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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Chagas Disease, Heart Failure

Intervention / Treatment
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* Drug: Sacubitril/valsartan
* Drug: Enalapril


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female ≥ 18 years of age Diagnosis of NYHA Class II-IV HFrEF established by: 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 NT-proBNP ≥ 600 pg/mL (or BNP ≥ 150 pg/mL) at Visit 1 OR 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: already on list for a heart transplantation 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: Previous cardiac surgery 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. Untreated arrhythmia or serious conduction disease e.g., bradyarrhythmias, atrial fibrillation with rapid ventricular response, second or third degree atrioventricular block, etc. Primary uncorrected valvar pathology like moderate to severe aortic stenosis, mitral stenosis and primary mitral regurgitation 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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacubitril/valsartan<br>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<br>* 50 (24/26) mg, 100 (49/51) mg and 200 (97/103) mg will be available for dose adjustments.<br>* Other names: LCZ696; Entresto; Vymada;|
| Active Comparator: Enalapril<br>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<br>* 5 mg and 10 mg will be available for dose adjustments.<br>* Other names: Renitec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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 | 
| 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. | 
| 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. | 
| 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. | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ACEI, angiotensin receptor-neprilysin inhibitor, ARNI, ARB, Chagas' disease, heart failure, sacubitril/valsartan, enalapril