Spinal Cord Injury Neuroprotection With Glyburide; Pilot Study: An Open-Label Prospective Evaluation of the Feasibility, Safety, Pharmacokinetics, and Preliminary Efficacy of Oral Glyburide (DiaBeta) in Patients With Acute Traumatic Spinal Cord Injury
Phase: PHASE1
Conditions: Acute Spinal Cord Injury
Sponsor: Ohio State University

IRB Approval Date: 2/6/2020 
IRB Protocol Number: 2014H0335 
 
 
 
 
 
 
Title: Spinal Cord Injury Neuroprotection with Glyburide 
(SCING) 
Pilot Study: An Open-Label Prospective Evaluation of the Feasibility, Safety, Pharmacokinetics, 
and Preliminary Efficacy of Oral Glyburide in Patients with Acute Traumatic Spinal Cord Injury 
Document Date: 02-06-2020 
NCT #: NCT02524379 
Study Protocol and Statistical Analysis Plan 
 
 
 
 
Principal Investigator: 
H. Francis Farhadi, M.D., Ph.D. 
Phone: 614-366-4961 
E-Mail: Francis.Farhadi@osumc.edu 
 
 
 
 
 
 
 
 

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Table of Contents 
1.0 
SYNOPSIS ........................................................................................................................... 4 
1.1 
Design............................................................................................................................... 4 
1.2 
Objectives ......................................................................................................................... 4 
1.3 
Interventions and Duration ............................................................................................... 4 
1.4 
Statistical Considerations ................................................................................................. 5 
2.0 
INTRODUCTION ............................................................................................................... 5 
2.1 
SCI Background ............................................................................................................... 7 
2.2 
Glyburide and Signaling Background .............................................................................. 8 
2.3 
Rationale for Glyburide following SCI ............................................................................ 9 
3.0 
OBJECTIVES .................................................................................................................... 10 
3.1 
Primary Objectives ......................................................................................................... 10 
3.2 
Secondary Objectives ..................................................................................................... 11 
4.0 
STUDY DESIGN............................................................................................................... 12 
4.1 
Inclusion/Exclusion Criteria ........................................................................................... 12 
4.2 
Number of Patients ......................................................................................................... 15 
4.3 
Study-related Management (standard-of-care) ............................................................... 15 
4.4 
Study-related management (non-standard of care) ........................................................ 15 
5.0 
STUDY ASSESSMENT AND PROCEDURES ............................................................... 16 
5.1 
Screening ........................................................................................................................ 16 
5.2 
Registration Procedures.................................................................................................. 17 
5.3 
Registration Process ....................................................................................................... 18 
5.4 
On-Study: Baseline ........................................................................................................ 18 
5.5 
Study Drug Description, Dose, and Administration ...................................................... 19 
5.6 
Prohibited Interventions ................................................................................................. 19 

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5.7 
Interventions Related to Blood Glucose ......................................................................... 20 
5.8 
Days 1-7 (0-168 hours) .................................................................................................. 21 
5.9 
Up to day of discharge (but no later than Day 14) ......................................................... 23 
5.10 
Post-treatment follow-up ............................................................................................ 23 
5.11 
Study Calendar ........................................................................................................... 24 
6.0 
ADVERSE EVENTS ......................................................................................................... 26 
6.1 
Adverse Event Reporting ............................................................................................... 26 
6.2 
Evaluating Adverse Events ............................................................................................ 28 
6.3 
Serious Adverse Event Collection and Expedited Reporting ......................................... 30 
6.4 
Criteria for Intervention Discontinuation ....................................................................... 31 
7.0 
STATISTICAL CONSIDERATIONS............................................................................... 32 
8.0 
DATA SAFETY MONITORING PLAN .......................................................................... 33 
9.0 
STUDY CONDUCT CONSIDERATIONS ...................................................................... 33 
9.1 
Regulatory and Ethical Consideration (including the informed consent process) ......... 33 
9.2 
Publication Policy .......................................................................................................... 36 
10.0 CONCLUSION .................................................................................................................. 36 
11.0 REFERENCES .................................................................................................................. 37 
APPENDIX 1: Modified NACTN Chart ...................................................................................... 40 
APPENDIX 2: SAE Case Report Form ........................................................................................ 40 
 
 
 

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1.0 SYNOPSIS 
1.1 Design 
This will be a prospective multi-center single arm open-label pilot study of oral 
glyburide in patients with acute traumatic cervical spinal cord injuries (SCI). The study 
population consists of subjects with acute traumatic ASIA A, B or C SCI, age 18-80 
years, and able to start study drug within 8 hours of injury. The study will enroll and 
treat up to a maximum of 10 patients who will be matched in a 1:3 ratio with historical 
controls collected from the North American Clinical Trials Network database. 
1.2 Objectives 
 
Primary Objectives 
• To assess the feasibility of recruiting subjects with ASIA A, B, or ASIA C 
acute SCIs within the specified 8-hour time frame.  
• To assess the preliminary safety of oral glyburide in subjects with ASIA A, 
B, or ASIA C acute ACIs 
Secondary Objectives 
• To study the pharmacokinetics of oral glyburide following acute SCI. 
• To undertake a preliminary assessment of the effects of study drug on 
measures of neurologic outcome using a matched cohort group for 
comparison. 
• To study the effects of study drug on serum biomarkers. 
• To study the effects of study drug on intramedullary MR imaging changes 
related to SCI. 
1.3 Interventions and Duration 
Standard of care treatment will be instituted for all patients including management of 
respiratory and hemodynamic parameters in a monitored setting for at least the first three 
days following SCI. All subjects meeting eligibility criteria will be approached as soon as 
possible following injury and informed consent obtained for enrollment. While all subjects 
will undergo standard of care computed tomography (CT) and magnetic resonance 
imaging (MRI) studies, only review of the CT studies will be required prior to enrollment. 

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As soon as feasible and if indicated, surgical intervention for spinal cord decompression 
and spinal stabilization will be undertaken. Safety labs and Adverse Events will be 
assessed through Day 14 or discharge (whichever is earlier). Serum biomarker levels will 
be assessed at baseline, and Days 1, 3, and 7. Adverse events will be further assessed, 
along with functional outcomes, at Day 28 (±7 days), Day 42 (±7 days), Day 84 (±14 
days), Day 182 (±14 days), and Day 365 (±30 days). Study participation is expected to last 
365 Days ± 30 days. Adverse Event and functional outcome assessments will be 
undertaken by ASIA-certified study personnel. 
1.4 Statistical Considerations 
Descriptive statistics will be generated for all variables of interest.  Categorical 
measures will be reported with frequencies, percentages and continuous measures with 
means and standard deviations. 
 
The primary outcomes of feasibility will be the rate of recruitment and the proportion 
of patients recruited versus screened. 
 
All adverse events that occur during the initial hospitalization period will be 
summarized. The frequency of adverse events during this period will be compared to 
matched NACTN Registry historical controls in a 1:3 ratio (along with corresponding 
confidence intervals). 
 
Matched tests will be utilized to compare neurologic outcomes and biomarker levels 
between enrolled subjects receiving oral glyburide and matched historical controls. 
2.0 INTRODUCTION 
In this initial phase open–label pilot study, we propose to enroll patients with defined 
inclusion/exclusion criteria at up to ten Level I/II trauma centers including Ohio State 
University Wexner Medical Center (Principal Site). The primary objectives are to assess the 
feasibility and safety of enrolling, evaluating, and treating acute cervical SCI patients with 
oral glyburide.  
 

