Short-term Effects of Dapagliflozin on Peak VO2 in HFrEF (DAPA-VO2)

• ClinicalTrials.gov Identifier: NCT04197635
• Recruitment Status: Completed
• First Posted: December 13, 2019
• Last Update Posted: April 27, 2022
• Sponsor: Fundación para la Investigación del Hospital Clínico de Valencia
• Information provided by (Responsible Party): Julio Nuñez, Fundación para la Investigación del Hospital Clínico de Valencia

Tracking Information

• First Submitted Date: November 1, 2019
• First Posted Date: December 13, 2019
• Last Update Posted Date: April 27, 2022
• Actual Study Start Date: June 1, 2019
• Actual Primary Completion Date: August 14, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 11, 2019)

Functional capacity [ Time Frame: At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. ]

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).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 21, 2022)

• Left ventricular volumes [ Time Frame: At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.
• Left ventricular ejection fraction [ Time Frame: At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.
• Left atrial volume [ Time Frame: At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.
• Echocardiographic parameters of diastolic function [ Time Frame: At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.
• Evaluation of health related quality of life by Minnesota Living with Heart Failure Questionnaire (MLHFQ) [ Time Frame: At 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.
• Submáximal functional capacity assesment by 6 minutes walk test [ Time Frame: at 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.

Original Secondary Outcome Measures (submitted: December 11, 2019)

• Echocardiografy parameters [ Time Frame: At baseline, 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  The following parameters will be evaluated in one measure: a) diastolic diameter (measured in millimeters, mm) and systolic diameter (measured in millimeters, mm) of left ventricle; b) diastolic volume (measured in milliliters, mL) and systolic volume (measured in milliliters, mL) of left ventricle; c) left ventricle systolic function (measured by simpson method and expressed in percentage, %); d) longitudinal strain of left ventricle (the amount of deformation of left ventricle expressed in percentages, %); e) systolic pulmonary arterial pressure (pressure measured in millimeters of mercury, expressed in mmHg ); and f) left atrium 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. One determination each visit.
• Evaluation of quality of life helath related: Minnesota Living with Heart Failure Questionnaire (MLHFQ) [ Time Frame: At 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.
• Submáximal functional capacity assesment by 6 minutes walk test [ Time Frame: at 30 and 90 days after starting treatment with dapagliflozin or placebo. ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Short-term Effects of Dapagliflozin on Peak VO2 in HFrEF
• Official Title: Short-term Effects of Dapagliflozin on Peak VO2 in Patients With Heart Failure With Reduced Ejection Fraction
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description:

After providing informed consent, patients will be randomly assigned, with a remote, web-based computer-generated block randomization procedure in an allocation 1:1 ratio, to either receive dapagliflozin 10 mg per day or placebo (one tablet a day orally). This system will allow the maintenance of the randomization codes and the opening of them if necessary. Investigators and patients will be blinded to treatment allocations.

Knowing that no treatment crossings between both groups are expected, there is no need of planning washing periods.

Primary Purpose: Treatment

• Condition: Heart Failure With Reduced Ejection Fraction

Intervention

• Diagnostic Test: Maximal functional capacity by cardiopulmonary exercise testing
  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.
  Other Name: peak oxygen consumption
• Diagnostic Test: Echocardiography
  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.
  Other Name: Diastolic and Systolic function
• Behavioral: Evaluation of health related quality of life
  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.
  Other Name: Quality of life
• Diagnostic Test: 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 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.
  Other Name: 6 minutes walk test
• Other: Clinical evaluation
  Evaluation of signs and symptoms of heart failure

Study Arms

• Active Comparator: Dapagliflozin 10 mg
  After providing informed consent, patients will be randomly assigned to receive dapagliflozin 10 mg per day.
  Interventions:

  • 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
• Placebo Comparator: Placebo identical to dapagliflozin 10 mg
  After providing informed consent, patients will be randomly assigned to receive placebo (one tablet a day orally).
  Interventions:

  • 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

Publications *

• Nunez J, Palau P, Dominguez E, Mollar A, Nunez E, Ramon JM, Minana G, Santas E, Facila L, Gorriz JL, Sanchis J, Bayes-Genis A. Early effects of empagliflozin on exercise tolerance in patients with heart failure: A pilot study. Clin Cardiol. 2018 Apr;41(4):476-480. doi: 10.1002/clc.22899. Epub 2018 Apr 17.
• Palau P, Amiguet M, Dominguez E, Sastre C, Mollar A, Seller J, Garcia Pinilla JM, Larumbe A, Valle A, Gomez Doblas JJ, de la Espriella R, Minana G, Mezcua AR, Santas E, Bodi V, Sanchis J, Pascual-Figal D, Gorriz JL, Bayes-Genis A, Nunez J; DAPA-VO2 Investigators (see Appendix). Short-term effects of dapagliflozin on maximal functional capacity in heart failure with reduced ejection fraction (DAPA-VO2 ): a randomized clinical trial. Eur J Heart Fail. 2022 Oct;24(10):1816-1826. doi: 10.1002/ejhf.2560. Epub 2022 Jun 6.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 11, 2019): 74
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: April 19, 2022
• Actual Primary Completion Date: August 14, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT04197635
• Other Study ID Numbers: ESR-17-13447(DAPA-HF); 2018-002614-12 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Julio Nuñez, Fundación para la Investigación del Hospital Clínico de Valencia
• Original Responsible Party: Same as current
• Current Study Sponsor: Fundación para la Investigación del Hospital Clínico de Valencia
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Julio Nuñez Villota; Fundación para la Investigación del Hospital Clínico de Valencia

• PRS Account: Fundación para la Investigación del Hospital Clínico de Valencia
• Verification Date: April 2022