Heart Failure
Conditions
Brief summary
The objective of this trial is to assess the effect of empagliflozin on cardiac physiology and metabolism aiming to provide a scientific explanation of the underlying mechanism by which empagliflozin improves HF related outcomes in patients with chronic heart failure
Interventions
DRUGEmpagliflozin
12 weeks
DRUGPlacebo
12 Weeks
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
* Chronic heart failure diagnosed at least 3 months before informed consent * NYHA class II-IV at screening * Age ≥ 18 years at screening * Male or female patients. Women of childbearing 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 ICH-GCP and local legislation prior to admission to the trial Cohort A Heart Failure with Reduced Ejection Fraction (HFrEF) * Left ventricular ejection fraction (LVEF) ≤ 40% as measured by ECHO at screening * The following signs of heart failure; * Elevated NT-proBNP (\>125 pg/mL) at screening in patient without atrial fibrillation (AF) * Elevated NT-proBNP (\>600 pg/mL) at screening in patient with AF * Appropriate dose of medical therapy for HF (such as ACEi, ARB, β-blocker, oral diuretics, MRA, ARNI, ivabradine) consistent with prevailing local and international HF guidelines, stable for at least one week prior to Visit 1 and during screening period until Visit 2 (Randomisation) with the exception of diuretics which must be stable for at least one week prior to Visit 2 to control symptoms. If required, the investigator must document in the source documents the reason why the patient is not on the target dose per local guidelines. Cohort B Heart Failure with Preserved Ejection Fraction (HFpEF) * Left ventricular ejection fraction (LVEF) ≥ 50% as measured by ECHO at screening and no previous measurement of LVEF ≤ 40%. * The following combined signs of heart failure; * Structural heart disease (LA enlargement \[LAVI \>34 mL/m2\] and/or LVH \[LVMI ≥ 115 g/m2 for males and ≥ 95 g/m2 for females\]) by ECHO at screening or within 3 months prior to informed consent AND * NT-proBNP \> 125pg/mL at screening in patient without AF or NT-pro-BNP \> 600 pg/mL in patient with AF * Oral diuretics, if prescribed, should be stable for at least one week prior to Visit 1 and during screening period until Visit 2 (Randomisation).
Exclusion criteria
* Stroke or transient ischaemic attack (TIA) within 6 months prior to informed consent. * Any patients with myocardial scars and/or non-viable myocardium in the interventricular septum, unstable angina due to significant coronary artery disease (CAD), or major (in the opinion of the investigator) cardiovascular surgery. * Any contraindication for MRI, CPET and/or dobutamine stress test in accordance with the institution guidance, including implanted left ventricular assist device (LVAD),implantable cardioverter defibrillator (ICD), cardiac resynchronisation therapy (CRT) or any cardiac device. * Heart transplant recipient or listed for heart transplant * Cardiomyopathy based on infiltrative diseases (e.g. amyloidosis), accumulation diseases (e.g. haemochromatosis, Fabry disease), muscular dystrophies, cardiomyopathy with reversible causes (e.g. stress cardiomyopathy), hypertrophic obstructive cardiomyopathy or known pericardial constriction * Moderate to severe uncorrected valvular heart disease, obstructive or regurgitant, or any valvular heart disease expected to lead to surgery in the Investigator's opinion * Acute decompensated HF (exacerbation of chronic HF) requiring intravenous (i.v.) diuretics, i.v. inotropes or i.v. vasodilators, or LVAD or hospitalisation within 1 week prior to Visit 1 (Screening), or during screening period until Visit 2 (Randomisation) * Systolic blood pressure (SBP) ≥ 180 mmHg at screening. If SBP \>150 mmHg and \<180mmHg at screening, the patient is ineligible if receiving 3 or more antihypertensive drugs * Symptomatic hypotension and/or a SBP \< 100 mmHg at Screening * Atrial fibrillation which is uncontrolled in the opinion of the investigator * Untreated ventricular arrhythmia with syncope documented within the 3 months prior to informed consent in patients without ICD * Diagnosis of cardiomyopathy induced by chemotherapy or peripartum within the 12 months prior to informed consent * Symptomatic bradycardia or second or third degree heart block in need of a pacemaker after adjusting beta-blocker therapy or any other negative inotropic agents, if appropriate * Chronic pulmonary disease requiring home oxygen, oral steroid therapy or hospitalisation for exacerbation within 12 months prior to informed consent, or significant chronic pulmonary disease in the Investigator's opinion, or primary pulmonary arterial hypertension * Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT),or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined at screening * Impaired renal function, defined as estimated Creatinine Clearance \< 30 mL/min (using Cockcroft-Gault formula) or requiring dialysis, as determined at screening * Haemoglobin \< 10 g/dL at screening * Type 1 Diabetes Mellitus (T1DM) * History of ketoacidosis * Major surgery (major according to the investigator's assessment) performed within 3 months prior to informed consent, or scheduled major elective surgery (e.g. hip replacement) within 3 months after Visit 1 * Gastrointestinal (GI) surgery or GI disorder that could interfere with absorption of trial medication in the investigator's opinion * Any documented active or suspected malignancy or history of malignancy within 6 months prior to informed consent, except appropriately treated basal cell carcinoma of the skin, in situ carcinoma of uterine cervix or low risk prostate cancer (patients with pretreatment PSA \<10 ng/mL, and biopsy Gleason score of ≤ 6 and clinical stage T1c or T2a) * Presence of any other disease than heart failure with a life expectancy of \<1 year in the investigator's opinion * Patients who must or wish to continue the intake of restricted medications or any drug considered likely to interfere with the safe conduct of the trial * Patients with requirement for treatment with empagliflozin according to local standard of care * Treatment with any SGLT-2 inhibitor or combined SGLT-1 and 2 inhibitor within 1 week prior to informed consent or during screening period until Visit 2 (Randomisation) * Currently enrolled in another investigational device or drug study, or less than 30 days between randomisation and ending another investigational device or drug study, or receiving other investigational treatment(s). Patients participating in a purely observational trial will not be excluded. * Known allergy or hypersensitivity to empagliflozin or other SGLT-2 inhibitors * Chronic alcohol or drug abuse or any condition that, in the investigator's opinion, makes them an unreliable trial subject or unlikely to complete the trial * Women who are pregnant, breastfeeding, or who plan to become pregnant while in the trial * Any clinical condition that would jeopardise patients safety while participating in this trial, or may prevent the subject from adhering to the trial protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS). | At baseline and at week 12. | The primary endpoint of efficacy was the change from baseline to Week 12 in phosphocreatine/adenosine triphosphate (PCr/ATP) ratio in the resting state measured by 31P cardiac magnetic resonance spectroscopy (MRS). Adjusted mean values were calculated using an analysis of variance (ANOVA) model, with treatment, history of diabetes, and history of atrial fibrillation (AF) as fixed effects. |
Countries
United Kingdom
Participant flow
Recruitment details
A randomised, double-blind, placebo controlled, mechanistic cardiac magnetic resonance study to investigate the effects of empagliflozin treatment on cardiac physiology and metabolism in patients with heart failure.