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Oral glyburide is a widely used blood glucose-lowering drug that belongs to the sulfonylurea 
class. Blood glucose is lowered acutely by stimulating the release of insulin from the pancreas, 
an effect dependent upon functioning beta cells in the pancreatic islets. Oral Glyburide has 
been used successfully in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) 
for more than 20 years. In treating NIDDM, the drug works by inhibiting ATP-sensitive 
potassium channels in pancreatic beta cells by antagonism of SUR1. This inhibition causes 
cell membrane depolarization, which causes voltage-dependent calcium channels to open, 
which in turn causes an increase in intracellular calcium in the beta cell, stimulating insulin 
release. 
 
The Sur1-Trpm4 channel is selectively expressed in the central nervous system (including the 
spinal cord) under conditions of ischemia, hypoxia, and trauma [6, 8-10] leading to vasogenic 
and cytotoxic edema followed by oncotic cell death [11]. A double-blind, multicenter, 
randomized trial of an intravenous form of glyburide (CiraraTM) in patients with large ischemic 
strokes likely to develop malignant cerebral edema (GAMES-RP study) identified the drug to 
be well-tolerated at 3 mg per day [2] with few treatment-related serious adverse events (SAEs) 
reported and reassuringly limited to hypoglycemia.  
 
Neurotrauma patients, including those with spinal cord injuries, typically have elevated blood 
glucose levels over the first three days following their injury. For example, a large 
retrospective review of 528 patients with SCI [35] indicated that 53% of patients were 
hyperglycemic on admission (glucose concentration ≥126 mg/dl) and that hyperglycemia was 
a significant risk predictor of poor functional outcome. As such, oral glyburide administration 
for its potential neuroprotective effects in the SCI population appears unlikely to cause 
significant adverse events related to hypoglycemia and may indeed be beneficial 
independently given its blood glucose lowering effects.  
 
Between August 2015 and August 2016, we screened patients with acute traumatic cervical 
SCIs (GOSCIP study; clinical trials NCT02524379) for potential treatment with CiraraTM. 
Sixteen patients were screened during this period but none met the eligibility criteria. Given 
the ongoing enrolment difficulty with this intravenous drug within the 6 hr timeline, we have 
decided to amend several elements of the trial including some of the inclusion/exclusion 

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criteria. First, the route of administration will be changed to the oral form allowing for easier 
and streamlined drug administration. An extension of the window of administration to 8 hours 
from the time of injury will also be implemented. Several screened patients fell out of the 
eligibility due to this constrained time window, especially considering that CiraraTM 
preparation takes in the order of 1-2 hours.  
 
The feasibility of screening, consenting, enrolling, and administering oral glyburide  in the 
acute setting following spinal cord trauma (≤8 hours from injury) will be assessed at the 
participating centers. Further, a comprehensive assessment of all-cause AEs will be 
undertaken in this study for spinal cord trauma patients. 
 
The data obtained from this pilot study should inform the design of further multicenter phase 
II/III clinical studies evaluating the efficacy and safety of oral glyburide in improving 
functional outcomes following SCI. 
2.1 SCI Background 
There are currently no standard of care neuro-protective strategies for the treatment 
of acute traumatic SCI. Methylprednisolone is no longer considered standard of care 
based on its dubious clinical benefit combined with its demonstrated adverse effect 
on immune function [3]. The sodium-channel blocker, Riluzole, was recently 
evaluated in a phase 1/2a trial of 36 patients by the North American Clinical Trials 
Network (NACTN) group [4]. While safety data appeared favorable, a larger phase 
2/3 study is currently underway to assess for efficacy in improving neurologic 
outcomes. Other potential therapies are either at the pre-clinical or early pilot stage 
[33] 
 
Progressive hemorrhagic necrosis (PHN) represents an increasingly well-characterized 
mechanism of secondary injury that negatively impacts neurologic outcomes. 
Structural failure of the integrity of intramedullary capillaries, so called ‘capillary 
fragmentation’ is thought to underlie this acute and dynamic secondary injury process. 
Animal studies modeling contusional SCIs across different laboratories have revealed 
a 2-2.5-fold increase in extravasated intramedullary blood within the first 12-24 hours 
following blunt impact trauma [5-7]. The formation of distinct microscopic 

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hemorrhages within the cord in turn is linked to the progressive secondary injury and 
neurologic deterioration following SCI. 
2.2 Glyburide and Signaling Background 
Glyburide (also known as Glibenclamide; 5-chloro-N-(4-[N-(cyclohexylcarbamoyl) 
sulfamoyl]phenethyl)-2-methoxybenzamide) is an anti-diabetic medication in a class 
of medications known as sulfonylureas. In treating NIDDM, the drug works by 
inhibiting ATP-sensitive potassium channels in pancreatic beta cells by antagonism of 
SUR1. This inhibition causes cell membrane depolarization, which causes voltage-
dependent calcium channels to open, which in turn causes an increase in intracellular 
calcium in the beta cell, stimulating insulin release. 
 
The Sur1-Trpm4 channel is selectively expressed in the central nervous system 
(including the spinal cord) under conditions of ischemia, hypoxia, and trauma [6, 8-
10], leading to vasogenic and cytotoxic edema followed by oncotic cell death [11]. 
With respect to micro vascular endothelial cells, this process leads to the formation of 
space- occupying edema and secondary hemorrhage. Spinal cord edema and micro 
hemorrhage formation   through   this mechanism is a critical secondary injury process 
that progressively exacerbates mechanical compression, ischemia, and neuronal/glial 
cell death following trauma [12]. 
 
Numerous pharmacokinetic studies of oral glyburide have assessed single-dose 
administrations in normal subjects and have demonstrated significant absorption 
within one hour, peak drug levels at about four hours, and low but detectable levels at 
twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the 
serum concentration-time curve, increase in proportion to corresponding increases in 
dose. Multiple-dose studies with glyburide (a widely available oral glyburide 
formulation) in diabetic patients demonstrate drug level concentration-time curves 
similar to single-dose studies, indicating no build-up of drug in tissue depots. The 
decrease of glyburide in the serum of normal healthy individuals is biphasic, the 
terminal half-life being about 10 hours [34]. 
 

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In a phase 1 study of intravenous glyburide (CiraraTM), the drug was administered as 
a bolus dose followed by a 3-day continuous infusion maintenance dose. Five groups 
of patients were dosed, totaling 26 patients on drug (4 dosing groups, with doses 
ranging from 0.4 to 10 mg/day) and 8 on placebo. There were no SAEs during the 
study. Two subjects (one in the 6 mg/day treatment group and one in the 10 mg/day 
treatment group) were discontinued from the study due to persistent hypoglycemia. 
The subject in the 6 mg/day treatment group who was discontinued from the study also 
experienced transient increases in ALT and AST levels beginning 3 days after study 
drug discontinuation, which returned to normal by Day 22. There were no other 
clinically significant drug-related AEs [1]. Based on this work, Phase 2a pilot and 
exploratory randomized trials were undertaken by Remedy Pharmaceuticals 
(GAMES-RP) wherein a total of 93 stroke patients were dosed at 3 mg/day for 3 days. 
There were no new safety concerns raised in these patients [36].  
2.3 Rationale for Glyburide following SCI 
Emerging evidence implicates the Sur1 – Trpm4 channel as the molecular precursor 
of PHN [6, 13-15]. Up-regulation and co-association of the regulatory and pore 
forming subunits of this ion channel have been demonstrated to occur in endothelial 
and other cells only after SCI, as demonstrated in rodents and humans [6, 16, 17]. 
PHN-associated secondary micro hemorrhage formation in turn is specifically 
associated with channel up- regulation and activation in micro vessels [6, 16, 18]. 
Following trauma, spinal cord edema and micro hemorrhage formation through this 
mechanism is a critical secondary injury process that exacerbates mechanical 
compression and ischemia, and contributes to neuronal/glial cell death. 
 
