Glyburide (RP-1127) for Traumatic Brain Injury (TBI)

Study Overview
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Brief Summary
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The primary objectives of this study are to assess whether participants with traumatic brain injury (TBI) administered glyburide begun within 10 hours of injury will show a decrease in magnetic resonance imaging (MRI)-defined edema and/or hemorrhage, compared to placebo and to assess the safety and tolerability of glyburide compared to placebo in participants with TBI. The secondary objectives include analyzing brain cell loss, computerized tomography (CT) scan /MRI abnormalities, reduction of mortality and or improvement of function or physiology, incidence of decompression craniectomy, incidence of neuroworsening, and to assess the steady state concentrations of glyburide in TBI participants.

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

Official Title
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A Randomized Clinical Trial of Glyburide (RP-1127) for TBI

Conditions
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Traumatic Brain Injury

Intervention / Treatment
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* Drug: Glyburide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented closed head TBI Clearly defined time of injury no more than 10 hours before administration of study drug/placebo GCS 4-14. The GCS will be obtained free of the effects of sedating and/or paralytic drug. Complicated mild must have GCS 13-14 and one or more of the following: Intraparenchymal clots or contusions in aggregate > 10cc; Midline shift > 5mm; IVH, SDH, EDH seen on more than one CT scan slice. Age 18-75 years Patients in whom a dedicated peripheral IV line can be placed for study drug administration Written consent obtained from legally authorized representative (LAR) Exclusion Criteria: No documented TBI or time of impact not certain Penetrating brain injury Spinal column instability and/or spinal cord injury with neurodeficit Concomitant severe non survivable injury Pregnant, or a positive pregnancy test Women who intend to breastfeed during Study Days 1-4. Blood glucose <50mg/dL Severe renal disorder from the patient's history (e.g. dialysis) or serum creatinine of > 2.5 mg/dL Severe liver disease or total bilirubin >1.5 times upper limit of normal INR>1.4 Systolic BP<90 mm Hg not responsive to fluid resuscitation Blood alcohol > 250mg/dL Inability to have MRI (pacemaker, non-MR compatible pressure monitor, etc.) Hospitalization for brain injury, psychiatric or neurological disease within previous 3 years Emergent or urgent surgical operation anticipated (in OR, bedside procedures excluded) that would prevent dosing with study drug within 8 hours of injury. Known use of Coumadin (warfarin), Plavix (clopidogrel), Effient (prasugrel) or Pletal (cilostazol), heparin, low molecular weight heparin, heparinoids, or abciximab or similar antiplatelet agents in the previous 72 hours (Note that patients later found to have taken these medications will not be automatically excluded from the study.) Use of sulfonylurea drugs within the prior 30 days Treatment with another investigational drug within the prior 30 days Allergy to sulfonylurea drugs Known diagnosis of G6PD enzyme deficiency PaO2 < 60 mm Hg on admission (for patients in whom blood gases are drawn per standard of care) Non-English speaking legally authorized representative and subjects (University of Maryland only) Prisoners or others who may be unable to make a truly voluntary and uncoerced decision whether or not to participate in the study Any other clinical condition which in the opinion of the investigator makes the patient unsuitable for inclusion into the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glyburide<br>Glyburide delivered by injection as an approximately 2 minute loading dose followed by 72 hours of continuous infusion. | Drug: Glyburide<br>* Administered as specified in the Treatment Arm.<br>* Other names: glybenclamide;|
| Placebo Comparator: Placebo<br>Matching placebo delivered by injection as an approximately 2 minute loading dose followed by 72 hours of continuous infusion. | Drug: Placebo<br>* Administered as specified in the Treatment Arm.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Edema | To be assessed using Magnetic Resonance Imaging (MRI). | Baseline, Day 3, Day 90, and Day 180 | 
| Change from Baseline in Hemorrhage | To be assessed using MRI. | Baseline, Day 3, Day 90, and Day 180 | 
| Number of Participants with Adverse Events and Serious Adverse Events | An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity during the course of the study. A serious adverse event is any AE that is fatal, life-threatening, requires or prolongs hospital stay, results in persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event | Up to 180 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Brain Volume | To be assessed using MRI. | Baseline, Day 3, Day 90, and Day 180 | 
| Number of Participants with Abnormalities Associated with Brain Swelling | To be assessed using MRI and computed tomography (CT). | Baseline, Day 3, Day 90, and Day 180 | 
| Change from Baseline in Glasgow Coma Scale (GCS) | The GCS is scored 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) | Baseline up to Day 7 | 
| Change from Baseline in Intracranial Pressure (ICP) |  | Baseline up to Day 7 | 
| Change from Day 30 in Extended Glasgow Outcome Scale (GOS-E) | The GOS-E assesses status in patients with traumatic brain injury on an 8-point scale. The minimum score is 1 and the maximum score is 8. The rating scale is as follows: 1- Dead, 2- Vegetative State, 3- Low Severe Disability, 4- Upper Severe Disability, 5- Low Moderate Disability, 6- Upper Moderate Disability, 7- Low Good Recovery, and 8- Upper Good Recovery | Day 30, Day 60, Day 90, and Day 180 | 
| Number of Participants Requiring Decompression Craniectomy |  | Baseline up to Day 7 | 
| Number of Participants Experiencing Neuroworsening |  | Baseline up to Day 7 | 
| PK Parameter: Steady State Concentration of Glyburide |  | Baseline and 36 hours | 
| Number of All-Cause and Neurological Mortalities |  | Up to Day 180 |