Heart Failure With Reduced Ejection Fraction, Heart Failure With Mid Range Ejection Fraction, Implantable Cardioverter-Defibrillators, Cardiac Resynchronization Therapy
Conditions
Keywords
Ertugliflozin, Sodium dependent glucose transporter-2 inhibitor (SGLT-2), Heart failure, ICD, CRT, ventricular tachycardia (VT)
Brief summary
The recent study is planned to investigate the impact of Ertugliflozin on total burden of ventricular arrhythmias. Further objectives will be number of therapeutic interventions of implanted devices, atrial fibrillation, heart failure biomarker and changes in physical function quality of life, stress and anxiety.
Detailed description
This is a randomized, double-blind (patients and physicians), placebo controlled multi-center study to evaluate the effect of ertugliflozin 5mg once daily (p.o.) for 52 weeks on the ventricular arrhythmic burden and markers of physical and mental well-being as well as biomarker for Heart Failure with reduced Ejection Fraction (HFrEF) and heart failure with mid-range ejection fraction (HFmrEF) patients with ICD±CRT therapy. The study will be conducted in 8 experienced sites in Austria with an aim to enrol 402 patients to evaluate the overall study hypothesis. Therefore, three study visits will be carried out (baseline, 1-year follow-up visit and a telephone visit 4 weeks after visit 2). As part of the two on-site study visits, study-specific measures, a blood sample and an echocardiographic examination will be performed. The trial is completed by a telephone visit 4 weeks after the second on-site visit (week 52). It is anticipated that the study will run for 30 months.
Interventions
The subject will receive Ertugliflozin 5mg orally once daily for 52 weeks.
DRUGPlacebo 5mg
The subject will receive Placebo 5mg orally daily for 52 weeks.
Sponsors
Klinikum Klagenfurt am Wörthersee
Elisabethinen Hospital
Medical University Innsbruck
Medical University of Vienna
General Hospital Linz
Landesklinkum Wiener Neustadt
Klinik Ottakring
Medical University of Graz
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
1. HFrEF or HFmrEF, and ICD±CRT therapy \> 3 months 2. at least 10 documented VT episodes (either nsVT (non-sustained ventricular tachycardia) or sVT (sustained ventricular tachycardia) ± ICD (mplantable cardioverter-defibrillator) treatment) within the last 12 months plus: * nt-proBNP \> 500pg/mL or * Left-ventricular Ejection Fraction (LV-EF) \< 35% or * hospitalization for heart failure within the last 12 months or * \> 100 nsVTs within the last 12 months * \> 1 sVT/VF (ventricular function) within the last 12 months 3. Informed consent has to be given in written form. 4. estimated glomerular filtration rate (eGFR) \> 30 ml/min/1.73m2 5. Blood pressure before first drug dosing: blood pressure systolic \> 100 mmHg 6. Blood pressure before first drug dosing: blood pressure diastolic \> 60 mmHg
Exclusion criteria
1. Any other form of diabetes mellitus than type 2 diabetes mellitus, history of diabetic ketoacidosis 2. Ongoing ventricular arrhythmia 3. Known allergy to SGLT-2 inhibitors 4. Haemodynamic instability as defined by intravenous administration of catecholamine, calciumsensitizers or phosphodiesterase inhibitors 5. \>1 episode of severe hypoglycemia within the last 6 months under treatment with insulin or sulfonylurea 6. Planned catheter ablation for ventricular arrhythmia 7. Planned explantation of ICD, or planned up/downgrade to/from CRT-D device 8. Existing therapy with SGLT-2 inhibitors
