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CompletedNCT03448406Updated Dec 8, 2020Results posted

This Study Tests Empagliflozin in Patients With Chronic Heart Failure With Preserved Ejection Fraction (HFpEF). The Study Looks at How Far Patients Can Walk in 6 Minutes and at Their Heart Failure Symptoms.

A Phase 3 interventional study of Empagliflozin and Placebo in Heart Failure, sponsored by Boehringer Ingelheim. Completed at 108 sites in 11 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-12-08.

Sponsored by Boehringer Ingelheim · Phase 3, Interventional, and Treatment

Phase
Phase 3
Study type
Interventional
Enrollment
315
Allocation
Randomized
Ages
18 Years and older
Sex
All
01

Study 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)

02

Conditions studied

  • Heart Failure

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03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
All
Accepts 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

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 exclusion criteria applies
04

Study design

Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
315 participants (actual)

Study arms

  • Experimental
    Empagliflozin

    Drug: Empagliflozin

  • Active comparator
    Placebo

    Drug: Placebo

Interventions

  • DrugEmpagliflozin

    Film-coated tablet

    Also known as: JARDIANCE, JARDIANZ, GIBTULIO

  • DrugPlacebo

    Film-coated tablet

05

What researchers measure

Primary outcomes

  1. 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

Secondary outcomes

  1. 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

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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.

06

Results

Posted Dec 8, 2020

Participant flow

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.

Participant flow — Overall Study
MilestonePlacebo10 mg Empagliflozin
Started158157
Completed147144
Not completed1113
Withdrew: Noncompliance of scheduled visits12
Withdrew: Withdrawal by subject12
Withdrew: Protocol violation10
Withdrew: Adverse event89