Glyburide-mediated blockade of the Sur1 – Trpm4 channel in rodent models of SCI 
leads to minimal secondary micro hemorrhage formation and the absence of capillary 
fragmentation, the pathologic hallmark of PHN. Lesion volumes and hind limb 
locomotor functional outcome measures, measured up to 6 weeks, are significantly 
improved in animals treated with Glyburide shortly after the time of injury [6, 13-16]. 
Delayed treatment at 3 hours following SCI in rats, a more clinically-relevant time 
frame, also yielded significant functional benefit [19]. While the magnitude of 

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Glyburide-mediated neurological benefit appears to correlate with the magnitude of 
the initial experimental injury, significant treatment effects have been consistently 
demonstrated for both lesion volume and functional scores in all studies to date [14, 
16, 19]. 
3.0 OBJECTIVES 
3.1 Primary Objectives 
• Feasibility: To assess the feasibility of running a larger phase II or III study among 
this population of patients where treatment must begin within a defined time 
frame. The number of patients who would otherwise be eligible for the study but 
did not receive study treatment within the 8-hour time frame will be recorded (ratio 
of recruited versus screened). The rate of recruitment will also be recorded. 
• Safety: Vital signs, clinical exams, ECG, and clinical laboratory results will be 
carefully and continuously monitored during the course of hospitalization. 
Adverse events (AEs) will be assessed throughout the course of hospitalization 
through Day 28. In addition to presenting a summary of all AEs, where possible, 
a comparison of AEs occurring in study subjects vs. those occurring in matched 
historical controls (as captured in the NACTN registry) will be made.  To facilitate 
this comparison, AEs will be grouped into one of 10 systems according to a 
modified NACTN chart [20, 21] (see appendix 1): cardiac, pulmonary, 
hematology, 
gastrointestinal/genitourinary, 
infections, 
skin, 
failure 
of 
stabilization, neuropsychiatric, hypoglycemia/other metabolic, and other.  These 
AEs will be described further with respect to the specific name of the event (that 
is, the “type” of event; for example, for cardiac events, the type could be 
bradycardia or other dysrhythmia, cardiac arrest, etc.). Severity (“intensity”, as per 
the NACTN chart) as well as relatedness to glyburide  will also be assessed. The 
frequency of AEs, as well as mortality (all-cause and cardiac-related), will be 
compared to that of a matched cohort from the NACTN registry [20, 21]. 
Specific outcome variables related to assessing blood glucose (BG)-related safety of 
glyburide  are: 

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• Hypoglycemia (i.e. Blood Glucose (BG) < 55 mg/dL 
• Symptomatic hypoglycemia i.e. hypoglycemia with investigator-identified 
hypoglycemic symptoms. 
The following table defines which BG values should be reported as AEs: 
Table 1: Blood Glucose Values and AE reporting 
BG Value 
Report as AE? 
70-79 mg/dL 
Mandatory AE reporting not required; may be reported as an AE (and coded 
appropriately in terms of severity) if the event meets the protocol-defined 
definitions. 
55- 69 mg/dL Must be reported as an AE, if confirmed by a point-of-care or lab value retest 
(and coded appropriately in terms of severity) 
< 55 mg/dL 
Must be reported as a SAE (appendix 2), if confirmed by either a point-of- 
care or lab value retest (and coded appropriately in terms of severity) 
 
Specific outcome variables related to assessing cardiac-related safety of glyburide 
are:  
• Incidence/severity of cardiac AEs and cardiac mortality 
• Incidence of QTc of > 500 ms 
• Mean QTc and mean change in QTc from baseline.  
 
3.2 Secondary Objectives 
• Pharmacokinetics of glyburide following acute cervical SCI: Plasma 
concentrations will be serially quantified through day 3 following SCI. 
Comparisons will be made to reported levels achieved healthy patient cohorts 
• Neurologic recovery following SCI: The neurologic status of patients will be 
assessed using the ASIA Impairment Scale (as assessed by ISNCSCI criteria) and 
the Spinal Cord Independence Measure (SCIM version III) [22]. The motor and 
sensory sub scores of the ASIA assessment will be determined on first contact, 

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every day until Day 4, at 1-2-4-6 weeks, and at 3-6-12 months of follow-up. The 
SCIM version III will be assessed at 3, 6 and 12 months of follow-up. 
Comparisons will be made to control subjects (with a 1:3 matching ratio in the 
NACTN registry matched based on age, co-morbidities, initial injury severity, 
and injury level. 
• Serum biomarker levels: Standard enzyme-linked immunosorbent assay (ELISA) 
techniques will be used to measure blood levels of neurofilament light chain, 
neuron- specific enolase, tau, S100b, and glial fibrillary acidic protein levels on 
admission, at 24 hours and on days 3, and 7following SCI. Comparisons will be 
made to (i) matched control serum values of non-treated subjects with acute 
cervical SCIs [23] and (ii) previously published values observed in non-treated 
control patients [24-26]. 
• Spinal cord lesion volumetric analysis: Standard sequences (T1, T2, FLAIR, SWI) 
at 3T field strength will be used to assess the extent of the hemorrhagic lesion and 
surrounding edema. Patients will be imaged on the day of admission and on day 2 
following injury (standard-of-care studies). Volumetric assessments of lesion size 
(based on manual outlines) will be performed and compared at the two time-points 
by the study neuroradiologist to assess for the progression of intrinsic cord signal 
changes [27]. 
4.0 STUDY DESIGN 
4.1 Inclusion/Exclusion Criteria  
All patients with ASIA A, B or C acute traumatic spinal cord injuries will be assessed 
for suitability and prospectively enrolled in the study. Only cervical level (C2-C8) level 
injuries in patients aged 18 to 80 years old will be included. Detailed eligibility criteria 
are listed below. 
The use of immunosuppressive therapy (including methylprednisolone and other 
corticosteroids) will be discouraged; however, use of such therapy will not require 
exclusion or discontinuation from the study. While once considered as an option for 
patients with acute SCI, it is noteworthy that more recent recommendations have all re- 

