Clinical trial NCT01143064
Conditions: Brain Injuries
Keywords: Brain Injury Trauma
Sponsor: BHR Pharma, LLC
Start date: 2010-06-01; Completion date: 2014-03-01
Enrollment: 1195 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The SyNAPSe trial will study if giving intravenous (i.v.) progesterone within 8 hours of the injury for a total of 120 hours to severe traumatic brain injury patients improves their recovery.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Progesterone intervention 2: Lipid emulsion without progesterone
Intervention descriptions: intervention 1: Intravenous administration of 0.71mg/kg/hr for 1hr followed by 0.5mg/kg/hr administered intravenously for an additional 119 hrs. intervention 2: Intravenous administration equal to 0.71mg/kg/hr for 1hr followed by 0.5mg/kg/hr administered intravenously for an additional 119 hrs.

Protocol documents:
Prot_000.pdf: 


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PROTOCOL REVIEW AND SIGNATURE FORM
Protocol Title:
A Randomized, Double-Blind, Placebo-Controlled
Phase 3 Study to Investigate the Efficacy and Safety of
Progesterone in Patients with Severe Traumatic Brain
Injury
Protocol Number:
BHR-100-301
BHR Pharma, LLC has reviewed the content and format of this protocol and approves Protocol
No. BHR-100-301 for issuance.
BHR Pharma, LLC Representative
Name (print)
Signature
Date
I agree to conduct the study as detailed herein and in compliance with ICH Guidelines for Good
Clinical Practice and other applicable regulatory requirements, and to inform all who assist me in
the conduct of this study of their responsibilities and obligations.
Principal Investigator
Name (print)
Signature
Date




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The subjects will be managed in accordance with the standard guidelines
for the management of severe TBI: BTF, ABIC, and EBIC (BTF, 2007;
ABIC, 2003; Maas et al., 1997, respectively).
An independent DSMB will be appointed to have responsibility for
safeguarding the interests of trial subjects, and assessing the safety and
efficacy of the study treatments during the trial.
Treatment allocation will be done using a centralized randomization
system.
Number of
Subjects
The planned total number of subjects will be 1180, randomized equally to
BHR-100 or placebo.
Diagnosis and
Main Criteria for
Inclusion
1. Male or female patients, age between 16 and 70 years, inclusive (or
other age limits as required by local regulations)
2. Weight from 45 to 135 kg, inclusive
3. Sustained a closed head trauma no more than 8 hours before initiation
of study drug infusion (exposed dura mater is acceptable in the case
of depressed skull fractures)
4. TBI diagnosed by history and clinical examination
5. GCS score between 3 and 8, inclusive
6. At least one reactive pupil (pinpoint pupils due to opioid pain
treatment are considered reactive)
7. Evidence of TBI confirmed by abnormalities consistent with trauma
on CT scan upon admission (Diffuse injury II-IV, evacuated and non-
evacuated mass lesion, Marshall’s CT Classification)
8. Indication for ICP monitoring
Exclusion Criteria
1. Life expectancy of less than 24 hours as determined by the
Investigator
2. Prolonged and/or uncorrectable hypoxia (Pa02< 60 mmHg) or
hypotension (systolic blood pressure < 90 mmHg) at the time of
randomization
3. Any spinal cord injury
4. Pregnancy
5. Penetrating head injury
6. Bilaterally fixed dilated pupils at the time of randomization/
7. Coma suspected to be primarily due to other causes (e.g. alcohol)
8. Pure epidural hematoma
9. Preexisting clinically significant disease or chronic condition that can
be ascertained at the time of admission and could affect functional
outcome
10. Severe cardiac or hemodynamic instability prior to randomization
11. Known treatment with another investigational drug, device, medical
therapy or procedure within 30 days of injury




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ventricular drainage
hyperosmolar therapy
blood pressure supportive agents
hyperventilation
barbiturates
surgical decompression for refractory ICP control
Primary Efficacy
Analysis
The primary efficacy variable is GOS evaluated at 6 months post injury.
The proportional odds model (POM) (McCullagh, 1980) will be used to
compare BHR-100 to placebo for the GOS outcome at six months
(categories of good recovery, moderate disability, severe disability, and
the combined vegetative state/death).
A test for the proportional odds
assumption will be conducted and if statistically significant, other
polytomous logistic models will be investigated.
The analyses will be
conducted on an intent-to-treat (ITT) basis, and the POM will be fitted
including the effect of treatment, geographic region (North America,
Europe, Asia, and South America), age, GCS motor score, pupil
response, and CT classification.
If the p-value from the test of the null hypothesis is less than 0.0003 (at
the interim analysis) or 0.0098 (at the final analysis), it will be concluded
that BHR-100 is statistically significantly different from placebo with
respect to the GOS at 6 months following injury.
Sample Size
Justification
A total sample size of 1180 patients is planned; patients will be
randomized in a 1:1 ratio to BHR-100 or placebo.
This sample size
estimate was determined using a proportional odds model (Whitehead,
1993) of the 6-month GOS outcome distribution from the population with
baseline GCS 3-8 in previous TBI Phase 3 trials in the IMPACT
Database (Marmarou et al., 2007). Randomization will be stratified by
major geographical regions of the site locations in order to maintain
overall equivalent treatment group size.
Baseline Data
Analysis
Baseline comparability of the treatment groups for the most important
prognostic factors (age, GCS motor score at baseline, pupillary response
and CT classification) will be illustrated using appropriate descriptive
statistics.
Safety
Monitoring/DSMB
An independent DSMB will review safety and efficacy data from the trial
in a blinded fashion. The data will be provided to the DSMB statistician
at approximately 100-subject intervals, with precise intervals to be
determined in consultation with the DSMB. The DSMB will determine
the type of data and statistical comparisons required for review.


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Interim Analysis
A formal interim analysis on the 6-month GOS will be performed once
the first 200 subjects in each arm (400 total) have been assessed. At the
planned interim analysis, a two-sided test will be conducted to detect
either an increase or decrease in the common odds ratio.
Any consideration to prematurely discontinue the trial will be discussed
by the study statistician with the DSMB and the sponsor. In order to stop
the trial at an interim analysis because of favorable outcome, the
significance level will need to be less than the critical p-value of 0.0003.
Safety Analysis
All AEs and SAEs will be summarized by counts of subjects with AEs
and individual occurrences according to the MedDRA coding.
The following will be summarized both as the observed values and,
where applicable, the changes from baseline of the values:
Vital signs
Safety labs
ECG variables
AE summaries will include abnormal, clinically significant lab results
deemed by the Investigator as AEs.
Counts
and
percentages
of
subjects
with
each
symptom
of
neuroworsening will be described.


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TABLE OF CONTENTS
Page
STUDY SYNOPSIS ................................................................................................................. 3
LIST OF TABLES.................................................................................................................. 10
LIST OF ABBREVIATIONS AND TERMS......................................................................... 10
1.
INTRODUCTION AND RATIONALE.......................................................................... 13
1.1
Background ............................................................................................................................ 13
1.2
Progesterone as a Neuroprotectant: Pre–Clinical Studies ...................................................... 13
1.3
Progesterone as a Neuroprotectant: Clinical Studies in TBI.................................................. 14
1.4
Rationale for Timing of Drug Administration ....................................................................... 15
2.
STUDY OBJECTIVES.................................................................................................... 16
2.1
Primary Objective .................................................................................................................. 16
2.2
Secondary Objectives............................................................................................................. 16
3.
STUDY DESIGN............................................................................................................. 17
3.1
Description of Overall Study Design ..................................................................................... 17
3.2
Study Endpoints ..................................................................................................................... 17
3.2.1
Primary Endpoint............................................................................................................. 17
3.2.2
Secondary Endpoints....................................................................................................... 17
4.
SELECTION OF STUDY POPULATION ..................................................................... 19
4.1
Inclusion Criteria.................................................................................................................... 19
4.2
Exclusion Criteria................................................................................................................... 19
4.3
Withdrawal of Subjects from the Study ................................................................................. 20
4.3.1
Subject Replacement ....................................................................................................... 20
5.
STUDY MEDICATION.................................................................................................. 21
5.1
Blinding and Unblinding........................................................................................................ 21
5.2
Formulation, Packaging, and Labeling................................................................................... 21
5.3
Storage.................................................................................................................................... 21
5.4
Dispensing.............................................................................................................................. 21
5.5
Dosage and Administration.................................................................................................... 22
5.6
Drug Accountability............................................................................................................... 22
5.7
Assessment of Compliance .................................................................................................... 22
5.8
Concomitant Medications ...................................................................................................... 22
5.8.1
Allowed Concomitant Medications/Procedures .............................................................. 22
5.8.2
Concomitant Medications/Therapies to be Avoided ....................................................... 22
6.
STUDY PROCEDURES ................................................................................................. 23
6.1
Screening................................................................................................................................ 23
6.2
Screening and Randomization Process (IWRS)..................................................................... 24
6.3
Study Drug Infusion Period: Days 1-5................................................................................... 24
6.4
Day 6: End-of-Infusion Evaluations....................................................................................... 25
6.5
Day 15: Post-Infusion Evaluations/Discharge ....................................................................... 25
6.6
Day 30 (Month 1) Assessments ............................................................................................. 26
6.7
Day 90 (Month 3) Assessments ............................................................................................. 26
6.8
Day 180 (Month 6) Assessments ........................................................................................... 26
6.9
Progesterone Blood Sample Collection.................................................................................. 26
7.
ASSESSMENTS OF EFFICACY AND SAFETY.......................................................... 27
7.1
Efficacy Parameters................................................................................................................ 27
7.2
Safety Parameters................................................................................................................... 27
7.2.1
Adverse Events and Serious Adverse Events .................................................................. 27
7.2.2
ECG ................................................................................................................................. 27


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7.2.3
Laboratory Safety Tests................................................................................................... 28
7.2.4
Vital Signs ....................................................................................................................... 28
7.2.5
Daily Fluid Balance......................................................................................................... 28
7.2.6
Arterial Blood Gases ....................................................................................................... 28
7.2.7
Neuroworsening............................................................................................................... 28
7.3
Selection of Efficacy Measurements Related To Management of TBI.................................. 28
7.3.1
Glasgow Outcome Scale (GOS)...................................................................................... 28
7.3.2
Glasgow Outcome Scale - Extended (GOS-E)................................................................ 28
7.3.3
Mortality.......................................................................................................................... 29
7.3.4
Intracranial Pressure/Cerebral Perfusion Pressure........................................................... 29
7.3.5
Therapeutic Intensity Level (TIL) ................................................................................... 29
7.3.6
CT Scans.......................................................................................................................... 30
7.3.7
QOL SF-36 ...................................................................................................................... 30
7.3.8
Glasgow Coma Scale....................................................................................................... 30
8.
STATISTICAL PLAN..................................................................................................... 31
8.1
Sample Size Justification ....................................................................................................... 31
8.2
Baseline Data ......................................................................................................................... 31
8.3
Primary Efficacy Analysis ..................................................................................................... 31
8.3.1
Alternate Primary Efficacy Analysis: Sliding Dichotomy Model.................................. 31
8.3.2
Sensitivity Analysis: Dichotomized Model.................................................................... 32
8.3.3
Handling of Missing Primary Efficacy Endpoint Data.................................................... 32
8.4
Secondary Endpoints and Exploratory Endpoints.................................................................. 33
8.4.1
Mortality Assessment at One and Six Months Post-injury.............................................. 33
8.4.2
Secondary Analyses of GOS at Three Months Post-injury ............................................. 33
8.4.3
GOS-E at Three and Six Months Post-injury .................................................................. 33
8.4.4
Quality of Life using SF-36............................................................................................. 34
8.4.5
Exploratory Clinical Parameters: ICP, CPP and TIL ...................................................... 34
8.4.6
Exploratory Parameter: CT Scan.................................................................................... 34
8.5
Adverse Event Safety Data .................................................................................................... 35
8.6
Interim Analysis..................................................................................................................... 35
8.6.2
Futility Analysis .............................................................................................................. 35
9.
ADVERSE EVENT COLLECTION AND REPORTING.............................................. 37
9.1
Adverse Event Collection....................................................................................................... 37
9.2
Reporting of Adverse Events ................................................................................................. 37
9.3
Assessment of Adverse Event Severity.................................................................................. 38
9.4
Serious Adverse Events and Expedited Reporting................................................................. 39
9.5
Notification of Sponsor.......................................................................................................... 40
9.6
Procedures for Reporting Pregnancy Exposure and Birth Events.......................................... 41
10.
REGULATORY AND PROCEDURAL REQUIREMENTS ....................................... 42
10.1
Ethical Conduct of the Study................................................................................................ 42
10.2
Independent Ethics Committee or Institutional Review Board............................................ 42
10.3
Subject Information and Consent......................................................................................... 42
10.4
Data Safety Monitoring Board............................................................................................. 43
10.5
Steering Committee.............................................................................................................. 43
10.6
ABIC (American Brain Injury Consortium) ........................................................................ 44
10.7
Investigator Obligations....................................................................................................... 44
10.8
Electronic Case Report Forms (eCRFs) ............................................................................... 44
10.9
Monitoring the Study ........................................................................................................... 44
10.10
Protocol Deviations............................................................................................................ 44
11.
DATA HANDLING AND RECORDKEEPING .......................................................... 45


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11.1
Disclosure of Data................................................................................................................ 45
11.2
Publication............................................................................................................................ 45
11.3
Record keeping and Retention ............................................................................................. 45
12.
REFERENCES .............................................................................................................. 46
APPENDIX A SCHEDULE OF EVENTS............................................................................. 51
APPENDIX B LABORATORY ASSESSMENTS (Screening, Day 6, Day 15).................. 52
LIST OF TABLES
Page
Table 1 Therapeutic Intensity Level Grading System ............................................................ 29
Table 2 Critical Values and p-Values for Planned Interim Analysis...................................... 35
Table 3 Futility Analysis: Power to Reject Null Hypothesis under Various Scenarios.......... 36
LIST OF ABBREVIATIONS AND TERMS
ABIC
American Brain Injury Consortium
ABG
Arterial Blood Gases
AE
Adverse Event
BTF
Brain Trauma Foundation
CPP
Cerebral Perfusion Pressure
CRF
Case Report Form (paper or other media)
CT
Computed Tomography
DRS
Disability Rating Scale
DSMB
Data Safety Monitoring Board
EBIC
European Brain Injury Consortium
ECG
Electrocardiogram
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GCS
Glasgow Coma Scale
GMP
Good Manufacturing Practice


