Glyburide Advantage in Malignant Edema and Stroke Pilot (GAMES-PILOT)

• Safety and tolerability [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
  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 SAE's will be followed for 90 days.
• Pharmacokinetics/pharmacodynamics [ Time Frame: 3 days ] [ Designated as safety issue: Yes ]
• Clinical and MRI outcome data [ Time Frame: 90 days ] [ Designated as safety issue: No ]

• Safety and tolerability [ Time Frame: 90 days ] [ Designated as safety issue: Yes ]
• Pharmacokinetics/pharmacodynamics [ Time Frame: 3 days ] [ Designated as safety issue: Yes ]
• Clinical and MRI outcome data [ Time Frame: 90 days ] [ Designated as safety issue: No ]

The study objective is to assess the feasibility of enrolling, evaluating, and treating with RP-1127 (Glyburide for Injection) severe anterior circulation ischemic stroke patients, whether or not treated with standard of care IV rtPA. Patients must be between 18-60 years of age, must have a baseline diffusion weighted image (DWI) lesion volume 82 - 210 cm3, and time from symptom onset to start of study infusion must be ≤10 hr.

This is a multi-center, prospective, open label, Phase IIa trial of RP-1127 (Glyburide for Injection) in 10 patients with a severe anterior circulation ischemic stroke who are likely to experience clinically significant brain swelling.

Subjects will receive RP-1127 (Glyburide for Injection), delivered as an IV bolus followed by an IV infusion for 72 hours.

Subjects 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 NIHSS, GCS and FOUR Score (baseline, 24±12 hour, 48±12 hour, 72±12 hour and 7±1 days) and 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.

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.

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 (rea-son to be documented).

• University of Maryland
• Massachusetts General Hospital