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

A Multicenter, Prospective, Randomized, Open-label, Blinded-endpoint, Phase 4 Study to Evaluate the Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With Chronic Chagas' Cardiomyopathy

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Heart Failure; Chagas Disease
• Intervention / Treatment: Drug: Sacubitril/valsartan; Drug: Enalapril

• Study Type: Interventional
• Enrollment (Actual): 920
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Novartis Pharmaceuticals; Phone Number: +41613241111; Email: novartis.email@novartis.com
• Study Contact Backup: Name: Novartis Pharmaceuticals

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1425AGP
    • Novartis Investigative Site
  • Buenos Aires, Argentina, C1155 AHD
    • Novartis Investigative Site
  • Cordoba, Argentina, X5004BAL
    • Novartis Investigative Site
  • Cordoba, Argentina, X5006CBI
    • Novartis Investigative Site
  • Cordoba, Argentina, X5003DCE
    • Novartis Investigative Site
  • Cordoba, Argentina, X5016KET
    • Novartis Investigative Site
  • Corrientes, Argentina, W3400
    • Novartis Investigative Site
  • Formosa, Argentina, P3600
    • Novartis Investigative Site
  • Formosa, Argentina, P3634XAR
    • Novartis Investigative Site
  • Mendoza, Argentina, M5500CHC
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000FWO
    • Novartis Investigative Site
  • Santa Fe, Argentina, S3000EOZ
    • Novartis Investigative Site
  • Santiago del Estero, Argentina, G4200AQK
    • Novartis Investigative Site
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1221ADC
      • Novartis Investigative Site
    • Caba, Buenos Aires, Argentina, C1425BEI
      • Novartis Investigative Site
    • Ramos Mejia, Buenos Aires, Argentina, B1704ETD
      • Novartis Investigative Site
    • San Martin, Buenos Aires, Argentina, 1604
      • Novartis Investigative Site
    • Temperley, Buenos Aires, Argentina, 1834
      • Novartis Investigative Site
  • Cordoba
    • Villa Maria, Cordoba, Argentina, X5900JKA
      • Novartis Investigative Site
  • Provincia De Salta
    • Ciudad de Salta, Provincia De Salta, Argentina, A4406BPF
      • Novartis Investigative Site
  • San Miguel De Tucuman
    • Tucuman, San Miguel De Tucuman, Argentina, T4000ICL
      • Novartis Investigative Site
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • Novartis Investigative Site
    • Rosario, Santa Fe, Argentina, S2000DIF
      • Novartis Investigative Site
  • Tucuman
    • San Miguel de Tucuman, Tucuman, Argentina, T4000IFL
      • Novartis Investigative Site
    • San Miguel de Tucuman, Tucuman, Argentina, T4000JCU
      • Novartis Investigative Site
• Brazil
  • Ijui, Brazil, 98700-000
    • Novartis Investigative Site
  • Sao Paulo, Brazil, 05403-000
    • Novartis Investigative Site
  • Sao Paulo, Brazil, 01223-001
    • Novartis Investigative Site
  • BA
    • Salvador, BA, Brazil, 40050-410
      • Novartis Investigative Site
    • Salvador, BA, Brazil, 41253-190
      • Novartis Investigative Site
    • Salvador, BA, Brazil, 40110060
      • Novartis Investigative Site
    • Salvador, BA, Brazil, 40323-010
      • Novartis Investigative Site
  • CE
    • Fortaleza, CE, Brazil, 60430 370
      • Novartis Investigative Site
  • DF
    • Brasila, DF, Brazil, 70673623
      • Novartis Investigative Site
    • Brasilia, DF, Brazil, 70390-903
      • Novartis Investigative Site
  • Distrito Federal
    • Brasilia, Distrito Federal, Brazil, 70710-100
      • Novartis Investigative Site
  • GO
    • Goiania, GO, Brazil, 74223-130
      • Novartis Investigative Site
    • Goiania, GO, Brazil, 74605-020
      • Novartis Investigative Site
  • Goias
    • Goiania, Goias, Brazil, 74223-060
      • Novartis Investigative Site
  • MA
    • Sao Luis, MA, Brazil, 65020-070
      • Novartis Investigative Site
  • MG
    • Belo Horizonte, MG, Brazil, 30140 062
      • Novartis Investigative Site
    • Belo Horizonte, MG, Brazil, 30150-221
      • Novartis Investigative Site
    • Belo Horizonte, MG, Brazil, 30130-100
      • Novartis Investigative Site
    • Uberaba, MG, Brazil, 38025-440
      • Novartis Investigative Site
    • Uberlândia, MG, Brazil, 38400-328
      • Novartis Investigative Site
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30130-100
      • Novartis Investigative Site
    • Montes Claros, Minas Gerais, Brazil, 39401-001
      • Novartis Investigative Site
    • Passos, Minas Gerais, Brazil, 37904-020
      • Novartis Investigative Site
    • Uberlandia, Minas Gerais, Brazil, 38400 500
      • Novartis Investigative Site
  • PA
    • Belem, PA, Brazil, 66087-660
      • Novartis Investigative Site
  • PE
    • Recife, PE, Brazil, 50100-060
      • Novartis Investigative Site
  • PR
    • Londrina, PR, Brazil, 86038-440
      • Novartis Investigative Site
  • Piaui
    • Teresina, Piaui, Brazil, 64001-380
      • Novartis Investigative Site
  • RJ
    • Rio de Janeiro, RJ, Brazil, 20551-030
      • Novartis Investigative Site
    • Rio de Janeiro, RJ, Brazil, 22240-006
      • Novartis Investigative Site
  • Rio Grande Do Norte
    • Natal, Rio Grande Do Norte, Brazil, 59020-035
      • Novartis Investigative Site
  • SP
    • Campinas, SP, Brazil, 13060 080
      • Novartis Investigative Site
    • Campinas, SP, Brazil, 13020-431
      • Novartis Investigative Site
    • Campinas, SP, Brazil, 13060-904
      • Novartis Investigative Site
    • Indaiatuba, SP, Brazil, 13330-570
      • Novartis Investigative Site
    • Marilia, SP, Brazil, 17515-000
      • Novartis Investigative Site
    • Ribeirao Preto, SP, Brazil, 14048-900
      • Novartis Investigative Site
    • Sao Jose do Rio Preto, SP, Brazil, 15090-000
      • Novartis Investigative Site
    • Sao Paulo, SP, Brazil, 04012 909
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 05403-000
      • Novartis Investigative Site
    • Tatuí, SP, Brazil, 18270-170
      • Novartis Investigative Site
    • Votuporanga, SP, Brazil, 15500 003
      • Novartis Investigative Site
  • Sao Paulo
    • Botucatu, Sao Paulo, Brazil, 3880-1001
      • Novartis Investigative Site
    • Braganca Paulista, Sao Paulo, Brazil, 13183-091
      • Novartis Investigative Site
    • Ribeirao Preto, Sao Paulo, Brazil, 14010-190
      • Novartis Investigative Site
    • Santo Andre, Sao Paulo, Brazil, 09080-001
      • Novartis Investigative Site
    • Sao Jose do Rio Preto, Sao Paulo, Brazil, 15015-210
      • Novartis Investigative Site
    • Sao Jose do Rio Preto, Sao Paulo, Brazil, 15015-750
      • Novartis Investigative Site
• Colombia
  • Bogota DC, Colombia, 110111
    • Novartis Investigative Site
  • Florida Blanca, Colombia, 681001
    • Novartis Investigative Site
  • Floridablanca, Colombia, 681004
    • Novartis Investigative Site
  • Cundinamarca
    • Bogota, Cundinamarca, Colombia, 110121
      • Novartis Investigative Site
  • Magdalena
    • Santa Marta, Magdalena, Colombia, 30360
      • Novartis Investigative Site
  • Santander
    • San Gil, Santander, Colombia, 684031
      • Novartis Investigative Site
• Mexico
  • Oaxaca, Mexico, 68000
    • Novartis Investigative Site
  • Xalapa, Mexico, 91193
    • Novartis Investigative Site
  • Cdmx
    • Ciudad de Mexico, Cdmx, Mexico, 14080
      • Novartis Investigative Site
  • Yucatan
    • Merida, Yucatan, Mexico, 97000
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• Male or female ≥ 18 years of age

