Clinical trial NCT04782245: Acute Reno-Cardiac Action of Dapagliflozin In Advanced Heart Failure Patients on Heart Transplant Waiting List
Official title: Acute Reno-Cardiac Action of Dapagliflozin In Advanced Heart Failure Patients on Heart Transplant Waiting List: a Multicenter, Double-blind, Randomized Clinical Trial.
Study type: INTERVENTIONAL
Overall status: WITHDRAWN
Phase: PHASE2
Conditions: End-stage Heart Failure
Keywords: End-stage heart failure,
Cardio-renal syndrome
Dapagliflozin
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2021-03-04
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: In the DAPA-HF trial, the use of dapagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduced significantly the risk of worsening heart failure or death from cardiovascular causes compared to placebo among patients with heart failure (HF) and a reduced ejection fraction. This new drug offers a very potent and interesting therapeutic pathway since it reduces clinical congestion, it preserves glomerular renal function, does not appear to cause symptomatic clinical hypotension and improves symptoms and quality of life compared to placebo.

Advanced heart failure patients with reduced ejection fraction represent a small and severe subgroup of heart failure of patients with frequent worsening heart failure events and high rates of death. The effect of dapagliflozin in this subgroup of patients was not assessed in the DAPA-HF study. The therapeutic profile of SGLT2 inhibitors appears to be of high interest, since this group of patients has a poor tolerance to usual heart failure drugs, frequent worsening renal function and congestive symptoms persistence with poor quality of life scores.

Soluble urokinase-type plasminogen activator receptor (suPAR) is a signaling glycoprotein considered to be involved in the pathogenesis of kidney disease. It is associated with the risk of acute kidney injury in different clinical and experimental situation. It is also a new validated biomarker predictive of adverse clinical outcome in heart failure patients. This biomarker allows a better risk stratification in heart failure patients after adjustment for Nt-proBNP.

As a useful biomarker implicated in both heart failure and acute kidney injury, suPAR seems to be an interesting biomarker to assess cardio-renal benefits of dapagliflozin.

The aim of this study is to investigate if a treatment by dapagliflozin reduces significantly suPAR compared to placebo in a population of advanced heart failure patients, candidates to heart transplantation. The effect of dapagliflozin compared to placebo will also be assessed on other secondary heart failure outcomes in this patient population.


Eligibility criteria: Inclusion Criteria:

1. Patient has signed informed consent form
2. Age ≥ 18 years
3. NYHA class ≥3
4. LVEF ≤ 35%
5. On optimal medical management (OMM) based on current heart failure practice guidelines at maximal tolerated dose for at least 30 days
6. On waiting list for heart transplantation after multidisciplinary Heart Team decision, with anticipated access to heart transplant ≥ 6 months

Exclusion Criteria:

1. Priority patient on waiting list for heart transplantation
2. Etiology of heart failure due to or associated with uncorrected thyroid disease, obstructive cardiomyopathy, pericardial disease, amyloidosis or restrictive cardiomyopathy
3. Inotrope dependent, existence of ongoing mechanical circulatory support
4. Current acute decompensated HF or hospitalization due to decompensated HF \<30 days prior to the enrolment
5. History of any organ transplant or prior implantation of a ventricular assistance device (VAD) or similar device, or implantation expected after randomization
6. Presence of an active, uncontrolled infection
7. Any recent interventional procedure likely to improve symptoms and heart failure status (coronary revascularization, percutaneous mitral valve intervention, cardiac resynchronization therapy) \< 60 days
8. Glomerular filtration rate \< 30 ml/min/1.73 m2, according to CKD-EPI formula
9. Unstable or rapidly progressing renal disease
10. Patients with severe hepatic impairment (Child-Pugh class C)
11. Chronic treatment with dapagliflozin or other SGLT2 inhibitors
12. Patient with known history of severe drug intolerance to dapagliflozin or any excipients of the dapagliflozin (galactose, lactase)
13. Type 1 diabetes mellitus
14. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or extraction of study drug at investigators' discretion
15. Participation in another clinical interventional trial
16. Any condition other than heart failure that could limit survival to less than 24 months
17. Positive pregnancy test if of childbearing potential or refusal to use adequate contraception or women breast-feeding
18. Patients with any legal protection measure
19. Patients without any health coverage
20. Psychiatric disease/disorder, irreversible cognitive dysfunction or psychological issues that are likely to impair compliance

Primary outcomes:
measure: Levels of suPAR (ng/ml)
timeFrame: 6 months
Secondary outcomes:
measure: VO2 max assessment
timeFrame: 6 months
measure: cardiac output assessed by right heart catheterization
timeFrame: 6 months
measure: pulmonary capillary wedge pressure assessed by right heart catheterization
timeFrame: 6 months
measure: pulmonary artery systolic and mean pressure assessed by right heart catheterization
timeFrame: 6 months
measure: mean pressure assessed by right heart catheterization
timeFrame: 6 months
measure: right atrial pressure assessed by right heart catheterization
timeFrame: 6 months
measure: Left Ventricular Ejection Function assessed by echocardiography
timeFrame: 6 months
measure: Left ventricular end-diastolic diameter assessed by echocardiography
timeFrame: 6 months
measure: Left ventricular end systolic volume assessed by echocardiography
timeFrame: 6 months
measure: mitral regurgitation grade assessed by echocardiography
timeFrame: 6 months
measure: left atrial volume assessed by echocardiography
timeFrame: 6 months
measure: Nt-proBNP level
timeFrame: 6 months
measure: Creatinine level
timeFrame: 6 months
measure: Quality of life assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ)
timeFrame: 6 months
Other outcomes:
Locations:
city: Bron
country: France
facility: Hôpital Pneumologique et Cardiovasculaire Louis Pradel
Study officials:
affiliation: Hospices Civils de Lyon
name: Guillaume BAUDRY, Dr
role: PRINCIPAL_INVESTIGATOR
References: