Short-term Effects of Dapagliflozin on Peak VO2 in HFrEF

Study Overview
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Brief Summary
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This study will be a double-blind multicenter randomized study (1:1) to evaluate the effect of dapagliflozin 10 mg per day or placebo on short-term functional capacity evaluated through changes in peak oxygen consumption.

Detailed Description
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This study will be a double-blind multicenter randomized study (1:1) to evaluate the effect of dapagliflozin 10 mg per day or placebo on short-term functional capacity evaluated through changes in peak oxygen consumption. This trial will include patients with stable symptomatic heart failure with reduced ejection fraction (HFrEF). Efficacy endpoints will be evaluated at 3 time points: 1) baseline (before dapagliflozin/placebo administration), 2) 30 days after randomization, and, 3) 90 days after randomization. An intermediate clinical visit will be performed one week after study initiation. Pre-and post-treatment evaluations (at baseline, 30 and 90 days) will include clinical assessment, cardiopulmonary exercise stress test, echocardiography, 6-minute walk test (6MWT), and quality of life indicators (Minnesota Living with Heart Failure Questionnaire -MLHFQ). The investigators postulate that dapagliflozin 10 mg/day improves short-term functional capacity of patients with symptomatic HFrEF through multifactorial mechanisms, such as diuretic effect and improvement in myocardial energetic efficiency.

Official Title
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Short-term Effects of Dapagliflozin on Peak VO2 in Patients With Heart Failure With Reduced Ejection Fraction

Conditions
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Heart Failure With Reduced Ejection Fraction

Intervention / Treatment
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* Diagnostic Test: Maximal functional capacity by cardiopulmonary exercise testing
* Diagnostic Test: Echocardiography
* Behavioral: Evaluation of health related quality of life
* Diagnostic Test: Submáximal functional capacity assesment by 6 minutes walk test
* Other: Clinical evaluation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant or his legal representative is willing and able to give informed consent for participation in the study. Male or female, aged ≥18 years. Established documented diagnosis of symptomatic HF (NYHA functional class II-III), which has been present for at least 2 months. LVEF ≤40% documented in the last 3 months by echocardiography or cardiac magnetic resonance. NT-proBNP ≥600 pg/ml. Patients should receive background standard of care for HFrEF at judgment of the investigator. Estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m2 (DMRD formula) at enrolment. Exclusion Criteria: Inability to perform a valid (respiratory exchange ratio -RER- ≥1.05) baseline cardiopulmonary exercise test (CPET) Patients receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment, or previous intolerance of an SGLT2 inhibitor Type 1 diabetes Symptomatic hypotension or systolic blood pressure <95 mmHg Current acute decompensated HF or hospitalization due to decompensated HF <4 weeks prior to enrolment Myocardial infarction, unstable angina, stroke, or transient ischemic attack within 12 weeks prior to enrolment Coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting) or cardiac valve repair/replacement within 12 weeks prior to enrolment, or planned to undergo any of these operations after randomization Implantation of a cardiac resynchronization therapy (CRT) device within 12 weeks prior to enrolment or intent to implant a CRT device 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 severe primary cardiac valve disease Symptomatic bradycardia or second or third-degree heart block without a pacemaker Severe renal dysfunction (eGFR<30 ml/min/1.73m2) or prior admission for acute renal failure in the last 4 weeks. Pregnant or lactating women Woman of childbearing age, unless they are using highly effective contraceptive methods. Patients with severe hepatic impairment (Child-Pugh class C).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: This study will be a double-blind multicenter randomized study (1:1) to evaluate the effect of dapagliflozin 10 mg per day or placebo on short-term functional capacity evaluated through changes in peak oxygen consumption The patients will be randomized to receive dapagliflozin or placebo. Once the inclusion criteria are fulfilled and the informed consent signed, patients will be randomized, and efficacy endpoints will be evaluated at 3 time points: 1) baseline (before dapagliflozin/placebo administration), 2) 30 days after randomization, and, 3) 90 days after randomization.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin 10 mg<br>After providing informed consent, patients will be randomly assigned to receive dapagliflozin 10 mg per day. | Diagnostic Test: Maximal functional capacity by cardiopulmonary exercise testing<br>* It will be done with cycle ergometer (CORTEX Metamax3B), starting with 10W of power and increasing 10W every minute. During the test, heart rate, rhythm and blood pressure will be monitored. Gas exchange data shall be evaluated every 10 seconds and the peak oxygen consumption (peak VO2) shall be considered the maximum value obtained during the last 20 seconds of exercise. The main parameters to be determined are: maximum functional capacity, peak VO2, slope of the VE/VCO2 ratio, and chronotropic incompetence variables. It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation.<br>* Other names: peak oxygen consumption;Diagnostic Test: Echocardiography<br>* The following parameters will be evaluated: a)left ventricular volumes; b) left ventricular systolic function; and c)left atrial volume and E/e' ratio. It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation.<br>* Other names: Diastolic and Systolic function;Behavioral: Evaluation of health related quality of life<br>* Assessment of the quality of life through the Minnesota Living with Heart Failure Questionnaire (MLHFQ), Spanish version. It will be completed at baseline and at 30 and 90 days after treatment initiation. The score of the questionnaire is 0 to 105 points.<br>* Other names: Quality of life;Diagnostic Test: Submáximal functional capacity assesment by 6 minutes walk test<br>* It will be performed in an area equipped for cardiopulmonary resuscitation. Subjects will be asked not to perform a vigorous physical exercise in the previous 2 hours. They will be allowed to have a light meal before the test. Before the test, the vital signs will be determined in a seated position after a rest of 10 minutes. Subjects will be instructed to walk at their own pace to cover as much distance as possible in 6 minutes. It will be performed by a trained nurse blind to study treatment at baseline and at 30 and 90 days after treatment initiation.<br>* Other names: 6 minutes walk test;Other: Clinical evaluation<br>* Evaluation of signs and symptoms of heart failure<br>|
| Placebo Comparator: Placebo identical to dapagliflozin 10 mg<br>After providing informed consent, patients will be randomly assigned to receive placebo (one tablet a day orally). | Diagnostic Test: Maximal functional capacity by cardiopulmonary exercise testing<br>* It will be done with cycle ergometer (CORTEX Metamax3B), starting with 10W of power and increasing 10W every minute. During the test, heart rate, rhythm and blood pressure will be monitored. Gas exchange data shall be evaluated every 10 seconds and the peak oxygen consumption (peak VO2) shall be considered the maximum value obtained during the last 20 seconds of exercise. The main parameters to be determined are: maximum functional capacity, peak VO2, slope of the VE/VCO2 ratio, and chronotropic incompetence variables. It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation.<br>* Other names: peak oxygen consumption;Diagnostic Test: Echocardiography<br>* The following parameters will be evaluated: a)left ventricular volumes; b) left ventricular systolic function; and c)left atrial volume and E/e' ratio. It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation.<br>* Other names: Diastolic and Systolic function;Behavioral: Evaluation of health related quality of life<br>* Assessment of the quality of life through the Minnesota Living with Heart Failure Questionnaire (MLHFQ), Spanish version. It will be completed at baseline and at 30 and 90 days after treatment initiation. The score of the questionnaire is 0 to 105 points.<br>* Other names: Quality of life;Diagnostic Test: Submáximal functional capacity assesment by 6 minutes walk test<br>* It will be performed in an area equipped for cardiopulmonary resuscitation. Subjects will be asked not to perform a vigorous physical exercise in the previous 2 hours. They will be allowed to have a light meal before the test. Before the test, the vital signs will be determined in a seated position after a rest of 10 minutes. Subjects will be instructed to walk at their own pace to cover as much distance as possible in 6 minutes. It will be performed by a trained nurse blind to study treatment at baseline and at 30 and 90 days after treatment initiation.<br>* Other names: 6 minutes walk test;Other: Clinical evaluation<br>* Evaluation of signs and symptoms of heart failure<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Functional capacity | Changes in peak oxygen consumption (VO2) at baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. VO2 is only one measure and is expressed as milliliters of oxygen per kilogram of body weight per minute (oxygen in milliliters, weight in kilograms, and time in minutes and expressed in ml/kg/min). | At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Left ventricular volumes | The following parameters will be evaluated: Left ventricular diastolic volume (measured in milliliters, mL) and systolic volume (measured in milliliters, mL) It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation. | At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. | 
| Left ventricular ejection fraction | The following parameter will be evaluated: Left ventricular ejection fraction (measured by simpson method and expressed in percentage, %). It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation. | At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. | 
| Left atrial volume | The following parameter will be evaluated: Determination of 2-dimensional derived left atrial volume (volumen measured in milliliters, mL) indexed for body surface area (body surface area expressed in square meters -m2-) and expressed in mL/m2. It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation. | At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. | 
| Echocardiographic parameters of diastolic function | The following parameter of diastolic function will be evaluated: - E/e' ratio: value of E velocity-expressed in cm/s- / averaged value of septal and lateral side e´velocity - expressed in cm/s- of the mitral annulus by pulsed tissue Doppler. It will be performed by a trained cardiologist blind to study treatment at baseline and at 30 and 90 days after treatment initiation. | At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. | 
| Evaluation of health related quality of life by Minnesota Living with Heart Failure Questionnaire (MLHFQ) | Assessment of the quality of life through the Minnesota Living with Heart Failure Questionnaire (MLHFQ). It will be completed at baseline and at 30 and 90 days after treatment initiation. The score values are ranged between 0 to 105 points. | At 30 and 90 days after starting treatment with dapagliflozin or placebo. | 
| Submáximal functional capacity assesment by 6 minutes walk test | It will be performed in an area equipped for cardiopulmonary resuscitation. Subjects will be asked not to perform vigorous physical exercise in the previous 2 hours. They will be allowed to have a light meal before the test. Before the test, the vital signs will be determined in a seated position after a rest of 10 minutes. Subjects will be instructed to walk at their own pace to cover as much distance (measured in meters) as possible in 6 minutes. It will be performed by a trained nurse blind to study treatment at baseline and at 30 and 90 days after treatment initiation. | at 30 and 90 days after starting treatment with dapagliflozin or placebo. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heart Failure with Reduced Ejection Fraction, Functional Capacity, Quality of life