Heart Failure With Preserved Ejection Fraction
Conditions
Brief summary
This is an international, multicentre, parallel-group, event-driven, randomised, double-blind, placebo-controlled study in HFpEF patients, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to background regional standard of care therapy, including treatments to control co-morbidities, in reducing the composite of CV death or heart failure events.
Detailed description
This is an international, multicentre, parallel-group, event-driven, randomised, double-blind study in patients with HFpEF, evaluating the effect of dapagliflozin 10 mg versus placebo, given once daily in addition to background regional standard of care therapy, including treatments to control co-morbidities, in reducing the composite of CV death and heart failure events (hospitalisations for HF or urgent HF visits). Adult patients aged ≥40 years with HFpEF (LVEF \>40% and evidence of structural heart disease) and New York Heart Association (NYHA) class II-IV who are eligible according to the inclusion/exclusion criteria will be randomised in a 1:1 ratio to receive either dapagliflozin 10 mg or placebo. Both out-patients and in-patients hospitalised for heart failure and off intravenous heart failure-therapy for 24 hours can be randomised. It is estimated that approximately 11000 patients at approximately 400-500 sites in 20-25 countries will need to be enrolled to reach the target of approximately 6100 randomised patients.
Interventions
DRUGDapagliflozin
10 mg tablets given once daily, per oral use.
DRUGPlacebo
Placebo matching dapagliflozin 10 mg
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
International, Double-blind, Randomised, Placebo-Controlled
Eligibility
Sex/Gender
ALL
Age
40 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed informed consent prior to any study specific procedures. 2. Male or female patients age ≥40 years. 3. Documented diagnosis of symptomatic heart failure (NYHA class II-IV) at enrolment, and a medical history of typical symptoms/signs of heart failure ≥6 weeks before enrolment with at least intermittent need for diuretic treatment. 4. Left Ventricular Ejection Fraction (LVEF) \>40% and evidence of structural heart disease (i.e. left ventricular hypertrophy or left atrial enlargement ) documented by the most recent echocardiogram, and/or cardiac MR within the last 12 months prior to enrolment. For patients with prior acute cardiac events or procedures that may reduce LVEF, e.g. as defined in exclusion criterion 6, qualifying cardiac imaging assessment at least 12 weeks following the procedure/event is required. 5. Elevated NT-pro BNP levels. 6. Both ambulatory and hospitalised patients may be enrolled and randomised. Patients currently hospitalised for HF, must be off intravenous HF medications for at least 24 before randomisation. Further details regarding inclusion criteria 4-6 may apply.
Exclusion criteria
1. Receiving therapy with an SGLT2 inhibitor within 4 weeks prior to randomisation or previous intolerance to an SGLT2 inhibitor. 2. Type 1 diabetes mellitus (T1D). 3. eGFR \<25 mL/min/1.73 m2 (CKD-EPI formula) at Visit 1. 4. Systolic blood pressure (BP) \<95 mmHg on 2 consecutive measurements at 5-minute intervals, at Visit 1 or at Visit 2. 5. Systolic BP≥160 mmHg if not on treatment with ≥3 blood pressure lowering medications or ≥180 mmHg irrespective of treatments, on 2 consecutive measurements at 5-minute intervals, at Visit 1 or at Visit 2. 6. MI, unstable angina, coronary revascularization (percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)), ablation of atrial flutter/fibrillation, valve repair/replacement within 12 weeks prior to enrolment. Before enrolment, these patients must have their qualifying echocardiography and/or cardiac MRI examination at least 12 weeks after the event. 7. Planned coronary revascularization, ablation of atrial flutter/fibrillation and valve repair/replacement. 8. Stroke or transient ischemic attack (TIA) within 12 weeks prior to enrolment. 9. Probable alternative or concomitant diagnoses which in the opinion of the investigator could account for the patient's HF symptoms and signs (e.g. anaemia, hypothyroidism). 10. Body mass index \>50 kg/m2. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure. | Up to 42.1 months | Dual primary efficacy Primary endpoint analysed in all patients randomised (Full analysis set). The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. |
| Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure for LVEF <60% Subpopulation | Up to 42.1 months | Dual primary efficacy Primary endpoint analysed in all patients randomised with LVEF \< 60% at baseline. The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the KCCQ Total Symptom Score at 8 Months | Baseline and 8 months or death before 8 months | 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 Total Symptom Score incorporates the symptom domains into a single score. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. |
| Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) | Up to 42.1 months | Secondary efficacy Total number of heart failure events (first and recurrent) and cardiovascular death, analysed in all randomized patients. The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. |
| Subjects Included in the Endpoint of All-cause Mortality | Up to 42.1 months | Secondary efficacy The analysis was assessed on Full Analysis Set, including deaths occurring on or prior to Primary Analysis Censoring Date. |
| Subjects Included in the Endpoint of Cardiovascular Death | Up to 42.1 months | Secondary efficacy The analysis was assessed on Full Analysis Set, including deaths occurring on or prior to Primary Analysis Censoring Date. |
| Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) for LVEF <60% Subpopulation | Up to 42.1 months | Secondary efficacy Total number of heart failure events (first and recurrent) and cardiovascular death, analysed in all randomized patients with LVEF \< 60% at baseline The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date. |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Hungary, Japan, Mexico, Netherlands, Peru, Poland, Romania, Russia, Saudi Arabia, Spain, Taiwan, United States, Vietnam
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapa 10 mg Dapagliflozin 10 mg tablets administered once daily per oral use | 3,131 |
| Placebo Placebo tablet to match dapagliflozin 10 mg, given once daily per oral use | 3,132 |
| Total | 6,263 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Withdrawal by Subject | 8 | 10 |
Baseline characteristics
| Characteristic | Dapa 10 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 71.8 Years STANDARD_DEVIATION 9.6 | 71.5 Years STANDARD_DEVIATION 9.5 | 71.7 Years STANDARD_DEVIATION 9.6 |
| Age, Customized <= 50 | 85 Participants | 74 Participants | 159 Participants |
| Age, Customized > 50 | 3046 Participants | 3058 Participants | 6104 Participants |
| Age, Customized <= 65 | 743 Participants | 761 Participants | 1504 Participants |
| Age, Customized > 65 | 2388 Participants | 2371 Participants | 4759 Participants |
| Age, Customized >65 - 75 | 1184 Participants | 1228 Participants | 2412 Participants |
| Age, Customized > 75 | 1204 Participants | 1143 Participants | 2347 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 632 Participants | 598 Participants | 1230 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2499 Participants | 2534 Participants | 5033 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| LVEF (%) at Baseline | 54.0 Percentage of blood leaving the heart STANDARD_DEVIATION 8.6 | 54.3 Percentage of blood leaving the heart STANDARD_DEVIATION 8.9 | 54.2 Percentage of blood leaving the heart STANDARD_DEVIATION 8.8 |
| Medical History of Type 2 Diabetes Yes | 1401 Participants | 1405 Participants | 2806 Participants |
| NYHA Class at Baseline I | 0 Participants | 1 Participants | 1 Participants |
| NYHA Class at Baseline II | 2314 Participants | 2399 Participants | 4713 Participants |
| NYHA Class at Baseline III | 807 Participants | 724 Participants | 1531 Participants |
| NYHA Class at Baseline IV | 10 Participants | 8 Participants | 18 Participants |
| Prior HF Hospitalization Yes | 1270 Participants | 1269 Participants | 2539 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 93 Participants | 96 Participants | 189 Participants |
| Race/Ethnicity, Customized Asian | 630 Participants | 644 Participants | 1274 Participants |
| Race/Ethnicity, Customized Black or African American | 81 Participants | 78 Participants | 159 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 113 Participants | 89 Participants | 202 Participants |
| Race/Ethnicity, Customized White | 2214 Participants | 2225 Participants | 4439 Participants |
| Sex: Female, Male Female | 1364 Participants | 1383 Participants | 2747 Participants |
| Sex: Female, Male Male | 1767 Participants | 1749 Participants | 3516 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 510 / 3,131 | 533 / 3,132 |
| other Total, other adverse events | 464 / 3,126 | 485 / 3,127 |
| serious Total, serious adverse events | 1,454 / 3,126 | 1,508 / 3,127 |
Outcome results
Primary
Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure.