Outcome measures

PrimaryChange 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
Reported as:
Median · Meter (m)
Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD)
Meter (m)Placebo10 mg Empagliflozin
Change From Baseline to Week 12 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes in Standardised Conditions (6MWTD)5.0 (-20.0 to 33.0)10.0 (-10.0 to 32.0)
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Wilcoxon rank test, normal approximation · p = 0.3660 · Median difference (hl-estimate): 4.0 · 95% CI -5.0 to 13.0Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodge-Lehman (HL) estimate for the median difference was calculated.
SecondaryChange 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
Reported as:
Median · Score on a scale
Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)
Score on a scalePlacebo10 mg Empagliflozin
Change From Baseline to Week 12 in Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score (TSS)2.08 (-6.25 to 20.83)4.17 (-3.13 to 16.67)
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Wilcoxon rank test, normal approximation · p = 0.2783 · Median difference (hl-estimate): 2.08 · 95% CI -2.08 to 6.25Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodges-Lehmann estimate for the median difference was calculated.
SecondaryChange 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
Reported as:
Median · Score on a scale
Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score
Score on a scalePlacebo10 mg Empagliflozin
Change From Baseline to Week 12 in Chronic Heart Failure Questionnaire Self- Administered Standardized Format (CHQ-SAS) Dyspnea Score0.20 (-0.40 to 1.00)0.10 (-0.40 to 1.00)
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Wilcoxon rank test, normal approximation · p = 0.5512 · Median difference (hl-estimate): -0.07 · 95% CI -0.35 to 0.20Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodges-Lehmann (HL) estimate for the median difference was calculated.
SecondaryChange 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
Reported as:
Median · Meter (m)
Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes
Meter (m)Placebo10 mg Empagliflozin
Change From Baseline to Week 6 in Exercise Capacity as Measured by the Distance Walked in 6 Minutes1.0 (-17.0 to 21.0)7.0 (-14.0 to 23.0)
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Wilcoxon rank test, normal approximation · p = 0.3657 · Median difference (hl-estimate): 3.0 · 95% CI -4.0 to 11.0Empagliflozin vs. Placebo. For estimation of effect, the non-parametric Hodges-Lehmann (HL) estimate for the median difference was calculated.
SecondaryChange 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
Reported as:
Mean · Score on scale
Change From Baseline in Clinical Congestion Score at Week 12
Score on scalePlacebo10 mg Empagliflozin
Change From Baseline in Clinical Congestion Score at Week 12-0.28 ± 0.08-0.36 ± 0.08
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Mixed Model Repeated Measure (MMRM) · p = 0.4440 · Difference of adjusted mean: -0.09 · 95% CI -0.31 to 0.14Covariates: visit-by-treatment interaction, baseline-by-visit interaction. Unstructured covariance structure was used to model within-patient errors.
SecondaryChange 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
Reported as:
Count of participants · Participants
Change From Baseline in Patient Global Impression of Severity (PGI-S) of Heart Failure Symptoms at Week 12
ParticipantsPlacebo10 mg Empagliflozin
4 categories improvement10
3 categories improvement21
2 categories improvement118
1 category improvement4642
No change7079
1 category deterioration1716
2 categories deterioration66
3 categories deterioration01
4 categories deterioration10
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Cochran-Mantel-Haenszel test · p = 0.3924Test on difference in mean treatment scores, based on modified ridit scores.
SecondaryChange 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
Reported as:
Count of participants · Participants
Change From Baseline in Patient Global Impression of Severity (PGI-S) of Dyspnea Severity at Week 12
ParticipantsPlacebo10 mg Empagliflozin
4 categories improvement10
3 categories improvement41
2 categories improvement813
1 category improvement4548
No change7070
1 category deterioration1820
2 categories deterioration71
3 categories deterioration10
4 categories deterioration00
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Cochran-Mantel-Haenszel test · p = 0.4435Test on difference in mean treatment scores, based on modified ridit scores.
SecondaryPatient 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
Reported as:
Count of participants · Participants
Patient Global Impression of Change (PGI-C) in Heart Failure Symptoms at Week 12
ParticipantsPlacebo10 mg Empagliflozin
Very much worse10
Much worse03
A little worse117
No change6255
A little better4148
Much better3135
Very much better85
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Cochran-Mantel-Haenszel test · p = 0.5124Test on difference in mean treatment scores, based on modified ridit scores.
SecondaryPatient 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
Reported as:
Count of participants · Participants
Patient Global Impression of Change (PGI-C) in Dyspnea at Week 12
ParticipantsPlacebo10 mg Empagliflozin
Very much worse00
Much worse23
A little worse67
No change7257
A little better3245
Much better3136
Very much better115
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Cochran-Mantel-Haenszel test · p = 0.5713Test on difference in mean treatment scores, based on modified ridit scores.
SecondaryRelative 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.
Reported as:
Mean · Ratio
Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 12
RatioPlacebo10 mg Empagliflozin
Relative Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NTproBNP) at Week 121.04 (0.96 to 1.13)0.99 (0.92 to 1.08)
Statistical analysis
  • Placebo vs 10 mg Empagliflozin · Mixed model repeated Measure (MMRM) · p = 0.4032 · Adjusted geometric mean ratio: 0.95 · 95% CI 0.85 to 1.07Adjusted geometric mean ratio \[Empagliflozin/Placebo\] of relative change to baseline.

Adverse events

Collected over From first intake of study medication, until 7 days after last intake of study medication, up to 92 days.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Placebo0/158 (0%)29/158 (18.4%)0/158 (0%)
10 mg Empagliflozin1/157 (0.6%)20/157 (12.7%)0/157 (0%)
Most frequent serious events
Showing 10 of 54
Most frequent serious events
EventPlacebo10 mg Empagliflozin
Cardiac failureCardiac disorders13/1586/157
Atrial fibrillationCardiac disorders2/1582/157
Angina unstableCardiac disorders0/1581/157
Atrial flutterCardiac disorders0/1581/157
Cardiac arrestCardiac disorders0/1581/157
HypothyroidismEndocrine disorders0/1581/157
DysphagiaGastrointestinal disorders0/1581/157
Chest painGeneral disorders0/1581/157
Generalised oedemaGeneral disorders0/1581/157
Drug-induced liver injuryHepatobiliary disorders0/1581/157

Baseline characteristics

Randomised Set: All randomised participants, regardless of whether treated or not.

