Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC

NCT04023227 | Completed Phase 4 DMC

• 1 other identifier: CLCZ696B3302
• Study Type: interventional
• Target: 918
• Locations: 4 countries
• Sites: 79

Brief Summary

The purpose of this study is to evaluate the effect of sacubitril/valsartan 200 mg BID compared with enalapril 10 mg BID, in addition to conventional heart failure (HF) treatment, in improving a hierarchical composite of cardiovascular (CV) events (i.e. CV death or the occurrence of first HF hospitalization) and causing a greater reduction in n terminal prohormone of brain natriuretic peptide (NT-proBNP, at Week 12 from Baseline) in participants with HF with reduced ejection fraction (HFrEF) caused by CCC.

Conditions

Chagas Disease; Heart Failure

Keywords

Chagas' disease; heart failure; angiotensin receptor-neprilysin inhibitor; ARNI; ARB; ACEI; sacubitril/valsartan; enalapril

Outcome Measures

Primary Outcomes (1)

• Hierarchical composite endpoint composed of time to CV death, time to first HF hospitalization, relative change in NT-proBNP from baseline to Week 12

  The primary efficacy endpoint will be analyzed using the win ratio approach comparing every participant in the sacubitril/valsartan arm to every participant in the enalapril arm to determine a winner. The estimated win ratio (the total number of winners in the sacubitril/valsartan arm divided by the total number of winners in the enalapril arm) will be provided. A winner in the pair-wise comparison has a delayed time to the occurrence of CV death; if time to the occurrence of CV death is censored, a winner has a delayed time to the occurrence of first HF hospitalization event; if the times to both CV events are censored, a winner has a more favorable (less increase or more decrease) change in NT-proBNP between Baseline and Week 12.

  Total follow up time up to approximately 36 months

Secondary Outcomes (7)

• Time to the first occurrence of a composite of CV events

  From the date of randomization to the first occurrence (total follow up time up to approximately 36 months)

• Time to all-cause mortality

  From date of randomization until the date of death from any cause assessed up to the end of the study, which is estimated to be up to approximately 36 months

• Time to sudden death or resuscitated sudden cardiac arrest

  From date of randomization until the date of the sudden death or resuscitated sudden cardiac arrest assessed up to the end of the study, which is estimated to be up to approximately 36 months

• Number of visits to an ER due to HF (where intravenous therapy is required)

  From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.

• Number of days alive out of the hospital

  From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.

Study Arms (2)

Sacubitril/valsartan

EXPERIMENTAL

Sacubitril/valsartan 200 mg b.i.d. Following randomization, patients will receive sacubitril/valsartan in titrated doses from level 1 up to level 3 (50, 100 and 200 mg twice daily). Participants taking ACEIs who are randomized to sacubitril/valsartan will do a 36-hour ACEI washout before they start taking the study drug Sacubitril/valsartan in dose levels of 50 mg, 100 mg, and 200 mg are equivalent to sacubitril/valsartan 24/26 mg, 49/51 mg and 97/103 mg, respectively

Drug: Sacubitril/valsartan

Enalapril

ACTIVE COMPARATOR

Enalapril 10 mg b.i.d. Following randomization, patients will receive the enalapril in titrated doses from level 1 up to level 3 (2.5, 5 and 10 mg twice daily).

Drug: Enalapril

Interventions

Sacubitril/valsartan DRUG

50 (24/26) mg, 100 (49/51) mg and 200 (97/103) mg will be available for dose adjustments.

Also known as: LCZ696; Entresto; Vymada

Sacubitril/valsartan

Enalapril DRUG

5 mg and 10 mg will be available for dose adjustments.

Also known as: Renitec

Enalapril

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 18 years of age
• Diagnosis of NYHA Class II-IV HFrEF established by:
• LVEF ≤ 40% within 12 months prior to Visit 1 made by any local measurement using echocardiography, multiple gated acquisition scan (MUGA), computerized tomography (CT) scanning, magnetic resonance imaging (MRI), or ventricular angiography, provided no subsequent measurement above 40% AND
• NT-proBNP ≥ 600 pg/mL (or BNP ≥ 150 pg/mL) at Visit 1 OR
• NT-proBNP ≥ 400 pg/mL (or BNP ≥ 100 pg/mL) at Visit 1 and a hospitalization for HF within the last 12 months
• Chagas' disease diagnosis confirmed by at least two different serological tests for anti-Trypanosoma cruzi based on different principles or with different antigenic preparations, such as: enzyme-linked immunosorbent assay \[ELISA\], indirect immunofluorescence \[IFI\], indirect hemagglutination \[IHA\], western blot (WB), chemiluminescent immunoassay (CLIA). If documented history is not available, the tests may be performed during the screening

You may not qualify if:

• Patients with history of suspected or proven angioedema or unable to tolerate ACEIs, ARBs or ARNI (e.g., due to cough, hypotension, renal dysfunction, hyperkalemia)
• Use of sacubitril/valsartan in the past 3 months
• Patients requiring continuous intravenous inotropic therapy or with indication of advanced support intervention for HF:
• already on list for a heart transplantation
• with current indication of left ventricular assist device, or cardiac resynchronization therapy (CRT)
• Systemic systolic blood pressure lower than 95 mmHg or symptomatic hypotension
• Serum potassium \> 5.2 mmol/L
• Estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73 m2 of body surface area
• Severe gastrointestinal form of chronic Chagas' disease (demonstrated megaesophagus and/or important megacolon, e.g.: with compromised oral intake or surgical indication).
• Clinical conditions or systemic diseases limiting proper patient participation
• Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception
• Presence of other cardiac conditions:
• Previous cardiac surgery
• Heart failure where, in the Investigator's judgement, there is a possible alternative primary etiology e.g., due to coronary artery disease, valve disease, congenital heart disease or other causes.
• Untreated arrhythmia or serious conduction disease e.g., bradyarrhythmias, atrial fibrillation with rapid ventricular response, second or third degree atrioventricular block, etc.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (79)

Novartis Investigative Site

CABA, Buenos Aires, C1221ADC, Argentina

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Novartis Investigative Site

CABA, Buenos Aires, C1425BEI, Argentina

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Ramos Mejía, Buenos Aires, B1704ETD, Argentina

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San Martín, Buenos Aires, 1604, Argentina

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Novartis Investigative Site

Temperley, Buenos Aires, 1834, Argentina

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Novartis Investigative Site

Villa María, Córdoba Province, X5900JKA, Argentina

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Novartis Investigative Site

Salta, Salta Province, A4406BPF, Argentina

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Novartis Investigative Site

San Miguel de Tucumán, San Miguel de Tucuman, T4000ICL, Argentina

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Rosario, Santa Fe Province, 2000, Argentina

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Novartis Investigative Site

Rosario, Santa Fe Province, S2000DIF, Argentina

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Novartis Investigative Site

San Miguel Tucuman, Tucumán Province, T4000IFL, Argentina

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San Miguel Tucuman, Tucumán Province, T4000JCU, Argentina

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Novartis Investigative Site

Buenos Aires, C1155 AHD, Argentina

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Novartis Investigative Site

Corrientes, W3400CDS, Argentina

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Córdoba, 5000, Argentina

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Córdoba, X5003DCE, Argentina

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Córdoba, X5004BAL, Argentina

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Córdoba, X5006CBI, Argentina

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Formosa, P3600, Argentina

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Formosa, P3634XAR, Argentina

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Mendoza, M5500CHC, Argentina

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Santa Fe, S3000EOZ, Argentina

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Novartis Investigative Site

Santa Fe, S3000FWO, Argentina

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Novartis Investigative Site

Santiago del Estero, G4200AQK, Argentina

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Novartis Investigative Site

Fortaleza, Ceará, 60430 370, Brazil

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Novartis Investigative Site

Salvador, Estado de Bahia, 40050-410, Brazil

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Novartis Investigative Site

Salvador, Estado de Bahia, 40110060, Brazil

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Salvador, Estado de Bahia, 40323-010, Brazil

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Novartis Investigative Site

Salvador, Estado de Bahia, 41253-190, Brazil

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Novartis Investigative Site

Brasila, Federal District, 70673623, Brazil

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Brasília, Federal District, 70390-903, Brazil

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Brasília, Federal District, 70710-100, Brazil

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Goiânia, Goiás, 74223-060, Brazil

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Goiânia, Goiás, 74223-130, Brazil

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Goiânia, Goiás, 74605-020, Brazil

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Novartis Investigative Site

São Luís, Maranhão, 65020-070, Brazil

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Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30130-100, Brazil

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Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30140 062, Brazil

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Belo Horizonte, Minas Gerais, 30150-270, Brazil

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Novartis Investigative Site

Montes Claros, Minas Gerais, 39401-001, Brazil

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Passos, Minas Gerais, 37904-020, Brazil

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Uberaba, Minas Gerais, 38025-440, Brazil

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Uberlândia, Minas Gerais, 38400 500, Brazil

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Novartis Investigative Site

Uberlândia, Minas Gerais, 38400-328, Brazil

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Novartis Investigative Site

Londrina, Paraná, 86038-440, Brazil

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Novartis Investigative Site

Belém, Pará, 66087-660, Brazil

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Recife, Pernambuco, 50100-060, Brazil

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Teresina, Piauí, 64001-380, Brazil

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Novartis Investigative Site

Rio de Janeiro, Rio de Janeiro, 20551-030, Brazil

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Rio de Janeiro, Rio de Janeiro, 22240-006, Brazil

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Natal, Rio Grande do Norte, 59020-035, Brazil

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Ijuí, Rio Grande do Sul, 98700-000, Brazil

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Novartis Investigative Site

Botucatu, São Paulo, 3880-1001, Brazil

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Bragança Paulista, São Paulo, 13183-091, Brazil

