Randomized Trial of Early Hemodynamic Management of Patients Following Acute Spinal Cord Injury
Phase: NA
Conditions: Spinal Cord Injury
Sponsor: Oregon Health and Science University

 
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Randomized Trial of Early Hemodynamic 
Management of Patients following Acute Spinal 
Cord Injury (TEMPLE) 
 
 
Protocol Number: TEMPLE - 004 
Grant Number: SC150250 
 
Principal Investigator: Miriam Treggiari, MD, PhD, MPH 
Co- Principal Investigator: David Zonies, MD, MPH 
Research Monitor: Peter Schulman, MD 
Biostatistician: N. David Yanez, PhD 
 
 
 
 
Version Number:  4.1 
08 AUGUST 2018 
 

 
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STATEMENT OF COMPLIANCE 
The study will be conducted in accordance with the International Conference on Harmonisation 
guidelines for Good Clinical Practice (ICH E6), the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46), and the Department of Defense Terms of Award. All 
personnel involved in the conduct of this study have completed human subjects protection 
training. 
 

 
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SIGNATURE PAGE 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this trial will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to local legal and 
regulatory requirements and applicable US federal regulations and ICH guidelines. 
Principal Investigator or Clinical Site Investigator: 
Signed: 
 
Date: 
 
 
 
 
 
 
Name:     
 
 
Title: 
 
 
 
 
 

 
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Contents 
STATEMENT OF COMPLIANCE .................................................................................................. I 
SIGNATURE PAGE ...................................................................................................................... II 
LIST OF ABBREVIATIONS ......................................................................................................... VI 
PROTOCOL SUMMARY ........................................................................................................... VIII 
KEY ROLES AND CONTACT INFORMATION .......................................................................... 10 
1 
ETHICS .............................................................................................................................. 11 
1.1 
Ethical Standard ..................................................................................................... 11 
1.2 
Institutional Review Boards .................................................................................... 11 
1.3 
Subject Information and Informed Consent ............................................................ 11 
1.4 
Patient Confidentiality ............................................................................................. 11 
1.5 
Protocol Compliance .............................................................................................. 12 
2 
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE .................................... 13 
2.1 Investigators and Trial Site Personnel ......................................................................... 13 
2.1.1 
Investigators ............................................................................................... 13 
2.1.2 
Trial Site Personnel Assigned Trial-Related Duties .................................... 13 
2.2 
Data Monitoring Committee .................................................................................... 13 
3 
INTRODUCTION ................................................................................................................ 14 
3.1 
Background Information ......................................................................................... 14 
3.2 
Specific Aims / Study Design ................................................................................. 15 
3.3 
Potential Risks and Benefits ................................................................................... 15 
3.3.1 
Potential Risks ............................................................................................ 15 
3.3.2 
Frequency of TPM Associated Risks .......................................................... 16 
3.3.3 
Mitigation of Potential Risks ....................................................................... 16 
3.3.4 
Potential Benefits ........................................................................................ 17 
4 
OBJECTIVES ..................................................................................................................... 18 
4.1 
Study Objectives .................................................................................................... 18 
4.2 
Study Outcome Measures ...................................................................................... 18 
4.2.1 
Primary Specific Aim .................................................................................. 18 
4.2.2 
Secondary Specific Aim for Efficacy ........................................................... 18 
4.2.3 
Specific Aims for Safety .............................................................................. 18 
5 
STUDY DESIGN ................................................................................................................ 19 
5.1 
Setting .................................................................................................................... 19 
STUDY ENROLLMENT AND WITHDRAWAL ............................................................................ 20 
5.2 
Subject Enrollment Procedure ................................................................................ 20 
5.3 
Inclusion/ Exclusion Criteria ................................................................................... 20 
5.3.1 
Inclusion Criteria ......................................................................................... 20 
5.3.2 
Exclusion Criteria ........................................................................................ 21 
5.3.3 
Inclusion of Women and Minorities ............................................................. 21 
5.3.4 
Exclusion of Vulnerable Populations .......................................................... 22 
5.4 
Strategies for Recruitment ...................................................................................... 22 
5.5 
Informed Consent Process ..................................................................................... 22 
5.6 
Point of Enrollment ................................................................................................. 23 

 
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5.6.1 
Subject Trial Cards ..................................................................................... 23 
5.6.2 
Subject Retention ....................................................................................... 23 
5.7 
Treatment Assignment Procedures ........................................................................ 24 
5.7.1 
Randomization Procedures ........................................................................ 24 
5.7.2 
Blinding ....................................................................................................... 24 
5.8 
Subject Discontinuation .......................................................................................... 25 
5.8.1 
Investigator Initiated Withdrawal ................................................................. 25 
5.8.2 
Subject Initiated Withdrawal ....................................................................... 25 
5.8.3 
Procedures for Handling Discontinued Subjects ........................................ 25 
5.9 
Premature Termination or Suspension of Study .................................................... 25 
6 
STUDY INTERVENTION ................................................................................................... 27 
6.1 
Study Treatment Protocols ..................................................................................... 27 
6.1.1 
Targeted blood Pressure Management ...................................................... 28 
6.1.2 
Volume Expansion to Achieve Euvolemia .................................................. 28 
6.2 
Assessment of Clinicians’ Compliance with Study Procedural Intervention ........... 28 
7 
STUDY SCHEDULE AND EVALUATIONS ........................................................................ 29 
7.1 
Pre-randomization Assessment ............................................................................. 29 
7.2 
ICU Visit Assessment ............................................................................................. 29 
7.2.1 
Concomitant Treatments and Supportive Care .......................................... 29 
7.2.2 
Documentation of post-72 hour ASIA Score ............................................... 30 
7.2.3 
Hospital Discharge ..................................................................................... 30 
7.2.4 
Adverse Event Monitoring .......................................................................... 31 
7.3 
Six Month Follow-Up Assessment .......................................................................... 31 
7.3.1 
Patient Tracking at Follow-Up .................................................................... 31 
8 
ASSESSMENT OF SAFETY .............................................................................................. 32 
8.1 
Specification of Safety Parameters ........................................................................ 32 
8.1.1 
Unanticipated Problems ............................................................................. 32 
8.1.2 
Protocol Deviation ...................................................................................... 32 
8.1.3 
Adverse Events .......................................................................................... 33 
8.1.4 
Serious Adverse Events ............................................................................. 33 
8.2 
Characteristics of an Adverse Event ...................................................................... 33 
8.2.1 
Relationship to Study Intervention .............................................................. 33 
8.2.2 
Expectedness of SAEs ............................................................................... 34 
8.2.3 
Severity of Event ........................................................................................ 34 
8.2.4 
Outcome of Event ....................................................................................... 34 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 34 
8.4 
Reporting Procedures ............................................................................................ 35 
8.4.1 
Unanticipated Problem Reporting ............................................................... 35 
8.4.2 
Serious Adverse Event Reporting .............................................................. 35 
8.5 
Stopping Rules ....................................................................................................... 36 
9 
STUDY OVERSIGHT ......................................................................................................... 37 
9.1 
Quality System ....................................................................................................... 37 
9.2 
Promoting and Monitoring Adherence to the Research Protocol ........................... 37 

 
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9.3 
Monitoring of Study Conduct .................................................................................. 37 
9.4 
Study Monitoring and Site Visits ............................................................................. 38 
9.5 
Adverse Event Monitoring ...................................................................................... 38 
9.6 
Research Monitor ................................................................................................... 39 
9.7 
Data Safety and Monitoring Board ......................................................................... 39 
9.8 
Steering Committee ................................................................................................ 40 
9.9 
Audits ..................................................................................................................... 40 
9.10 
Inspections ............................................................................................................. 40 
10 
STATISTICAL CONSIDERATIONS ................................................................................... 41 
10.1 
Assessment of Study Variables .............................................................................. 41 
10.1.1  Primary Endpoint ........................................................................................ 41 
10.1.2  Secondary Endpoints for Efficacy ............................................................... 41 
10.1.3  Secondary Endpoints for Safety ................................................................. 42 
10.2 
Sample Size Estimation and Statistical Power ....................................................... 44 
10.3 
Statistical Analysis Plan ......................................................................................... 45 
11 
DATA HANDLING AND RECORD KEEPING .................................................................... 47 
11.1 
Data Management Responsibilities ........................................................................ 47 
11.2 
Source Data ........................................................................................................... 47 
11.3 
Case Report Forms ................................................................................................ 47 
11.4 
Identifiers ................................................................................................................ 48 
11.5 
Confidentiality ......................................................................................................... 48 
11.6 
Data Entry Completion ........................................................................................... 49 
11.7 
Study Records Retention ....................................................................................... 49 
11.8 
Data and Resources Sharing Plan ......................................................................... 50 
11.9 
Data Quality Assurance .......................................................................................... 50 
12 
PUBLICATION/DATA SHARING POLICY ......................................................................... 51 
13 
LITERATURE REFERENCES ........................................................................................... 52 
APPENDIX A: SCHEDULE OF EVENTS ................................................................................... 53 
APPENDIX B: INTERVENTION ALGORITHMS ......................................................................... 55 
 
 
 

 
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LIST OF ABBREVIATIONS 
ABP 
Augmented Blood Pressure 
AE 
Adverse Event/Adverse Experience 
AIS 
ASIA Impairment Scale 
ASIA 
American Spinal Injury Association 
CBP 
Conventional Blood Pressure 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CT 
Computerized Axial Tomography 
CVP 
Central Venous Pressures 
DHHS 
Department of Health and Human Services 
DMU 
Data Management Unit 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic Case Report Form 
EKG 
Electrocardiogram 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR 
Heart Rate 
HIPAA 
Health Insurance Portability and Accountability Act 
ICH 
International Conference on Harmonisation 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISCIBPDS 
International Spinal Cord Injury Basic Pain Data Set 
ISCIQOL 
International Spinal Cord Injury Quality of Life Basic Data Set 
LAR 
Legally Authorized Representative 
MAP 
Mean Arterial Pressure 
MOO 
Manual of Operations 
MRI 
Magnetic Resonance Imaging 
NIDCR 
National Institute of Dental and Craniofacial Research, NIH, DHHS 
NIH 
National Institutes of Health 
OHSU 
Oregon Health and Science University 

 
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PI 
Principal Investigator 
PP 
Pin Prick 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SAH 
Subarachnoid Hemorrhage 
SCI 
Spinal Cord Injury 
SCIM III 
Spinal Cord Independence Measure III 
SOFA 
Sequential Multiple Organ Failure Score 
SOP 
Standard Operating Procedure 
TPM 
Targeted blood Pressure Management 
 
 
 
 
 
 
 
 
 

 
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PROTOCOL SUMMARY 
Title: 
Randomized Trial of Early Hemodynamic Management of Patients 
following Acute Spinal Cord Injury (TEMPLE) 
Study Design 
This is a multicenter, randomized, controlled study. Subjects will be 
randomized 1:1 to one of two treatment arms, monitored for up to 7 
days, and assessed at a 6 month follow up visit. 
Objectives: 
Primary:  To determine the differential effects of two levels of MAP on 
long-term motor and sensory outcomes after acute SCI. 
 
Secondary:  To determine the differential efficacies of two levels of 
MAP based on long-term pain and functional independence 
measures. 
 