Age, Continuous
Age, Continuous(Years)Placebo10 mg EmpagliflozinTotal
Mean73.9 ± 8.673.0 ± 9.073.5 ± 8.8
Sex: Female, Male
Sex: Female, Male(Participants)Placebo10 mg EmpagliflozinTotal
Female6670136
Male9287179
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Placebo10 mg EmpagliflozinTotal
Hispanic or Latino191837
Not Hispanic or Latino139138277
Unknown or Not Reported011
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Placebo10 mg EmpagliflozinTotal
American Indian or Alaska Native000
Asian235
Native Hawaiian or Other Pacific Islander000
Black or African American191332
White135140275
More than one race202
Unknown or Not Reported011
Exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance at baseline
Exercise capacity as measured by the 6-Minutes-Walking-Test (6MWT) distance at baseline(Meter)Placebo10 mg EmpagliflozinTotal
Median299.5 (245.0 to 331.0)297.0 (246.0 to 326.0)299.0 (245.0 to 330.0)
07

Study locations

108 sites
  • Mobile Heart Specialists, PC
    Mobile, Alabama 36608, United States
  • The Center for Clinical Trials, Inc.
    Saraland, Alabama 36571, United States
  • California Heart Specialists
    Huntington Beach, California 92648, United States
  • Manshadi Heart Institute, Inc
    Stockton, California 95204, United States
  • University of California Los Angeles
    Torrance, California 90502, United States
  • University of Colorado Denver
    Aurora, Colorado 80045, United States
  • Western Connecticut Health Network
    Danbury, Connecticut 06810, United States
  • Bio1 Clinical Research
    Miami Beach, Florida 33140, United States
  • Infinite Clinical Research
    Miami, Florida 33133, United States
  • Advance Medical Research Center
    Miami, Florida 33135, United States
  • Pharmacology Research, LLC
    North Miami Beach, Florida 33169, United States
  • Palm Beach Gardens Research Center, LLC
    Palm Beach Gardens, Florida 33410, United States
  • East Coast Institute for Research, LLC
    Saint Augustine, Florida 32086, United States
  • Cozy Research LLC
    Zephyrhills, Florida 33541, United States
  • Grady Memorial Hospital
    Atlanta, Georgia 30303, United States
  • Georgia Arrhythmia Consultants and Research Institute
    Warner Robins, Georgia 31093, United States
  • St Luke's Clinic - Idaho Cardiology Associates
    Boise, Idaho 83712, United States
  • Northwest Heart Clinical Research, LLC
    Arlington Heights, Illinois 60005, United States
  • Clinical Investigation Specialists, Inc
    Gurnee, Illinois 60031, United States
  • Chicago Medical Research
    Hazel Crest, Illinois 60429, United States
  • Midwest Heart and Vascular Specialists
    Overland Park, Kansas 66211, United States
  • Grace Research, LLC
    Bossier City, Louisiana 71111, United States
  • Grace Research, LLC
    Shreveport, Louisiana 71107, United States
  • Clinical Trials of America LA, LLC
    West Monroe, Louisiana 71291, United States
  • Beth Israel Deaconess Medical Center
    Boston, Massachusetts 02215, United States
  • John D. Dingell VA Medical Center
    Detroit, Michigan 48201, United States
  • Med Research One
    Florissant, Missouri 63031, United States
  • Cox Medical Center South
    Springfield, Missouri 65807, United States
  • The DOCS
    Las Vegas, Nevada 89113, United States
  • Rutgers Robert Wood Johnson Medical School
    New Brunswick, New Jersey 08901, United States
  • Albany Stratton VA Medical Center Albany, NY
    Albany, New York 12208, United States
  • UNC REX Healthcare
    Raleigh, North Carolina 27607, United States
  • PMG Research of Rocky Mount, LLC
    Rocky Mount, North Carolina 27804, United States
  • PMG Research of Wilmington, LLC
    Wilmington, North Carolina 28401, United States
  • Rama Research LLC
    Marion, Ohio 43302, United States
  • Columbia Heart Clinic
    Columbia, South Carolina 29203, United States
  • Black Hills Cardiovascular Research
    Rapid City, South Dakota 57701, United States
  • The Jackson Clinic, PA
    Jackson, Tennessee 38301, United States
  • DiscoveResearch, Inc.
    Beaumont, Texas 77701, United States
  • Angiocardiac Care of Texas
    Houston, Texas 77025, United States
  • Acacia Medical Research Institute,LLC
