A Multicenter, Randomized, Double-blind, Parallel Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction.
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 225
- 试验地点
- 1
- 主要终点
- Number of Participants Who Had CEC (Clinical Endpoint Committee) Confirmed Composite Endpoints
研究概览
简要总结
The purpose of this study was to assess the effect of LCZ696 at a target dose of 200 mg b.i.d. compared to enalapril 10 mg b.i.d., in addition to the background heart failure (HF) treatment, on delaying time to first occurrence of either cardiovascular (CV) death or HF hospitalization events in Japanese patients with stable chronic heart failure (CHF), New York Heart Association (NYHA) classes II-IV and reduced ejection fraction (left ventricular ejection fraction (LVEF) ≤ 35%).
详细描述
The study consisted of two parts: the core part and the Open label extension (OLE) epoch.
The core part of this study was a multicenter, randomized, double-blind, double-dummy, parallel-group, active-controlled study to assess the effect of LCZ696 at a target dose of 200 mg b.i.d. and enalapril 10 mg b.i.d. on CV mortality and morbidity reduction in Japanese HF patients with reduced ejection fraction. Patients who met the eligibility criteria at screening entered a 2 week, single-blind, active treatment run-in epoch in which they received LCZ696 50 mg b.i.d. Patients who tolerated LCZ696 50 mg b.i.d. for 2 weeks were randomized in a 1:1 ratio to receive LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. for 4 weeks during the double-blind treatment epoch. The patient randomization was stratified by using NT-proBNP measured at the screening visit as a stratification factor. The patients were then titrated up to the target dose of LCZ696 200 mg b.i.d. or enalapril 10 mg b.i.d. if they tolerated 4 weeks treatment of LCZ696 100 mg b.i.d. or enalapril 5 mg b.i.d. Dose adjustment (LCZ696 50-100 mg b.i.d. & enalapril 2.5-5 mg b.i.d.) was permitted if not tolerated at the target dose of study drugs during the double-blind treatment epoch.
This was an event-driven study in which subjects remained on the study (regardless of whether receiving investigational medications) until the projected number of patients with primary events (approximately 57 events) had been reached.
The Open label extension (OLE) epoch was conducted following the completion of the core part, with the aim to provide access to LCZ696 for eligible subjects until the marketed product was available in Japan or 2 years from the date of the first subject enrolled in the OLE epoch, whichever occurred first, and also to obtain the safety and tolerability data of long-term treatment with LCZ696.
Upon completion of the core part, the eligibility of the subjects to enter the OLE epoch was assessed by the investigator at OLE baseline (Visit 301), which occurred on the same day as the end of study (EOS) visit of the core part (Visit 299). At this visit, subjects were switched to open-label LCZ696.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written informed consent must be obtained before any assessment is performed.
- •Outpatients with a diagnosis of CHF NYHA class II-IV and reduced ejection fraction:
- •LVEF ≤ 35% at Visit 1 (any local measurement, made within the past 6 months using echocardiography, MUGA, CT scanning, MRI or ventricular angiography is also acceptable, provided no subsequent measurement above 35%)
- •NT-proBNP ≥ 600 pg/ml at Visit 1 OR NT-proBNP ≥ 400 pg/ml at Visit 1 and a hospitalization for HF within the last 12 months (according to central laboratory measurements)
- •Patients must be on an ACEI or an ARB at a stable dose for at least 4 weeks before Visit
- •Patients must be treated with a β-blocker, unless contraindicated or not tolerated, at a stable dose for at least 4 weeks prior to Visit 1 (reason should be documented if patients reported contraindications or intolerance).
- •An aldosterone antagonist should also be considered in all patients, taking account of renal function, serum potassium and tolerability. If given, the dose of aldosterone antagonist should be optimized according to guideline recommendations and patient tolerability, and should be stable for at least 4 weeks prior to Visit
- •Other evidence-based therapy for HF should also be considered e.g. cardiac resynchronization therapy and an implantable cardioverter-defibrillator in selected patients, as recommended by guidelines.
排除标准
- •History of hypersensitivity to any of the study drugs or to drugs of similar chemical classes, ACEIs, ARBs, NEP inhibitors as well as known or suspected contraindications to the study drugs.
- •Previous documented history of intolerance to ACEIs or ARBs.
- •Known history of angioedema.
- •Requirement of treatment with both ACEIs and ARBs.
- •Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy).
- •Symptomatic hypotension and/or a SBP < 100 mmHg at screening or < 95 mmHg at the end of run-in.
- •Estimated GFR < 30 mL/min/1.73 m2 as measured by the Japanese formula at screening, or the end of run-in or > 35% decline in eGFR between screening and end of run-in (according to local measurements).
- •Serum potassium > 5.2 mmol/L (mEq/L) at screening or > 5.4 mmol/L (mEq/L) at the end of run-in (according to local measurements).
- •Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or other major CV surgery, percutaneous coronary intervention (PCI) or carotid angioplasty within the 3 months prior to Visit
- •Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit
- •Symptomatic bradycardia or second (except asymptomatic Wenckebach block) or third degree heart block without a pacemaker.
- •Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation.
- •Presence of other hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic and sub-aortic stenosis.