Safety: To determine the differential safety profiles of maintaining two 
different levels of MAP for up to 7 days.  
Population: 
Adult patients of either gender with a diagnosis of acute traumatic 
spinal cord injury involving neurological levels. 
Sample Size: 
A total of 152 patients will be enrolled (76 in each group) 
Phase: 
III 
Number of Sites: 
At least 5 sites 
Description of  
Intervention: 
Two different blood pressure control strategies: conventional blood 
pressure control (CBP) versus augmented blood pressure (ABP) will 
be targeted based on study group assignment. The CBP group will 
have a target mean arterial pressure (MAP) of 65-70 mm Hg for 7 
days after randomization or until ICU discharge; the ABP group will 
have a goal of MAP 85-90 mm Hg for 7 days after randomization or 
until ICU discharge. 
Study Duration: 
32 months 
Subject Participation 
Duration: 
Until completion of 6-month follow up 
Estimated Time to 
Complete 
Enrollment: 
24 months 
 

 
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Schematic of Study Design 
 
Pre-Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ICU & Hospital  
Until H discharge 
 
 
 
 
 
 
 
Follow-Up 
6 mo (+1 month) 
post H discharge 
 
 
 
 
 
Perform pre-randomization assessments. 
1) Screen potential subjects by inclusion and exclusion 
criteria; 2) Informed consent; 3) Demographic data; 4) Pre-
randomization ASIA impairment scale; 5) Spinal column injury, 
imaging, and  spinal procedures data; 6) Concomitant injuries 
and past medical history; 7) Pre-randomization vital signs. 
Perform ICU assessments. 
1) ICU vital signs data (Days 1-7); 2) Sequential Organ Failure 
Assessment Score Form (SOFA) score; 3) Vasopressors and 
concomitant medications data; 4) Treatments non-compliance 
and discontinuation tracking; 5) Post 72 hour ASIA impairment 
scale; 6) ICU and hospital discharge. 
Perform 6 month follow-up assessments. 
1) Follow-up ASIA impairment scale; 2) International SCI Basic 
Pain Data Set; 3) Spinal Cord Independence Measure (SCIM);  
4) Quality of life data; 5) Cardiovascular function data. 
Randomize 
Complete Randomization Form 
MAP 65-70 
N subjects = 76
MAP 85-90 
N subjects = 76

 
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KEY ROLES AND CONTACT INFORMATION 
Principal 
Investigator:   
Miriam Treggiari, MD, PhD, MPH  
Oregon Health & Science University 
(503) 494-5735 
treggiar@ohsu.edu 
Project Co-PI: 
David Zonies, MD, MPH 
Oregon Health & Science University 
(503) 494-5300 
zonies@ohsu.edu 
Research Monitor: 
Peter Schulman, MD 
Oregon Health & Science University 
(503) 494-7641 
schulman@ohsu.edu 
 
 
Project 
Biostatistician:  
N. David Yanez, PhD 
Oregon Health & Science University 
(503) 494-5354 
yanezn@ohsu.edu 
Project Manager: 
Michael Kampp, BS, CCRP 
Oregon Health & Science University 
(503) 494-5224 
kamppm@ohsu.edu 
Clinical Research 
Associate: 
Laura Sissons-Ross 
Oregon Health & Science University 
(503) 494-9545 
sissonsr@ohsu.edu 
 

 
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1 
ETHICS 
1.1 
Ethical Standard 
 
This trial will be conducted according to the ethical principles that have their origin in the 
Declaration of Helsinki, good clinical practice (GCP), and applicable regulatory requirements. The 
investigator will ensure that this study is conducted in full conformity with the principles set forth 
in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of 
Research, as drafted by the US National Commission for the Protection of Human Subjects of 
Biomedical and Behavioral Research (April 18, 1979) and codified in 45 CFR Part 46 and/or the 
ICH E6.  
1.2 
Institutional Review Boards 
 
The relevant institutional review boards (IRBs) for this trial will be provided with all documents 
required to fulfill their responsibilities. Any updates thereof will be provided according to GCP and 
applicable regulatory requirements. Trial activities will only start when approval from the relevant 
IRB is available. Documentation of all involved IRBs will be maintained according to GCP and 
applicable regulatory requirements.  
1.3 
Subject Information and Informed Consent 
 
Before any trial-related procedure will be performed, freely given informed consent must be 
obtained. The informed consent discussion, the information sheet (if used), and the informed 
consent form provided to subjects will adhere to GCP and applicable regulatory requirements and 
will be approved by the relevant IRB prior to use. The informed consent discussion with the subject 
will be performed by the investigator or an appropriately trained delegate. The consent process 
will be documented in the clinical or research record.  Subjects will be informed as soon as 
possible if new information becomes available that may be relevant to their willingness to continue 
participation in the trial. The communication of this information will be documented. Subject 
withdrawal of their consent for participation in the trial will also be documented.  
1.4 
Patient Confidentiality 
 
In order In order to maintain patient privacy, data capture tools, study drug accountability records, 
study reports, and communications will identify the patient only by initials and the assigned patient 
number. The investigator will grant monitor(s) and auditor(s) from OHSU Coordinating Center or 
its designee and regulatory authorities access to the patient’s original medical records, including 
medical history, laboratory studies, and medication administrations, for verification of data 
gathered and to audit the data collection process. This information will be accessed for the 
duration of the research study, including the follow-up period, for the purpose of data 
reconciliation. The patient’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 

 
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1.5 
Protocol Compliance 
 
The Investigator will conduct the trial in compliance with the protocol provided by the Study 
Principal Investigators, and with approval/favorable opinion given by the IRB and the appropriate 
regulatory authorities. Modifications to the protocol may not be made without agreement of the 
Study Principal Investigators. Changes to the protocol will require a written IRB approval/favorable 
opinion prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB may provide, if applicable regulatory authorities permit, expedited 
review and approval/favorable opinion for minor change(s) in ongoing trials that have the 
approval/favorable opinion of the IRB. OHSU Coordinating Center will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations. When 
immediate deviation from the protocol is required to eliminate an immediate hazard(s) to patients, 
the investigator will contact the Study Principal Investigators at the OHSU Coordinating Center 
and/or the Research Monitor, if circumstances permit, to discuss the planned course of action. 
Any departures from the protocol must be fully documented on the appropriate case report form 
(CRF) and in the source documentation. 
 
 

 
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2 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 
2.1 Investigators and Trial Site Personnel 
2.1.1 
Investigators 
 
The investigator, in general, is the person responsible for the conduct of the trial at the trial site 
and the safety of trial subjects. If the trial is conducted by a team of individuals at the trial site, the 
investigator leading and responsible for the team may be called the principal investigator (PI). All 
persons assigned responsibility as PI will be required to sign a declaration of their responsibilities 
before any trial-related procedure is performed. Curriculum vitae and/or other relevant documents 
confirming the qualifications of the investigator are required. This should include any previous 
training in the principles of GCP, experience obtained from work with clinical trials, and experience 
with subject care. Documentation of all involved investigators will be maintained according to GCP 
and applicable regulatory requirements. 
2.1.2 
Trial Site Personnel Assigned Trial-Related Duties 
 
The investigators may define personnel at a trial site to perform significant trial-related procedures 
and/or to make trial-related decisions under his/her supervision. The investigator must maintain 
a signed list of appropriately qualified persons to whom he or she delegates significant trial-related 
duties/responsibilities; the delegated trial-related responsibilities must be specified in the list. 
When personnel or responsibility changes are made, the relevant documentation must be 
updated before any trial-related activities are performed. Documentation of all involved trial site 
personnel performing significant trial-related procedures and/or making trial-related decisions will 
be maintained according to GCP and applicable regulatory requirements.  
2.2 
Data Monitoring Committee 
 
A Data and Safety Monitoring Board (DSMB) will periodically review safety information from the 
trial and monitor trial conduct and overall progress. The DSMB will have access to un-blinded 
treatment information to investigate unexpected safety findings of larger than expected 
differences in adverse events or other safety data between treatment arms. Procedures and 
management of the DSMB will follow the manual of operations (MOO) and standard operating 
procedures (SOPs) and will be documented in the DSMB Charter.  

 
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3 
INTRODUCTION  
3.1 
Background Information 
 
Systemic hypotension is a hallmark physiological response immediately following spinal cord 
injury (SCI).  Prevention of hypotension (systolic blood pressure <90 mm Hg) appears to be an 
essential component of the early management of victims of SCI. While it is well documented that 
early aggressive management in an Intensive Care Unit (ICU) setting involving respiratory and 
cardiovascular support has been accompanied by considerable improvement in vital and 
functional outcomes in patients with SCI, the goals of hemodynamic resuscitation have not been 
investigated in a systematic manner. 
 
The Congress of Neurological Surgeons recently published guidelines recommend maintenance 
of a mean arterial pressure (MAP) between 85 and 90 mm Hg for the first 7 days following the 
acute SCI.1 However, this recommendation is only based on level III evidence from case series, 
non-experimental, and non-comparative studies.2,3 These studies were not specifically designed 
to investigate the role of Targeted blood Pressure Management (TPM), rather were focused on 
process improvement for the overall management of patients with SCI. Considering the 
inadequate methodological quality, the generally small sample sizes, the lack of a comparison 
group, the uncontrolled conditions in the setting of concomitant therapies, and the non-
contemporary overall management described in these historic study cohorts, there is an important 
need to provide high quality data from prospective trials that can be used to guide optimal 
hemodynamic care. 
  
There is in theory a strong rationale for TPM to prevent secondary spinal cord insult. A series of 
animal based investigations performed in the 1970s and 1980s suggested that systemic 
hypotension after SCI was associated with reduced spinal cord perfusion and worse neurologic 
outcomes. Several case series in the subsequent decade suggested that maintaining a MAP >85 
mmHg for 7 days was not associated with deleterious effects and may have provided benefit.   
 
Of the major human studies, Levi et al studied SCI patients with a MAP >90 mm Hg to evaluate 
the role of invasive monitoring in the early management of such patients.  Another hemodynamic 
study by Vale et al.4 failed to show any clinical improvement with a MAP >85 mm Hg among 
patients who presented in shock. Taken together, these data call into question the validity of TPM 
and the basis of the proposed targets.  
 
Targeted blood Pressure Management may require parenteral administration of vasopressor 
agents to maintain high MAP targets. Although considered safe in this patient population, high 
dose vasopressor support is not without consequence.  While norepinephrine might have direct 
toxic effect on myocytes by inducing apoptosis,5 phenylephrine use might be limited by the 
occurrence of reflex bradycardia.  
 

 
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The concept of TPM in neurological resuscitation assumes that the spinal cord blood flow is 
pressure passive when there is loss of autoregulation. However, not only the extent of impairment 
of spinal cord autoregulation is unknown, but also potent constrictors could potentially impair 
spinal cord blood flow by limiting collateral flow through intercostal anastomosis when increased 
pressure occurs at the expense of excessive vasoconstriction.  The inability to measure or monitor 
spinal cord blood flow while managing blood pressure with potent vasoconstrictors, raises 
concerns regarding the beneficial effects of TPM.  
3.2 
Specific Aims / Study Design 
 
The early critical care management of patients with SCI may have great influence over their 
inpatient morbidity and subsequent neurological prognosis.  While the evidence supporting the 
avoidance of hypotension is strong, the role of TPM is much less well established. With clinical 
equipoise, it is critically important to determine the optimal targets for blood pressure management 
for cardiopulmonary support to maximize spinal cord perfusion. We propose a multi-center, 
randomized, controlled study to assess the efficacy and safety of early TPM in an ICU setting in 
patients with acute SCI. The study will equally randomize 152 acute SCI patients to either a MAP 
target between 65 and 70 mm Hg or MAP target between 85 and 90 mm Hg for a duration of 7 
days or until ICU discharge. The randomization design will be unrestricted 1:1 or “fair-coin” design. 
We hypothesize that TPM, by enhancing spinal cord perfusion, will improve long term neurological 
and functional outcomes in patients with SCI. Our specific aims are as follows: 
 
This multi-center, randomized, controlled study will assess the efficacy and safety of early TPM 
in an ICU setting in patients with acute SCI with blunt injury. The study will equally randomize 152 
acute SCI patients to either Conventional Blood Pressure (CBP) with a MAP target between 65 
and 70 mm Hg or Augmented Blood Pressure (ABP) with a MAP target between 85 and 90 mm 
Hg for a duration of 7 days or until ICU discharge. The study will include patients with acute SCI 
of American Spinal Injury Association (ASIA) grade A, B, or C involving the cervical or thoracic 
spine as documented by a combination of clinical exam and Computerized Axial Tomography 
(CT) or Magnetic Resonance Imaging (MRI) findings of cervical or thoracic abnormalities 
consistent with the clinical findings. The study will test the overall hypothesis that ABP will improve 
long term neurological and functional outcomes in patients with SCI by maintaining adequate 
spinal cord perfusion. 
3.3 
Potential Risks and Benefits 
3.3.1 
Potential Risks 
 
Risks associated TPM include:  pulmonary edema, generalized edema, and cerebral edema for 
volume replacement and increased cardiac work, cardiac ischemia, bradycardia, and organ 
hypoperfusion from the administration of vasopressors or inotropes for blood pressure 
manipulations. These treatment strategies are widely utilized in clinical practice with presumed 
significant potential benefits and the risks of the research do not exceed current usual care; 

 
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therefore, the ethical principles of beneficence and non-maleficence are respected.Though there 
is no invasive monitoring requirement, hemodynamic management may require invasive 
monitoring with the risk associated with placement and presence of indwelling catheters as 
dictated by clinical needs. Additionally, the patients who have been randomized in the study will 
undergo cerebral MRI and/or spine CT as part of standard of care imaging for SCI and may suffer 
from claustrophobia and anxiety due to the tight configuration of the apparatus.  
 
Additional laboratory work is not required for study purposes.  
 
There is always a risk of breach of confidentiality when accessing patients’ records. However, 
every necessary precaution will be taken to minimize such risk. 
3.3.2 
Frequency of TPM Associated Risks  
 
Less likely (happen in less than 20% of people) 
• pulmonary and generalized edema 
• cardiac ischemia 
• organ hypoperfusion 
 
Rare (happen in less than 3% of people) 
• cerebral edema 
• bradycardia 
3.3.3 
Mitigation of Potential Risks 
 
As the management strategies proposed are within the range of current clinical practice in this 
population, there is no anticipated incremental risk associated with the participant assignment to 
any of the proposed treatment strategies. Therapies will be implemented by experienced and 
certified personnel, familiar with the clinical monitoring and the proposed hemodynamic 
management strategies. Therefore, the risks associated with TPM, as proposed in this protocol, 
do not exceed the risks taken as part of current routine patient care.  
 
