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The feasibility (recruitment) of the high number of patients (402 patients with HFrEF or HFmrEF) was impossible due to the rapid increase in SGLT2 inhibitors in patients with heart failure.
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| Name | Class |
|---|---|
| Klinikum Klagenfurt am Wörthersee | OTHER |
| Elisabethinen Hospital | OTHER |
| Medical University Innsbruck | OTHER |
| Medical University of Vienna |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ertugliflozin | Active Comparator | The subject will receive Ertugliflozin 5mg. |
|
| Placebo | Placebo Comparator | The subject will receive Placebo 5mg. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ertugliflozin 5 mg | Drug | The subject will receive Ertugliflozin 5mg orally once daily for 52 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 52 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Nonsustained Ventricular Tachycardia (nsVT) Episodes | Number of nonsustained ventricular tachycardia (nsVT) episodes from baseline to week 52 | 52 weeks |
| Number of Episodes of Appropriate Implantable Cardioverter-defibrillator Therapies |
Not provided
Inclusion Criteria:
HFrEF or HFmrEF, and ICD±CRT therapy > 3 months
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:
Informed consent has to be given in written form.
estimated glomerular filtration rate (eGFR) > 30 ml/min/1.73m2
Blood pressure before first drug dosing: blood pressure systolic > 100 mmHg
Blood pressure before first drug dosing: blood pressure diastolic > 60 mmHg
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Dirk von Lewinski, Assoc-Prof. | Medical University of Graz | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Klinikum Klagenfurt am Wörthersee | Klagenfurt | Carinthia | 9020 | Austria | ||
| Kepler Universitätsklinikum Linz |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 39217453 | Derived | Benedikt M, Oulhaj A, Rohrer U, Manninger M, Tripolt NJ, Pferschy PN, Aziz F, Wallner M, Kolesnik E, Gwechenberger M, Martinek M, Nurnberg M, Roithinger FX, Steinwender C, Widkal J, Leiter S, Zirlik A, Stuhlinger M, Scherr D, Sourij H, von Lewinski D. Ertugliflozin to Reduce Arrhythmic Burden in Patients with ICDs/CRT-Ds. NEJM Evid. 2024 Oct;3(10):EVIDoa2400147. doi: 10.1056/EVIDoa2400147. Epub 2024 Sep 1. | |
| 35045327 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Ertugliflozin | The subject will receive Ertugliflozin 5mg. Ertugliflozin 5 mg: The subject will receive Ertugliflozin 5mg orally once daily for 52 weeks. |
| FG001 | Placebo | The subject will receive Placebo 5mg. Placebo 5mg: The subject will receive Placebo 5mg orally daily for 52 weeks. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Dec 22, 2021 | Nov 19, 2024 |
Not provided
| OTHER |
| General Hospital Linz | OTHER |
| Landesklinkum Wiener Neustadt | OTHER |
| Klinik Ottakring | UNKNOWN |
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| Placebo 5mg | Drug | The subject will receive Placebo 5mg orally daily for 52 weeks. |
|
|
Number of episodes of appropriate Implantable cardioverter-defibrillator therapies from baseline to week 52.
