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

Novartis

Status and phase: Completed; Phase 4

Conditions: Chagas Disease; Heart Failure

Treatments: Drug: Enalapril; Drug: Sacubitril/valsartan

Study type: Interventional

Funder types: Industry

Identifiers

NCT04023227

CLCZ696B3302

Details and patient eligibility

About

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.

Enrollment: 918 patients

Sex: All

Ages: 18 to 100 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion 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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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918 participants in 2 patient groups

Sacubitril/valsartan

Experimental group

Description:

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

Treatment:

Drug: Sacubitril/valsartan

Enalapril

Active Comparator group

Description:

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).

Treatment:

Drug: Enalapril