Particular attention has been paid in the designing of the treatment strategies to prevent treatment 
misalignment. All patients in the two pressure arms will receive treatment, so that no participant 
will be precluded of appropriate management. Likewise, participants with lower hemodynamic 
goals should not experience under-treatment, as all participants in both groups are receiving 
treatment, allowing for treatment intensity increases.   
 
As added protection for study participants, the protocol is designed so that per-protocol treatments 
will be discontinued in the event the participant develops worsening neurological symptoms. In 
such cases, additional therapy escalation will be allowed for temporary periods when a blood 
pressure challenge might be transiently clinically indicated. Patients will continue to receive 
standard clinical care from their physician.  

 
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3.3.4 
Potential Benefits 
 
Potential benefits to subjects enrolling in this trial may include a greater recovery of neurological 
symptoms, allowing to achieve higher level of functioning and performance as assessed by a 
neurological evaluation, functional independence measures, and quality of life assessment at six 
months, as well as benefits of medical supervision from being in a clinical trial. 
 
Improvement of lack of symptoms progression may occur following either treatment arm. Patients 
randomized to the higher MAP will benefit by adhering to the current guideline for the 
management of acute spinal cord injury issued by the Consortium for Spinal Cord Medicine who 
recommend maintaining a MAP target of 85-90 mm Hg for seven days after the injury. The 
rationale of the guidelines is that higher MAP might maintain better perfusion to the spinal cord 
and improve long term neurological function. Therefore, there is potential for better neurological 
outcome, higher functioning and improved quality of life in this group. However, this is hypothetical 
and it has not been demonstrated. Patients randomized to the lower MAP will benefit from lower 
doses of vasopressors which have associated risks of excess fluid in the lungs, swelling of the 
brain, general swelling, heart attack, and inadequate oxygen supply. Future patients might benefit 
if the lower MAP approach was found not result in worse long term neurological function. 
 
All these outcome benefits will result in a reduction in institutional and societal costs and disability 
burden. These benefits are particularly meaningful as this disease frequently affects young, 
previously healthy individuals, who are typically key contributing members of society. Indirect 
benefits will be shared by family members and society as a whole. 

 
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4 OBJECTIVES 
4.1 
Study Objectives 
 
The primary hypothesis for the current study is that ABP will enhance spinal perfusion pressure, 
prevent hypoperfusion and improve preservation of spinal cord viability in areas suffering from 
ischemia, hemorrhage or edema. Preservation of adequate spinal cord perfusion pressure may 
result in clinical benefits, as indicated by at least the equivalent of a 5 point difference in the ASIA 
motor or sensory scores at six months. The study is designed to prove that the study treatments, 
when started in the immediate post-injury period, work well to prevent secondary injury and to 
attenuate its deleterious effects. If the study intervention does not have an impact on outcome, 
then these findings would indicate that there is no need to provide hemodynamic augmentation 
after acute SCI other than preventing hypotension.  
4.2 
Study Outcome Measures 
4.2.1 
Primary Specific Aim 
 
The primary aim of this study is to determine the differential effects of two levels of MAP on long-
term motor and sensory outcomes after acute SCI. Compared to maintaining a MAP target 
between 65 and 70 mm Hg, maintaining a MAP target between 85 and 90 mm Hg for a duration 
of seven days or until ICU discharge may improve motor and sensory ASIA scores at six months 
relative to baseline.   
4.2.2 
Secondary Specific Aim for Efficacy 
 
The secondary specific aim for efficacy is to determine the differential efficacies of two levels of 
MAP based on long-term pain and functional independence measures. Compared to maintaining 
a MAP target between 65 and 70 mm Hg, maintaining a MAP target between 85 and 90 mm Hg 
for a duration of seven days or until ICU discharge may improve functional outcome measures at 
six months on the Spinal Cord Independence Measure III, the International Spinal Cord Injury 
Basic Pain Data Set, Quality of Life and Cardiovascular Function. 
4.2.3 
Specific Aims for Safety 
The specific aim for safety is to determine the differential safety profiles of maintaining two 
different levels of MAP for seven days or until ICU discharge. Compared to maintaining a MAP 
target between 65 and 70 mm Hg, maintaining a MAP target between 85 and 90 mm Hg for a 
duration of seven days or until ICU discharge may have a more favorable safety profile as 
measured by respiratory complications (a composite of acute respiratory distress syndrome, 
hypoxemia as indicated by PaO2/FiO2 ratio, and pneumonia), occurrence of myocardial ischemia 
or infarction (troponin levels), maximum organ dysfunction as measured by the Sequential 
Multiple Organ Failure score (SOFA) in the first seven days after injury or until ICU discharge - 
whichever comes first -, duration of mechanical ventilation, and hospital stay. 

 
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5 
STUDY DESIGN 
This Phase III multicenter, randomized, controlled study will investigate the efficacy and safety of 
a strategy consisting of ABP to a MAP of 85-90 mm Hg compared to a strategy of CBP with a 
MAP goal of 65-70 mm Hg in patients suffering from acute SCI.  
 
All patient volume status will be managed with fluid administration with the goal of maintaining 
euvolemia. Approximately 152 patients will be randomized to detect the main effects of TPM. 
Investigators will make the best effort to randomize and start study procedures within 24 hours, 
however, longer delays can be considered up to a 48 hour window. Prior to randomization, the 
patient ASIA status will be recorded. For study purposes, ASIA score documentation will be 
repeated between 72 hours after randomization and prior to hospital discharge, and then at six 
months post-randomization.  
 
After obtaining informed consent from the participant or legally authorized representative (LAR), 
subjects will be randomly allocated to one of the two treatment arms: CBP and ABP goals. A 
computerized randomization system will verify eligibility and randomly assign eligible participants 
to one of the two different study arms.  Randomization will be performed using an unrestricted 
or “fair-coin” design; participants will be allocated 1:1 to the two treatment groups. The group 
assignment will remain the same throughout the study duration.  
 
The TPM protocol will be maintained for seven days or until ICU discharge. Vital signs and urine 
output will be monitored hourly during seven days or until ICU discharge. There will be daily 
monitoring of hemodynamic data, fluid intake/output and fluid balance. Subjects will be evaluated 
at 6 months after SCI for complete ASIA score assessment, evaluation of pain levels using the 
basic pain dataset, functional independence measures, quality of life, and assessment 
cardiovascular status. 
5.1 
Setting 
 
The study coordinating center will be located at Oregon Health & Science University (OHSU) in 
Portland, Oregon. This will be a multi-center trial where OHSU will act as both the coordinating 
center and as a participating site. 
 

 
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STUDY ENROLLMENT AND WITHDRAWAL 
5.2 
Subject Enrollment Procedure 
 
Before the informed consent is signed, patients will be screened to identify subjects who could 
potentially be enrolled into the trial. Potentially eligible subjects or their LAR will be asked by the 
investigator to enroll into the trial by giving written informed consent. The investigator will keep a 
subject screening log and a subject identification and enrollment log. 
5.3 
Inclusion/ Exclusion Criteria 
 
Subjects eligible to participate in the trial will be adult patients of either gender, admitted to any of 
the participating centers for the treatment of acute SCI. Subjects who meet all inclusion criteria 
and no exclusion criteria will be considered for enrollment in this clinical investigation. 
5.3.1 
Inclusion Criteria 
 
Clinical 
Inclusion 
Criteria 
IC1. 
 
Acute traumatic SCI involving neurological levels as defined by the 
ASIA neurological examination between C0 and T8 (tetraplegia) and 
resulting in new onset neurological deficits consistent with an ASIA 
motor assessment of level A, B, or C.                                  
IC2. 
18 years of age or older. 
IC3. 
Signed consent by study participant or applicable LAR. 
 
 
 

 
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5.3.2 
Exclusion Criteria 
 
Clinical 
Exclusion 
Criteria 
EC1. 
Penetrating SCI injury. 
EC2.  
Isolated cauda equine syndrome or injury at bony level Th9 or below. 
EC3. 
Pre-existing motor deficit secondary to chronic myelopathy. 
EC4. 
History of demyelinating disease or central nervous system 
autoimmune disorder. 
EC5. 
History within the past six months and/or physical findings on admission 
of decompensated congestive heart failure (NYHA functional class III 
or IV, or objective class C or D). 
EC6. 
Acute, evolving or recent (30 days) myocardial infarction. 
EC7. 
Chronic renal failure requiring dialysis. 
EC8. 
Suspected or confirmed pregnancy. 
EC9. 
Severe terminal disease with life expectancy less than 6 months. 
EC10. 
Severe traumatic brain injury at presentation (GCS ≤8) with 
confirmation of injury on brain imaging. 
EC11. 
A condition that would preclude the performance of an accurate 
neurological exam due to a prior diagnosis of Alzheimer’s disease, 
stroke, degenerative condition, cerebral tumor, or mental retardation. 
EC12. 
Non-English or Non-Spanish Speaking. 
EC13. 
Refusal of consent. 
5.3.3 
Inclusion of Women and Minorities 
 
There will not be exclusions for women or minorities and recruitment of these populations will be 
monitored by the OHSU Coordinating Center. Women will be included in this study in proportion 
to their representation in the target population. Female and male subjects will be recruited equally 
for participation in this study. Only women with a positive pregnancy test will be excluded in order 
to prevent exposure to any potential incremental risks that could be associated with participation 
in a research trial in the absence of known benefits. 
 
All planned study sites serve diverse multi-ethnic populations. To ensure adequate enrollment of 
minorities we will conduct the neurological assessment of Spanish speakers with the assistance 
of Spanish translators. Since the neurological exam depends on patient’s participation, groups 
speaking other languages than English or Spanish will not be included because it would not 

 
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possible to reliably find in-person translators available to assist with the clinical evaluation in other 
languages. 
5.3.4 
Exclusion of Vulnerable Populations 
 
The following populations will be excluded from the study: children, pregnant women, prisoners, 
and decisionally impaired adults for whom a LAR is not available. 
5.4 
Strategies for Recruitment 
A research coordinator will review daily the medical records of neurosurgical patients admitted to 
ICUs at any of the participating clinical sites for study eligibility of their patient population. Use of 
the medical records for review of data for study eligibility will be performed in accordance with 
institutional, state and Health Insurance Portability and Accountability Act (HIPAA) regulation.  
Patients suffering from acute SCI admitted to one of the participating centers will be prospectively 
identified. Potential study subjects will be identified from patients presenting to the Emergency 
Department or directly admitted to the Trauma/Surgical or Neurocritical Care Units at the 
participating sites. Patients who have a documented acute SCI based on clinical findings and 
radiological abnormalities on CT or MRI of either vertebral fractures, ligamentous injury, disc 
herniation, or spinal cord contusion, compression, edema, or infarct will be immediately evaluated 
by the on-call attending physician with documentation of the ASIA score and evaluated for 
eligibility as soon as possible after presentation.  
A de-identified log of patients not approached within 48 hours of hospital admission or refusing 
participation in the study will be maintained to define the characteristics of this population. If a 
non-enrolled patient refuses to allow the investigator to access the medical record, no data will 
be maintained. All procedures for obtaining consent will be approved by the institutional human 
subjects review board. 
5.5 
Informed Consent Process 
 
Adults 18 years or older with an acute traumatic SCI involving neurological levels as defined by 
the ASIA neurological examination between C0 and T8 (tetraplegia) and resulting in new onset 
neurological deficits consistent with an ASIA motor assessment of level A, B, or C will be eligible 
for participation in the study if approached within 48 hours of hospital admission. 
 
Potential study subjects/LAR will be able to learn about the study in a variety of ways. They may 
be approached after admission to the ICU by the study Research Coordinator, who will provide 
study documentation approved by the IRB, which will discuss the purpose of the study and the 
procedures involved. They may also learn about the clinical trial via the clinical trial website or be 
given information about the study by a critical care physician or certified nurse while staying in 
the ICU. 

 
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If a patient/LAR expresses interest in participation in the trial, the Research Coordinator will 
provide further information regarding the objectives of the study, study requirements, procedures 
and the potential risks. 
 
