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

• ClinicalTrials.gov Identifier: NCT04023227
• Recruitment Status: Recruiting
• First Posted: July 17, 2019
• Last Update Posted: April 14, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: July 10, 2019
• First Posted Date: July 17, 2019
• Last Update Posted Date: April 14, 2023
• Actual Study Start Date: December 10, 2019
• Estimated Primary Completion Date: September 16, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 16, 2019)

Hierarchical composite endpoint composed of time to CV death, time to first HF hospitalization, relative change in NT-proBNP from baseline to Week 12 [ Time Frame: Total follow up time up to approximately 36 months ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 16, 2019)

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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

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.

Masking: Single (Outcomes Assessor)
Masking Description:

Endpoint Adjudication Committee will be blinded to treatment allocation.

Primary Purpose: Treatment

Condition

• 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.
  Other Name: LCZ696; Entresto; Vymada
• Drug: Enalapril
  5 mg and 10 mg will be available for dose adjustments.
  Other Name: Renitec

Study Arms

• 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

  Intervention: Drug: Sacubitril/valsartan
• 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).

  Intervention: Drug: Enalapril

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 16, 2019): 900
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 16, 2024
• Estimated Primary Completion Date: September 16, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Novartis Pharmaceuticals; +41613241111; Novartis.email@novartis.com

Contact: Novartis Pharmaceuticals

• Listed Location Countries: Argentina, Brazil, Colombia, Mexico

Administrative Information

• NCT Number: NCT04023227
• Other Study ID Numbers: CLCZ696B3302
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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.

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: April 2023