An Open-Label, Non-randomized, Multi-center Pilot Study to Evaluate the Safety and Efficacy of 4-week, Daily Oral Use of Dapagliflozin 10mg Tablet in Adults With a Fontan Circulation
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 发起方
- 入组人数
- 29
- 试验地点
- 1
- 主要终点
- Peripheral venous pressure (millimeters of mercury) at rest measured by manometry
研究概览
简要总结
The goal of this clinical trial is to study if an investigational study drug called Dapagliflozin could prevent heart failure from getting worse in adults with Fontan circulation. The main questions it aims to answer are:
- Does Dapagliflozin decrease Fontan pressure?
- Does Dapagliflozin improve exercise capacity and heart failure symptoms?
Participants will have 4 study visits and 2 follow-up phone calls. The total duration of participation in the study will be up to 5 weeks from the time of screening to the completion of the final safety evaluation. Study procedures include the collection of study-related health information and blood samples, physical examination, exercise testing, total body water assessment, blood laboratory testing, health status survey, safety evaluation phone calls, and home blood pressure monitoring.
详细描述
Background:
The Fontan palliation is subject to progressive physiologic deterioration over time due to chronic elevation in central venous pressures (CVP), compromised cardiac output, and chronic lymphatic congestion and dysfunction. As a result, in adulthood Fontan patients have high rates of hospitalization of ~30% per year and nearly universally succumb to heart failure in the patients' 40s without heart transplant. Currently, there are no medical therapies of proven benefit in prolonging the lifespan of the Fontan palliation or in improving outcomes in Fontan patients.
Rationale:
Given the unusual physiologic stress established by the Fontan palliation, there is reason to believe that sodium-glucose cotransporter-2 (SGLT2) inhibitors might be uniquely beneficial in this small but growing patient population with an orphan disease process. SGLT2 inhibitors may be beneficial for the following reasons. a) Fontan patients are set up for cardiorenal syndrome. The severe end-organ congestion and increased total body water which characterizes Fontan failure are due to compromised cardiac output and chronically and uniquely elevated CVP. SGLT2 inhibitors appear to be uniquely beneficial in this setting based on findings from Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA) trial, CANagliflozin cardioVascular Assessment Study (CANVAS) and Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients. Moreover, Griffin and Rao et al recently demonstrated the benefits of empagliflozin on renal sodium handling resulting in decreases in both plasma volume (which would be anticipated to decrease CVP) and total body water (which would be expected to decrease end-organ parenchymal edema and dysfunction). Based on similar mechanisms of action and similarly beneficial effects of dapagliflozin, the investigators anticipate that benefits will be b) Fontan patients who are overweight have a worse prognosis and SGLT2 inhibitors may facilitate modest weight loss. c) Activation of the Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in the progression of Fontan circulatory deterioration, although clinical trials to investigate this hypothesis have not yielded positive results. In case the RAAS hypothesis is true, SGLT2 inhibitors should decrease renin tone by increasing sodium delivery to the macula densa. d) Fontan physiology frequently deteriorates as a result of progressively worsening ventricular systolic and diastolic function. Activation of inflammatory pathways and cardiac myocyte calcium overload have been implicated in this process in non-Fontan related heart failure, and likely play a role as well in Fontan-related heart failure. Putative anti-inflammatory effects and inhibition of the sodium/hydrogen transporter mediated by SGLT2 inhibition may therefore be of benefit in preventing progressive heart failure in Fontan palliated patients.
Study design rationale:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
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
- •For inclusion in the study subjects should fulfil the following criteria based on local regulations:
- •Provision of informed consent prior to any study specific procedures
- •Female and/or male subjects aged ≥18 years
- •Subjects with Fontan circulation (in the opinion of the PI)
- •Subjects with clinical stability for 6 months preceding enrollment (in the opinion of the PI)
- •Subjects with no planned changes in medical therapy in the 1 months after enrollment
- •Subjects with no planned interventional procedures in the 1 months after enrollment
- •Negative pregnancy test (urine or serum) for female subjects of childbearing potential.
- •Female subjects must be 1 year post-menopausal, surgically sterile, or using an acceptable method of contraception (an acceptable method of contraception is defined as a barrier method in conjunction with a spermicide) for the duration of the study (from the time the subjects sign consent) and for 3 months after the last dose of Drug A/matching placebo to prevent pregnancy. In addition, oral contraceptives, approved contraceptive implant, long-term injectable contraception, intrauterine device, or tubal ligation are allowed. Oral contraception alone is not acceptable; additional barrier methods in conjunction with spermicide must be used.
- •Male subjects must be surgically sterile or using an acceptable method of contraception (defined as barrier methods in conjunction with spermicides) for the duration of the study (from the time the subjects sign consent) and for 3 months after the last dose of Drug A/matching placebo to prevent pregnancy in a partner.
- •Subjects who are blood donors should not donate blood during the study and for 3 months following the subject's last dose of dapagliflozin.
排除标准
- •Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
- •Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
- •Previous enrollment or randomisation in the present study
- •Participation in another clinical study with an investigational product during the last 6 months
- •Pregnancy or breast feeding or desire to become pregnant or breast feed during the study period
- •Hospitalization within 6 months prior to enrollment
- •Arrhythmia requiring change in therapy within 6 months prior to enrollment
- •Interventional procedure of any kind (including cardioversion) within 6 months prior to enrollment
- •Difficulty with upper extremity IV placement in the past
- •Known obstruction anywhere within the venous circulation including at the level of the Glenn or Fontan anastomosis or within the pulmonary vasculature.
- •Symptomatic hypotension or systemic systolic blood pressure of <95 millimeters of mercury (mmHg)
- •Estimated glomerular filtration rate of <25ml per minute per 1.73m2 body surface area as assessed by Modification of Diet in Renal Disease (MDRD) calculation
- •Prior use of SGLT2 inhibitors with intolerable side effects
- •Type 1 diabetes
- •Inability to comply with the study protocol
- •Lack of English-proficiency
- •History of hypersensitivity to SGLT2 inhibitors
- •Severe hepatic impairment defined as a Model for End-stage Liver Disease (MELD) XI score of >10
研究组 & 干预措施
Dapagliflozin
4-week, Daily Oral Use of Dapagliflozin 10mg Tablet in Adults with Fontan Circulation
干预措施: Dapagliflozin 10mg Tab (Drug)
结局指标
主要结局
Peripheral venous pressure (millimeters of mercury) at rest measured by manometry
时间窗: From baseline at week 0 and to follow up at week 4
To investigate the impact of Dapagliflozin on changing central venous pressure in Fontan patients
次要结局
- oxygen pulse (milliliters oxygen per beat per kilogram) as measured by cardiopulmonary exercise test(From baseline at week 0 and to follow up at week 4)
- oxygen uptake efficiency slope (no unit) as measured by cardiopulmonary exercise test(From baseline at week 0 and to follow up at week 4)
- Total body water (liter) as measured by bioelectrical impedance analyzer(From baseline at week 0 and to follow up at week 4)
- Maximal oxygen uptake (milliliters/kilograms/minutes) as measured by cardiopulmonary exercise test(From baseline at week 0 and to follow up at week 4)
- Peripheral venous pressure (mmHg) at exercise measured by manometry(From baseline at week 0 and to follow up at week 4)
- ventilator efficiency slope (no unit) as measured by cardiopulmonary exercise test(From baseline at week 0 and to follow up at week 4)
- Patient reported health status as measure by the ACHD PRO metric score(From baseline at week 0 and to follow up at week 4)