Dapagliflozin on Volume Vascular Outcomes.

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Dapagliflozin on Blood Volume Status and Vascular Function in Clinically Compensated Heart Failure Patients After an Acute Heart Failure Event.

Conditions
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Heart Failure，Congestive

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female, age of 18 or older; 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; eGFR ≥ 30 mL/min/1.73 m2 (CKD-EPI formula) at enrolment; Provision of signed informed consent prior to any study specific procedure; Exclusion criteria: Contraindications to the class of drugs under study, e.g. known hypersensitivity or allergy to class of drugs or the investigational product; Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor; Participation in another study with investigational drug within the 30 days preceding and during the present study; Type 1 diabetes mellitus; Symptomatic hypotension or systolic blood pressure <90 mmHg at 2 out of 3 measurements either at visit 1 or visit 2; 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; 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]; Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization; HF due to restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, hypertrophic obstructive cardiomyopathy or uncorrected primary valvular disease; Symptomatic bradycardia or second or third degree heart block without a pacemaker; Severe (eGFR <20 mL/min/1.73 m2 by CKD-EPI), unstable or rapidly progressing renal disease; Women who are pregnant or breast feeding; Intention to become pregnant during the course of the study; Known or suspected non-compliance, drug or alcohol abuse; Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. of the participant; Patients with severely restricted liver function; Patients with recurrent mycotic genital infections;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A double-blind randomized placebo-controlled phase IV clinical trial.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin<br>Dapagliflozin tablet (10mg/tablet), orally, once daily for 12 weeks. | Drug: Dapagliflozin<br>* Dapagliflozin propanediol (FORXIGA) tablet: 10 mg once daily p.o. on top of recommended standard therapy, duration of administration: 12 weeks.<br>* Other names: Forxiga;|
| Placebo Comparator: Placebo<br>Placebo tablet, matching Dapglilflozin, orally, once daily for 12 weeks. | Drug: Placebo<br>* Placebo tablet, matching Dapagliflozin, once daily p.o. on top of recommended standard therapy, duration of administration: 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in relative plasma volume status (PVS). | Change in relative plasma volume status (PVS) from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The plasma volume (PV) will be measured via optimized CO-rebreathing technique. | Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in blood volume (BV). | Change in BV from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The BV will be measured via optimized CO-rebreathing technique. | Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment. | 
| Change in red blood cell volume (RBCV). | Change in RBCV from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The RBCV will be measured via optimized CO-rebreathing technique. | Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment. | 
| Change in total hemoglobin mass (Hbmass). | Change in Hbmass from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The Hbmass will be measured via optimized CO-rebreathing technique. | Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment. | 
| Change in extracellular to total body water ratio (ECW/TBW). | Change in ECW/TBW ratio from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The ECW/TBW ratio will be measured via direct segmental multi-frequency bioelectrical impedance analaysis (DSM-BIA). | Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment. | 
| Change in intracellular to total body water ratio (ICW/TBW). | Change in ICW/TBW ratio from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The ICW/TBW ratio will be measured via direct segmental multi-frequency bioelectrical impedance analaysis (DSM-BIA). | Change between baseline (0 weeks) and after 2, 6 and 12 weeks of treatment. | 
| Change in flicker-light induced retinal arteriolar dilatation (FIDa). | Change in FIDa from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The FIDa will be measured via dynamic retinal vessel analysis (DVA). | Change between baseline (0 weeks) and after 12 weeks of treatment. | 
| Change in flicker-light induced retinal venular dilatation (FIDv). | Change in FIDv from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The FIDv will be measured via dynamic retinal vessel analysis (DVA). | Change between baseline (0 weeks) and after 12 weeks of treatment. | 
| Change in retinal arterial to venous ratio (AVR). | Change in AVR from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The AVR will be measured via static retinal vessel analysis (SVA). | Change between baseline (0 weeks) and after 12 weeks of treatment. | 
| Change in pulse wave velocity (PWV). | Change in PWV from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The PWV as measure of arterial stiffness (AS) will be assessed via planar tonometry pulse wave analysis (PWA). | Change between baseline (0 weeks) and after 12 weeks of treatment. | 
| Change in flow-mediated dilatation (FMD) of the brachial artery. | Change in FMD from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The FMD as measure of endothelial function will be assessed via arm sonography and short-term cuff-mediated arm ischemia. | Change between baseline (0 weeks) and after 12 weeks of treatment. | 
| Change in glyceryl-trinitrate-(GTN) induced dilatation of the brachial artery. | Change in GTN-induced dilatation of the brachial artery from baseline to 12 weeks of dapagliflozin treatment in comparison to placebo will be assessed. The GTN-induced dilatation of the brachial artery will be measured via arm sonography and sublingual GTN-puff. | Change between baseline (0 weeks) and after 12 weeks of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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heart failure, congestive, hospitalization, blood volume, vascular function