Clinical trial NCT06858436: SGLT2 Inhibitor Utilization Re-perfusion Therapy
Official title: The Role of SGLT2 Inhibitors in Stroke-reperfusion Injury:A Multi-Center, Randomized, Open-Label, Controlled Trial
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Acute Ischemic Stroke From Large Vessel Occlusion
Keywords: reperfusion therapy
SGLT2 inhibitor
malignant edema and transformation hemorrhage
Lead sponsor: Taichung Veterans General Hospital
Sponsor class: OTHER
First posted: 2025-03-05
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Background:

Reperfusion therapies, including intravenous rt-PA and mechanical thrombectomy, significantly improve outcomes in acute ischemic stroke. However, these interventions also increase the risk of hemorrhagic transformation and malignant edema. Preclinical studies have demonstrated that Canagliflozin, an SGLT2 inhibitor, reduces astrocyte swelling and brain edema in a transient middle cerebral artery occlusion (tMCAo) model. While SGLT2 inhibitors have shown neuroprotective effects in the acute phase of ischemic stroke, their potential to mitigate hemorrhagic transformation and malignant edema following reperfusion therapy in humans remains unexamined.

Aims:

This study aims to evaluate the effect of SGLT2 inhibitors on hemorrhagic transformation and malignant edema in patients undergoing reperfusion therapy for acute ischemic stroke.

Methods:

This is a multi-center, randomized, open-label, controlled study enrolling ischemic stroke patients aged 18 years or older who meet predefined inclusion and exclusion criteria. Participants will be randomized to receive Canagliflozin 100 mg once daily for 14 days or no additional treatment before undergoing mechanical thrombectomy. Clinical data collection will include baseline demographics, medical and medication history, NIHSS scores at admission and 24 hours post-reperfusion, stroke subtype, modified Thrombolysis in Cerebral Infarction (TICI) scores, laboratory results, and modified Rankin Scale (mRS) scores at discharge and 3 months post-stroke.

The primary outcome is to assess the association between Canagliflozin use and the severity of hemorrhagic transformation and malignant edema. Hemorrhagic transformation will be classified using the Heidelberg criteria, and malignant edema will be defined as a midline shift of ≥5 mm. Brain imaging, including CT scans at 24 hours post-intervention and additional scans as clinically indicated, will be reviewed by blinded radiologists. Brain MRA will also be performed to assess infarct size and edema progression.

Importance:

This study aims to explore the potential for repurposing SGLT2 inhibitors as a therapeutic strategy in acute ischemic stroke. If Canagliflozin is shown to reduce hemorrhagic transformation and malignant edema, it could offer a novel adjunctive treatment to improve patient outcomes following reperfusion therapy.

Detailed description: 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

1. 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:

1. Occurrence of malignant edema
2. mRS at 3 months post-stroke
3. Mortality at 3 months

Secondary Efficacy Endpoints:

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

Primary Safety Endpoint:

* Incidence of adverse events (AEs)

  2. 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

  3. 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

  4. 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

  1. Hypoglycemia (\~4%)

     * Symptoms: Sweating, confusion, dizziness
     * Management: Monitor blood glucose levels and adjust diabetes medications as needed
  2. 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
  3. Urinary Tract Infections (UTIs) (\~5%)

     o Symptoms: Painful urination, urgency, fever

     o Management: Increase fluid intake and use antibiotics if symptoms persist
  4. 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
  5. Hypotension (1-2%) o Symptoms: Dizziness, fainting, fatigue o Management: Monitor blood pressure, stay hydrated, and avoid sudden posture changes

  5. 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

  6. 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.

  7. 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

  8. Funding \& Insurance
* Funding: Provided by Veterans General Hospital
* Insurance: Coverage provided for participants due to study interventions

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

Eligibility criteria: 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

Primary outcomes:
measure: Occurrence of malignant edema
timeFrame: On the 3rd to 5th day for MRI after EVT
measure: mRS at 3rd month after stroke onset
timeFrame: 3 months after stroke onset
measure: Mortality rate at 3rd month after stroke onset
timeFrame: After stroke onset in 3 months.
Secondary outcomes:
measure: Occurrence of hemorrhagic transformation
timeFrame: During hospitalization for 14 days
measure: Occurrence f parenchymal hematoma type2
timeFrame: During hospitalization for 14 days
measure: NIHSS 24 hours later
timeFrame: 24 hours after EVT
measure: mRS at discharge
timeFrame: Day 14 at hospital discharge
measure: EQ-5D at 3rd month after stroke onset
timeFrame: 3 months after stroke onset
measure: infarct size on brain MRI
timeFrame: Day 1 after EVT
measure: upregulation of arterial biomarkers (MMP-9) after EVT
timeFrame: Day 1 before EVT is executed and after EVT finished
Other outcomes:
measure: Occurrence of adverse events as assessed by CTCAE v5.0
timeFrame: During hospitalization for 14 days
Locations:
Study officials:
affiliation: Taichung Veterans General Hospital
name: Po-Lin Chen
role: STUDY_DIRECTOR
References: