SGLT2 Inhibitor TrEatment iN Patients Awaiting cOronary arTery bYpass Surgery to Reduce Post-opErative AF

Study Overview
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Brief Summary
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The goal of this randomized, double-blinded, controlled clinical trial is to investigate if treatment with an sodium-glucose cotransporter-2 inhibitor (SGLT2) during the unique time window before coronary artery bypass surgery (CABG), can reduce the incidence of post-operative atrial fibrillation and/or acute kidney injury in patients with chronic coronary syndrome. The main questions it aims to answer are: Does treatment with an SGLT2 inhibitor during the waiting time and stable post-operative period, in patients with chronic coronary syndrome scheduled for CABG, reduce the risk of new onset atrial fibrillation compared to placebo? Does treatment with an SGLT2 inhibitor during the waiting time and stable post-operative period, in patients with chronic coronary syndrome scheduled for CABG, reduce the risk of acute kidney injury before hospital discharge compared to placebo? Participants will be administered dapagliflozin 10 mg once daily or placebo for a minimum of seven days while awaiting scheduled CABG and up until discharge, with a short interruption for surgery. Researchers will compare the active arm to the placebo arm to see if dapagliflozin can reduce the incidence of post-operative atrial fibrillation and/or acute kidney injury in patients with chronic coronary syndrome.