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evaluated the routine use of methylprednisolone [28]. The most recent guidelines 
published by a panel convened by the Joint Section on Spine and Peripheral Nerves of 
the American Association of Neurological Surgeons and Congress of Neurological 
Surgeons has in fact recommended against its use following acute SCI given its negative 
risk- benefit profile [3]. In the words of the panel: “Administration of 
methylprednisolone for the treatment of acute SCI is not recommended. Clinicians 
considering methylprednisolone therapy should bear in mind that the drug is not 
approved by the Food and Drug Administration for this application. There is no Class I 
or Class II medical evidence supporting the clinical benefit of methylprednisolone in the 
treatment of acute SCI. Scattered reports of Class III evidence claim inconsistent effects 
likely related to random chance or selection bias. However, Class I, II, and III evidence 
exists that high-dose steroids are associated with harmful side effects, including death.” 
Of note, the recent phase 1/2a riluzole study reported that corticosteroids were 
administered at the time of admission to only 39% of the patients (while 58% of historic 
NACTN registry patients had received this treatment) [4]. 
• Inclusion Criteria: 
1. Age: ≥ 18 years and ≤ 80 years 
2. Written informed consent by patient or legal authorized representative 
3. No other life-threatening injury  
4. No evidence of sepsis 
5. Acute cervical SCI with ASIA Impairment Scale grade A, B or C on admission 
6. Non-penetrating SCI at neurologic level from C2 to C8 
7. Initiation of study drug within 8 hours of injury 
• Exclusion Criteria 
1. Unconsciousness or other mental impairment that prevents neurological 
assessment within the first 8 hours 
2. Acute SCI with ASIA Impairment Scale grade D or E 
3. Currently involved in another non-observational SCI research study or receiving 
another investigational drug 
4. History of hypersensitivity to sulfonylureas, in particular glyburide, or any of its 
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5. Other illness (including mental disorder) that could preclude accurate medical 
and neurological evaluation (at discretion of the site investigator) 
6. Unable to commit to the follow-up schedule 
7. A recent history of regular substance abuse (illicit drugs, alcohol), which in the 
opinion of the investigator would interfere with the subject’s participation in the 
study 
8. Any condition likely to result in the patient’s death within the next 12 months 
9. Prisoner 
10. Severe renal disorder from the patient’s history (e.g. dialysis) or baseline eGFR 
of < 30 mL/min/1.73 m2 
11. Known severe liver disease, or ALT > 3 times upper limit of normal or bilirubin 
> 2 times upper limit normal. Subjects may be randomized if liver function tests 
have been drawn but are not yet available and the subject has no known history 
of liver disease; however, treatment with glyburide will be discontinued prior to 
the second dose if liver function tests indicate ALT > 3 times upper limit of 
normal or bilirubin > 2 times upper limit of normal 
12. Blood glucose <55 mg/dL at enrollment or immediately prior to administration 
of glyburide, or a clinically significant history of hypoglycemia 
13. Acute ST elevation myocardial infarction, and/or acute decompensated heart 
failure, and/or QTc > 520 ms, and/or known history of cardiac arrest  (PEA, VT, 
VF, asystole), and/or admission for an acute coronary syndrome, myocardial 
infarction, or coronary intervention (percutaneous coronary intervention or 
coronary artery surgery) within the past 3 months 
14. Known treatment with Bosentan within past 7 days 
15. Known G6PD enzyme deficiency 
16. Pregnancy: Women must be either post-menopausal, permanently sterilized or, 
if ≤ 50 years old, must have a negative test for pregnancy obtained before 
enrollment 
17. Breast-feeding women who do not agree to stop breast-feeding during and for 7 
days following the end of oral glyburide administration 
18. Subjects who in the opinion of the investigator are not suitable for inclusion in 
the study (reason to be documented). 

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4.2 Number of Patients 
To assess the feasibility of recruitment and of the protocol procedures (specifically the 
≤ 8 hr injury-to-drug timeframe), the study will plan to enroll and treat 10 patients across 
all study sites. 
4.3 Study-related Management (standard-of-care) 
The following items will be performed as standard-of-care:  
 
• Vital signs (Temperature, Blood Pressure, Pulse, Respiration Rate, O2 
saturation) 
• Blood  work; CT scans of the spine and head (as indicated); pre- and post- 
operative (Day 2) MRI of the cervical spine 
 
Cervical CT studies will reveal the nature of the associated spinal fracture and/or 
misalignment. Subjects with bilateral cervical facet dislocations or with fracture patterns 
associated with > 75% canal compromise will be excluded from the study given that a 
significant component of their underlying SCI likely involves direct parenchymal and/or 
ischemic mechanisms [29].  Adherence to acute SCI management guidelines most 
recently revised by a consensus panel in 2013 [3] will be strongly encouraged. These 
guidelines include avoidance of hypoxia and hypotension with induced hypertension as 
needed to keep mean arterial pressure ≥ 85mmHg for 7 days. Early intervention with 
surgical decompression and stabilization within 24-48 hrs (when medically feasible) will 
be encouraged for all patients [30] but will ultimately be left to the discretion of the 
treating surgeon. 
4.4 Study-related management (non-standard of care) 
Non-standard-of-care blood work will be obtained at the following time points 
following the SCI: 
• Pharmacokinetic Analysis: Daily, baseline through Day 3 
• Biomarkers Levels: Enrollment/Baseline, 24 hours, Day 3, and Day 7 
Clinical, imaging, and safety assessments will be performed throughout the study 
period: 

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• Patients will be closely monitored clinically for all AEs during the first 28 days of 
the study. SAEs will be monitored for the entire duration of the study. For the initial 
hospitalization period, the incidence of AEs will be compared where possible to that 
of matched controls obtained from the NACTN registry (1:3 ratio with respect to 
age, co-morbidities, injury level, and injury severity). The 1:3 patient matching will 
be undertaken by the study statistician. 
• Neurological evaluation will be carried out at specific time-points up to one year 
following SCI to assess for changes in neurological status. The 3, 6, and 12-month 
ISNCSCI motor/sensory and SCIM vIII scores of the patients will also be 
compared where possible to that of matched controls from the literature and from 
the NACTN registry. 
5.0 STUDY ASSESSMENT AND PROCEDURES  
5.1 Screening 
Patients with suspected acute cervical SCI will be screened upon arrival to 
hospital. These evaluations will occur prior to enrolment: 
• Vital signs (Temperature, Blood Pressure, Respiration rate, Pulse, O2  saturation, 
Height, Weight) 
o Note: Height and Weight can be estimated if patient cannot be measured.  
• Physical examination and Medical History 
• Cervical SCI Time, Cause, and Level of injury 
• Demographics and Clinical Variables (age, race, gender, and BMI) 
• Neurological examination including ISNCSCI motor and sensory assessments 
• ECG (12-lead), read within 12 hours and recorded as clinically significant or 
non- clinically significant by study team member 
• Clinical laboratory tests: 
o Pregnancy test for women of child-bearing potential 
o Hematology: complete blood count 
o Chemistry: electrolytes (sodium, potassium, chloride, bicarbonate), BUN, 
creatinine, glucose 

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o Liver Function Tests: AST, ALT, bilirubin (total and direct), and alkaline 
phosphatase. 
 Glyburide can commence if liver function tests are not yet available but 
will be discontinued if ALT > 3 times upper limit or bilirubin > 2 times 
upper limit of normal. 
 
Because pertinent patient information will already be collected as part of the standard of 
care, and to reduce additional study-specific procedures, screening and baseline 
information may be taken from the patient’s medical records prior to obtaining informed 
consent.  However, informed consent will be obtained prior to performing any study-
specific procedures. 
 
Once study eligibility has been confirmed (inclusion/exclusion criteria are met) and 
informed consent obtained, the patient will be enrolled into the study. 
5.2 Registration Procedures 
General Guidelines 
Primary health care personnel (residents, attending staff, and nurse practitioners) at 
participating centers will identify potential subjects and will then contact the site 
coordinator who will then verify eligibility and register the patient using the electronic 
data capture system (REDCap) 
 
Following registration, patients should begin protocol treatment within 8 hours of the 
injury. Issues that would cause treatment delays should be discussed with the Study 
Principal Investigator. 
 
Patients may be registered by a participating site only after the initial IRB approval for 
the site has been forwarded to the Coordinating Center and the Coordinating Center has 
activated the site. Eligible patients who consent to participate in the study will be entered 
on the study by the local site. 

