The Fontan Dapagliflozin Pilot Study (FonDap)

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

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.

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: This is a standard study design for a pilot study to investigate the use of an FDA approved drug, dapagliflozin in a new population, namely that of adult patients with a Fontan circulation. The dose and method of administration will be identical to those currently FDA approved. The Fontan circulation was selected as a study condition as it is characterized by a circulatory state that, at baseline, mimics heart failure (elevated central venous pressure, compromised cardiac output). Given this, the investigators believe the efficacy seen in the general heart failure population will be similarly enjoyed in the Fontan population. This study is designed to define more closely the physiologic changes which dapagliflozin create in the Fontan circulation, with the goal of providing data in support of a future larger study of the drug in this population with clinical endpoints. Study objectives: The primary objective is to determine the efficacy (as assessed by changes in peripheral venous pressure (PVP) measured by manometry) of Dapagliflozin in decreasing CVPs in Fontan patients. The secondary objective is to Investigate the impact of Dapagliflozin on CVP, total body water, exercise capacity, and patient-reported health status in Fontan patients. Sample size: Based on variability in PVP in Fontan patients as published by Tan et al(14) 18.4 + 5 millimeters of mercury (mmHg) with a drop of 4 mmHg is assumed to be of clinical significance, with alpha = 5% powered at 80% a total of 26 patients would be required. Allowing for ~10%, this yields a target recruitment of 29 patients. Statistical analyses: For the primary endpoint, the investigators will compare the change in PVP and total body water at baseline and at the end of the study period for differences using ANOVA for the primary endpoint. For the secondary endpoint, the investigators will compare change in total body water, maximum rate of oxygen your body is able to use during exercise, the minute ventilation/carbon dioxide production, oxygen pulse, and oxygen uptake efficiency slope assessed during cardiopulmonary exercise testing, patient reported health status outcome metric score as assessed by Adult Congenital Heart Disease Patient Reported Outcome (ACHD PRO) between baseline and at the end of the study period using ANOVA for the secondary endpoints.

To Investigate the impact of Dapagliflozin on patient-reported health status in Fontan patients The overall score ranges from 0 to 100, with 0 being worst and 100 being excellent.

Inclusion Criteria: 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. Exclusion Criteria: 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

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