Chagas Disease, Heart Failure
Conditions
Keywords
Chagas' disease, heart failure, angiotensin receptor-neprilysin inhibitor, ARNI, ARB, ACEI, sacubitril/valsartan, enalapril
Brief summary
The purpose of this study was 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 chronic Chagas' cardiomyopathy (CCC).
Detailed description
This was a multinational, multicenter, parallel-group, prospective, randomized, open-label, with blinded-endpoint adjudication, active-controlled study. The target projected sample size was approximately 900 participants (450 in each arm). It was estimated that approximately 1800 participants would be screened at sites in Latin America, including Argentina, Brazil, Colombia, and Mexico. Participants who met the eligibility requirements were randomly assigned in a 1:1 ratio to receive sacubitril/valsartan (target dose of 200 mg twice daily) or enalapril (target dose of 10 mg twice daily), in addition to their usual therapy, stratified by country, using a central, concealed, web-based, automated randomization system. Both groups entered a titration period of 3 to 6 weeks, aiming to achieve the target dose of sacubitril/valsartan 200 mg twice daily or enalapril 10 mg twice daily. The study follow-up succeeded the titration period and was to last until a total number of 302 events was reached and all randomized participants had a minimum follow-up of 12 weeks.
Interventions
DRUGSacubitril/valsartan
Participants randomized to sacubitril/valsartan who were previously treated with angiotensin-converting enzyme inhibitors (ACEIs) had a 36-hour washout prior to receiving oral treatment with 50, 100, or 200 mg, film-coated tablets.
DRUGEnalapril
Oral treatment with 5 or 10 mg tablets.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Endpoint Adjudication Committee will be blinded to treatment allocation.
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 cardiovascular (CV) events (CV death or first heart failure \[HF\] hospitalization), or in causing greater reduction or lesser increase in NT-proBNP levels at Week 12 in participants with HFrEF caused by CCC.
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hierarchical Composite Endpoint Composed of Time to Cardiovascular (CV) Death, Time to First Heart Failure (HF) Hospitalization, and Relative Change in NT-proBNP From Baseline to Week 12 | Total follow-up time up to approximately 36 months | The primary efficacy endpoint was 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. A winner in the pair-wise comparison had a delayed time to the occurrence of CV death; if time to the occurrence of CV death was censored, a winner had a delayed time to the occurrence of first HF hospitalization event; if the times to both CV events were censored, a winner had a more favorable (less increase or more decrease) change in NT-proBNP between Baseline and Week 12. The estimated win ratio was defined as the total number of winners in the sacubitril/valsartan arm divided by the total number of winners in the enalapril arm. A win ratio \>1 represents a favorable outcome for the study drug being assessed. |
| Percentage of Participants Who Died From Cardiovascular Causes | Total follow up time up to approximately 36 months | — |
| Percentage of Participants With First Hospitalization for Worsening Heart Failure | Total follow up time up to approximately 36 months | — |
| Change From Baseline to Week 12 in NT-proBNP Levels | Baseline to Week 12 | Geometric mean factor change was derived from a linear regression model of log(NT-proBNP), adjusted for country and baseline value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With First Hospitalization Due to Heart Failure or Death From Cardiovascular Causes | From the date of randomization to the first occurrence (total follow up time up to approximately 36 months) | — |
| Percentage of Participants Who Died From Any Cause | From date of randomization until the date of death from any cause assessed up to the end of the study, up to approximately 36 months | — |
| Number of Participants Who Had Sudden Death or Resuscitated Sudden Cardiac Arrest | From date of randomization until the date of the sudden death or resuscitated sudden cardiac arrest assessed up to the end of the study, up to approximately 36 months | — |
| Number of Participants Who Had Visits to an Emergency Room Due to Heart Failure (HF) Where Intravenous Therapy Was Required | From the date of randomization up to end of study. Total follow up time up to approximately 36 months. | — |
| Number of Days Alive and Out of the Hospital | From the date of randomization up to end of study. Total follow up time up to approximately 36 months. | The duration of hospital-free survival within 1 year from randomization was summarized. |
| Number of Hospitalizations Due to Heart Failure (HF) or Death Due to Cardiovascular (CV) Causes (Recurrent Events) | From the date of randomization up to end of study. Total follow up time up to approximately 36 months. | — |
Countries
Argentina, Brazil, Colombia, Mexico
Contacts
STUDY_DIRECTORNovartis Pharmaceuticals
Novartis Pharmaceuticals
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 10.8 |
| Race/Ethnicity, Customized Black | 70 Participants |
| Race/Ethnicity, Customized Caucasian | 502 Participants |
| Race/Ethnicity, Customized Indigenous | 42 Participants |
| Race/Ethnicity, Customized Mixed Ethnicity | 122 Participants |
| Sex: Female, Male Female | 186 Participants |
| Sex: Female, Male Male | 259 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 129 / 462 | 134 / 460 | 263 / 922 |
| other Total, other adverse events | 102 / 462 | 145 / 460 | 247 / 922 |
| serious Total, serious adverse events | 169 / 462 | 183 / 460 | 352 / 922 |
Outcome results
None listed