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Number of Supraventricular Tachycardia (svT)/ Ventricular Fibrillation (VF) Episodes | 52 weeks | Change in number of supraventricular tachycardia (svT)/ ventricular fibrillation (VF) episodes from baseline to week 52 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiovascular Mortality | 56 weeks | Difference in Cardiovascular mortality between treatment groups from randomisation to week 56 |
| Number of Nonsustained Ventricular Tachycardia (nsVT) Episodes | 52 weeks | Number of nonsustained ventricular tachycardia (nsVT) episodes from baseline to week 52 |
| Number of Episodes of Appropriate Implantable Cardioverter-defibrillator Therapies | 52 weeks | Number of episodes of appropriate Implantable cardioverter-defibrillator therapies from baseline to week 52. |
| Change in NTproBNP Levels | 52 weeks | Change in NTproBNP levels from baseline to week 52 |
| Duration of Hospital Stay | 56 weeks | It is the number of days of hospital stay from baseline to 56 weeks |
| Number of Hospitalizations | 56 weeks | Number of hospitalizations from baseline to week 56 |
| Atleast One Hospitalization Due to Heart Failure | 56 weeks | It is the number of patients with at least one hospital re-admission due to heart failure from baseline to 56 weeks |
| Number of Hospitalizations Due to Heart Failure | 56 weeks | It is the number of hospital re-admissions due to heart failure from baseline to 56 weeks. |
| Change in HbA1c Levels | 52 weeks | Change in HbA1c levels from baseline to week 52 |
Countries
Austria
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ertugliflozin The subject will receive Ertugliflozin 5mg.
Ertugliflozin 5 mg: The subject will receive Ertugliflozin 5mg orally once daily for 52 weeks. | 22 |
| Placebo The subject will receive Placebo 5mg.
Placebo 5mg: The subject will receive Placebo 5mg orally once daily for 52 weeks. | 24 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 5 |
Baseline characteristics
| Characteristic | Ertugliflozin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 65 years STANDARD_DEVIATION 11 | 66 years STANDARD_DEVIATION 12 | 65 years STANDARD_DEVIATION 11 |
| Baseline arrhythmic burden, 12 months prior Non-sustained Ventricular tachycardia episodes | 22 Number of episodes STANDARD_DEVIATION 33 | 27 Number of episodes STANDARD_DEVIATION 57 | 25 Number of episodes STANDARD_DEVIATION 47 |
| Baseline arrhythmic burden, 12 months prior Sustained ventricular tachycardia or Ventricular fibrillation | 19 Number of episodes STANDARD_DEVIATION 44 | 6 Number of episodes STANDARD_DEVIATION 10 | 12 Number of episodes STANDARD_DEVIATION 32 |
| Baseline medications Amiodarone/sotalol | 4 Participants | 6 Participants | 10 Participants |
| Baseline medications Angiotensin-converting enzyme inhibitor/ Angiotensin receptor blocker | 13 Participants | 12 Participants | 25 Participants |
| Baseline medications Angiotensin receptor blocker and neprilysin inhibitor | 6 Participants | 8 Participants | 14 Participants |
| Baseline medications Anticoagulants | 15 Participants | 12 Participants | 27 Participants |
| Baseline medications Beta-blockers | 18 Participants | 21 Participants | 39 Participants |
| Baseline medications Digitalis | 2 Participants | 2 Participants | 4 Participants |
| Baseline medications Dihydropyridine (CCB) | 2 Participants | 2 Participants | 4 Participants |
| Baseline medications Loop diuretics | 9 Participants | 15 Participants | 24 Participants |
| Baseline medications Mineralocorticoid receptor blocker | 12 Participants | 14 Participants | 26 Participants |
| Baseline medications Platelet aggregation inhibitors | 4 Participants | 6 Participants | 10 Participants |
| Baseline medications Statins | 14 Participants | 15 Participants | 29 Participants |
| Baseline medications Supplemental Magnesium | 6 Participants | 5 Participants | 11 Participants |