Detailed Description
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Name of investigational treatment: Dapagliflozin. Title of study: SGLT2 inhibitor TrEatment iN patients awaiting cOronary arTery bYpass surgery to reduce Post-opErative atrial fibrillation and kidney injury (STENOTYPE). Study centers: Up to 6 centers in Sweden and Denmark. Planned study period: 2023-2025. Follow up to 2026 via registries. Phase of development. Phase IV. Objectives: In a multicenter, prospective, randomized, controlled clinical trial to compare dapagliflozin 10 mg once daily and placebo in preventing post-operative atrial fibrillation and kidney injury in patients undergoing coronary artery bypass surgery (CABG). Methodology: Following informed consent, participants are randomized in a 1:1 fashion to dapagliflozin 10 mg once daily or placebo for a minimum of 7 days while awaiting scheduled CABG. Number of subjects: 800 Primary endpoint: Incidence of new onset post-operative atrial fibrillation (AF). Secondary endpoints: Acute kidney injury defined as at least 50% increase or absolute increase of 26.5 µmol/L in serum creatinine (Kidney Disease Improving Global Outcomes grade 1 or above) before discharge (key secondary outcome). Atrial fibrillation burden on telemetry. Troponin-I (end of CABG, and after 6±2, 12±2 hours, and 3 days). N-terminal pro-B-type natriuretic peptide (end of CABG, after 6±2, 12±2 hours, and 3 days). New onset heart failure. Interleukin 1 and 6, tumor necrosis factor α, high-sensitivity C-reactive protein (end of CABG, and after 6±2, 12±2 hours, and 3 days). Change in glycated haemoglobin from before to 3 days after CABG. Length of hospital stay. Length of intensive care unit stay. Stroke. In-hospital mortality. 30-day mortality. All events will be adjudicated by an independent clinical endpoint committee. Quality assurance (registries). It is compulsory to register all patients undergoing CABG in Sweden and Denmark in national registries. All registry data are routinely validated in the participating countries as part of routine registry function. Sites will be monitored according to a specific study monitoring plan. Data checks are part of the registries used and uses predefined rules for range and consistency with other data fields in the registry. Source data verification is part of routine registry maintenance by comparing the data to medical records. Overall agreement between registry data and medical records is >95% . Standard Operating Procedures: Before starting the clinical trial all centers will have a telephone/web-based start meeting with presentation of the study, study procedures and documentation. The first visit at site will be when the center has included some patients into the study. During the study period, monitors will have regular contact with the participating departments to ensure that the trial is conducted in compliance with the protocol and applicable regulatory requirements. The monitors will also provide information and support to the investigator(s). The number of monitoring visits will be limited and unless no specific problems occur the main part of the monitoring will be centralized by regular checks of the data quality in the database. Moreover logs of signed informed consents and AE forms will be sent to the sponsor for follow-up. The monitors will review source documents for verification of consistency with the study data recorded in CRF according to risk based monitoring. Investigators and other responsible personnel must be available during the monitoring visits, possible audits and inspections and should devote sufficient time to these processes. Patient recruitment status is continuous (updated every 24 hours on weekdays) and will be available on the trial website. Reporting for adverse events: Registration of adverse events will start after informed consent and when treatment with study medication has been given and continue until the patient leaves the hospital after the CABG. The same time limit will be used in both treatment groups. The patients will be informed to contact the investigator or study nurse if any adverse event should occur during this timeframe. An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal investigational product. Medical occurrences that are symptoms of existing disease, and that do represent an exacerbation of that disease, or the CABG procedure are not defined as AE's in this clinical trial. Also elective hospitalisations for pre-treatment conditions are not AE's. AEs not to be reported are also those defined as study endpoints. An IEC will evaluate for safety after 100 patients. Serious Adverse Events - SAE: A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose: results in death, is life-threatening, requires hospitalisation or prolongation of existing inpatients' hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth effect, other important medical event. Hospitalisation or prolongation for existing inpatient hospitalisation disease and that do represent an exacerbation of that disease and the CABG procedure as well as other events non-related to the study medication will not be reported as an SAE. Suspected Unexpected Serious Adverse Reaction - SUSAR: All serious adverse events (SAE) must be evaluated unexpected and drug related or not. The definition of an unexpected adverse reaction is an adverse event, which has not been documented or reported earlier. If the responsible investigator judges the SAE as being drug related and unexpected it must be promptly reported to the sponsor, who is responsible for reporting SUSARs to the Regulatory Authorities and the Ethics Committee. Whether the reaction is expected or not will be assessed against the SPC. Assessment of severity. For all adverse events, serious as well as non-serious, the investigator must make an assessment of severity. Relationship should be classified according to the following definitions. Mild: Awareness of sign or symptom, but easily tolerated and cause no interference with daily activities. Moderate: Discomfort enough to cause interference with daily activities. Severe: Inability to perform normal daily activities. Relationship to study drug. The investigator will judge whether or not, in his/her opinion, the adverse event is associated with the study treatment. Relationship should be classified according to the following definitions: Probable: An adverse event, which might be due to the use of the drug. The relationship in time is suggestive (e.g. confirmed by dechallenge). An alternative explanation is less likely, e.g. concomitant drug(s), concomitant disease(s). Possible: An adverse event, which might be due to the use of the drug. An alternative explanation, e.g. concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is reasonable; therefore, the causal relationship cannot be excluded. Unlikely: An adverse event for which an alternative explanation is more likely, e.g., concomitant drug(s), concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely. Reporting procedures for Adverse Events and Serious Adverse Events: Only adverse events and serious adverse events that are not considered as signs and symptoms expected and related to CABG or known side effects from the study drug will be reported in this study. Events defined as endpoints in the study (e.g. all-cause death, stroke, new onset heartfailure) will not be reported as adverse events. This means that other clinical signs and symptoms, which are reported by the patient and observed by the investigator, and in the opinion of the investigator are unexpected in relation to actual diagnosis, will be reported. SUSAR reporting procedure: If the responsible investigator judges the SAE as being drug-related and unexpected the event must be reported to the sponsor within one working day. The documentation will be on a CIOMS form (http://www.cioms.ch/index.php/cioms-form-i). The sponsor is then responsible for reporting SUSAR to the regulatory authorities and ethics committee. The sponsor is also responsible for information to all involved investigators in the study. A SUSAR resulting in death or judged as life threatening must be reported to regulatory authorities and the ethics committee within 7 days after the sponsor has been notified about the event. A full report has to be sent to the authorities within 15 days. A SUSAR which is not resulting in death or is life threatening has to be reported to regulatory authorities and ethics committee within 15 days after the sponsor has been notified about the event. A full report has to be sent to the authorities as soon as possible. Annual report: A safety report, including assessment of overall safety and all reported SUSARs will be submitted yearly to the Regulatory Authorities and if requested to the Ethics Committee. Sample size: Sample size is calculated on the basis of previous studies. We assumed an incidence of post-operative AF of 22% in the control group and of 14% in the SGLT2 inhibitor group (a 36% relative decrease). With a power of 80% and alpha of 5%, a total of 361 participants completing the trial in each of the two groups are required. To account for drop-out, 400 participants will be randomly assigned to each of the two groups. Statistical analysis: All results will be reported and analyzed according to the intention-to-treat principle. Baseline characteristics will be reported by randomized treatment and overall. For continuous variables we will report the frequency and the mean and standard deviation, or median and interquartile, range as appropriate. For binary or categorical variables, the frequency and percentage will be reported. The number of missing values, if any, will be reported. The disposition of patients in the trial, including the number randomized, the number lost to follow-up/withdrawn and the number of patients at each follow-up visit will be summarized in a CONSORT figure. For binary outcomes (including the primary and key secondary endpoints) we will report the number and percentage of patients with the outcome by randomized group. A risk ratio and 95% confidence interval (CI) will be calculated and reported along with the corresponding p-value from a chi-squared test. For continuous outcomes we will report the frequency, mean and standard error of the change from baseline by randomized group. The between group difference in mean change from baseline and 95% CI will be estimated using a linear regression model including the baseline value and randomized treatment as covariates in the model. If the change from baseline is found to seriously violate the required assumption of normality an appropriate transformation may be applied. For time-to-event outcomes the number of patients with the event and the cumulative percentage (estimated using the Kaplan-Meier method) will be reported by randomized group. Hazard ratios and 95% CIs will be estimated using a Cox proportional hazards model and a p-value estimated using a log-rank test. Two-sided statistical significance levels of 5% will be used and all estimates will be presented with 95% confidence intervals. Full detail of the statistical analysis will be described in a statistical analysis plan which will be completed and signed before the final study database is locked and unblinded. Interim Safety Analysis: A maximum of three months following inclusion of the first 100 patients an independent endpoint committee will monitor study endpoints. Variables to be assessed are all-cause death, AKI, dialysis, new onset AF, heart failure, and diabetic ketoacidosis. Premature termination of the study will be mandated in the event that one of the treatment strategies shows statistically significance at the 0.001 alpha level for the composite of the above variables.