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5.3 Registration Process 
To register a patient, the following documents should be completed and uploaded to 
the electronic data capture system (REDCap) by the research team: 
• Copy of required clinical and radiologic tests 
• Signed patient consent form 
• HIPAA authorization form 
• Eligibility Screening Worksheet 
• Registration Form 
 
Eligible patients will be enrolled within the first 8 hours after documented trauma, so 
that oral glyburide administration can begin no later than 8 hours after injury. This 
injury-to-drug timeframe appears feasible given the injury-to-admission times reported 
in recent SCI studies. For instance, in the phase 1/2a Riluzole study [4], the mean injury-
to-admission time was 3.0 ± 1.8 hours (median 2.3 hours). The median injury-to-drug 
time of 8.5 hours in that study likely reflects the time taken for additional MRI studies 
(in addition to CT imaging). 
5.4 On-Study: Baseline 
These evaluations occur following subject enrollment, prior to the subject receiving 
glyburide 
• Concomitant medications (including all medications taken within 7 days prior 
to screening) 
• Medical procedures (performed since acute SCI) 
• Baseline AEs (beginning at the time of enrollment) 
• PK sample (serum) 
• Biomarker sample (serum) 
• CT and MRI studies 
o CT studies will be performed and reviewed prior to enrollment. Standard 
of care cervical MRI may be initiated prior to start of study drug but this is 
not a requirement. Study drug will be administered as soon as possible 
following enrollment irrespective of whether MRI has been performed. 

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5.5 Study Drug Description, Dose, and Administration 
Enrolled patients will receive 12 doses of glyburide starting within 8 hours of SCI. The 
dosing regimen involves an initial dose of 1.25 mg followed by eleven consecutive doses 
of 0.625 mg every 6 hours. The total daily dose of glyburide on Day 1, Day 2 and Day 
3 will be 3.125 mg, 2.5 mg, and 2.5 mg respectively (see Table 2). 
 
Table 2: Study Dosing 
Day 1  
Day 2  
Day 3  
Total Dose 
3.125 mg 
2.5 mg 
2.5 mg 
 
First dose of 1.25 
mg then 0.625 mg 
every 6 hours 
0.625 mg every 6 
hours 
0.625 mg every 6 
hours 
 
This injury-to-drug timeframe will apply to patients managed non-operatively as well as 
to patients undergoing surgery (likely a majority of patients in the trial). Drug 
administration should not be stopped as the standard of care diagnostic studies and 
treatment is provided, including if the patient is transferred to the OR for decompression 
and stabilization. Hard stop rules for glyburide  administration are listed below. 
 
In the event a dose of glyburide is missed (beyond 2.5 hours from the expected 
administration time), the next dose should be administered at 1.25 mg followed by the 
usual 0.625 mg dose for subsequent administrations. If the missed dose is acknowledged 
within 2.5 hours of the expected administration time the dose should be given and the 
deviation noted.  
5.6 Prohibited Interventions 
 
No sulfonylurea agents may be administered during the first 4 days of admission. 
Subsequently, it is preferable that no sulfonylureas be administered through study 
completion. However, use of sulfonylureas starting beyond Day 4 will not result in study 
discontinuation. 

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The use of therapeutic steroids or hypothermia (cooling to below 36 Celsius) is 
discouraged for treatment of the patient’s acute SCI. If the patient requires steroid 
therapy for the treatment of another condition, this is allowable. 
 
No other investigational drugs may be administered during the study follow-up period. 
Decisions on whether to withdraw the patient from the study will be made on a case-by-
case basis should another investigational drug nevertheless have been administered. 
5.7 Interventions Related to Blood Glucose 
 
• Insulin 
Insulin is not permitted during the period of study drug administration when BG < 
120 mg/dL. “Tight” BG control (80 – 110 mg/dL) is not permitted during the period 
of study drug administration. 
 
• Supplemental Fluids 
Supplemental fluids are to be standard of care except that during glyburide 
administration, D5NS or D10NS must be used instead of NS if necessary to maintain 
BG above 80 mg/dL. Total fluid volume should be consistent with site clinical 
practice and the clinical status of the subject. 
 
• Hypoglycemia treatment 
Any BG of < 70 mg/dL must be promptly treated with a bolus of D50W at a volume 
(ml) of (100 – BG in mg/dL) x 0.4 as per Juneja et al. 2009 [31]. If supplemental 
fluids are NS, D5NS should be started. If supplemental fluids are D5NS, D10NS 
should be substituted. All BG < 70 mg/dL also should preferably be verified by 
laboratory testing, but repeat point-of-care tests may be used as well. To avoid false 
readings, blood for the repeat test must be drawn prior to treatment with D50W 
or switching supplemental fluids. 
 

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• Glyburide Dose Reduction 
Glyburide dosing must be reduced if subject is being administered D5NS or D10NS 
and (i) there is one confirmed BG < 55 mg/dL; or (ii) there are three confirmed BG 
< 70 mg/dL within a 12-hour period. If (i) or (ii) above occurs and the subject is on 
NS, D5NS or D10NS must first be started. If criteria (i) or (ii) are still met, then 
glyburide dosing should be adjusted to every 8 hours until three consecutive blood 
glucose readings of >70 are noted. If appropriate levels of BG are not reached within 
8 hours of the first dose reduction, the next dose of glyburide should be skipped as 
an additional dose reduction. Glyburide dosage must only be adjusted based on 
verified laboratory or repeat point-of-care test values that are taken 15 minutes or 
more following the last administration of insulin. 
 
• Glyburide Discontinuation 
The dosing regimen can only be reduced twice; if (i) or (ii) above occurs a third 
time, glyburide must be discontinued. Glyburide dosage must only be stopped based 
on verified laboratory test values or, if not available, a repeat point-of-care that are 
taken 15 minutes or more following the last administration of insulin. When 
glyburide is stopped as a result of low BG, D50W should be administered by bolus 
in order to maintain BG > 80 mg/dL. Multiple D50W boluses may be administered, 
the timing and volume of which are at the discretion of the clinician. BG monitoring 
is required every 15 (± 10) minutes until BG ≥ 80 for 3 consecutive readings without 
bolus glucose supplementation, then hourly (± 30 minutes) for the next 6 hours. 
5.8 Days 1-7 (0-168 hours) 
• The first dose of glyburide must be administered within 8 hours of injury and 
stopped after 72 hours.  Hard stop rules for glyburide administration are listed below. 
• As per recommended standard-of-care guidelines [3], subjects will be admitted to 
the intensive care unit following initial diagnostic testing where continuous 
respiratory, cardiac, and hemodynamic monitoring will be undertaken [32]. 
Maintenance of normal blood oxygenation and a mean arterial blood pressure of 
85-90 mmHg will be emphasized in this monitored setting continuously over the 
first full 7 days following injury. 

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• The following assessments will be performed through day 7 following injury (during 
and after study drug regimen ): 
o Safety labs: 24 hours (±12 hours), 48 hours (±12 hours) 72 hours (±12 hours) 
and 96 hours (±12 hours). 
 Hematology: complete blood count 
 Chemistry: electrolytes (sodium, potassium, chloride, bicarbonate), 
BUN, creatinine 
 Liver Function Tests: AST, ALT, bilirubin (total and direct), and 
alkaline phosphatase 
o Blood glucose (BG) monitoring will be hourly (± 30 minutes) for Hours 1-
24, every 2 hours (± 30 minutes) for Hours 25-48 and every 4 hours (± 60 
minutes) for Hours 49-88. If BG < 70 mg/dL, BG monitoring is required 
every 15 (± 10 minutes) minutes until BG ≥ 80 for 3 consecutive readings 
without exogenous bolus glucose supplementation, then hourly (± 30 
minutes) for the next 12 hours and every 2 hours (± 30 minutes) thereafter. 
o Continuous bedside cardiac telemetry monitoring from Hour 0 through Hour 
72 
o ECG (12-lead) at 4-6 hours, 24±6 hours, 48±6 hours and 60-72 hours (from 
the start of study drug regimen). The ECGs will be read within 12 hours, 
recorded as clinically significant or non-clinically significant, and signed off 
on by study team member. 
o Blood sampling for PK prior to dosing, at 4-6 hr (prior to the second 
study drug administration), 24±6 hours, 48±6 hours and 60-72 hours. 
 PK Samples to be drawn as close as possible to ECGs 
o Start time of drug and time of subsequent dosing.  Record reason for any 
missed doses. 
o Concomitant medications and procedures/therapies 
o Review safety and AEs 
o ASIA  Impairment  Scale  scoring  at  24±12  hours,  48±12  hours,  72±12 
hours, and 96±12 hours. In the event of spinal fracture reduction (closed or 
open with additional stabilization), an additional ASIA evaluation must be 
recorded as close to the start of the procedure as possible, preferably within 