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GOS
Glasgow Outcome Scale
GOS-E
Glasgow Outcome Scale - Extended
HCO3
Bicarbonate (in ABG)
ICH
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use
ICP
Intracranial Pressure
ICU
Intensive Care Unit
IEC
Independent Ethics Committee
i.m.
intramuscular
IMPACT
International Mission for Prognosis and Analysis of Clinical Trials in TBI
IND
Investigational New Drug
IRB
Institutional Review Board
ITT
Intent-to-treat
i.v.
intravenous
IWRS
Interactive Web Response System
KPS
Karnofsky Performance Scale
LOCF
Last Observation Carried Forward
LAR
Legally Authorized Representative [per U.S. F.D.A. regulations 45 CFR
46.102(c) and 21 CFR 50.3(l)] and
Legally Acceptable Representative [per ICH E6 CPMP/ICH/135/95]
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
PIP
Progressive Intracranial Pathology
PaCO2
Carbon Dioxide (in ABG)
PaO2
Partial Pressure of Oxygen (in ABG)
POM
Proportional Odds Model
ProTECTTM
Progesterone for Acute Traumatic Brain Injury Trial Experimental Clinical
Treatment


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QOL
Quality of Life
SAE
Serious Adverse Event
SaO2
Arterial Oxygen Saturation (in ABG)
SAP
Statistical Analysis Plan
SD
Standard Deviation
SF-36
Short Form (36) Health Survey
TBI
Traumatic Brain Injury
TIL
Therapeutic Intensity Level
TNF
Tumor Necrosis Factor


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1.
INTRODUCTION AND RATIONALE
1.1
Background
Traumatic Brain Injury (TBI) is a leading cause of death and disability worldwide. In Europe, an
overall average TBI incidence rate derived from estimates of hospitalized patients plus deaths is
about 235 per 100,000 (Tagliaferri et al., 2006) and in China, severe TBI accounts for
approximately 20% of brain injuries (Wu et al., 2008). The U.S. Centers for Disease Control and
Prevention (CDC) estimate that more than 1.7 million Americans sustain TBI each year. Of
these, approximately 1.36 million require emergency department visits, 275,000 are hospitalized,
and 52,000 die (Faul et al., 2010). In the U.S. children aged 0 to 4 years, older adolescents aged
15 to 19 years, and adults aged 65 years and older are the age groups most likely to sustain a TBI
(Faul et al., 2010)
TBI is graded as mild, moderate, or severe on the basis of the Glasgow Coma Scale (GCS).
In severe injury (GCS 3-8) the subject is comatose, unable to open their eyes or follow
commands (Teasdale and Jennett, 1974). Severe TBI accounts for more than 57,000 hospitalized
patients in the U.S. each year, and mortality rates are highest in the severe category of TBI.
Studies involving about 6000 severe TBI patients (GCS ≤8) observed mortality rates ranging
from 20% to as high as 39%, translating into perhaps 11,000 – 22,000 deaths per year in this
population (Marmarou et al., 2007). According to the CDC, 5.3 million Americans (2% of the
population) are living with some degree of disability from a prior TBI (Brown et al. 2008; CDC,
2008). These patients have a long-term or lifelong need for help to perform activities of daily
living as a result of TBI. In the US, the direct and indirect costs of TBI are estimated at $60
billion (Langlois et al., 2006).
1.2
Progesterone as a Neuroprotectant: Pre–Clinical Studies
Progesterone, primarily known as a gonadal hormone, is an important agent affecting many
functions in the central nervous system, where it is also locally synthesized, and it may play an
important role in promoting and enhancing repair after traumatic brain injury and stroke (Stein,
2005).
A
systematic
review
of
experimental
studies
indicates
that
progesterone
is
neuroprotective, in terms of reducing lesion volume, following either cerebral ischemia or
traumatic brain injury (Gibson et al., 2008). Progesterone also has been shown to reduce post-
injury edema in rats (Roof et al., 1993) as well as improve cognitive recovery and secondary
neuronal loss caused by contusion injury (Roof et al., 1994). The protection against post-
traumatic edema was seen in animals treated up to 24 hours post injury (Roof et al., 1996).
Progesterone also has been shown to protect against lipid peroxidation following TBI in rats
(Roof et al., 1997).
Progesterone has a membrane stabilizing effect that serves to reduce the damage caused by lipid
peroxidation.
In
addition,
it
may
provide
neuroprotection
by
suppressing
neuronal
hyperexcitability (Sayeed et al., 2007).
Experimental studies by several investigators have
documented the neuroprotective effects of progesterone in various models of traumatic brain
injury and stroke (Cutler et al., 2007; Cutler et al., 2005; Cutler et al., 2006; Djebaili et al., 2005;
Djebaili et al., 2004; Duvdevani et al., 1995; Galani et al., 2001; Grossman et al., 2004; Guo et
al., 2006; He et al., 2004; Pettus et al., 2005; Roof et al., 1994; Roof et al., 1996; Roof et al.,
2000; Sayeed et al., 2007; Shear et al., 2002; VanLandingham et al., 2007; Wright et al., 2001).


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1.3
Progesterone as a Neuroprotectant: Clinical Studies in TBI
Based upon a large and growing body of preclinical evidence demonstrating the powerful
neuroprotective properties of progesterone, the feasibility of progesterone therapy was studied to
assess its applicability in patients with acute TBI. One pilot study (Xiao et al., 2007) and two
Phase 2 trials (Wright et al., 2007; Xiao et al., 2008) have been conducted with parenterally-
administered progesterone, and the results have revealed an acceptable safety profile and
promising efficacy outcomes to support further studies.
A Phase 2 randomized, double blind, placebo-controlled trial (the Progesterone for Acute
Traumatic Brain Injury Trial Experimental Clinical Treatment (ProTECT™) study) was
conducted by Wright et al. (2007) in 100 adult TBI patients arriving within 11 hours of injury
and with a pre-resuscitation GCS ranging from 4 to 12. Patients were randomized on a 4:1 basis
to receive either intravenous (i.v.) progesterone or placebo. Subjects were assessed daily for
adverse events and signs of recovery. Safety and efficacy outcomes were assessed at 30 days
post-injury. The primary safety measures were adverse event rates and mortality. The primary
measure of benefit was the dichotomized Glasgow Outcome Scale Extended (GOS-E).
In the ProTECT™study (Wright et al., 2007), 77 subjects were randomized to progesterone and
23 to placebo. The mean time from injury to initiation of progesterone/placebo infusion was 6.3
hours.
A progesterone alcohol solution was mixed with Intralipid® 20% (Fresenius Kabi,
Clayton, NC), and the mixture infused at an initial rate of 14 mL/hr (0.71 mg/kg/h) for 1 hour
followed by a decrease in infusion rate to 10 mL/hr (0.5mg/kg/hr) for overall treatment duration
of 72 hours.
Subjects treated with placebo received the same infusion regimen minus the
progesterone.
The
treatment
groups
had
similar
baseline
demographic
and
clinical
characteristics. Laboratory and physiologic values were similar throughout treatment.
No serious adverse events were attributed to progesterone. Adverse and serious adverse event
rates were similar in both groups, except that subjects treated with progesterone had a lower 30-
day mortality rate than those in the placebo group (Relative Risk [RR] 0.43; 95% confidence
interval 0.18 to 0.99).
The majority of severe (GCS 4-8) TBI survivors in both groups had
relatively poor GOS-E and Disability Rating Scale (DRS) scores. However, moderate TBI (GCS
9-12) survivors who received progesterone were more likely to have a moderate-to-good
outcome than those randomized to placebo.
It was concluded that, in this small study,
progesterone caused no discernible harm and showed possible signs of benefit.
The pharmacokinetics of progesterone intravenous infusion were examined in the above trial in
33 subjects (Wright et al., 2005). Multiple blood samples were obtained from 11 female and 21
male subjects receiving progesterone infusions and 1 female and 3 males receiving placebo
infusions for 72 hours. Analyses demonstrated that stable progesterone concentrations can be
rapidly achieved via progesterone infusion following TBI.
In a pilot randomized trial (Xiao et al., 2007), the therapeutic effects of intramuscular (i.m.)
progesterone were studied in 56 TBI patients with baseline GCS of 5 to 8. Twenty six were
treated with progesterone and 30 subjects received placebo. Neurologic outcome was assessed
using the Glasgow Outcome Scale (GOS) and the Karnofsky Performance Scale (KPS). Three-
month follow up indicated that GOS, KPS, and the degree of verbal impairment were better in
the progesterone-treated group than in the control group (p< 0.05); however there was no


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significant difference in mortality. Serum 15-F(2t)-isoprostane and tumor necrosis factor (TNF)-
alpha levels were reduced significantly in the progesterone-treated group on the 5th and 10th day
after injury (p<0.05), supporting the notion that the positive effects of progesterone may be due
to its alleviating inflammatory and lipid peroxidation response .
Following the above study, Xiao et al. conducted a prospective, randomized, placebo-controlled
trial of progesterone in 159 severe TBI patients with a GCS 3-8 who arrived within 8 hours of
injury (Xiao et al., 2008).
Patients were randomized to receive intramuscularly either
progesterone (n=82) or placebo (n=77).
At 3 months and 6 months after treatment, subjects
given progesterone had significantly more favorable functional outcomes and decreased
mortality compared with placebo-treated subjects (mortality at 6 months p < 0.05).
In summary, studies have shown that administering relatively large doses of progesterone during
the first few hours to days after injury significantly limits central nervous system damage,
reduces loss of neural tissue, and improves functional recovery. Although the research published
to date has focused primarily on progesterone's effects on blunt TBI, there is evidence that the
hormone affords protection from several forms of acute central nervous system injury, including
penetrating brain trauma, stroke, anoxic brain injury, and spinal cord injury.
Progesterone
appears to exert its protective effects by protecting or restoring the blood-brain barrier,
attenuating cerebral edema, down-regulating the inflammatory cascade, and limiting cellular
necrosis and apoptosis. All are plausible mechanisms of neuroprotection (Stein, 2008).
1.4
Rationale for Timing of Drug Administration
The start of infusion in this clinical trial must occur within 8 hours of the time of injury,
preferably as soon as possible, in accordance with the “Golden Hour” principle of emergency
medicine that earlier treatment is better. While one animal model of TBI suggests progesterone
has a therapeutic window that continues out to 24 hours post-injury (Roof et al., 1996), efficacy
seemed to diminish as a function of time prior to treatment.
Moreover, the presumed
mechanisms of action for progesterone in TBI argue for earlier intervention.
While
progesterone has many pro-trophic effects that affect damage repair and could be responsible for
the large observed treatment window, an ideal neuroprotective agent should prevent damage, and
the pathogenesis of TBI begins very early post-injury.
Although the mechanistic and preclinical considerations drive earlier treatment, there are
practical obstacles of informed consent and study treatment preparation that must be considered.
Patients are unable to provide consent due to level of consciousness, therefore consent must be
sought from a relative or other authorized representative, as permitted by local regulations.
Feasibility research indicates that obtaining informed consent will be rate-limiting and if, for
example, only 6 hours are allowed for treatment initiation, timely enrollment becomes
problematic.
The 8-hour window required in this protocol strikes the appropriate balance
between the need for early initiation of treatment and the requirement to obtain appropriate
informed consent.


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2.
STUDY OBJECTIVES
2.1
Primary Objective
The aim of the study is to determine the efficacy and safety of BHR-100 utilizing the 6-month
GOS in severe TBI patients (GCS 3-8) following 120 hours of study treatment.
2.2
Secondary Objectives
In addition, the clinical benefit of progesterone treatment will be further assessed through the
evaluation of:
1.
mortality at 1 month and 6 months post injury
2.
GOS at 3 months
3.
GOS-E at 3 and 6 months
4.
Quality of Life using Short Form (36) Health Survey (SF-36) at 3 and 6 months
5.
the effect on Intracranial Pressure (ICP), Cerebral Perfusion Pressure (CPP), and
Therapeutic Intensity Level (TIL)
6.
the effect on the progression of intracranial pathology as assessed by the admission
and the Day 6 (+/- 1 Day) computed tomography (CT) scans


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3.
STUDY DESIGN
3.1
Description of Overall Study Design
This is a multi-center, randomized, double blind, placebo controlled study conducted on 1180
severe TBI patients at 100 or more international trauma centers (sites).
All subjects will be
managed in accordance with standard guidelines for TBI from the Brain Trauma Foundation
(BTF), American Brain Injury Consortium (ABIC) and European Brain Injury Consortium
(EBIC) (BTF, 2007; ABIC, 2003; Maas et al., 1997).
Randomization will be implemented using Interactive Web-based Response System (IWRS)
technology.
Randomization will be stratified by major geographical regions.
The post-
stabilization GCS of 3 to 8, assessed at the study center, will serve as the index (randomization)
GCS. If a true index GCS at arrival is not feasible due to medically indicated measures (i.e.,
GCS is 3 due to sedation and paralysis), the Investigator needs to obtain a reliable GCS
assessment obtained by the Emergency Team at the scene of injury (field GCS) and/or other
transferring medical facility. The score must include each component of the score (eye opening,
verbal and motor responses), and must total 3-8. Any reliable GCS of 3 to 8, inclusive, qualifies
the patient for study enrollment. To maintain the blind, all study procedures are to be performed
by site personnel blind to treatment assignment.
Subjects will be intensively monitored during the five-day infusion period and their Intensive
Care Unit (ICU) stay. The start and duration of ICP monitoring will be at the discretion of the
site based on the subject’s clinical condition. If the ICP monitor is placed, ICP and TIL will be
recorded for a period of up to six days. The baseline CT scan used for randomization and a
second CT scan obtained on Day 6 (+/- 1 day) will be centrally analyzed for progressive
intracranial pathology (PIP).
Adverse events (AEs) will be collected beginning at the start of study drug infusion and through
Day 10 post-infusion (Days 1-15). Serious adverse events (SAEs) will be collected beginning at
the start of study drug infusion, continuing throughout the six-month subject duration in the
study.
The GOS will be collected at three and six months as well as the GOS-E.
The Schedule of Events is shown in Appendix A.
3.2
Study Endpoints
3.2.1
Primary Endpoint
GOS evaluated at Month 6 post-injury.
3.2.2
Secondary Endpoints
Secondary endpoints will be assessed by the following measures:

Mortality assessment at 1 month and 6 months post TBI

Evaluation of GOS at 3 months


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
Evaluation of the GOS-E at Months 3 and 6

SF-36 at Months 3 and 6

Changes in ICP, CPP, and TIL

Changes in intracranial pathology as assessed by the admission and end-infusion Day 6
(+/-1 Day) CT scans.


