Heart Failure
Conditions
Brief summary
The primary objective of the study is to evaluate the effect of empagliflozin 10 mg versus placebo on exercise ability using the 6 minute walk test (6MWT) in patients with chronic heart failure (CHF) with preserved ejection fraction (LVEF \> 40%). Secondary objectives are to assess Patient-Reported Outcome (PRO)
Interventions
DRUGEmpagliflozin
Film-coated tablet
DRUGPlacebo
Film-coated tablet
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Of full age of consent (according to local legislation, usually ≥ 18 years) at screening. * Male or female patients. Women of child bearing potential (WOCBP) must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. * Signed and dated written informed consent in accordance with ICHGCP and local legislation prior to admission to the trial * Six minute walk test (6MWT) distance ≤350 m at screening and at baseline. * Patients with CHF diagnosed for at least 3 months before Visit 1, and currently in NYHA class II-IV * Chronic heart failure (CHF) with preserved Ejection fraction (EF) defined as left ventricle ejection fraction(LVEF) \> 40 % as per echocardiography at Visit 1 per local reading and no prior measurement of LVEF ≤ 40% under stable conditions. * Elevated N-Terminal Pro-Brain Natriuretic Peptide (NT-proBNP) \> 300 pg/ml for patients without atrial fibrillation (AF), OR \> 600 pg/ml for patients with AF, as analysed at the Central laboratory at Visit 1 * Patients must have at least one of the following evidence of heart failure (HF): * Structural heart disease (left atrial enlargement and/or left ventricular hypertrophy) documented by echocardiogram at Visit 1, OR * Documented Hospitalization for Heart Failure (HHF) within 12 months prior to Visit 1 * Consistent with prevailing CV guidelines, if oral diuretics are prescribed to control symptoms, patients must be on an appropriate and stable dose of oral diuretics for at least 2 weeks prior to Visit 1 to control symptoms. * Clinically stable at randomization with no signs of heart failure decompensation (as per investigator judgement).
Exclusion criteria
* Myocardial infarction (increase in cardiac enzymes in combination with symptoms of ischaemia or newly developed ischaemic ECG changes), coronary artery bypass graft surgery or other major cardiovascular surgery, stroke or transient ischemic attack in past 90 days prior to Visit 1 * Acute decompensated HF (exacerbation of CHF) requiring intravenous (i.v.) diuretics, i.v. inotropes or i.v. vasodilators, or left ventricular assist device within 4 weeks prior to Visit 1, and/or during screening period until Visit 2 * Previous or current randomisation in another Empagliflozin Heart Failure trial (i.e. studies 1245.110, 1245.121, 1245-0168) * Type 1 Diabetes Mellitus (T1DM) * Impaired renal function, defined as eGFR \< 20 mL/min/1.73 m2 (CKD-EPIcr) or requiring dialysis, as determined at Visit 1 * Symptomatic hypotension or a systolic blood pressure (SBP) \< 100 mmHg at Visit 1 or 2 * SBP ≥ 180 mmHg at Visit 1 or 2, or SBP \>160mmHg at both Visit 1 and 2 * Atrial fibrillation or atrial flutter with a resting heart rate \> 110 bpm documented by ECG at Visit 1 (Screening) * Unstable angina pectoris in past 30 days prior to Visit 1 * Largest distance walked in 6 minutes (6MWTD) at baseline \<100m. * Any presence of condition that precludes exercise testing such as: * claudication, * uncontrolled (according to investigator judgement) bradyarrhythmia or tachyarrhythmia, * significant musculoskeletal disease, * primary pulmonary hypertension, * severe obesity (body mass index ≥40.0 kg/m2), * orthopedic conditions that limit the ability to walk (such as arthritis in the leg, knee or hip injuries) * amputation with artificial limb without stable prosthesis function for the past 3 months * Any condition that in the opinion of the investigator would contraindicate the assessment of 6MWT * Patients in a structured (according to Investigator judgement) exercise training program in the 1 month prior to screening or planned to start one during the course of this trial. * ICD implantation within 1 month prior to Visit 1 or planned during the course of the trial * Implanted cardiac resynchronisation therapy (CRT) * Treatment with i.v. iron therapy or erythropoietin (EPO) within 3 months prior to screening. * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD) | At baseline and at Week 12 | Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions (6MWTD). If repeated 6-minutes walk test (6MWT) measurements were available for the same day, the longest distance was used for analysis. Change from baseline was defined as the distance walked in 6 minutes at Week 12 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at Week 12 but did not perform the 6MWT, the participant was evaluated as having walked a distance of 0 meter. If no value was available for Week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score | At baseline and at Week 12 | Change from baseline in CHQ-SAS was defined as the endpoint value at week 12 minus the last available endpoint value before start of treatment with randomised study medication. The CHQ-SAS evaluates 3 domains: dyspnoea, fatigue, and emotional function. Scores of the domains range from 1 to 7, with higher score indicating better quality of life. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed. |
| Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes | At baseline and at Week 6 | Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. Change from baseline was defined as the distance walked in 6 minutes at Week 6 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at Week 6 but did not perform the 6-Minuted Walking Test, the participant was evaluated as having walked a distance of 0 meter. If no value was available for Week 6, an imputed value was used. |
| Change From Baseline in Clinical Congestion Score at Week 12 | At baseline and at Week 12 | Change from baseline to week 12 in Clinical Congestion score is defined as the score-value at week 12 minus the score-value at baseline. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. The Clinical Congestion Score (summary score) is based on 3 items: orthopnoea, jugular venous distention (JVD) and oedema. Each item was assessed through a 4-measure questionnaire, which was further converted to a standardised 4-point scale ranging from 0 to 3, with 0 indicating no or fewer symptoms and 3 indicating continous or more symptoms. If at least 2 of the 3 items are not missing, the summary score is calculated as: (average over items JVD, orthopnea and oedema actually answered)\*3. The summary score ranges from 0 to 9, with lower value indicating better health, and higher value indicating worse health. Mean is adjusted mean. |
| Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | At baseline and at Week 12 | Change from baseline to week 12 in PGI-S of Heart Failure Symptoms. The Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the Patient to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-category scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12. |
| Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS) | At baseline and at Week 12 | Change from baseline in KCCQ-TSS was defined as the endpoint value at week 12 minus the last available measurement before start of treatment with randomised study medication. The KCCQ is 23 item self-administered questionnaire and comprises 7 domains: physical limitation, symptom frequency, symptom burden, symptom stability, social limitation, self-efficacy and quality of life. Additionally 3 summary scores exist: TSS, clinical summary score, and overall summary score. The scores of the KCCQ domains and summary scores range from 0 to 100, with higher score indicating better outcome. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed. |
| Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Week 12 | The Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of change in heart failure symptoms, specifically: shortness of breath, fatigue, and swelling. The PGI-C asks the patient to choose one Response that best describes the overall change (if any) in his/her heart failure symptoms, specifically: shortness of breath, fatigue, and swelling since he/she started taking the study medication on a 7- category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3). |
| Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Week 12 | The PGI-C in Dyspnoea is a 1-item questionnaire designed to assess the patient's Impression of change in dyspnoea. The PGI-C asks the patient to choose one response that best describes the change (if any) in his/her shortness of breath when performing usual activities since he/she started taking the study medication on a 7-category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3). |
| Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12 | Within 3 weeks prior to treatment start and at Week 12. | Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP). Relative change from baseline is expressed as ratio of week 12 to baseline. Baseline value was defined as the mean of all available measurements from the screening visit until start of treatment with randomised study medication. Mean is adjusted mean. |
| Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | At baseline and at Week 12 | Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea. The PGI-S of Dyspnoea is a 1-item questionnaire designed to assess the participant´s impression of symptom severity, specifically dyspnoea. The PGI-S item asks the participant to choose one response that best describes how his/her dyspnoea is now on a 5-category scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12. |
Countries
Australia, Canada, Germany, Greece, Italy, Norway, Poland, Portugal, Spain, Sweden, United States
Participant flow
Recruitment details
Randomised, double-blind, placebo-controlled, parallel-group trial in patients with chronic Heart Failure with preserved Ejection Fraction (HFpEF) to evaluate the effect of Empagliflozin versus Placebo on exercise and heart failure symptoms.
Pre-assignment details
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 1 film-coated tablet of Placebo matching Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with preserved ejection fraction (LVEF \> 40%). | 158 |
| 10 mg Empagliflozin 1 film-coated tablet of 10 milligram (mg) of Empagliflozin was administered orally once daily for 12 weeks in participants with chronic Heart Failure (CHF) with with preserved ejection fraction (LVEF \> 40%). | 157 |
| Total | 315 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 9 |
| Overall Study | Noncompliance of scheduled visits | 1 | 2 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Total | 10 mg Empagliflozin |
|---|---|---|---|
| Age, Continuous | 73.9 Years STANDARD_DEVIATION 8.6 | 73.5 Years STANDARD_DEVIATION 8.8 | 73.0 Years STANDARD_DEVIATION 9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 37 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 139 Participants | 277 Participants | 138 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance at baseline | 299.5 Meter | 299.0 Meter | 297.0 Meter |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 19 Participants | 32 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 135 Participants | 275 Participants | 140 Participants |
| Sex: Female, Male Female | 66 Participants | 136 Participants | 70 Participants |
| Sex: Female, Male Male | 92 Participants | 179 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 158 | 1 / 157 |
| other Total, other adverse events | 0 / 158 | 0 / 157 |
| serious Total, serious adverse events | 29 / 158 | 20 / 157 |
Outcome results
Primary
Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD)
Change from baseline to week 12 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions (6MWTD). If repeated 6-minutes walk test (6MWT) measurements were available for the same day, the longest distance was used for analysis. Change from baseline was defined as the distance walked in 6 minutes at Week 12 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at Week 12 but did not perform the 6MWT, the participant was evaluated as having walked a distance of 0 meter. If no value was available for Week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above.
Time frame: At baseline and at Week 12
Population: Randomised Set: All participants that were randomised, regardless of whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD) | 5.0 Meter (m) |
| 10 mg Empagliflozin | Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD) | 10.0 Meter (m) |
Comparison: H0: There is no difference between the effect of Placebo and the effect of empagliflozin.p-value: 0.36695% CI: [-5, 13]Wilcoxon rank test, normal approximation
Secondary
Change From Baseline in Clinical Congestion Score at Week 12
Change from baseline to week 12 in Clinical Congestion score is defined as the score-value at week 12 minus the score-value at baseline. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. The Clinical Congestion Score (summary score) is based on 3 items: orthopnoea, jugular venous distention (JVD) and oedema. Each item was assessed through a 4-measure questionnaire, which was further converted to a standardised 4-point scale ranging from 0 to 3, with 0 indicating no or fewer symptoms and 3 indicating continous or more symptoms. If at least 2 of the 3 items are not missing, the summary score is calculated as: (average over items JVD, orthopnea and oedema actually answered)\*3. The summary score ranges from 0 to 9, with lower value indicating better health, and higher value indicating worse health. Mean is adjusted mean.
Time frame: At baseline and at Week 12
Population: Only participants in the randomised set (RS) who have values at baseline and at week 12.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Clinical Congestion Score at Week 12 | -0.28 Score on scale | Standard Deviation 0.08 |
| 10 mg Empagliflozin | Change From Baseline in Clinical Congestion Score at Week 12 | -0.36 Score on scale | Standard Deviation 0.08 |
p-value: 0.44495% CI: [-0.31, 0.14]Mixed Model Repeated Measure (MMRM)
Secondary
Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12
Change from baseline to week 12 in Patient Global Impression of Severity (PGI-S) of dyspnoea. The PGI-S of Dyspnoea is a 1-item questionnaire designed to assess the participant´s impression of symptom severity, specifically dyspnoea. The PGI-S item asks the participant to choose one response that best describes how his/her dyspnoea is now on a 5-category scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.
