Glyburide Advantage in Malignant Edema and Stroke - Remedy Pharmaceuticals (GAMES-RP)

• The proportion of patients with a modified Rankin Scale (mRS) at Day 90 ≤ 4 without the need for decompressive craniectomy [ Time Frame: 90 Days ] [ Designated as safety issue: No ]
• Safety of RP-1127 in subjects with a severe anterior circulation ischemic stroke who are likely to develop malignant edema. [ Time Frame: 90 Days ] [ Designated as safety issue: Yes ]
  Addressed by comparing the frequency and severity of Adverse Events (AEs) and Serious Adverse Events (SAEs)in the RP-1127 and placebo groups, with a specific focus on all cause mortality, cardiac mortality, and cardiac-related and blood glucose-related AEs/SAEs.

• Proportion of subjects that develop malignant edema [ Time Frame: 7 days ] [ Designated as safety issue: No ]
• Proportion of subjects undergoing DC, and DC-associated AEs and SAEs [ Time Frame: 90 Days ] [ Designated as safety issue: Yes ]
• Proportion of subjects that experience early neurological deterioration [ Time Frame: 72 Hours ] [ Designated as safety issue: No ]
• Proportion of subjects that develop parenchymal hematomas [ Time Frame: 7 Days ] [ Designated as safety issue: No ]
• Ipsilateral hemispheric swelling measured by MRI [ Time Frame: 96 Hours ] [ Designated as safety issue: No ]
• Proportion of subjects with 90 day mRS 0-3 and 0-4 [ Time Frame: 90 Day ] [ Designated as safety issue: No ]
• Activities of Daily Living (as measured by the Barthel Index) at 90 days [ Time Frame: 90 Days ] [ Designated as safety issue: No ]
• All-cause mortality at 90 days [ Time Frame: 90 Days ] [ Designated as safety issue: Yes ]

This is a randomized, multi-center, prospective, double blind, two-stage, adaptive study. The primary objective is to demonstrate the efficacy of RP-1127 compared to placebo in subjects with a severe anterior circulation ischemic stroke who are likely to develop malignant edema. This objective will be addressed by comparing the proportion of RP-1127 treated patients and placebo treated patients with a Day 90 modified Rankin Scale (mRS) ≤ 4 without the need for decompressive craniectomy (DC).

The study population consists of subjects with a clinical diagnosis of acute severe anterior circulation ischemic stroke, a baseline diffusion weighted image (DWI) lesion between 82 and 210 cm3, age 18-75 years, and time from symptom onset to start of study infusion of ≤10 hours. The study will enroll both patients that do not receive IV rtPA and those that receive IV rtPA within 4.5 hours of stroke.

The study will enroll up to a maximum of 240 subjects (120 subjects per treatment arm). Once 50 subjects (25 per arm) are enrolled and followed through Day 90, an interim analysis will be conducted. If the trial is to continue, the sample size will be re-estimated (based on the nuisance parameter). Total enrollment will therefore be a minimum of 50 subjects (25 subjects per treatment arm) and a maximum of 240 subjects (120 subjects per treatment arm).

Enrollment will be randomized controlling for site, age ≤60 (yes/no), and IV rtPA treatment at baseline (yes/no). Subjects will be randomized equally between RP-1127 and placebo.

• Ischemic Stroke
• Malignant Edema

• Placebo Comparator: Matching Placebo
  Subjects will receive matching placebo.
• Experimental: RP-1127 (Glyburide for Injection)
  Subjects will receive the active agent, RP-1127 (Glyburide for Injection)
  Intervention: Drug: RP-1127 (Glyburide for Injection)

Inclusion Criteria:

• A clinical diagnosis of acute ischemic stroke in the MCA or MCA/ACA territory.
• Pre-morbid mRS 0 - 1 [prior to stroke, no disability, or no significant disability despite symptoms (able to carry out all usual duties and activities)].
• A baseline DWI lesion between 82 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 at the time of rtPA administration (if rtPA is administered in the 3-4.5 hr time window, the NIHSS must be ≤ 25 at the time of rtPA administration).
• The time to the start of infusion of Study Drug must be ≤ 10 hours after time of symptom onset, if known, or the time last seen well [termed "time last known at neurologic baseline" (TLK@B)].
• Age ≥18 years and ≤75 years.
• Provision of written informed consent by a legally authorized representative according to institutional guidelines and national regulations.

Exclusion Criteria:

• Commitment to decompressive craniectomy (DC) prior to enrollment, or following enrollment and prior to start of Study Drug.
• Treatment with intra-arterial (IA) rtPA or by mechanical means for clot disruption or with hypothermia.
• Patients unable to tolerate MRI scanning, e.g. those with pacemakers or automatic defibrillators.
• 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.
• Hemorrhage (other than small petechial hemorrhages) on CT/MRI, or CT/MRI evidence of anteroseptal/pineal shift greater ≥2 mm prior to enrollment that is due to cerebral edema.
• 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 Study Drug, or a clinically significant history of hypoglycemia.
• Acute ST elevation myocardial infarction, and/or acute decompensated HF, and/or QTc>520 ms, and/or known history of cardiac arrest (PEA, VT, VF, asystole), and/or admission for an ACS, MI, or coronary intervention (PCI or coronary artery surgery) within the past 3 months.
• Known sulfonylurea treatment within 7 days. Sulfonylureas include glyburide /glibenclamide (Diabeta, Glynase); glyburide plus metformin (Glucovance); glimepiride (Amaryl); repaglinide (Prandin); nateglinide (Starlix); glipizide (Glucotrol, GlibeneseR, MinodiabR); gliclazide (DiamicronR); tolbutamide (Orinase, Tolinase); glibornuride (Glutril).
• Known allergy to sulfa or specific allergy to sulfonylurea drugs.
• Known G6PD enzyme deficiency.
• Pregnant women. Women must be either post-menopausal (as confirmed by the LAR), permanently sterilized or, if ≤ 50 years old must have a negative test for pregnancy obtained before enrollment.
• Breast-feeding women who do not agree (or their LAR does not agree) to stop breast- feeding during Study Drug infusion and for 7 days following the end of Study Drug infusion.
• 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 compliant with follow up.
• Patients currently receiving an investigational drug.
• Patients in whom a peripheral IV line cannot be placed.
• Mentally incompetent (prior to qualifying stroke) patients and wards of the state.
• Patients who, in the opinion of the investigator, are not suitable for the study (reason to be documented).