All protocols will require that all study participants or a member of a patient’s family sign and date 
an IRB approved informed consent form. Many patients may not be able to grant consent during 
the window required for enrollment in the study; therefore, their family members will receive the 
information about the study and asked to sign the informed consent form.  However, the patient 
will be notified and asked for verbal consent for continued participation as soon as the participant 
regains legal competency. If the study participant is legally competent but is physically unable to 
talk or write, an unbiased witness who is neither a study team member nor a family member of 
the participant can sign the witnessed line on the consent form to enter the patient into the trial. 
The unbiased witness must observe the consent process. 
5.6 
Point of Enrollment 
 
A subject will be considered enrolled in the study at the time that the informed consent form is 
signed. Subjects who are discontinued prior to randomization are considered “enrolled but not 
randomized.” Only randomized subjects will be included in the study analysis.  
5.6.1 
Subject Trial Cards 
 
Subjects who are randomized in the trial will receive a trial card. The trial card will list the following 
information: 1) Name of the subject and a statement that he/she is currently participating in a 
clinical trial; 2) Trial code; 3) Dates of all individual visits; 4) Name of investigator; and 5) Contact 
telephone number at the trial site.  The card will be collected at the subject’s last trial visit. 
5.6.2 
Subject Retention 
 
Once a participant enrolls in this study, the study site will make every effort to retain him/her for 
six months of follow-up to preserve the integrity of the study and to minimize possible bias 
associated with loss due to dropouts. To enhance participant retention, patients or their LAR will 
be adequately educated during the informed consent process. Study staff will be trained to explain 
to the participant or their LAR the importance of the follow-up visit and the scientific relevance of 
their data for the study and the potential deleterious effect that missing data could on the trial's 
integrity and credibility. Appropriately worded informed consent forms will enable patients to make 
more informed decisions about their willingness to join the trial and to participate in continued 
follow-up without feeling pressured to doing so.  
 
At time of enrollment the research coordinator will collect the participants’ mailing address, contact 
number, email address as well as contact information for an emergency contact who will know 
how to get in touch with subject, as well as the primary care physician information. A clinical 
medical records release form will also be obtained to allow review of the patient’s outside medical 

 
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record for ASIA assessment and cardiovascular data related to the 6-month follow-up visit. The 
study coordinator will initiate follow-up contact with the patient beginning four to six weeks prior 
to the six month mark from the patient’s enrollment. The study coordinator will attempt to contact 
the patient by telephone or email. Should the patient not respond within two weeks, the study 
coordinator will call the patient’s emergency contact and request a current phone number for the 
patient. Contact attempts will continue for four additional weeks. If the patient still has not 
responded he or she will be considered lost to follow-up. For patients who are able to be reached, 
a window of six weeks beginning two weeks prior to the six month mark and continuing four weeks 
after will be suitable for conducting follow-up.  
 
For participants unable or unwilling to return to the study site for the six month follow-up visit, 
research study coordinators will be available to travel to the participant’s residence to conduct the 
assessment. All participants will be contacted for follow-up, including participants that did not 
complete study treatment, unless they have formally withdrawn consent. 
5.7 
Treatment Assignment Procedures 
5.7.1 
Randomization Procedures  
 
Subjects should be approached as soon as possible after hospital admission and will be 
randomized within 48 hours of being approached for study participation to allow for adequate time 
for patient identification, the informed consent process, patient enrollment, and collection of 
baseline variables. Subjects who meet the inclusion and exclusion criteria and consent to the 
study will be assigned to one of two study groups using a computer-based randomization 
procedure. The randomization procedure will require confirmation of the eligibility criteria and 
ensure that the integrity of the randomization is maintained. Subjects will be randomized to a 
treatment arm based on an unrestricted or “fair-coin” randomization procedure. The 
randomization will be carried out in SAS using proc plan with a specific random number seed so 
that the results are reproducible. This list will be used at clinic sites to randomize subjects as they 
enroll in the study. Subject randomization assignments will only be accessible to the bioanalytical 
staff assigned to the project who have been designated to be unblinded.   
5.7.2 
Blinding 
 
This is an assessor-blinded study. Due to the requirement for targeting specific blood pressure 
goals, the primary caregivers (attending physician and nurse in charge of the patient) will not be 
blinded to the treatment allocation. In order to maintain blinding, a baseline neurological exam will 
be conducted and ASIA score will be documented immediately prior to obtaining informed consent 
and randomization assignment. Subjects will not be notified of the treatment arm assignment and 
he/she will be unlikely to identify which treatment has been administered. In order to ascertain 
whether subject blinding was maintained, the subject will be asked whether he/she learned the 
subject’s group assignment at the end of follow-up assessment. The outcome examiner that will 
collect the 6-month study endpoints will be blinded to treatment assignment. The DSMB will 

 
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remain blinded to treatment assignment when outcome data is reported. The treatment 
assignment groups will be reported as group A and group B. 
5.8 
Subject Discontinuation 
5.8.1 
Investigator Initiated Withdrawal 
 
There are no compulsorily reasons to withdraw a patient from the study unless, in the clinical 
opinion of the investigators, continuing participation in the study represents an excessively high 
risk for the study participant. Investigators are reminded that it is important to minimize missing 
data for safety and efficacy evaluation; therefore, subjects should be kept in the trial unless 
medically necessary.  
5.8.2 
Subject Initiated Withdrawal 
 
While study withdrawal is discouraged, subjects may withdraw from the study at any time, with or 
without reason and without prejudice to further treatment. In all cases of withdrawal or 
discontinuation, the investigator will make all reasonable efforts to determine the reason for the 
subject’s withdrawal. All subjects enrolled in the clinical study shall be accounted for and 
documented. If such withdrawal is due to problems related to the investigation, the investigator 
shall ask for the subject’s permission to follow his/her status or condition outside of the clinical 
study.  
5.8.3 
Procedures for Handling Discontinued Subjects 
 
The investigator must document any discontinuation of a subject. Where applicable, the relevant 
IRB must also be informed with a detailed written explanation. The following must be done for all 
discontinued subjects: 1) Document reason for discontinuation; 2) Document status of all new 
and ongoing (serious) adverse events; 3) Document all demographic data, including the date of 
the signature on the informed consent form; and 4) Complete any other trial-related formalities.  
5.9 
Premature Termination or Suspension of Study 
 
The relevant IRB, the regulatory authorities, or the PI or assigned delegate alone or in conjunction 
have the power to make a binding decision to prematurely terminate or suspend the trial at any 
or all trial sites. The DSMB also may recommend termination of the trial. In addition, for an 
individual trial site, this decision can be made by the PI. The party prematurely terminating or 
suspending the trial must promptly inform all other parties (i.e., the PI(s), the relevant IRB, the 
relevant regulatory authorities, or OHSU Coordinating Center or assigned delegate, as 
applicable). 
 
In addition, if the investigator decides to terminate or suspend the trial at the trial site, the 
investigator must promptly inform the subjects, ensure appropriate follow-up for any enrolled 

 
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subjects, and provide the relevant IRB, OHSU Coordinating Center or assigned delegate as 
applicable, with a written explanation of the termination or suspension.  

 
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6 
STUDY INTERVENTION 
6.1 
Study Treatment Protocols 
 
After obtaining informed consent, acute SCI participants will be equally randomized to be 
maintained on two different blood pressure targets for seven days or until ICU discharge. 
Participants will be monitored by the critical care team during the ICU stay. Patients will be treated 
with standardized volume replacement therapy with crystalloids with the goal of maintaining 
euvolemia. Vasopressors, including phenylephrine, norepinephrine, vasopressin, dopamine, or a 
combination of these agents as per standard of care at each participating institution, will be used 
to maintain blood pressure within the specified targets. Participants will have their standard of 
care vasopressors titrated to a target MAP of 85-90 mm Hg for seven days or until ICU discharge 
(as recommended in the guidelines for the hemodynamic management of acute SCI) or to a target 
MAP of 65-70 mm Hg for seven days or until ICU discharge (considered to be a general standard 
MAP aiming at preventing hypotension). It is anticipated that the high blood pressure target group 
will be exposed to vasopressors more frequently, in higher doses and for a longer duration. 
 
After randomization, the nurse in charge of the patient will implement the fluid and pressure 
protocol according to assigned treatment. Patients will be maintained in the same treatment arm 
to which they were initially assigned throughout the duration of the study. Overlapping of the 
therapeutic goals across each assignment group will be avoided to ensure adequate distinction 
among the treatment arms.  
 
The hemodynamic assessment used to guide the pressure management protocol will be obtained 
at least every four hours for all patients. This includes blood pressures and vital signs, and 
recording of central venous pressure, if available. From these data, the appropriate action 
(initiation or continuation of pressors, or anti-hypertensives) will be implemented. If, prior to the 
next scheduled 4-hour assessment, a change in one of the monitored parameters occurs (e.g., 
decrease in blood pressure), then the appropriate action can be taken earlier. If a study participant 
becomes hypertensive during the course of the study period, his/her home anti-hypertensive 
should be restarted in the conventional blood pressure group and can be restarted in the 
augmented blood pressure group, as clinically indicated. In the case of hypertension, clinical 
management should be directed to maintain participants in their blood pressure assignment 
range.  
 
To evaluate appropriateness of organ perfusion, we will also collect daily urine output and fluid 
balance, and clinical assessment of the effectiveness of the arterial circulation, using the organ 
system listed in the Sequential Organ Failure Assessment score, and troponin values.  
 
Detailed management algorithms with instructions for systematic adjustment to allow immediate 
adaptation to the evolving clinical course. The treatment algorithms are outlined in APPENDIX B. 
 

 
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6.1.1 
Targeted blood Pressure Management 
 
Immediately after randomization, two different blood pressure control strategies: CBP versus ABP 
will be targeted based on study group assignment. The CBP group will have a target MAP of 65-
70 mm Hg for seven days after randomization or until ICU discharge, whichever comes first; the 
ABP group will have a goal of MAP 85-90 mm Hg for seven days after randomization or until ICU 
discharge, whichever comes first. The blood pressure targets will be achieved by the 
administration of vasoactive medications (vasopressors or antihypertensives) to maintain the 
MAP within the target range. 
6.1.2 
Volume Expansion to Achieve Euvolemia 
 
Volume resuscitation will be achieved according to standard of care at each participating 
institution. The standardized fluid administration strategies will be initiated in all patients with the 
goal of maintaining normovolemia. Depending on local standard of care, normovolemia will be 
based on a combination of hemodynamic and laboratory parameters including daily fluid balance, 
lactate and base deficit, and/or central venous pressures (CVP) if a central venous catheter is in 
place. It is expected that for typical maintenance of normovolemia the administration of 
intravenous or enteral fluid replacement approximate 30 mL/kg/day. 
6.2 
Assessment of Clinicians’ Compliance with Study Procedural Intervention 
 
Compliance with protocol instructions will be monitored daily, preferably during a morning 
reference period and again at a randomly selected time. A 100 percent audit of all instructions will 
be conducted for the first 5 enrolled patients at each site to ensure high protocol compliance; 
random checks will be conducted subsequently. 
 
Non-compliance with the study algorithm should be discouraged at all times. If for any reasons 
the patient blood pressure needed to be altered outside the ranges of study algorithms, a 
temporary blood pressure challenge will be documented in the treatment non-compliance log of 
the case report form, specifying new target of augmentation, the duration of the challenge, and 
the reason why this was necessary. Patients should be returned to their assigned randomization 
group and follow the per-protocol instructions at the earliest possible time. If a treatment needed 
to be permanently and prematurely discontinued, then the time and reason for discontinuation 
should be documented and the event should be reported within 24 hours to the OHSU 
Coordinating Center. 
 
We will track each event of blood pressure non-compliance using a designated event tracking 
form that documents the time of onset and termination of the out-of-range period, its duration, and 
the new target levels. 
 
We define treatment failure as the requirement for permanent discontinuation of the assigned 
treatment algorithms.  
 

 
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7 
STUDY SCHEDULE AND EVALUATIONS 
7.1 
Pre-randomization Assessment 
 
Written informed consent must be obtained for all patients who are potential study candidates. 
Inclusion and Exclusion criteria listed above respectively, will be assessed to determine study 
candidate eligibility. Subjects who have provided informed consent and who have been 
determined to not meet all eligibility requirements will be withdrawn. Study candidates must sign 
the informed consent form before any study-specific tests or procedures are performed.  
 
Pre-randomization assessments will be performed immediately prior to randomization and 
include: 1) Date and time of symptom onset; 2) Demographic Data (sex, race/ethnicity, age, 
height, weight); 3) Neurological exam (ASIA Assessment) with documentation of SCI severity and 
level and mechanism of injury; 4) Neuroimaging findings from spine CT or MRI Clinical ICU 
Assessment; 5) Spinal intervention and spinal procedures data; 6) Concomitant injuries and past 
medical history, in particular history related to hypertension and respiratory issues; 7) Injury 
severity score; 8) Monitoring of pre-randomization vital signs (Non-invasive BP and MAP with 
indication of the location of measurement, e.g., either the left upper extremity or the right upper 
extremity); 9) Mechanical ventilation; 10) Fluid Intake/Output; 11) Current vasopressors. 
7.2 
ICU Visit Assessment 
 
All subjects will be monitored in the ICU or acute care for hemodynamic vital signs, e.g., heart 
rate (HR) and MAP starting at screening (baseline), prior to initiating the study protocols, and 
every 4 hours thereafter until study day 7 or ICU discharge. Non-invasive blood pressure and 
MAP will be recorded from the same side of the body to minimize measurement error. Central 
venous catheterization or other types of invasive monitoring will not be required for study 
purposes, but the decision will be left to the discretion of the treating physicians. Likewise, invasive 
arterial blood pressure monitoring will not be required for study purposes and it will be initiated 
based on clinical indication. If a study participant is discharged from the ICU or the intermediate 
care unit to the general ward prior to day 7 after inclusion in the study, the study hemodynamic 
goals may be continued using enteral vasoactive agents, e.g. midodrine or ephedrine. Vital signs, 
physiologic variables including systemic pressure and HR will be monitored frequently and at least 
every four hours while the patient is in the ICU, and until study day 7. Complications will be 
collected until hospital discharge. 
7.2.1 
Concomitant Treatments and Supportive Care 
 
All participants should be given appropriate supportive therapy during the course of the study. 
During the hemodynamic management protocols, all the vasoactive agents administered 
parenterally or internally will be collected. For the parenteral administration, vasopressor agents 
will be converted to norepinephrine equivalents using the conversion table below.  
 

 
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Vasopressors Conversion Table 
Agent 
Dose 
Norepinephrine equivalent 
Epinephrine 
0.1 mcg/kg/min 
0.1 mcg/kg/min 
Norepinephrine 
0.1 mcg/kg/min 
0.1 mcg/kg/min 
Dopamine 
15 mcg/kg/min 
0.1 mcg/kg/min 
Phenylephrine 
1.0 mcg/kg/min 
0.1 mcg/kg/min 
Vasopressin 
0.04 U/min 
0.1 mcg/kg/min 
 
 
During the time of study and in addition to the pressure treatment strategies provided according 
to the study protocol, associated treatments for the protection of the spinal cord and overall care 
will be recorded. These include steroid class agents. These medication classes that are 
administered during the study will be recorded on the appropriate CRF along with the start and 
stop date(s), dose and amount administered, and indication. Steroids will be converted to 
methylprednisolone equivalents using the conversion table below. 
 
Corticosteroid Conversion Table 
Glucocorticoid 
Approximate Equivalent Dose (mg) 
Half-life (hours) 
Short-Acting 
Cortisone 
25 
8-12 
Hydrocortisone 
20 
8-12 
Intermediate-Acting 
Methylprednisolone 
4 
8-36 
Prednisolone 
5 
8-36 
Prednisone 
5 
8-36 
Triamcinolone 
4 
8-36 
Long-Acting 
Betamethasone 
0.6-0.75 
36-54 
Dexamethasone 
0.75 
36-54 
7.2.2 
Documentation of post-72 hour ASIA Score 
 
Between 72 hours after the injury and prior to ICU discharge, a complete ASIA assessment will 
be repeated to document the post-resuscitation ASIA score. 
7.2.3 
Hospital Discharge 
 
The duration of hospitalization, duration of mechanical ventilation, and discharge disposition will 
be recorded at the time of hospital discharge and transfer to inpatient or outpatient rehabilitation. 
 
 

 
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7.2.4 
Adverse Event Monitoring 
 
In the case of an adverse event (AE), the subject will be treated by the primary physician or 
referred for care as appropriate. Data pertaining to any AE will be entered into the CRF. For any 
AEs, a causal or symptomatic treatment according to standard medical practice will be performed 
if deemed necessary by the investigator. The medical care given to and medical decision made 
on behalf of the subjects will always be the responsibility of a qualified physician. 
7.3 
Six Month Follow-Up Assessment 
 
Patients will be evaluated at 6 months (+1month) after SCI given the time required for neurological 
recovery and stabilization of their clinical condition. A complete ASIA score assessment, 
evaluation of pain levels, independence measures, quality of life, and cardiovascular function data 
will be collected during an in-person visit. For sites that routinely have 6-month follow up visits, 
the study visit will be arranged in conjunction with their scheduled clinic visit. By six months, the 
vast majority of the patients should attain a level of recovery that approximates their final 
condition. Every effort will be made to collect 6-month data for all study outcomes to best insure 
the integrity of randomization and the trial results. The only two valid reasons a patient can be off 
study are: 1) withdrawal of consent or 2) the achievement of all required efficacy and safety end 
point information. All reasonable efforts should be made to ensure patients who go off study 
treatment are consistently followed for outcomes unless they withdraw consent. 
7.3.1 
Patient Tracking at Follow-Up 
 
There is high mortality in this population. We will capture deaths among participants lost to follow 
up, using various mechanisms including review of the medical record, contacting the legal next of 
kin or the contact provided at the time of study enrollment. For patients who are lost to follow up, 
we will also contact the primary care physicians and safety net clinics to ascertain the participant’s 
vital status. In addition, local obituaries and newspapers will be screened for potential 
identification of lost to follow-up study participants.   
 

 
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8 
ASSESSMENT OF SAFETY 
8.1 
Specification of Safety Parameters 
 
The following safety data will be collected during the trial: AEs and vital signs. Clinically relevant 
abnormal values, based on investigator judgment, will be recorded as AEs.  
8.1.1 
Unanticipated Problems 
 
Unanticipated problems include any incident, experience, or outcome that meets all of the 
following criteria:  
 
 
Unexpected in terms of nature, severity, or frequency give 1) the research procedures 
that are described in the protocol and related documents; and 2) the characteristics of 
the subject population being studied; 
 
 
Related or possibly related to participation in the research; and 
 
 
Suggests that the research places subjects or others at a greater risk of harm, including 
physical, psychological, economic, or social harm, than was previously known or 
recognized.  
 
Incidents, experiences, or outcomes meeting all three criteria above will warrant corrective 
actions in order to protect the safety, welfare, and rights of subjects. 
8.1.2 
Protocol Deviation 
 
A protocol deviation is any accidental or unintentional change to, or non-compliance with the 
research protocol that does not increase risk or decrease benefit; does not have a significant 
effect on the subject’s rights, safety or welfare; and/or the integrity of the data.  A deviation may 
be due to the research subject’s non-compliance, or an unintentional change to or non-
compliance with the research protocol on the part of a researcher. When a protocol deviation is 
discovered, it is the PI’s responsibility to assess all protocol deviations.  
 
Protocol deviations must be submitted to the Study PIs at the OHSU Coordinating Center or 
designated authority within 10 days of first knowledge of the investigator using the Protocol 
Deviation Form and must include: 1) Detailed narrative describing the deviation, how the deviation 
was discovered, the risks the subjects were exposed to and the measures taken to minimize risk; 
2) A detailed corrective action plan to prevent similar deviations in the future.  
 
Protocol deviations must be tracked in a protocol deviation log. Protocol deviation logs should be 
submitted at the time of continuing review. Research teams should review the protocol deviation 
logs periodically and determine if the deviations indicate a larger systemic problem with the 

 
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implementation of the research. Appropriate corrective measures should be taken to rectify any 
systemic problems. 
8.1.3 
Adverse Events 
 
An AE is any untoward medical occurrence in a subject enrolled in a clinical trial. An AE can 
therefore be any unfavorable or unintended sign, symptom, or disease temporally associated with 
the trial procedures. Pre-existing diseases or conditions occurring before enrollment are not 
considered to be AEs unless there is an untoward change in intensity, frequency, or quality after 
enrollment. Lack of efficacy is not considered to be an AE. 
8.1.4 
Serious Adverse Events 
 
A serious adverse event (SAE) is any untoward medical occurrence that: 1) Results in death; 2) 
Is life-threatening; 3) Requires inpatient hospitalization or prolongation of existing hospitalization; 
4) Results in persistent or significant disability or incapacity; 5) Is a congenital anomaly or birth 
defect; or 6) Is considered a clinically important medical event. 
 
An elective hospital admission (e.g., for pre-planned surgery) will not be considered a SAE if 
documented at enrollment. Short-lasting (<24 hours) hospital admissions (e.g., for clinical check-
ups) not meeting any of the other above mentioned criteria will also not be considered SAEs.  
8.2 
Characteristics of an Adverse Event 
8.2.1 
Relationship to Study Intervention 
 
The causal relationship of an AE to the study protocol will be classified using the following 
terminology. The given criteria for each term are neither exhaustive nor required to be fulfilled in 
total for the selection of the respective term: 
 
Relationship to Study 
Intervention 
Conditional/
Unclassified 
Additional data for proper assessment are under 
examination. 
Not 
Classifiable 
The available data cannot be judged because 
information is insufficient or contradictory, and cannot 
be supplemented or verified. 
Not Related 
Data with sufficient evidence to accept that there is 
no causal relationship. 
Unlikely 
Data without sufficient evidence to accept that there 
is no causal relationship, but also with no evidence or 
argument to suggest a causal relationship. 

 
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Relationship to Study 
Intervention (cont.) 
Possible 
Data with limited evidence or argument to suggest a 
causal relationship.  
Probable/ 
Likely 
Data with sufficient evidence or argument to suggest 
a causal relationship. 
Certain 
Data with clear evidence for a causal relationship. 
8.2.2 
Expectedness of SAEs 
 
Expectedness of (serious) adverse events will be assessed by the OHSU Coordinating Center. 
An unexpected AE is one where the nature or intensity is not consistent with available information. 
Furthermore, reports that add significant information about the specificity or severity of a known, 
already documented, adverse reaction constitute unexpected AEs. For example, an AE that is 
more specific or more severe than expected would be considered “unexpected”. 
8.2.3 
Severity of Event 
 
The clinical intensity of an unanticipated problem or AE will be classified as described below. For 
problems or events where the intensity changes over time, the maximum intensity observed 
during the whole duration will be documented. 
 
Severity of Event 
Mild 
Signs and symptoms that can be easily tolerated, 
ignored, and disappear when the subject is distracted. 
Moderate 
Symptoms cause discomfort but are not tolerable, 
cannot be ignored, and affect concentration. 
Severe 
Symptoms affect usual daily activity.  
8.2.4 
Outcome of Event 
 
The outcome at the time of last observation will be classified as: 1) Recovered/Resolved; 2) 
Recovering/Resolving; 3) Recovered/Resolved with sequelae; 4) Not Recovered/Not Resolved; 
5) Fatal; or 6) Unknown. 
8.3 
Time Period and Frequency for Event Assessment and Follow-Up 
 
All AEs will be documented from the time of enrollment (i.e., the time the informed consent form 
is signed) up to the time of the last protocol scheduled contact has occurred (i.e., date of last 
visit/contact, including phone call). Subjects will be monitored daily for unanticipated problems 
and AEs for the duration of the study. Any unexpected problem, unanticipated problem, or 
clinically relevant abnormal laboratory or vital sign result will be followed until it reaches a 

 
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satisfactory conclusion, becomes stable, or clinical judgment indicates that further evaluation is 
not warranted.  
8.4 
Reporting Procedures 
 
For the duration of patient therapy, the investigators will be responsible for monitoring and 
recording AEs related to vasopressors related side effects, new neurological event or new or 
worsening organ dysfunction. When possible, severity of AEs will also be recorded. Possible AEs 
due to treatment include pulmonary edema, cardiac or other organ ischemia, organ dysfunction 
or failure, and arrhythmia and will be monitored during treatment. Study site investigators will also 
be responsible for recording unanticipated AEs observed by patients or investigators. 
 
Subjects will be questioned about possible unanticipated problems and AEs with non-leading 
questions daily. All unanticipated problems and AEs reported spontaneously by subjects at any 
time point will also be documented. All unanticipated problems and AEs will be documented with 
the following information, as appropriate: 1) Description (verbatim term); 2) Start date/time; 3) End 
date/time or continuation; 4) Relationship to intervention; 5) Seriousness; 6) Intensity; 7) 
Outcome; and 8) Action taken. 
8.4.1 
Unanticipated Problem Reporting 
 
Federal regulations require prompt reporting of unanticipated problems and AEs to the IRB, 
appropriate officials, the funding agency or coordinating center, and the federal departments or 
agency heads as applicable. 
 
Unanticipated 
Problem 
Reporting 
Unanticipated Problem 
Report within 5 working days of the 
researcher becoming aware of the event. 
Internal Adverse Event 
Report within 5 working days of the 
researcher becoming aware of the event. 
External Adverse Event 
Report within 10 working days of the 
researcher becoming aware of the event. 
Any permanent or 
temporary hold on some 
or all research activities. 
Report within 10 working days of the 
researcher becoming aware of the event. 
 
8.4.2 
Serious Adverse Event Reporting 
 
All SAEs (including death, irrespective of cause) must be reported to the OHSU Coordinating 
Center as soon as possible and no later than 24 hours after learning of the event. The trial site 
will be provided with contact details for these personnel before any trial related procedure is 
performed. The investigator must submit a safety reporting form, which includes a description of 

 
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the event, therapy instituted, and trial procedures. The following information must be 
communicated with the first notification of a SAE: 1) Trial identifier; 2) Subject identifier; 3) Subject 
date of birth or age; 4) Subject sex; 5) SAE (verbatim term); 6) SAE onset; 7) Brief description of 
event, course, and countermeasures taken; 8) Relatedness; 9) Intensity; 10) Seriousness; 11) 
Outcome; and 12) Relevant history/pre-existing medical conditions.  
 
All additional information concerning the SAE until trial termination or definite outcome should be 
communicated per follow-up report without delay. The immediate and follow-up reports must only 
identify the subjects using the unique subject identifier. The investigator is obligated to comply 
with applicable regulatory requirement(s) related to the reporting of SAE to the regulatory 
authorities and the relevant IRB. 
8.5 
Stopping Rules 
 
If SAEs occur that are not tolerable, the investigator will decide for that subject whether to stop 
the trial and/or treatment of the subject. This study may be prematurely terminated, if after review 
by the DSMB, there is sufficient reasonable cause. Written notification documenting the reason 
for study termination will be provided to the investigators and the OHSU Coordinating Center.  
Circumstances that may warrant termination include, but are not limited to: 1) Determination of 
unexpected, significant, or unacceptable risk to patients; 2) Inadequate enrollment with failure to 
enter patients at an acceptable rate; 3) Insufficient adherence to protocol requirements; and 4) 
Insufficient complete and/or evaluable data. This study may be discontinued at any time by the 
DSMB’s and or responsible IRB’s recommendation. 
 
 

 
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9 
STUDY OVERSIGHT 
9.1 
Quality System 
 
The OHSU Coordinating Center is responsible for implementing and maintaining quality 
assurance and quality control systems with a written manual of operating procedures and 
standard operating procedures.  
9.2 
Promoting and Monitoring Adherence to the Research Protocol 
 
Adherence to protocol is important since it is impossible to blind caregivers to the study regimens. 
The research coordinator will monitor compliance to the study protocol by auditing instructions 
given to comply with the study protocol. We will conduct 100% audits of the protocol instructions 
in the first 5 patients per site, and with random checks subsequently, to monitor protocol 
compliance. All study personnel will undergo extensive training in the conduct of the protocol, the 
measurement of vascular pressure, and the neurological exam for ASIA scoring.  
 
An academic detailing process will be used to educate practitioners about the use of guidelines 
and the procedures to correctly implement the study protocol, the importance of the clinical goals 
and the achievement of the established targets, and the importance of the study in improving the 
knowledge of the short and long term effects of blood pressure management. Maintenance of 
nurses and physicians adherence to the study protocol will be enhanced by quarterly meetings 
with sites PIs (phone calls) to facilitate discussion and stress the importance of compliance. The 
meetings will also provide an opportunity to discuss deviation from protocol in specific instances. 
 
Additional strategies include minimizing the complexity of the treatment regimen, maximizing the 
therapeutic relationship between study staff, clinical staff and subjects (e.g., frequent friendly 
contacts such as telephone calls, newsletters, post cards, birthday cards and limiting the number 
of staff who work directly with subjects), providing sufficient information/education, ensuring 
important communication with subjects is simple, direct and repeated, making it convenient for 
subjects to participate, and involving family or other social supports in the process.  
9.3 
Monitoring of Study Conduct 
 
The study will be monitored in accordance with current GCPs. The Clinical Research Associates 
at the Coordinating Center will be in contact with the participating sites to ensure that the study is 
being conducted in accordance with the protocol and that AE data is entered in a timely fashion. 
Audits of compliance with protocol instructions will be carried out intensively especially at the 
beginning of the trial to ensure complete understanding of such instructions. AE data entered on 
the CRFs will be reviewed by the Research Monitor as indicated above. The DSMB will be notified 
of any serious events, deaths, unexpected events or potential trends in accordance with the data 
safety plan. The site investigators will grant permission to the OHSU Coordinating Center or 
authorized designee, and appropriate regulatory authorities to conduct on-site monitoring of all 

 
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appropriate study documentation. When necessary, the monitoring visits will be conducted in poor 
performing sites due to poor enrollment, incomplete data entry, or any other potential problem 
with study conduct, to promote collection of high data quality and preserve the integrity of the 
study, and also further ensure patient safety in the event that unreported events or other 
unintentional study misconduct is occurring. Protocols exceptions and violations will be 
scrutinized on a case-by-case basis, and exceptions granted if appropriate. Queries and data 
clarifications requests will be also generated by the data and biostatistical group to assist in 
monitoring the conduct of the study and ensure high data quality. 
9.4 
Study Monitoring and Site Visits 
 
Trial site monitoring will be performed by OHSU personnel on an as-needed basis depending on 
the progress of the trial. The authorized delegates, applicable SOPs, the frequency of monitoring 
visits, and the reporting modus, will be defined in writing as required by sponsor SOPs. Monitored 
sites will be informed about visit outcomes using a follow-up letter.  
 
Monitoring and auditing procedures developed by OHSU Coordinating Center or its designee will 
be followed, in order to comply with GCP/ICH guidelines. When needed, on-site checking of the 
database for completeness, clarity, and consistency as compared with source documents and 
clarification of administrative matters will be performed. Monitoring will be done by personal visits 
from a representative of OHSU Coordinating Center (site monitor) who will review the source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent communications (letter, telephone, fax, etc.). 
 
The site investigators will grant permission to the OHSU PI or authorized designee, and 
appropriate regulatory authorities to conduct on-site monitoring of all appropriate study 
documentation. Each site will have an initiation visit and will be monitored yearly if more than 10 
patients have been enrolled in the study. A close out study visit will be carried out when all the 
patients have completed the study. Protocols exceptions and violations will be scrutinized on a 
case-by-case basis, and exceptions granted if appropriate. Queries and data clarifications 
requests will be also generated by the data and biostatistical group to assist in monitoring the 
conduct of the study and ensure high data quality. Corrections, amendments, or clarifying 
statements resulting from the monitoring visit will be made by the investigator where necessary. 
9.5 
Adverse Event Monitoring 
 
The Research Monitor will remain blinded to treatment assignment and will review listings of AEs 
regularly throughout the trial to assess for trends or unexpected events. If potential trends or 
unexpected events are noted, a summary will be provided to the DSMB for further review and 
evaluation. In the case of a SAE (as defined in 21 CFR 312.32) the investigators will notify the 
DSMB chair in a timely manner according to the agreed schedule. A complete report documenting 
the AE and including a description of the event, signs and symptoms, severity, any interventions 
initiated, the duration and the outcome, as well as the probable cause will be generated. The 

 
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study PIs will provide a written notification of reportable events to the funding agency in 
accordance with federal regulations. All SAEs will be followed until resolution or stabilization. 
9.6 
Research Monitor 
 
The Research Monitor is responsible to oversee the safety of the research and report 
observations/findings to the IRB or a designated institutional official. The Research Monitor will 
review all unanticipated problems involving risks to subjects or others associated with the protocol 
and provide an independent report of the event to the IRB. The Research Monitor may discuss 
the research protocol with the investigators; shall have authority to stop a 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 until the IRB can assess 
the monitor’s report; and shall have the responsibility to promptly report their observations and 
findings to the IRB or other designated official and the HRPO. 
9.7 
Data Safety and Monitoring Board 
 
Safety will be monitored on an ongoing basis throughout the trial by a DSMB appointed by OHSU 
Coordinating Center. The DSMB will include an orthopedic surgeon, an epidemiologist, and a 
biostatistician.  
 
Reports providing a comprehensive overview of enrollment information, safety summaries (AE 
and SAE tabulations), and other pertinent data will be generated for review by the DSMB at 
agreed upon intervals. However, SAEs related to study treatments and any deaths will be reported 
immediately to the DSMB. 
 
The DSMB will not be blinded to interim data, and will evaluate pre-specified safety endpoints in 
all interim analyses. Efficacy data will be reviewed, but no formal efficacy analyses will be 
conducted. The committee will meet before the trial begins to review the study protocol and the 
DSMB charter. The DSMB will meet at intervals via teleconference or in person as pre-specified 
in the DSMB Charter, with the first teleconference taking place about six months after the first 
patient has been enrolled to review the interim safety data to determine if the trial should stop for 
safety. An in-person meeting will occur after 50% of the study participants have completed the 
follow up. A final DSMB meeting will take place 6 months after the last patient completes follow-
up. In addition to scheduled meetings to review interim results, the DSMB will meet as needed to 
review safety concerns raised by investigators.  
 
The DSMB will review safety data, enrollment data, protocol violations, rates of treatment non-
compliance, and overall study progress. Interim safety reports for the DSMB will be generated 
prior to each meeting or as requested by the DSMB. The DSMB can recommend early stopping 
of study or of any of the study arms for concerns of participant safety at any time during the study. 
The DSMB will decide, based on the committee members’ judgment, what constitutes a significant 

 
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safety concern that would potentially lead to stopping the trial early. There are no priori stopping 
rules for efficacy.  
9.8 
Steering Committee 
 
A Steering Committee will have oversight on site performance. There will be an initial planning 
meeting and the members will meet regularly after the DSMB meeting. To maintain site 
enthusiasm and momentum with patient enrollment, a quarterly study update newsletter will also 
be distributed. There will be several attempts to remediate poor performing sites in terms of 
enrollment rates or study conduct, including on-site monitoring visits. If these issues cannot be 
corrected or if there are patient safety issues, further enrollment at that site will be terminated and 
the site replaced with one of the back-up sites.   
9.9 
Audits 
 
Audits as defined by GCP will be performed for this trial. Regulatory authorities, the IRB, and/or 
the quality assurance group of OHSU Coordinating Center or its designee may request access to 
all source documents, printouts of the CRFs, and other study documentation for on-site audit or 
inspection. Direct access to these documents must be guaranteed by the investigator, who must 
provide support at all times for these activities. The investigator will permit the OHSU Coordinating 
Center personnel or authorized delegates to audit the trial facilities and documentation at agreed 
times.  
9.10 
Inspections 
 
The investigator and/or personnel at other establishments are obliged to cooperate with any 
inspection of the documents, facilities, records, and other resources deemed appropriate by the 
inspecting authorities to be related to the trial and that may be located at the trial site, OHSU 
Coordinating Center or at other establishments. The investigator or personnel at other 
establishments should notify the OHSU Coordinating Center as soon as possible about any 
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10 STATISTICAL CONSIDERATIONS 
10.1 
Assessment of Study Variables 
10.1.1 
Primary Endpoint 
 
The study primary endpoint is the average change in the motor and sensory ASIA Impairment 
Scale (AIS) scores at six months from baseline. The AIS score will be determined in accordance 
to the recommendation issued by the International Standards for Neurological Classification of 
SCI. The structured evaluation includes five steps for the determination of the sensory and motor 
level, the neurological level of injury and the completeness of the injury. Each step is described 
in detail below: 
 
Step 1 determines the sensory level as the most caudal intact dermatome on the right and left 
sides. The best score with normal pin prick (PP) sensation will be considered the sensory level. 
The sensory sub-score will be used as primary sensory endpoint, defined as the sum the PP 
score on the right and left side. The maximum sensory score for both right and left sides is 112.  
 
Step 2 determines the motor level as the most caudal key muscle group that has a strength grade 
of at least 3. For regions where there is no testable myotome, the motor level is presumed to be 
at the same level as the sensory one. The motor sub-score will be used as primary motor 
endpoint, defined as the sum the upper and lower extremities scores on the right and left side. 
The maximum score for both right and left sides is 100, however, due to our inclusion criteria, the 
maximum motor score at baseline will be 50.  
 
Step 3 determines the neurological level of injury which is defined as the most caudal segment of 
the cord with intact sensation and antigravity muscle strength (at least strength of 3), e.g. the most 
cephalad of the sensory and motor levels determined in Step 1 and 2. Zone of partial preservation 
will also be noted. 
 
Step 4 determines AIS Grade. For this study, only AIS grades A and B will be considered, though 
patients could progress and improve to grades C or higher. To determine whether the injury is 
complete (Grade A) a patient needs to have lost voluntary anal sphincter contraction and all S4-
5 sensory scores and deep anal pressure. Grade B is defined as, “sensory but not motor function 
preserved below the neurological level and includes the sacral segments S4-5 (light touch or PP 
at S4-5 or deep anal pressure) AND no motor function is preserved more than three levels below 
the motor level on either side of the body.”  
 
10.1.2 
Secondary Endpoints for Efficacy 
 
In addition to the neurological exam, secondary endpoints will include measures of functional 
status and quality of life. The endpoints selected emphasize the ability to detect clinically 

 
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meaningful differences between study groups and to facilitate comparison of these study results 
to published studies from around the world. The following measured secondary endpoints will be 
assessed: 
 
The International Spinal Cord Injury Basic Pain Data Set (ISCIBPDS) is a self-reported instrument 
that has been found to have high internal consistency and validity for 23 of the 27 pain interference 
items and scales. According to the guidelines for clinical assessment following acute cervical SCI, 
the ISCIBPDS is recommended as level I evidence as the preferred means to assess pain and 
its severity, physical and emotional functioning in SCI patients.  
 
The Spinal Cord Independence Measure (SCIM III) is a disability scale developed specifically for 
patients with SCI that measures basic functional independence and accounts for functional 
impairments associated with tetraplegia or quadriplegia. The SCIM III is comprised of 19 items in 
three sub-scales including: 1) Self-care (6 items, sub-score 0-20); 2) Respiration and sphincter 
management (4 items, sub-score 0-40); and 3) Mobility (9 items, 0-40), which is subdivided into 
“room and toilet” and “indoors and outdoors”. The items are weighted in terms of their clinical 
relevance and the total score ranges from 0 to 100. To ensure consistency, the SCIM III will be 
scored by the study personnel via observation and interview.  
 
The International Spinal Cord Injury Quality of Life Basic Data Set (ISCIQOL) is a brief 3-item 
instrument that assesses the general quality of life, and physical and psychological health 
satisfaction with life. The variables are rated on a scale ranging from 0 (completely dissatisfied) 
to 10 (completely satisfied). This instrument was developed by a committee of experts for the 
inclusion in the International Spinal Cord Injury Basic Data Set. 
 
Data will also be collected on the following instruments: 
 
 
Activities and Participation 
 
Cardiovascular Function 
 
Pulmonary Function 
 
The primary and secondary endpoints will be measured during the hospitalization and at the 6-
month follow up, as appropriate.  
 
10.1.3 
Secondary Endpoints for Safety 
 
Participants will be monitored for complications throughout the trial. Safety data will be collected 
during the study period to determine the safety profile of TPM. Safety will be addressed by 
assessing AEs, blood pressure, HR, and urine output. Routine clinical safety laboratory testing 
includes blood chemistry and hematology values that contribute to the computation of the organ 
dysfunction score, as described below. The following complications will be prospectively 
measured and evaluated. 

 
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Respiratory complications: Measured by a composite score of acute respiratory distress 
syndrome, hypoxemia as indicated by PaO2/FiO2 ratio, pulmonary edema requiring diuretics, and 
pneumonia;  
 
Occurrence of myocardial ischemia or infarction: Measured by troponin levels; 
 
Maximum organ dysfunction: Measured by the sequential multiple organ failure score (SOFA) in 
the first seven days or until ICU discharge after injury. The SOFA score is made of six variables, 
each representing an organ system. Each organ system is assigned a point value from 0 (normal) 
to 4 (high degree of dysfunction/failure), with a range from 0 to 24. Components of the SOFA 
score include PaO2/FiO2 ratio, Glasgow Coma Scale, MAP or administration of vasopressors, 
bilirubin, platelets, and creatinine. All components of the SOFA score will be collected daily for 
seven days or until ICU discharge, by selecting the worst physiological value. The worst 
measurement is defined as the measure that yields the highest number of points. When 
components (laboratory values) are not measured, they will be considered missing (9 points 
assigned); 
 
1Respiratory support is defined as any form of invasive or noninvasive ventilation including mask CPAP or CPAP delivered through a 
tracheostomy/tracheotomy or endotracheal tube.     
  
2Or any dose of phenylephrine, vasopressin or metaraminol. 
 
Duration of mechanical ventilation and hospital stay, and discharge disposition: Defined as any 
form of invasive or noninvasive ventilation including mask CPAP or CPAP delivered through a 
tracheostomy/tracheotomy or endotracheal tube. 
Organ System 
0 
1 
2 
3 
4 
9 
Respiratory 
PaO2 / FiO2 
(mmHg) 
>400 
301-400 
201-300 (with or w/o 
respiratory support1) 
<201 (w/o respiratory 
support1) 
101-200  
(with respiratory 
support1) 
≤100  
(with respiratory 
support1) 
Not 
measured 
Hematologic 
Coagulation 
Platelets (x 109/L) 
>150 
101-150 
51-100 
21-50 
<20 
Not 
measured 
Hepatic 
Bilirubin 
mg/dl (or µmol/L) 
<1.2 
<20 
1.2 – 1.9 
20-32 
2.0-5.9 
33-101 
6.0-11.9 
102-204 
>12.0 
>204 
Not 
measured 
 
Cardiovascular 
Hypotension 
 
 
MAP>70 
mmHg 
 
MAP<70 
mmHg 
Dopamine≤5.0 
(µg/kg/min) 
or any dose of: 
Dobutamine, Milrinone, 
Levosimendan 
Dopamine 5.1-15.0 
(µg/kg/min) 
or Epinephrine≤0.1 
or Norepinephrine≤0.12 
Dopamine >15.0 
(µg/kg/min) 
or Epinephrine>0.1 
or Norepinephrine>0.12 
Not 
measured 
Neurologic 
Glasgow Coma 
Score 
15 
13-14 
10-12 
7-9 
<6 
Not 
measured 
Renal 
creatinine 
mg/dl (or µmol/L) 
urine output 
< 1.2 
< 110 
1.2-1.9 
110-170 
2.0-3.4 
171-299 
3.5-4.9 
300-440 
or <500 ml/day 
>5.0 
>440 
or <200 ml/day 
Not 
measured 

 
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10.2 
Sample Size Estimation and Statistical Power 
 
For the study’s primary aim to compare the change in the 6-month ASIA scores (change from 
baseline) between the ABP and the CBP groups, a total of 126 patients will be needed to 
participate in the study to have statistical power of 80 percent to detect a 5-point mean between 
the two treatment groups. We assume a 10 point standard deviation in the ASIA measurements, 
a modest correlation between the baseline and six-month ASIA scores of 0.50, using a 2-sided 
five percent alpha-level test. To account for some data loss to follow-up, the sample size will be 
increased to 152. We chose a 5-point difference in the mean change score between the two 
treatment groups as a conservative effect size because the magnitude is considered a clinically 
meaningful difference in neurological recovery.  Additionally, our calculations assume that the 
correlation between the pre-randomization ASIA scores and the 6-month ASIA scores is only 
modest (r >0.50). For higher levels of correlation between the two scores, the statistical power 
well exceeds 80 percent. See Figure below. 
 
Figure: Minimum effect sizes (ES) changes in ASIA scores between the treatment groups. These 
estimates assume a statistical power of 80 percent, sample sizes of n=63 per treatment group 
and a 2-sided, five percent alpha-level test.  The correlations (horizontal axis) indicate the degree 
of correlation between the baseline and 6-month ASIA scores. 
 
 
 
 

 
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10.3 
Statistical Analysis Plan 
 
An intent-to-treat analysis will be performed. The primary outcome is the mean six-month ASIA 
motor function test score, comparing the ABP group to the CBP group. The primary analysis 
method will be linear regression. We will use robust (sandwich) standard error estimates in for 
test statistics and confidence intervals to remedy the possible minor violations of modeling 
assumptions (e.g., variance heterogeneity) in the six-month ASIA scores. The statistical model 
used for this analysis will be: 
 
E[Y1 | X, Y0] = 0 + 1X + 0Y0  
 
Where E[Y1]  is the mean six-month ASIA score, X an indicator of the treatment assignment (1 = 
ABP, 0 = CBP), Y0 is the pre-randomization (baseline) ASIA score, and (0, 1, 2) are the model 
parameters that are to be estimated from the patient data. This regression model is often referred 
to as an analysis of covariance (ANCOVA) model because we control for between patient 
variance in the baseline ASIA scores by including the baseline ASIA scores as a concomitant 
variable, in our treatment comparisons of the mean six-month ASIA scores. The estimates model 
parameter for the treatment assignment, 1, can be represented as 
 
1 = E[Y1 | X = 1, Y0] – E[Y1 | X = 0, Y0], 
 
is interpreted as the difference in the mean six-month ASIA motor function test score for the ABP 
and CBP treatment groups, given that the patients being compared have the same baseline ASIA 
scores. In randomized trials 1 is often interpreted as the mean change (from baseline) because 
the average baseline ASIA scores should be approximately equal in the two treatment groups. 
We chose to model the effect of treatment using analysis of covariance instead of comparing the 
intra-patient differences between the groups because the ANCOVA model yields a more precise 
test. The Figure above illustrates that the variance from the ANCOVA model us uniformly lower 
than the CHANGE model for varying levels of correlation between the baseline and 6-month ASIA 
scores.  
 
For the analysis of quantitative secondary endpoints (i.e., SCIM III, ISCIBPDS, ISCIQOL, hospital 
length of stay, etc.) where the desired statistical summary is the comparison of mean changes 
between the treatment groups, we will employ the same linear regression strategy as the primary 
endpoint above. For binary (e.g., occurrence of myocardial ischemia or infarction) we will analyze 
the data using a logistic regression model 
 
log[odds(X)] = 0 + 1X 
 
where the odds(X) = (X) /[1‐(X)] and (X) is the probability of a given event.  Here, the model 
parameter for the treatment assignment, 1 = log[odds(ABP)/ odds(CBP)] and exp(1) is the odds 
ratio (OR) comparing the odds of the event for the ABP group to the CBP group. 

 
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Finally, we will descriptively present baseline characteristics (e.g., age, gender, etc.) and safety 
endpoints (e.g., respiratory complications, SOFA scores, duration of mechanical ventilation, 
discharge disposition, etc.) in tabular format using means (SD) for quantitative characteristics and 
frequencies (with percentages) for categorical characteristics, in aggregate and stratified by 
treatment group. 
 
 
  
 

 
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11 DATA HANDLING AND RECORD KEEPING 
11.1 
Data Management Responsibilities 
 
This study will use a combination of paper-based and electronic data capture. All study personnel 
doing data collection will be carefully trained in the task. The Manual of Operations/Data 
Dictionary will contain detailed instructions for each variable.  The study nurses/coordinators and 
outcome examiners will have separate but parallel systems for ensuring that data are collected 
consistently and accurately. 
 
The main study database will be maintained on a secure server cloud with established provisions 
delineated in the information system security plan. The data security plan prepared by the within 
the Data Management Unit (DMU) addresses confidentiality, security measures, back-ups, and 
other aspects of the operational status. Data encryption and authentication methods will be used. 
Data will be entered at the individual sites and uploaded on a regular basis. Data from the central 
reader will also be uploaded regularly. Data collection screens/forms will be designed so that 
questions are unambiguous and require a response.  The use of text fields will be minimized. 
Language will be kept as simple as possible, using standard terminology.   
11.2 
Source Data 
Source data is defined by GCP as “all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction or evaluation of the trial. Source data are contained in source documents (original 
records or certified copies). Source data comprise clinical documentation, data, and records that 
describe or track the methods, conduct, or results of the trial, the factors affecting the trial, and 
the actions taken. All source data arising from the trial will be kept by the investigator, who must 
provide direct access for trial-related monitoring, audits, ethics committee review, and regulatory 
inspection. The nature and location of all source data will be identified and documented by the 
investigator to ensure that all sources of original data required to complete CRFs are known to 
the OHSU Coordinating Center and/or trial site personnel and are accessible for verification 
during trial-related monitoring, audits, relevant IRB review, and inspections. 
11.3 
Case Report Forms 
This trial will utilize a combination of paper-based case report forms and electronic case report 
forms (eCRFs) with data capture, coding, and cleaning provided by the DMU. CRFs for each 
subject will be provided to the investigator by the coordinating center in paper and electronic 
format to document trial data. The investigator and personnel to whom this task is delegated will 
use the CRFs to record information required by the protocol. The investigator will verify and 
confirm by signature that the CRFs have been checked and are complete, accurate, and 
compatible with source documents. All CRF entries, corrections, and alterations will be made by 
the investigator or other authorized personnel under their supervision. Entries will be checked 
against appropriate source documents by the OHSU Coordinating Center. 

 
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11.4 
Identifiers 
Consenting participants will be assigned a unique study ID.  This ID will be constructed from the 
site number (10, 11, 12, 13, 14, 15) and a unique randomization number for each site participant 
(001, 002, 003…). 
The OHSU Coordinating Center will provide each clinical site with a list of valid study IDs.  Clinical 
sites will maintain the only link between the participant ID and the actual participant identity.  
Unless local regulation stipulates otherwise, this link will be maintained on paper filed in locked 
cabinets at the clinical site (Participant ID Log).  The security of this documentation will be verified 
at on-site monitoring visits. 
11.5 
Confidentiality 
 
The DMU security policy provides data confidentiality and maintains data integrity while providing 
appropriate access.  In addition, we have built extensive redundancy into our systems. The DMU 
provides access control and authentication in four domains: 1) physical security, 2) network 
access, 3) database access, and 4) data transmission.  All data are collected on paper forms and 
entered into the password-protected database at each site. Only trained study personnel are 
allowed access to the database and the identity of the person entering or editing the data is 
tracked. Local databases are stored on password-protected computers that are backed up nightly.  
The databases are encrypted and uploaded weekly to the DMU.  The DMU incorporates the new 
or modified data into the study master database. The DMU is located in a secure building in a 
room that is locked when it is unoccupied. Access to the computer, computer system, network 
drive and database are all password-controlled. The master database is kept on a secure server 
under conditions identical to that used for the hospital electronic medical records. This includes 
access by key-card and regularly scheduled backup.  
Except for dates, study data will contain no personally identifying information (e.g., name, social 
security number, address, telephone numbers, email address, etc.).  Identifiable data (associated 
with a study assigned ID) will be retained only on participants who have signed informed consent.  
The consent will contain a statement on confidentiality explaining how the data will be 
safeguarded and who will or might have access to the data, including representatives from the 
Department of Defense as required by the Program Announcement. 
Clinical sites will be required to maintain study files on each consenting participant in order to 
provide source documentation for the data collected.  These files will be secured according to 
local requirements for medical records since they will contain personally identifying information.  
Where the clinical site has completely migrated to an electronic medical records (EMR) system, 
the study staff at the site will need to give EMR access to study monitors or provide printed copies 
of relevant source documentation for onsite monitoring visits.  Printed copies of relevant source 
documentation will be destroyed following the monitoring visit per local regulation for medical 
records. 

 
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All data will be entered electronically at the clinical site by trained, authorized study staff using the 
web based system. Access to the eCRF system requires knowledge of an individually assigned 
userID and password.  Passwords are required to meet certain strength levels and to be changed 
every 90 days.  All activity (entering, updating data and responding to queries) is logged 
electronically with the userID of the person entering or making the change to the data.  eClinical 
OS uses a group security model.  Clinical site study staff will be able to add patients, enter, review 
and modify data and respond to data queries regarding participants enrolled at their site.   
Study coordinating center staff who have a need to review study data online will have read-only 
access to the eCRF system.  Study data coordinators and monitors will have read-only access to 
the study data and will be able to post, review and close queries. Statisticians will have the 
capability to download study data and randomization data for analysis.  Each staff member will 
be trained on the use of the system and will be assigned an individual userID.   
11.6 
Data Entry Completion 
 
OHSU Coordinating Center or its designee will instruct the study center regarding data capture 
procedures on electronic and/or paper CRFs. It is the investigator’s responsibility to ensure the 
accuracy, completeness, and timeliness of the data reported for each patient. Source 
documentation supporting the data should indicate the patient’s participation in the study and 
should document the dates and details of study procedures, AEs, and patient status. The 
investigator, or designated representative, should complete data entry as soon as possible after 
information is collected, preferably on the same day that a study patient is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be completed 
immediately after the final examination. An explanation should be given for all missing data. The 
investigator must sign and date the Investigator’s Statement that will be supplied to endorse the 
recorded data. 
11.7 
Study Records Retention 
The investigator is responsible for the filing of all essential documents in an investigator’s site file 
and the OHSU Coordinating Center is responsible for the timely filing of all essential documents 
in the trial master file. As applicable, these files must be available at monitoring visits and during 
audits or regulatory inspections. After trial completion, the investigator will ensure that all source 
data/documentation related to the trial is recorded, handled, and stored in a way that allows its 
accurate reporting, interpretation, and verification. The investigator will take measures to prevent 
accidental or premature destruction of these documents. The investigator will keep the 
investigator’s site file, the source data/documentation related to the trial according to the 
prescribed record retention period according to the hospital policy, or at least until informed by 
the OHSU Coordinating Center that the trial-related records are no longer required. 

 
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11.8 
Data and Resources Sharing Plan 
Because a significant amount of the support for this study is being possibly provided by the 
Department of Defense (DoD), the DoD will have access to both the identified and the de-
identified data. It is the intent of the investigators to share a copy of the final study database to 
the funding Institution. Primary interest in these data will be from the trauma, orthopedics, 
neurosurgery, and critical care community. Further, the Department of Defense has the 
infrastructure to ensure that the data will be used only for legitimate purposes. The trial database 
will be de-identified in accordance with HIPAA privacy requirements and will be delivered no 
sooner than publication of the primary results paper from this clinical trial. Details of the data 
sharing plans will be discussed with the program official and verified for compliance with 
institutional policies, IRB rules as well as local, state and Federal regulations. 
11.9 
Data Quality Assurance 
The accuracy and reliability of the trial data will be assured by the performance of a combination 
of trial site visits, training, monitoring visits, data cleaning, and audits. 

 
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12 PUBLICATION/DATA SHARING POLICY 
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal. A Publications and Presentation 
Committee, comprised of investigators participating in the study and representatives of the 
steering committee, as appropriate, will be formed to oversee the publication of the study results, 
which will reflect the experience of all participating study centers. Subsequently, individual 
investigators may publish results from the study in compliance with their agreement with OHSU 
Coordinating Center. A pre-publication manuscript is to be provided to the funding agency when 
accepted by the publisher.  
 
 

 
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13 LITERATURE REFERENCES 
1. 
Ryken TC, Hurlbert RJ, Hadley MN, et al. The acute cardiopulmonary management of 
patients with cervical spinal cord injuries. Neurosurgery. 2013;72 Suppl 2:84-92. 
2. 
Hurlbert RJ, Hadley MN, Walters BC, et al. Pharmacological therapy for acute spinal cord 
injury. Neurosurgery. 2013;72 Suppl 2:93-105. 
3. 
Levi L, Wolf A, Belzberg H. Hemodynamic parameters in patients with acute cervical cord 
trauma: 
description, 
intervention, 
and 
prediction 
of 
outcome. 
Neurosurgery. 
1993;33(6):1007-1016; discussion 1016-1007. 
4. 
Vale FL, Burns J, Jackson AB, Hadley MN. Combined medical and surgical treatment after 
acute spinal cord injury: results of a prospective pilot study to assess the merits of 
aggressive medical resuscitation and blood pressure management. J Neurosurg. 
1997;87(2):239-246. 
5. 
Communal C, Singh K, Pimentel DR, Colucci WS. Norepinephrine stimulates apoptosis in 
adult rat ventricular myocytes by activation of the beta-adrenergic pathway. Circulation. 
1998;98(13):1329-1334. 
6. 
Schoenfeld AJ, Laughlin MD, McCriskin BJ, Bader JO, Waterman BR, Belmont PJ, Jr. 
Spinal injuries in United States military personnel deployed to Iraq and Afghanistan: an 
epidemiological investigation involving 7877 combat casualties from 2005 to 2009. Spine 
(Phila Pa 1976). 2013;38(20):1770-1778. 
 
 

 
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APPENDIX A: SCHEDULE OF EVENTS 
Visit Description 
Pre-
randomizat
ion 
          Treatment Phase                                
Discharge 
Follow-Up 
Study Visits/ Study Days  
(or weeks) 
ICU Day 0 
ICU 
Day 1a 
ICU 
Day 2 
ICU 
Day 3 
ICU 
Day 4 
ICU 
Day 5 
ICU 
Day 6 
ICU 
Day 7 
Hospital 
Discharge 
6 Month f/u 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verbal Consent and Continued 
Participation Form 
(if applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Injuries and Past 
Medical History 
Xb 
 
 
 
 
 
 
 
 
 
Injury Assessment 
(date/time of symptom onset;  
mechanism of injury) 
X 
 
 
 
 
 
 
 
 
 
Injury Severity Score 
X 
 
 
 
 
 
 
 
 
 
ASIA Assessment 
X 
 
 
Xc 
 
 
 
 
 
X 
Spine Imaging Data 
X 
 
 
 
 
 
 
 
 
 
Spine Procedure Data 
X 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
Targeted blood Pressure 
Management 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
BP Non-Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

 
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ICU: Intensive Care Unit; SCI: Spinal Cord Injury; ASIA: American Spinal Injury Association; SOFA: Sequential Organ Failure Assessment. 
a – ICU Day 1 begins at 0700 the day following randomization. 
b – Medical history relevant to the trial and specific to hypertension will be documented. 
c – ASIA assessment will be collected between 72 hours after injury and prior to ICU discharge. 
d – Vitals and fluid intake/output will be collected every 4 hours while the patient is in the ICU. 
 
 
 
 
Vital Signs 
X 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xd 
 
 
Mechanical Ventilation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluid Intake/Output 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
SOFA Assessment 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Vasopressor Log 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant Medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Discharge Disposition 
 
 
 
 
 
 
 
 
X 
 
SCI Basic Pain Dataset 
 
 
 
 
 
 
 
 
 
X 
SCI Independence Measure 
 
 
 
 
 
 
 
 
 
X 
Quality of Life 
 
 
 
 
 
 
 
 
 
X 
Hemodynamic Status 
 
 
 
 
 
 
 
 
 
X 
Serious Adverse Event 
Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
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APPENDIX B: INTERVENTION ALGORITHMS 
ALGORITHM — Conventional blood pressure (CBP) 
 
CONVENTIONAL BLOOD PRESSURE MANAGEMENT 
Actual MAP <65 
Norepinephrine or 
phenylephrine drip 
or other vasopressor 
Actual MAP 65‐70 
Continue Current Care 
>>  Measure and record MAP every 4 hours 
>>  On algorithm, select corresponding patient MAP interval 
>>  Follow instruction in corresponding colored cell 
 

 
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TEMPLE 
Trial of Early Management of Pressure Following Acute Spinal Cord Injury 
 
 
Date:  ___/___/___ 
Time: ___:___ 
 
 
  
Document Non-Invasive Blood Pressure in the medical record every 4 hours  
 
 
 
 
Maintain MAP 65-70 mm Hg  
 
 
 
 
 
 
 
 
If MAP <65 mm Hg 
 
 
  
Start phenylephrine infusion at 0.5 mcg/kg/min or _____________ mcg/kg/min and 
adjust rate by 0.1 mcg/kg/min or ___________ mcg/kg/min at 5 minute intervals, as 
needed. 
 
  
Start norepinephrine infusion at 0.02 mcg/kg/min or ___________ mcg/kg/min and 
double rate and adjust rate by 0.1 mcg/kg/min or ___________ mcg/kg/min at 5 minute 
intervals, as needed. 
 
  
Start vasopressin infusion at 0.4 IU/min, range 0.1-0.4 IU/min 
 
 
 
 
 
 
 
 
_____________________ 
 
 
 
_______________________ 
MD  
 
 
 
 
 
 
VORV 
 
 
Research Coordinator: [Name]:   Pager xxx-xxxx; 
 
Principal Investigator: 
[Name]:   Pager xxx-xxxx 
Patient Name/ID 
CBP 

 
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ALGORITHM — Augmented blood pressure (ABP) 
 
AUGMENTED BLOOD PRESSURE MANAGEMENT 
Actual MAP <85 
Norepinephrine or 
phenylephrine drip 
or other vasopressor 
Actual MAP 85‐90 
Continue Current Care 
>>  Measure and record MAP every 4 hours 
>>  On algorithm, select corresponding patient MAP interval 
>>  Follow instruction in corresponding colored cell  
 
 
 

 
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TEMPLE Study 
Trial of Early Management of Pressure Following Spinal Cord Injury 
 
 
 
Date:  ___/___/___ 
Time: ___:___ 
 
 
 
  
Document Non-Invasive Blood Pressure in the medical record every 4 hours  
 
 
 
 
 
Maintain MAP 85-90 mm Hg  
 
 
 
 
 
 
 
If MAP <85 mm Hg, 
 
 
  
Start phenylephrine infusion at 0.5 mcg/kg/min or _____________ mcg/kg/min and 
adjust rate by 0.1 mcg/kg/min or ___________ mcg/kg/min at 5 minute intervals, as 
needed. 
 
  
Start norepinephrine infusion at 0.02 mcg/kg/min or ___________ mcg/kg/min and 
double rate and adjust rate by 0.1 mcg/kg/min or ___________ mcg/kg/min at 5 minute 
intervals, as needed. 
 
  
Start vasopressin infusion at 0.4 IU/min, range 0.1-0.4 IU/min 
 
 
 
______________________  
 
 
_______________________ 
MD  
 
 
 
 
 
 
VORV 
 
 
 
Research Coordinator: [Name]:   Pager xxx-xxxx; 
 
Principal Investigator: 
[Name]:   Pager xxx-xxxx 
 
Patient Name/ID 
ABP