Paulo, Brazil F. Guhl L.R. Bonilla Ruz A. Avezum, A. Mattos, J.R. Zappiello Mendes S. Connolly R. Figueroa de Bonilla J. Lazdins J. Pogue A. Rassi Jr. A. Rassi Sr. F. Rosas E. Villena

BENEFIT Investigators ARGENTINA BRAZIL BOLIVIA NC: S. Sosa Estani M. del Carmen Bangher NC: A. Rassi Jr D. Correia NC: E. Villena T. Orduna L. Gomez A. Luquetti T. Luíz da Silva Júnior F. Silva Nieto V.I. Volverg A. Schmidt A. Avelino Steffens COLOMBIA M.P. Bernachea M.H. Mallagray A. Fragata Filho C. Pereira da Cunha NC: F. Rosas R. Carrizo Paez G. Mazo L. Nigro Maia L.F. Avezum Oliveira F.R. Quiroz R.E. Manzur M.A. Auteri A. Menezes Lorga A.C. Alves de Souza S. Navarrete C.A. Cuneo O.A. Reyes A. Silvestre de Sousa J.F. Kerr Saraiva R. Onate G. Perez Prados M. Leguizamò R. Coury Pedrosa C. Mady J.G. Pérez J. Beloscar R.J. Fernandez R. Morais Torres M. Hernandes E. Oshiro W. Alves C. Bastos EL SALVADOR R. Aras Junior L. Amaganijan NC: R. de Bonilla G. Soares Feitosa V. Rodriguez R. Bonilla *NC=National Coordinator