• Diagnosis of NYHA Class II-IV HFrEF established by:

  1. 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
  2. NT-proBNP ≥ 600 pg/mL (or BNP ≥ 150 pg/mL) at Visit 1 OR
  3. 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

Key Exclusion Criteria:

• 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:

  1. already on list for a heart transplantation
  2. 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:

  1. Previous cardiac surgery
  2. 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.
  3. Untreated arrhythmia or serious conduction disease e.g., bradyarrhythmias, atrial fibrillation with rapid ventricular response, second or third degree atrioventricular block, etc.
  4. Primary uncorrected valvar pathology like moderate to severe aortic stenosis, mitral stenosis and primary mitral regurgitation
  5. Planned organ transplantation (or in listing for transplantation), planned cardiac or other major surgery (including ventricular assist device implantation)
• History of malignancy of any organ system within the past 5 years.
• Current confirmed COVID19 infection
• Past COVID19 infection with persistent symptom burden suspected due to COVID19 (persistent symptoms may include, but are not limited to, continued cough, breathing difficulty, muscle/joint aches, and gastrointestinal symptoms from the time of COVID19 infection onward)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacubitril/valsartan; 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; 50 (24/26) mg, 100 (49/51) mg and 200 (97/103) mg will be available for dose adjustments.; Other Names: LCZ696; Entresto; Vymada
Active Comparator: Enalapril; 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; 5 mg and 10 mg will be available for dose adjustments.; Other Names: Renitec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to the first occurrence of a composite of CV events	Time from randomization to the first occurrence of HF hospitalization or CV death	From the date of randomization to the first occurrence (total follow up time up to approximately 36 months)
Time to all-cause mortality	The time to all-cause mortality will be determined.	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	The time to sudden death or resuscitated sudden cardiac arrest will be determined.	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)	The rate of visits to an emergency room (ER) due to HF (where intravenous therapy is required) will be determined.	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	The number of days alive out of the hospital will be determined.	From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.
Number of ventricular fibrillation or sustained ventricular tachycardia	The number of ventricular fibrillation or sustained ventricular tachycardia needing specific pharmacological, electrical or other treatment will be determined.	From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.
Number of anti-tachycardia pacing or shock therapies	This will be determined in a subset on a subset of participants who have an ICD or CRT-D at Randomization.	From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2019
• Primary Completion (Estimated): September 16, 2024
• Study Completion (Estimated): September 16, 2024

Study Registration Dates

• First Submitted: July 10, 2019
• First Submitted That Met QC Criteria: July 16, 2019
• First Posted (Actual): July 17, 2019

Study Record Updates

• Last Update Posted (Actual): October 23, 2023
• Last Update Submitted That Met QC Criteria: October 19, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: heart failure; enalapril; ACEI; ARB; Chagas' disease; angiotensin receptor-neprilysin inhibitor; ARNI; sacubitril/valsartan
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Trypanosomiasis; Euglenozoa Infections; Heart Failure; Chagas Disease; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Enzyme Inhibitors; Protease Inhibitors; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Valsartan; Enalapril; Sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: CLCZ696B3302

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No