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

Heart Failure Clinical Trial

— PARACHUTE-HF  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04023227
• Other study ID #: CLCZ696B3302
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: December 10, 2019
• Est. completion date: September 16, 2024

Study information

• Verified date: November 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 919
• Est. completion date: September 16, 2024
• Est. primary completion date: September 16, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Chagas Disease
• Heart Failure

Intervention

Drug:
• Sacubitril/valsartan
50 (24/26) mg, 100 (49/51) mg and 200 (97/103) mg will be available for dose adjustments.
• Enalapril
5 mg and 10 mg will be available for dose adjustments.

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Ciudad de Salta	Provincia De Salta
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Cordoba
Argentina	Novartis Investigative Site	Corrientes
Argentina	Novartis Investigative Site	Formosa
Argentina	Novartis Investigative Site	Formosa
Argentina	Novartis Investigative Site	Mendoza
Argentina	Novartis Investigative Site	Ramos Mejia	Buenos Aires
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	Rosario	Santa Fe
Argentina	Novartis Investigative Site	San Martin	Buenos Aires
Argentina	Novartis Investigative Site	San Miguel de Tucuman	Tucuman
Argentina	Novartis Investigative Site	San Miguel de Tucuman	Tucuman
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Santa Fe
Argentina	Novartis Investigative Site	Santiago del Estero
Argentina	Novartis Investigative Site	Temperley	Buenos Aires
Argentina	Novartis Investigative Site	Tucuman	San Miguel De Tucuman
Argentina	Novartis Investigative Site	Villa Maria	Cordoba
Brazil	Novartis Investigative Site	Belem	PA
Brazil	Novartis Investigative Site	Belo Horizonte	Minas Gerais
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Botucatu	Sao Paulo
Brazil	Novartis Investigative Site	Braganca Paulista	Sao Paulo
Brazil	Novartis Investigative Site	Brasila	DF
Brazil	Novartis Investigative Site	Brasilia	DF
Brazil	Novartis Investigative Site	Brasilia	Distrito Federal
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Campinas	SP
Brazil	Novartis Investigative Site	Fortaleza	CE
Brazil	Novartis Investigative Site	Goiania	Goias
Brazil	Novartis Investigative Site	Goiania	GO
Brazil	Novartis Investigative Site	Goiania	GO
Brazil	Novartis Investigative Site	Ijui
Brazil	Novartis Investigative Site	Indaiatuba	SP
Brazil	Novartis Investigative Site	Londrina	PR
Brazil	Novartis Investigative Site	Marilia	SP
Brazil	Novartis Investigative Site	Montes Claros	Minas Gerais
Brazil	Novartis Investigative Site	Natal	Rio Grande Do Norte
Brazil	Novartis Investigative Site	Passos	Minas Gerais
Brazil	Novartis Investigative Site	Recife	PE
Brazil	Novartis Investigative Site	Ribeirao Preto	Sao Paulo
Brazil	Novartis Investigative Site	Ribeirao Preto	SP
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Rio de Janeiro	RJ
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Salvador	BA
Brazil	Novartis Investigative Site	Santo Andre	Sao Paulo
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto	Sao Paulo
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto	Sao Paulo
Brazil	Novartis Investigative Site	Sao Jose do Rio Preto	SP
Brazil	Novartis Investigative Site	Sao Luis	MA
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo
Brazil	Novartis Investigative Site	Sao Paulo
Brazil	Novartis Investigative Site	São Paulo	SP
Brazil	Novartis Investigative Site	Tatuí	SP
Brazil	Novartis Investigative Site	Teresina	Piaui
Brazil	Novartis Investigative Site	Uberaba	MG
Brazil	Novartis Investigative Site	Uberlandia	Minas Gerais
Brazil	Novartis Investigative Site	Uberlândia	MG
Brazil	Novartis Investigative Site	Votuporanga	SP
Colombia	Novartis Investigative Site	Bogota	Cundinamarca
Colombia	Novartis Investigative Site	Bogota DC
Colombia	Novartis Investigative Site	Florida Blanca
Colombia	Novartis Investigative Site	Floridablanca
Colombia	Novartis Investigative Site	San Gil	Santander
Colombia	Novartis Investigative Site	Santa Marta	Magdalena
Mexico	Novartis Investigative Site	Ciudad de Mexico	Cdmx
Mexico	Novartis Investigative Site	Merida	Yucatan
Mexico	Novartis Investigative Site	Oaxaca
Mexico	Novartis Investigative Site	Xalapa

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

Argentina,  Brazil,  Colombia,  Mexico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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
Secondary	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
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.