- •Presence of bilateral renal artery stenosis.
研究组 & 干预措施
LCZ696
Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.
干预措施: LCZ696 (Drug)
LCZ696
Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind epoch, randomized patients in this arm started with 100 mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 200 mg b.i.d. at week 4 if they were tolerant to 100 mg b.i.d. Total duration of treatment was up to approximately 40 months.
干预措施: Placebo to Enalapril (Drug)
Enalapril
Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.
干预措施: Enalapril (Drug)
Enalapril
Before randomization, all patients received 2 week LCZ696 50 mg twice daily (b.i.d) as single blind run-in active treatment epoch. In double blind period, all randomized patients in this arm received enalapril 5mg twice daily (b.i.d.) for 4 weeks. Patients were then up-titrated to 10 mg b.i.d. at week 4 if they were tolerant to 5 mg b.i.d. Total duration of treatment was up to approximately 40 months.
干预措施: Placebo to LCZ696 (Drug)
结局指标
主要结局
Number of Participants Who Had CEC (Clinical Endpoint Committee) Confirmed Composite Endpoints
时间窗: up to 40 months
Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. The composite endpoint events occurred on and after End-of-study (EOS) declaration were reported by investigators but those events were not required to be adjudicated by Clinical Endpoint Committee (CEC) and not included in the efficacy analysis.
Exposure-adjusted Incident Rate (EAIR) of CEC Confirmed Composite Endpoints
时间窗: up to 40 months
Composite endpoint is defined as either cardiovascular (CV) death or heart failure (HF) hospitalization in Japanese patients with chronic heart failure (CHF) and reduced ejection fraction. EAIR = n/T where n = Total number of events included in the analysis. T (100 patient years) = total up-to-event/censoring duration-time summarized over participants in the respective treatment group. The composite endpoint events occurred on and after EOS declaration were reported by investigators but those events were not required to be adjudicated by CEC and not included in the efficacy analysis.
次要结局
- Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From OLE Baseline to Predefined Timepoints (OLE)(Baseline, Weeks 2-4, Week 8, Months 4 and 12 (OLE))
- Association Between Change in NT-proBNP Concentration and Change in Echocardiographic Parameters From OLE Baseline at Month 12 (OLE)(Month 12)
- Key Secondary: Change From Baseline in Clinical Summary Score for Heart Failure Symptoms and Physical Limitations Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ).(Baseline, Week 8 and Month 6)
- EAIR of All-cause Mortality(up to 40 months)
- Percentage of Participants Hospitalized(up to 40 months)
- Changes in Urine Cyclic Guanosine 3',5'-Monophosphate (cGMP) From Baseline(Baseline, Weeks 4, 8 and Month 6)
- Change in Urine cGMP From OLE Baseline to Predefined Timepoints (OLE)(Weeks 2-4, Week 8, Months 4 and 12 (OLE))
- Key Secondary: Number of Participants With CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients)(up to 40 months)
- Key Secondary: Number of Participants by Changes in New York Heart Association (NYHA) Classification From Baseline at Predefined Timepoints(Baseline, Weeks 4, 8 and Month 6)
- Total Number of CEC Confirmed Composite of CV Death and Total (First and Recurrent) HF Hospitalizations for Heart Failure(up tp 40 months)
- Key Secondary: EAIR of CEC-confirmed First Triple Composite Endpoint (Cardiovascular (CV) Death, Heart Failure (HF) Hospitalization, or Worsening of HF in Outpatients)(up to 40 months)
- Key Secondary: Change From Baseline to the Pre-defined Time-points in Log-transformed Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)(Baseline, Weeks 4, 8 and Month 6)
- Number of Participants by Changes in Clinical Composite Score (as Assessed by NYHA Classification and Patient Global Assessment) at Predefined Timepoints(Baseline, Month 6)
- Number of Participants With All-cause Mortality(up to 40 months)
- Change in Blood NT-proBNP From Baseline(Baseline, Weeks 2, 4, 8 and Month 6)
- Hospitalization Admissions Events Per-participant Per Year(up to 40 months)
- Days in Intensive Care Unit (ICU) Per Participant Per Year(up to 40 months)
- Percentage of Re-hospitalizations(up to 40 months)
- Emergency Department/Urgent Care Facility Visits for HF Per Patient Per Year(up to 40 months)
- Change in Procollagen Type III N-Terminal Propeptide From Baseline(Baseline and Month 18)
- Change in NYHA Classification From OLE Baseline (OLE)(OLE Baseline, Month 12 (OLE))
- Change in Key Echocardiographic Parameters From OLE Baseline at Month 12 (OLE)(Baseline, Month 12 (OLE))
- Percentage of Participants Reaching Target Dose Level 3 at Week 8 and Maintained at Month 4 (Open Label Extension (OLE))(Month 4 of OLE)
- Change in Cardiac Measurements by Key Echocardiographic Parameter LVEF, From OLE Baseline at Month 12 (OLE)(Baseline, Month 12 (OLE))
- Change in B-type Natriuretic Peptide (BNP) From OLE Baseline to Predefined Timepoints (OLE)(Baseline, Weeks 2-4, Week 8, Months 4 and 12 (OLE))