Glyburide Advantage in Malignant Edema and Stroke - Remedy Pharmaceuticals

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
300 cm3, age 18-80 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.

Stage 1 of the study will enroll and treat up to a maximum of 50 subjects (25 per arm) who
meet all inclusion/exclusion.

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.

Inclusion Criteria:

- A clinical diagnosis of acute ischemic stroke in the MCA territory (PCA and/or ACA
territory involvement in addition to primary MCA territory stroke is acceptable).

- 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 300 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 ≤80 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.

- Patients unable to tolerate MRI scanning, e.g. those with pacemakers or automatic
defibrillators.

- Evidence (clinical or imaging) of concurrent infarction in the contralateral
hemisphere deemed by the investigator to be sufficiently serious so as to affect
functional outcome.

- Clinical signs of herniation, e.g. one or two dilated, fixed pupils; unconsciousness
(i.e., ≥ 2 on item 1a on the NIHSS); and/or loss of other brain stem reflexes
attributable to edema or 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 >3 times normal, 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); netaglinide (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).