Time frame: At baseline and at Week 12
Population: Only participants in the randomised set (RS) who have values at baseline and at week 12.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 3 categories improvement | 4 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 1 category deterioration | 18 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 1 category improvement | 45 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 2 categories deterioration | 7 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 2 categories improvement | 8 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 3 categories deterioration | 1 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | No change | 70 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 4 categories deterioration | 0 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 4 categories improvement | 1 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 4 categories deterioration | 0 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 4 categories improvement | 0 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 3 categories improvement | 1 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 2 categories improvement | 13 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 1 category improvement | 48 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | No change | 70 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 1 category deterioration | 20 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 2 categories deterioration | 1 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12 | 3 categories deterioration | 0 Participants |
p-value: 0.4435Cochran-Mantel-Haenszel test
Secondary
Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12
Change from baseline to week 12 in PGI-S of Heart Failure Symptoms. The Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of symptoms severity, specifically: shortness of breath, fatigue and swelling. The PGI-S asks the Patient to choose one response that best describes how his/her heart failure symptoms, specifically: shortness of breath, fatigue and swelling are now on a 5-category scale, ranging from 'Not at all' (1) to 'Very severe' (5). Number of participants by change in score are reported. Change in score was defined as the number of categories improved/deteriorated from baseline to week 12.
Time frame: At baseline and at Week 12
Population: Only participants in the randomised set (RS) who have values at baseline and at week 12.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 3 categories improvement | 2 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 1 category deterioration | 17 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 1 category improvement | 46 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 2 categories deterioration | 6 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 2 categories improvement | 11 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 3 categories deterioration | 0 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | No change | 70 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 4 categories deterioration | 1 Participants |
| Placebo | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 4 categories improvement | 1 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 4 categories deterioration | 0 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 4 categories improvement | 0 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 3 categories improvement | 1 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 2 categories improvement | 8 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 1 category improvement | 42 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | No change | 79 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 1 category deterioration | 16 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 2 categories deterioration | 6 Participants |
| 10 mg Empagliflozin | Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12 | 3 categories deterioration | 1 Participants |
p-value: 0.3924Cochran-Mantel-Haenszel test
Secondary
Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score
Change from baseline in CHQ-SAS was defined as the endpoint value at week 12 minus the last available endpoint value before start of treatment with randomised study medication. The CHQ-SAS evaluates 3 domains: dyspnoea, fatigue, and emotional function. Scores of the domains range from 1 to 7, with higher score indicating better quality of life. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.
Time frame: At baseline and at Week 12
Population: Participants in the randomised set (RS) who have no missing values at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score | 0.20 Score on a scale |
| 10 mg Empagliflozin | Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score | 0.10 Score on a scale |
Comparison: H0: There is no difference between the effect of Placebo and the effect of empagliflozin.p-value: 0.551295% CI: [-0.35, 0.2]Wilcoxon rank test, normal approximation
Secondary
Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)
Change from baseline in KCCQ-TSS was defined as the endpoint value at week 12 minus the last available measurement before start of treatment with randomised study medication. The KCCQ is 23 item self-administered questionnaire and comprises 7 domains: physical limitation, symptom frequency, symptom burden, symptom stability, social limitation, self-efficacy and quality of life. Additionally 3 summary scores exist: TSS, clinical summary score, and overall summary score. The scores of the KCCQ domains and summary scores range from 0 to 100, with higher score indicating better outcome. If no questionnaire was available at week 12, an imputed value was used. Patients with missing week 12 data who had no clinical event were ranked below any patient with non-missing data, but above the patients who had clinical events. Patients who died before week 12 were ranked below the patients in all categories above. If no questionnaire was available at baseline, change from baseline was not imputed.