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4.
SELECTION OF STUDY POPULATION
One thousand one hundred and eighty subjects (1180) will be enrolled in this trial. Patients who
have severe TBI and who meet the following inclusion/exclusion criteria will be eligible.
4.1
Inclusion Criteria
1. Male or female patients, age between 16 and 70 years, inclusive (or other age limit as
required by local regulations)
2. Weight from 45 to 135 kg, inclusive
3. Sustained a closed head trauma no more than 8 hours before initiation of study drug
infusion (exposed dura mater is acceptable in the case of depressed skull fractures)
4. TBI diagnosed by history and clinical examination
5. GCS score between 3 and 8, inclusive
6. At least one reactive pupil (pinpoint pupils due to opioid pain treatment are considered
reactive)
7. Evidence of TBI confirmed by abnormalities consistent with trauma on CT scan upon
admission (diffuse injury II-IV, evacuated and non-evacuated mass lesion, Marshall’s CT
Classification)
8. Indication for ICP monitoring
4.2
Exclusion Criteria
1. Life expectancy of less than 24 hours as determined by the Investigator
2. Prolonged and/or uncorrectable hypoxia (Pa02< 60 mmHg) or hypotension (systolic
blood pressure < 90 mmHg) at the time of randomization
3. Any spinal cord injury
4. Pregnancy
5. Patients with penetrating head injury
6. Bilaterally fixed dilated pupils at the time of randomization
7. Coma suspected to be primarily due to other causes (e.g. alcohol)
8. Pure epidural hematoma
9. Preexisting clinically significant disease or chronic condition that can be ascertained at
the time of admission and could affect functional outcome
10. Severe cardiac or hemodynamic instability prior to randomization
11. Known treatment with another investigational drug, device, medical therapy or procedure
within 30 days of injury
12. A history of allergic reaction to progesterone and related drugs or any of the components
of the infusion
13. Any disease, in the opinion of the Investigator, that is unstable or which could jeopardize
the safety of the patient and his/her compliance in the study.
14. Patients who, in the opinion of the Investigator, would not be able or willing to comply
with the protocol through the final visit (6 months post-injury)


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4.3
Withdrawal of Subjects from the Study
A good faith effort will be made to ensure that subjects complete the study through the 6-month
assessments, consistent with the provisions of informed consent and good clinical judgment with
respect to safety. The following are potential reasons to terminate the participation of a subject
in the study:

The subject’s health would be jeopardized by continued participation.

Lost to follow-up: subject fails to return to the study site for scheduled visits and does not
respond to multiple telephone or written attempts to contact.
(Note: if subject cannot
return to the study site due to relocation, but moves to an area near another participating
site, all efforts should be made to continue study participation at that site).

Withdrawal of consent: subject or the subject’s legally authorized representative or
legally acceptable representative (LAR), as applicable in the region where the study is
conducted, decides to stop participation in the study for any reason other than an AE, or
is unable to complete the study as described in the study protocol. Although a subject or
LAR is not obliged to give his/her reason for withdrawing prematurely, the Investigator
will make a reasonable effort to obtain the reason while fully respecting the subject’s
rights. Every effort will be made to contact a subject or LAR who fails to attend any
follow-up appointments/contacts in order to complete study assessments.

Administrative: the Sponsor decides to terminate or discontinue the study (either at the
study site or the entire study).
The reason for withdrawal will be captured on the appropriate electronic case report form
(eCRF). The Study Termination form must be completed for all randomized subjects, including
subjects discontinuing prior to any study drug administration.
The Medical Monitor will be
informed of early withdrawal of a subject from the study.
4.3.1
Subject Replacement
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5.5
Dosage and Administration
Subjects will be administered either BHR-100 or placebo infusion utilizing a peristaltic infusion
pump. An i.v. loading dose of BHR-100 or placebo for the first hour at 0.71 mg/kg/hr will be
followed by a 119-hr continuous maintenance infusion of 0.5 mg/kg/hr, for a total of 120 hours
of treatment. The IWRS calculates the loading and maintenance infusion rates according to the
subject’s weight entered into the IWRS. The rates assigned for the subject (loading dose,
followed by maintenance infusion) must be used to administer the study drug.
Study drug infusion treatment must be started within 8 hours after injury using a dedicated i.v.
line (central or peripheral line).
5.6
Drug Accountability
The Investigator will maintain accurate records of the disposition of all clinical drug supplies
received during the study and the dates on which drug supplies were received from the Sponsor
or authorized representative.
5.7
Assessment of Compliance
Study drug will be administered by qualified clinical personnel. At the end of the study drug
administration a clinical research staff member will verify that the entire dose (120 total hours
from start to finish) has been administered to the subject. All details of the study drug infusion
will be recorded, including any interruption and the reason. Any dose interruptions greater (>)
than 30 minutes will be recorded as a protocol deviation.
5.8
Concomitant Medications
All other medications administered to or taken by the subject during the study (from time of
consent through Study Day 15) are to be recorded on the eCRF. Information should be recorded
for: name of drug, dose, route of administration, start and end dates and time (for i.v. drugs), and
indication, including medications used for ICP management.
5.8.1
Allowed Concomitant Medications/Procedures
All medications and procedures required to treat the subject’s TBI should be administered as
recommended in the standard guidelines for the management of severe TBI (BTF, ABIC, and
EBIC). Any therapeutic or surgical procedure performed for concurrent conditions from the time
of informed consent through Study Day 15 should be recorded, including the date, description of
the procedure, and clinical findings. The nature and volume of i.v. fluids will be measured on a
daily basis and any other fluid/blood/blood product replacement will be documented.
5.8.2
Concomitant Medications/Therapies to be Avoided
Investigational drugs, devices, procedures or therapies should not be used at any time during the
subject’s 6-month participation in the study because of their potential to confound the results.
Subjects participating in this clinical trial should not also be enrolled in another trial utilizing
any investigational drug, device, procedure or therapy. Enrollment into a strictly observational
trial is permitted, as long as the study assessments in this trial are not compromised.


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6.
STUDY PROCEDURES
The Schedule of Events (Appendix A) summarizes the frequency and timing of the required
study assessments.
The subject should be managed for TBI as recommended in the BTF, ABIC, and EBIC
guidelines for the management of severe TBI.
In order not to interfere with the standard of medical care and to minimize additional study-
specific procedures, some of the subject’s baseline characteristics will be recorded from
procedures performed routinely for the management of severe TBI.
Except where otherwise
specified below, the last available values prior to study randomization will be recorded. These
may include general (physical and neurological) examination findings. These data may even be
obtained in another hospital, and are acceptable to record in the eCRF.
6.1
Screening
The following assessments will be conducted after arrival of the patient at the study hospital.

Demographic data

Review of inclusion/exclusion criteria

Review of relevant medical history

Review of medication history

Informed Consent

Full physical examination including:

Body weight

Right and left pupil response must be recorded

Injury Cause and Severity Assessment

Vital signs

Obtain blood samples for local lab assessments (see Appendix B for details)

Serum or urine pregnancy test for women of child-bearing potential

ECG

GCS (all components: Eye opening, Verbal Response, and Motor Response)

Baseline CT scan

If the ICP monitor is placed, monitoring of:

ICP

TIL

Arterial Blood Gases (ABG): While the subject is intubated, the highest value of the day
for the PaCO2 and the lowest value of the day for PaO2, pH, HCO3 and SaO2, along with
the accompanying Fio2 setting, will be recorded.

Concomitant medications/procedures


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6.2
Screening and Randomization Process (IWRS)
Subjects will be randomized to either placebo or active drug on a 1:1 ratio. Randomization is
stratified by region (North America, South America, Europe, and Asia).
Once a subject is
determined eligible for the study and informed consent has been obtained, the Investigator or
designee will access the web-based randomization system (IWRS), and will reply to the system
questions as prompted. All subjects (or the subject’s LAR) from whom informed consent is
obtained should be entered into IWRS. Screening information will be entered into the IWRS for
the screened subject:

Date and time of injury, date and time of informed consent, date of birth

GCS

Subject initials, gender, and weight
The IWRS will assign the Subject identification (ID) number. This assigned ID number will be
used throughout the subject’s participation in the study.
All screening procedures should be completed and inclusion/exclusion criteria confirmed prior to
the randomization in the IWRS. Once the subject is ready to be randomized into the study, the
Investigator or designee will log into IWRS, select the screened subject number and confirm
inclusion/exclusion criteria.
Upon confirmation, IWRS will provide a Randomization
Notification including the following information:

Assigned bottle numbers for the five day infusion;

The loading dose infusion rate in milliliters per hour for the first hour;

The maintenance dose infusion rate in milliliters per hour for the remaining 119 hours of
administration.
Careful attention should be paid to correctly administering the assigned study drug as well
as administering the assigned loading and maintenance dose infusion rates as these are
calculated according to the subject’s weight (see Section 5.5).
6.3
Study Drug Infusion Period: Days 1-5
The study treatment infusion MUST be initiated no later than 8 hours after the
documented time of injury.
The following evaluations and assessments will be performed:

Start and stop times of each infusion; record bottle changes

Recording of any deviation [greater than 30 minutes] from the specified dosing times (1-
hour loading dose, then 119-hour maintenance infusion) and assigned infusion rates

Progesterone level sampling (all subjects on Day 2 (48 +/- 6 hours after initiation of the
study drug infusion); additional sampling on PK subjects only)

Daily GCS (best), if possible to assess without interfering with the subject’s condition (if
sedation is deemed necessary for medical reasons it should not be (temporarily) halted
just to assess GCS)


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
ICP, TIL for ICP management, and vital signs: The ICP, TIL and vital signs [heart rate
(bpm), respiration rate (per min), systolic and diastolic blood pressure (mm Hg),
temperature (Cº) and pupil response] will be recorded at 00:00, 06:00, 12:00 and 18:00
hrs (+/- 30 minutes). In addition ICP, TIL and vital signs will be recorded whenever ICP
management changes. If the ICP monitor is not placed, vital signs will still be collected.

ABGs: Daily while the subject is intubated, as described in Section 6.1

Daily fluid balance

Neuroworsening assessment, if applicable

Concomitant medications and procedures

AEs

SAEs

Pre-injury narrative for GOS assessment: complete no later than 14 days post-
randomization
6.4
Day 6: End-of-Infusion Evaluations

GCS (best), if possible to assess (see Section 6.3)

End-infusion CT scan (+/- 1 day scheduled at the discretion of the Investigator). It is
recommended that the CT scan be completed at or near the end of the infusion; however,
if the Investigator deems it necessary to obtain the CT scan on Day 5, this is acceptable.

Full physical examination including body weight

ICP, TIL, and vital signs, including pupil responses

Local lab assessments (see Appendix B for details) within 1 hour after study drug
infusion is completed (A pregnancy test for women of child-bearing potential is not
required on Day 6)

ABGs: While the subject is intubated, as described in Section 6.1

ECG

Daily fluid balance

Concomitant medications and procedures

Neuroworsening assessment, if applicable

AEs (to be collected through Day 15)

SAEs
6.5
Day 15: Post-Infusion Evaluations/Discharge
Day 15 assessments must be completed 15 days post-injury, + 5 days or at ICU discharge,
whichever occurs earlier.

GCS (best), if possible to assess (see Section 6.3)

Local lab assessments (see Appendix B for details) (A pregnancy test for women of
child-bearing potential is not required on Day 15)

Concomitant medications and procedures


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
Dates of ICU discharge and hospital discharge

Neuroworsening assessment, if applicable

AEs

SAEs
6.6
Day 30 (Month 1) Assessments
Day 30 assessments must be completed 30 days post-injury, + 2 days.

Subject status, including mortality and dates of ICU discharge and hospital discharge

SAEs
6.7
Day 90 (Month 3) Assessments
Day 90/Month 3 assessments should be completed 90 days post-injury, + 14 days, during an in-
person visit.

Subject status, including dates of ICU discharge and hospital discharge

GOS and GOS-E

SF-36 (must be completed by the subject)

SAEs
6.8
Day 180 (Month 6) Assessments
Day 180/Month 6 assessments should be completed at 180 days post-injury + 28 days, during an
in-person visit.

Subject status, including mortality and dates of ICU discharge and hospital discharge

GOS and GOS-E

SF-36 (must be completed by the subject)

SAEs
6.9
Progesterone Blood Sample Collection
Blood will be collected by venipuncture on Day 2 (48 +/- 6 hours after initiation of the study
drug infusion) for each subject for determination of progesterone levels by the Central
Bioanalytical Laboratory.
At selected sites (10-15 US-based sites) ten (10) serial blood samples for pharmacokinetics (PK)
analysis will be collected at the following times relative to the beginning of the infusion: 1, 8, 24,
48, 56, 72, 96, 104, 120, and 138 hours.
The blood samples will be taken from the arm not used for the study drug infusion. Guidelines
for sample preparation, storage, packaging, and shipping will be provided to the Investigator by
the Central Bioanalytical Laboratory.


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7.
ASSESSMENTS OF EFFICACY AND SAFETY
7.1
Efficacy Parameters
The following primary and secondary efficacy parameters will be assessed in this trial. These
endpoints are described in detail in Section 7.3.
Primary: GOS assessment at Month 6 post- injury
Secondary (all timepoints are post-injury):

Mortality at Month 1 and 6

GOS at Month 3

GOS-E at Months 3 and 6

SF-36 at Months 3 and 6

ICP, CPP and TIL

Comparison of CT scans at admission and end-infusion Day 6 (+/-1 Day)
7.2
Safety Parameters
Safety and tolerability will be determined by AEs, ECGs, safety labs, vital signs, fluid balance,
ABGs, and neuroworsening.
7.2.1
Adverse Events and Serious Adverse Events
Adverse events whether reported, observed, or elicited by indirect questioning will be captured
from the time of infusion start through 10 days post-infusion (Days 1-15).
SAEs will be
captured from the time of infusion start throughout the course of the subject’s participation in the
study (6 months). The AE/SAE relationship to the study treatment will be judged as not related,
possibly related, probably related, or related. Ongoing AEs will be followed to resolution,
whenever possible.
Particular attention should be paid to the following potential risks previously identified as
associated with administration of progesterone: serious thromboembolic events such as
thrombotic myocardial infarction, pulmonary embolism, deep vein thrombosis, ischemic stroke;
allergic reactions; marked liver function abnormalities; serious infections such as pneumonia,
sepsis, meningitis.
All SAEs will be reported by telephone or written report within 24 hours of being notified of the
event to the Sponsor’s Medical Monitor and then reported to each site's IRB/IEC according to
the local regulations.
Serious adverse events that persist at Month 6 post-injury will be
documented as to their final status.
7.2.2
ECG
The ECGs will be analyzed at the site and documented on the CRF by the Investigator. All
clinically significant abnormal ECGs, assessed for clinical relevance by the Investigator, must be
documented as an AE on the CRF.