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2 hours. Every attempt should be made to collect the ASIA grading free of 
the effects of sedating drugs. 
o Blood sampling for additional laboratory tests to identify biomarkers prior 
to dosing and at 1, 3 and 7 days 
• Cervical MRI scans performed on admission and on Day 2 will be uploaded to 
REDCap. 
5.9 Up to day of discharge (but no later than Day 14) 
In addition to continuous review of safety and AEs during the second week of 
hospitalization (up until discharge, as applicable), the following evaluations and 
assessments will be performed prior to Day 14 or Discharge, whichever is earlier: 
• ASIA Impairment Scale scoring. Every attempt will be made to collect scores free 
of the effects of sedating and/or paralytic drugs. 
• Concomitant medications 
• Safety labs: 
o Hematology: complete blood count 
o Chemistry: electrolytes (sodium, potassium, chloride, bicarbonate), BUN, 
creatinine, glucose 
• Liver Function Tests: AST, ALT, bilirubin (direct and total), and alkaline 
phosphatase 
• Concomitant procedures and therapies 
• Contact information for the subject (home and cellular telephone numbers, email 
addresses, home addresses, rehabilitation or nursing home information including fax 
and phone numbers); LAR (home and cellular telephone numbers, email addresses, 
home addresses); family members (home and cellular telephone numbers, email 
addresses, home addresses); and personal physician (phone and fax numbers) 
5.10 Post-treatment follow-up 
• Post-treatment follow-up: Day 28 (± 7 days) 
o Review unresolved AEs 
o Record additional AEs 
o ASIA Impairment Scale 

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• Post-treatment Follow-up: Day 42 (± 7 days) 
o Review unresolved AEs 
o Record additional SAEs 
o ASIA Impairment Scale 
• Post-treatment Follow-up: Day 84 (± 14 days) 
o Review unresolved AEs 
o Record additional SAEs 
o ASIA Impairment Scale 
o Spinal Cord Independence Measure (vIII) 
• Post-treatment Follow-up: Day 182 (± 14 days) and Day 365 (± 30 days) 
o Review unresolved AEs 
o Record additional SAEs 
o ASIA Impairment Scale 
o Spinal Cord Independence Measure (vIII) 
 
 
 
 
 
 
 
5.11 Study Calendar 
Test and 
Observations 
Screening / 
Enrollment 
(up to 6 
hours prior 
to treatment) 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
14 or 
D/C 
Day 
28 
(+/- 7 
days) 
Day 
42 
(+/- 7 
days) 
Day 
84 
(+/- 
14 
days) 
Day 
182 
(+/- 
14 
days) 
Day 
365 
(+/- 
30 
days) 
Day 
7 
 History &Physical   
X 

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Vital Signs a 
X 
Consent 
X 
 Demographic b  
 
X 
 Operative Data f  
 
X 
 Length of Stay  
 
X 
 Adverse Eventsk  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 Pregnancy Test  d 
X 
 SCI (Cervical) e 
X 
Inclusion/Exclusion 
X 
Concomitant 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
Procedures 
X 
MRI 
X 
X 
CT 
X 
 Labs  c 
X 
X 
X 
X 
X 
X 
ECG(12-lead) 
X 
X 
X 
X 
Drug 
 Drug Administration i,j 
X 
X 
X 
X 
Serum Biomarkers 
h 
X 
X 
X 
X 
 Pharmacokinetic g 
X 
X 
X 
X 
Outcome 
Measures 
AIS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SCIM vIII 
X 
X 
X 
a. 
Temperature, blood pressure, pulse, O2, respiration, BMI, height and weight (can be estimated if patient cannot be measured). 
Vitals are to be collected at screening (prior to enrolment). 
b. 
Demographics: age, race, and gender. 
c. 
Labs: hematology (complete blood count); chemistry (sodium, potassium, chloride, creatinine, electrolytes, bicarbonate, bun); liver 
function (AST, ALT, bilirubin total, bilirubin direct, and alkaline phosphatase); blood glucose (Blood glucose (BG) monitoring will 
be hourly (± 30 minutes) for Hours 1-24, every 2 hours (± 30 minutes) for Hours 25-48 and every 4 hours (± 60 minutes) for Hours 
49- 
88. If BG < 70 mg/dL, BG monitoring is required every 15 (± 10 minutes) minutes until BG ≥ 80 for 3 consecutive readings 
without exogenous bolus glucose supplementation, then hourly (± 30 minutes) for the next 12 hours and every 2 hours (± 30 
minutes) thereafter) 
d. 
Pregnancy test (only complete if woman is of childbearing 
potential). e. SCI (cervical): time, cause, and level of injury. 
f. 
Optional: only required if patient has surgery. 
g. 
Blood sampling for PK prior to dosing, at 4-6 hr. (prior to the second dose of glyburide (glyburide), 24±6 hours, 48±6 hours and 
60-72 hours. PK samples to be drawn as close as possible to ECGs. 
h. 
Serum biomarkers: enrollment/baseline, 24 hours, Day 3, and Day 7. 
i. 
Cannot continue until enrollment liver function test are available and indicate ALT≤ 3 X upper limit of normal and Bilirubin ≤2 X 
upper limit of normal 
j. 
Dosing regimen is 12 doses of glyburide; an initial dose of 1.25 mg followed by eleven consecutive doses of 0.625 mg every 6 
hours. The total daily dose of glyburide on Day 1, Day 2 and Day 3 will be 3.125 mg, 2.5 mg, and 2.5 mg respectively (see table 2) 
k.      AEs/SAEs recorded through Day 28; new SAEs and unresolved AEs recorded through end of study. 
 

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6.0 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.  Intercurrent illnesses or injuries should be 
regarded as adverse events.  Abnormal results of diagnostic procedures are considered to be 
adverse events if the abnormality: 
 
• results in study withdrawal, or 
• is associated with a serious adverse event, or 
• is associated with clinical signs or symptoms, or 
• leads to additional treatment or to further diagnostic tests, or 
• is considered by the investigator to be of clinical significance. 
 
For this study, all AE’s whether reported, observed, or elicited by direct or indirect 
questioning will be recorded from the time of study enrollment through study completion. 
Minimum information required for each AE includes type of event, duration (start and end 
dates), severity, seriousness, causality to Study Drug, action taken, and outcome. 
 
All unresolved AEs will be followed, whenever possible, until the events are resolved or 
stabilized, the subject is lost to follow-up, and/or it has been determined that the study 
treatment or participation in the study is not the cause.  At the last scheduled assessment, the 
investigator should instruct each subject to report any subsequent event(s) that the subject or 
the subject’s personal physician believes might reasonably be related to participation in this 
study. 
 
Information on AEs should be recorded in the patient record, and also in the appropriate AE 
page of the REDCap database. 
6.1 Adverse Event Reporting 
Preexisting Condition 
A preexisting condition is one that is present at the start of study drug administration. A 
preexisting condition should be reported as an adverse event if the frequency, severity, 
or the character of the condition worsens during the study period. 
 
