Glyburide Advantage in Malignant Edema and Stroke Pilot

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to assess the feasibility of enrolling, evaluating, and treating with glyburide for injection severe anterior circulation ischemic stroke participants, whether or not treated with standard of care intravenous (IV) recombinant tissue plasminogen activator (rtPA). Participants must be between 18-80 years of age, must have a baseline diffusion weighted image (DWI) lesion volume 82 -210 centimeters cubed (cm3), and time from symptom onset to start of study infusion must be ≤10 hour(hr). The secondary objectives are to assess the initial safety and tolerability, and pharmacokinetics (PK) /pharmacodynamics (PD) of glyburide in severe stroke participants, as well as to compare the clinical and magnetic resonance imaging (MRI) outcome data to benchmark data derived from published literature.

Detailed Description
-----------------
This is a multi-center, prospective, open label, phase IIa trial of glyburide for injection in 10 participants with a severe anterior circulation ischemic stroke who are likely to experience clinically significant brain swelling. Participants will receive glyburide, delivered as an IV bolus followed by an IV infusion for 72 hours. Participants will have a baseline (pretreatment) MRI scan as standard of care, and three follow up MRI scans (at 24+12 hours, 48+12 hours, and 72±12 hours). Since recanalization may have an effect on outcome, the results of vascular studies, obtained as part of standard of care and defined as CTA, MRA or catheter angiography of the head and neck, will be recorded. Additionally, clinical endpoints such as the National Institutes of Health Stroke Scale (NIHSS), Glasgow Coma Scale (GCS) and Full Outline of UnResponsiveness Score (FOUR) Score (baseline, 24±12 hour, 48±12 hour, 72±12 hour and 7±1 days) and Modified Rankin Scale (mRS) (30±5 days and 90±7 days) will be assessed. Safety parameters will be assessed through Day 7 or discharge (whichever is sooner), and then again at Day 30±5 and Day 90±7. Study participation is expected to last 90±7 days. This study was previously posted by Remedy Pharmaceuticals, Inc. and has since been acquired by Biogen.

Official Title
-----------------
A Multi-Center, Prospective, Open Label, Phase IIa Trial of RP-1127 (Glyburide for Injection) in Patients With a Severe Anterior Circulation Ischemic Stroke Who Are Likely to Experience Clinically Significant Brain Swelling.

