Clinical trial NCT01268683: Glyburide Advantage in Malignant Edema and Stroke Pilot
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Ischemic Stroke
Lead sponsor: Remedy Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
Collaborators: name: University of Maryland
name: Massachusetts General Hospital
First posted: 2010-12-31
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Rate of Enrollment
timeFrame: Day 1
measure: Percentage of Enrolled Participants to Screened Participants
timeFrame: Day 1
measure: Percentage of Participants Completing 90-Day Follow-Up
timeFrame: Day 90
measure: Percentage of Dose Reductions/ Dose Suspensions
timeFrame: Up to Day 3
measure: Percentage of Participants With All Four MRI Assessments Per Protocol
timeFrame: Up to Day 3
measure: Number of MRI Assessments Per Participant
timeFrame: Up to Day 3
measure: Percentage of Participants Requiring One or More Hypoglycemia Treatments
timeFrame: Up to Day 4
measure: Percentage of Participants With Pre-specified Adverse Events Associated With Glyburide According to Protocol
timeFrame: Up to Day 4
Secondary outcomes:
measure: Number of Participants With Adverse Events and Serious Adverse Events
timeFrame: Up to Day 90
measure: Infarcted Hemisphere Volume
timeFrame: Baseline, Day 1, Day 2, and Day 3
measure: Absolute Diffusion Weighted Imaging (DWI) Lesion Volume
timeFrame: Baseline, Day 1, Day 2, and Day 3
measure: Change From Baseline in DWI Lesion Volume
timeFrame: Baseline, Day 1, Day 2, and Day 3 (Day 3 reported)
measure: Midline Shift
timeFrame: Baseline, Day 1, Day 2, and Day 3
measure: Ipsilateral Ventricle Volume
timeFrame: Baseline, Day 1, Day 2, and Day 3
measure: Frequency of Hemorrhagic Events
timeFrame: Day 1, Day 2, and Day 3
measure: National Institute of Health Stroke Scale (NIHSS) Score
timeFrame: Baseline, Day 1, Day 2, Day 3, and Day 7
measure: Glasgow Coma Scale (GCS) Score
timeFrame: Baseline, Day 1, Day 2, Day 3, and Day 7
measure: Full Outline of UnResponsiveness (FOUR) Score
timeFrame: Baseline, Day 1, Day 2, Day 3, and Day 7
measure: Number of Participants Requiring Decompressive Craniectomy (DC)
timeFrame: Up to Day 90
measure: Number of Participants With a Modified Rankin Scale (mRS) Score ≤ 4
timeFrame: Day 30, Day 90
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
Study officials:
affiliation: Remedy Pharmaceuticals
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Kimberly WT, Battey TW, Pham L, Wu O, Yoo AJ, Furie KL, Singhal AB, Elm JJ, Stern BJ, Sheth KN. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit Care. 2014 Apr;20(2):193-201. doi: 10.1007/s12028-013-9917-z.
citation: Sheth KN, Kimberly WT, Elm JJ, Kent TA, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, del Zoppo G, Simard JM, Stern BJ, Mandava P. Exploratory analysis of glyburide as a novel therapy for preventing brain swelling. Neurocrit Care. 2014 Aug;21(1):43-51. doi: 10.1007/s12028-014-9970-2.
citation: Sheth KN, Kimberly WT, Elm JJ, Kent TA, Mandava P, Yoo AJ, Thomalla G, Campbell B, Donnan GA, Davis SM, Albers GW, Jacobson S, Simard JM, Stern BJ. Pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke. 2014 Jan;45(1):281-3. doi: 10.1161/STROKEAHA.113.003352. Epub 2013 Nov 5.