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

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 measurementusing echocardiography, multiple gated acquisition scan (MUGA), computerizedtomography (CT) scanning, magnetic resonance imaging (MRI), or ventricularangiography, 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 forHF within the last 12 months

• Chagas' disease diagnosis confirmed by at least two different serological tests foranti-Trypanosoma cruzi based on different principles or with different antigenicpreparations, such as: enzyme-linked immunosorbent assay [ELISA], indirectimmunofluorescence [IFI], indirect hemagglutination [IHA], western blot (WB),chemiluminescent immunoassay (CLIA). If documented history is not available, thetests 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 ofadvanced support intervention for HF:

1. already on list for a heart transplantation

2. with current indication of left ventricular assist device, or cardiacresynchronization 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 megaesophagusand/or important megacolon, e.g.: with compromised oral intake or surgicalindication).

• Clinical conditions or systemic diseases limiting proper patient participation

• Pregnant or nursing women or women of child-bearing potential unless they are usinghighly 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 possiblealternative primary etiology e.g., due to coronary artery disease, valvedisease, 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 degreeatrioventricular 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), plannedcardiac or other major surgery (including ventricular assist deviceimplantation)

• 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, breathingdifficulty, muscle/joint aches, and gastrointestinal symptoms from the time ofCOVID19 infection onward)