EntrestoTM (LCZ696) In Advanced Heart Failure (LIFE Study)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 365
- 试验地点
- 38
- 主要终点
- Change in NT-proBNP
研究概览
简要总结
The primary objective of the study is to determine whether, in patients with symptomatic, advanced heart failure due to left ventricular systolic dysfunction, treatment with LCZ696 for 24 weeks will improve Pro-B-type Natriuretic Peptide (NT-proBNP) levels, which reflect hemodynamic and clinical status, compared to treatment with valsartan.
详细描述
Patients with advanced heart failure with reduced ejection fraction (HFrEF) have extremely high morbidity and mortality with 1 year outcomes of death and hospitalization of approximately 50%. For the most advanced heart failure patients, the evidence base for medical treatment is limited with consensus guidelines recommending consideration for either cardiac transplant or ventricular assist device, or palliative care.
The PARADIGM-HF trial showed that LCZ696, which consists of the neprilysin inhibitor sacubitril and the ARB valsartan, improved morbidity and mortality in patients with chronic HFrEF in comparison to enalapril. However, limited experience with advanced heart failure patients was gained from patients enrolled in the trial. Because the information on the effects of sacubitril/valsartan in patients with NYHA class IV heart failure is limited, the updated 2016 ACC/AHA/HFSA guidelines for the treatment of heart failure do not yet endorse the use of sacubitril/valsartan in patients with NYHA class IV heart failure. Accordingly, experience is needed on the use of, and outcomes with LCZ696 in patients unable to tolerate target doses of angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin receptor blocker (ARB).
This study will be a randomized, double-blinded trial of advanced heart failure subjects with 1:1 randomization to either LCZ696 (sacubitril and valsartan) or valsartan. Study drug will be administered in a double-dummy fashion, in which subjects take active (LCZ696 or valsartan) and placebo. Approximately 400 subjects will be randomized into the study.
Subjects will have an initial screening evaluation, including baseline laboratory tests as well as an assessment of left ventricular (LV) ejection fraction, at which time preliminary subject eligibility will be determined. The LV ejection fraction may have been obtained within the prior 12 months by 2-D echocardiogram, LV angiogram or radionuclide scintigraphy. Willing subjects meeting entry criteria will be consented. Those who meet all entry criteria and are interested in study participation will be enrolled.
Enrolled subjects will complete baseline assessments and undergo a run-in period of 3-7 days with LCZ696 50 mg (equivalent to Entresto™ 24/26 mg) po BID (taken by mouth twice a day) prior to randomization. For subjects taking an ACEI, the ACEI will be withheld for ≥ 36 hours prior to first dose of 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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Advanced HFrEF defined as including ALL
- •LVEF≤ 35% documented during the preceding 12 months
- •NYHA class IV symptomatology, defined as chronic dyspnea or fatigue at rest or on minimal exertion in the previous 3 months, or patients who require chronic inotropic therapy
- •Minimum of 3 months GDMT for HF and/or intolerant to therapy
- •Systolic blood pressure ≥ 90 mmHg
- •Serum NT-proBNP ≥ 800 pg/mL OR BNP ≥ 250 pg/mL (most recent - less than 3 months old)
- •Any one or more of the following objective findings of advanced HF including:
- •Current inotropic therapy or use of inotropes in the past 6 months
- •≥ 1 hospitalization for heart failure in the past 6 months (not including the index hospitalization for inpatient participants)
- •LVEF ≤ 25% (within the past 12 months)
- •Peak VO2 < 55% predicted or peak VO2 ≤ 16 for men or ≤ 14 for women (Respiratory Exchange Ratio (RER) ≥ 1.05) (within the past 12 months)
- •6 min walk test distance < 300 m (within the past 3 months)
- •Age ≥18 years and ≤ 85 years
- •Signed Informed Consent form
排除标准
- •Currently taking Entresto™
- •History of hypersensitivity or intolerance (unmodifiable) to Entresto™, an ACEI or ARB as well as known or suspected contraindications (including hereditary angioedema) to the study drugs.
- •Estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m2 at baseline
- •Co-morbid conditions that may interfere with completing the study protocol (e.g. recent history of drug or alcohol abuse) or cause death within 1 year
- •Symptomatic hypotension at randomization or systolic blood pressure < 90 mmHg
- •Serum potassium > 5.5 mmol/L
- •Severe liver dysfunction (Childs-Pugh Class C)
- •Acute coronary syndrome within 4 weeks as defined by electrocardiographic (ECG) changes and biomarkers of myocardial necrosis (e.g. troponin) in an appropriate clinical setting (chest discomfort or anginal equivalent)
- •Planned or recent (≤ 4 weeks) PCI, coronary artery bypass grafting, or biventricular pacing
- •Currently hospitalized and listed status 1A, 1B or 1-4 for heart transplant
- •Current or scheduled for LVAD implantation within 30 days of study enrollment
- •Active infection (current use of oral or IV antimicrobial agents)
- •Primary hypertrophic or infiltrative cardiomyopathy, acute myocarditis, constrictive pericarditis or tamponade
- •Complex congenital heart disease
- •Concomitant use of aliskiren in patients with diabetes or renal impairment (eGFR <60 mL/min/1.73 m²)
- •Known pregnancy or anticipated pregnancy within the next 6 months or breastfeeding mothers
- •Enrollment in any other investigational clinical trial within 30 days prior to screening
- •Inability to comply with study procedures
研究组 & 干预措施
LCZ696 (Entresto) + placebo
LCZ696 50 mg, 100 mg, or 200 mg orally twice daily for 24 weeks, plus valsartan placebo (to match 40 mg, 80 mg, or 160 mg) orally twice daily for 24 weeks
干预措施: LCZ696 (Drug)
LCZ696 (Entresto) + placebo
LCZ696 50 mg, 100 mg, or 200 mg orally twice daily for 24 weeks, plus valsartan placebo (to match 40 mg, 80 mg, or 160 mg) orally twice daily for 24 weeks
干预措施: valsartan placebo (Drug)
valsartan + placebo
valsartan 40 mg, 80 mg, or 160 mg orally twice daily for 24 weeks, plus LCZ696 placebo (to match 50 mg, 100 mg, or 200 mg) orally twice daily for 24 weeks
干预措施: valsartan (Drug)
valsartan + placebo
valsartan 40 mg, 80 mg, or 160 mg orally twice daily for 24 weeks, plus LCZ696 placebo (to match 50 mg, 100 mg, or 200 mg) orally twice daily for 24 weeks
干预措施: LCZ696 placebo (Drug)
结局指标
主要结局
Change in NT-proBNP
时间窗: Baseline, 2, 4, 8, 12, and 24 weeks
The proportional change from baseline in the AUC for NT-proBNP levels measured at 2, 4, 8, 12, and 24 weeks. AUC was normalized for time and divided by the baseline value of NTproBNP so it has no unitshas no units. With the log-scale, the value of 0 indicates, on average, no change in NTproBNP from baseline. A value \> 0 indicates an increase in log NT Pro BNP relative to baseline and a value \< 0 indicates a decrease in log NT Pro BNP relative to baseline.
次要结局
- Composite Endpoint of the Effects of LCZ696 (Number of Days)(Randomization through 24 weeks)
- Tolerability - Hypotension(Randomization through 24 weeks)
- Tolerability - Renal Function(Randomization through 24 weeks)
- Tolerability - Hyperkalemia(Randomization through 24 weeks)
- Tolerability - Target Dose(Randomization through 24 weeks)