Heart Failure With Reduced Ejection Fraction (HFrEF)
Conditions
Brief summary
International, Multicentre, Parallel-group, Randomised, Double-blind, Placebo-controlled, Phase III Study Evaluating the effect of Dapagliflozin on Exercise Capacity in Heart Failure Patients with Reduced Ejection Fraction (HFrEF)
Interventions
DRUGDapagliflozin
Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.
OTHERPlacebo
Tablets administered orally once daily. Treatment start within 24h after randomisation for 16 weeks.
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 150 Years
Healthy volunteers
No
Inclusion criteria
* Provision of signed informed consent prior to any study specific procedures * Male or female, aged ≥18 years * Documented diagnosis of symptomatic HFrEF (NYHA functional class II-IV), which has been present for at least 8 weeks * LVEF≤40% * Elevated NT-proBNP levels * Patients should receive background standard of care as described below: All HFrEF patients should be treated according to locally recognised guidelines on standard of care treatment with both drugs and devices, as appropriate. Guideline-recommended medications should be used at recommended doses unless contraindicated or not tolerated. Therapy should have been individually optimised and stable for ≥4 weeks (this does not apply to diuretics) before visit 1 and include (unless contraindicated or not tolerated): * an ACE inhibitor, or ARB or sacubitril/valsartan and * a beta-blocker and * if considered appropriate by the patient's treating physician; a mineral corticoid receptor antagonist * 6MWD≥100 metres and ≤425 metres at enrolment and randomization.
Exclusion criteria
* Presence of any condition that precludes exercise testing * Participation in a structured exercise training programme in the 1 month prior to screening or planned to start during the trial * Receiving therapy with an SGLT2 inhibitor within 4 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor * Type 1 diabetes mellitus * eGFR \<25 mL/min/1.73 m2 (CKD-EPI formula) at enrolment, unstable or rapidly progressing renal disease at time of randomisation * Systolic BP \<95 mmHg on 2 consecutive measurements * Systolic BP ≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications or ≥180 mmHg irrespective of treatments, on 2 consecutive measurements * Current acute decompensated HF or hospitalisation due to decompensated HF \<4 weeks prior to enrolment * MI, unstable angina, coronary revascularization ablation of atrial flutter/fibrillation, valve repair/replacement, implantation of a cardiac resynchronization therapy device within 12 weeks prior to enrolment or planned to undergo any of these operations after randomization. * Stroke or transient ischemic attack within 12 weeks prior to enrolment. * Primary pulmonary hypertension, chronic pulmonary embolism, severe pulmonary disease including COPD. * Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after randomization * HF due to infiltrative cardiomyopathy, active myocarditis, constrictive pericarditis, cardiac tamponade, known genetic hypertrophic cardiomyopathy or obstructive hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia, or uncorrected primary valvular disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 16 (Higher Scores Represent Less HF Symptom Frequency and Burden). | At baseline and at week 16 or death before week 16 | Change from baseline in KCCQ-TSS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-TSS incorporates the symptom frequency (4 items) and symptom burden (3 items) domains into a single summary score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have KCCQ-TSS values. |
| Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at Week 16 (Higher Scores Represent Less Physical Limitation Due to HF) | At baseline and at week 16 or death before week 16 | Change from baseline in KCCQ-PLS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-PLS incorporates the 6 physical limitation items into a single score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have KCCQ-PLS values. |
| Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity). | At baseline and at week 16 or death prior to week 16 | Change from baseline in 6-minute walk distance (6MWD) (exercise capacity) at week 16 was defined as the distance walked in 6 minutes at week 16 minus the baseline value. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have 6MWD values. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at the End of the Study in the Total Time Spent in Light to Vigorous Physical Activity, as Assessed Using a Wearable Activity Monitor (Accelerometer). | At baseline and at end of study or death before week 16. | Change from baseline at the end of the study in total time spent in light to vigorous physical activity (LVPA), as assessed using a wearable activity monitor, was defined as the total time \[per day\] spent in LVPA at the end of the study minus the baseline value. Baseline is the 7 day period starting on the day of enrolment and ending before randomization. End of study is defined as the period starting on the day of week 14 and prior to the week 16 visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. |
Countries
Brazil, Canada, Denmark, Japan, Slovakia, South Africa, South Korea, Sweden, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapa 10mg Dapagliflozin 10 mg, given once daily per oral use. | 156 |
| Placebo Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use. | 157 |
| Total | 313 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Dapa 10mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 68.4 Years STANDARD_DEVIATION 9.84 | 67.3 Years STANDARD_DEVIATION 10.95 | 67.8 Years STANDARD_DEVIATION 10.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 21 Participants | 39 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 138 Participants | 136 Participants | 274 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 19 Participants | 27 Participants | 46 Participants |
| Race/Ethnicity, Customized Black or African American | 25 Participants | 22 Participants | 47 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 12 Participants | 10 Participants | 22 Participants |
| Race/Ethnicity, Customized White | 100 Participants | 98 Participants | 198 Participants |
| Sex: Female, Male Female | 45 Participants | 35 Participants | 80 Participants |
| Sex: Female, Male Male | 111 Participants | 122 Participants | 233 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 156 | 2 / 157 |
| other Total, other adverse events | 0 / 156 | 0 / 157 |
| serious Total, serious adverse events | 19 / 156 | 23 / 157 |
Outcome results
Primary
Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity).