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7.2.3
Laboratory Safety Tests
Standard clinical safety labs will be measured locally at the sites and recorded for the specified
time points (see Appendix B for details). The Investigator will assess all abnormal lab values at
these time points for clinical significance; if categorized as adverse events, they will be collected
and recorded similarly to other AEs.
All clinically significant abnormal lab values will be
followed until resolution, whether or not they are deemed AEs by the investigator. If resolution
is not seen, a justification as to the cause for such an abnormality, such as if due to an underlying
pre-existing condition, associated co-morbidity, etc, will be recorded.
7.2.4
Vital Signs
Vital signs (heart rate (bpm), respiration rate (per min), systolic and diastolic blood pressure (mm
Hg), and temperature (Cº), and pupil response) will be monitored in parallel with and per the
same timing as ICP and TIL (Sections 7.3.4 and 7.3.5 below).
7.2.5
Daily Fluid Balance
The total amount of fluids administered and the total excreted once per 24 hour period will be
recorded during Day 1 through Day 6.
7.2.6
Arterial Blood Gases
While the subject is intubated, the highest value of the day for the PaCO2 and the lowest value of
the day for PaO2, pH, HCO3 and SaO2 along with the accompanying Fio2 setting will be recorded
before randomization (Day 1 pre-dose) and daily during Day 1 through Day 6.
7.2.7
Neuroworsening
Instances
of
neuroworsening
will
be
recorded
daily
from
Day
1
through
Day
15.
Neuroworsening is defined as any one of the following: a decrease in GCS motor score ≥2,
development of pupillary abnormalities, any other neurological deterioration or progression of
lesion on CT scan leading to a change in patient management.
7.3
Selection of Efficacy Measurements Related To Management of TBI
7.3.1
Glasgow Outcome Scale (GOS)
The GOS (Jennett and Bond, 1975) is the primary endpoint of this study and assesses mortality
and disability in TBI patients according to the designation Good Recovery, Moderate Disability,
Severe Disability, Vegetative State or Dead. The GOS will be administered using a standard
questionnaire and accompanying narratives at 3 and 6 months post-injury. A baseline narrative
will also be recorded by the Investigator.
A central review will be performed of all GOS
recordings.
7.3.2
Glasgow Outcome Scale - Extended (GOS-E)
The GOS-E will be administered at 3 months and 6 months post injury.
A standardized
questionnaire structuring the interview will be used, as well as the narrative completed by the
Investigator. A central review will be performed of all GOS-E recordings.


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The GOS-E assessment of mortality and disability in TBI patients extends the original five GOS
categories of functional outcome to eight categories (Jennett et al., 1981; Wilson et al., 1998;
Teasdale et al., 1998):

Dead

Vegetative State

Lower Severe Disability

Upper Severe Disability

Lower Moderate Disability

Upper Moderate Disability

Lower Good Recovery

Upper Good Recovery
7.3.3
Mortality
Any SAE which results in death at any time during the study will be recorded both as an SAE
and a Death Report. The Death Report will include the primary cause of death, secondary cause
if any, and the date and time of death. If an autopsy is performed, the report should be collected
and provided in a de-identified manner.
7.3.4
Intracranial Pressure/Cerebral Perfusion Pressure
If an ICP monitor is placed, ICP measures will be recorded as early as before randomization
(Day 1 pre-dose, or as soon as the monitor is placed) and for up to 6 days while ICP is being
monitored. The ICP will be recorded daily at the specific times of: 00:00, 06:00, 12:00 and
18:00 hour (+/- 30 minutes), along with vital signs [heart rate (bpm), respiration rate (per min),
systolic and diastolic blood pressure (mmHg), temperature (Cº) and pupil response]. In addition
to the 4 daily timepoints, ICP and vital signs will be recorded whenever ICP management
changes.
If the ICP monitor is not placed, vital signs will still be collected at these four
timepoints per day.
ICP will be monitored preferentially using a catheter connected to an external strain gauge
(intraparenchymal ICP device or ventricular catheter for the ICP measurement). If placement of
an intraventricular catheter is not possible, an intraparenchymal catheter placed away from the
lesion may be used. The timing and duration of ICP monitoring will be at the discretion of the
Investigator.
The CPP will be calculated automatically as the difference of mean arterial pressure and ICP,
based on the blood pressure and ICP readings recorded in the eCRF.
7.3.5
Therapeutic Intensity Level (TIL)
TIL data will be recorded for up to 6 days or while ICP is being monitored. TIL scores will be
automatically calculated based on the medications and procedures used to manage the subject’s
ICP, as recorded into the eCRF. Table 1 lists the specific known treatments commonly used to
manage ICP and CPP and the corresponding scoring system (modified from Maset et al., 1987).
If no therapies were utilized, then the scoring is zero during a given time period.
Table 1
Therapeutic Intensity Level Grading System
Therapy
Score


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Surgical Decompression
1
Barbiturate Induced Coma
1
Hypothermia for ICP reduction
1
Hyperventilation (pCO2<30)
1
Pressor Administration (to keep CPP 60)
1
Hypertonic Saline
1
Mannitol
1
Ventricular Drainage
1
Paralysis Induction
1
Sedation
1
Maximum Total Score
10
TIL scores will be analyzed based on the therapies recorded. Because of the stepwise
progression of therapy (from sedation to barbiturate use), barbiturate administration or
surgical decompression constitutes a total score of 10 when performed.
Modified from Maset et al., 1987
7.3.6
CT Scans
A baseline CT scan will be performed before randomization as part of eligibility assessment. A
follow-up CT scan will be performed end-infusion on Day 6 (+/- 1 day) post-injury to assess the
progression of lesion volume and brain edema. The findings will be classified in accordance
with the Marshall criteria (Marshall et al., 1992). Baseline and Day 6 (+/- 1 Day) CT scans will
be sent to the central reader, who will evaluate them for study analysis purposes only.
7.3.7
QOL SF-36
The Quality of Life (QOL) SF-36 questionnaire will be assessed at 3 and 6 months post injury.
The SF-36 is a validated generic, easily administered survey of patient health consisting of eight
scaled scores, which are the sums of the responses to questions in each section (Ware and
Sherbourne, 1992; McHorney et al., 1993). Each scale is directly transformed into a 1-100 scale
on the assumption that each question carries equal weight. The eight sections are:

Vitality

physical functioning

bodily pain

general health perceptions

role physical

role emotional

role mental

mental health
The 8 scales can also be summarized into two summary scores for physical and mental health,
respectively. The SF-36 must be completed by the subject.
7.3.8
Glasgow Coma Scale
The Glasgow Coma Scale (Teasdale and Jennett, 1974) will be performed before randomization
and once daily (best) during Days 1 to 6 and on Day 15. The GCS is a neurological scale which
aims to give a reliable, objective way of recording the conscious state of a person. A patient is
assessed against each of three criteria, eye, verbal and motor responses, and the resulting values
are summed for the total GCS score. The lowest possible total GCS is 3 (deep coma or death),
while the highest is 15 (fully awake person).


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8.
STATISTICAL PLAN
8.1
Sample Size Justification
It is planned to recruit a total of 1180 patients randomized in a 1:1 ratio to BHR-100 or placebo
(590 in each treatment group). This sample size estimation is based on the use of a proportional
odds model (Whitehead, 1993) to analyze the primary outcome variable, namely the
conventional 5-point GOS at six months after injury.
Assuming approximately 31% good
outcome, 21% moderate disability, 19% severe disability and 29% combined vegetative state and
death, the total sample size of 1180 subjects will give 90% power to detect a common odds ratio
of 1.5 of improvement in outcome (i.e. 10% effect size) at the 1% significance level (two-sided).
The baseline outcome distribution used is based on the six-month GOS outcome distribution
from the head injury population with GCS 3-8 in the previous TBI Phase 3 trials in the
International Mission for Prognosis and Analysis of Clinical Trials in TBI Project (IMPACT)
Database (Marmarou et al., 2007).
8.2
Baseline Data
Baseline comparability of the randomized groups will be illustrated using appropriate descriptive
statistics.
8.3
Primary Efficacy Analysis
The primary efficacy variable is GOS evaluated at 6 months post injury.
The proportional odds model (POM) (McCullagh, 1980) will be used to compare BHR-100 to
placebo for the GOS outcome at six months (categories of good recovery, moderate disability,
severe disability, and the combined vegetative state/death).
A test for the proportional odds
assumption will be conducted and if statistically significant, other polytomous logistic models
will be investigated.
The analyses will be conducted on an intent-to-treat (ITT, i.e. all
randomized subjects) basis, and the POM will be fitted including the effect of treatment,
geographic region (North America, Europe, Asia, and South America), age, GCS motor score,
pupil response, and CT classification.
If the p-value from the test of the null hypothesis is less than 0.0003 (at the interim analysis) or
0.0098 (at the final analysis), it will be concluded that BHR-100 is statistically significantly
different from placebo with respect to the GOS at 6 months following injury.
In the event that the primary efficacy analysis does not show statistical significance at the study
wise 1% significance level, i.e. the final analysis p-value is not less than 0.0098, a final adjusted
p-value will be calculated and the result considered statistically significant at the 5% level if the
adjusted p-value is less than 0.05. The adjusted p-value will be calculated using EAST(Cytel
Statistical Software, Cambridge, MA) or other appropriate statistical software package to adjust
for the interim analysis using the pre-specified boundaries.
8.3.1
Alternate Primary Efficacy Analysis: Sliding Dichotomy Model
If the proportional odds assumption cannot be justified, an analysis will be conducted using a
sliding dichotomy (Maas et al., 2006; Murray et al., 2005) of the GOS outcome at 6 months
following injury, following categorization of patients into different prognosis groups (worst,


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intermediate, and best) based on baseline prognostic factors. The hypothesis that the proportion
of favorable responses observed in each treatment group is the same will be tested both within
the baseline prognosis grouping (best, intermediate and worst) and overall using the Cochran-
Mantel Haenszel Chi-Square test, adjusted for region.
If the p-value from the test of the null hypothesis of no difference in the proportion of favorable
responses observed in each treatment group is less than 0.0003 (at the interim) or 0.0098 (at the
final analysis), it will be concluded that there is a statistically significantly difference in the
proportion of favorable responses between the 2 treatment groups.
If this analysis is not required as an alternate analysis to the Proportional Odds Model analysis, it
will still be performed as an additional sensitivity analysis.
8.3.2
Sensitivity Analysis: Dichotomized Model
In addition, the GOS at 6 months post injury will be dichotomized into Good Recovery,
Moderate Disability versus Severe Disability, Vegetative Status/Dead.
The binary outcome will be analyzed using logistic regression analysis. The logistic regression
model will be fitted including the effect of treatment, geographic region (North America, Europe,
Asia, and South America), age, GCS motor score, pupil response, and CT classification.
The logistic regression model will be used to test the null hypothesis that the odds of an ‘event’,
i.e. observing a response of moderate disability or good recovery on the outcome variable, GOS
at 6 months following injury, adjusted for region, age, GCS motor score, pupil response, and CT
classification is the same in both treatment groups, i.e.
Null Hypothesis:
H0 : β1 = 0
Alternative Hypothesis:
H1 : β1 ≠0
If the p-value from the test of the null hypothesis of 1 = 0 is less than 0.05, it will be concluded
that BHR-100 is statistically significantly different from placebo with respect to the GOS at 6
months following injury. The odds of an ‘event’ (moderate disability, or good recovery) in the
GOS at 6 months will be modeled and the corresponding common odds ratio for treatment,
1

e
,
can then be interpreted to determine the direction of the treatment difference as follows: with the
placebo group being considered as the reference category, if the odds ratio (ORBHR-100/placebo) is
greater than 1, the odds of a favorable outcome in the GOS at 6 months is greater in the BHR-
100 treatment group compared to placebo.
8.3.3
Handling of Missing Primary Efficacy Endpoint Data
When the primary efficacy endpoint is missing, the last observation carried forward (LOCF)
principle will be used to populate the primary endpoint, i.e. the Month 3 GOS assessment will be
carried forward. In the event that a subject has neither the 3 nor the 6-month GOS, the missing
values would be imputed based upon the proportional odds model. It is anticipated that there
will be minimal missing data, however sensitivity analyses will be carried out, if necessary, to
confirm that the imputation method(s) did not have an impact on the primary efficacy analysis
results.


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8.4
Secondary Endpoints and Exploratory Endpoints
Secondary efficacy parameters include:
1. Mortality at Month 6
2. Mortality at Month 1
3. GOS at Month 3
4. GOS-E at Month 6
5. GOS-E at Month 3
6. SF-36 at Month 6
7. SF-36 at Month 3
Exploratory parameters include:
1. Assessment of CT scans (admission vs. end-infusion Day 6 +/-1 Day)
2. ICP
3. CPP
4. TIL
These parameters are described briefly in the sections that follow.
8.4.1
Mortality Assessment at One and Six Months Post-injury
The mortality rate at one and six months will be compared between the two treatment groups.
The hypothesis that the mortality rate at one month (and at 6 months) observed in each treatment
group is the same will be tested using the Fisher’s Exact test. A two-sided, 5% significance level
will be used to test the null hypothesis. If rejected (p<0.05), it will be concluded that there is a
statistically significant difference in the proportion of deaths between the 2 treatment groups.
The time from injury to death will be analyzed using Kaplan-Meier analysis and Cox
Proportional Hazard Modeling.
8.4.2
Secondary Analyses of GOS at Three Months Post-injury
The GOS at three months will be analyzed following the same analyses and procedures for the
primary efficacy analysis described in Section 8.3. This will provide a measure of functional
improvement between BHR-100 and placebo.
8.4.3
GOS-E at Three and Six Months Post-injury
The extended GOS is an 8-point scale with the following categories: Dead, Vegetative State,
Lower Severe Disability, Upper Severe Disability, Lower Moderate Disability, Upper Moderate
Disability, Lower Good Recovery, and Upper Good Recovery.
The null hypothesis that the global assessment of outcome, as measured by the GOS-E at 3 or 6
months, is the same in each treatment group will be tested using the 2-sided Wilcoxon Rank-Sum
test, which can be obtained from the NPAR1WAY procedure in SAS®.
A two-sided, 5% significance level will be used to test the null hypothesis. If rejected at the 5%
level (p < 0.05), it will be concluded that there is a statistically significant difference in the
global assessment of outcome between the 2 treatment groups, as measured by the GOS-E. The


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magnitude of the summary statistics will be examined to determine the direction of the treatment
difference.
8.4.4
Quality of Life using SF-36
Summary statistics for the 8 scales and the physical and mental composite summary scores of the
SF-36 will be presented for each treatment group.
In addition to summarizing the data, the physical and mental composite summary scores at
Month 3 and 6 will be analyzed using an analysis of covariance (ANCOVA) model. The
ANCOVA model will include treatment group, age as a covariate and the stratification factors as
outlined for the primary efficacy analysis, namely region (North America, Europe, Asia, and
South America), GCS motor score, pupil response, and CT classification.
The null hypothesis that the mean physical and mental summary scores are the same for both
treatment groups (BHR-100 and placebo) will be tested against the 2-sided alternative hypothesis
that the mean physical and mental summary scores are different in each treatment group, at the
0.05 significance level.
8.4.5
Exploratory Clinical Parameters: ICP, CPP and TIL
Impact of study treatment on three clinical assessment parameters - ICP, CPP and TIL - will be
analyzed. Please also refer to the Statistical Analysis Plan (SAP) for further details.

