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

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

Jan 17, 2023 149 likes •354 views

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

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Randomized Trial of Randomized Trial of Benznidazole Benznidazole for for Chronic Chagas Cardiomyopathy Chronic Chagas Cardiomyopathy BEN BENznidazole E Evaluation F For I Interrupting T Trypanosomiasis (BENEFIT Trial)

Carlos A. Morillo and Jose Antonio Marin-Neto Co-Principal Investigators

  • n behalf of the BENEFIT Investigators
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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
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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
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SLIDE 5

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.
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Study Design

Placebo BNZ 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

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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.

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BENEFIT: 49 sites, 5 countries 2854 patients randomized (2004 to 2011)

Brazil (1359) Colombia (502) Argentina (559) *PCR Core labs: Argentina, Brazil & Colombia **BENEFIT Echo Core lab: Riberao Preto, Brazil LA Coordinating Center: Instituto Dante Pazzanese Sao Paulo, Brazil CANADA Global Coordinating Center: Population Health Research Institute El Salvador (78) Bolivia (357)

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BENEFIT Trial Flow and Adherence

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

1431 BNZ

84% took ≥75% of target dose

1423 Placebo

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)

2854 randomized

Mean FU 5.4 yrs.

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SLIDE 10

Baseline Characteristics

Benznidazole 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%

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PCR Negativization

  • No. of

Patients Placebo 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 317 245 230 45.6 38.5 40.2 43.9 42.6 35.4 Brazil E.O.T. Year 2 >5 Years 213 96 141 24.3 31.1 27.4 86.3 60.8 35.3 Argentina, Bolivia E.O.T. Year 2 >5 Years 388 332 276 28.6 34.1 30.2 73.0 62.9 61.4

(Pts with Events%)

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Primary Outcome

Years of Follow-up Proportion with Events

# at Risk BNZ Pl 1431 1312 1246 1178 936 695 484 323 1423 1316 1233 1155 881 649 459 294

0.0 0.1 0.2 0.3 0.4 1 2 3 4 5 6 7

BNZ Placebo Log-Rank p-value=0.31

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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

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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 580 1358 916 1148 748 1428 1426 1445 1409 1309 890 389 2465 0.16 0.96 0.56 0.81 0.45 25.6 37.6 18.5 26.9 25.3 25.6 32.7 25.1 33.4 16.2 33.3 63.0 23.9

Benznidazole Placebo Hazard Ratio

  • No. of

Patients Placebo (Rate %) Interaction P value

24.1 33.2 21.4 24.6 23.7 22.8 32.1 24.1 30.8 16.8 29.9 62.5 21.8

Benznidazole (Rate %)

High 655 0.55 50.0 45.1

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Primary Outcome: Subgroups (2)

0.2 0.5 1.0 2.0 4.0

Benznidazole Placebo Hazard Ratio

  • No. of

Patients Placebo (Rate %) Interaction P 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 674 1548 2302 551 2375 478 1397 853 2342 341 1946 0.41 0.008 0.49 0.92 0.88 17.9 36.6 24.1 50.9 23.5 57.0 22.4 43.6 29.9 28.2 29.2 Yes 907 0.46 29.0

Benznidazole (Rate %)

13.7 34.6 24.7 39.1 21.6 56.8 21.2 41.1 28.7 25.8 28.6 25.4

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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 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 < 1.9 103/mm3 neutrophil 0.1% 0.1% 1 Alanine aminotransferase >2X ULN 4.9% 1.6% <0.001

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SLIDE 17

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.

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SLIDE 18

Available Online at www.NEJM.org

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SLIDE 19

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

Instituto Dante Pazzanese São 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
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SLIDE 20

BENEFIT Investigators

ARGENTINA NC: S. Sosa Estani

  • T. Orduna
  • F. Silva Nieto

M.P. Bernachea

  • R. Carrizo Paez

R.E. Manzur C.A. Cuneo

  • G. Perez Prados
  • J. Beloscar
  • E. Oshiro
  • M. del Carmen Bangher
  • L. Gomez

V.I. Volverg M.H. Mallagray

  • G. Mazo

M.A. Auteri O.A. Reyes

  • M. Leguizamò

R.J. Fernandez *NC=National Coordinator BRAZIL NC: A. Rassi Jr

  • A. Luquetti
  • A. Schmidt
  • A. Fragata Filho
  • L. Nigro Maia
  • A. Menezes Lorga
  • A. Silvestre de Sousa
  • R. Coury Pedrosa
  • R. Morais Torres
  • W. Alves
  • R. Aras Junior
  • G. Soares Feitosa
  • D. Correia
  • T. Luíz da Silva Júnior
  • A. Avelino Steffens
  • C. Pereira da Cunha

L.F. Avezum Oliveira A.C. Alves de Souza J.F. Kerr Saraiva

  • C. Mady
  • M. Hernandes
  • C. Bastos
  • L. Amaganijan

BOLIVIA NC: E. Villena COLOMBIA NC: F. Rosas F.R. Quiroz

  • S. Navarrete
  • R. Onate

J.G. Pérez EL SALVADOR NC: R. de Bonilla

  • V. Rodriguez
  • R. Bonilla