Change from baseline in 6-minute walk distance (6MWD) (exercise capacity) at week 16 was defined as the distance walked in 6 minutes at week 16 minus the baseline value. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have 6MWD values.
Time frame: At baseline and at week 16 or death prior to week 16
Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapa 10mg | Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity). | 20.0 meters |
| Placebo | Change From Baseline in 6-minute Walk Distance (6MWD) at Week 16 (Larger Distances Represent Better Functional Capacity). | 13.5 meters |
Comparison: For the primary efficacy endpoint 6MWD, the following hypothesis was tested using the significance level 0.00010:~H0: m(r(A)) = m(r(C)) versus H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, 6MWD, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.p-value: 0.6862695% CI: [-6.5, 13]Rank ANCOVA
Primary
Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at Week 16 (Higher Scores Represent Less Physical Limitation Due to HF)
Change from baseline in KCCQ-PLS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-PLS incorporates the 6 physical limitation items into a single score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have KCCQ-PLS values.
Time frame: At baseline and at week 16 or death before week 16
Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not, excluding participants with non-calculable baseline or week 16 KCCQ-PLS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapa 10mg | Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at Week 16 (Higher Scores Represent Less Physical Limitation Due to HF) | 4.17 Score on a scale |
| Placebo | Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Physical Limitation Score (KCCQ-PLS) at Week 16 (Higher Scores Represent Less Physical Limitation Due to HF) | 0.00 Score on a scale |
Comparison: For the primary efficacy endpoint KCCQ-PLS, the following hypothesis was tested at significant level of 0.04990~* H0: m(r(A)) = m(r(C)) versus~* H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, KCCQ-PLS, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.p-value: 0.0584295% CI: [0.03, 8.33]Rank ANCOVA
Primary
Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 16 (Higher Scores Represent Less HF Symptom Frequency and Burden).
Change from baseline in KCCQ-TSS was defined as the endpoint value at week 16 minus the baseline value. KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. The KCCQ-TSS incorporates the symptom frequency (4 items) and symptom burden (3 items) domains into a single summary score. The score is transformed to a range of 0-100, in which a higher score reflects better health status. Baseline value is the last value on or prior to the randomization visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive. In rank ANCOVA and HL estimation, multiple imputation was performed on missing values for participants who were alive at the visit at week 16 but did not have KCCQ-TSS values.
Time frame: At baseline and at week 16 or death before week 16
Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapa 10mg | Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 16 (Higher Scores Represent Less HF Symptom Frequency and Burden). | 2.08 Score on a scale |
| Placebo | Change From Baseline in Kansas-City Cardiomyopathy Questionnaire-Total Symptom Score (KCCQ-TSS) at Week 16 (Higher Scores Represent Less HF Symptom Frequency and Burden). | 0.00 Score on a scale |
Comparison: For the primary efficacy endpoint KCCQ-TSS, the following hypothesis was tested using the significance level 0.04990~* H0: m(r(A)) = m(r(C)) versus~* H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in the primary efficacy endpoint, KCCQ-TSS, from baseline to week 16, among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.p-value: 0.0216495% CI: [0.96, 8.22]Rank ANCOVA
Secondary
Change From Baseline at the End of the Study in the Total Time Spent in Light to Vigorous Physical Activity, as Assessed Using a Wearable Activity Monitor (Accelerometer).
Change from baseline at the end of the study in total time spent in light to vigorous physical activity (LVPA), as assessed using a wearable activity monitor, was defined as the total time \[per day\] spent in LVPA at the end of the study minus the baseline value. Baseline is the 7 day period starting on the day of enrolment and ending before randomization. End of study is defined as the period starting on the day of week 14 and prior to the week 16 visit. Deaths are treated as the worst outcome and ordering among deaths is based on last value while alive.
Time frame: At baseline and at end of study or death before week 16.
Population: Full Analysis Set: All participants that were randomized, regardless of whether treated or not, including participants from investigator sites having wearable activity monitor data collected.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dapa 10mg | Change From Baseline at the End of the Study in the Total Time Spent in Light to Vigorous Physical Activity, as Assessed Using a Wearable Activity Monitor (Accelerometer). | -0.19 hours |
| Placebo | Change From Baseline at the End of the Study in the Total Time Spent in Light to Vigorous Physical Activity, as Assessed Using a Wearable Activity Monitor (Accelerometer). | -0.15 hours |
Comparison: For the secondary efficacy endpoint, total time spent in LVPA, the testing hypothesis is~* H0: m(r(A)) = m(r(C)) versus~* H1: m(r(A)) ≠ m(r(C)) Where H0 and H1 are the null and alternative hypotheses, respectively, and m(r(A)) and m(r(C)) represent the median of the ranked changes in secondary efficacy endpoint, total time spent in LVPA, from baseline to End of study among patients receiving dapagliflozin (Active) and placebo (Control) treatment, respectively.p-value: 0.1974895% CI: [-0.55, 0.22]Rank ANCOVA