The Inorganic Nitrate and eXercise performance in Heart Failure (iNIX-HF): - a phase II clinical trial

无机硝酸盐和运动在心力衰竭中的表现 (iNIX-HF)：- II 期临床试验

基本信息

批准号：
10449833
负责人：
ANDREW R COGGAN
金额：
$ 80.38万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10449833
关键词：
Activities of Daily Living Acute Aerobic Aerobic Exercise Affect Biological Availability Breath Tests Cachexia Cardiac Cardiomyopathies Cardiovascular Diseases Cardiovascular system Case Report Form Chronic Cities Clinical Clinical Trials Clinical Trials Data Monitoring Committees Clinical trial protocol document Consent Forms Data Databases Development Disease Disease Outcome Dose Double-Blind Method EFRAC Effectiveness Enrollment Event Exercise Exercise Test Exercise Tolerance FDA approved Failure Functional disorder Future Goals Grant Half-Life Heart Heart failure Hospitalization Hour Human Impairment Infrastructure Ingestion Institutional Review Boards Iowa Isotonic Exercise Kansas Left Left Ventricular Ejection Fraction Manuals Measurement Measures Minnesota Monitor Muscle Muscle Contraction Muscle function New York Nitrates Nitric Oxide Nitrites Nitrogen Dioxide Nursing Protocols Oral Oxygen Consumption Participant Pathway interactions Patients Performance Persons Pharmacodynamics Pharmacologic Substance Pharmacology Phase Phase II Clinical Trials Phenotype Physicians Placebo Control Placebos Plasma Procedures Production Prognosis Protocols documentation Pump Questionnaires Randomized Randomized Clinical Trials Research Research Design Rest Safety Skeletal Muscle Speed Sum Surveys Symptoms Testing Time Translational Research Treatment Failure Universities Update Vasodilation Ventricular Visit arm base capsule clinical care clinical center dietary disability drug testing effective therapy effectiveness evaluation effectiveness testing exercise capacity hemodynamics improved mortality novel novel therapeutics operation phase 2 study phase 3 study physically handicapped primary endpoint quadriceps muscle recruit reduce symptoms respiratory gas safety testing screening secondary endpoint side effect skeletal abnormality targeted agent treadmill trial design

项目摘要

ABSTRACT Heart failure with reduced ejection fraction (HFrEF) affects ~3 million people in the U.S. and is a mortal and morbid disease. HFrEF impairs a patient’s ability to exercise and perform activities of daily living. Although weak cardiac pumping ability clearly contributes to chronic disability associated with HFrEF, abnormal skeletal muscle function in patients with HFrEF is also a key debilitating factor. Skeletal muscle is therefore a vital target for treatment of HFrEF. Dietary inorganic nitrate enhances aerobic exercise capacity and muscle power in patients with HFrEF, as demonstrated in our preliminary studies. The overarching aim of the proposed clinical trial is to determine whether inorganic nitrate in a once-a-day oral gelcap format, offers a new, safe, and effective treatment for ameliorating the impaired exercise performance due to HFrEF. The Aim of the R61 component of this grant is to set up the infrastructure necessary for the phase II clinical trial and to begin the trial. This includes compounding the inorganic nitrate (KNO3)/placebo capsules and all safety testing, obtaining Institutional Review Board approval, ClinicalTrials.gov registration, REDCap database development, Recruitment Enhancement Core (REC) engagement, Clinical Translational Research Unit (CTRU) project approval, enrollment and assessment and dose administration of the first subjects. The Aims of the R33 component are to determine the effectiveness of acute (2 hours after a single dose) and chronic (after 6 weeks of once-a-day dosing) KNO3 treatment (10mmol) vs. placebo on quadriceps muscle power and on aerobic exercise performance (V̇O2peak) in patients with HFrEF (left ventricular ejection fraction <45%). We hypothesize that both acute and chronic dosing of 10mmol of KNO3 will improve exercise performance in HFrEF. To test this hypothesis, we will perform a randomized, double-blind, placebo-controlled, parallel-arm design study. Patients with stable New York Heart Association class I-III HFrEF will undergo screening and phenotyping before completing baseline peak muscle power and aerobic performance measurements. On visit 2, subjects will receive a single dose (1 capsule) of their assigned treatment (10mmol KNO3 or placebo) and will repeat the measurements of exercise performance after 2h. Subjects will then continue with their assigned treatment (KNO3 or placebo, 1 capsule daily) for 6 weeks. On visit 3, subjects will repeat the tests of exercise performance. The primary endpoints are maximum quadriceps muscle power, measured using an isokinetic dynamometer, and aerobic exercise performance, based on V̇O2peak. Max exercise time and max muscle velocity, tolerability and safety of KNO3 vs. placebo treatment and their effects on hemodynamics, plasma nitrate, plasma nitrite, breath nitric oxide (NO), and heart failure symptoms (using well-validated questionnaires) will also be quantified in this phase II, single-center clinical trial. The potential impact of finding a new, safe and effective treatment that helps millions of patients beat the physical disability of HFrEF is enormous.

抽象的减少射血分数（HFREF）的心力衰竭影响了美国约300万人，是致命的，是凡人病态疾病。 HFREF会损害患者运动和执行日常生活活动的能力。虽然很弱心脏抽水能力显然有助于与HFREF，异常骨骼肌相关的慢性残疾 HFREF患者的功能也是一个关键的使人衰弱因素。因此，骨骼肌是 HFREF的处理。饮食中无机硝酸盐增强患者有氧运动能力和肌肉力量与HFREF一起，如我们的初步研究所证明的那样。拟议的临床试验的总体目的是确定是否以每天一次的口服凝胶格式以硝酸盐的形式提供新的，安全且有效的改善因HFREF而减轻运动障碍的治疗方法。该赠款的R61组件的目的是设置II期所需的基础架构临床试验并开始试验。这包括使无机硝酸盐（KNO3）/安慰剂胶囊和所有安全测试，获得机构审查委员会的批准，临床。数据库开发，招聘增强核心（REC）参与，临床翻译研究单位（CTRU）项目批准，入学和评估和剂量给药。 R33组件的目的是确定急性的有效性（单剂量后2小时）和慢性（每天6周后）KNO3治疗（10mmol）与股四头肌上的安慰剂 HFREF患者的功率和有氧运动性能（VİO2PEAK）（左心室射血分数 <45％）。我们假设急性和慢性剂量的10mmol kno3都可以改善运动 HFREF的性能。为了检验这一假设，我们将执行一个随机，双盲，安慰剂对照，平行臂设计研究。纽约心脏协会稳定的I-III级HFREF患者将接受在完成基线峰值肌肉力量和有氧性能之前进行筛查和表型测量。在访问2时，受试者将获得分配的治疗的单剂量（1胶囊）（10mmol KNO3或安慰剂），将在2H后重复运动性能的测量。然后，受试者将继续通过分配的治疗（KNO3或安慰剂，每天1胶囊）持续6周。在访问3时，受试者将重复运动表现的测试。主要终点是最大股四头肌肌肉力量，使用基于vïo2peak的等速测力计和有氧运动性能。最大运动时间和最大 KNO3与安慰剂治疗及其对血液动力学的影响，血浆的肌肉速度，耐受性和安全性硝酸盐，血浆亚硝酸盐，呼吸一氧化氮（NO）和心力衰竭症状（使用验证良好的问卷）也将在此II期单中心临床试验中进行量化。寻找新的安全的潜在影响有效的治疗方法可以帮助数百万患者击败HFREF的身体残疾。