Abnormal Laboratory Values 

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A clinical laboratory abnormality should be reported as an adverse event if the following 
conditions are met: 
• The laboratory abnormality is not otherwise refuted by a repeat test to confirm the 
abnormality, and 
• The abnormality suggests a disease and/or organ toxicity, and 
• The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic 
investigation, etc. 
However: 
• Electrolyte imbalances that are asymptomatic and not considered clinically 
significant by the investigator should not be reported as AEs even if they are treated; 
and 
• Table 1 in Section 3.1 defines which blood glucose values should be reported as 
AEs. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any AE that results in hospitalization or prolonged hospitalization, according to the 
judgment of the clinical investigator, should be documented and reported as a Serious 
Adverse Event (SAE). 
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are to be 
reported as an adverse event in the following circumstances: 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery should not be reported as an 
outcome of an adverse event if the purpose of the surgery was elective or 
diagnostic and the outcome was uneventful. 
• Hospitalization or prolonged hospitalization required to allow efficacy 
measurement for the study. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is a worsening or increase in frequency of hospital admissions as 
judged by the clinical investigator. 

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6.2 Evaluating Adverse Events  
All AEs must be evaluated by the Investigators for severity, seriousness, and relationship 
to Study Drug. 
 
Adverse Event Severity and Seriousness 
All AEs will be evaluated by the Investigators separately for both severity (mild, 
moderate, severe respectively coded as 1, 2, or 3; see appendix 1) and for seriousness 
(AE versus SAE).  
 
Relationship to Study Drug 
The relationship of the AE to glyburide will be specified by the Investigators as either 
Unrelated, Possibly/Probably related, and definitely related. When considering the 
potential relationship of an AE, the Study Investigators’ assessment will include 
consideration of the incidence of complications anticipated in the SCI population in the 
absence of glyburide administration.  For instance, in 485 subjects with acute SCIs 
recruited into the NACTN database, 1376 total complications were recorded during the 
initial hospitalization (Table 4) [21]. 
 
Table 4: Acute care complications: type, frequency, and incidence 
Complication Type 
Frequency (%) 
Incidence Rate (%) 
Pulmonary 
348 (25.3) 
36.7 
Infection 
285 (20.7) 
33.2 
Hematology 
213 (15.5) 
26.6 
Cardiac 
178 (12.9) 
25.6 
GI/GU 
115 (8.4) 
17.1 
Skin 
113 (8.2) 
16.7 
Neuropsychiatric 
106 (7.7) 
19.2 
Death 
18 (1.3) 
3.7 
 
Specifically, the following events are commonly anticipated in the SCI population in 
the absence of Study Drug (also see appendix 1): 
 

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• Abscess 
• Acute Lung Injury and Acute Respiratory Distress Syndrome 
• Adjustment disorder/depression 
• Autonomic dysreflexia/dysregulation 
• Bradycardia 
• Acute renal failure 
• Anemia 
• Cardiac Arrest 
• Cholecystitis 
• Congestive heart failure/cardiogenic pulmonary edema 
• CNS infections 
• Coagulopathy 
• Cognitive deterioration 
• Construct failure 
• Deep venous thrombosis 
• Depression/Adjustment disorder 
• Failure of orthosis 
• GI hemorrhage 
• Hematuria 
• Ileus 
• Infectious diarrhea 
• Loss of reduction 
• Myocardial infarction 
• Other dysrhythmia 
• Pancreatitis 
• Neuropathic pain 
• Pulmonary embolus 
• Pneumonia 
• Progressive neurologic decline (motor and/or sensory) 
• Psychosis 
• Respiratory failure 
• Seizure 
• Sepsis 

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• Shock 
• Skin complication (e.g., sacral or operative wound) 
• Spinal cord edema and hemorrhage 
• Thrombocytopenia 
• Urinary Tract Infection 
• Wound infection 
 
In this study, AEs will be continually monitored through Day 14 or up until discharge 
(whichever is earlier). AEs will be further reviewed and additional AEs recorded on 
Day 28 (±7 days); AEs will be followed for resolution through the end of the study.  
Beyond Day 28 through the end of the study, only new SAEs will be recorded. 
6.3 Serious Adverse Event Collection and Expedited Reporting  
A serious adverse event is any AE that is: 
• fatal, or 
• life-threatening, or 
• requires or prolongs hospital stay, or 
• results in persistent or significant disability or incapacity, or a congenital anomaly 
or birth defect, or 
• an important medical event. Important medical events are those that may not be 
immediately life threatening, but are clearly of major clinical significance. They may 
jeopardize the subject, and may require intervention to prevent one of the other 
serious outcomes noted above.  For example, drug overdose or abuse, a seizure that 
did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious. 
Reporting of Serious Adverse Events 
SAEs and unanticipated problems posing risks to subjects or others should be reported 
to the study PI using the SAE case report form (Appendix 2) by the study sites within 
24 hours of occurrence.   

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Investigators are responsible for complying with local  IRB  reporting  requirements. 
Copies of each report and documentation of IRB notification and receipt will be kept in 
the investigator’s study file. Participating sites will provide the coordinating site with 
the appropriate documentation of IRB SAE notification and receipt. 
 
The PI will notify the FDA of any unexpected drug-related fatal or life- threatening 
experience as soon as possible but no later than 7 calendar days from original receipt of 
the information.  All other unexpected drug-related SAEs will be reported no later than 
15 calendar days after determination that the event qualifies for reporting. 
 
If a previous AE that was not initially deemed reportable is later found to fit the criteria 
for reporting, the PI will submit the AE in a written report to the FDA as soon as possible, 
but no later than 15 calendar days from the time the determination is made. 
6.4 Criteria for Intervention Discontinuation  
A high incidence of medical complications occurs acutely following cervical SCI. As 
recently reported by Grossman and colleagues, overall complication rates range from 
0.15 to 0.30 following SCI in the NACTN registry [20, 21]. 
• Blood Glucose 
Glyburide must be discontinued if the dose has already been reduced in accordance 
with the defined guidelines and following the reduction (i) there is one lab or repeat 
point-of-care confirmed BG < 55 mg/dL; OR (ii) there are three lab or repeat point- 
of-care confirmed BG  <  70  mg/dL  within  a  12-hour  period.  When glyburide is 
stopped as a result of BG, D50W or an equivalent amount of dextrose using D5W, 
D10W, D25W, or D70W (or other concentration) should be administered by bolus 
in order to maintain BG > 80 mg/dL. Multiple such boluses may be administered, 
the timing and volume of which are at the discretion of the clinician. BG monitoring 
is required every 15 (± 10) minutes until BG ≥ 80 for 3 consecutive readings without 
bolus glucose supplementation, then hourly (± 30 minutes) for the next 6 hours. 
 