ICP: If an ICP monitor is placed, the ICP will be recorded daily at designated timepoints,
as well as whenever ICP management changes (see Section 7.3.4) up to six days post
admission. These data will be summarized descriptively for each treatment group.

CPP: CPP will be calculated from blood pressure and ICP readings.
Data will be
summarized descriptively for each treatment group. Summary statistics of the number of
non-missing observations, absolute and relative frequency of CPP measurements in the
following categories will be presented for each treatment group: less than 50 mmHg, 50-
60 mmHg, 60-70 mmHg and greater than 70 mmHg.

TIL: The therapies used for ICP management will be calculated based on the time that
each therapy was received.
The percentage of time each therapy is used will be
calculated for each 24-hour period post dosing and for all time periods. The hours of use
for each therapy will be summarized descriptively for each treatment.
8.4.6
Exploratory Parameter: CT Scan
Effect of study treatment on the progression of intracranial pathology will be assessed by a
central reader from baseline (admission) and end-infusion Day 6 (+/- 1 Day) CT scans to assess
the progression of lesion volume and brain edema. The findings will be classified in accordance
with the Marshall classification.
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The number of non-missing observations, absolute and relative frequency (n and percentages)
will be tabulated by treatment group. The magnitude of the summary statistics will be examined
to determine the direction of the treatment difference.
8.5
Adverse Event Safety Data
Data on adverse events will be presented descriptively, grouping events by body system. Results
will be presented for all adverse events, including instances of neuorworsening and abnormal
clinically significant laboratory findings deemed as AEs by the Investigator.
The occurrence of adverse events will be compared between treatment groups, including the
proportion of subjects in each arm suffering at least one episode of the event as well as the
comparison of the distribution of the number of occurrences of the event. Additional
presentations of AE data may be requested by the Data and Safety Monitoring Board (DSMB)
(see Section 10.4).
8.6
Interim Analysis
A formal interim analysis will be performed once 200 subjects in each treatment arm (400 total
subjects) have completed the study, i.e. have been assessed for the 6-month GOS.
8.6.1
Interim Analysis for Efficacy
At the planned interim analysis, the test statistic based on the effect size (common odds ratio)
will be compared to the critical value shown below. If the test statistic exceeds the critical value,
continuation of the trial will be evaluated. In order to stop the trial at the interim analysis, the
significance level will need to be less than the critical p-value.
At the planned interim analysis, a two-sided test will be performed to detect either an increase or
decrease in the common odds ratio. In order to preserve the over-all type I error rate at 1%, the
critical value for the test statistic will be inflated above 2.575, the value that would be used if no
repeated testing were used (Table 2). The actual critical values and p-values will be computed
using statistical methods for group sequential testing with the O’Brien Fleming method (O’Brien
and Fleming, 1979; Lee and Quan, 1993).
Table 2
Critical Values and p-Values for Planned Interim Analysis
Interim and
Final Analyses
Total Sample
Critical
Value
p-value
Cumulative
Type I Error
Interim (1)
400
3.65
0.0003
0.0003
Final (2)
1180
2.58
0.0098
0.0101
8.6.2
Futility Analysis
Under the condition that the proportional odds model assumption holds, the statistical power to
reject the null hypothesis of equal six-month GOS is shown below under a variety of scenarios.
Conditional power is the estimate of the power to observe a difference in treatment groups
different from that observed at the interim analysis. The conditional power is calculated based


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upon the observed critical value and measure of the completion of the trial. Methods for this
calculation have been proposed by Lan, DeMets and Halperin (1984) and Lan, Simon and
Halperin (1982) (Table 3).
Table 3
Futility Analysis: Power to Reject Null Hypothesis under Various Scenarios
1
A common odds ratio of 1.27, 1.5 and 2.33 is equivalent to a 5%, 10% and 20% effect size respectively.
2
Interim analysis is based on the assessment of 400 completed subjects (200 in each arm).
3
Final analysis is based on total study recruitment at 1180 subjects with 590 in each arm. This sample size is
calculated based on the defined baseline outcome distribution (30% GR, 21% MD, 19% SD and 30% VS/D) to
detect a common odds ratio of 1.5 of improvement in outcome with 90% power and 1% significance level (two-
sided).
8.6.3
Outcomes of Interim Analysis
If the p-value from the test of the null hypothesis of no treatment difference is less than 0.0003 at
the interim analysis, the study could be stopped for efficacy.
No formal stopping rule for futility will be established for this study.
An assessment of
conditional power at the interim analysis will be provided to the DSMB for consideration with
the safety summaries in the evaluation of the overall risk/benefit of the study treatment.
Common odds ratio1
Power at interim and final analysis
Placebo
BHR-100
Interim analysis2
Final analysis3
1.0
1.27
1.54%
39.36%
1.0
1.50
10.93%
90.66%
1.0
2.33
88.49%
99.99%


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9.
ADVERSE EVENT COLLECTION AND REPORTING
9.1
Adverse Event Collection
All AEs will be recorded for the first 15 days after the start of administration of the study drug (5
days of drug infusion and 10 days post infusion). SAEs will be recorded for the entire 6-month
period. The Adverse Events eCRF must be completed for all reported AEs and SAEs.
An adverse event is defined as:
“Any untoward medical occurrence in a subject or clinical
investigation subject administered a pharmaceutical product that does not necessarily have a
causal relationship with this treatment.” An adverse event can therefore be any unfavorable and
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally
associated with the use of a medicinal (investigational) product, whether or not related to the
medicinal (investigational) product.
This includes any newly occurring event or previous
condition that has increased in severity or frequency since the administration of study drug.
Instances of neuroworsening are considered AEs.
Details of any adverse or unexpected events, signs, and symptoms will be collected including
details of onset, resolution, frequency, severity (as defined below), seriousness, relationship to
the drug, effect on the study drug, treatments administered, and outcome.
Any AE will be
followed, whenever possible, until it returns to the baseline condition or becomes stable with no
further change expected.
9.2
Reporting of Adverse Events
Diagnoses vs. signs/symptoms:
Each AE should be recorded to represent a single diagnosis. Accompanying signs (including
abnormal laboratory values if not constituting AEs themselves or ECG findings) or symptoms
should NOT be recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s)
should be recorded as an adverse event(s).
Laboratory values and ECG findings:
Changes in laboratory values or ECG parameters may be considered AEs if they are judged to be
clinically significant (i.e., if some action or intervention is required or if the Investigator judges
the change to be beyond the range of normal physiological fluctuation). Clinically significant
abnormal lab values not considered AEs by the Investigator will be followed as indicated in
Section 7.2.3. If abnormal laboratory values or ECG findings are the result of pathology for
which there is an overall diagnosis (e.g., increased creatinine in renal failure), the diagnosis only
should be reported as an AE.
Pre-existing conditions:
Pre-existing conditions (present before the start of the AE collection period) are considered
concurrent medical conditions and should NOT be recorded as AEs. However, if the subject
experiences a worsening or complication of such a concurrent condition, the worsening or
complication should be recorded as an AE.
Investigators should ensure that the AE term
recorded captures the change in the condition (e.g., “worsening of….”).


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Preplanned surgeries or procedures:
Preplanned procedures (surgeries or therapies) that were scheduled prior to the start of adverse
event collection are not considered AEs. However, if a preplanned procedure is performed early
(e.g., as an emergency) due to a worsening of the preexisting condition, the worsening of the
condition should be captured as an AE.
Elective surgeries or procedures:
Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as AEs, but should be documented in the subject’s source documents.
Insufficient clinical response (lack of efficacy):
Insufficient clinical response, efficacy, or pharmacological action, should NOT be recorded as an
AE. The Principal Investigator must make the distinction between exacerbation of pre-existing
illness and lack of therapeutic efficacy.
Overdose:
Cases of drug overdose without manifested side effects are NOT considered AEs.
Relationship to Study Drug:
The AE/SAE relationship to the study treatment will be judged as not related, possibly related,
probably related, or related. It should be noted that the half-life of progesterone in BHR-100 was
found to be 5.30 hrs (SD 0.66) in BHR’s Phase 1 trial of healthy male subjects, with
progesterone largely cleared by 24 hours.
9.3
Assessment of Adverse Event Severity
The following guidelines for rating severity of adverse events should be used:
Mild:
Awareness of signs or symptoms, but easily tolerated; are of minor irritant type; no loss of time
from normal activities; symptoms would not require medication or a medical evaluation; signs
and symptoms may be transient, disappearing during continued treatment with study medication.
Moderate:
Discomfort enough to cause interference with usual activities; the study medication may have
been interrupted.
Severe:
Incapacitating with inability to do work or do usual activities; signs and symptoms may be of
systemic nature or require medical evaluation; the study drug may have been stopped, and
treatment for the event may be required.
The term “severe” is often used to describe the intensity of a specific event, as in mild, moderate,
or severe myocardial infarction; the event itself, however, may be of relatively minor medical
significance, such as severe headache.
This is not the same as serious, which is based on


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subject/event outcome or action criteria usually associated with events that pose a threat to a
subject’s life or functioning. The Investigator must decide whether each AE meets the definition
of an SAE.
9.4
Serious Adverse Events and Expedited Reporting
An SAE is any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening.
Life-threatening, in the definition of serious, refers to an event in
which the subject was at risk of death at the time of the event; it does not refer to an event
which hypothetically might have caused death if it were more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Is considered medically significant by the Investigator or requires intervention to prevent
any one of the outcomes above.
Medically significant are those events considered
important in the Investigator’s opinion that may not be immediately life-threatening or
result in death or hospitalization but may jeopardize the subject or may require
intervention to prevent one of the other outcomes listed in the definition above. These
will also usually be considered serious.
All SAEs will be recorded from the time of the start of the study infusion through the subject’s
participation in the study (6 months). The Medical Monitor must be notified within 24 hours.
All SAEs should be monitored until they are resolved or are clearly determined to be due to a
patient’s stable or chronic condition or intercurrent illness(es).
Cause of death is required whenever known. If an autopsy was performed, an autopsy report
should be provided. Death should usually be reported as the outcome of a specific SAE.
Reports for hospitalization of elective procedures do not need to be reported as SAEs if there are
no precipitating signs/symptoms or worsening of a pre-existing condition that necessitated the
procedure. However, SAEs must be reported for any complications resulting from a procedure
that prolonged the hospitalization.
The following is a list of events that are anticipated to occur in the targeted severe TBI
population, in the absence of study drug.

hypoxemia

hypotension

dyspnoea

increased ICP

pneumonia

sepsis

cerebral infarction






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10.
REGULATORY AND PROCEDURAL REQUIREMENTS
10.1
Ethical Conduct of the Study
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for
designing, conducting, recording, and reporting studies that involve the participation of human
subjects.
This study will be conducted in compliance with GCP and the applicable national
regulations so as to assure that the rights, safety, and wellbeing of the participating study subjects
are protected consistent with the ethical principles that have their origin in the Declaration of
Helsinki.
10.2
Independent Ethics Committee or Institutional Review Board
The Sponsor (or an authorized representative) or the Investigator (according to national
provisions) is responsible for following the regional law where the study is to be conducted to
obtain written approval for the clinical study protocol (including all substantial protocol
amendments), the subject informed consent (including written assent, when applicable),
informed consent updates, subject recruitment procedures (e.g., advertisements) and any other
information to be provided to subjects from an IEC/IRB that complies with the local regulatory
requirements.
Written approval of the study must be obtained from the IEC/IRB prior to the study being
implemented (i.e., shipment of clinical supplies to the Investigator or screening of subjects).
Copies of the approval documentation will be maintained by both the Investigator and the
Sponsor (or an authorized representative) in the designated study documentation files.
The Sponsor (or an authorized representative) or the Investigator (according to national
provisions) will submit written reports of the clinical study status to the IEC/IRB annually, or
more frequently if requested by the IEC/IRB. A final study notification should be forwarded to
the IEC/IRB within 90 days after the study has completed, or in the event of premature
termination of the study within 15 days, with the rationale for study termination clearly
explained. Copies of all clinical study status reports (including termination) will be maintained
by both the Investigator and the Sponsor (or an authorized representative) in the study
documentation files.
In accordance with national provisions and the rules of the Food and Drug Administration (FDA),
European Parliaments Clinical Trial Directive, or applicable national or state laws, the Sponsor
(or an authorized representative) will inform all participating IECs/IRBs and national authorities
of all SAEs or other safety-related information, which occur during the clinical study as
appropriate.
10.3
Subject Information and Consent
As patients in this study will not be able to provide informed consent at baseline due to clinical
status, informed consent will be obtained following the regional law where the study is being
conducted, under the guidance of the IRB/IEC while remaining fully compliant with ICH
guidelines.
The Investigator is responsible for assuring the appropriate content of the informed consent form
and that informed consent is obtained for each subject in accordance with the applicable local


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regulations and guidelines. The original signed informed consent is to be retained in the study
documentation files.
The Investigator shall maintain a log of all subjects for whom informed consent is obtained and
indicate if the subject received study drug or, if not, the reason why.
The subject’s medical
records should also document that the informed consent was obtained, including date and time,
and that the appropriate local legal requirements regarding informed consent were followed.
The Investigator will give the subject’s LAR information about the trial in a form that the LAR
can read and understand. If the LAR is unable to read, oral information on the trial will need to
be provided to the LAR using the Patient Information Sheet in the presence of a witness, if
applicable, according to regional law.
Informed consent will be obtained for this trial in two phases: First, where applicable by local
law, a LAR or other authorized representative may provide consent and second, subjects may
provide consent later if and when they become capable of self-consent. The subject (and/or the
subject’s LAR) will be informed that he/she could withdraw from the trial at any time for any
reason.
The subject will be informed about the trial if and whenever he/she becomes competent to give
an opinion on continuation in the trial, and the subject will be given the opportunity to withdraw
from the trial. If the subject consents to continue in the trial, the subject will be requested to
record consent by signing the Subject Informed Consent Form.
If consent is denied by the
subject, the subject will be immediately withdrawn from the trial.
If a subject dies before
becoming able to consent, then the above rights to trial data will remain with the LAR.
10.4
Data Safety Monitoring Board
An independent DSMB will be appointed to have responsibility for safeguarding the interests of
trial subjects, and assessing the safety and efficacy of the study treatments during the trial. The
DSMB’s assessments will be based on safety and efficacy data periodically sent to the DSMB
statistician at approximately 100-subject intervals, with precise intervals to be determined in
consultation with the DSMB. The DSMB will have the authority to recommend stopping the
trial at any point based upon stopping rules agreed upon with the Sponsor.
Based on its review, the DSMB might also provide the Sponsor with recommendations regarding
study modification. The DSMB will consist of independent clinicians and biostatisticians that,
collectively, have experience in the management of patients with TBI and in the conduct and
monitoring of randomized clinical trials.
The DSMB will function in accordance with a
dedicated charter and the study protocol.
10.5
Steering Committee
A TBI Steering Committee, composed of members of American Brain Injury Consortium
(ABIC) and European Brain Injury Consortium (EBIC), and other experts in the fields of TBI
clinical research, provides scientific and academic leadership for this study in consultation with
the Sponsor. The goals and study design have been endorsed by ABIC and EBIC.


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10.6
ABIC (American Brain Injury Consortium)
ABIC is a group of distinguished neurosurgeons and clinicians dedicated to improving the
outcome of brain injury patients, and whose mission is to increase the scientific merit of TBI
clinical trials.
ABIC Quality Review:
For quality assurance purposes, ABIC will review clinical data in the eCRF of selected trial
subjects to ensure that all medications and procedures required to treat the subject’s TBI were
administered according to the study protocol.
Based on its Quality Review, ABIC will provide the Sponsor or its designee with Quality
Review Reports regarding clinical sites’ compliance with the study protocol.
10.7
Investigator Obligations
The Principal Investigator agrees to conduct the clinical study in compliance with this protocol
which was approved by the IEC/IRB in compliance with local regulatory requirements.
The
Investigator and the Sponsor will sign the protocol (Page 2) to confirm this agreement.
10.8
Electronic Case Report Forms (eCRFs)
Data collection for this protocol will be accomplished using an Electronic Data Capture system
(EDC). Therefore, the term eCRF will be utilized.
eCRFs are required and must be completed for each randomized subject. It is the Investigator’s
responsibility to ensure the accuracy, completeness, , and timeliness of the data reported on the
subject’s eCRF. eCRFs should be completed in a timely fashion to support the study timelines.
Source documentation supporting the eCRF data should indicate the subject’s participation in the
study and should document the dates and details of informed consent, study procedures, adverse
events, and status. The Investigator or designee should complete and the Investigator should
verify the source documents as the information is collected. Completed case report forms must
be submitted for each randomized subject. The Investigator will retain a copy of all completed
source documents.
10.9
Monitoring the Study
Site visits and inspections will be conducted by the Sponsor or designee at regular intervals in
accordance with FDA and International Conference on Harmonization (ICH) guidelines. The
Investigator will permit representatives of the sponsor’s monitoring team, FDA or local health
authority auditors to inspect facilities and records relevant to this study.
10.10
Protocol Deviations
The Investigator will make every attempt to avoid deviations from the protocol, except in
medical emergencies.
In the event of a medical emergency, the Medical Monitor must be
notified as soon as possible. The governing IRB/IEC will be informed of all protocol changes
issued by the Sponsor by the investigator in accordance with the IRB/IEC’s established
procedure.


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11.
DATA HANDLING AND RECORDKEEPING
11.1
Disclosure of Data
Individual subjects’ medical information obtained as a result of this study is considered
confidential and disclosure to third parties other than those noted below is prohibited. Subject
confidentiality will be further assured by utilizing subject identification code numbers. If results
of this study are reported in medical journals or at meetings, the subject’s identity will remain
confidential.
Medical information may be provided to the subject’s personal physician or to
other appropriate medical personnel responsible for the subject’s welfare.
Data generated as a result of this study are to be available for inspection on request by FDA/local
health authority auditors, the sponsor’s monitors, and by the IRBs/IECs. If the FDA or other
regulatory agency should schedule an inspection, the Medical Monitor should be advised
immediately.
11.2
Publication
By signing the study protocol, the Investigator agrees that the results of the study may be used
for the purposes of national and international registration, publication, and information for
medical and pharmaceutical professionals by the Sponsor.
Publications or presentations based on the study may not be made until the study is completed,
unless so decided by the Sponsor. Once the Sponsor or designee publishes the final report and
main study manuscript, or if publication has not occurred within 18 months after completion of
the study (final database lock), an Investigator may individually publish or present information
on this study, preferably providing the manuscript to the Sponsor for review prior to
publication. The Clinical Trial Agreement between the Investigator and the Sponsor may
provide additional terms regarding publication or presentation based on the study.
11.3
Record keeping and Retention
The Investigator must maintain adequate records for the study including completed case report
forms, medical records, laboratory reports, signed informed consent documents, drug disposition
records, adverse experience reports, information regarding subjects who discontinued, all
correspondence with the IRB/IEC and the sponsor, and other pertinent data.
All records are to be retained by the Investigator for a minimum period of 2 years after the
United States Food and Drug Administration/local health authority approves the New Drug
Application (NDA); or a minimum period of 2 years following the termination or withdrawal of
the health regulatory agency exemption (e.g., Investigational New Drug (IND) or clinical trial
application) under which the study was conducted. To avoid any possible errors, the Investigator
must contact the Sponsor prior to the destruction of any study records. The Investigator will also
notify the Sponsor in the event of accidental loss or destruction of any study records.


Progesterone in Patients with Severe Traumatic Brain Injury
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Page 46 of 53
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November 15, 2011
12.
REFERENCES
American Brain Injury Consortium. (2003). ABIC Patient Care Guidelines. October 7,
2003. http://www.abic.vcu.edu/guidelines/abicguidelines.cfm
Brain Trauma Foundation (BTF), American Association of Neurological Surgeons,
Congress of Neurological Surgeons, Joint Section on Neurotrauma and Critical Care,
AANS/CNS, Bratton, S.L., Chestnut, R.M., Ghajar, J., et al. (2007). Guidelines for the
management of severe traumatic brain injury. J. Neurotrauma. 24 Suppl 1, S77-82.
Brown, A.W., Elovic, E.P., Kothari, S., Flanagan, S.R., and Kwasnica, C. (2008).
Congenital and acquired brain injury. 1. Epidemiology, pathophysiology, prognostication,
innovative treatments, and prevention. Arch. Phys. Med. Rehabil., 89 (Suppl 1), S3-8.
Cutler, S.M., Cekic, M., Miller, D.M., Wali, B., VanLandingham, J.W., Stein, D.G., et al.
(2007). Progesterone improves acute recovery after traumatic brain injury in the aged rat. J.
Neurotrauma, 24(9), 1475-1486.
Cutler, S.M., Pettus, E.H., Hoffman, S.W., Stein, D.G. (2005). Tapered progesterone
withdrawal enhances behavioral and molecular recovery after traumatic brain injury. Exp.
Neurol., 195(2), 423-429.
Cutler, S.M., VanLandingham, J.W., Murphy, A.Z., Stein, D.G. (2006). Slow-release and
injected progesterone treatments enhance acute recovery after traumatic brain injury.
Pharmacol. Biochem. Behav. 84(3), 420-428.
Djebaili, M., Guo, Q., and Pettus, E.H. (2005). The neurosteroids progesterone and
allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain
injury in rats. J. Neurotrauma, 22, 106-118.
Djebaili, M., Hoffman, S.W., and Stein, D.G. (2004). Allopregnanolone and progesterone
decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex.
Neurosci., 123, 349-359.
Duvdevani, R., Roof, R.L., and Fulop, Z. (1995). Blood-brain barrier breakdown and edema
formation following frontal cortical contusion: does hormonal status play a role? J.
Neurotrauma, 12, 65-75.
Faul, M., Xu, L., Wald, M.M., Coronado, V.G. (2010). Traumatic Brain Injury in the
United States: Emergency Department Visits, Hospitalizations and Deaths 2002–2006.
Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury
Prevention and Control.
Galani, R., Hoffman, S.W., Stein, D.G. (2001). Effects of the duration of progesterone
treatment on the resolution of cerebral edema induced by cortical contusions in rats. Restor.
Neurol. Neurosci. 18(4), 161-166.


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November 15, 2011
Gibson, C.L., Gray, L.J., Bath, P.M.W., Murphy, S.P. (2008). Progesterone for the
treatment of experimental brain injury; a systematic review. Brain. 131(Pt 2), 318-328.
Grossman, K.J., Goss, C.W., and Stein, D.G. (2004). Effects of progesterone on the
inflammatory response to brain injury in the rat. Brain Res., 1008, 29-39.
Guo, Q., Sayeed, I., and Baronne, L.M. (2006). Progesterone administration modulates
AQP4 expression and edema after traumatic brain injury in male rats. Exper. Neurol., 198,
469-478.
He, J., Hoffman, S.W., and Stein, D.G. (2004). Allopregnanolone, a progesterone
metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain
injury. Restor. Neurol. Neurosci., 22, 19-31.
Hukkelhoven, C.W.P.M., Steyerberg, E.W., Rampen, A.J.J., et al. (2003). Patient age and
outcome following severe traumatic brain injury: an analysis of 5600 patients. J.
Neurosurg., 99(4), 666-673.
Jennett, B., and Bond, M. (1975). Assessment of outcome after severe brain damage.
Lancet., 1(7905), 480-484.
Jennett, B., Snoek, J., Bond, M.R., Brooks, N. (1981). Disability after severe head injury:
observations on the use of the Glasgow Outcome Scale. J. Neurol. Neurosurg. Psychiatr.,
44(4), 285-293.
Lan, K.K.G., DeMets, D.L., Halperin, M. (1984). More flexible sequential and non-
sequential designs in long-term clinical terms. Commun Statist-Theor. Meth. 13, 2339-2353.
Lan, K.K.G., Simon, R., Halperin, M. (1982). Stochastically curtailed tests in long-term
clinical trials. Commun. Stat.-Sequential Analysis, 1, 207-219.
Langlois, J.A., Rutland-Brown, W., and Wald, M.M. (2006). The Epidemiology and Impact
of Traumatic Brain Injury. J. Head Trauma Rehabil., 21(5), 375-378.
Lee, Y.J., and Quan, H. (1993). P-values after repeated significance testing: a simple
approximation method. Stat Med., 12(7), 675-684.
Maas, A.I., Dearden, M., Teasdale, G.M., et al. (1997). EBIC-guidelines for management
of severe head injury in adults. European Brain Injury Consortium. Acta Neurochir (Wien).
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Maas, A.I.R., Murray, G., Henney, H., et al. (2006). Efficacy and safety of dexanabinol in
severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical
trial. Lancet Neurol. 5(1), 38-45.
Marmarou, A., Lu, J., Butcher, I., et al. (2007). IMPACT database of traumatic brain injury:
design and description. J. Neurotrauma, 24(2), 239-250.


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Marshall, L.F., Marshall, S.B., Klauber, M.R., et al. (1992). The diagnosis of head injury
requires a classification based on computed axial tomography. J. Neurotrauma. 9 Suppl 1,
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Maset, A.L., Marmarou, A., Ward, J.D., Choi, S., Lutz, H.A., Brooks, D., Moulton, R.J.,
DeSalles, A., Muizelaar, J.P., Turner, H., et al. (1987). Pressure-volume index in head
injury. J. Neurosurg. 67(6), 832-840.
McCullagh, P. (1980). Regression-models for ordinal data. J. R. Statist. Soc. Ser. B
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517.
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Pettus, E.H., Wright, D.W., Stein, D.G., and Hoffman, S.W. (2005). Progesterone treatment
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Roof, R.L., Duvdevani R., Heyburn, J.W., and Stein, D.G. (1996). Progesterone rapidly
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Progesterone in Patients with Severe Traumatic Brain Injury
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Shear, D.A., Galani, R., Hoffman, S.W., and Stein, D.G. (2002). Progesterone protects
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the Glasgow Outcome Scale. J. Neurotrauma, 15(8), 587-597.
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Wright, D.W., Bauer, M.E., Hoffman, S.W., and Stein, D.G. (2001). Serum progesterone
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Wright, D.W., Ritchie, J.C., Mullins, R.E., Kellerman, A.L., and Denson, D.D. (2005).
Steady-state serum concentrations of progesterone following continuous intravenous
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Wu, X., Hu, J., Zhuo, L., Fu, C., Hui, G., Wang, Y., et al. (2008). Epidemiology of
traumatic brain injury in eastern China, 2004: a prospective large case study. J. Trauma,
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Xiao, G., Wei, J., Yan W., Wang, W., and Lu, Z. (2008). Improved outcomes from the
administration of progesterone for patients with acute severe traumatic brain injury: a
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Xiao, G.M., Wei, J., Wu, Z.H., Wang, W.M., Jiang, Q.Z., Cheng, J., et al. (2007). Clinical
study on the therapeutic effects and mechanism of progesterone in the treatment for acute
severe head injury. Zhonghua Wai Ke Za Zhi (Chinese Journal of Surgery), 45, 106-108.


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APPENDIX A
SCHEDULE OF EVENTS
Study Procedure
Screening
(Within 8 hrs of
injury)
Day 1-5
(infusion period:
120 hours)
Day 6
(post-infusion)
Days
7-15
Day 30
(1 month)
Day 90
(3 months)
Day 180
(6 months)
Inclusion/exclusion criteria
X
Informed consent
X
Demographics
X
Medical history
X
Concomitant medications/procedures1
X
X
X
X
Physical exam
X
X
Body Weight
X
X
Serum/urine pregnancy test2
X
Study treatment
X
ECG
X
X
Vital Signs, pupil response3
X
X
X
ICP3 and TIL4
X
X
X
CT scan
X
X
Local labs/urinalysis
X
X
Day 15
Arterial blood gases5
X
X
X
Daily fluid balance
X
X
GCS6
X
X
X
Day 15
Pre-Injury Narrative for GOS Assessment7
X
GOS (in-person assessment)
X
X
GOS-E (in-person assessment)
X
X
Adverse Events
X
X
X
Neuroworsening (if applicable)
X
X
X
Serious Adverse Events
X
X
X
X
X
X
SF-36 (in-person assessment)
X
X
Progesterone sampling8
X
ICU/hospital discharge dates
X
X
X
X
Mortality
X
X
1 To be recorded starting after informed consent has been obtained; 2 Only for females of childbearing potential
3 Vital Signs [heart rate (bpm), respiration rate (per min), systolic and diastolic blood pressure (mm Hg), temperature (Cº), and pupil response] and ICP recorded for a period of
up to 6 days; duration of ICP monitoring at discretion of the Investigator; ICP at 4 times per day, and ICP and vital signs whenever TIL changes
4 TIL recorded for up to 6 days while ICP being monitored; 5 ABGs daily while subject is intubated; 6 GCS best score daily if possible to obtain
7 Must complete within 14 days of Randomization; 8 To be analyzed by the Central Lab; 1 blood draw on Day 2 ( 48+/- 6 hrs after initiation of the study drug infusion);
additional PK sampling only at selected sites.


