SGLT2 Inhibitor Utilization Re-perfusion Therapy

Clinical Study Protocol The Role of SGLT2 Inhibitors in Stroke-Reperfusion Injury: A Multi-Center, Randomized, Open-Label, Controlled Trial Version 6.0 | Date: 2024-12-10

• Study Overview 1.1 Study Objectives Evaluate the efficacy of Canagliflozin 100 mg daily versus no treatment in reducing hemorrhagic transformation and malignant edema following reperfusion therapy in acute ischemic stroke.

1.2 Study Design

• Type: Multi-center, randomized, open-label, controlled trial
• Blinding: Open-label
• Randomization: Yes
• Design: Parallel-group
• Treatment Duration: 14 days
• Study Period: 3 years (2025-2027)
• Study Sites: Two medical centers in Taiwan
• Dose Adjustment: No 1.3 Endpoints

Primary Efficacy Endpoints:

• Occurrence of malignant edema
• mRS at 3 months post-stroke
• Mortality at 3 months

Secondary Efficacy Endpoints:

• Hemorrhagic transformation
• Parenchymal hematoma type 2
• NIHSS at 24 hours
• mRS at discharge
• EQ-5D at 3 months
• Infarct size on MRI
• MMP-9 upregulation after EVT

Primary Safety Endpoint:

• Incidence of adverse events (AEs)

• Study Population 2.1 Inclusion Criteria
• Age ≥18 years
• Acute ischemic stroke with large vessel occlusion, confirmed by CT perfusion
• Scheduled for mechanical thrombectomy 2.2 Exclusion Criteria
• CKD stage 4/5 (eGFR <30 mL/min/1.73m² or dialysis)
• Current or recent (≤3 months) SGLT2i use
• Hypersensitivity to Canagliflozin
• Type 1 diabetes
• Pregnancy or lactation 2.3 Withdrawal Criteria
• Voluntary withdrawal at any time
• Investigator-initiated withdrawal due to safety concerns or non-compliance

• Study Procedures
• Enrollment: ~105 patients/year (total 315 participants)
• Randomization: Canagliflozin 100 mg QD vs. control (no treatment) before thrombectomy
• Assessments:

o Pre- & Post-EVT: Arterial blood sampling

• 24h Post-EVT: Brain dual-energy CT, NIHSS
• Day 3-Discharge: Brain MRA
• At Discharge: mRS assessment
• 3 Months Post-Stroke: mRS, EQ-5D 3.1 Imaging & Biomarker Analysis
• Malignant Edema: Midline shift ≥5 mm or symptomatic swelling requiring decompressive craniectomy
• Hemorrhagic Transformation: Classified by Heidelberg criteria, assessed via CT at 24 hours
• Infarct Volume: Measured via MRI using the ABC/2 method
• MMP-9 Analysis: Blood collected pre-/post-EVT, analyzed via ELISA

• Safety & Adverse Event Reporting
• Physicians will oversee patient safety and medication management.
• Participants will have direct access to study personnel for AE reporting.
• AEs will be reported to the IRB per regulatory guidelines. 4.1 Adverse Events (AE) and Management

• Hypoglycemia (~4%)

• Symptoms: Sweating, confusion, dizziness
• Management: Monitor blood glucose levels and adjust diabetes medications as needed
• Genital Infections (10-11% in women, 4% in men) o Symptoms: Itching, pain, discharge

o Management: Maintain proper hygiene and use antifungal treatments if necessary

• Urinary Tract Infections (UTIs) (~5%)

o Symptoms: Painful urination, urgency, fever

o Management: Increase fluid intake and use antibiotics if symptoms persist

• Dehydration (1-2%)

o Symptoms: Thirst, dark-colored urine, dizziness

o Management: Stay hydrated and avoid excessive intake of diuretics such as caffeine and alcohol

• Hypotension (1-2%) o Symptoms: Dizziness, fainting, fatigue o Management: Monitor blood pressure, stay hydrated, and avoid sudden posture changes

• Criteria for Trial Termination

The trial may be stopped if:

• Safety concerns: Unexpected SAEs or high AE incidence outweighs benefits
• Regulatory issues: Recommendations from IRB/DSMB
• Operational issues: Insufficient enrollment or funding
• Interim analysis: Evidence of harm or lack of benefit

• Statistical Considerations 6.1 Sample Size
• Total required: 314 participants (157 per group)
• Power: 80%
• Alpha: 0.1 (one-sided) 6.2 Statistical Analysis
• Categorical Data: Fisher's exact test or χ² test
• Continuous Data: Mann-Whitney U-test, independent t-test
• Kaplan-Meier plots: Cumulative risk analysis
• Cox Proportional-Hazards Model: Malignant edema & hemorrhagic transformation incidence
• Repeated Measures ANOVA: NIHSS score changes
• Significance:

o p < 0.1 (*); p < 0.05 (**) 6.3 Population for Analysis

• Intent-to-treat (ITT) for efficacy & safety assessments 6.4 Data Handling
• Poor-quality/missing data will be excluded.
• Protocol deviations will be documented and justified.

• Ethical & Regulatory Considerations 7.1 Ethical Approval & Patient Rights
• IRB Approval: Required before initiation
• Informed Consent: Participants will receive detailed study information and can withdraw at any time
• Data Security: Encrypted storage at two hospitals, access restricted to investigators 7.2 Data Access
• IRB permitted access for monitoring, audits, and inspections

• Funding & Insurance
• Funding: Provided by Veterans General Hospital
• Insurance: Coverage provided for participants due to study interventions

• References Key literature supporting Canagliflozin's neuroprotective potential in ischemic stroke and reperfusion injury.

Inclusion criteria

• Patients must have been diagnosed with acute ischemic stroke and large vessel occlusion by a neurologist, with confirmation supported by CT perfusion scans.
• Patients must be scheduled to undergo mechanical thrombectomy.

Exclusion criteria

• Patients with have stage 4 or 5 chronic kidney disease (estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m² on dialysis)
• Patients with currently taking an SGLT2i or within 3 months prior to enrollment
• Patients with a known hypersensitivity or allergic reaction to Canagliflozin
• Patients with type 1 diabetes mellitus
• Patients with pregnancy or lactation