Clinical trial NCT01794182: Glyburide Advantage in Malignant Edema and Stroke - Remedy Pharmaceuticals
Official title: A Randomized, Multi-Center, Prospective, Double Blind, Phase II Trial of RP- 1127 (Glyburide for Injection) in Patients With a Severe Anterior Circulation Ischemic Stroke Who Are Likely to Develop Malignant Edema
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Ischemic Stroke
Malignant Edema
Lead sponsor: Remedy Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2013-02-18
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: This is a randomized, multi-center, prospective, double blind study. The primary objective is to assess the efficacy and safety of glyburide (RP-1127) compared to placebo in participants with a severe anterior circulation ischemic stroke who are likely to develop malignant edema.This objective will be addressed by comparing the proportion of glyburide treated particpants and placebo treated participants with a Day 90 modified Rankin Scale (mRS) ≤ 4 without decompressive craniectomy (DC). The secondary objective is to assess the efficacy of RP-1127 compared to placebo in participants with a severe anterior circulation ischemic stroke who were likely to develop malignant edema.

Detailed description: The study population consists of participants 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 participants that do not receive intravenous (IV) recombinant tissue plasminogen activator (rtPA) and those that receive IV rtPA within 4.5 hours of stroke.

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

Eligibility criteria: Key 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 \[termed "time last known at neurologic baseline" (TLK@B)\].
* Provision of written informed consent by a legally authorized representative according to institutional guidelines and national regulations.

Key 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).

NOTE: Other protocol defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: Percentage of Participants with a Modified Rankin Scale (mRS) score of ≤ 4 Without Decompressive Craniectomy (DC)
timeFrame: Day 90
measure: Number of Participants with Adverse Events and Serious Adverse Events
timeFrame: Up to 1 Year
Secondary outcomes:
measure: Percentage of Participants Undergoing DC or Dead
timeFrame: Baseline and Day 14
measure: Change from Baseline in Ipsilateral Hemispheric Swelling
timeFrame: Baseline up to 72-96 Hours
measure: Change from Baseline in Lesional Swelling
timeFrame: Baseline up to 72-96 Hours
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona Medical Center
state: Arizona
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Jacksonville
country: United States
facility: University of Florida, Jacksonville
state: Florida
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
city: Scarborough
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Worcester
country: United States
facility: UMASS Memorial Medical Center
state: Massachusetts
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University Hospital
state: Oregon
city: Abington
country: United States
facility: Abington Memorial Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Presbyterian Hospital
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Salt Lake City
country: United States
facility: University of Utah Healthcare
state: Utah
Study officials:
affiliation: Remedy Pharmaceuticals
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Payabvash S, Falcone GJ, Sze GK, Jain A, Beslow LA, Petersen NH, Sheth KN, Kimberly WT. Poor Outcomes Related to Anterior Extension of Large Hemispheric Infarction: Topographic Analysis of GAMES-RP Trial MRI Scans. J Stroke Cerebrovasc Dis. 2020 Feb;29(2):104488. doi: 10.1016/j.jstrokecerebrovasdis.2019.104488. Epub 2019 Nov 29.
citation: Vorasayan P, Bevers MB, Beslow LA, Sze G, Molyneaux BJ, Hinson HE, Simard JM, von Kummer R, Sheth KN, Kimberly WT. Intravenous Glibenclamide Reduces Lesional Water Uptake in Large Hemispheric Infarction. Stroke. 2019 Nov;50(11):3021-3027. doi: 10.1161/STROKEAHA.119.026036. Epub 2019 Sep 20.
citation: Kimberly WT, Bevers MB, von Kummer R, Demchuk AM, Romero JM, Elm JJ, Hinson HE, Molyneaux BJ, Simard JM, Sheth KN. Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial. Neurology. 2018 Dec 4;91(23):e2163-e2169. doi: 10.1212/WNL.0000000000006618. Epub 2018 Nov 16.
citation: Sheth KN, Petersen NH, Cheung K, Elm JJ, Hinson HE, Molyneaux BJ, Beslow LA, Sze GK, Simard JM, Kimberly WT. Long-Term Outcomes in Patients Aged </=70 Years With Intravenous Glyburide From the Phase II GAMES-RP Study of Large Hemispheric Infarction: An Exploratory Analysis. Stroke. 2018 Jun;49(6):1457-1463. doi: 10.1161/STROKEAHA.117.020365. Epub 2018 May 22.
citation: Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA, Sze GK, Ostwaldt AC, Del Zoppo GJ, Simard JM, Jacobson S, Kimberly WT. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016 Oct;15(11):1160-9. doi: 10.1016/S1474-4422(16)30196-X. Epub 2016 Aug 23.