The Fontan Dapagliflozin Pilot Study (FonDap)

November 28, 2023 updated by: Johns Hopkins University

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:

  1. Does Dapagliflozin decrease Fontan pressure?
  2. 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.

Study Overview

Status

Enrolling by invitation

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Interventional

Enrollment (Estimated)

29

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • California
      • Los Angeles, California, United States, 90095
        • Ronald Reagan UCLA Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

For inclusion in the study subjects should fulfil the following criteria based on local regulations:

  1. Provision of informed consent prior to any study specific procedures
  2. Female and/or male subjects aged ≥18 years
  3. Subjects with Fontan circulation (in the opinion of the PI)
  4. Subjects with clinical stability for 6 months preceding enrollment (in the opinion of the PI)
  5. Subjects with no planned changes in medical therapy in the 1 months after enrollment
  6. Subjects with no planned interventional procedures in the 1 months after enrollment
  7. Negative pregnancy test (urine or serum) for female subjects of childbearing potential.
  8. 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.
  9. 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.
  10. 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:

  1. Involvement in the planning and/or conduct of the study (applies to both Investigator staff and/or staff at the study site)
  2. Previous enrollment or randomisation in the present study
  3. Participation in another clinical study with an investigational product during the last 6 months
  4. Pregnancy or breast feeding or desire to become pregnant or breast feed during the study period
  5. Hospitalization within 6 months prior to enrollment
  6. Arrhythmia requiring change in therapy within 6 months prior to enrollment
  7. Interventional procedure of any kind (including cardioversion) within 6 months prior to enrollment
  8. Difficulty with upper extremity IV placement in the past
  9. Known obstruction anywhere within the venous circulation including at the level of the Glenn or Fontan anastomosis or within the pulmonary vasculature.
  10. Symptomatic hypotension or systemic systolic blood pressure of <95 millimeters of mercury (mmHg)
  11. 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
  12. Prior use of SGLT2 inhibitors with intolerable side effects
  13. Type 1 diabetes
  14. Inability to comply with the study protocol
  15. Lack of English-proficiency
  16. History of hypersensitivity to SGLT2 inhibitors
  17. Severe hepatic impairment defined as a Model for End-stage Liver Disease (MELD) XI score of >10

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Dapagliflozin
4-week, Daily Oral Use of Dapagliflozin 10mg Tablet in Adults with Fontan Circulation
Drug: Dapagliflozin 10mg Tab
Participants will take one Dapagliflozin 10mg tablet once per day for 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peripheral venous pressure (millimeters of mercury) at rest measured by manometry
Time Frame: 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
From baseline at week 0 and to follow up at week 4

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total body water (liter) as measured by bioelectrical impedance analyzer
Time Frame: From baseline at week 0 and to follow up at week 4
To Investigate the impact of Dapagliflozin on changing total body water
From baseline at week 0 and to follow up at week 4
Maximal oxygen uptake (milliliters/kilograms/minutes) as measured by cardiopulmonary exercise test
Time Frame: From baseline at week 0 and to follow up at week 4
To Investigate the impact of Dapagliflozin on maximal oxygen uptake
From baseline at week 0 and to follow up at week 4
oxygen pulse (milliliters oxygen per beat per kilogram) as measured by cardiopulmonary exercise test
Time Frame: From baseline at week 0 and to follow up at week 4
To Investigate the impact of Dapagliflozin on oxygen pulse
From baseline at week 0 and to follow up at week 4
ventilator efficiency slope (no unit) as measured by cardiopulmonary exercise test
Time Frame: From baseline at week 0 and to follow up at week 4
To Investigate the impact of Dapagliflozin on ventilator efficiency slope
From baseline at week 0 and to follow up at week 4
oxygen uptake efficiency slope (no unit) as measured by cardiopulmonary exercise test
Time Frame: From baseline at week 0 and to follow up at week 4
To Investigate the impact of Dapagliflozin on oxygen uptake efficiency slope
From baseline at week 0 and to follow up at week 4
Peripheral venous pressure (mmHg) at exercise measured by manometry
Time Frame: 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
From baseline at week 0 and to follow up at week 4
Patient reported health status as measure by the ACHD PRO metric score
Time Frame: From baseline at week 0 and to follow up at week 4
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.
From baseline at week 0 and to follow up at week 4

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Johns Hopkins University

Collaborators

University of California, Los Angeles
AstraZeneca
Brett Boyer Foundation

Investigators

  • Principal Investigator: Ari Cedars, Johns Hopkins University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 8, 2023

Primary Completion (Estimated)

November 1, 2024

Study Completion (Estimated)

June 1, 2025

Study Registration Dates

First Submitted

February 14, 2023

First Submitted That Met QC Criteria

February 14, 2023

First Posted (Actual)

February 23, 2023

Study Record Updates

Last Update Posted (Actual)

November 30, 2023

Last Update Submitted That Met QC Criteria

November 28, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB00254477
  • ESR-21-21445 (Other Identifier: AstraZeneca)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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