Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Urine sodium excretion
研究概览
简要总结
This is a double-blind, randomized, two x two crossover (aprepitant vs placebo) during both initiation of Entresto, LCZ696, (50 mg dose) and at steady-state of Entresto (200 mg bid dose or the highest tolerated dose).
详细描述
LCZ696, a molecular complex of the angiotensin receptor blocker (ARB) valsartan with an inhibitor of neprilysin (NEP, neutral endopeptidase-24.11) sacubitril improved mortality compared to enalapril in patients with heart failure (HF), reduced ejection fraction (EF), and increased brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT-proBNP) in the PARADIGM-HF trial. The PIONEER-HF study demonstrated the efficacy of LCZ696 in preventing rehospitalization in patients with acutely decompensated HF.
LCZ696 has been underutilized in heart failure, in part due to concerns about hypotension. NEP degrades several vasodilator peptides including bradykinin, substance P and brain-type natriuretic peptide. Decreased degradation of endogenous substance P could contribute to hypotension at initiation of LCZ696 through vasodilation or through increased natriuresis and diuresis. Antagonism of the NK1 receptor using aprepitant would be expected to prevent this effect.
Objectives
The main objectives of this mechanistic randomized, double-blind, crossover-design study are:
The primary objective is to test the hypothesis that endogenous substance P contributes to effects of ARB/NEP inhibition on blood pressure, natriuresis, and diuresis at initiation.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Black and white men and women
- •Stable patients with a reduced ejection fraction (EF)
- •EF ≤55%, and
- •history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF)
- •stable clinical symptoms including no hospitalizations for the last three months, or one month if hospitalized only once for initial diagnosis of HF
- •who are not already taking LCZ696
- •treatment with a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks
- •for patients with NYHA Class II or III HF and EF ≤35%, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or adverse reaction
- •For female subjects, the following conditions must be met:
- •postmenopausal status for at least one year
- •status post-surgical sterilization
- •or if childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β-HCG testing on every study day
- •Age 18 years of age or older
排除标准
- •History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or neutral endopeptidase inhibitor (NEPi), as well as known or suspected contraindications to the study drugs
- •History of angioedema
- •History of decompensated HF within the last 3 months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization) or one month if hospitalized only once for initial diagnosis of HF
- •History of heart transplant or on a transplant list or with left ventricular assistance device
- •Symptomatic hypotension and/or a systolic blood pressure (SBP)<100 mmHg at screening or <95 mmHg during the study
- •Serum potassium >5.2 mmol/L at screening or during the study
- •Impaired renal function (eGFR of <30mL/min/1.73 m2) as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dL and age in years:
- •a. eGFR (mL/min/1.73 m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female)
- •Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening
- •Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening
- •History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack with clinically significant residual deficits
- •History of ventricular arrhythmia with syncopal episodes
- •Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker
- •Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricular (LV) dilatation
- •Presence of other hemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis
- •Type 1 diabetes
- •Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9%
- •In T2DM, dipeptidyl peptidase-4 inhibitor use for one month prior to enrollment will be excluded due to possible interaction with LCZ696
- •Hematocrit <35%
- •Breast feeding and pregnancy
- •History or presence of immunological or hematological disorders
- •History of malignancy not felt to be cured, except non-melanoma skin cancer
- •Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
- •History of hypersensitivity reaction to contrast
- •Clinically significant gastrointestinal impairment that could interfere with drug absorption
- •History of pancreatitis or known pancreatic lesions
- •Impaired hepatic function with evidence of advanced fibrosis or cirrhosis [stable aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) trend if >3.0 x upper limit of normal range as deemed of minimal clinical relevance by the investigators]
- •Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal anti-inflammatory drugs
- •Treatment with greater than 5 mg of prednisone or equivalent dose of chronic systemic glucocorticoid therapy within the last year or recent (within 6 weeks of first study day) treatment with burst dosed glucocorticoid therapy
- •Treatment with lithium salts
- •History of alcohol or drug abuse
- •Treatment with any investigational drug in the one month preceding the study
- •Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
- •Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study
研究组 & 干预措施
placebo, aprepitant, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: LCZ 696 (Drug)
placebo, aprepitant, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Placebo (Drug)
placebo, aprepitant, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Para-aminohippurate (Drug)
placebo, aprepitant, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Iohexol (Drug)
placebo, aprepitant, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Aprepitant (Drug)
placebo, aprepitant, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: LCZ 696 (Drug)
placebo, aprepitant, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Placebo (Drug)
placebo, aprepitant, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Para-aminohippurate (Drug)
placebo, aprepitant, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Iohexol (Drug)
placebo, aprepitant, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and placebo (vehicle). After a 96-hr washout period, subjects will be given LCZ696 50 mg and aprepitant. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Aprepitant (Drug)
aprepitant, placebo, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: LCZ 696 (Drug)
aprepitant, placebo, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Placebo (Drug)
aprepitant, placebo, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Para-aminohippurate (Drug)
aprepitant, placebo, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Iohexol (Drug)
aprepitant, placebo, placebo, aprepitant
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive placebo and aprepitant, respectively.
干预措施: Aprepitant (Drug)
aprepitant, placebo, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: LCZ 696 (Drug)
aprepitant, placebo, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Placebo (Drug)
aprepitant, placebo, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Para-aminohippurate (Drug)
aprepitant, placebo, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Iohexol (Drug)
aprepitant, placebo, aprepitant, placebo
After a 48-hr washout, participants in this arm will be given LCZ696 50 mg and aprepitant. After a 96-hr washout period, subjects will be given LCZ696 50 mg and placebo. Participants will then undergo uptitration of LCZ696 over seven weeks. On the 7th and 10th days of the 200 mg bid or highest tolerated dose of LCZ696, participants in this arm will receive aprepitant and placebo, respectively.
干预措施: Aprepitant (Drug)
结局指标
主要结局
Urine sodium excretion
时间窗: Total urine output from drug administration to six hours following drug administration
Urine sodium excretion will be measured for six hours following administration of LCZ696 on each of the four study days.
Mean arterial pressure (MAP)
时间窗: Over six hours on each of the four study days
Mean arterial pressure (MAP) will be measured before and after administration of LCZ696 on each of the four study days
次要结局
- Urine albumin-to-creatinine ratio(Over six hours on each of four study days)
- Glomerular filtration rate(Over six hours on each of four study days)
- Renal plasma flow(Over six hours on each of four study days)
- Heart rate(Over six hours on each of four study days)
- Urine volume(Over six hours on each of four study days)
研究者
Nancy Brown
Professor of Internal Medicine
Yale University