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

NCT04023227 | Completed Phase 4 Results DMC

• 1 other identifier: CLCZ696B3302
• Study Type: interventional
• Target: 922
• Locations: 4 countries
• Sites: 79

Brief Summary

The purpose of this study was 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 chronic Chagas' cardiomyopathy (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 (4)

• Hierarchical Composite Endpoint Composed of Time to Cardiovascular (CV) Death, Time to First Heart Failure (HF) Hospitalization, and Relative Change in NT-proBNP From Baseline to Week 12

  The primary efficacy endpoint was 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. A winner in the pair-wise comparison had a delayed time to the occurrence of CV death; if time to the occurrence of CV death was censored, a winner had a delayed time to the occurrence of first HF hospitalization event; if the times to both CV events were censored, a winner had a more favorable (less increase or more decrease) change in NT-proBNP between Baseline and Week 12. The estimated win ratio was defined as the total number of winners in the sacubitril/valsartan arm divided by the total number of winners in the enalapril arm. A win ratio \>1 represents a favorable outcome for the study drug being assessed.

  Total follow-up time up to approximately 36 months

• Percentage of Participants Who Died From Cardiovascular Causes

  Total follow up time up to approximately 36 months

• Percentage of Participants With First Hospitalization for Worsening Heart Failure

  Total follow up time up to approximately 36 months

• Change From Baseline to Week 12 in NT-proBNP Levels

  Geometric mean factor change was derived from a linear regression model of log(NT-proBNP), adjusted for country and baseline value.

  Baseline to Week 12

Secondary Outcomes (6)

• Percentage of Participants With First Hospitalization Due to Heart Failure or Death From Cardiovascular Causes

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

• Percentage of Participants Who Died From Any Cause

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

• Number of Participants Who Had 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, up to approximately 36 months

• Number of Participants Who Had Visits to an Emergency Room Due to Heart Failure (HF) Where Intravenous Therapy Was Required

  From the date of randomization up to end of study. Total follow up time up to approximately 36 months.

• Number of Days Alive and Out of the Hospital

  From the date of randomization up to end of study. Total follow up time up to approximately 36 months.

Other Outcomes (2)

• Number of Ventricular Fibrillation or Sustained Ventricular Tachycardia

  From the date of randomization up to end of study. Total follow up time up to approximately 36 months.

• Number of Anti-tachycardia Pacing or Shock Therapies

  From the date of randomization up to end of study. Total follow up time up to approximately 36 months.

Study Arms (2)

Sacubitril/valsartan

EXPERIMENTAL

Participants received 3 to 6 weeks of titrated dosing with sacubitril/valsartan to achieve the target dose of 200 mg twice daily.

Drug: Sacubitril/valsartan

Enalapril

ACTIVE COMPARATOR

Participants received 3 to 6 weeks of titrated dosing with enalapril to achieve the target dose of 10 mg twice daily.

Drug: Enalapril

Interventions

Sacubitril/valsartan DRUG

Participants randomized to sacubitril/valsartan who were previously treated with angiotensin-converting enzyme inhibitors (ACEIs) had a 36-hour washout prior to receiving oral treatment with 50, 100, or 200 mg, film-coated tablets.

Also known as: LCZ696; Entresto; Vymada

Sacubitril/valsartan

Enalapril DRUG

Oral treatment with 5 or 10 mg tablets.

