Enhancing the Natriuretic Peptide System in HFpEF: A Randomized Double-Blind Placebo-Controlled Triple Crossover Study
试验速览
- 阶段
- 1 期
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- Change in Composite Score of cGMP, sodium excretion, GFR, and Anx-A1 Plasma cGMP, urinary cGMP, urinary sodium excretion, GFR, ANX-A1acute VE with MANP
研究概览
简要总结
The purpose of this study is to look at the differences in how individuals with heart failure with preserved ejection fraction in the presence of chronic kidney disease (HFpEF-CKD) and exercise induced dyspnea without objective findings of fluid retention (HFpEF-EI) bodies function using drugs Sacubatril/Valsartan (Entresto) and MANP.
详细描述
Visit 1
Consent Visit: Possible study participants will meet with study coordinator to review consent form. After enrollment into the study. Diet instructions will be given by a dietician about a no added salt diet, 120 mEq Na/day, which will be maintained throughout the study period. Comprehensive metabolic panel and complete blood count with differential and uring pregnancy test (for premenopausal women) will be obtained as well as a brief physical exam or nursing assessment. Visit 2 will be scheduled at least one week out from consent visit to accommodate diet compliance, unless participant is already compliant with salt intake parameter. Instructions for completing a 24-hour urine collection, and container for Study Visit 2, will be given.
Subjects who are taking angiotensin converting enzyme inhibitors (ACEI) will be switched over to an equivalent dose of Valsartan or Losartan which will be maintained for the rest of the study period.
Visit 2
Participants will start a twenty-four hour urine collection one day prior to the active study day.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
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
- •Group 1: HFpEF-CKD-will consist of 30 subjects with:
- •Ejection fraction of equal or greater than 55%; and
- •Evidence of increased LV filling pressures, including at least 2 of the following: average septal-lateral E/e' ratio ≥ 15; tricuspid regurgitation (TR) peak velocity > 2:8 m/s;
- •Left atrial volume index >34mL/m^2 assessed by echocardiography; and
- •Previous diagnosis of HF with New York Heart Association (NYHA) functional class II-III symptoms on chronic diuretic therapy; and
- •CKD defined as glomerular filtration rate (eGFR) of 15-80 mL/min/1.73 m^2 as estimated by the Modification of Diet in Renal Disease equation. Subject needs to be on stable dose of chronic diuretic for at least 4 weeks prior to study and maintained on the same dose for the duration of the study. In addition to the exclusion criteria listed below, to ensure a more homogenous group of subjects, we will exclude subjects with Diabetes or BMI > 35 (because endogenous natriuretic peptide levels are low in obese subjects).
- •Group 2: HFpEF-EI-will consist of 30 subjects with:
- •Ejection fraction of equal or greater than 55%; and
- •Previous invasive determination of normal pulmonary capillary wedge pressure ≤ 15 mmHg) at rest and ≥ 25 mmHg during exercise; and
- •New York Heart Association (NYHA) functional class II-III symptoms; and
- •Glomerular filtration rate (eGFR) of > 50 mL/min/1.73 m^2 as estimated by the Modification of Diet in Renal Disease equation. In addition to the exclusion criteria listed below, to ensure a more homogenous group of subjects, we will exclude subjects with Diabetes or BMI>35 (because endogenous natriuretic peptide levels are low in obese subjects).
排除标准
- •Body mass index >
- •Blood pressure < 100/60 or > 180/100 mmHg.
- •Diabetes.
- •Myocardial infarction within 6 months of screening.
- •Unstable angina within 6 months of screening, or any evidence of myocardial ischemia.
- •Significant valvular heart diseases.
- •Hypertrophic, restrictive or obstructive cardiomyopathy.
- •Constrictive pericarditis.
- •Primary pulmonary hypertension.
- •Biopsy proven active myocarditis.
- •Severe congenital heart diseases.
- •Cardiac amyloidosis.
- •Fabry disease.
- •Sarcoidosis.
- •Sustained ventricular tachycardia or ventricular fibrillation within 14 days of screening.
- •Second or third degree heart block without a permanent cardiac pacemaker.