Dual primary efficacy Primary endpoint analysed in all patients randomised (Full analysis set). The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date.
Time frame: Up to 42.1 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure. | 512 Participants |
| Placebo | Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure. | 610 Participants |
Comparison: Comparison Group: Placebop-value: 0.000895% CI: [0.73, 0.92]Regression, Cox
Primary
Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure for LVEF <60% Subpopulation
Dual primary efficacy Primary endpoint analysed in all patients randomised with LVEF \< 60% at baseline. The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date.
Time frame: Up to 42.1 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure for LVEF <60% Subpopulation | 381 Participants |
| Placebo | Subjects Included in the Composite Endpoint of CV Death, Hospitalization Due to Heart Failure or Urgent Visit Due to Heart Failure for LVEF <60% Subpopulation | 440 Participants |
Comparison: Comparison Group: Placebop-value: 0.008595% CI: [0.73, 0.95]Regression, Cox
Secondary
Change From Baseline in the KCCQ Total Symptom Score at 8 Months
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 Total Symptom Score incorporates the symptom domains into a single score. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.
Time frame: Baseline and 8 months or death before 8 months
Population: Full analysis set population, including only assessments performed or planned prior to March 11th, 2020, when COVID-19 was declared a pandemic by the WHO.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapa 10 mg | Change From Baseline in the KCCQ Total Symptom Score at 8 Months | 8.3 Scores on a scale | Standard Deviation 20.3 |
| Placebo | Change From Baseline in the KCCQ Total Symptom Score at 8 Months | 5.2 Scores on a scale | Standard Deviation 21.1 |
Comparison: Comparison Group: Placebop-value: 0.008695% CI: [1.03, 1.21]Win Ratio
Secondary
Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit)
Secondary efficacy Total number of heart failure events (first and recurrent) and cardiovascular death, analysed in all randomized patients. The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date.
Time frame: Up to 42.1 months
Population: Full analysis set population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapa 10 mg | Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) | 815 Number of events |
| Placebo | Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) | 1057 Number of events |
Comparison: Comparison Group: Placebop-value: 0.000395% CI: [0.67, 0.89]LWYY proportional rates model
Secondary
Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) for LVEF <60% Subpopulation
Secondary efficacy Total number of heart failure events (first and recurrent) and cardiovascular death, analysed in all randomized patients with LVEF \< 60% at baseline The analysis was assessed on Full Analysis Set, including events occurring on or prior to Primary Analysis Censoring Date.
Time frame: Up to 42.1 months
Population: Full analysis set population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dapa 10 mg | Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) for LVEF <60% Subpopulation | 605 Number of events |
| Placebo | Events Included in the Composite Endpoint of CV Death or Recurrent Heart Failure Event (Hospitalization Due to Heart Failure or Urgent Heart Failure Visit) for LVEF <60% Subpopulation | 782 Number of events |
Comparison: Comparison Group: Placebop-value: 0.001795% CI: [0.65, 0.9]LWYY proportional rates model
Secondary
Subjects Included in the Endpoint of All-cause Mortality
Secondary efficacy The analysis was assessed on Full Analysis Set, including deaths occurring on or prior to Primary Analysis Censoring Date.
Time frame: Up to 42.1 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Endpoint of All-cause Mortality | 497 Participants |
| Placebo | Subjects Included in the Endpoint of All-cause Mortality | 526 Participants |
Comparison: Comparison Group: Placebop-value: 0.342595% CI: [0.83, 1.07]Regression, Cox
Secondary
Subjects Included in the Endpoint of Cardiovascular Death
Secondary efficacy The analysis was assessed on Full Analysis Set, including deaths occurring on or prior to Primary Analysis Censoring Date.
Time frame: Up to 42.1 months
Population: Full analysis set
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dapa 10 mg | Subjects Included in the Endpoint of Cardiovascular Death | 231 Participants |
| Placebo | Subjects Included in the Endpoint of Cardiovascular Death | 261 Participants |
Comparison: Comparison Group: Placebop-value: 0.167895% CI: [0.74, 1.05]Regression, Cox