Conditions
-----------------
Ischemic Stroke

Intervention / Treatment
-----------------
* Drug: Glyburide for Injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: A clinical diagnosis of acute ischemic stroke in the MCA or MCA/ACA territory. Pre-morbid mRS 0 - 1. A baseline DWI lesion between 82 cm3 and 210 cm3 on MRI. Patients treated with IV rtPA should meet established criteria for IV rtPA administration in the 0-3 and 3-4.5 hr time periods, respectively. The time to the start of infusion of study compound must be ≤ 10 hr after time of symptom onset Age ≥18 years and ≤70 years. Provision of written informed consent by the patient or from a legally authorized representative according to institutional guidelines and national regulations. Key Exclusion Criteria: Evidence from imaging or pre-enrollment investigation of any diagnosis other than acute ischemic stroke likely to cause the presenting symptoms and signs. Commitment to decompressive craniectomy (DC) prior to enrollment, or follow-ing enrollment and prior to start of study compound. Treatment with IA rtPA or by mechanical means for clot disruption or with hypo-thermia. Patients unable to tolerate MRI scanning, e.g. those with pacemakers or automatic defibrillators. Pre-morbid mRS ≥ 2. Clinical signs of herniation, e.g. one or two dilated, fixed pupils; unconsciousness (i.e., ≥ 2 on item 1a on the NIHSS); loss of other brain stem reflexes attributable to herniation according to the investigator's judgment. CT or MRI evidence of hemorrhage or anteroseptal/pineal shift greater ≥2 mm prior to enrollment. Rapidly improving symptoms. Severe renal disorder from the patient's history (e.g. dialysis) or eGFR of < 30 mL/min/1.73 m2. Severe liver disease or ALT, AST, or bilirubin >2 times normal. Blood glucose <55 mg/dL at enrollment or immediately prior to administration of RP-1127, or a clinically significant history of hypoglycemia. Diagnosis of decompensated heart failure (e.g. clinical diagnosis of pulmonary edema, chest x-ray consistent with heart failure, tachypnea > 20, etc.) Sulfonylurea treatment within 30 days. Known allergy to sulfa or specific allergy to sulfonylurea drugs. Known G6PD enzyme deficiency. Pregnancy or breast-feeding. Women must be either post-menopausal (judged by the investigator), permanently sterilized or, if of childbearing age, must have a negative test for pregnancy obtained before enrollment. Patients already enrolled in a non-observation-only stroke study, or with life-expectancy <3 months not related to current stroke, or those unlikely to be com-pliant with follow up. Patients who, in the opinion of the investigator, are not suitable for the study (reason to be documented). NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glyburide for Injection<br>This arm is administered a glyburide bolus followed by continuous infusion of glyburide for 72 hours | Drug: Glyburide for Injection<br>* Administered as specified in the treatment arm.<br>* Other names: glybenclamide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Enrollment | The number of months to enroll 10 participants. | Day 1 | 
| Percentage of Enrolled Participants to Screened Participants |  | Day 1 | 
| Percentage of Participants Completing 90-Day Follow-Up |  | Day 90 | 
| Percentage of Dose Reductions/ Dose Suspensions |  | Up to Day 3 | 
| Percentage of Participants With All Four MRI Assessments Per Protocol |  | Up to Day 3 | 
| Number of MRI Assessments Per Participant |  | Up to Day 3 | 
| Percentage of Participants Requiring One or More Hypoglycemia Treatments |  | Up to Day 4 | 
| Percentage of Participants With Pre-specified Adverse Events Associated With Glyburide According to Protocol |  | Up to Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events and Serious Adverse Events | Adverse Events (AE's) of special interest (cardiac events, difficulty controlling blood sugar, liver problems, and blood disorders, including anemia) will be followed for 30 days and all Severe Adverse Events (SAE's) will be followed for 90 days. SAE's and AE's were reviewed, and the number of participants with unanticipated adverse events, or drug-related SAE's were assessed. | Up to Day 90 | 
| Infarcted Hemisphere Volume |  | Baseline, Day 1, Day 2, and Day 3 | 
| Absolute Diffusion Weighted Imaging (DWI) Lesion Volume |  | Baseline, Day 1, Day 2, and Day 3 | 
| Change From Baseline in DWI Lesion Volume |  | Baseline, Day 1, Day 2, and Day 3 (Day 3 reported) | 
| Midline Shift |  | Baseline, Day 1, Day 2, and Day 3 | 
| Ipsilateral Ventricle Volume |  | Baseline, Day 1, Day 2, and Day 3 | 
| Frequency of Hemorrhagic Events |  | Day 1, Day 2, and Day 3 | 
| National Institute of Health Stroke Scale (NIHSS) Score | The NIHSS is composed of 11 categories, each of which is scored between 0 and 4. A score of 0 indicates normal function, a higher score indicates more impairment. Category scores are summed to generate the total NIHSS score (possibles scores range from 0-42). | Baseline, Day 1, Day 2, Day 3, and Day 7 | 
| Glasgow Coma Scale (GCS) Score | The GCS is scored on a scale between 3 and 15 (3 = the worst, and 15 = best). It is composed of three parameters : Best Eye Response (scored on a scale of 1-4), Best Verbal Response (scored on a scale of 1-5), Best Motor Response (scored on a scale of 1-6) | Baseline, Day 1, Day 2, Day 3, and Day 7 | 
| Full Outline of UnResponsiveness (FOUR) Score | The FOUR Score is a 17-point scale (with potential scores ranging from 0 - 16). Decreasing FOUR Score is associated with worsening level of consciousness. The FOUR Score assesses four domains of neurological function: eye responses, motor responses, brainstem reflexes, and breathing pattern. | Baseline, Day 1, Day 2, Day 3, and Day 7 | 
| Number of Participants Requiring Decompressive Craniectomy (DC) |  | Up to Day 90 | 
| Number of Participants With a Modified Rankin Scale (mRS) Score ≤ 4 | The mRS scale runs from 0-6, the scoring is as follows: 0 - No symptoms, 1 - No significant disability, 2 - Slight disability, 3 - Moderate disability, 4 - Moderately severe disability, 5 - Severe disability, 6 - Dead | Day 30, Day 90 |