HypOthermia for Patients Requiring Evacuation of Subdural Hematoma: a Multicenter, Randomized Clinical Trial
Phase: NA
Conditions: Subdural Hematoma, Traumatic
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-MS-12-0762 
IRB APPROVAL DATE: 03/12/2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HypOthermia for Patients requiring Evacuation of Subdural Hematoma: 
a Multicenter, Randomized Clinical Trial 
“The HOPES Trial” 
 
NCT02064959 
 
Version Date: 03/12/2018 
 
 

IRB NUMBER: HSC-MS-12-0762 
IRB APPROVAL DATE: 03/12/2018 
 
 
HypOthermia for Patients requiring Evacuation of Subdural Hematoma: 
a Multicenter, Randomized Clinical Trial 
“The HOPES Trial” 
Study PIs: 
Dong H. Kim, MD 
Professor and Chair 
The Vivian L. Smith Department of Neurosurgery 
University of Texas at Houston 
 
David O. Okonkwo, MD, PhD 
Associate Professor 
Department of Neurological Surgery 
University of Pittsburgh 
 
Jonathan Jagid, MD 
Associate Professor of Neurological Surgery and Neurology 
Department of Neurological Surgery 
University of Miami 
 
Shoji Yokobori, MD, PhD 
Senior Assistant Professor, Lecturer 
Department of Emergency and Critical Care Medicine 
Division of Neurological Emergency 
Nippon Medical School 
 
Laura Benjamin Ngwenya, MD, PhD 
Assistant Professor Department of Neurosurgery, Neurology and Rehabilitation Medicine 
Director, Division of Neurotrauma and Director Neurotrauma Center 
University of Cincinnati Neuroscience Institute 
 
Jed Hartings, PhD 
Associate Professor, Department of Neurosurgery 
University of Cincinnati 
 
Faiz Ahmad, MD, MCh 
Assistant Professor 
Department of Neurological Surgery 
Emory University School of Medicine, Director Surgical Neurotrauma 
Director Neurosurgery Spine, Grady Memorial Hospital 
 
Georgene W. Hergenroeder, PhD 
Assistant Professor and Study Director 
The Vivian L. Smith Department of Neurosurgery 
University of Texas at Houston 
 
Study Sponsors:  The Vivian L. Smith Foundation 
U.S. Army Medical Research and Materiel Command 
ZOLL Circulation 
 
Sponsor of IND (IDE): 
 
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TABLE OF CONTENTS .....................................................................................................PAGE 
CLINICAL SITES PARTICIPATING IN THE STUDY. ......................................................... 4 
STUDY TEAM ROSTER. ........................................................................................................... 6 
SYNOPSIS ..................................................................................................................................... 8 
1. 
STUDY OBJECTIVES ................................................................................................... 12 
1.1 
Primary Objective ....................................................................................................... 12 
1.2 
Secondary Objectives .................................................................................................. 12 
2. 
BACKGROUND ............................................................................................................. 12 
2.1 
Rationale ...................................................................................................................... 12 
2.2 
Supporting Data ........................................................................................................... 13 
3. 
STUDY DESIGN ............................................................................................................. 15 
4. 
SELECTION AND ENROLLMENT OF SUBJECTS ................................................ 15 
4.1 
Inclusion Criteria......................................................................................................... 15 
4.2 
Exclusion Criteria ....................................................................................................... 15 
4.3 
Study Enrollment Procedures ...................................................................................... 16 
5. 
STUDY INTERVENTIONS........................................................................................... 17 
5.1 
Interventions, Administration, and Duration............................................................... 17 
5.2 
Handling of Study Interventions ................................................................................. 18 
5.3 
Concomitant Interventions .......................................................................................... 18 
5.4 
Adherence Assessment ............................................................................................... 21 
6. 
CLINICAL AND LABORATORY EVALUATIONS ................................................. 21 
6.1 
Schedule of Evaluations .............................................................................................. 22 
6.2 
Timing of Evaluations ................................................................................................. 23 
6.3 
Special Instructions and Definitions of Evaluations ................................................... 24 
7. 
MANAGEMENT OF ADVERSE EXPERIENCES.................................................... 26 
8. 
CRITERIA FOR INTERVENTION DISCONTINUATION .................................... 28 
9. 
STATISTICAL CONSIDERATIONS ......................................................................... 28 

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9.1 
General Design Issues ................................................................................................. 28 
9.2 
Outcomes .................................................................................................................... 28 
9.3 
Sample Size and Accrual ............................................................................................ 29 
9.4 
Data Monitoring .......................................................................................................... 29 
9.5 
Data Analyses ............................................................................................................. 29 
10. 
DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE 
REPORTING ............................................................................................................... 35 
10.1 
Records to be Kept ...................................................................................................... 35 
10.2 
Role of Data Management .......................................................................................... 36 
10.3 
Quality Assurance ....................................................................................................... 37 
10.4 
Adverse Experience Reporting ................................................................................... 37 
11. 
HUMAN SUBJECTS ................................................................................................... 38 
11.1 
Institutional Review Board (IRB) Review and Informed Consent ............................. 38 
11.2 
Subject Confidentiality ............................................................................................... 39 
11.3 
Study Modification/Discontinuation .......................................................................... 39 
11.4 
Risk Analysis… .......................................................................................................... 39 
12. 
PUBLICATION OF RESEARCH FINDINGS ......................................................... 41 
13. 
REFERENCES ............................................................................................................. 42 
 
APPENDICES 
 
I. 
Model Informed Consent 
II. 
Glasgow Outcome Scale Extended (GOSE) 
III. 
Disability Rating Scale (DRS) 
IV. 
Shivering Protocol 

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CLINICAL SITES PARTICIPATING IN THE STUDY 
1) University of Texas at Houston 
Principal Investigator: Dong Kim, MD 
The Vivian L. Smith Department of Neurosurgery 
The University of Texas at Houston 
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Project Director & Co-PI: Georgene W. Hergenroeder, PhD MHA RN CCRC 
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2) University of Pittsburgh Medical Center 
Principle Investigator: David O. Okonkwo, MD, PhD 
Department of Neurological Surgery 
University of Pittsburgh Medical Center 
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3) University of Miami 
Principal Investigator: Jonathan Jagid, MD 
Ross Bullock, MD, PhD Co-PI 
University of Miami Miller School of Medicine 
Department of Neurological Surgery 
Department of Neurosurgery 
University of Miami 
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4) Nippon Medical School 
Principal Investigator: Shoji Yokobori, MD, PhD 
Senior Assistant Professor, Lecturer 
Department of Emergency and Critical Care Medicine 
Division of Neurological Emergency 
Nippon Medical School, Tokyo 
 
5) University of Cincinnati Medical School 
Principal Investigator: Laura Benjamin Ngwenya, MD, PhD 
Jed A. Hartings, PhD 
Assistant Professor Department of Neurosurgery, 
Associate Professor 
Neurology and Rehabilitation Medicine 
Dept of Neurosurgery 
Director, Division of Neurotrauma 
Univ of Cincinnati 
University of Cincinnati Neuroscience Institute 

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6) Yamaguchi University Hospital 
Principal Investigator: Eiichi Suehiro, MD PhD 
Department of Neurosurgery 
Yamaguchi University School of Medicine, Yamaguchi 
 
7) Kagawa University Hospital 
Principal Investigator: Yasuhiro Kuroda, MD PhD 
Department of Emergency and Critical Care Medicine 
Kagawa University Hospital, Kagawa 
 
8) Osaka Mishima Emergency Critical Care 
Principal Investigator: Hitoshi Kobata, MD PhD 
Department of Neurosurgery 
Osama Mishima Emergency Critical Care, Osaka 
 
9) National Disaster Medical Center 
Principal Investigator: Hiroshi Yatsushige, MD PhD 
Department of Neurosurgery 
National Disaster Medical Center, Tokyo 
 
10) Nippon Medical School Tamanagayama 
Principal Investigator: Kyoko Unemoto, MD PhD 
Department of Emergency and Critical Care Medicine 
Nippon Medical School Tamanagayama, Tokyo 
 
11) Nagasaki University Hospital 
Principal Investigator: Osamu Tasaki, MD PhD 
Department of Emergency and Critical Care Medicine 
Nagasaki University Hospital, Osamu Tasaki 
 
12) Kurume University Hospital 
Principal Investigator: Yukihiko Nakamura, MD PhD 
Department of Emergency and Critical Care Medicine 
Kurume University Hospital, Fukuoka 
13) Saiseikai Fukuoka General Hospital 
Principal Investigator: Tomoya Miyagi, MD PhD 
Department of Neurosurgery 
Saiseikai Fukuoka General Hospital, Fukuoka 
 
14) Emory University School of Medicine/Grady Memorial Hospital 
Principal Investigator: Faiz Ahmad, M.D., M.Ch. 
Assistant Professor 
Department of Neurological Surgery, Emory University School of Medicine 
Director Surgical Neurotrauma, Director Neurosurgery Spine 
Grady Memorial Hospital 
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STUDY TEAM ROSTER 
The sites study team roster is maintained in a separate document. 
 
Berry Consultants 
Donald A Berry, PhD, Principal Evaluator/Investigator 
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Michelle Detry, PhD, Statistician 
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Baylor College of Medicine 
Stephen McCauley, PhD Neuropsychologist 
Associate Professor, Baylor College of Medicine 
Departments of Physical Medicine and Rehabilitation, Neurology and Radiology 
 
Elisabeth A. Wilde, PhD, Neuropsychologist 
Associate Professor, University of Utah School of Medicine 
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Independent Data Safety Monitoring Board 
Michael N. Diringer, MD, Professor of Neurology, Neurological Surgery, 
Anesthesiology, and Occupational Therapy, Washington University School of 
Medicine, St. Louis, MO. 
Director Neurology/Neurosurgery Intensive Care Unit 
Washington University School of Medicine at Washington University Medical Center 
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Nancy R. Temkin, Ph.D. 
Professor of Neurological Surgery and Biostatistics 
University of Washington, |
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Shelly D. Timmons, MD, PhD, FACS, FAANS 
Professor of Neurosurgery, Vice Chair for Administration, and Director of 
Neurotrauma 
Penn State University Milton S. Hershey Medical Center 
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Data Monitor 
Cristina Falo, PhD 
Clinical Research Director, NeuroICU 
Columbia University Medical Center Department of Neurology 

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SYNOPSIS 
 
Study Title 
HypOthermia for Patients requiring Evacuation of Subdural Hematoma: 
a Multicenter, Randomized Clinical Trial (“The HOPES Trial”) 
 
Primary Objective 
The objective is to test whether hypothermia improves outcome following TBI with subdural 
hematoma requiring evacuation. The primary objective is to determine if rapid induction of 
hypothermia prior to emergent craniotomy for traumatic subdural hematoma (SDH) will improve 
outcome as measured by Glasgow Outcome Scale-Extended (GOSE) at 6 months. 
 
Secondary Objectives 
 
Safety Objective: To demonstrate the safety of intravascular cooling in the management of acute 
traumatic SDH. 
 
Exploratory Objective: To determine the effect of hypothermia on TBI  biomarkers:  glial fibrillary 
acid protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1). 
 
Mechanistic Objective: To determine if therapeutic hypothermia to 33°C for 48 hours reduces 
the incidence of cortical spreading depolarization in patients with acute traumatic SDH. 
 
Design and Outcomes 
This is a prospective, pragmatic, randomized, controlled, multi-center trial of the safety and 
efficacy of intravascular cooling to induce hypothermia in TBI patients prior to and after surgical 
evacuation of traumatic SDH. The hypothesis of the study is that early induction and 
maintenance of therapeutic hypothermia in patients with TBI undergoing hematoma evacuation 
will improve global neurologic outcome as measured by GOSE at 6 months. Patients with 
moderate to severe acute TBI with SDH who require emergent craniotomy will be enrolled into 
this study. Patients will be randomized into two groups: 1) intervention - rapid induction of 
hypothermia to 35°C followed by maintenance at 33°C or 2) standard care - normothermia (37°C). 
All patients will have an intravascular temperature management catheter inserted into the femoral 
vein. 
The trial is aimed for N=120 subjects, but allows an extension up to a maximum of up to 350 
patients. The design includes multiple interim looks at the data, after 60, 120, 180, 240, and 300 
patients randomized. At each interim, Bayesian predictive probabilities will be used to determine 
if enrollment should stop before the maximum, either due to futility or expected success. 
 
Patients may have a 6-lead platinum strip electrode placed on the surface of the brain at the  time 
of craniotomy and hematoma evacuation with subsequent monitoring for cortical spreading 
depression for up to 7 days following injury. The relative incidence of cortical spreading 
depression in patients treated with hypothermia will be compared against patients treated with 
normothermia. 
 
Patients will undergo neuropsychological assessment of their level of recovery at 4 weeks and 6 
months post-injury. These outcomes assessments will be performed by investigators who are 
unaware of the treatment group assignment. GOSE (dichotomous: Good recovery and  moderate 
disability will be designated as favorable outcomes; severe disability, vegetative state, 

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and death as poor outcomes) at 6 months post-injury will be the primary outcome. Disability Rating 
Scale (DRS) at 4 weeks will be used to impute missing GOS/GOSE scores and will be 
incorporated into the Bayesian monitoring model. 
 
Patients will have blood and CSF (when available) samples taken at 3 time points [T1, within 6 
hrs and as close to time of injury as possible (pre-hypothermia for the treatment arm); T2, post- 
surgical evacuation of hematoma (7-48 hrs); and T3, 5-14 days post-injury or discharge (DC)], 
whichever comes first. 
 
Study Schematic 

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Study Schematic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Enrollment is intended for N=120 subjects but allows for an extension to a maximum sample size of 
350;enrollment may stop after 60, 120, 180, 240, or 300 subjects enrolled, as determined by the results of 
the interim analyses. 
†ECoG Monitoring will be performed at approved centers only. 
Allocation 
Allocated to normothermia (n= 30-175) 
Up to 2 L IV fluid 
Intravascular catheter placed, 
ECoG Monitoring† 
Temperature maintained 37°C 
Blood/CSF samples T1, T2, T3 
Allocated to hypothermia (n= 30-175) 
Up to 2 L chilled IV fluid 
Intravascular catheter placed, cooled to 35°C 
prior to opening dura, ECoG Monitoring† 
Maintained at 33°C for 48hrs-5 days 
Blood/CSF samples T1, T2, T3 
Follow-Up 
4 week DRS; 6 month DRS, GOSE 
Lost to follow-up 
Discontinued intervention 
4 week DRS; 6 month DRS, GOSE 
Lost to follow-up 
Discontinued intervention 
Analysis 
Analysed (Intent to treat) 
□ Excluded from analysis 
Analysed as treated 
Analysed (Intent to treat) 
□ Excluded from analysis 
Analyzed as treated 
Screening 
Assess for eligibility 
+SDH 
<5hrs post injury 
Excluded 
 Not meeting inclusion criteria 
 Declined to participate 
 Other reasons 
Randomized (n=350)* 
Enrollment 

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Interventions and Duration 
Patients will be evaluated for enrollment criteria and once confirmed, randomized to standard care 
(normothermia) or hypothermia. Hypothermia will be initiated immediately after enrollment criteria 
are confirmed with up to 2 liters of chilled IV fluids. Normothermia patients will receive  up to 2 
liters of room temperature IV fluids. Intravascular temperature control utilizing the ZOLL CoolGard 
3000 or Thermogard XP and femoral catheter ICY or Quattro will be used to induce and maintain 
normothermia or hypothermia.  Normothermia patients will be maintained at  37°C 
±0.5°C. Hypothermia patients will be cooled to a temperature of 35°C prior to opening the dura 
and maintained at a temperature of 33°C±0.5°C. They will remain cooled for at least 48 hours. 
Cooling may last for up to 5 days in patients who are refractory to re-warming (e.g., intracranial 
pressure elevates). Re-warming will be controlled at 0.25°C per hour. The intravascular cooling 
catheter will remain in place for the planned 48 hour cooling and 16-24 hour re-warming  periods. 
However, once the goal temperature (33°C) has been met if for  any reason the  femoral cooling 
catheter needs to be removed or if the subject requires extended cooling, a subclavian cooling 
catheter may be placed or external cooling pads (Arctic Sun) may be used. 
 
Sample Size and Population 
 
 
We plan to enroll patients among the clinical sites into two study groups: 
 
1. Patients who undergo emergent craniotomy and evacuation of acute  subdural 
hematoma within 6 hours of injury treated with hypothermia (intervention). 
2. Patients who undergo emergent craniotomy and evacuation of acute  subdural 
hematoma within 6 hours of injury treated at normothermia (standard care). 
 
Only TBI patients who are not following commands and who require emergent surgical evacuation 
of an acute subdural hematoma will be enrolled in this study. To reduce the likelihood of imbalance 
of important prognostic factors between centers, a blocked randomization scheme will be used in 
this study. Randomization will be divided among the centers by the Biostatistics Center of Berry 
Consultants. 
 
A randomized design will be used in this study. The trial is intended for N=120 subjects but may 
extend to a maximum of 350 patients will be randomized equally at a 1:1 ratio to each of two arms 
(hypothermia versus control). The final analysis will use a one-sided Fisher’s exact test with a 
significance level of 0.02 to compare proportions of patients with good outcome as measured by 
GOSE at 6 months between two treatment arms. Interim analyses will be performed after 60, 120, 
180 240, or 300 patients randomized. The significance level of 0.02 accounts for the multiple 
interim looks to maintain overall type I error below 0.025. At each interim analysis, we will evaluate 
the predictive probability of statistical significance with the current sample size and with the 
maximum sample size. If the predictive probability of statistical significance with the current 
sample size is sufficiently high, then enrollment will stop and follow up will continue for 6 months. 
If the predictive probability of statistical significance with 350 patients is sufficiently low, then the 
study will stop for futility. Otherwise, enrollment will continue to the next analysis. Complete details 
may be found in Section 9. Operating characteristics of the design, such as power, type I error 
rate, and average sample size, were assessed by simulation and are described in Section 9. 

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HypOthermia for Patients requiring Evacuation of Subdural Hematoma: 
a Multicenter, Randomized Clinical Trial 
 
“The HOPES Trial” 
 
 
1. 
STUDY OBJECTIVES 
1.1 Primary Objective 
The primary objective is to determine if rapid induction of hypothermia prior to emergent 
craniotomy for traumatic subdural hematomas (SDH) will improve outcomes as measured by 
Glasgow Outcome Scale-Extended (GOSE) at 6 months. Treatment with hypothermia will lead to 
at least a 15% improvement in good outcomes. The primary outcome measure will be a 
dichotomized GOSE at 6 months. 
 
 
1.2 Secondary Objectives 
There are four secondary objectives of the study: 
 
Safety Objective: To demonstrate the safety of intravascular cooling in the management of acute 
traumatic SDH. 
 
Exploratory Objective: To determine the effect of hypothermia on TBI  biomarkers:  glial fibrillary 
acid protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1). 
 
Mechanistic Objective: To determine if the incidence of cortical spreading depolarization is 
reduced in patients undergoing therapeutic hypothermia compared to patient undergoing 
normothermia. 
 
Impact on Resource Utilization Objective: To determine the effect of moderate hypothermia on 
ICU length of stay (LOS) and hospital LOS. 
 
2. 
BACKGROUND 
 
2.1 Rationale 
 
Nearly 2 million Americans sustain a TBI annually and of these over 50,000 die and 90,000 remain 
permanently disabled(1). Brain damage as a result of TBI is caused both by the primary injury, 
and by a number of secondary pathological processes that occur as a result of the initial 
trauma(2). While there is presently no cure for the primary injury, there is ongoing work to develop 
neuroprotective treatments to prevent secondary injury. Early hypothermia is one modality shown 
to be neuroprotective in ischemia-reperfusion injuries such as in animal TBI models(3;4) after 
cardiac arrest (5-7) and in infants with moderate or severe hypoxic-ischemic encephalopathy(8). 
However, while clinical trials show that hypothermia can lower intracranial pressure, results of the 
effect of hypothermia on outcome have been inconclusive, in part because of mixed injury types, 
inexperience of centers in the use of hypothermia, initiation and period of cooling, and duration of 
rewarming (9;10). 
Retrospective subgroup analysis of NABIS:H I (11) and NABIS:H II (12) hypothermia trials 
revealed  that   TBI   patients   treated   with   hypothermia   undergoing   surgical  evacuation of 

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intracranial hematomas had significantly improved neurologic outcomes compared to patients 
treated with normothermia(13). We propose to perform a randomized trial to prospectively study 
the effect of very early cooling in patients undergoing surgical evacuation of acute subdural 
hematomas (35°C prior to opening the dura followed by maintenance at 33°C for a minimum of 
48h). In the previous trials, hypothermia was induced via surface cooling, a strategy that carries 
significant challenges when treating patients with emergent neurosurgical conditions requiring 
surgery. In the trial proposed herein, hypothermia will be induced with intravascular cooling 
catheters, which, if successful, would greatly increase the generalizability of the treatment. 
Additionally, intravascular catheters will be employed to maintain normothermia as it is 
established that fever is detrimental to TBI patients(14-16). Furthermore, intravascular 
temperature management combines effective temperature control with central venous access and 
has been shown to effectively reach the target temperature rapidly and safely(17-21). Moreover, 
intravascular cooling has been shown to be efficient at quickly lowering body temperature and 
maintaining it with a lower variation of target temperature than surface cooling(17) . The proposed 
trial will employ several novel features that represent a major leap forward in clinical trial design 
and execution in traumatic brain injury. These innovative features include: 
1. The trial will involve patients with TBI who all have similar injury morphology and 
pathophysiology. Previous clinical trials in TBI have employed the Glasgow Coma Scale 
score as the principal inclusion criterion and ignored the fact that TBI is a spectrum of 
heterogeneous pathophysiologies that may not all respond to a single treatment. Only patients 
with subdural hematomas requiring surgical evacuation will be included in this proposed study. 
2. The trial will be conducted in centers that have sufficient volume to ensure swift trial 
completion, a strong track record of collaboration in multi-center clinical trials in TBI, and all 
are experienced in utilizing hypothermia. This will reduce cost, accommodate uniformity of 
study interventions, and reduce the effect of inter-center variance on trial statistics. 
3. The trial will employ both exception from informed consent (EFIC) from the start of the  trial 
and written informed consent per institutional and state requirements. EFIC will significantly 
reduce barriers to patient recruitment and help ensure timely completion of the trial. Houston 
and Pittsburgh have a documented track record in obtaining community and ethical approval 
for EFIC and both centers successfully employed EFIC in the most recent hypothermia trial. 
A plan to address EFIC requirements is attached. 
4. The trial will assess whether cortical spreading depression is a mechanistic target in this 
TBI patient population. Previous studies, relying heavily on data from Pittsburgh and Miami, 
have documented that 55% of patients undergoing emergent craniotomy for traumatic 
intracranial hematomas develop cortical spreading depression. Further work has 
demonstrated that the occurrence of cortical spreading depression increases as body 
temperature increases (22). This trial will represent the first attempt to assess the impact of a 
therapeutic intervention (hypothermia) on cortical spreading depression.  Cortical spreading 
depression will be monitored in IRB approved centers only. 
5. The trial will assess if hypothermia will decrease the levels of markers for brain injury. We will 
also determine whether 4-6week DRS is an accurate predictor of 6-month GOSE outcomes, 
and thus a substitute endpoint. 
 
 
2.2 Supporting Data 

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Because of differences of trial design and broad entry criteria, the results of 23 clinical trials of 
hypothermia treatment involving 1614 patients with severe traumatic brain injury (TBI) have been 
inconsistent(23). While the two U.S. prospective randomized clinical trials of hypothermia in TBI 
[The National Acute Brain Injury Study: Hypothermia, NABIS:H I (11) and, NABIS:H  II(12)] failed 
to confirm the utility of hypothermia as a primary neuroprotectant for all TBI patients, retrospective 
subgroup analyses of both of these trials revealed that in the subgroup of patients who underwent 
surgical evacuation of intracranial hematomas, patients treated with hypothermia had better 
neurological outcomes than patients treated with normothermia.  It makes far more intuitive sense 
that hypothermia would be beneficial to the specific subset of  TBI patients with ischemia-
reperfusion injury than to the global, extremely heterogeneous population of severe TBI patients 
as a whole. Reperfusion after evacuation of intracranial hematomas likely leads to excessive free 
radical production, release of inflammatory molecules and excitotoxicity leading to cell death. To 
date, no trial to investigate specifically the effect of hypothermia on patients undergoing surgical 
evacuation of intracranial hematomas has been performed. 
 
In October 2007, a workshop convened by the NINDS and co-sponsored by several other national 
brain injury organizations concluded that future TBI trials should use targeted pathoanatomic 
injury type as an initial diagnostic entry criteria(24). Furthermore, the workshop stressed the need 
for establishing pathophysiologic mechanisms relevant to specific pathoanatomic types of TBI 
and verifying that a given therapeutic approach improves outcome  in these targeted TBI 
types(24). 
 
In 2009, the COSBID group demonstrated that patients who underwent craniotomy for TBI were 
at a 3-fold higher risk for cortical depolarization phenomena when they were hyperthermic 
(>38.4°C) as opposed to normothermic (≤38.4°C)(25). Recently, the same group has collected 
data that suggest that depolarizations are a causal pathomechanism with adverse effects on the 
traumatically injured brain(26). Taken together, these data  suggest  that  therapeutic hypothermia 
may decrease the frequency of cortical depolarizations and thus improve outcomes. 
 
As recommended by the 2007 NINDS TBI workshop, our proposed study would be the first TBI 
trial to use a specific pathoanatomic injury as opposed to the Glasgow Coma Scale (GCS) as the 
principal inclusion criterion. Additionally, it would be the first trial to study the efficacy and safety 
of hypothermia induction using intravascular cooling catheters. In previous trials, hypothermia 
was induced via surface cooling, a technique that is associated with both significant temperature 
variability as well as challenges for temperature control in TBI patients requiring emergent 
neurosurgical operations. Demonstration of safety and efficacy of hypothermia induction with 
intravascular cooling catheters would increase the generalizability of hypothermia as an 
intervention. Finally, our study could both confirm the NABIS:H I and NABIS:H II data regarding 
the benefit of hypothermia for TBI patients who undergo surgical evacuation of intracranial 
hematomas and potentially provide a mechanism to explain this phenomenon. 
 
Significant morbidity and mortality occurs in traumatic SDH. Mortality rate estimates range from 
40-70% of surgical SDH patients(27;28). SDH patients may experience elevated intracranial 
pressure (ICP), seizures, coagulopathy and hypotension(29-33). SDH patients enrolled in this 
study are expected to require mechanical ventilation and monitoring of intracranial pressure as 
part of their routine care(28). Risks associated with hypothermia may include shivering, 
hypovolemia, electrolyte disorders, hyperglycemia, pneumonia, (small risk of skin lesions if water-
circulating surface cooling pads are used), and some risk of catheter-related   thrombosis 

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or possible catheter-related infection with intravascular cooling devices. Risks are minimized by 
reaching the goal temperature as quickly as possible, rewarming slowly and removing the 
intravascular catheter within 5 days of placement(33). 
 
Exploratory analysis is to assess if therapeutic hypothermia will decrease blood/CSF levels of two 
TBI biomarkers. Two markers (GFAP and UCH-L1) will be interrogated. GFAP is a monomeric 
intermediate filament protein expressed by astrocytes that is released after TBI(34;35). Elevated 
serum GFAP level following severe TBI is predictive of poorer outcome and has shown to be 
correlated with intracranial pressure (ICP), mean arterial pressure (MAP), cerebral perfusion 
pressure (CPP), Glasgow Outcome Score (GOS) and  mortality.  GFAP serum concentrations 
above a cut-off level of 1.5 µg/L were predictive of death or poor outcome (GOS at 6 months) with 
85% sensitivity and 52% specificity, and 80% sensitivity and 59% specificity, respectively(35). 
UCH-L1 is a 24kDa protein thought to be involved with the removal of oxidized or misfolded 
proteins(36). It has been associated with neurodegenerative diseases and brain ischemia(37). 
UCH-L1 has been detected in both CSF and serum within 6 hours of injury, it has distinguished 
injury severity and predicted death(37;38). 
 
 
3. 
STUDY DESIGN 
 
 
This is a randomized clinical trial of patients with acute traumatic subdural hematomas who are 
not following commands and who require emergent craniotomy within 6 hours of injury. Patients 
meeting enrollment criteria will be randomized to hypothermia or normothermia as soon as the 
decision to perform emergent craniotomy is made by the attending neurosurgeon. Patients will 
undergo insertion of a femoral intravascular temperature management catheter. Patients 
randomized to hypothermia will be rapidly cooled to 35°C before removal of the subdural 
hematoma and then maintained at 33°C±0.5°C for a minimum of 48 hours. Patients randomized 
to normothermia will be maintained at 37°C±0.5°C. Neurologic outcome will be assessed in all 
subjects at 4-6 weeks and 6 months+/-3 weeks post-injury using the GOSE and DRS. 
 
Multiple interim analyses will be performed to determine whether enrollment may stop for futility 
or expected success before the maximum sample size is reached. In the interim analysis, we will 
model the relationship between the short-term response (4-week DRS) and the long-term 
response (6-month GOSE) in order to impute final outcomes for those patients with only short- 
term data. Decisions to stop or continue enrollment will be based on Bayesian predictive 
probabilities of study success. 
 
4. 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 Inclusion Criteria 
1. Non-penetrating traumatic brain injury 
2. GCS motor score ≤5 (not following commands) 
3. Estimated or known age 22-65 years 
4. Acute subdural hematoma requiring emergent craniotomy within 6 hours of initial 
injury 
5. Estimated time of injury to time to reach temp of 35°C<6 hrs 
 
4.2 Exclusion Criteria 

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1. Total GCS = 3 and bilateral fixed and dilated pupils 
2. Following commands after an initial period of coma (GSC motor score of 6) 
3. Known pre-existing neurological deficit (e.g., previous TBI, stroke) 
4. Concomitant signs/symptoms of spinal cord injury (i.e., priapism, no spontaneous 
movement off of paralytics/sedation, no rectal tone, incontinent of stool, obvious 
presence of injury on imaging.) 
5. Arrival temperature is <35°C 
6. Hemodynamic instability (i.e., MAP<60mmHg for 30 minutes) 
7. Active cardiac dysrhythmia resulting in hemodynamic instability 
8. Pregnancy 
9. Duret hemorrhage 
10. Prisoner or Ward of the State 
11. Known history of clotting disorder (e.g., heparin induced thrombocytopenia, PE/DVT) 
12. Injury to other body organ where hypothermia would be precluded because of bleeding 
risk (e.g., grade 3 liver laceration; bowel laceration; flail lung or  INR>1.4) 
13. Inability to obtain informed consent or utilize exception to informed consent for 
emergency research. 
 
 
4.3 Study Enrollment Procedures 
4.3.1 Identifying and Recruiting Candidates. Potential subjects for this trial will be recruited 
from all patients with a TBI presenting within 5 hours of injury to one of the participating trial 
centers. The therapeutic window of reaching 35°C within 6 hours of injury and before the dura is 
cut was selected based on evidence from previous studies in which patients with intracranial 
hematoma requiring evacuation reaching 35°C early post-injury had fewer experiencing poor 
outcomes compared to those  who were treated with normothermia or late hypothermia (41%  vs. 
62% poor outcome, p<0.009)(13). In these multicenter, randomized controlled NABIS:H I and 
NABIS:H II trials surgery commenced within 3.1+/-3.6hrs and 3.9+/-4.3hrs of admission 
respectively. Analysis showed the goal of reaching 35°C prior to hematoma evacuation appears 
to be neuroprotective, reducing the biochemical cascade associated with  reperfusion.  Therefore 
the HOPES trial aims to achieve early cooling prior to surgery, without causing a  delay in care. 
Each clinical site is staffed by trained research personnel capable of performing screening 
procedures for each potential subject according to the inclusion/exclusion criteria described above 
as well as clinicians skilled in the placement and management of intravascular cooling catheters. 
Acute subdural hematoma will be diagnosed by standard imaging used at enrolling centers. 
Decision regarding the need for emergent craniotomy is left to the opinion of the treating 
neurosurgeon. 
 
4.3.2 Screen Failure Logs. A log of all screen failures will be maintained at each site. The 
information collected on the screen failure log will include basic demographic information as well 
as the reason for excluding the patient from randomization. The Screen Failure Log allows for the 
assessment of any selection bias in the enrollment of patients(39). 
 
4.3.3 Informed Consent Procedures. Upon confirmation of a patient’s eligibility for the trial, 
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member whom the clinical site PI has delegated authority to obtain informed consent. The 
delegation of authority must be documented and a current copy of this document must be 
maintained at the clinical site. As with all delegated clinical trial responsibilities, it is the 
responsibility of each site PI to ensure that the delegation is made only to those individuals who 
are qualified and that there is adherence to all applicable regulatory requirements and Good 
Clinical Practices (GCP) Guidelines. Additionally, it is the investigator’s responsibility to ensure 
that the patient’s legally authorized representative (LAR) has been given an adequate explanation 
of the purpose, methods, risks, potential benefits and patient responsibilities of the study. In 
Houston, Cincinnati, Emory and Pittsburgh, if no legally authorized representative is available, 
Exception from Informed Consent for Emergency Research (EFIC) will be employed. EFIC is not 
permitted under Florida State law and will not be employed in Miami. EFIC is not permitted at the 
Japanese sites at this time. The consent form must be an up-to-date document that has been 
approved by the clinical site’s IRB. A sample informed consent form is provided as Appendix I. 
 
In this trial, all subjects will have an altered mental status and, therefore, either exception from 
informed consent will be employed or, when available, informed consent will be obtained from a 
LAR or person with power of attorney for the patient. Every attempt will be made to contact the 
patient’s LAR/family as soon as possible after the patient’s admission, and in accordance with the 
individual hospital’s protocol. To the extent possible, these discussions should be carried  out in 
a private setting without distraction. No coercion will be applied, and the LAR and other family 
members will be given an opportunity to read the informed consent document, ask and have 
answered any questions they may have about the study. 
 
4.3.4 Randomization Procedure. Once all eligibility criteria have been confirmed the 
randomization process will begin. Block randomization within each site will produce a 1:1 ratio 
between subjects treated with hypothermia and subjects treated with normothermia. Block 
randomization within each site will be employed for the randomization to enroll comparable 
numbers of patients among the treatment groups at each trial center. Each study site will have 
sealed sequentially numbered opaque envelopes with the patient assignment at the respective 
site. The statistician will generate the study randomization codes using a computer program.  The 
randomization series will yield codes for assignment of subjects to each of the study arms. The 
codes will be placed in sealed, sequentially numbered opaque envelopes. Envelopes will  be 
opened in sequential order to determine study subject assignment. 
 
 
5. 
STUDY INTERVENTIONS 
 
5.1 Interventions, Administration, and Duration 
This is a pragmatic study; patients will be treated with standard care as established at each 
enrolling center. All of the enrolling sites utilize Brain Trauma Foundation Guidelines as foundation 
for delivery of care(40). Intravascular cooling catheters may be placed in the emergency room, 
the operating room or neurotrauma intensive care unit (NTICU). Patients randomized to 
hypothermia will be rapidly cooled to 35°C before opening the dura and then maintained at 
33°C±0.5°C for a minimum of 48 hours and a maximum of 5 days. After evacuation of SDH all 
patients will be cared for in the ICU by teams experienced in hypothermia and the management 
of TBI. 
 
Intravascular cooling will be provided by CoolGard 3000 or Thermogard XP which use an 
intravenous central catheter circulating cooled saline in a closed loop system.   These    devices 

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are currently in clinical use at the enrolling centers. The cooling system is cleared by the FDA  as 
510K devices (Thermogard System – K072234 and Quattro – K101987). Indications for use 
includes in cardiac surgery patients to achieve and or maintain normothermia during surgery and 
recovery/intensive care, and to induce maintain and reverse mild hypothermia in neurosurgery 
patients in surgery and recovery/intensive care. The intravascular cooling system is a portable 
temperature regulation system that contains a computerized user interface and a cooling and 
warming unit that circulates sterile saline through polymeric balloons that surround catheters. 
(This is a closed system; additional fluid is not introduced into the circulatory system for 
temperature management purposes.) The system continuously compares a patient’s core body 
temperature to the programmed target body temperature and automatically adjusts the 
temperature of the saline flowing through the catheter to maintain the programmed temperature. 
 
Arctic Sun temperature transfer pad device by Medivance (cleared by the FDA, K010338) may 
be utilized after reaching core temperature if the intravascular cooling device must be removed. 
Each of these devices utilizes a temperature feedback loop provided by a urinary/rectal  
catheter. 
 
Spreading depolarizations will be monitored using electrocorticography (ECoG) electrode strips 
(Wyler, platinum, 4 mm diameter, 10 mm interval between electrode centers; Ad-Tech Medical 
Instruments Corp., Racine, WI, USA) placed in the subdural space. The electrodes that are  used 
are not being evaluated in the proposed research. The strip has received FDA approval under 
section 510(k) for the temporary placement on the surface of the brain for recording or stimulating 
electrical activity of the brain. 
 
 
5.2 HANDLING OF STUDY INTERVENTIONS 
All sites currently have intravascular cooling systems and use them as part of standard care. 
ZOLL Circulation has agreed to provide the study with the catheters required for cooling with the 
Thermogard System (Quattro – K101987) for use in study patients.  Catheters provided for  study 
use will be maintained in a separate secure area so that they are accessible at the  location of 
use (ED, OR or NTICU) but are not intermingled with standard care catheters. Study personnel 
will be responsible for accountability of catheters, maintaining a log of catheters used per study 
subject (e.g., successful placement, wasted due to contamination, etc.). 
 
5.3 Concomitant Interventions 
 
5.3.1 
Required Interventions. 
Enrolled subjects will be randomized to standard 
care/normothermia or standard care with the intervention of  hypothermia.  Required interventions 
include the administration of up to 2 liters of IV fluid per standard head trauma resuscitation 
(chilled for hypothermia arm) prior to evacuation of SDH, and the placement of the intravascular 
temperature management catheter. Core body temperature will be measured by urinary bladder 
Foley catheter, rectal probe or esophageal probe whichever is standard care at each institution. 
 
Patients in the control arm will be maintained at normothermia 37°C. Patients in the treatment 
arm will be cooled to 35°C prior to opening the dura and maintained at 33°C for a minimum of 48 
hours up to a maximum of 5 days. Cooling will be initiated with the up to 2 liters of chilled IV fluids, 
and intravascular cooling with the Thermogard System and catheter which is to be placed in the 
femoral vein 

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The surgical procedure will be tailored according to the pathology of the patient. Frontal,  parietal, 
temporal or occipital craniotomies or any combination of those will be performed as per standard-
of-care for the injury each patient has sustained. Following hematoma evacuation and 
hemostasis, a subdural strip electrode will be placed on the brain surface near the lesion. 
Considering the lesion distribution on pre-operative scans and the craniotomy location/size, the 
ECoG electrode strip is placed radiating outward from, or lying parallel to, an accessible injured 
region such that the closest electrode contacts are placed on viable, but often edematous or 
contused cortex with a low degree of sub-arachnoid blood. The intention is to monitor peri- lesion 
(“penumbral”) cortex that is at greatest risk for further deterioration.  The strip is placed,  so far as 
possible, along a single gyrus. The strip may be tunneled under intact skull, so that distal 
electrodes lie outside the visible craniotomy field, or may be placed entirely within the  field. 
 
Following placement of the electrode, the lead will be externalized through the dura and 
craniotomy. If the bone flap is replaced, the lead will be exteriorized through a burr hole to facilitate 
subsequent removal. Furthermore, the lead wire will be exteriorized in a straight line with the 
electrode strip, also to facilitate removal. Finally, the lead is tunneled under the scalp and out 
through a stab wound distant from the craniotomy incision line in order to reduce the  risk of 
infection. When ECoG recordings are complete, the strip is removed by gently pulling it through 
the stab wound followed by watertight closure of the skin incision. 
 
The technique of ECoG strip placement is a standard surgical procedure in epilepsy 
neurosurgery, and has been used as described to monitor surgical patients with severe stroke  or 
traumatic brain injury at more than a dozen neurosurgical centers.(41-45) 
 
Upon admission to the neuro-intensive care unit (NICU), following surgery, the leads from the 
ECoG electrode strip will be connected to an EEG amplifier. External ground and reference 
electrodes will be placed and continuous ECoG recordings will then commence. The reference 
electrode is a platinum needle placed under the scalp. 
 
Continuous ECoG monitoring will be performed for at least the same duration as ICP  monitoring. 
In patients randomized to hypothermia, this is until at least 24 hours after re- warming is complete. 
In normothermia patients, patients will be monitored a minimum of 96 hours, and longer if 
continued ICP monitoring is clinically indicated. When monitoring is complete, the electrode strip 
will be removed at the bedside under sterile conditions, as is performed for standard-of-care 
intracranial devices. 
 
 
Blood samples for biomarker analysis will be taken at 3 time points (T1, within 6 hrs and as close 
to time of injury as possible (pre-hypothermia for the treatment arm); T2, post-surgical evacuation 
of hematoma (7-48 hrs); T3, 5-14 days post-injury or DC whichever comes first. If the patient has 
a ventricular drain in place, CSF samples will also be collected. 
 
As part of standard care all patients are expected to have an intracranial pressure monitor (either 
extraventricular drain or intraparenchymal monitor). 
 
 
5.3.2 Prohibited Interventions. Please see re-warming protocol regarding fluids and 
electrolytes. 

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5.3.3 Precautionary Interventions 
 
5.3.3.1 Induction of Hypothermia. Cold fluid infusion with up to 2 liters of chilled (4°C) IV fluids 
over approximately 30 minutes should be initiated after randomization. Once the intravascular 
cooling catheter is in place, goal temperature should be 35°C prior to dura opening, with 
maintenance at 33°C (32.5-33.5°C). 
 
 
5.3.3.2 Procedure for Re-warming. At or shortly after the 48-hours of cooling, re-warming will 
be done very gradually. This will allow body temperature to increase no faster than 0.25ºC every 
hour. This will be accomplished by setting the following method: 
 
1. Set the intravascular cooling catheter controls to automatic with the target temperature 
to be 37.0°C. (The machine itself should be set to 36.5°C to avoid overshooting the target 
temperature.) 
 
2. Set machine to rewarm at a rate of 0.25°C/hour. (The machine itself may need to be 
set to 0.1°C/hour to achieve this goal.) 
 
3. It takes 16-20 hours to rewarm a patient successfully and the unit must be on automatic 
at all times. 
 
4. Continue use of room temperature ventilated air until 37.0oC is reached. 
a. If the ICP is elevated (>20mmHg) do not rewarm at 48 hours, may keep the subject 
cool up to 5 days. 
b. If the ICP elevates as rewarming hold the temperature where it is and add 
additional standard measures for treating elevated ICP. If no response to 
treatments in 6 hours and ICP is >25mmHg, re-cool to 33°C. 
c. Goal is to have the subject re-warmed within 5 days. 
 
8 Hours Prior to Re-warming: 
1. Stop all potassium and magnesium administration 8 hours before the start of re- 
warming to reduce the likelihood of hyperkalemia and hyper-magnesium during re- 
warming. 
 
2. Determine fluid balance 8 hours prior to the start of re-warming: 
a. If <0 cc, administer additional intravenous fluid (colloid, crystalloid, or a 
combination) to achieve a positive balance. 
b. Administer 1000cc volume load to all subjects who have a cumulative fluid balance 
of 0 – 999cc. 
c. It is important to ensure that there is adequate circulating blood volume (Hgb>8 
grams and Hct > 30%) when the patient begins to vasodilate with re-warming. 
 
During re-warming: 
1. Monitor bladder temperature, ICP, MAP, and CPP hourly. 
 
2. If ICP increases above 20mmHg, rewarming will be suspended per protocol. 

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3. Maintain CPP between 50 and 70 mmHg using volume expansion and vasopressors, as 
needed. If MAP <90 mm Hg, start a vasopressor agent and evaluate response, additional agents 
may be used if necessary. 
 
4. The ICP monitor must remain in place for at least 24 hours after re-warming is complete, (even 
if the ICP’s are within normal limits) in order to detect rebound increase in ICP after re- warming. 
 
 
5.4 
Adherence Assessment 
 
Compliance with the study intervention will be assessed by monitoring temperature data. Analysis 
will be performed on time to reach goal temperature, duration of cooling, and temperature ranges 
for each group during the intervention period. 
 
6. 
CLINICAL AND LABORATORY EVALUATIONS 
 
Management is per standard care at each institution. All centers practice in accordance with 
Brain Trauma Foundation Guidelines. 

 
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6.1 
Schedule of Evaluations (Table 1.) 
 
Evaluation 
Screening 
(<5hrs of 
injury) 
Entry 
T1 
<6hrs of injury 
7 to 48hrs 
T2 
>48 hrs-5d 
5-14d 
T3 
4-6 wk 
6mons+/-3 
weeks 
Documentation of Injury (Head CT/MRI) 
SOC 
SOC 
Medical/Treatment History 
SOC 
Clinical Assessment 
SOC 
X 
X 
X 
Physical Exam 
SOC 
Informed Consent 
Per center approved process 
Hypothermia (Control) 
X 
X 
Dura Opening/SDH Evacuation 
SOC 
Brain Activity Monitoring 
X 
X 
X 
Rewarming 
X 
Hematology 
SOC 
SOC 
SOC 
Chemistry 
SOC 
SOC 
SOC 
Pregnancy Testing 
SOC 
Stored Plasma/CSF 
X 
X 
X 
Adherence Assessments 
X 
X 
Adverse Event Assessments 
X 
X 
X 
X 
X 
X 
Outcome (DRS; GOSE) 
X 
X 
SOC=per standard care 
 
 
 
 
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6.2 
Timing of Evaluations 
 
 
6.2.1 Pre-Randomization Evaluations 
 
These evaluations occur prior to the subject receiving any study interventions. 
 
Screening 
Subjects enrolled in this study will have a goal of SDH evacuation within 6 
hours of injury. Screening must be completed to allow time for catheter 
placement and cooling down to 35°C prior to opening of the dura. All 
screening evaluations are part of routine patient management for TBI 
patients. 
 
Pre-Entry 
T1 blood draw may be taken with routine blood draw, processed and held 
(discarded if subject is not enrolled). 
 
Entry 
Randomization should occur immediately upon confirmation of enrollment 
criteria. Initiation of study intervention should commence immediately after 
randomization. 
 
 
6.2.2 On-Study/On-Intervention Evaluations 
 
Within 6 hours of injury (T1) 
Blood (and CSF if available) should be collected 
Up to 2 liters IV fluid administered 
Placement of intravascular catheter 
Cooling to 35°C for hypothermia arm; 37°C for normothermia 
Opening of dura (followed by evacuation of SDH) 
Adverse events monitored 
 
>6 to 48 hours post-injury (T2) 
Following hematoma evacuation and hemostasis ECoG Electrode strips 
should be placed 
Upon admission to the ICU, following surgery, the leads from the ECoG 
electrode strip will be connected to an EEG amplifier. External ground  and 
reference electrodes will be placed and continuous ECoG recordings will 
then commence. 
Repeat head CT as indicated for clinical care 
Temperature maintenance of 33°C for hypothermia arm; 37°C for 
normothermia arm 
Blood (and CSF if available) should be collected 
Adverse events monitored 
 
>48 hours to 5 days 
Rewarming initiated according to rewarming protocol (37°C for 
normothermia arm) 
Continuous ECoG monitoring will be performed for at least the same 
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until at least 24 hours after re-warming is complete. In normothermia 
patients, patients will be monitored a minimum of 96 hours, and longer if 
continued ICP monitoring is clinically indicated. When monitoring is 
complete, the electrode strip will be removed at the bedside under sterile 
conditions, as is performed for standard-of-care intracranial devices. 
Adverse events monitored 
(±0.5°C for all temperatures) 
 
 
6.2.3 
Intervention Discontinuation Evaluations 
 
Subjects who prematurely discontinue study intervention will complete controlled 
rewarming per protocol for patient safety. This trial follows an intention-to-treat 
design, subjects who discontinue intervention will continue to be followed and 
evaluated on study. Efforts will be made to retain such subjects on study for the 4-
6 week and 6 month outcome assessments. Once a subject discontinues from the 
study intervention they will not receive continued intravascular hypothermia. 
 
6.2.4 
On Study/Off-Intervention Evaluations 
 
     5-14 days (T3) 
Blood (and CSF if available) should be collected 
Adverse events monitored 
 
4-6 weeks 
DRS 
GOSE 
Adverse events monitoring 
 
4 weeks – 6 months 
Follow-up on adverse events as necessary 
Maintain subject contact (Phone calls/emails as necessary) 
 
i.   Final On-Study Evaluations 
 
 
6 months±3 weeks 
DRS 
GOSE 
Adverse events monitoring 
 
 
6.3 
Special Instructions and Definitions of Evaluations 
 
 
6.3.1 
Informed Consent. Patients will be randomized within 5 hours of arrival to the ED. If a 
patient arrives in the ED with family members present or before craniotomy is performed, then a 
prospective informed consent will be obtained. In Houston, Cincinnati, Atlanta and Pittsburgh, 
every attempt will be made to identify family as soon as possible but randomization will not be 
delayed for this purpose. If no family is identified the study team will continue to make every 
attempt to locate the family throughout the patient’s hospital stay. In Miami, exception from 
informed consent is not permitted according to state law; consent will be obtained per state 
regulations. The Japanese sites will obtain consent per their local regulations. 

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Centers must comply with Federal standards for community consultation and notification. In 
particular, community consultation as directed by each site’s institutional review board. (Please 
see attached plan.) For those patients enrolled and randomized under waiver, a study team 
member must meet with the family as soon as possible and explain the study in detail to them. 
The Legally Authorized Representative must be identified and permission to continue the study 
must be requested. Should permission be denied then those patients assigned to hypothermia 
will be gradually re-warmed. If the patient has been cooled to 33°C then the re-warming should 
be performed per protocol. 
 
In Randomized patients, permission must be obtained from the Legally Authorized Representative 
or the patient to use the data collected for that patient. This will be documented on the appropriate 
HIPPA forms. 
 
6.3.2 
Documentation   of   Traumatic   Brain   Injury   requiring   Emergent   Craniotomy. 
Subdural hematoma will be documented by standard of care brain imaging (head CT or MRI) 
 
6.3.3 
Medical History. Medical history will be obtained from family member if available. 
 
6.3.4 
Concomitant Treatments. Documentation of therapeutic intensity level (TIL) and 
concomitant treatments per the Common Data Elements (CDE) forms will be collected. 
 
6.3.5 
Study Intervention Modifications. Any modification to hypothermia/normothermia will 
be documented with rationale. 
 
6.3.6 
Clinical Assessments. A targeted physical exam is completed on presentation to the 
emergency department. Clinical events should be recorded on the case report forms (CRFs) and 
will include adverse events, temperature, ICP, MAP, pupil size and reactivity, hematoma size, 
midline shift, GCS, GOSE, and DRS. GOSE and DRS will be assessed by evaluator who  is 
unaware of (blind) the study group assignment. 
 
6.3.7 
Laboratory Evaluations. Baseline standard care laboratory studies will be recorded 
utilizing the CDE data elements, thereafter relevant abnormal laboratory studies during the 
treatment period will be evaluated against the USDHHS Common Terminology Criteria for 
Adverse Events V4.0 USDHHS criteria for adverse events(46). Those with a grade >3 will be 
documented. 
 
 
6.3.8 
Other Laboratory Studies. Plasma for biomarker analysis: Blood will be withdrawn  from 
existing lines or by venipuncture and collected into two pink top K2EDTA 6ml (plasma) Vacutainers 
per time point (36 ml). The samples will be placed on ice and will be centrifuged at 1,459 X g for 
10min at 4oC. The supernatant solution will be removed and centrifuged at 1,459  X g for 10min 
at 4oC to generate platelet-poor plasma. Plasma will be divided into aliquots and frozen at -80°C 
until needed. For those subjects providing consent, any residual sample and buffy coat will be 
frozen at -80°C for future study. 
 
CSF for biomarker analysis: Patients with a ventriculostomy drain will have 1-5 ml of CSF sampled 
from the receptacle at each of 3 time points. The receptacle will be emptied into the collection bag 
(the volume will be noted in the nursing notes) to start with an empty receptacle, several drops of 
CSF will then be allowed to drip into the chamber. The drain will be re- clamped; the chamber port 
will be cleaned with chlorhexidine as per hospital specifications  and 

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the CSF sample drawn from the port with a sterile syringe. CSF will be centrifuged (4°C, 1,459  X 
g for 10 minutes) and portioned into aliquots and frozen at -80oC; any residual sample will be 
frozen at -80°C for future study. The CSF pellet should be covered in a 10% DMSO solution (e.g., 
100µl CSF plus 11µl DSMO) and frozen at -80oC and transferred to -145°C after 24hrs when 
possible. 
 
Samples will be labeled with bar-coded subject study identification numbers, sample type and 
time point. They will be stored indefinitely at the University of Texas Health Science Center at 
Houston, Neuroscience Research Repository, Hergenroeder Laboratory, The Vivian L. Smith 
Department of Neurosurgery, |
 
 
| 
6.3.9 
Adherence Assessments. Temperature will be monitored for adherence to study 
assignment. 
 
 
7. 
MANAGEMENT OF ADVERSE EXPERIENCES 
 
 
Adverse events will be graded according to the USDHHS Common Terminology Criteria for 
Adverse Events V4.0 (USDHHS, Table 2) and summarized according to body system. Primary 
focus for analysis will be on 6-month mortality rate, incidence of pneumonia, incidence of DVT/PE, 
incidence of bleeding and incidence of arrhythmia. For the purpose of safety monitoring, adverse 
events in the table below of Grade 3 or higher will be classified as “Important AEs” or selected 
AEs of interest. 
 
Table 2. Selected AEs from USDHHS Common Terminology Criteria for Adverse Events V4.0 USDHHS 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Sinus Bradycardia 
Asymptomatic, 
Symptomatic, 
Severe, 
Life-threatening 
Death 
intervention 
medical 
medically 
consequences; 
not indicated 
intervention 
significant, 
urgent 
indicated 
medical 
intervention 
intervention 
indicated 
indicated 
Supraventricular 
Asymptomatic, 
Non-urgent 
Medical 
Life-threatening 
Death 
tachycardia 
intervention 
medical 
intervention 
consequences; 
not indicated 
intervention 
indicated 
hemodynamic 
indicated 
compromise; 
urgent 
intervention 
indicated 
Ventricular arrhythmia 
Asymptomatic, 
Non-urgent 
Medical 
Life-threatening 
Death 
intervention 
medical 
intervention 
consequences; 
not indicated 
intervention 
indicated 
hemodynamic 
indicated 
compromise; 
urgent 
intervention 
indicated 
Thromboembolic 
Venous 
Venous 
Thrombosis 
Life-threatening 
Death 
event 
thrombosis 
thrombosis 
(e.g., 
(e.g., 
(e.g., 
(e.g., 
uncomplicated 
pulmonary 
superficial 
uncomplicated 
pulmonary 
embolism, 
thrombosis) 
deep vein 
embolism 
cerebrovascular 
thrombosis), 
[venous], 
event, arterial 

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medical 
nonembolic 
insufficiency); 
intervention 
cardiac mural 
hemodynamic 
indicated 
[arterial] 
or neurologic 
thrombus), 
instability; 
medical 
urgent intervention 
intervention 
indicated 
indicated 
Pneumonia 
Dyspnea and 
Life-threatening 
Death 
pneumonia 
respiratory or 
symptoms (e.g., 
hemodynamic 
aspiration 
compromise; 
pneumonia); 
intubation or urgent 
hospitalization 
intervention 
indicated; unable 
indicated 
to aliment 
orally 
Pulmonary edema 
Radiologic 
Moderate 
Severe dyspnea 
Life-threatening 
Death 
findings only; 
dyspnea on 
or dyspnea 
respiratory 
minimal 
exertion; 
at rest; oxygen 
compromise; 
dyspnea on 
medical 
indicated; 
urgent 
exertion 
intervention 
limiting self care 
intervention or 
indicated; 
ADL 
intubation with 
limiting 
ventilatory support 
instrumental 
indicated 
ADL 
Bleeding/hemorrhage 
Mild; 
Moderate 
Transfusion, 
Life-threatening 
Death 
intervention 
symptoms; 
radiologic, 
consequences; 
not indicated 
medical 
endoscopic, or 
urgent 
intervention or 
elective 
intervention 
minor 
operative 
indicated 
cauterization 
intervention 
indicated 
indicated 
Intraoperative 
Postoperative 
Life-threatening 
Death 
hemorrhage 
radiologic, 
consequences; 
endoscopic, or 
urgent 
operative 
intervention 
intervention 
indicated 
indicated 
Infection (culture 
Oral 
IV antibiotic, 
Life-threatening 
Death 
positive) (e.g., blood 
intervention 
antifungal, or 
consequences; 
stream infection, 
indicated 
antiviral 
urgent 
urinary tract infection, 
(e.g., 
intervention 
intervention 
ventriculitis) 
antibiotic, 
indicated; 
indicated 
antifungal, 
radiologic, 
antiviral) 
endoscopic, or 
operative 
intervention 
indicated 
Device-related 
IV antibiotic, 
Life-threatening 
Death 
infection 
antifungal, or 
consequences; 
antiviral 
urgent 
intervention 
intervention 
indicated; 
indicated 
radiologic or 
operative 

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intervention 
indicated 
Death 
Death 
 
8. 
CRITERIA FOR INTERVENTION DISCONTINUATION 
 
Subjects may be discontinued from hypothermia at any time for patient safety per the 
decision of the site PI. 
 
 
9. 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
This is a randomized study of hypothermia for patients with traumatic brain injury. The 
primary hypothesis of the study is that early induction and maintenance of hypothermia in patients 
with traumatic brain injury undergoing hematoma evacuation will improve global neurologic 
outcome. Global neurologic outcome will be assessed using the Glasgow Outcome Scale 
(GOSE). The primary outcome measure is the GOSE at 6 months. 
 
 
9.2 
Outcomes 
 
9.2.1 Primary outcome. Primary outcome is GOSE at 6 months±3weeks post injury. GOSE 
(dichotomous: Good recovery and moderate disability will be designated as favorable outcomes; 
severe disability, vegetative state, and death as poor outcomes) at 6 months post-injury will be 
the primary outcome. Disability Rating Scale (DRS) at 4-6 weeks will be used to impute missing 
GOS/GOSE scores for futility analysis.  Outcome scales will be assessed by an evaluator who  is 
blind to study group assignment. 
 
Glasgow Outcome Scale-Extended (GOSE) is a widely used global outcome score including 8 
categories: dead, vegetative state, lower/upper severe disability, lower/upper moderated disability 
, lower/upper good recovery(47). GOSE assesses consciousness, independence, work status, 
return of lifestyle via a structured interview. It is relatively easy to administer and has good inter-
rater reliability and content validity. (Appendix II) 
 
Disability Rating Scale (DRS) is a global outcome scale that measures the level of arousal, 
cognitive ability related to activities of daily living and level of functioning. It includes eye opening, 
communication ability, motor response, feeding, toileting, grooming and employability(48). Scores 
range from 0 (no disability) to 29 (profound vegetative state) and death is scored at 30. It has 
been shown to be a good predictor of later outcome with the one month exam having an 87% 
correlation with the 6 month GOSE(12). (Appendix III) 
 
9.2.2 Secondary outcomes. Secondary outcomes will include: 
 
 
adverse event rates (e.g., infection, pneumonia, hemorrhage, thrombosis) 
 
 
ICU LOS, hospital LOS 
 
 
incidence of cortical spreading depolarization 

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 
levels of biomarkers (e.g., GFAP, UCH-L1) 
 
 
9.3 
Sample Size and Accrual 
 
A randomized design will be used in this study. Enrollment is intended to be N=120 but the trial 
allows an extension to a maximum of 350 patients randomized equally at a 1:1 ratio to each of 
two arms (hypothermia versus control). The final analysis will use a one-sided Fisher’s exact test 
with significance level of 0.02 to compare proportions of patients with good outcome of GOSE at 
6 months between two treatment arms. Interim analyses will be performed after 31, 60, 120, 180, 
240, and 300 patients randomized. The 0.02 significance level has been  calibrated to adjust for 
the multiple interim analyses and maintain an overall study type I error rate below 0.025. At each 
interim analysis, we will evaluate the predictive probability of  statistical significance with the 
current sample size and with the maximum sample size. If the predictive probability of statistical 
significance with the current sample size is sufficiently high, then enrollment will stop and follow 
up will continue for 6 months. If the predictive probability of statistical significance with 350 
patients is sufficiently low, then the study will stop for futility. Otherwise, enrollment will continue 
to the next analysis. 
 
 
9.4 
Data Monitoring 
 
A Data and Safety Monitoring Board (DSMB) will be established. The DSMB will include a 
biostatistician with expertise in research design and an expert in management of brain injured 
patients. Site PIs will monitor safety of each enrolled subject. In addition, safety analysis will be 
ongoing with interim monitoring for safety and study performance for every 20 patients or at  least 
annually following the randomization of the first subject. Interim analysis for consideration of 
discontinuing the study for futility or discontinuing enrollment for predicted success will be 
performed after 31, 60, 120, 180, 240, and 300 patients have been randomized. Enrollment will 
be ongoing during this assessment. 
 
Authorized representatives of the US Army Medical Research and Materiel Command 
(USAMRMC), who is one of the funding agency for this study, may review or obtain identifiable 
information (including the case ID number) related to participation in this research study for the 
purpose of monitoring the accuracy and completeness of the research data, for performing 
required scientific analyses of the research data, and as part of their responsibility to protect 
human research volunteers. 
 
 
 
9.5 
Data Analyses 
The primary analysis population will be an Intention-to-Treat population, all randomized subjects, 
followed by an As-Treated analysis for sensitivity. As described below, for the primary outcome, 
4-week DRS will be used to impute missing 6-month GOSE for the interim analyses. Demographic 
and baseline laboratory results will be summarized using descriptive statistics, including means, 
standard deviations, medians, ranges, histograms and box-plots. Fisher’s exact test and Wilcoxon 
rank sum test will be used in the data analyses of categorical and continuous variables, 
respectively. Adverse events will be reported by type, frequency and severity. 

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9.5.1 Statistical Modeling. The National Acute Brain Injury Study: Hypothermia II (NABIS:H II) 
shows that there was a strong correlation between 4-week Disability Rating Scale (DRS) and 6- 
month GOSE (Table 1). In particular, there were 2 false negatives out of 45 patients (4%) and 6 
false positives out of 30 patients (20%). It shows that the short-term response is a good predictor 
for 6-month GOSE. 
 
Table 3 summarizes the historical data (NABIS:H II study) comparing the 4-week DRS score and 
6-month outcome; 80% (24/30) of good short-term DRS had a good long-term GOSE, while 4% 
(2/45) poor DRS had a good GOSE: 
 
Table 3 
6-month GOSE 
4-week DRS Score 
Poor 
Good 
Total 
Poor (19 or larger) 
43 (96%) 
2 (4%) 
45 
Good (18 or less) 
6 (20%) 
24 (80%) 
30 
 
The statistical model used in this study explicitly models the relationship between 4-week DRS 
and 6-month GOSE score. Let pDc and pDt  be the probabilities of good 4-week DRS scores in  the 
control and treatment groups. Furthermore, define 
 
pGc0 = Pr(GOSE good | control, DRS poor) 
pGc1 = Pr(GOSE good | control, DRS good) 
pGt0 = Pr(GOSE good | treatment, DRS poor) 
pGt1 = Pr(GOSE good | treatment, DRS good) 
 
These probabilities define the conditional probabilities of achieving a good GOSE score given the 
DRS score and treatment group. 
 
Together, pDc, pDt, pGc0, pGc1, pGt0, and pGt1 define a joint distribution over DRS and GOSE  scores. 
The key parameter of interest is the probability of a good GOSE score within each group, which 
can be derived from these parameters. 
 
We estimate these parameters in a Bayesian fashion, placing Beta(2,3) priors on pDc and pDt, 
Beta(1,4) priors on pGc0 and pGt0, and Beta(4,1) priors on pGc1 and pGt1. These priors reflect the 
historical data but are weak in that each prior has 5 observations worth of weight, meaning that 
accumulating data in contrast to the historical data above will result in inferences based on the 
current data, not the historical data. Thus this model is sufficiently flexible that it may be used 
when DRS is highly predictive of GOSE and also may be used if DRS is not predictive of GOSE. 
 
The final analysis is a one-sided Fisher exact test with significance level 0.02 conducted only on 
the GOSE scores. Thus, the DRS values are only used in the analysis to predict GOSE scores 
for subjects who have a DRS score but not a GOSE score. For the final analysis, 6-month GOSE 
scores will be used. If the 6-month GOSE score is missing the 4-week DRS score will be used to 
impute the 6-month GOSE score. 
 
At each interim analysis we compute two predictive probabilities. The first is the predictive 
probability of trial success if enrollment stops, the current subjects are followed to completion, 
and the Fisher’s exact test is conducted on the final data. For this predictive probability many of 
the  subjects  will  have  6-month  GOSE  scores  reported.    The  uncertainty  in  the predictive 

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probability involves the potential GOSE scores for subjects with 4-week DRS observations, but 
have not reached their 6-month visit, and also potential GOSE scores for subjects with neither 4-
week DRS nor 6-month GOSE scores (recent enrollees). The predictive probability accounts for 
the uncertainty in those two sets of incomplete subjects. If this probability is sufficiently high 
(indicating the current data, when complete, is very likely to produce a significant result) then  the 
trial stops enrollment and follows the current subjects to completion. 
 
The second predictive probability is the probability of trial success if the trial is continued to 350 
subjects. In addition to the uncertainty for incomplete subjects, this predictive probability also 
incorporates uncertainty for subjects that have not yet enrolled, but will be enrolled in the future 
in order to reach a sample size of 350. If this probability is sufficient low (indicating that extending 
the trial to its maximum is unlikely to result in statistical significance) then the trial is discontinued 
for futility. 
 
 
9.5.2 Interim Analyses for Futility or Expected Success. Interim analyses will occur at 31, 
60,120,180, 240, and 300 subjects enrolled. 
 
The analysis plan is as follows for the N=31 subjects: 
 
When N=31 subjects are complete, we will observe the number of subjects on each arm (n_ctrl 
and n_trmt), and the number of observed successes on each arm Y_ctrl and Y_trmt. The 
predictive probability of success at N=60 subjects will be computed. This predictive probability 
incorporates uncertainty both in the true underlying treatment effect, for which we only have the 
random data on N=31 subjects, and the random variation in the N=29 potential future subjects  in 
the trial. To compute this probability, we place noninformative Beta(0.5,0.5) priors on the true 
underlying success rates in both the control and treatment arms p_ctrl and p_trmt. The resulting 
posterior distributions based on the N=31 observations result in p_ctrl | data ~ Beta(0.5+Y_ctrl, 
0.5+n_ctrl-Y_ctrl) and p_trmt | data ~ Beta(0.5 + Y_trmt, 0.5+n_trmt-Y_trmt) capturing the 
uncertainty in the true rates. Conditional on those rates, the future successes among the 29 
remaining subjects will follow a Binomial distribution with a known number of future patients on 
each arm and the unknown true rate. Averaging across the uncertainty in the unknown true rate, 
we observe that the unknown number of future successes in each arm follows a Beta Binomial 
distribution. 
 
These Beta Binomial predictive distributions provide the likely range of values for future 
observations. For example, if at the interim we observe 9 successes in 16 control patients, with 
14 control patients remaining, we would observe that the true rate currently has a Beta(9.5,7.5) 
distribution and the number of future control successes is distributed BetaBinom(14,9.5,7.5), a 
distribution whose most likely value is 8/14 future successes, in line with our current observed 
rate and with approximately a 96-97% predictive probability the number of future successes will 
be between 3 and 12 inclusive, reflecting the high uncertainty in the true underlying rates and the 
sampling variability in the future subjects. The predictive distribution will likely have a high 
variance reflecting the small sample size at the interim. Performing this prediction for both the 
control and treatment arms, we may compute the predictive probability the future data will lie in a 
region where the final analysis will result in p<0.025 and trial success, known as the predictive 
probability of success. 
 
This predictive probability will be provided to the DSMB. The trial should continue for predictive 
probabilities greater than 60% and stop for futility for predictive probabilities below 40%. If the 

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predictive probability is between 40-60% the DSMB will provide a recommendation for whether 
the trial should continue based on the totality of the evidence. The DSMB will only report 
“continue" or "stop for futility" to the sponsor to maintain blinding of the exact predictive probability. 
 
 
 
 
The next interim analyses if applicable will be performed at 60,120,180, 240, and 300 subjects 
enrolled. At each interim analysis (60,120,180, 240, and 300 subjects enrolled), we will evaluate 
two predictive posterior probabilities: 
 
Let ppnow be the predictive probability that the final efficacy analysis (Fisher’s exact test) will be 
statistically significant if enrollment stops at the current sample size and all subjects are followed 
to the 6-month GOSE outcome. If this probability is sufficiently high, then enrollment will stop for 
expected success. 
 
Let ppmax be the predictive probability that the final efficacy analysis (Fisher’s exact test) will be 
statistically significant if enrollment continues to 350 patients and all subjects are followed to the 
6-month GOSE outcome. If this probability is sufficiently low, then the trial will stop for futility. 
 
Table 4 presents the stopping boundaries for the interim analyses. The trial will stop for success 
if ppnow exceeds the given success threshold, while the trial will stop for futility if ppmax is below 
the futility threshold. Note the values are calibrated to increase the likelihood of stopping at N=120 
subjects. The trial has been powered to detect a moderately large effect at N=120 while 
maintaining the option of extending the trial should the results appear promising with a more 
moderate effect. 
 
Table 4.  Summary of Stopping Boundaries for Interim Analyses 
N=60 
N=120 
N=180 
N=240 
N=300 
success 
threshold for 
ppnow 
0.95 
0.85 
0.95 
0.95 
0.95 
futility 
threshold for 
ppmax 
0.10 
0.40 
0.10 
0.10 
0.10 
 
The operating characteristics of this design (type I error, power, and expected sample size) were 
computed by simulation in a variety of possible scenarios. These scenarios were constructed by 
crossing four possible treatment effects with two possible relationships between 4-week DRS and 
6-month GOSE scores (predictive and nonpredictive). Table 5 shows the values of the parameters 
for each of the simulated scenarios. In all scenarios the probability 6- month GOSE is good in the 
control arm is 0.347. In the null scenarios, scenarios where there is no difference between the 
scores, the probability 6-month GOSE is good in the treatment arm is also 0.347 (no treatment 
effect). We also consider low scenarios where the probability 6-month GOSE is good in the 
treatment arm is 0.498, medium scenarios where the probability 6-month GOSE is good in the 
treatment arm is 0.536, and alternative scenarios where the probability 6- month GOSE is good 
in the treatment arm is 0.604. The trial is powered for values closer to the 0.604 6-month scenario. 

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In the non-predictive scenarios, 6-month GOSE and 4-week DRS scores are independent, while 
in the predictive scenarios the relationship between 6-month GOSE and 4-week DRS is equal to 
the observed relationship in the historical data above. 

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Table 5. The values of the parameters in each of the eight simulated scenarios 
pDc 
pDt 
pGc0 
pGc1 
pGt0 
pGt1 
Pr(GOSE 
good 
in 
ctrl) 
Pr(GOSE 
good 
in 
trmt) 
Null Pred. 
0.40 
0.40 
0.045 
0.800 
0.045 
0.800 
0.347 
0.347 
Null Non. 
0.50 
0.50 
0.347 
0.347 
0.347 
0.347 
0.347 
0.347 
Low Pred. 
0.40 
0.60 
0.045 
0.800 
0.045 
0.800 
0.347 
0.498 
Low Non. 
0.50 
0.50 
0.347 
0.347 
0.498 
0.498 
0.347 
0.498 
Med Pred. 
0.40 
0.65 
0.045 
0.800 
0.045 
0.800 
0.347 
0.536 
Med Non. 
0.50 
0.50 
0.347 
0.347 
0.536 
0.536 
0.347 
0.536 
Alt Pred. 
0.40 
0.74 
0.045 
0.800 
0.045 
0.800 
0.347 
0.604 
Alt None. 
0.50 
0.50 
0.347 
0.347 
0.604 
0.604 
0.347 
0.604 
 
The table below provides the operating characteristics (probabilities of success or futility at each 
possible sample size). As noted above, the trial is powered for effect sizes closer to the 
“alternative” scenarios, where the trial has over 90% power and a high likelihood of stopping 
(typically for success) at or before the N=120 interim analysis. Similarly, type I error is controlled 
at 0.025 for the null scenarios and they are quite likely to stop (typically for futility) at or before the 
N=120 interim analysis. Power is as expected reduced for effect sizes below where the trial is 
powered, although the medium scenarios still retain power in the 75-80% range. 
 
Operating characteristics for each of the eight scenarios is summarized in Table 6. The first 
column provides the scenario name, while the next 6 columns (N=60 through N=350) provides 
the probability of futility (top number in each cell) and success (bottom number in each cell) at 
those sample sizes. Thus, for example, in the low predictive scenario the probability of stopping 
at N=120 and having a successful trial is 0.179. The expected sample size for each trial is given 
in the E[N] column while the probability of trial success (the sum of the bottom numbers in the 
N=60 through N=350 cells) is given in the Pr(success) column. The trial is powered for the 
alternative (bottom two) scenarios, where power is over 90%, although the trial retains modest 
(75-80%) power for more moderate effect sizes. In the null and alternative scenarios the trial is 
quite likely to stop at or before the N=120 interim analysis. Results in this table were computed 
by simulating 10,000 trials in each scenario. 

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Table 6.  Operating Characteristics 
N=60 
N=120 
N=180 
N=240 
N=300 
N=350 
E[N] 
Pr(success) 
Null Pred 
0.344 
0.003 
0.513 
0.009 
0.024 
0.004 
0.039 
0.002 
0.030 
0.002 
0.026 
0.004 
118.3 
0.024 
Null Non 
0.322 
0.002 
0.527 
0.006 
0.026 
0.003 
0.042 
0.003 
0.033 
0.001 
0.030 
0.005 
121.9 
0.021 
Low Pred 
0.061 
0.057 
0.227 
0.179 
0.006 
0.136 
0.012 
0.114 
0.016 
0.075 
0.040 
0.078 
180.0 
0.637 
Low Non 
0.083 
0.030 
0.248 
0.160 
0.007 
0.125 
0.013 
0.112 
0.013 
0.077 
0.042 
0.091 
182.8 
0.594 
Med Pred 0.035 
0.088 
0.137 
0.289 
0.003 
0.179 
0.005 
0.130 
0.006 
0.068 
0.016 
0.044 
166.9 
0.798 
Med Non 
0.053 
0.050 
0.165 
0.254 
0.004 
0.178 
0.005 
0.138 
0.005 
0.078 
0.014 
0.059 
173.3 
0.756 
Alt Pred 
0.014 
0.200 
0.042 
0.438 
0.001 
0.195 
0.000 
0.083 
0.000 
0.019 
0.001 
0.007 
134.3 
0.942 
Alt Non 
0.024 
0.115 
0.058 
0.452 
0.000 
0.220 
0.000 
0.096 
0.000 
0.025 
0.001 
0.009 
143.2 
0.917 
 
 
9.5.3 Interim Analysis on Safety. 
The probability of selected adverse events of interest (defined in Section 7), and separately of 
deaths, will be monitored based on a beta-binomial model. Enrollment will be placed on hold 
pending DSMB review if the proportion of selected adverse events of interest in the treatment arm 
is too high in comparison to the control arm or if the proportion of deaths in the treatment arm is 
too high in comparison to the control arm. The selected adverse events of interest will also include 
patient deaths. 
 
The DSMB will perform a more detailed review of the selected AEs of interest to determine if the 
study should continue.  In particular, enrollment will be placed on hold if, 
Pr(p1  > p0  | data) > 0.98 OR Pr(pdeath1 > pdeath0 | data) > 0.98 , 
 
where p1 and p0 are the proportion of patients with selected AEs of interest in the hypothermia 
and control arms, respectively, and pdeath1 and pdeath0 are the proportion of patients that  died. 
The prior distributions for  p1, p0, pdeath1, and pdeath0 are  independent,  non- informative Beta 
(1, 1). The 0.98 thresholds were selected to adjust partially account for the multiple interim 
analyses scheduled to occur. We will start to perform the interim analysis on safety for the first 10 
patients in each arm randomized, and then other interim analyses will be carried out every 10 
patients in both arms (20 patients). The operating characteristics for the stopping rules under 
various scenarios are summarized in Table 5, with results based on 10000 simulations. 

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Table 7. summarized the simulation results with interim analyses for safety every 20 patients 
randomized, assuming there will be 120 patients (60 per arm). 
 
Table 7 
Scenario 
Selected AEs of 
Interest 
proportions 
Death 
proportions 
% trials with at least one 
hold for safety evaluation 
Mean number 
of pts 
(Control, Treatment) (Control, Treatment) 
1 
(0.25, 0.10) 
(0.125), 0) 
0.08% 
120 
2 
(0.25, 0.15) 
(0.125, 0.025) 
0.4% 
120 
3 
(0.25, 0.25) 
(0.125, 0.125) 
7.5% 
115 
4 
(0.20, 0.30) 
(0.10, 0.20) 
39.7% 
96 
5 
(0.20, 0.40) 
(0.10, 0.30) 
81.1% 
66 
6 
(0.20, 0.50) 
(0.10, 0.40) 
97.4% 
45 
7 
(0.20, 0.60) 
(0.10, 0.50) 
99.8% 
33 
 
 
For a trial with 120 patients, there would be five interims (after 20, 40, 60, 80, and 100 patients). 
We summarized in Table 8 the number of times per simulated trial that enrollment was held. For 
example, in scenario 7, over half of the simulated trials met the “hold” criterion at every single 
interim assuming that at each hold the DSMB recommended the trial continue. 
 
Table 8. Number of holds per trial in the safety simulation study. 
Scenario Important AE proportions % of trials with 0, 1, 2, 3, 4, or 5 holds per trial 
(Control, Hypothermia) 
0 
1 
2 
3 
4 
5 
1 
(0.25, 0.10) 
99.9 
0.1 
0 
0 
0 
0 
2 
(0.25, 0.15) 
99.6 
0.4 
0.1 
0 
0 
0 
3 
(0.25, 0.25) 
92.5 
3.9 
2.0 
1.1 
0.4 
0.2 
4 
(0.20, 0.30) 
60.3 
13.7 
10.1 
8.1 
5.5 
2.4 
5 
(0.20, 0.40) 
18.9 
13.3 
16.4 
18.9 
19.8 
12.6 
6 
(0.20, 0.50) 
2.6 
4.8 
9.4 
19.8 
33.5 
30.0 
7 
(0.20, 0.60) 
0.2 
0.7 
2.7 
11.0 
33.0 
52.4 
 
 
10. 
DATA COLLECTION, SITE MONITORING, AND ADVERSE EVENT REPORTING 
 
10.1 Records to Be Kept 
Data collection will be based off Case Report Forms (CRFs) derived directly from the NIH TBI 
Common Data Elements project (www.commondataelements.ninds.nih.gov/TBI.aspx). This trial 
will leverage the CRFs and web-based database already developed by REDCap (Research 
Electronic Data Capture - Vanderbilt University) to utilize the TBI Common Data Elements project 
in which the University of Pittsburgh (David Okonkwo, site PI) participated. The CRFs have 
already been designed and implemented, which will contribute significantly to rapid, smooth 
rollout of the trial proposed herein. 
 
Study personnel will collect information on subject characteristics such as demographics, medical 
history, and injury information. The initial assessment of the subject will be recorded including 
physical and neurological examination, vital signs, laboratory tests, and   radiographic 

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imaging. In addition, as part of the baseline data collection, family members will be asked to 
complete a contact information form with the names, addresses and phone numbers of other 
people who could assist in locating him/her if the study coordination cannot locate him/her for the 
scheduled phone interviews. The study will consider the use of a locator service for patients 
potentially lost to follow-up. 
 
Additional CRFs will be generated to record disease and injury-related events, treatments and 
interventions during the initial hospitalization, and safety data for adverse event reporting. The 
outcome end points will be based off the Core measures of the TBI Common Data Elements. 
 
Federal law now holds the statute of limitations at six years to bring forward an allegation of 
research misconduct. In response to this extension, research records must be retained for a 
sufficient period to investigate an allegation of research misconduct - - a minimum period of six 
years. Additionally, existing Federal regulations [56 CFR 56.115(b)] require that IRB records be 
retained for at least 3 years after completion of the research. All records must be accessible for 
inspection and copying by authorized representatives of HHS and Food and Drug  Administration 
at reasonable times and in a reasonable manner. At the end of the three year period, the IRB 
records may be boxed, labeled and sent to central storage for an additional 3-10 years. A log of 
stored records is maintained in the IRB office for retrieval if files are needed for audit or other 
purposes. 
 
Records will be maintained in a de-identified manner in a secure, locked location to ensure 
confidentiality. Subjects will not be identified in any manner in any publications resulting from  this 
project. 
 
 
10.2 Role of Data Management 
 
De-identified data will be collected from the pre-hospital period through 6 months post injury. A 
linking list will be maintained by the investigative team at each site to allow for patient follow-up. 
Protected health information (PHI) is confidential and not shared outside the study team. Written 
data will be stored in locked areas; electronic data will be password protected in secure zones. 
Patient name and contact information will be separated from subject data. The PI will monitor 
protocol compliance and data integrity. Routine data audits will be conducted internally to  assure 
consistency and integrity of the data. Additionally, an independent data auditor will verify data 
quality. 
 
 
10.2.1 Data Management Overview. The statistical center will manage the study specific 
database. Data will be linked by unique ID. The study statistician will independently review the 
forms and the entered data. The database will incorporate quality control checks at data entry, 
and quality assurance programs will be written for acquisition, management, tracking and retrieval 
and will be run regularly. The database will be backed up onto separate media. The database is 
maintained for statistical analysis purpose only; thus, all electronic files will be de- identified. The 
database will be password protected and maintained in secure research offices  in a secure 
research building. Data validation checks identifying outliers will generate queries which will be 
evaluated and if necessary returned to the clinical study site for data validation.   An audit trail will 
be maintained on changes to the database. 

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10.3 Quality Assurance 
The Medical Monitor will oversee the Quality Assurance procedures related to the ICU 
management of episodes of intracranial hypertension. Dr. Elisabeth Wilde will ensure all 
outcomes personnel are properly trained and will review scoring of all outcome measures. 
 
Database queries will be designed and implemented to oversee compliance with all study 
documentation and timely completion of CRFs. Protocol deviations, record completion, and 
regulatory compliance will be reviewed by PIs and Site Study Coordinators at each monthly 
conference call. All study documents and pertinent records will be available for inspection by the 
DSMB, the sponsor, or other designated monitoring authority. 
 
 
10.4 ADVERSE EVENT REPORTING 
 
 
Complications due to hypothermia include bradycardia or arrhythmias, a reduced immune system, 
blood clotting, increased insulin resistance, and electrolytes to shift, causing potassium levels to 
appear low because of increased absorption into cells(33;49). However,  patients treated with 
intravascular cooling do not experience the complications of skin rashes, burns and skin 
death(33). Intravascular cooling catheters function as central venous catheters and contain 
working ports that facilitate routine critical care such as administering drugs and fluids and drawing 
blood. 
 
Safety assessments will consist of monitoring and reporting adverse events (AEs), selected 
adverse events of interest, and serious adverse events (SAEs), both anticipated and 
unanticipated. An Adverse Event is any undesirable and unintended, although not necessarily 
unexpected, event occurring in human subjects as a result of (a) the interventions and interactions 
used in the research; or (b) the collection of identifiable private information under the research. A 
Serious adverse event is an adverse event that led to death, or to serious deterioration in the 
health of the subject, that resulted in death, was life-threatening, required hospitalization (initial 
or prolonged), resulted in disability or permanent damage, congenital anomaly/birth defect, 
required intervention to prevent permanent impairment or damage, or other serious events 
(Important Medical Events). NOTE: Planned hospitalization for a preexisting condition, or a 
procedure required, without serious deterioration in health, is not considered a serious adverse 
event. An unanticipated adverse device effect as defined by FDA regulations, 2CFR 812.3(s) is 
any serious adverse effect on health or safety or any life- threatening problem or death caused 
by, or associated with, a device, if that effect, problem, or death was not previously identified in 
nature, severity, or degree of incidence in the investigational plan or application (including a 
supplementary plan or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects. 
 
 
Each clinical site is instructed to report all fatal events, SAEs, and other unanticipated problems 
in the central database within 24 hours of first knowledge of the event. Additionally, all current 
study data for that particular subject must be entered to allow for timely review by the internal and 
external medical monitors. Upon entry of a SAE, the central database triggers notification  of the 
SAE to the medical monitor. Following formal review, the SAE is forwarded to the DSMB for 
review. 

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The independent Research Monitor for the HOPES Trial is Michael Diringer, MD, Chairman of 
the DSMB. Dr Diringer has applicable expertise in managing neuro-critical care patients, the  use 
of temperature management and treatment with hypothermia; he is a former member of his local 
IRB and is an experienced, highly regarded researcher. He is an expert with the nature of risk(s) 
identified in the research protocol, and he is independent of the team conducting the research 
involving human subjects. He has no conflict of interest and is not be under the supervision of the 
PI, other investigators or research staff. Dr Diringer, as the independent research monitor, will 
identify to the research team any concerns regarding safety, ethical and scientific integrity.  
Serious, unexpected, related events are reported to the IRB by the site PI.  Dr. Diringer’s 
comments on these events will be included in the IRB reporting. Dr Diringer as  the independent 
Research Monitor has the authority to stop the research protocol in progress, remove individual 
human subjects from a research protocol, and take whatever steps are necessary to protect the 
safety and well-being of human subjects. The research monitor will review adverse events 
reported to him by the study team and, report if he agrees with the site- PI’s assessment of 
relationship to the study. The research monitor reviews the principal investigators reports on 
serious adverse eents and indicats whether he agrees with the assessment provided by PI. 
Reports for events determined by either the  investigator  or research monitor to be possibly or 
definitely related to participation and reports of events resulting in death will be promptly forwarded 
to the USAMRMC ORP HRPO by the study team. 
 
If the investigator and/or the medical monitor believe the AE is serious, study related (possibly, 
probably or definitely), and unexpected, the SAE will be sent immediately to the DSMB. The 
determination of a probable or possible relationship to the hypothermia treatment will be 
discussed with the DSMB to determine what, if any, action should be taken with regard to 
continuation of the trial. 
 
Following the determinations made by the DSMB, the PI will distribute all appropriate  information 
to the clinical sites and their respective IRBs per local requirements. Finding of a significant 
number of study-related AEs and SAEs may lead to a change in consent forms or lead to decisions 
about modifying the protocol or discontinuing the trial. 
 
 
 11.      HUMAN SUBJECTS 
 
11.1 Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document and any subsequent modifications will be 
reviewed and approved by the IRB responsible for oversight of the trial at each of the participating 
centers. A signed consent form will be obtained for every subject when feasible. Since subjects 
in this trial cannot consent for themselves, a LAR, or person with power of attorney, must sign the 
consent form. The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A copy of the consent form will be given to 
the LAR, and this fact will be documented in the subject’s record. A proposed Informed Consent 
template is attached as Appendix I. If a subject is enrolled in the study and subsequently dies 
prior to obtaining consent, when feasible, the investigator will inform the subject’s LAR or family 
members about the subject’s participation personally at the earliest feasible opportunity.  The 
study team will work within existing hospital practices to  locate patients’ next of kin. The study 
will maintain copies of medical record documentation indicating efforts made to identify the 
subject and their next of kin. If the hospital team (e.g., 

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social work) identifies next of kin, after the hospital team has contacted the next of kin and 
informed them of the subject’s death we will attempt to talk with family about the subject’s 
participation in the study for up to 5 days after death. In cases where it is not feasible to provide 
information to the subject (e.g.,death, mentally incompetent) or the LAR/family (e.g., identitiy 
never determined) each site is requested to obtain a HIPAA Privacy Rule waiver to allow study 
use and retention of the data. 
 
 
11.2 Subject Confidentiality 
All CT scans, evaluation forms, reports, and other records required by this trial that leave the  site 
will be identified only by the Uniform Identification Number (UID) to maintain subject 
confidentiality. All on-site records will be kept in a locked file cabinet. All computer entry and 
networking programs will be done using SIDs only. Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by IRB, or the Office of 
Human Research Protection (OHRP). 
 
 
11.3 Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the sponsor, the OHRP, or other 
government agencies as part of their duties to ensure that research subjects are protected. An 
individual IRB may discontinue the study at the clinical site it oversees, but the action is limited to 
that individual site. 
 
11.4 Risk Analysis 
Biocompatibility, bench, animal, other clinical studies (IDE 990263) and long-term use in  humans 
have all shown that the ZOLL IVTM System appears to be safe for use. The system is made of 
materials that are commonly used in other medical devices with comparable applications and all 
materials have been tested in accordance with ISO 10993-1. All  components of the ZOLL IVTM 
Catheters and ZOLL Thermogard XP System, and accessories have been cleared for commercial 
use by the FDA under 510(k) (K101987 and K072234). 
 
11.4.1 
Increased Risks and Benefits to Study Participants Elevated ICP secondary to TBI 
which is associated with increased morbidity and mortality is responsive to hypothermia. 
Increasingly, therapeutic hypothermia is used to treat refractory intracranial hypertension in TBI. 
Additionally, experimental evidence suggests induced hypothermia of 32-35°C early post injury 
may be neuroprotective. It is this early neuroprotective effect of hypothermia that is therapeutic 
aim of this study. TBI resulting in SDH occurs in over 40,000 Americans annually with up to  70% 
of these injuries resulting in death or severe disability(27). Risks associated with hypothermia may 
include shivering, hypovolemia, electrolyte disorders, hyperglycemia, pneumonia, and some risk 
of catheter-related thrombosis or possible catheter-related infection with intravascular cooling 
devices. Risks are minimized by reaching the goal temperature as quickly as possible, rewarming 
slowly and removing the intravascular catheter within 5 days of placement(33). Risk is relative in 
an entity with high mortality, and may be considered relative to a procedure that may increase the 
chances of good neurological outcome. The risk of ECoG brain activity monitoring includes the 
risk of infection or bleeding in approximately 1-5%, but no such complications have been observed 
previously in similar patients who have undergone this procedure. The electrode strip will be 
removed at the bedside by the neurosurgeon. There is approximately a 1-2% risk for difficulty in 
removing the strip.(43) 

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11.4.2 
Potential Benefits Use of therapeutic hypothermia (cooling) following traumatic SDH 
may offer certain advantages to subjects prior to surgical evacuation of the SDH. Cerebral 
ischemia and hypoxia along with excitotoxicity, inflammation, disruption of blood brain barrier and 
edema are some of the pathological consequences of TBI. Therapeutic hypothermia may 
attenuate hypoxia, ischemia and energy dysfunction and it may reduce reperfusion injury. 
Hypothermia may decrease the frequency of cortical depolarizations which are a pathological 
mechanism associated with TBI. 
 
Benefits known to be associated with therapeutic hypothermia as described in the scientific 
literature include: 
 
Improved neurologic outcome 
 
Improved management of elevated intracranial pressure. 
 
Potential benefits that may be associated with use of the ZOLL IVTM System include: 
 
Improved neurologic outcome 
 
Improved management of elevated intracranial pressure. 
 
Potential benefits to all subjects may be associated with participation in the study this may include: 
 
Serial assessments performed by the study team and others including monitoring for 
shivering, monitoring compliance with brain trauma guidelines and/or local guidelines; 
research team members monitoring of subjects for adverse events. 
 
Controlled temperature management (at least 48hrs) will minimize risk of fever in subjects 
during that period. 
 
Follow-up care including functional outcomes assessments performed at 4-6 weeks and 
6months (±3 weeks). 
 
There is no guarantee that participation in this study or use of hypothermia will benefit the study 
subject. However, collection of such study data may provide added benefit for future traumatic 
SDH subjects. 
 
11.4.3 
Methods to Minimize Risk Although no assurances or guarantees can be made, there 
is a reasonable expectation that the use of this device is safe within the context of the trial and 
may be beneficial. Cooling using the IVTM System, for instance, may result in improved 
temperature control relative to the standard techniques already in use (i.e., surface cooling). 
 
Additionally, the following measures will be taken to minimize risk to subjects: 
 
 
The protocol will be evaluated by the investigators, institution review boards and DSMB to 
ensure subject safety and welfare throughout the study. 
 
 
Potential subjects will be carefully evaluated against the inclusion/exclusion criteria before 
entering the clinical study to ensure that their medical status is appropriate. 
 
 
Physicians and staff will receive adequate training 1) in the protocol before first enrollment, 
and 2) in the IVTM System prior to first use. Physicians will employ sterile technique during 
catheter insertion and extraction and will follow aseptic wound care procedures.  The 
puncture site will be evaluated on a regular basis. 

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 
Patients will be carefully monitored for potential side effects (shivering, electrolyte 
disorders, infections, arrhythmias) and rewarming will be slow and controlled to avoid 
rebound elevated ICP. Duration of cooling (48hr-5d) and timing of rewarming will be 
individualized (based on ICP, potassium levels, etc.). 
 
 
Conventional means of temperature control (cooling/warming blankets, etc.) may be kept 
on “standby” should use be deemed necessary by the Investigator. Subjects will receive 
standardized critical care with careful monitoring of: vital signs, cardiac rhythm, pulmonary 
status, renal function, fluid electrolytes and blood coagulation, etc. 
 
 
Study procedures will be performed in appropriate treatment rooms using trained 
emergency, neurosurgery or other personnel. Therefore, should a subject require 
additional interventions, these procedures may be initiated as soon as possible. Subjects 
will be carefully monitored throughout the treatment and follow-up period. Subjects will 
have frequent physical exams that include general physical assessment and evaluation 
for symptoms and assessment existing or developing adverse events. Subjects who 
require additional procedures will be carefully monitored in a method appropriate for that 
procedure. 
 
 
Data will be monitored as it is submitted to the coordinating center. The study monitor and 
statistical team will conduct monitoring throughout the course of the study to assess 
protocol compliance and identify any issues that could affect study subject safety or 
welfare. 
 
 
The DSMB and Sponsor will receive regular reports of subject outcomes and adverse 
events. Should any trend substantiate possible harm, the study will be terminated. 
Unanticipated adverse device effects/events will be reported to the IRB, DSMB, Sponsor 
and FDA. 
 
11.4.4 
Justification of the Study Based on the risks identified and the procedural and 
monitoring methods employed to minimize these risks, the investigators believe that the  potential 
benefits of treatment with the ZOLL IVTM System outweigh the associated risks with the treatment 
procedure. 
 
 
12. 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by the policies and procedures developed 
by the institutional agreements and Principal Investigators. Any presentation, abstract, or 
manuscript may be made available for review by the sponsor prior to submission. 

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