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

Primary Purpose

Ischemic Stroke

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Glyburide for Injection

About this trial

This is an interventional treatment trial for Ischemic Stroke

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Rush University Medical Center
University of Maryland Medical Center
Massachusetts General Hospital
University of Pittsburgh Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Glyburide for Injection

Arm Description

This arm is administered a glyburide bolus followed by continuous infusion of glyburide for 72 hours

Outcomes

Primary Outcome Measures

Rate of Enrollment

The number of months to enroll 10 participants.

Percentage of Enrolled Participants to Screened Participants

Percentage of Participants Completing 90-Day Follow-Up

Percentage of Dose Reductions/ Dose Suspensions

Percentage of Participants With All Four MRI Assessments Per Protocol

Number of MRI Assessments Per Participant

Percentage of Participants Requiring One or More Hypoglycemia Treatments

Percentage of Participants With Pre-specified Adverse Events Associated With Glyburide According to Protocol

Secondary Outcome Measures

Number of Participants With Adverse Events and Serious Adverse Events

Adverse Events (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 Severe Adverse Events (SAE's) will be followed for 90 days. SAE's and AE's were reviewed, and the number of participants with unanticipated adverse events, or drug-related SAE's were assessed.

Infarcted Hemisphere Volume

Absolute Diffusion Weighted Imaging (DWI) Lesion Volume

Change From Baseline in DWI Lesion Volume

Midline Shift

Ipsilateral Ventricle Volume

Frequency of Hemorrhagic Events

National Institute of Health Stroke Scale (NIHSS) Score

The NIHSS is composed of 11 categories, each of which is scored between 0 and 4. A score of 0 indicates normal function, a higher score indicates more impairment. Category scores are summed to generate the total NIHSS score (possibles scores range from 0-42).

Glasgow Coma Scale (GCS) Score

The GCS is scored on a scale between 3 and 15 (3 = the worst, and 15 = best). It is composed of three parameters : Best Eye Response (scored on a scale of 1-4), Best Verbal Response (scored on a scale of 1-5), Best Motor Response (scored on a scale of 1-6)

Full Outline of UnResponsiveness (FOUR) Score

The FOUR Score is a 17-point scale (with potential scores ranging from 0 - 16). Decreasing FOUR Score is associated with worsening level of consciousness. The FOUR Score assesses four domains of neurological function: eye responses, motor responses, brainstem reflexes, and breathing pattern.

Number of Participants Requiring Decompressive Craniectomy (DC)

Number of Participants With a Modified Rankin Scale (mRS) Score ≤ 4

The mRS scale runs from 0-6, the scoring is as follows: 0 - No symptoms, 1 - No significant disability, 2 - Slight disability, 3 - Moderate disability, 4 - Moderately severe disability, 5 - Severe disability, 6 - Dead

Full Information

NCT ID

NCT01268683

First Posted

December 29, 2010

Last Updated

August 4, 2021

Sponsor

Biogen

Collaborators

University of Maryland, College Park, Massachusetts General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT01268683

Brief Title

Glyburide Advantage in Malignant Edema and Stroke Pilot

Acronym

GAMES-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

2. Study Status

Record Verification Date

August 2021

Overall Recruitment Status

Completed

Study Start Date

May 26, 2011 (Actual)

Primary Completion Date

June 7, 2012 (Actual)

Study Completion Date

June 7, 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Biogen

Collaborators

University of Maryland, College Park, Massachusetts General Hospital

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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. This study was previously posted by Remedy Pharmaceuticals, Inc. and has since been acquired by Biogen.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Ischemic Stroke

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

10 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Glyburide for Injection

Arm Type

Experimental

Arm Description

This arm is administered a glyburide bolus followed by continuous infusion of glyburide for 72 hours

Intervention Type

Drug

Intervention Name(s)

Glyburide for Injection

Other Intervention Name(s)

RP-1127, glibenclamide, glybenclamide

Intervention Description

Administered as specified in the treatment arm.

Primary Outcome Measure Information:

Title

Rate of Enrollment

Description

The number of months to enroll 10 participants.

Time Frame

Day 1

Title

Percentage of Enrolled Participants to Screened Participants

Time Frame

Day 1

Title

Percentage of Participants Completing 90-Day Follow-Up

Time Frame

Day 90

Title

Percentage of Dose Reductions/ Dose Suspensions

Time Frame

Up to Day 3

Title

Percentage of Participants With All Four MRI Assessments Per Protocol

Time Frame

Up to Day 3

Title

Number of MRI Assessments Per Participant

Time Frame

Up to Day 3

Title

Percentage of Participants Requiring One or More Hypoglycemia Treatments

Time Frame

Up to Day 4

Title

Percentage of Participants With Pre-specified Adverse Events Associated With Glyburide According to Protocol

Time Frame

Up to Day 4

Secondary Outcome Measure Information:

Title

Number of Participants With Adverse Events and Serious Adverse Events

Description

Time Frame

Up to Day 90

Title

Infarcted Hemisphere Volume

Time Frame

Baseline, Day 1, Day 2, and Day 3

Title

Absolute Diffusion Weighted Imaging (DWI) Lesion Volume

Time Frame

Baseline, Day 1, Day 2, and Day 3

Title

Change From Baseline in DWI Lesion Volume

Time Frame

Baseline, Day 1, Day 2, and Day 3 (Day 3 reported)

Title

Midline Shift

Time Frame

Baseline, Day 1, Day 2, and Day 3

Title

Ipsilateral Ventricle Volume

Time Frame

Baseline, Day 1, Day 2, and Day 3

Title

Frequency of Hemorrhagic Events

Time Frame

Day 1, Day 2, and Day 3

Title

National Institute of Health Stroke Scale (NIHSS) Score

Description

Time Frame

Baseline, Day 1, Day 2, Day 3, and Day 7

Title

Glasgow Coma Scale (GCS) Score

Description

Time Frame

Baseline, Day 1, Day 2, Day 3, and Day 7

Title

Full Outline of UnResponsiveness (FOUR) Score

Description

Time Frame

Baseline, Day 1, Day 2, Day 3, and Day 7

Title

Number of Participants Requiring Decompressive Craniectomy (DC)

Time Frame

Up to Day 90

Title

Number of Participants With a Modified Rankin Scale (mRS) Score ≤ 4

Description

Time Frame

Day 30, Day 90

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

80 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director

Organizational Affiliation

Biogen

Official's Role

Study Director

Facility Information:

Facility Name

Rush University Medical Center

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60612

Country

United States

Facility Name

University of Maryland Medical Center

City

Baltimore

State/Province

Maryland

Country

United States

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

Country

United States

Facility Name

University of Pittsburgh Medical Center

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

24072459

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.

Results Reference

background

PubMed Identifier

24671831

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.

Results Reference

background

PubMed Identifier

24193798

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.

Results Reference

result

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Glyburide Advantage in Malignant Edema and Stroke Pilot

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