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

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ClinicalTrials.gov Identifier: NCT04023227
Recruitment Status : Recruiting
First Posted : July 17, 2019
Last Update Posted : July 9, 2020
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease Intervention/treatment Phase
Chagas Disease Heart Failure Drug: Sacubitril/valsartan Drug: Enalapril Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 900 participants
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
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
Actual Study Start Date : December 10, 2019
Estimated Primary Completion Date : December 16, 2022
Estimated Study Completion Date : December 16, 2022

Resource links provided by the National Library of Medicine


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 Name: 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 Name: Renitec




Primary Outcome Measures :
  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 [ 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.


Secondary Outcome Measures :
  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 2 different serological tests for anti-Trypanosoma cruzi (enzyme-linked immunosorbent assay [ELISA], indirect immunofluorescence [IFI], and indirect hemagglutination [IHA]). 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 or ARBs (e.g., due to cough, hypotension, renal dysfunction, hyperkalemia)
  • Previous use of sacubitril/valsartan
  • 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
  • Known gastrointestinal form of chronic Chagas' disease: demonstrated megaesophagus; important megacolon
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04023227


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

Locations
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Argentina
Novartis Investigative Site Recruiting
Rosario, Santa Fe, Argentina, 2000
Novartis Investigative Site Recruiting
Cordoba, Argentina, X5003DCE
Novartis Investigative Site Recruiting
Cordoba, Argentina, X5004CDT
Novartis Investigative Site Recruiting
Cordoba, Argentina, X5006CBI
Novartis Investigative Site Recruiting
Santa Fe, Argentina, S3000FWO
Brazil
Novartis Investigative Site Recruiting
Salvador, BA, Brazil, 40323-010
Novartis Investigative Site Recruiting
Campinas, SP, Brazil, 13060 080
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT04023227    
Other Study ID Numbers: CLCZ696B3302
First Posted: July 17, 2019    Key Record Dates
Last Update Posted: July 9, 2020
Last Verified: July 2020
Individual Participant Data (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


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Chagas' disease
heart failure
angiotensin receptor-neprilysin inhibitor
ARNI
ARB
ACEI
sacubitril/valsartan
enalapril
Additional relevant MeSH terms:
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Chagas Disease
Heart Failure
Heart Diseases
Cardiovascular Diseases
Trypanosomiasis
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Valsartan
Enalapril
LCZ 696
Antihypertensive Agents
Angiotensin II Type 1 Receptor Blockers
Angiotensin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action
Angiotensin-Converting Enzyme Inhibitors
Protease Inhibitors
Enzyme Inhibitors