    Sugar Land, Texas 77478, United States
  • Mary Washington Hospital Research Department
    Fredericksburg, Virginia 22401, United States
  • York Clinical Research, LLC
    Norfolk, Virginia 23510, United States
  • Canberra Hospital
    Garran, Australian Capital Territory 2605, Australia
  • University of the Sunshine Coast
    Birtinya, Queensland 4575, Australia
  • Peninsular Health CV Research Unit
    Frankston, Victoria 3199, Australia
  • University of Calgary
    Calgary, Alberta T2N 4Z6, Canada
  • KMH Cardiology Centres Inc.
    Mississauga, Ontario L5K 2L3, Canada
  • Toronto Heart Centre
    Toronto, Ontario M4P 1E4, Canada
  • Sameh Fikry Medicine Professional Corporation
    Waterloo, Ontario N2J 1C4, Canada
  • CIMS Studienzentrum Bamberg GmbH
    Bamberg, 96049, Germany
  • Klinische Forschung Berlin GbR
    Berlin, 10787, Germany
  • Charité - Universitätsmedizin Berlin
    Berlin, 13353, Germany
  • Cardiologicum Dresden und Pirna
    Dresden, 01277, Germany
  • Universitätsklinikum Düsseldorf
    Düsseldorf, 40225, Germany
  • IKF Pneumologie GmbH & Co. KG
    Frankfurt, 60596, Germany
  • Universitäts-Herzzentrum Freiburg, Bad Krozingen GmbH
    Freiburg, 79106, Germany
  • Universitätsklinikum Köln (AöR)
    Köln, 50937, Germany
  • Universitätsklinikum Leipzig
    Leipzig, 04103, Germany
  • Universitätsklinikum Magdeburg AöR
    Magdeburg, 39120, Germany
  • Universitätsmedizin der Johannes Gutenberg-Universität Mainz
    Mainz, 55131, Germany
  • Universitätsklinikum Ulm
    Ulm, 89081, Germany
  • Universitätsklinikum Würzburg
    Würzburg, 97080, Germany
  • General Hospital of Athens Konstantopoulio-Agia Olga
    Athens, 14233, Greece
  • General Hospital of Athens "G. Gennimatas"
    Athens, 15669, Greece
  • General Hospital of Chalkida
    Chalkida, 34100, Greece
  • University General Hospital of Heraklion
    Herakleion, Crete, 71110, Greece
  • Univ. Gen. Hosp. of Ioannina
    Ioannina, 45500, Greece
  • University Hospital of Thessaloniki AHEPA
    Thessaloniki, 54636, Greece
  • Centro Cardiologico Monzino-IRCCS
    Milano, 20138, Italy
  • Asst Santi Paolo E Carlo
    Milano, 20142, Italy
  • ASST Grande Ospedale Metropolitano Niguarda
    Milano, 20162, Italy
  • Ospedale Regina Montis Regalis
    Mondovì (CN), 12084, Italy
  • Università Federico II
    Napoli, 80131, Italy
  • Università degli studi di Palermo
    Palermo, 90133, Italy
  • IRCCS San Raffaele
    Roma, 00163, Italy
  • Sykehuset Østfold Kalnes
    Grålum, N-1714, Norway
  • Oslo Universitetssykehus HF, Rikshospitalet
    Oslo, N-0372, Norway
  • Helse Stavanger, Stavanger Universitetssykehus
    Stavanger, N-4011, Norway
  • St. Olavs Hospital, Universitetssykehuset i Trondheim
    Trondheim, N-7030, Norway
  • INTERCORE Medical Center
    Bydgoszcz, 85-605, Poland
  • 10.Military Clin.Hospital&Polyclinic
    Bydgoszcz, 85681, Poland
  • Leszek Bryniarski Specialized Medical Cabinet
    Krakow, 30-082, Poland
  • Card.Cli.Mil.Med.Ac.Uni.Cli.Hosp. Cent.Vetera.Hosp.Lodz
    Lodz, 91-425, Poland
  • Cent.Clin.Hosp.Med.Univ.Lodz,Electrocard
    Lodz, 92-213, Poland
  • Provincial Specialist M. Kopernik Hospital
    Lodz, 93-513, Poland
  • Independent Public Healthcare, Dept. of Cardiology, Pulawy
    Pulawy, 24100, Poland
  • Central Hospital of Medical Academy, Warsaw
    Warsaw, 02-097, Poland
  • 4. Military Clinical Hospital with Polyclinic SP ZOZ
    Wroclaw, 50 981, Poland
  • CHLO, EPE - Hospital de Santa Cruz
    Carnaxide, 2795, Portugal
  • CHUC - Centro Hospitalar e Universitário de Coimbra, EPE
    Coimbra, 3041-801, Portugal
  • Centro Hosp. de Leiria-Pombal
    Leiria, 2410-197, Portugal
  • CHLC, EPE - Hospital de Santa Marta
    Lisboa, 1169-024, Portugal
  • CHLO, EPE - Hospital S. Francisco Xavier
    Lisboa, 1449-005, Portugal
  • CHULN, EPE - Hospital de Santa Maria
    Lisboa, 1649-035, Portugal
  • Centro Hospitalar Universitário São João,EPE
    Porto, 4200-319, Portugal
  • Hospital General Universitario de Alicante
    Alicante, 03010, Spain
  • Hospital Germans Trias i Pujol
    Badalona, 08916, Spain
  • Hospital San Rafael
    Granada, 18001, Spain
  • Hospital de la Inmaculada Concepción
    Granada, 18004, Spain

