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

摘要 心力衰竭伴射血分数降低(HFrEF)在美国影响着约300万人，是一种致命和 病态的疾病。HFrEF损害患者的运动能力和日常生活活动能力。虽然软弱 心脏泵血能力明显导致与HFrEF相关的慢性残疾，即骨骼肌异常 HFrEF患者的功能也是一个关键的衰弱因素。因此，骨骼肌是一个重要的目标 HFrEF的治疗。饮食中无机硝酸盐提高患者的有氧运动能力和肌力 HFrEF，正如我们的初步研究所表明的那样。拟议的临床试验的总体目标是 确定一天一次口服凝胶胶囊形式的无机硝酸盐是否提供了一种新的、安全有效的 改善HFrEF所致运动能力受损的治疗。 这笔赠款的R61部分的目的是建立第二阶段所需的基础设施 临床试验并开始试验。这包括将无机硝酸盐(KNO3)/安慰剂胶囊和 所有安全测试，获得机构审查委员会批准，ClinicalTrials.gov注册，RedCap 数据库开发、招聘增强核心(REC)参与、临床转化研究 单位(CTRU)项目审批、招生和评估以及第一批受试者的剂量管理。 R33组分的目的是确定急性(单次服药后2小时)的有效性 股四头肌的慢性(每天给药6周后)硝酸钾治疗(10 Mmol)与安慰剂治疗 左心室射血分数患者的功率和有氧运动能力(V̇O2峰值) &lt；45%。我们假设，急性剂量和慢性剂量的10 mmo3硝酸钾都能改善运动。 在HFrEF中的表现。为了验证这一假设，我们将进行一项随机、双盲、安慰剂对照、 平行臂设计研究。稳定的纽约心脏协会I-III级HFrEF患者将接受 完成基线峰值肌力和有氧运动前的筛查和表型分析 测量。在访问2中，受试者将接受单剂(1粒)他们指定的治疗(10 mmol. 硝酸钾或安慰剂)，并将在2小时后重复运动性能的测量。受试者随后将继续 接受指定的治疗(硝酸钾或安慰剂，每天1粒)，为期6周。在访问3中，受试者将重复 锻炼能力的测试。主要终点是股四头肌的最大肌力，使用 基于V̇O2峰值的等速测功器和有氧运动表现。最大锻炼时间和最大锻炼时间 硝酸钾与安慰剂治疗的肌肉速度、耐受性和安全性及其对血流动力学、血浆的影响 硝酸盐、血浆亚硝酸盐、呼吸一氧化氮(NO)和心力衰竭症状(使用经过充分验证的问卷) 也将在这一II阶段的单中心临床试验中进行量化。寻找一种新的、安全的 帮助数百万患者战胜HFrEF身体残疾的有效治疗是巨大的。

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.