Pr o gester o ne i n P atie nts wit h Se vere Tr a u m atic Br ai n I nj ur y 
B H R P h ar m a, L L C 
Pa ge 5 2  of 53  
A me n d me nt 3 
N o ve m ber 1 5, 2 0 1 1 
A P P E N DI X B 
L A B O R A T O R Y A S S E S S M E N T S  
( S C R E E NI N G, D A Y 6, D A Y 1 5) 
 
Ser u m C he mistr y: 
 
 
•  As partate a mi n otra nsferase ( A S T) 
•  Ala ni ne a mi n otra nsferase ( A L T) 
•  Al kali ne p h os p hatase 
•  Ga m ma gl uta m yl tra nsferase ( G G T) 
•  S o di u m 
•  P otassi u m 
•  C hl ori de 
•  Gl uc ose 
•  T otal pr otei n 
•  T otal C h olester ol 
•  Tri gl yceri des 
 
 
He m at ol o g y: 
 
•  W hite bl o o d cell c o u nt ( W B C) 
•  Re d bl o o d cell c o u nt ( R B C) 
•  He m o gl o bi n 
•  He mat ocrit 
•  Platelet c o u nt 
•  Differe ntial W B C 
•  Retic ul oc yte c o u nt 
 
Uri n al ysis: 
 
•  Micr osc o pic e xa mi nati o n 
•  S pecific gra vit y 
•  p H 
•  Pr otei n 
•  Gl uc ose 
•  Bl o o d 
 
 
Arteri al Bl o o d G ases: 
(if t he s u bject is i nt u bate d or has a n arterial 
li ne place d; n ot re q uire d at Da y 1 5): 
 
•  p H 
•  Pa O 2 
•  H C O 3 
•  Pa C O 2 
•  Sa O 2 
•  Fi O 2 
 


Pr o gester o ne i n P atie nts wit h Se vere Tr a u m atic Br ai n I nj ur y 
B H R P h ar m a, L L C 
Pa ge 5 3  of 53  
A me n d me nt 3 
N o ve m ber 1 5, 2 0 1 1 
 
Ot her: 
 
•  I nter nati o nal N or malize d Rati o 
(I N R) 
•  Ser u m or uri ne pre g na nc y test 
(fe males of c hil d beari n g p ote ntial) – 
Scree ni n g O nl y  
 
 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 1 of 213 
STATISTICAL ANALYSIS PLAN 
BHR-100-301 
A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study to Investigate the Efficacy 
and Safety of Progesterone in Patients with Severe Traumatic Brain Injury 
Prepared for: 
BHR Pharma, LLC 
Version and Author details: 
Version Date: 
19APR2014 
Version Number 
2.0 
Author: 
 
 
 
 
 
 
 
 


 
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Protocol No. BHR-100-301 
 
 
Page 2 of 213 
SIGNATURES 
The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
  
 
 
 
 
 
 
 
 
 
Date 
 
  
 
 
 
 
 
 
 
Date 
 
  
 
 
 
 
 
 
 
 
 
Date 
 
 
 
 


 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 3 of 213 
TABLE OF CONTENTS 
1 
INTRODUCTION ............................................................................................................. 5 
1.1 
Changes from the protocol ............................................................................................. 5 
2 
STUDY OBJECTIVES ........................................................................................................ 5 
3 
STUDY DESIGN ............................................................................................................... 5 
3.1 
Sample Size Considerations ............................................................................................ 7 
3.2 
Randomization .............................................................................................................. 7 
4 
STUDY VARIABLES AND COVARIATES ........................................................................... 8 
4.1 
Primary Outcome Variable .............................................................................................. 8 
4.2 
Secondary Outcome Variables ........................................................................................ 8 
4.2.1 
Efficacy ................................................................................................................... 8 
4.2.2 
Safety ..................................................................................................................... 8 
4.3 
Predetermined Covariates and Prognostic Factors ............................................................ 8 
5 
DEFINITIONS ................................................................................................................. 9 
6 
ANALYSIS SETS ............................................................................................................ 13 
6.1 
Modified Intention-to-Treat .......................................................................................... 13 
6.2 
Per Protocol ................................................................................................................ 13 
6.3 
Safety ......................................................................................................................... 14 
7 
INTERIM ANALYSIS ..................................................................................................... 14 
8 
DATA REVIEW ............................................................................................................... 16 
8.1 
Data Handling and Transfer ......................................................................................... 16 
8.2 
Data Screening ............................................................................................................ 16 
9 
STATISTICAL METHODS ............................................................................................... 17 
9.1 
Subject Disposition ...................................................................................................... 18 
9.2 
Protocol Deviations and Violations ................................................................................ 18 
9.3 
Treatments ................................................................................................................. 18 
9.3.1 
Extent of Study Drug Exposure ............................................................................... 18 
9.3.2 
Concomitant Medications, Concomitant Procedures and Surgical Therapy ................. 19 
9.4 
Demographic and Baseline Characteristics..................................................................... 19 
9.5 
Efficacy Analyses ......................................................................................................... 19 
9.5.1 
Primary Efficacy Analysis ........................................................................................ 19 
9.5.1.1 Proportional Odds Model ..................................................................................... 20 
9.5.1.2 Alternate Primary Efficacy Analysis (Sliding Dichotomy) ......................................... 23 
9.5.1.3 Sensitivity Analysis (Dichotomized Model) ............................................................. 24 
9.5.1.4 Interpretation of Statistical Significance of Primary Efficacy Analysis....................... 25 
9.5.1.5 Handling of Missing Data ..................................................................................... 26 
9.5.1.6 Exploratory Analysis ............................................................................................ 26 
9.5.2 
Secondary Variables .............................................................................................. 26 
9.5.2.1 Mortality at Month 1, Month 6 .............................................................................. 27 
9.5.2.2 GOS at Month 3 .................................................................................................. 27 
9.5.2.3 GOS-E at Month 3 and Month 6 ........................................................................... 27 
9.5.2.4 Quality of Life: SF-36 .......................................................................................... 28 
9.5.3 
Exploratory Variables ............................................................................................. 29 
9.5.3.1 Time to Death..................................................................................................... 29 


 
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9.5.3.2 Comparison of CT scans at admission and Day 6................................................... 30 
9.5.3.3 ICP .................................................................................................................... 30 
9.5.3.4 CPP .................................................................................................................... 31 
9.5.3.5 TIL ..................................................................................................................... 31 
9.6 
Safety Analyses ........................................................................................................... 31 
9.6.1 
Adverse Events ..................................................................................................... 31 
9.6.2 
Neuroworsening .................................................................................................... 33 
9.6.3 
Deaths and Serious Adverse Events ........................................................................ 33 
9.6.4 
Laboratory Data .................................................................................................... 33 
9.6.5 
Vital Signs ............................................................................................................. 33 
9.6.6 
Physical Examinations, ECGs, and Other Observations Related to Safety ................... 33 
9.6.6.1 Arterial Blood Gases ............................................................................................ 34 
9.6.7 
Progesterone Levels .............................................................................................. 34 
10 VALIDATION ................................................................................................................. 34 
11 REFERENCES................................................................................................................. 34 
APPENDIX 1 
GLOSSARY OF ABBREVIATIONS ............................................................... 36 
APPENDIX 2 
 LIST OF POST-TEXT TABLES, FIGURES, LISTINGS, AND SUPPORTIVE SAS 
OUTPUT APPENDICES......................................................................................................... 38 
APPENDIX 3 SHELLS FOR POST-TEXT TABLES, FIGURES, AND LISTINGS .......................... 57 
LISTINGS .......................................................................................................................... 147 
 


 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical methods to be used during the 
reporting and analysis of data collected under BHR Pharma Protocol BHR-100-301. 
  
This SAP should be read in conjunction with the study protocol and electronic case report form 
(eCRF).  This version of the plan has been developed using the protocol Amendment 3.0 dated 
November 15, 2011 and eCRF dated September 24, 2012.  Changes to the SAP based on 
protocol and/or eCRF revisions are reflected in this final verion. This version is approved prior to 
unblinding and analysis of the global trial 
 
The SAP has  been developed in two stages.  This amendment, SAP version 2.0, is is the final 
version prior to the global study database lock.  Versions of the SAP up to initial sponsor 
approval were known as SAP1.  PRA and the Sponsor (BHR Pharma) have agreed on the 
changes from version 1.0 to enable the final programming for the Clinical Study Report (CSR) 
and a potential New Drug Application (NDA). This final version of the SAP, version 2.0, has 
been approved by PRA and the sponsor prior to database lock. 
 
1.1 
Changes from the protocol 
 The protocol states that the primary efficacy analysis will be conducted on all 
randomized subjects.  BHR was advised by the Data and Safety Monitoring Board and 
the Steering Committee to redefine the intent-to-treat (ITT) population as all randomized 
subjects who received any amount of study drug treatment. This modified intent-to-treat 
(mITT) analysis was approved by the FDA in its Special Protocol Assessment Agreement 
Modification Letter dated April 4, 2013.  This version of the SAP defines the mITT 
population, which will be used for all efficacy analyses. 
 The protocol states that the Extended Glasgow Outcome Scale (GOS-E) will be analyzed 
using the 2-sided Wilcoxon Rank-Sum test.  This version of the SAP states that the 
GOS-E will be analyzed similarly to the GOS, using a proportional odds model (POM) 
and sliding dichotomy (SD). 
2 
STUDY OBJECTIVES 
The aim of this study is to determine the efficacy and safety of BHR-100 (intravenous (i.v.) 
progesterone lipid emulsion) compared to placebo infusion in the treatment of subjects with 
severe traumatic brain injury (TBI). 
3 
STUDY DESIGN 
This trial is a multicenter, randomized, double-blind, placebo-controlled study, conducted in 
approximately 140 Level I (or equivalent) trauma centers in a number of geographical areas 
including North America, Europe, Asia and South America, to compare the efficacy and safety 
of i.v. BHR-100 with placebo in the treatment of subjects following severe TBI.  Severe TBI is 
defined as a Glasgow Coma Scale (GCS) score at randomization of 3-8 (inclusive).  During their 
involvement in the study, subjects will be managed in accordance with standard guidelines for 


 
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Protocol No. BHR-100-301 
 
 
Page 6 of 213 
the management of severe TBI (Brain Trauma Foundation, American Brain Injury Consortium, 
and European Brain Injury Consortium). 
     
The planned duration of the study will be 6 months for each subject, with the study consisting of 
the 3 phases: 
 Screening, 
 Treatment, and 
 Follow-up. 
 
During the screening period, subjects will be assessed for inclusion into the study and informed 
consent will be obtained.  Medical and medication histories, physical exam including weight and 
pupil response, vital signs, ECG, laboratory tests (hematology, serum chemistry, urinalysis, and 
coagulation) and arterial blood gases (ABG: partial pressure of oxygen in arterial blood (PaO2), 
partial pressure of carbon dioxide in arterial blood (PaCO2), bicarbonate (HCO3), pH, saturation 
of oxygen in arterial blood (SaO2), and fraction of inspired oxygen (FiO2)) will be performed 
prior to the initiation of study drug treatment.  Intracranial pressure (ICP) and therapy intensity 
level (TIL) will be obtained prior to treatment initiation, if the ICP monitor is placed.  Pre-
treatment/baseline assessment of TBI will be recorded using GCS and computed tomography 
(CT) scan.   
Once a subject is determined to be eligible for inclusion into the study, he/she will be 
randomized (1:1) to receive either i.v. BHR-100 or placebo, stratified by geographic region 
(North America, Europe, Asia and South America) using an Interactive Web-based 
Randomization System (IWRS). 
During the treatment period, subjects will be administered continuous i.v. infusion of BHR-100 
or matching placebo for 120 hours and the GCS and neuroworsening (defined as any one of the 
following: a decrease in GCS motor score ≥ 2, development of pupillary abnormalities, any other 
neurological deterioration, or progression of lesion on CT scan leading to a change in subject 
management) will be assessed daily.  Vital signs, ABGs, ICP, and CPP will be recorded 
periodically, and TIL, concomitant medications, and adverse events (AEs) will be monitored 
continuously. 
 
During the follow-up period, subjects will be assessed at the following post-injury timepoints: 
 Day 6, 
 Day 15 (or ICU discharge), 
 Day 30 (Month 1), 
 Day 90 (Month 3), 
 Day 180 (Month 6). 
 
See the protocol schedule of events for further details of the efficacy and safety assessments 
conducted at each timepoint. 
An independent Data Safety Monitoring Board (DSMB) will monitor data periodically during 
the course of the study and will update the sponsor.  Reviews will occur at approximately 


 
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100-subject intervals.  A DSMB charter and Data Monitoring and Analysis Plan (DMAP) have 
been written to provide further details. 
There will be one interim analysis conducted when 200 subjects in each treatment group (400 
subjects total) have reached a study endpoint (completed the study and been assessed for 6-
month Glasgow Outcome Scale (GOS), died, or lost to follow up).  At the interim analysis, 
stopping for efficacy will be assessed using statistical methods for group sequential testing with 
the O’Brien Fleming method.   
Additionally, stopping the study for futility will be assessed by review of the conditional power 
at the interim analysis. 
3.1 
Sample Size Considerations 
The primary efficacy measurement for this study is GOS at 6 months after injury; see section 4.1. 
For the purposes of the analysis and sample size calculation, the first 2 categories of the GOS 
(vegetative state and dead) will be combined.  Based on the 6-month GOS outcome distribution 
from the head injury population with GCS 3-8 in the previous TBI Phase 3 trials in the 
International Mission for Prognosis and Analysis of Clinical Trials in TBI Project (IMPACT) 
Database, it is assumed that the following GOS responses will be observed at 6 months, in 
subjects treated with placebo: 31% good recovery, 21% moderate disability, 19% severe 
disability, and 29% vegetative state or dead (Lu, 2011).   
A sample size of 1,180 subjects receiving study drug (590 in each treatment group) will be 
needed to detect a common odds ratio of 1.5, of improvement in GOS at 6 months in BHR-100 
compared to placebo, at 90% power and a significance level of 0.01 (2-sided).  This calculation 
used the sample size equation for comparing 2 groups of ordinal data using the technique of 
ordinal logistic regression proposed by Whitehead (1997). 
3.2 
Randomization 
Subjects will be randomized to either BHR-100 or placebo on a 1:1 ratio, using an IWRS.  The 
randomization will be stratified by geographic region of the site locations in order to avoid 
imbalance in the distribution of treatment groups within regions.   
The following countries are planned to be involved in the study: Argentina, Austria, Belgium, 
China, Czech Republic, Finland, France, Germany, Hungary, Israel, Italy, Malaysia, 
Netherlands, Romania, Russia, Singapore, Spain, Taiwan, Thailand, United Kingdom, and 
United States.  Additional countries may be considered. 
These countries will be grouped into the following regions: North America (US), Europe 
(Austria, Belgium, Czech Republic, Finland, France, Germany, Hungary, Israel, Italy, 
Netherlands, Romania, Russia, Spain and UK), Asia (China, Malaysia, Singapore, Taiwan, and 
Thailand) and South America (Argentina). 