Showing the first 100 of 108 sites across 11 countries.

08

References and documents

Publications

  • Anker SD, Ponikowski P, Wanner C, Pfarr E, Hauske S, Peil B, Salsali A, Ritter I, Koitka-Weber A, Brueckmann M, Lindenfeld J, Abraham WT; EMPERIAL Investigators and National Coordinators. Kidney Function After Initiation and Discontinuation of Empagliflozin in Patients With Heart Failure With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials. Circulation. 2021 Oct 12;144(15):1265-1267. doi: 10.1161/CIRCULATIONAHA.121.054669. Epub 2021 Aug 16. No abstract available. Erratum In: Circulation. 2022 Feb 22;145(8):e641. doi: 10.1161/CIR.0000000000001059. PubMed 34397263 ↗
  • Abraham WT, Ponikowski P, Brueckmann M, Zeller C, Macesic H, Peil B, Brun M, Ustyugova A, Jamal W, Salsali A, Lindenfeld J, Anker SD; EMPERIAL Investigators and National Coordinators. Rationale and design of the EMPERIAL-Preserved and EMPERIAL-Reduced trials of empagliflozin in patients with chronic heart failure. Eur J Heart Fail. 2019 Jul;21(7):932-942. doi: 10.1002/ejhf.1486. Epub 2019 Jun 19. PubMed 31218819 ↗
  • Nassif ME, Kosiborod M. Effects of sodium glucose cotransporter type 2 inhibitors on heart failure. Diabetes Obes Metab. 2019 Apr;21 Suppl 2:19-23. doi: 10.1111/dom.13678. PubMed 31081589 ↗

Study documents

  • Statistical analysis plan · Oct 21, 2019
  • Study protocol · May 16, 2018

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT03448406
Lead sponsor
Boehringer Ingelheim
Collaborators
Eli Lilly and Company
Responsible party
Sponsor
First posted
Feb 28, 2018
Start date
Mar 20, 2018
Primary completion
Oct 4, 2019
Completion
Oct 9, 2019
Results posted
Dec 8, 2020
Last update
Dec 8, 2020

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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