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

Location

Novartis Investigative Site

CABA, Buenos Aires, C1425BEI, Argentina

Location

Novartis Investigative Site

Ramos Mejía, Buenos Aires, B1704ETD, Argentina

Location

Novartis Investigative Site

San Martín, Buenos Aires, 1604, Argentina

Location

Novartis Investigative Site

Temperley, Buenos Aires, 1834, Argentina

Location

Novartis Investigative Site

Villa María, Córdoba Province, X5900JKA, Argentina

Location

Novartis Investigative Site

Salta, Salta Province, A4406BPF, Argentina

Location

Novartis Investigative Site

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

Location

Novartis Investigative Site

Rosario, Santa Fe Province, 2000, Argentina

Location

Novartis Investigative Site

Rosario, Santa Fe Province, S2000DIF, Argentina

Location

Novartis Investigative Site

San Miguel Tucuman, Tucumán Province, T4000IFL, Argentina

Location

Novartis Investigative Site

San Miguel Tucuman, Tucumán Province, T4000JCU, Argentina

Location

Novartis Investigative Site

Buenos Aires, C1155 AHD, Argentina

Location

Novartis Investigative Site

Corrientes, W3400CDS, Argentina

Location

Novartis Investigative Site

Córdoba, 5000, Argentina

Location

Novartis Investigative Site

Córdoba, X5003DCE, Argentina

Location

Novartis Investigative Site

Córdoba, X5004BAL, Argentina

Location

Novartis Investigative Site

Córdoba, X5006CBI, Argentina

Location

Novartis Investigative Site

Formosa, P3600, Argentina

Location

Novartis Investigative Site

Formosa, P3634XAR, Argentina

Location

Novartis Investigative Site

Mendoza, M5500CHC, Argentina

Location

Novartis Investigative Site

Santa Fe, S3000EOZ, Argentina

Location

Novartis Investigative Site

Santa Fe, S3000FWO, Argentina

Location

Novartis Investigative Site

Santiago del Estero, G4200AQK, Argentina

Location

Novartis Investigative Site

Fortaleza, Ceará, 60125-025, Brazil

Location

Novartis Investigative Site

Fortaleza, Ceará, 60430 370, Brazil

Location

Novartis Investigative Site

Salvador, Estado de Bahia, 40050-410, Brazil

Location

Novartis Investigative Site

Salvador, Estado de Bahia, 40110060, Brazil

Location

Novartis Investigative Site

Salvador, Estado de Bahia, 40323-010, Brazil

Location

Novartis Investigative Site

Salvador, Estado de Bahia, 41253-190, Brazil

Location

Novartis Investigative Site

Brasila, Federal District, 70673623, Brazil

Location

Novartis Investigative Site

Brasília, Federal District, 70390-700, Brazil

Location

Novartis Investigative Site

Brasília, Federal District, 70673-416, Brazil

Location

Novartis Investigative Site

Goiânia, Goiás, 74223-060, Brazil

Location

Novartis Investigative Site

Goiânia, Goiás, 74223-130, Brazil

Location

Novartis Investigative Site

Goiânia, Goiás, 74605-020, Brazil

Location

Novartis Investigative Site

São Luís, Maranhão, 65020-070, Brazil

Location

Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30130-100, Brazil

Location

Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30140 062, Brazil

Location

Novartis Investigative Site

Belo Horizonte, Minas Gerais, 30150-270, Brazil

Location

Novartis Investigative Site

Montes Claros, Minas Gerais, 39401-001, Brazil

Location

Novartis Investigative Site

Passos, Minas Gerais, 37904-020, Brazil

Location

Novartis Investigative Site

Uberaba, Minas Gerais, 38025-440, Brazil

Location

Novartis Investigative Site

Uberlândia, Minas Gerais, 38400 500, Brazil

Location

Novartis Investigative Site

Uberlândia, Minas Gerais, 38400-328, Brazil

Location

Novartis Investigative Site

Londrina, Paraná, 86038-440, Brazil

Location

Novartis Investigative Site

Belém, Pará, 66087-660, Brazil

Location

Novartis Investigative Site

Recife, Pernambuco, 50100-060, Brazil

Location

Novartis Investigative Site

Teresina, Piauí, 64001-380, Brazil

Location

Novartis Investigative Site

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

Location

Novartis Investigative Site

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

Location

Novartis Investigative Site

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

Location

Novartis Investigative Site

Botucatu, São Paulo, 3880-1001, Brazil

Location

Novartis Investigative Site

Bragança Paulista, São Paulo, 13183-091, Brazil

Location

Novartis Investigative Site

Campinas, São Paulo, 13020-431, Brazil

Location

Novartis Investigative Site

Campinas, São Paulo, 13060 080, Brazil

Location

Novartis Investigative Site

Campinas, São Paulo, 13060-904, Brazil

Location

Novartis Investigative Site

Indaiatuba, São Paulo, 13330-570, Brazil

Location

Novartis Investigative Site

Marília, São Paulo, 17515-000, Brazil

Location

Novartis Investigative Site

Ribeirão Preto, São Paulo, 14010-190, Brazil

Location

Novartis Investigative Site

Ribeirão Preto, São Paulo, 14048-900, Brazil

Location

Novartis Investigative Site

Santo André, São Paulo, 09080-001, Brazil

Location

Novartis Investigative Site

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

Location

Novartis Investigative Site

São Paulo, São Paulo, 04012 909, Brazil

Location

Novartis Investigative Site

São Paulo, São Paulo, 05403-000, Brazil

Location

Novartis Investigative Site

Tatuí, São Paulo, 18270-170, Brazil

Location

Novartis Investigative Site

Votuporanga, São Paulo, 15500 003, Brazil

Location

Novartis Investigative Site

São Paulo, 05403-000, Brazil

Location

Novartis Investigative Site

São Paulo, 15015-210, Brazil

Location

Novartis Investigative Site

Bogota, Cundinamarca, 110121, Colombia

Location

Novartis Investigative Site

Santa Marta, Magdalena Department, 30360, Colombia

Location

Novartis Investigative Site

San Gil, Santander Department, 684031, Colombia

Location

Novartis Investigative Site

Bogota DC, 110111, Colombia

Location

Novartis Investigative Site

Florida Blanca, 681001, Colombia

Location

Novartis Investigative Site

Floridablanca, 681004, Colombia

Location

Novartis Investigative Site

Mérida, Yucatán, 97000, Mexico

Location

Novartis Investigative Site

Ciudad de, 14080, Mexico

Location

Novartis Investigative Site

Oaxaca City, 68000, Mexico

Location

Novartis Investigative Site

Xalapa, 91193, Mexico

Location

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

Novartis.email@Novartis.com

+ 1 862 778 8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

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 cardiovascular (CV) events (CV death or first heart failure \[HF\] 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: May 11, 2026
• Results First Posted: May 11, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share

Locations

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