Clinical trial NCT04869124: Dapagliflozin on Volume Vascular Outcomes.
Official title: Effects of Dapagliflozin on Blood Volume Status and Vascular Function in Clinically Compensated Heart Failure Patients After an Acute Heart Failure Event.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Heart Failure，Congestive
Keywords: heart failure
congestive
hospitalization
blood volume
vascular function
Lead sponsor: University of Zurich
Sponsor class: OTHER
Collaborators: name: AstraZeneca
First posted: 2021-05-03
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A double-blind randomized placebo-controlled phase IV clinical trial.
Primary purpose: TREATMENT

Brief summary: The purpose of the DAPA-VOLVO trial is to investigate the effects of Dapagliflozin on top of recommended standard therapy on volume status and vascular function in clinically stable de novo or chronic heart failure patients after hospitalization because of an acute decompensated heart failure event.

Detailed description: Recent clinical trials found that Dapagliflozin can reduce the risk of cardiovascular events, hospitalization and death in heart failure (HF) patients with reduced left ventricular ejection fraction (HFrEF) in the presence of absence of diabetes. Additional trials are ongoing to investigate whether these results can be translated also to HF-patients with preserved ejection fraction (HFpEF). However, the underlying mechanisms leading to the improved clinical outcomes are not completely understood but the beneficial effects of Dapagliflozin on volume status and vascular function are discussed as potential key factors. This study is designed as a mechanistic study to investigate the impact of Dapagliflozin on volume status and vascular function in clinically stable de novo or chronic heart failure patients after hospitalization/ ambulatory care because of an acute decompensated heart failure (ADHF) event. After being informed about the study and potential risks all patients given written informed consent will be screened for the defined eligibility criteria and thereafter randomized in a double-blind manner (patients, investigators) 1:1 ratio to either receive the sodium-glucose co-transporter 2 inhibitor (SGLT2i) Dapagliflozin (10mg/day) or Placebo on top of recommended standard therapy for in total 12 weeks. The results of this study may provide new mechanistic insight into the beneficial effects of Dapagliflozin on volume regulation and vascular function and have great potential to contribute to change current clinical guidelines in the management of patients with heart failure.

Eligibility criteria: Inclusion criteria:

1. Male or female, age of 18 or older;
2. Patients with documented diagnosis of chronic or de novo heart failure (NYHA II-IV) and clinically stabilized (considered for hospital discharge) after hospitalization/ ambulatory care because of an acute decompensated (congestive) heart failure (ADHF) event;
3. eGFR ≥ 30 mL/min/1.73 m2 (CKD-EPI formula) at enrolment;
4. Provision of signed informed consent prior to any study specific procedure;

Exclusion criteria:

1. Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product;
2. Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor;
3. Participation in another study with investigational drug within the 30 days preceding and during the present study;
4. Type 1 diabetes mellitus;
5. Symptomatic hypotension or systolic blood pressure \<90 mmHg at 2 out of 3 measurements either at visit 1 or visit 2;
6. Coronary revascularization (percutaneous coronary intervention because of STEMI or coronary artery bypass grafting) or valvular repair/replacement within 12 weeks prior to enrolment or planned to undergo any of these operations after randomization;
7. Implantation of a CRT device within 12 weeks prior to enrolment or intent to implant a CRT device during 12 weeks of study observation period if indicated according to the actual guidelines \[11\];
8. Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization;
9. HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic obstructive cardiomyopathy or uncorrected primary valvular disease;
10. Symptomatic bradycardia or second or third degree heart block without a pacemaker;
11. Severe (eGFR \<20 mL/min/1.73 m2 by CKD-EPI), unstable or rapidly progressing renal disease;
12. Women who are pregnant or breast feeding;
13. Intention to become pregnant during the course of the study;
14. Known or suspected non-compliance, drug or alcohol abuse;
15. Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant;
16. Patients with severely restricted liver function;
17. Patients with recurrent mycotic genital infections;

Primary outcomes:
measure: Change in relative plasma volume status (PVS).
timeFrame: Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment.
Secondary outcomes:
measure: Change in blood volume (BV).
timeFrame: Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment.
measure: Change in red blood cell volume (RBCV).
timeFrame: Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment.
measure: Change in total hemoglobin mass (Hbmass).
timeFrame: Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment.
measure: Change in extracellular to total body water ratio (ECW/TBW).
timeFrame: Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment.
measure: Change in intracellular to total body water ratio (ICW/TBW).
timeFrame: Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment.
measure: Change in flicker-light induced retinal arteriolar dilatation (FIDa).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in flicker-light induced retinal venular dilatation (FIDv).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in retinal arterial to venous ratio (AVR).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in pulse wave velocity (PWV).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in flow-mediated dilatation (FMD) of the brachial artery.
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in glyceryl-trinitrate-(GTN) induced dilatation of the brachial artery.
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
Other outcomes:
measure: First episode of worsening of heart failure (WHF).
timeFrame: From baseline (0 weeks) to 12 weeks of treatment.
measure: Change in Kansas City cardiomyopathy questionnaire (KCCQ) score.
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in Pittsburgh sleep quality index (PSQI) score.
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in left ventricular ejection fraction (LVEF).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in pulmonary artery systolic pressure (PASP).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in peak oxygen uptake (VO2peak).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in ventilation to end-tidal carbon dioxide partial pressure (VE/ETCO2) slope.
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in stimulus response to cold pressor test (CPT) of muscle sympathetic nerve activity (MSNA) .
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
measure: Change in leg skin tissue sodium content (Skin-Na).
timeFrame: Change between baseline (0 weeks) and after 12 weeks of treatment.
Locations:
city: Zurich
country: Switzerland
facility: University Heart Center Zurich
Study officials:
affiliation: Cardiology, University Heart Center Zurich
name: Frank Ruschitzka, M.D.
role: PRINCIPAL_INVESTIGATOR
References: