Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose
研究概览
简要总结
This study will be performed to determine the safety, tolerability, and dose-response to inorganic nitrate on exercise capacity in HFpEF. There are two primary goals for this study:
- Determine the population-specific pharmacokinetics and dose of KNO3 that can be safely given to subjects with HFpEF.
- Determine if there is a dose-response effect of nitrate supplementation on exercise capacity, evidenced by peak oxygen consumption (peak VO2), and physiologic adaptations to exercise.
详细描述
This study randomized subjects to either placebo (n=3) or KNO3 (n=9) given a sequential dosing regimen: 6 mmol twice daily for 1 week followed by dose escalation to 6 mmol thrice daily for 1 week). Although a primary goal of the study was to assess the safety of KNO3 and within-group changes in various end points in KNO3-treated subjects, a small number of placebo-treated (PB, n=3) subjects were included only to assess for any potential training effect on repeated exercise and Kansas City Cardiomyopathy Questionnaire (KCCQ) measurements. Potassium chloride, given in equivalent doses, was used as the PB to account for differences in blood pressure or flow that could be attributed to potassium.
The study was initially designed to be single-blinded to allow the principal investigator to be aware of arm allocation because of potential concerns for methemoglobinemia with drug administration. One investigator, who was the primary investigator responsible for supervising all visits and measurements during the study, remained blinded to treatment allocation throughout the entirety of the study. All physiological and imaging data were analyzed in a double-blind manner.
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
- Single (Participant)
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
- •NYHA Class II-III symptoms.
- •LV EF > 50%.
- •Stable medical therapy for at least 1 month.
- •Evidence of significant diastolic dysfunction, meeting the European Society of Echocardiography criteria for HFpEF.
- •Exclusion Criteria
- •Any rhythm other than sinus with native conduction.
- •Inability to exercise.
- •Moderate or greater valvular disease.
- •Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
- •Pericardial disease.
- •Current angina.
- •Acute coronary syndrome or coronary intervention within the past 2 months.
- •Primary pulmonary arteriopathy.
- •Clinically significant lung disease.
- •Ischemia on stress testing without subsequent revascularization.
- •Treatment with phosphodiesterase inhibitors that cannot be withheld.
- •Treatment with organic nitrates or allopurinol.
- •Significant liver disease impacting synthetic function or volume control.
- •Poor echocardiographic windows.
- •eGFR < 30 mL/min/m2 or Cr >2.
- •Current smoking.
- •Alcohol dependency.
- •History of Barret's esophagus.
- •G6PD deficiency
- •Methemoglobinemia - baseline methemoglobin level >3% prior to any study medication.
排除标准
- 未提供
研究组 & 干预措施
KNO3 active comparator
KNO3 will be given at a dose of 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated
干预措施: KNO3 (Drug)
KCl placebo comparator
KCl will be used as a placebo and will be given as 6 mmol twice daily for the first week, increasing to 6 mmol three times daily for the second week if well tolerated
干预措施: KCl (Drug)
结局指标
主要结局
Change in Peak Oxygen Uptake (VO2) From Baseline Upto 1 Week of Administration for Each Dose
时间窗: Baseline, end of week 1, end of week 2
Peak oxygen uptake (VO2) defined as the average value obtained during the last 30 seconds of exercise.
次要结局
- Change in Mitochondrial Oxidative Capacity for Each Dose(Baseline, end of week 1, end of week 2)
- Change in Vasodilatory Reserve for Each Dose(Baseline, end of week 1, end of week 2)
- Change in Aortic Augmentation Index(Baseline, end of week 1, end of week 2)