| Baseline medications Verapamil/Diltiazem (CCB) | 0 Participants | 0 Participants | 0 Participants |
| Body Mass Index (BMI) | 28.6 kg/m² STANDARD_DEVIATION 5.3 | 28.2 kg/m² STANDARD_DEVIATION 6.3 | 28.4 kg/m² STANDARD_DEVIATION 5.8 |
| C-reactive protein level | 3 mg/l STANDARD_DEVIATION 3 | 2 mg/l STANDARD_DEVIATION 2 | 2 mg/l STANDARD_DEVIATION 3 |
| Diastolic blood pressure | 87 mmHg STANDARD_DEVIATION 12 | 81 mmHg STANDARD_DEVIATION 15 | 84 mmHg STANDARD_DEVIATION 14 |
| Estimated glomerular filtration rate | 65 ml/min/1.73m² STANDARD_DEVIATION 21 | 57 ml/min/1.73m² STANDARD_DEVIATION 16 | 61 ml/min/1.73m² STANDARD_DEVIATION 18 |
| Heart rate | 68 beats/minute STANDARD_DEVIATION 12 | 72 beats/minute STANDARD_DEVIATION 13 | 70 beats/minute STANDARD_DEVIATION 13 |
| Left ventricular ejection fraction, 12 months prior | 36 percentage STANDARD_DEVIATION 8 | 38 percentage STANDARD_DEVIATION 14 | 37 percentage STANDARD_DEVIATION 11 |
| Magnesium concentration | 0.9 mmol/l STANDARD_DEVIATION 0.1 | 0.8 mmol/l STANDARD_DEVIATION 0.1 | 0.9 mmol/l STANDARD_DEVIATION 0.1 |
| NTproBNP levels | 1141 ng/l STANDARD_DEVIATION 1598 | 2370 ng/l STANDARD_DEVIATION 2714 | 1782 ng/l STANDARD_DEVIATION 2311 |
| Potassium concentration | 4.5 mmol/l STANDARD_DEVIATION 0.6 | 4.5 mmol/l STANDARD_DEVIATION 0.5 | 4.5 mmol/l STANDARD_DEVIATION 0.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 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 | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 24 Participants | 46 Participants |
| Region of Enrollment Austria | 22 Participants | 24 Participants | 46 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 20 Participants | 22 Participants | 42 Participants |
| Systolic blood pressure | 136 mmHg STANDARD_DEVIATION 13 | 131 mmHg STANDARD_DEVIATION 21 | 133 mmHg STANDARD_DEVIATION 18 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 25 | 3 / 30 |
| other Total, other adverse events | 4 / 25 | 2 / 30 |
| serious Total, serious adverse events | 10 / 25 | 21 / 30 |
Outcome results
Primary
Change in Number of Supraventricular Tachycardia (svT)/ Ventricular Fibrillation (VF) Episodes
Change in number of supraventricular tachycardia (svT)/ ventricular fibrillation (VF) episodes from baseline to week 52
Time frame: 52 weeks
Population: We randomized 55 patients, 25 in the ertugliflozin group and 30 in the placebo group. 5 patients from the placebo group and 3 from the placebo group withdrew consent before termination of the trial. 1 patient from the placebo group died without sufficient telemetric data. Consequently, only 46 patients were analysed including 22 in the ertugliflozin group and 24 in the placebo group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin | Change in Number of Supraventricular Tachycardia (svT)/ Ventricular Fibrillation (VF) Episodes | 3 Number of episode | Standard Deviation 6 |
| Placebo | Change in Number of Supraventricular Tachycardia (svT)/ Ventricular Fibrillation (VF) Episodes | 13 Number of episode | Standard Deviation 34 |
Comparison: We compared the rate of sVT/VF episodes between experimental arms after 52 weeks.The initial sample calculation was based on the mathematical formula provided by Zhu and Lakkis for comparing event rates of two negative binomial distributiuons. To detect a 30% reduction in VT/VF episode rates in the ertugliflozin group compared to placebo group, with 80% power and an alpha level of 0.05, accounting for 5% drop out in each group, a total sample size of 402 was estimated to be required.p-value: <0.00195% CI: [0.04, 0.61]Negative binomial regression model
Secondary
Atleast One Hospitalization Due to Heart Failure
It is the number of patients with at least one hospital re-admission due to heart failure from baseline to 56 weeks