Time frame: At baseline and at Week 12
Population: Randomised Set: All participants that were randomised, regardless of whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS) | 2.08 Score on a scale |
| 10 mg Empagliflozin | Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS) | 4.17 Score on a scale |
Comparison: H0: There is no difference between the effect of Placebo and the effect of empagliflozin.p-value: 0.278395% CI: [-2.08, 6.25]Wilcoxon rank test, normal approximation
Secondary
Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes
Change from baseline to week 6 in exercise capacity as measured by the distance walked in 6 minutes in standardised conditions. Change from baseline was defined as the distance walked in 6 minutes at Week 6 minus the baseline value. Baseline value was defined as the last available measurement before start of treatment with randomised study medication. If a participant was present at the visit at Week 6 but did not perform the 6-Minuted Walking Test, the participant was evaluated as having walked a distance of 0 meter. If no value was available for Week 6, an imputed value was used.
Time frame: At baseline and at Week 6
Population: Randomised Set: All participants that were randomised, regardless of whether treated or not.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes | 1.0 Meter (m) |
| 10 mg Empagliflozin | Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes | 7.0 Meter (m) |
Comparison: H0: There is no difference between the effect of Placebo and the effect of empagliflozin.p-value: 0.365795% CI: [-4, 11]Wilcoxon rank test, normal approximation
Secondary
Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12
The PGI-C in Dyspnoea is a 1-item questionnaire designed to assess the patient's Impression of change in dyspnoea. The PGI-C asks the patient to choose one response that best describes the change (if any) in his/her shortness of breath when performing usual activities since he/she started taking the study medication on a 7-category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).
Time frame: Week 12
Population: Only participants in the randomised set (RS) who have values at week 12.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | A little worse | 6 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | A little better | 32 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Much worse | 2 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Much better | 31 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | No change | 72 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Very much better | 11 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Very much worse | 0 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Very much better | 5 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Very much worse | 0 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Much worse | 3 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | A little worse | 7 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | No change | 57 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | A little better | 45 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12 | Much better | 36 Participants |
p-value: 0.5713Cochran-Mantel-Haenszel test
Secondary
Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12
The Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms is a 1-item questionnaire to assess the patient's impression of change in heart failure symptoms, specifically: shortness of breath, fatigue, and swelling. The PGI-C asks the patient to choose one Response that best describes the overall change (if any) in his/her heart failure symptoms, specifically: shortness of breath, fatigue, and swelling since he/she started taking the study medication on a 7- category scale ranging from 'Very much better' (+3) to 'Very much worse' (-3).
Time frame: Week 12
Population: Only participants in the randomised set (RS) who have values at week 12.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | A little worse | 11 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | A little better | 41 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Much worse | 0 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Much better | 31 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | No change | 62 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Very much better | 8 Participants |
| Placebo | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Very much worse | 1 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Very much better | 5 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Very much worse | 0 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Much worse | 3 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | A little worse | 7 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | No change | 55 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | A little better | 48 Participants |
| 10 mg Empagliflozin | Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12 | Much better | 35 Participants |
p-value: 0.5124Cochran-Mantel-Haenszel test
Secondary
Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12
Relative change from baseline to week 12 in N-terminal pro-brain natriuretic peptide (NTproBNP). Relative change from baseline is expressed as ratio of week 12 to baseline. Baseline value was defined as the mean of all available measurements from the screening visit until start of treatment with randomised study medication. Mean is adjusted mean.
Time frame: Within 3 weeks prior to treatment start and at Week 12.
Population: Only participants in the randomised set (RS) who had values at baseline and at week 12.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12 | 1.04 Ratio |
| 10 mg Empagliflozin | Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12 | 0.99 Ratio |
p-value: 0.403295% CI: [0.85, 1.07]Mixed model repeated Measure (MMRM)