| 52 weeks |
| Change in NTproBNP Levels | Change in NTproBNP levels from baseline to week 52 | 52 weeks |
| Change in HbA1c Levels | Change in HbA1c levels from baseline to week 52 | 52 weeks |
| Number of Hospitalizations | Number of hospitalizations from baseline to week 56 | 56 weeks |
| 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 | 56 weeks |
| Number of Hospitalizations Due to Heart Failure | It is the number of hospital re-admissions due to heart failure from baseline to 56 weeks. | 56 weeks |
| Duration of Hospital Stay | It is the number of days of hospital stay from baseline to 56 weeks | 56 weeks |
| Cardiovascular Mortality | Difference in Cardiovascular mortality between treatment groups from randomisation to week 56 | 56 weeks |
| Linz |
| Upper Austria |
| 4021 |
| Austria |
| Medical University of Graz | Graz | 8010 | Austria |
| Universitätsklinikum Innsbruck | Innsbruck | 620 | Austria |
| Ordensklinikum Linz Elisabethinen | Linz | 4020 | Austria |
| Medizinische Universität Wien, AKH Wien | Vienna | 1090 | Austria |
| Wilhelminenspital | Vienna | 1160 | Austria |
| Landesklinikum Wiener Neustadt | Wiener Neustadt | 2700 | Austria |
| Derived |
| von Lewinski D, Tripolt NJ, Sourij H, Pferschy PN, Oulhaj A, Alber H, Gwechenberger M, Martinek M, Seidl S, Moertl D, Nurnberg M, Roithinger FX, Steinwender C, Stuhlinger M, Zirlik A, Benedikt M, Kolesnik E, Wallner M, Rohrer U, Manninger M, Scherr D; ERASe study group. Ertugliflozin to reduce arrhythmic burden in ICD/CRT patients (ERASe-trial) - A phase III study. Am Heart J. 2022 Apr;246:152-160. doi: 10.1016/j.ahj.2022.01.008. Epub 2022 Jan 16. |
| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Ertugliflozin | The subject will receive Ertugliflozin 5mg. Ertugliflozin 5 mg: The subject will receive Ertugliflozin 5mg orally once daily for 52 weeks. |
| BG001 | Placebo | The subject will receive Placebo 5mg. Placebo 5mg: The subject will receive Placebo 5mg orally once daily for 52 weeks. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | The inclusion criteria for age was 18 to 80 years. | Mean | Standard Deviation | years |
| ||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||
| Region of Enrollment | Count of Participants | Participants |
| ||||||||||||||||
| Body Mass Index (BMI) | Height was meausred at the screening visit. Weight was measured at all visits. BMI was calculated using the formula as follows: BMI = weight (kg) / height² (m²) | Mean | Standard Deviation | kg/m² |
| ||||||||||||||
| Systolic blood pressure | Systolic blood pressure was meausred in sitting position at all visits. | Mean | Standard Deviation | mmHg |
| ||||||||||||||
| Diastolic blood pressure | Diastolic blood pressure was measured in sitting position at all visits. | Mean | Standard Deviation | mmHg |
| ||||||||||||||
| Heart rate | Heart rate was recorded at all visits after resting for 5 minutes in a sitting position. | Mean | Standard Deviation | beats/minute |
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| Baseline medications | Count of Participants | Participants |
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| Baseline arrhythmic burden, 12 months prior | Mean | Standard Deviation | Number of episodes |
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| Left ventricular ejection fraction, 12 months prior | Mean | Standard Deviation | percentage |
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| Potassium concentration | Mean | Standard Deviation | mmol/l |
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| Magnesium concentration | Mean | Standard Deviation | mmol/l |
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| C-reactive protein level | Mean | Standard Deviation | mg/l |
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| Estimated glomerular filtration rate | Mean | Standard Deviation | ml/min/1.73m² |
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| NTproBNP levels | Mean | Standard Deviation | ng/l |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 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. | Posted | Mean | Standard Deviation | Number of episode | 52 weeks |
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| Secondary | Number of Nonsustained Ventricular Tachycardia (nsVT) Episodes | Number of nonsustained ventricular tachycardia (nsVT) episodes from baseline to week 52 | Posted | Mean | Standard Deviation | Number of episodes | 52 weeks |
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| Secondary | Number of Episodes of Appropriate Implantable Cardioverter-defibrillator Therapies | Number of episodes of appropriate Implantable cardioverter-defibrillator therapies from baseline to week 52. | Posted | Mean | Standard Deviation | Number of ICD therapies | 52 weeks |
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| Secondary | Change in NTproBNP Levels | Change in NTproBNP levels from baseline to week 52 | Posted | Median | Inter-Quartile Range | ng/l | 52 weeks |
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| Secondary | Change in HbA1c Levels | Change in HbA1c levels from baseline to week 52 | Posted | Mean | Standard Deviation | mmol/mol | 52 weeks |
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| Secondary | Number of Hospitalizations | Number of hospitalizations from baseline to week 56 | Posted | Mean | Standard Deviation | number of hospitalizations | 56 weeks |
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| 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 | Posted | Count of Participants | Participants | 56 weeks |
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| 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. | Posted | Number | Number of patients | 56 weeks |
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| Secondary | Duration of Hospital Stay | It is the number of days of hospital stay from baseline to 56 weeks | Posted | Mean | Standard Deviation | Number of days | 56 weeks |
