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. The Study is Also Know as Prevention And Reduction of Adverse Outcomes in Chagasic Heart failUre Trial Evaluation (PARACHUTE-HF).
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 922
- 试验地点
- 79
- 主要终点
- Hierarchical composite endpoint composed of time to CV death, time to first HF hospitalization, relative change in NT-proBNP from baseline to Week 12
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
盲法说明
Endpoint Adjudication Committee will be blinded to treatment allocation.
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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)
研究组 & 干预措施
Enalapril
Participants received 3 to 6 weeks of titrated dosing with enalapril to achieve the target dose of 10 mg twice daily.
干预措施: Enalapril (Drug)
Sacubitril/valsartan
Participants received 3 to 6 weeks of titrated dosing with sacubitril/valsartan to achieve the target dose of 200 mg twice daily.
干预措施: Sacubitril/valsartan (Drug)
结局指标
主要结局
Hierarchical composite endpoint composed of time to CV death, time to first HF hospitalization, relative change in NT-proBNP from baseline to Week 12
时间窗: 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.
次要结局
- Number of visits to an ER due to HF (where intravenous therapy is required)(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(From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.)
- Time to all-cause mortality(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(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)
- Time to the first occurrence of a composite of CV events(From the date of randomization to the first occurrence (total follow up time up to approximately 36 months))
- Number of anti-tachycardia pacing or shock therapies(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(From the date of randomization up to End of Study (EOS) assessment. Total follow up time up to approximately 36 months.)