• Cardiac 
Glyburide must be halted if: 

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1. A life threatening cardiac-related SAE occurs, whether or not believed by 
the clinician to be related to glyburide, and/or 
2. Subject experiences QTc of > 550 ms (Bazett’s formula) for 15 minutes, 
whether or not believed by the clinician to be related to glyburide. Before a 
decision to stop glyburide is made, ECG leads must be repositioned and must 
be confirmed to be in the correct position, following which the ECG  must  
be repeated  in  order to confirm QTc > 550 ms. 
• Hemolytic Anemia 
Glyburide must be discontinued if hemolytic anemia, which in the judgment of the 
investigator is severe, is detected. In the event of hemolytic anemia, a G6PD 
deficiency test should be performed following resolution of anemia. This test 
generally has a multi-day turnaround and will be used for information purposes only.  
• Liver Function 
Glyburide must be discontinued if ALT raises to greater than 8-fold the upper limit 
of normal. Glyburide must be discontinued if the subject develops cholestatic 
jaundice or hepatitis. 
7.0 STATISTICAL CONSIDERATIONS 
Descriptive statistics will be generated for all variables of interest.  Categorical measures will 
be reported with frequencies and percentages and continuous measures with means and 
standard deviations. The frequency of AEs will be reported (as captured on the modified 
NACTN form) and, where possible, will be compared to those of the matched controls (along 
with corresponding confidence intervals). We will match study patients and the historical 
NACTN cohort data on criteria including:  age, co-morbidities, injury level, and injury 
severity (ASIA A, B or C SCI). Additionally, the number of patients who were otherwise 
eligible for the study but did not enroll due to lack of infusion within 6 hours will be reported.  
Secondarily, matched tests will be utilized to compare neurologic outcomes between those 
receiving glyburide and matched historical controls. 

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8.0 DATA SAFETY MONITORING PLAN 
The data and safety monitoring plan will involve the continuous evaluation of safety, data 
quality and data timeliness. Investigators will conduct continuous review of accrual and 
patient safety. The frequency and severity of AEs will be reviewed by the PI and compared to 
other sources, including published literature and scientific meetings. SAEs will also be 
reviewed by the Data and Safety Monitoring Committee (DSMC). The PI in conjunction with 
the DSMC will determine if the trial should be terminated early based on the AE reviews. 
 
The DSMC will consist of an ethicist, an independent biostatistician and an independent 
clinician with specialty in neurologic surgery. The DSMC will meet prior to study initiation 
and on accrual of every 3 patients (but at a minimum of twice a year). DSMC meetings will 
be scheduled within a month of every 3rd patient being enrolled in the study.  Prior to each 
scheduled DSMC meeting, the PI will prepare a progress report that will be reviewed by the 
DSMC. 
9.0 STUDY CONDUCT CONSIDERATIONS  
9.1 Regulatory and Ethical Consideration (including the informed consent process) 
Subject Withdrawal 
Subjects may voluntarily withdraw from the study at any time for any reason, and 
without prejudice to further treatment.  Subject participation in the study may be 
terminated at any time at the discretion of the Investigator. 
 
Possible reasons for discontinuation include, but are not limited to, the following: 
• The subject’s health would be jeopardized by continued participation (e.g., the 
patient required restricted medication, or alternative treatment seems to be in the 
subject’s best interest.) 
• Occurrence of a significant or intolerable clinical or laboratory AE that, in the 
opinion of the investigator, requires early termination. 

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• Withdrawal of subject consent.  Subject withdrawal may occur any time the subject 
wishes to no longer continue with the study.  Every attempt must be made to obtain 
information about the reason(s) for discontinuation, and any possible adverse events. 
• Subject is enrolled but does not receive study drug, due (for example) to insufficient 
time to prepare and administer study drug, or elevated liver enzymes at screening. 
The date the subject is discontinued from the clinical investigation and the reason for 
discontinuation will be recorded in the case report form (CRF).  Subjects whose study 
therapy is discontinued for any reason should be treated and followed according to 
established medical practice. 
Note that if a site learns, while a patient is receiving Study Drug, that the patient had 
taken sulfonylureas within 7 days of study enrollment, this will not be a cause for 
automatic discontinuation of Study Drug, or of withdrawal from the study. 
Project Management 
OSU Coordinating Center will be responsible for project management of the Study. 
Data Management 
Data entry will occur at the enrolling sites using the electronic data capture system 
(REDCap). Data quality assurance and analyses will be performed by the OSU 
Coordinating Center. 
Data Monitoring 
All aspects of the study will be monitored at regular intervals by qualified individuals 
from the OSU Coordinating Center. Monitoring will be conducted in accordance with 
FDA and International Conference on Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines, and will be described in a Data Monitoring Plan. The investigators 
must agree to allow monitors, FDA, or other relevant health authorities to inspect 
facilities and records relevant to this study. 
Institutional Review Board (IRB) Review and Informed Consent 

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This protocol and the informed consent document and any subsequent modifications 
will be reviewed and approved by the IRB or ethics committee responsible for oversight 
of the study.  A signed and dated consent form will be obtained from the subject. 
Record Retention 
Investigators must retain all study records required by the applicable regulations in a 
secure and safe facility.  All records are to be retained by the Investigator for at least 2 
years after the United States Food and Drug Administration/local health authority 
approves the New Drug Application (NDA); or a minimum period of 2 years following 
the termination or withdrawal of the health regulatory agency exemption (e.g., 
Investigational New Drug (IND) or clinical trial application) under which the study was 
conducted, or for a period consistent with the record retention policies of the country 
where the study is being conducted.   
Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the 
site will be identified only by the Study Patient Number (SPN) to maintain subject 
confidentiality.  All records will be kept in a locked file cabinet.  All computer entry 
and networking programs will be done using SPNs only. Identifiable clinical 
information will not be released without written permission of the subject, except as 
necessary for monitoring by the IRB, the FDA, or other relevant health authority 
representative. 
Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the PI, IRB, the FDA, or 
other government agencies as part of their duties to ensure that research subjects are 
protected. 

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9.2 Publication Policy 
Publications and oral presentations of any results from the study shall be in accordance 
with accepted scientific practice, academic standards and customs and in accordance 
with the specific policy developed for the study. 
10.0 CONCLUSION 
 
In summary, this is a small and open-label study by design, therefore necessitating cautious 
interpretation. However, the study’s findings may provide invaluable data on glyburide’s 
safety and pharmacokinetic profile as well as preliminary data on its ability to improve 
neurologic outcomes following SCI. Taken together, this data will allow for a more rational 
subsequent phase II/III trial design. 
 
 

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11.0 REFERENCES 
 
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2. Sheth, K.N., et al., Pilot study of intravenous glyburide in patients with a large ischemic 
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3. Walters, B.C., et al., Guidelines for the management of acute cervical spine and spinal 
cord injuries: 2013 update. Neurosurgery, 2013. 60 Suppl 1: p. 82-91. 
4. Grossman, R.G., et al., A prospective, multicenter, phase I matched-comparison group 
trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with 
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6. Simard, J.M., et al., Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels 
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7. Balentine, J.D., Pathology of experimental spinal cord trauma. I. The necrotic lesion as a 
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8. Chen, M., Y. Dong, and J.M. Simard, Functional coupling between sulfonylurea receptor 
type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J 
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9. Chen, M. and J.M. Simard, Cell swelling and a nonselective cation channel regulated by 
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10. Simard, J.M., et al., Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates 
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rat model of spinal cord injury. Spinal Cord, 2013. 51(11): p. 823-7. 

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14. Simard, J.M., et al., Spinal cord injury with unilateral versus bilateral primary 
hemorrhage--effects of glibenclamide. Exp Neurol, 2012. 233(2): p. 829-35. 
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p. 243-50. 

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28. Hurlbert, R.J., Strategies of medical intervention in the management of acute spinal cord 
injury. Spine (Phila Pa 1976), 2006. 31(11 Suppl): p. S16-21; discussion S36. 
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36. Remedy Pharmaceuticals’ Drug CIRARATM Cut Death Rates From Severe Stroke by 
More Than Half. [Press Release]. Scottsdale, AZ: Neurocritical Care Society Annual 
Meeting. October 9, 2015.  
 
 

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APPENDIX 1: Modified NACTN Chart 
See attached document 
APPENDIX 2: SAE Case Report Form 
See attached document