Pre-assignment details
All subjects were screened for eligibility to participate in trial. Subjects attended specialist site to ensure that they (the subjects) met all implemented inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Cohort A Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks.
Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF). | 19 |
| Placebo Cohort B Once a day oral administration of a single film-coated placebo tablet matching to empagliflozin for 12 weeks.
Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF). | 18 |
| Empagliflozin 10mg Cohort A Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks.
Cohort A: Heart failure (HF) with reduced ejection fraction (HFrEF). | 17 |
| Empagliflozin 10mg Cohort B Once a day oral administration of a single 10 milligram (mg) film-coated empagliflozin tablet for 12 weeks.
Cohort B: Heart failure (HF) with preserved ejection fraction (HFpEF). | 18 |
| Total | 72 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Not treated | 0 | 1 | 0 | 0 |
| Overall Study | worsening of disease under study | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo Cohort A | Total | Empagliflozin 10mg Cohort B | Empagliflozin 10mg Cohort A | Placebo Cohort B |
|---|---|---|---|---|---|
| Age, Continuous | 64.7 Years STANDARD_DEVIATION 12.7 | 68.3 Years STANDARD_DEVIATION 11.5 | 69.1 Years STANDARD_DEVIATION 10.9 | 67.5 Years STANDARD_DEVIATION 14.1 | 72.1 Years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 72 Participants | 18 Participants | 17 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 70 Participants | 16 Participants | 17 Participants | 18 Participants |
| Ratio of phosphocreatine to adenosine triphosphate concentration | 1.924 Ratio STANDARD_DEVIATION 0.354 | 1.859 Ratio STANDARD_DEVIATION 0.413 | 1.896 Ratio STANDARD_DEVIATION 0.462 | 1.889 Ratio STANDARD_DEVIATION 0.407 | 1.719 Ratio STANDARD_DEVIATION 0.431 |
| Sex: Female, Male Female | 6 Participants | 30 Participants | 8 Participants | 7 Participants | 9 Participants |
| Sex: Female, Male Male | 13 Participants | 42 Participants | 10 Participants | 10 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 36 | 0 / 35 |
| other Total, other adverse events | 3 / 36 | 8 / 35 |
| serious Total, serious adverse events | 7 / 36 | 1 / 35 |
Outcome results
Primary
Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS).
The primary endpoint of efficacy was the change from baseline to Week 12 in phosphocreatine/adenosine triphosphate (PCr/ATP) ratio in the resting state measured by 31P cardiac magnetic resonance spectroscopy (MRS). Adjusted mean values were calculated using an analysis of variance (ANOVA) model, with treatment, history of diabetes, and history of atrial fibrillation (AF) as fixed effects.
Time frame: At baseline and at week 12.
Population: Per protocol set (PPS):~The primary endpoint analysis was performed using the per protocol (PP) set of patients with valid PCr/ATP ratio measurements available at baseline and Week 12, and no important protocol violation relevant to the primary endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Cohort A | Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS). | 0.068 PCr / ATP Ratio | Standard Error 0.114 |
| Placebo Cohort B | Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS). | 0.259 PCr / ATP Ratio | Standard Error 0.156 |
| Empagliflozin 10mg Cohort A | Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS). | -0.179 PCr / ATP Ratio | Standard Error 0.117 |
| Empagliflozin 10mg Cohort B | Change From Baseline to Week 12 in PCr/ATP Ratio in the Resting State Measured by 31P Cardiac Magnetic Resonance Spectroscopy (MRS). | 0.100 PCr / ATP Ratio | Standard Error 0.143 |
Comparison: ANOVA on the PCr/ATP ratio absolute change using treatment (empagliflozin vs. placebo), history of diabetes (yes vs, no) and history of atrial fibrillation (yes vs no) as between subjects factor.p-value: 0.141895% CI: [-0.582, 0.087]ANOVA
Comparison: ANOVA on the PCr/ATP ratio absolute change using treatment (empagliflozin vs. placebo), history of diabetes (yes vs, no) and history of atrial fibrillation (yes vs no) as between subjects factor.p-value: 0.46595% CI: [-0.604, 0.286]ANOVA