Official Title
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SGLT2 Inhibitor TrEatment iN Patients Awaiting cOronary arTery bYpass Surgery to Reduce Post-opErative Atrial Fibrillation and Kidney Injury (STENOTYPE Trial)

Conditions
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Chronic Coronary Syndrome, Atrial Fibrillation

Intervention / Treatment
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* Drug: Dapagliflozin 10mg Tab
* Drug: Placebo Tab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with chronic coronary syndrome scheduled for CABG with extra corporeal circulation. or Patients with chronic coronary syndrome scheduled for CABG and aortic valve replacement with extra corporeal circulation. or Patients with chronic coronary syndrome scheduled for CABG and mitral valve surgery with extra corporeal circulation. or Patients with chronic coronary syndrome scheduled for CABG and aortic root surgery Exclusion Criteria: Current, recent or planned treatment with, or intolerance or contraindications, of a SGLT2 inhibitor. Type 1 diabetes mellitus. Symptoms of hypotension or systolic blood pressure <95 mmHg. Recent worsening of heart failure or other cardiovascular events or procedures. Any non-cardiovascular condition, e.g. malignancy, with a life expectancy of less than 2 years based on the investigator´s clinical judgement. Estimated glomerular filtration rate <20 mL/min/1.73 m2 or rapidly declining renal function. Cardiac surgery planned within seven days. Emergency surgery or hemodynamic instability. Previous history of atrial fibrillation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In a multicenter, prospective, randomized, controlled clinical trial to compare dapagliflozin 10 mg once daily and placebo in preventing postoperative atrial fibrillation and kidney injury in patients undergoing coronary artery bypass surgery (CABG).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active arm<br>Treatment with dapagliflozin 10 mg once daily. | Drug: Dapagliflozin 10mg Tab<br>* Dapagliflozin once daily for a minimum of seven days while awaiting scheduled CABG and up until discharge with a short interruption for surgery.<br>|
| Placebo Comparator: Placebo arm<br>Treatment with matching placebo once daily. | Drug: Placebo Tab<br>* Matching placebo once daily for a minimum of seven days while awaiting scheduled CABG and up until discharge with a short interruption for surgery.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of new onset post-operative atrial fibrillation of at least 30 seconds | ECG or telemetry | From CABG to discharge up to 8 weeks post-operatively | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute kidney injury | Defined as at least 50% increase or absolute increase of 26.5 µmol/L in serum creatinine (Kidney Disease Improving Global Outcomes grade 1 or above) before discharge. Key secondary outcome. | From CABG to discharge up to 8 weeks post-operatively | 
| Atrial fibrillation burden on telemetry | Time in atrial fibrillation (%) | From CABG to discharge up to 8 weeks post-operatively | 
| New onset heart failure |  | From CABG to discharge up to 8 weeks post-operatively | 
| Length of hospital stay | Days | From CABG to discharge up to 8 weeks post-operatively | 
| Length of intensive care unit stay | Days | From CABG to discharge up to 8 weeks post-operatively | 
| Stroke | Ischemic stroke including transient ischemic attack | From CABG to discharge up to 4 weeks post-operatively | 
| Mortality | Death | From CABG to discharge up to 8 weeks post-operatively | 
| Electrical cardioversion |  | From CABG to discharge up to 8 weeks post-operatively | 
| Use of amiodarone |  | From CABG to discharge up to 8 weeks post-operatively | 
| Change in cardiac biomarkers | Blood sampling for change in troponin I and N-terminal pro-B-type natriuretic peptide | After skin closure, and 6±2 hours, 12±2 hours, and 3 days after CABG surgery | 
| Change in markers of inflammation | Blood sampling for change in interleukin 1 and 6, tumor necrosis factor α, high-sensitivity C-reactive protein | After skin closure, and 6±2 hours, 12±2 hours, and 3 days after CABG surgery | 
| Change in glycated haemoglobin | Change from baseline to 3 days after CABG | Baseline and 3 days after CABG surgery | 
| Mortality | Death | 30 days after CABG surgery | 
| All-cause death | Death by any cause | 12 months after CABG surgery | 
| Myocardial infarction |  | 12 months after CABG surgery | 
| Stroke | Ischemic stroke including transient ischemic attack | 12 months after CABG surgery | 
| Hospital admission with atrial fibrillation or heart failure, dialysis treatment |  | 12 months after CABG surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Atrial fibrillation, Acute Kidney Injury, Coronary artery bypass grafting