- •Stroke within 3 months of screening, or other evidence of significantly compromised CNS perfusion.
- •Hemoglobin < 9 g/dl
- •ALT > 2 times the upper limit of normal;
- •Serum sodium of < 135 mEq/dL or > 150 mEq/dL
- •Serum potassium of < 3.5 mEq/dL or > 5.7 mEq/dL.
- •Other acute or chronic medical conditions or laboratory abnormality which may increase the risks associated with study participation or may interfere with interpretation of the data.
- •Received an investigational drug within 1 month prior to dosing.
- •Patients with an allergy to iodine;
- •female subject who is pregnant or breastfeeding.
- •In the opinion of the investigator, is unlikely to comply with the study protocol or is unsuitable for any reasons.
研究组 & 干预措施
HFpEF-CKD with MANP and oral placebo
Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug MANP and an oral placebo followed by a 1 week washout period.
干预措施: MANP (Drug)
HFpEF-CKD with MANP and oral placebo
Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug MANP and an oral placebo followed by a 1 week washout period.
干预措施: Oral Placebo (Drug)
HFpEF-EI with MANP and oral placebo
Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug MANP and an oral placebo followed by a 1 week washout period.
干预措施: MANP (Drug)
HFpEF-EI with MANP and oral placebo
Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug MANP and an oral placebo followed by a 1 week washout period.
干预措施: Oral Placebo (Drug)
HFpEF-CKD with Sacbitril/Valsartan with an injected placebo
Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug Sacbitril/Valsartan and an injected placebo followed by a 1 week washout period.
干预措施: Sacubitril/Valsartan (Drug)
HFpEF-CKD with Sacbitril/Valsartan with an injected placebo
Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug Sacbitril/Valsartan and an injected placebo followed by a 1 week washout period.
干预措施: Injection Placebo (Drug)
HFpEF-EI with Sacbitril/Valsartan with an injected placebo
Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug Sacbitril/Valsartan and an injected placebo followed by a 1 week washout period.
干预措施: Sacubitril/Valsartan (Drug)
HFpEF-EI with Sacbitril/Valsartan with an injected placebo
Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive study drug Sacbitril/Valsartan and an injected placebo followed by a 1 week washout period.
干预措施: Injection Placebo (Drug)
HFpEF-CKD with an oral and injected placebo
Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive an oral and injected placebo followed by a 1 week washout period.
干预措施: Oral Placebo (Drug)
HFpEF-CKD with an oral and injected placebo
Subjects with with HFpEF volume overload in the presence of chronic kidney diseases and clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive an oral and injected placebo followed by a 1 week washout period.
干预措施: Injection Placebo (Drug)
HFpEF-EI with an oral and injected placebo
Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive an oral and injected placebo followed by a 1 week washout period.
干预措施: Oral Placebo (Drug)
HFpEF-EI with an oral and injected placebo
Subjects with with HFpEF with exercise induced dyspnea (difficult or labored breathing) without clinical symptoms at rest (e.g. peripheral edema, weight gain, and abdominal distention) will receive an oral and injected placebo followed by a 1 week washout period.
干预措施: Injection Placebo (Drug)
结局指标
主要结局
Change in Composite Score of cGMP, sodium excretion, GFR, and Anx-A1 Plasma cGMP, urinary cGMP, urinary sodium excretion, GFR, ANX-A1acute VE with MANP
时间窗: 24 hours
A composite score of change in urinary cGMP (pmol/min), sodium excretion (mEq/min), GFR (ml/min), and Anx-A1 (pg/ml) after administration of study drug/placebo compared to baseline in response to volume expansion in HFpEF-EI vs HFpEF-CKD within each treatment group.
Change in Plasma ANP
时间窗: 24 hours
Change in Plasma ANP (pg/ml) level after administration of study drug/placebo compared to baseline in response to volume expansion in HFpEF-EI vs HFpEF-CKD.
次要结局
- Change in Plasma NT-pro BNP(24 hours)
- Change in Plasma cGMP(24 hours)
研究者
Horng Chen
Regulatory Sponsor
Mayo Clinic