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| Secondary | Cardiovascular Mortality | Difference in Cardiovascular mortality between treatment groups from randomisation to week 56 | Posted | Count of Participants | Participants | 56 weeks |
|
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Adverse events are recorded from baseline to 56 weeks
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ertugliflozin | The subject will receive Ertugliflozin 5mg. Ertugliflozin 5 mg: The subject will receive Ertugliflozin 5mg orally once daily for 52 weeks. | 3 | 25 | 10 | 25 | 4 | 25 |
| EG001 | Placebo | The subject will receive Placebo 5mg. Placebo 5mg: The subject will receive Placebo 5mg orally daily for 52 weeks. | 3 | 30 | 21 | 30 | 2 | 30 |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hospitalization due to cardiovascular event | Cardiac disorders | Non-systematic Assessment |
| ||
| Cardiovascular death | Cardiac disorders | Non-systematic Assessment |
| ||
| Hospitalization due to non-cardiovascular causes | General disorders | Non-systematic Assessment |
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| Non-cardiovascular death | General disorders | Non-systematic Assessment |
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| Infectious disease | Infections and infestations | Non-systematic Assessment |
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| Cancer | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Non-systematic Assessment |
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| Seizure | Nervous system disorders | Non-systematic Assessment |
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| Any Hospitalization | General disorders | Non-systematic Assessment |
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| Death | General disorders | Non-systematic Assessment |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hepatic Injury | Hepatobiliary disorders | Non-systematic Assessment | Adverse event of special interest |
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| Renal Injury | General disorders | Non-systematic Assessment | Adverse event of special interest |
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| Metabolic acidosis and diabetic ketoacidosis | Metabolism and nutrition disorders | Non-systematic Assessment | Adverse event of special interest |
| |
| Event involving lower limb amputation | Musculoskeletal and connective tissue disorders | Non-systematic Assessment | Adverse event of special interest |
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| Urinary tract infection | Infections and infestations | Non-systematic Assessment | Other adverse event |
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| Genital fungal infection | Infections and infestations | Non-systematic Assessment | Other adverse event |
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| Hypotension | Blood and lymphatic system disorders | Non-systematic Assessment | Other adverse event |
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| Polyuria | General disorders | Non-systematic Assessment | Other adverse event |
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| Total Hypoglycemia | Metabolism and nutrition disorders | Non-systematic Assessment | Other adverse event |
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An important limitation is the lack of generalizability because our study predominantly included White men. A second limitation is that our trial was prematurely stopped, and thus we did not achieve the planned power to accurately assess our primary end point. In addition, seven patients withdrew their consent to continue in the trial. Therefore, the results of our primary and key secondary end points must be interpreted with caution.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Dirk von Lewinski | Department of Internal Medicine, Division of Cardiology, Medical University of Graz | +4331638580684 | dirk.von-lewinski@medunigraz.at |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Feb 19, 2024 | Nov 21, 2024 | SAP_001.pdf |
| ID | Term |
|---|---|
| D006333 | Heart Failure |
| D017180 | Tachycardia, Ventricular |
| ID | Term |
|---|---|
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D013610 | Tachycardia |
| D001145 | Arrhythmias, Cardiac |
| D000075224 | Cardiac Conduction System Disease |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| C570288 | ertugliflozin |
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| Male |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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| Beta-blockers |
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| Mineralocorticoid receptor blocker |
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| Angiotensin receptor blocker and neprilysin inhibitor |
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| Loop diuretics |
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| Dihydropyridine (CCB) |
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| Verapamil/Diltiazem (CCB) |
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| Digitalis |
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| Amiodarone/sotalol |
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| Supplemental Magnesium |
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| Platelet aggregation inhibitors |
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| Anticoagulants |
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| Statins |
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| Non-sustained Ventricular tachycardia episodes |
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Ertugliflozin is the numerator and the placebo is the denominator. |
| Superiority |
The parameters required to calculate sample size were the expected rate of VT/VF episodes/year in the placebo group, the minimal VT/VF rate ratio to be detected in the ertugliflozin group compared with the placebo group, the average follow-up of treatment duration, the negative binomial dispersion parameter, type 1 error probability, and the desired power. |
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