Time frame: 56 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ertugliflozin | Atleast One Hospitalization Due to Heart Failure | 1 Participants |
| Placebo | Atleast One Hospitalization Due to Heart Failure | 4 Participants |
Secondary
Cardiovascular Mortality
Difference in Cardiovascular mortality between treatment groups from randomisation to week 56
Time frame: 56 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ertugliflozin | Cardiovascular Mortality | 0 Participants |
| Placebo | Cardiovascular Mortality | 2 Participants |
Secondary
Change in HbA1c Levels
Change in HbA1c levels from baseline to week 52
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin | Change in HbA1c Levels | -0.9 mmol/mol | Standard Deviation 5.1 |
| Placebo | Change in HbA1c Levels | -1.33 mmol/mol | Standard Deviation 4.9 |
Comparison: The change in HbA1c levels from baseline to week 52 was analyzed by multiple linear regression model.95% CI: [-1.69, 3.13]
Secondary
Change in NTproBNP Levels
Change in NTproBNP levels from baseline to week 52
Time frame: 52 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ertugliflozin | Change in NTproBNP Levels | 143 ng/l |
| Placebo | Change in NTproBNP Levels | 101 ng/l |
Comparison: The change in NTproBNP levels was analyzed by using a multiple linear regression model.p-value: >0.0595% CI: [-0.35, 0.69]Regression, Linear
Secondary
Duration of Hospital Stay
It is the number of days of hospital stay from baseline to 56 weeks
Time frame: 56 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin | Duration of Hospital Stay | 3.6 Number of days | Standard Deviation 5.3 |
| Placebo | Duration of Hospital Stay | 10.4 Number of days | Standard Deviation 23.5 |
Secondary
Number of Episodes of Appropriate Implantable Cardioverter-defibrillator Therapies
Number of episodes of appropriate Implantable cardioverter-defibrillator therapies from baseline to week 52.
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin | Number of Episodes of Appropriate Implantable Cardioverter-defibrillator Therapies | 5 Number of ICD therapies | Standard Deviation 8 |
| Placebo | Number of Episodes of Appropriate Implantable Cardioverter-defibrillator Therapies | 10 Number of ICD therapies | Standard Deviation 33 |
Comparison: The number of appropriate ICD therapies were analyzed by using beta binomial model.95% CI: [0.13, 1.81]
Secondary
Number of Hospitalizations
Number of hospitalizations from baseline to week 56
Time frame: 56 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin | Number of Hospitalizations | 0.7 number of hospitalizations | Standard Deviation 1 |
| Placebo | Number of Hospitalizations | 1.3 number of hospitalizations | Standard Deviation 2.2 |
95% CI: [0.2, 1.7]
Secondary
Number of Hospitalizations Due to Heart Failure
It is the number of hospital re-admissions due to heart failure from baseline to 56 weeks.
Time frame: 56 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ertugliflozin | Number of Hospitalizations Due to Heart Failure | 1 Number of patients |
| Placebo | Number of Hospitalizations Due to Heart Failure | 12 Number of patients |
Secondary
Number of Nonsustained Ventricular Tachycardia (nsVT) Episodes
Number of nonsustained ventricular tachycardia (nsVT) episodes from baseline to week 52
Time frame: 52 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ertugliflozin | Number of Nonsustained Ventricular Tachycardia (nsVT) Episodes | 28 Number of episodes | Standard Deviation 54 |
| Placebo | Number of Nonsustained Ventricular Tachycardia (nsVT) Episodes | 130 Number of episodes | Standard Deviation 322 |
Comparison: The number of incident nsVT episodes were analyzed using a beta binomial model.95% CI: [0.12, 0.97]