A Phase 1, Crossover, Pharmacokinetic Study of Nutritional Ketosis on Exercise Capacity, Metabolic Adaptations, and Myocardial Function in Chronic Ambulatory Heart Failure
试验速览
- 阶段
- 1 期
- 入组人数
- 16
- 主要终点
- Insulin concentration
研究概览
简要总结
Chronic, ambulatory heart failure patients will be given ketone ester dietary supplementation to determine therapeutic efficacy, metabolic adaptation, pharmacokinetics, associated cognitive changes, and safety within this patient cohort in order to establish preliminary data to later conduct a multi-center randomized clinical trial.
详细描述
We previously demonstrated a metabolic signature of increased ketone utilization-increased peripheral blood concentration of beta-hydroxybutyrate (BHB) and decreased myocardial concentration of BHB-and markedly decreased acylcarnitine levels in the failing human myocardium procured from lean, non-diabetic patients with advanced heart failure at the time of cardiac transplantation. In this working model of the metabolic adaptations in human heart failure where the mobilization of lipids and ketones are required for an energetically deficient, failing heart it is likely that the development of insulin resistance may be adaptive since increased insulin or insulin signaling would put a brake on the hydrolysis of lipids and hepatic ketogenesis. In parallel with the recent discovery that the failing human heart is reliant on ketones, investigators at Oxford and the NIH have identified a nutritional ketone supplement that reliably increases the serum concentration of BHB in humans.
We hypothesize that the induction of ketosis by exogenous administration of the nutritional ketone monoester will improve myocardial function in heart failure by increasing the energetic substrate available to the myocardium, in essence supporting the energetic deficit of the failing human heart which we have demonstrated to be reliant on ketone bodies for fuel given the limited myocardial oxidation of glucose.
This is a prospective, double-blinded, sequence control crossover trial enrolling NYHA Class II-III ambulatory heart failure patients to receive either ketone mono-ester drink versus placebo for two weeks. Following 2 weeks of therapy, echocardiogram and peak exercise test will be performed. There will be a 1-week "washout" period between phases. Subjects will serve as their own controls for this crossover study, as each will have both baseline testing and testing in the setting of mild nutritional ketosis.
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
- Triple (Participant, Care Provider, 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
- •Equal to or greater than 18 years of age
- •Diagnosis of heart failure and be classified as NYHA Class II or III either pre-enrollment or at the time of enrollment
- •Stable medical therapy for at least 1 month prior to enrollment
- •Taking appropriate daily cardiac medications as determined by the principal investigator, who is a heart failure specialist
排除标准
- •Atrial fibrillation
- •Inability to exercise on a supine bicycle.
- •Moderate or greater valvular disease.
- •Hemoglobin <10 g/dL.
- •Daily insulin use
- •Hypertrophic, infiltrative, or inflammatory cardiomyopathy.
- •Pericardial disease.
- •Current angina due to clinically significant obstructive epicardial coronary disease
- •Acute coronary syndrome or coronary intervention within the past 2 months.
- •Primary pulmonary arteriopathy.
- •Known clinically significant lung disease defined as:
- •Current use of supplemental oxygen, aside from nocturnal O2 for the treatment of obstructive sleep apnea
- •The use of steroids/antibiotics within the past 6 months for an acute exacerbation of obstructive pulmonary disease
- •Most proximal pulmonary function test indicating severe obstructive disease, defined as an FEV1<50% predicted in the context of an FEV1/FVC ratio of <0.70 ("Stage III COPD according to GOLD Criteria). (note: only to be used if the subject had PFTs prior to screening)
- •Most proximal 6-minute walk test during which the subject experienced arterial desaturation (<94%) without a subsequent normal study.
- •Ischemia on stress testing without subsequent revascularization or left heart catheterization showing non-obstructive epicardial coronary disease.
- •Significant liver disease impacting synthetic function or volume control.
- •Uncontrolled hypertension: BP >180/110 at baseline.
- •eGFR <30 mL/min/m2 or Cr >2.
- •Alcohol dependence
- •Chronic narcotic use that cannot be interrupted
- •Pregnant or lactating females
研究组 & 干预措施
Group A
These patients will receive ketone supplementation between visits 1 and 2 and will receive placebo drink between visits 2 and 3 (after the washout period).
干预措施: beta hydroxybutyrate (BHB) ester (Drug)
Group A
These patients will receive ketone supplementation between visits 1 and 2 and will receive placebo drink between visits 2 and 3 (after the washout period).
干预措施: Placebo (Drug)
Group B
These patients will receive ketone supplementation between visits 2 and 3 (after the washout period) and will receive placebo drink between visits 1 and 2
干预措施: beta hydroxybutyrate (BHB) ester (Drug)
Group B
These patients will receive ketone supplementation between visits 2 and 3 (after the washout period) and will receive placebo drink between visits 1 and 2
干预措施: Placebo (Drug)
结局指标
主要结局
Insulin concentration
时间窗: 1 Year
Insulin concentration in blood
Bicarbonate concentration
时间窗: 1 Year
Bicarbonate concentration in blood
Left ventricular ejection fraction (%)
时间窗: 1 Year
Left ventricular ejection fraction, measured by echocardiogram
Cardiac output (L/min)
时间窗: 1 Year
Cardiac output, measured by echocardiogram
BHB Concentration in blood
时间窗: 1 Year
Beta-hydroxybutyrate concentration in blood
Minutes at maximum exertion [Exercise Capacity]
时间窗: 1 Year
Minutes at maximum exertion
Left ventricular end diastolic diameter (LVEDD) (cm)
时间窗: 1 Year
LVEDD, measured by echocardiogram
次要结局
未报告次要终点