ERTU-SODIUM: Double-blind, Prospective, Randomized, Crossover, Placebo-control Study on the Effects of the SGLT2 Inhibitor Ertugliflozin on the Regulation of Interstitial Volume, Plasma Volume, Subcutaneous Sodium Storage, and the Functionality of the Subcutaneous Glycosaminoglycan Network in Patients With Heart Failure With Reduced Ejection Fraction (HFrEF)
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 1
- 主要终点
- Change in the skin water content
研究概览
简要总结
The overall hypothesis is that treatment with the SGLT2 inhibitor Ertugliflozin induces a differential regulation in interstitial fluid vs plasma volume, with more reduction of the volume from the interstitial fluid than from the circulating plasma volume, which results in Ertugliflozin inducing more potent congestion relief with minimal impact on blood volume and organ perfusion. Ertugliflozin reduces the levels of sodium and water from the skin and the interstitial tissue (which improves tissue congestion).
详细描述
The glucosaminoglycan (GAG) network in the subcutaneous interstitium can non-osmotically bind large amounts of sodium. Therefore, the GAG network creates a hypertonic sodium concentration without fluid accumulation. This means that the subcutaneous GAG act as a third compartment that is able to non-osmotically store sodium without inducing congestion, thus serving as buffer in the case of sodium overload.
The researchers hypothesize that the SGLT2 inhibitor Ertugliflozin enhances the functionality of the subcutaneous GAG network. The hypothesis is that Ertugliflozin-induced GAG functionality induces more potent congestion relief (reduction in sodium and water content in the interstitial tissue) with minimal impact on blood volume and organ perfusion.
The research team will perform a randomized clinical trial with a cross-over design. Patients with heart failure with reduced ejection fraction (HFrEF) will be randomized to the SGLT2 inhibitor Ertuglifozin or to placebo. Skin punch biopsy will be performed before treatment and after treatment (one month) to evaluate skin content of water and sodium. At each time point, an oral salt challenge will be performed to investigate the functionality of the GAG network, and whether Ertugliflozin mitigates the degree of tissue and vascular congestion after this oral salt challenge as compared with placebo.
The overall hypothesis is that treatment with the SGLT2 inhibitor Ertugliflozin induces a differential regulation in interstitial fluid vs plasma volume, with more reduction of the volume from the interstitial fluid than from the circulating plasma volume, which results in Ertugliflozin inducing more potent congestion relief with minimal impact on blood volume and organ perfusion. Ertugliflozin reduces the levels of sodium and water from the skin and the interstitial tissue (which improves tissue congestion). This overarching hypothesis causes:
- in the baseline situation, chronic treatment with Ertugliflozin:
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
- •age >18 years;
- •males and females (females of child bearing potential must be using adequate contraceptive precautions)
- •diagnosis of heart failure (New York Heart Association [NYHA] functional class II to III);
- •Left ventricular ejection fraction <40%;
- •stable symptoms and medical therapy within the last month.
- •Informed consent has to be given in written form
排除标准
- •taking SGLT2i in the last month
- •acute coronary syndrome or cardiac surgery within the last month;
- •estimated glomerular filtration rate <20 ml/kg/min;
- •use of continuous parental inotropic agents;
- •systolic blood pressure <90 mm Hg;
- •LVAD implantation or cardiac transplantation
- •pregnant or lactating women; and
- •any other medical condition considered unappropriated by a study physician
研究组 & 干预措施
Ertugliflozin then Placebo
Treatment with Ertugliflozin for one month, washout period for one month, and then with Placebo for one month
干预措施: Ertugliflozin (Drug)
Placebo
Treatment with matching placebo for one month, washout period for one month, and then Ertugliflozin for one month
干预措施: Placebo (Drug)
Ertugliflozin then Placebo
Treatment with Ertugliflozin for one month, washout period for one month, and then with Placebo for one month
干预措施: Placebo (Drug)
Placebo
Treatment with matching placebo for one month, washout period for one month, and then Ertugliflozin for one month
干预措施: Ertugliflozin (Drug)
结局指标
主要结局
Change in the skin water content
时间窗: Baseline and One month
Skin water content is measured as total (wet) weight - dry weight, determined after desiccation at 90°C for 24 hours to stable weight
次要结局
- Change in skin sodium content(Baseline and One month)
- Change in the number of pulmonary Kerley's B-lines(Baseline and One month)
- Change in vascular congestion(Baseline and One month)
- Change in plasma concentrations of catecholamines(Baseline and One month)
- Change in interstitial Fluid(Baseline and One month)
- Change in left ventricular filling pressures(Baseline and One month)
- Change in pulmonary fluid(Baseline and One month)
- Change in the plasma volume(Baseline and One month)
- Change in plasma concentrations of aldosterone(Baseline and One month)
- Change in plasma concentrations of plasma renin activity(Baseline and One month)
研究者
Carlos Santos-Gallego
Principal Investigator
Icahn School of Medicine at Mount Sinai