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Campinas, São Paulo, 13020-431, Brazil

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Campinas, São Paulo, 13060 080, Brazil

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Campinas, São Paulo, 13060-904, Brazil

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Novartis Investigative Site

Indaiatuba, São Paulo, 13330-570, Brazil

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Novartis Investigative Site

Marília, São Paulo, 17515-000, Brazil

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Ribeirão Preto, São Paulo, 14010-190, Brazil

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Ribeirão Preto, São Paulo, 14048-900, Brazil

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Novartis Investigative Site

Santo André, São Paulo, 09080-001, Brazil

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Novartis Investigative Site

Sao Jose Rio Preto, São Paulo, 15090-000, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 04012 909, Brazil

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Novartis Investigative Site

São Paulo, São Paulo, 05403-000, Brazil

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Novartis Investigative Site

Tatuí, São Paulo, 18270-170, Brazil

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Novartis Investigative Site

Votuporanga, São Paulo, 15500 003, Brazil

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Novartis Investigative Site

São Paulo, 05403-000, Brazil

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Novartis Investigative Site

São Paulo, 15015-210, Brazil

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Novartis Investigative Site

Bogota, Cundinamarca, 110121, Colombia

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Santa Marta, Magdalena Department, 30360, Colombia

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Novartis Investigative Site

San Gil, Santander Department, 684031, Colombia

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Novartis Investigative Site

Bogota DC, 110111, Colombia

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Novartis Investigative Site

Florida Blanca, 681001, Colombia

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Floridablanca, 681004, Colombia

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Novartis Investigative Site

Mérida, Yucatán, 97000, Mexico

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Novartis Investigative Site

Ciudad de, 14080, Mexico

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Novartis Investigative Site

Oaxaca City, 68000, Mexico

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Novartis Investigative Site

Xalapa, 91193, Mexico

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Related Publications (2)

• Lopes RD, Bocchi EA, Echeverria LE, Demacq C, de Barros E Silva PGM, Barbosa LM, Damiani L, Sayyed S, Yoshida LAF, Furtado RHM, Morillo CA, Kevorkian R, Ramires F, Bahit MC, Magana A, Chavez-Mendoza A, Miguel da Silva AH, Coelho da Silva A, Freitas AF Jr, Romano AA, Parneix A, Segura A, Franca CCB, Botta CE, de Barros E, Perna ER, Montenegro E, Quiroz Diaz FR, Feitosa-Filho GS, Severini GV, Molina I, Miranda JDSS, Sala J, Kerr Saraiva JF, Carbajales J, Maia LN, Santana Passos LC, Simoes MV, Moreira MDCV, Nunes MCP, Hernandes ME, Hominal M, Zarandon RS, Leon de la Fuente R, Aras R, Bazan SGZ, Luiz da Silva T Jr, Madrini V, de Oliveira WA Jr, Saporito WF, Gimpelewicz C, McMurray JJV; Prevention and Reduction of Adverse Outcomes in Chagasic Heart Failure Trial Evaluation (PARACHUTE-HF) Investigators. Sacubitril/Valsartan vs Enalapril in Heart Failure Due to Chagas Disease: An Open-Label, Multicenter Randomized Clinical Trial. JAMA. 2026 Jan 6;335(1):49-59. doi: 10.1001/jama.2025.19808.

  PMID: 41335448 DERIVED

• Bocchi EA, Echeverria LE, Demacq C, de Barros E Silva PGM, Mazza Barbosa L, Chiang LM, Damiani L, Morillo CA, Kevorkian R, Ramires F, Bahit MC, Ferrari A, Chavez-Mendoza A, Magana-Serrano JA, McMurray JJV, Gimpelewicz C, Lopes RD; PARACHUTE-HF Investigators. Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial. JACC Heart Fail. 2024 Aug;12(8):1473-1486. doi: 10.1016/j.jchf.2024.05.021.

  PMID: 39111953 DERIVED

MeSH Terms

Conditions

Chagas Disease; Heart Failure

Interventions

sacubitril and valsartan sodium hydrate drug combination; Enalapril

Condition Hierarchy (Ancestors)

Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases; Heart Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Dipeptides; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Endpoint Adjudication Committee will be blinded to treatment allocation.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is a Phase 4, multinational, multicenter, parallel-group, prospective, randomized, open-label, blinded-endpoint adjudication, active-controlled study to demonstrate superiority of sacubitril/valsartan over enalapril in improving a composite of CV events (CV death or first HF hospitalization), or in causing greater reduction or lesser increase in NT-proBNP levels at Week 12 in participants with HFrEF caused by CCC.

Study Record Dates

• First Submitted: July 10, 2019
• First Posted: July 17, 2019
• Study Start: December 10, 2019
• Primary Completion: March 16, 2025
• Study Completion: March 31, 2025
• Last Updated: November 19, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will share

Locations

AR (24); BR (45); CO (6); ME (4)