 
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4 
STUDY VARIABLES AND COVARIATES 
4.1 
Primary Outcome Variable 
The primary efficacy variable is the GOS at Month 6, post-injury assessment.  The GOS is a     
5-point scale used to assess the mortality and disability in TBI subjects and consists of the 
following 5 categories: 
 
Dead, 
 
Vegetative state, 
 
Severe disability, 
 
Moderate disability, and 
 
Good recovery. 
 
For this study the first 2 categories of the GOS (dead and vegetative state) will be combined. 
4.2 
Secondary Outcome Variables 
4.2.1 Efficacy 
The secondary efficacy parameters for this study will be as follows: 
 Mortality at Months 1 and 6, 
 GOS at Month 3, 
 Extended Glasgow Outcome Scale (GOS-E) at Months 3 and 6, 
 Quality of Life Short Form-36 Health Survey (SF-36) at Months 3 and 6. 
 
The exploratory efficacy parameters for this study will be as follows: 
 Changes in intracranial pathology as assessed by admission and Day 6 (+/- 1 day) CT 
scans, 
 Changes in ICP, CPP, and TIL. 
4.2.2 Safety 
In order to determine if i.v. BHR-100 is safe and well-tolerated, the following safety variables 
will be summarized: 
 AEs,  
 Vital signs,  
 Laboratory data, 
 Physical examinations, 
 Electrocardiogram (ECG), 
 ABG, and 
 Neuroworsening. 
4.3 
Predetermined Covariates and Prognostic Factors 
A number of predetermined prognostic covariates have been defined for consideration within this 
study: 


 
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 Age,  
 Motor response component of GCS (1-2, 3, 4, or 5-6) used to determine eligibility,  
 Pupillary response (bilateral, unilateral/no reactive pupils/not testable) used to determine 
eligibility,  
 Presence of hypoxia (yes/suspected, no/unknown) any time prior to randomization,  
 Presence of hypotension (yes/suspected, no/unknown) any time prior to randomization,  
 CT result at baseline (Marshall’s CT Classification I/II, III, IV, or evacuated/non-
evacuated mass lesion),   
 Presence of traumatic subarachnoid hemorrhage (yes, no), and 
 Region (North America, Europe, Asia, South America). 
All covariates will be measured at baseline, prior to randomization. 
Randomization is expected to balance covariates amongst the treatment groups; consequently, no 
formal testing of baseline comparability will be conducted. 
5 
DEFINITIONS 
Baseline and Change from Baseline, Repeated Observations 
The baseline value for each assessment is defined as the last measurement taken prior to 
randomization. 
For any parameter at a specific visit, change from baseline is calculated as the value of that 
parameter at that visit minus the baseline value of that parameter, as defined above. 
For data with repeated observations at a given visit, for example, vital signs, the first collected 
value will be used in summaries, with repeat values being included in the data listings only. 
Endpoint Completer 
A subject is considered an endpoint completer if they provide a GOS assessment at Month 6 or 
die before Month 6. 
Study Completer 
A subject is considered a study completer if they complete a 6 month assessment. 
Duration of study drug exposure (in hours) 
The duration of study drug exposure (in hours) = date:hour of last study medication administered 
– date:hour of first study medication administered  – sum of recorded durations of infusion rate 
interruptions. 
Please note, date:hour is used since both the date and time of medication administration is 
recorded in the CRF.  Only interruptions greater than 30 minutes are recorded on the eCRF and 
will be accounted for in the duration of study drug exposure derivation. 
Total Dose (in mg/kg) 
The total dose in mg for each study drug administration record will be calculated as: 
Infusion rate from eCRF (ml/hr) * total duration of study drug administration record (hr) * 2 
(mg/ml). 


 
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The total dose in mg will be summed across all study drug administration records for a subject 
and then divided by the weight in kg (from IWRS).  
Relative Dose 
The relative dose for a subject will be the total dose received in mg/kg divided by the total 
protocol expected dose of 60.21 mg/kg.  Relative dose will only be summarized for subjects who 
receive study drug for 120 hours +/- 5%, i.e. 114-126 hours. 
Study Medication Compliance (%) 
The study medication percent compliance will be calculated as: 
Number of hours of medication taken, as outlined in the protocol x 100 
120 (intended duration of medication intake) 
Primary Endpoint: GOS at Month 6 assessment (6 months after injury), missing data imputation 
When the primary efficacy endpoint is missing, the last observation carried forward (LOCF) 
principle will be used to populate the primary endpoint, i.e. the Month 3 GOS assessment will be 
carried forward.  In the event that a subject is lost to follow-up and has neither the 3 nor the 6-
month GOS, the missing values will be imputed based upon the primary proportional odds model 
(POM).   
To obtain values for the missing responses using the POM the predicted response probabilities 
will be used.  Specifying the PREDICTED option on the OUTPUT statement of PROC 
LOGISTIC, 3 (number of categories in response variable – 1) predicted probabilities will be 
provided for each subject; these are the ordered cumulative probability of each response 
category, i.e.  
 
Probability(Y≤1)=P(Y=1)=Probability GOS=1 
P(Y≤2)=Probability that GOS is 1 or 2 
P(Y≤3)=Probability that GOS is 1, 2 or 3 
 
Therefore, to obtain the predicted probability of each individual response, for example, the 
probability that the response was GOS=2, the following calculation is performed: 
 
P(Y=2)=P(Y≤2)-P(Y=1) 
 
Similarly,  
 
P(Y=3)=P(Y≤3)-P(Y≤2) 
 
and finally, 
 
P(Y=4)=1-[P(Y≤3)] 
 
since the individual probabilities must sum to one.   
 


 
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The missing GOS response will then be set to the most probable category, i.e. the response with 
the largest predicted probability. 
It is anticipated that there will be minimal missing data, however sensitivity analyses will be 
carried out to confirm that the imputation method(s) did not have an impact on the primary 
efficacy analysis results.  Therefore, the primary efficacy analyses will also be conducted on 
observed values only, without any imputation. 
Covariates, missing data imputation 
For the primary efficacy analyses, missing data for the following covariates will be imputed as 
the most commonly occurring value over subjects with non-missing data: motor response 
component of GCS, pupillary response, presence of hypoxia, presence of hypotension, CT 
classification, and presence of traumatic subarachnoid hemorrhage. 
GOS assessment – Dead responses 
Subjects without a GOS response assessment at Month 6 but who have a death date from the 
Death Report eCRF within 6 months + 28 days of their randomization date (calculated as death 
date – randomization date + 1 ≤ 208) will be assigned a Month 6 GOS response of Dead.  
Similarly, subjects without a GOS response assessment at Month 3 but who have a death date 
from the Death Report eCRF within 3 months + 28 days of their randomization date (calculated 
as death date – randomization date + 1 ≤ 118) will be assigned a Month 3 GOS response of 
Dead. 
Secondary Endpoint: Mortality at Month 1 
Survival status from the date of injury (Day 1 of the study) until Day 30 (Month 1) will be 
monitored and recorded as lost to follow-up, consent withdrawn, alive, dead or other.  Only 
subjects with a mortality assessment post-injury of alive or dead will be used in the assessment 
of mortality. 
Secondary Endpoint: Mortality at Month 6 
Survival status from the date of injury (Day 1 of the study) until Day 180 (Month 6) will be 
monitored and recorded as lost to follow-up, consent withdrawn, alive, dead or other.  Only 
subjects with a mortality assessment post-injury of alive or dead will be used in the assessment 
of mortality. 
Time to death 
The time to death (in days) will be defined as: 
Date of death – date of TBI + 1 
If a subject does not die during the conduct of the study, they will be censored at the earliest 
(minimum) of their Month 6 GOS assessment date and end of study date, and censor time (in 
days) will be defined as: 
Minimum(month 6 GOS assessment date, end of study date) – date of TBI + 1 
Since subjects were not followed for death after their Month 6 GOS assessment, subjects who 
have a death recorded after the assessment will be censored on the date of their Month 6 
assessment.    
 
 


 
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Exploratory Endpoint: CPP 
The following formulae are used to derive CPP: 
Mean Arterial Pressure (MAP) = 2/3 diastolic BP + 1/3 systolic BP; 
CPP = MAP – ICP.  
MAP will be recorded as missing if either systolic BP and/or diastolic BP measurements are not 
recorded.  CPP will be calculated where MAP and ICP have both been recorded; if either is 
missing the CPP will be recorded as missing. 
Exploratory Endpoint: TIL  
TIL will be monitored during Study Days 1 – 6 (inclusive).  The administration of each of the 
following unique treatments will have a score of 1 and the maximum score (sum of the 
individual items) per assessment period (study day) is 10: 
 Surgical decompression, 
 Barbiturate induced coma, 
 Hypothermia for ICP reduction, 
 Hyperventilation (pCO2 < 30), 
 Pressor administration, 
 Hypertonic saline, 
 Mannitol, 
 Ventricular drainage, 
 Paralysis induction, 
 Sedation. 
Neuroworsening 
Neuroworsening will be defined as the occurrence of any one of the following:  
 A decrease in GCS motor score ≥ 2,  
 Development of pupillary abnormalities,  
 Any other neurological deterioration or progression of lesion on CT scan leading to a 
change in subject management.  
 
Pupillary Response 
Pupillary response will come from the assessment of right and left pupil reactivity as follows: 
 
 If both right and left pupils react, pupillary response = bilateral,  
 If only one of the right or left pupil reacts, pupillary response = unilateral, and  
 If neither right nor left pupil reacts = no reactive pupils, or  
 If the eyes are closed and reactivity is untestable = not testable. 
Treatment-Emergent Adverse Events 
Treatment-emergent adverse events (TEAEs) are defined as events that start on or after the first 
dose of study medication.  For this study it is intended that AEs will be collected for 15 days 


 
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after the initiation of study treatment; serious adverse events (SAEs) will be collected from the 
time of infusion start throughout the course of the subject’s participation in the study (6 months).  
All AE tables will be presented for TEAEs only, listings will present all AEs (including those not 
deemed to be TE). 
6 
ANALYSIS SETS 
The following analysis populations will be defined for this study: 
 Modified Intention-to-treat (mITT), 
 Per Protocol (PP), and  
 Safety. 
The assignment of subjects to the study populations will occur at the blinded review meeting 
which will encompass discussion of major protocol violations. 
6.1 
Modified Intention-to-Treat 
The mITT population will include all randomized subjects in whom treatment with i.v. study 
drug was initiated.  Following the ITT principle, subjects will be analyzed according to the 
treatment they were assigned at randomization regardless of any randomization errors or amount 
of study drug infusion administered. 
The mITT population will be the primary efficacy population, and all efficacy analyses and 
summaries will be performed using this population.  All demographic and baseline summaries 
will also be summarized using the mITT population. 
6.2 
Per Protocol 
The PP population will include all subjects in the mITT population who meet all the 
inclusion/exclusion criteria, received at least 96 hours over the course of 120 hours of study 
treatment (however, not excluding those subjects who die or are discontinued for an AE prior to 
receiving the full dose of 120 hours), and have a non-missing 6-month GOS score that was 
assessed at least 152 days from randomization.  Subjects who initiate study drug infusion > 8 
hours from time of injury but within 9 hours will be included in the PP population.  The rationale 
for this is that the best available time of injury to the nearest hour is used at randomization, 
however a different time of injury may be determined later.   
Study drug administration errors will be handled according to the following table when 
determining inclusion in the PP population: 
 
 
 
 
 


 
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Table 1 
Handling of Study Drug Administration Errors in the Per Protocol Analysis 
Medication Error Scenario 
 
Inclusion in PP Population  
Randomized to 
Study Drug of Erroneously 
Received Bottle 
Placebo 
Placebo 
Included in placebo arm 
Placebo 
BHR-100 
Not included 
BHR-100 
BHR-100 
Included in BHR-100 arm 
BHR-100 
Placebo received as first 
administration of study drug or 
2 or more bottles of placebo 
received at any time 
Not included 
BHR-100 
1 placebo bottle received at any 
time except the first 
administration of study drug 
Included in BHR-100 arm 
Subjects at any site that is removed from the study for noncompliance with ABIC/EBIC/ Brain 
Trauma Foundation guidelines will be excluded from the PP population. 
No imputation of the 6-month GOS score will occur in the PP analysis, but missing covariates 
will be imputed as described in Section 5. 
The PP population will be used to perform confirmatory analyses of the primary efficacy 
evaluation. 
6.3 
Safety 
The safety population will include all subjects who received any study drug.  Subjects will be 
analyzed according to treatment received regardless of the randomization schedule.  If a subject 
received any amount of BHR-100, they will be summarized according to treatment BHR-100 for 
the safety population. 
The safety population will be used for all summaries of safety data and treatment exposure data. 
7 
INTERIM ANALYSIS 
A formal interim analysis will be performed once the first 200 subjects in each treatment arm 
(total of 400 subjects) have reached a study endpoint (death, lost to follow up, or completed the 
study and assessed for the 6-month GOS). The database used for the interim analysis will only 
contain these 400 subjects.   
 
At the planned interim analysis, the test statistic based on the effect size (common odds ratio) 
will be compared to the critical value shown below. If the test statistic exceeds the critical value, 
the unblinded study statisticians will discuss the continuation of the trial with the DSMB and the 
DSMB will inform the Sponsor. In order to stop the trial at the interim analysis, the significance 
level will need to be less than the critical p-value (i.e. p < 0.0003). 
 


 
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At the planned interim analysis, a 2-sided test will be performed to detect either an increase or 
decrease in the common odds ratio, as described in the section of this document on primary end 
point analysis, section 9.5.1. In order to preserve the over-all type I error rate at 1%, the critical 
value for the test statistic will be inflated above 2.575, the value that would be used if no 
repeated testing were used. The actual critical values and p-values will be computed using 
statistical methods for group sequential testing with the O’Brien Fleming method. 
 
If the p-value from the test of the null hypothesis of no treatment difference is less than 0.0003 at 
the interim analysis, the study may be stopped for efficacy.  Table 2 indicates the critical values, 
p-values and cumulative type I error for this study:  
 
Table 2 
Critical Values and p-Values of Interim and Final Analyses 
Interim and 
final analyses 
Total sample 
Critical Value 
p-value 
Cumulative 
Type I Error 
Interim (1) 
400 
3.65 
0.0003 
0.0003 
Final (2) 
1180 
2.58 
0.0098 
0.0101 
 
No formal stopping rule for futility will be established for this study.  An assessment of 
conditional power at the interim analysis will be provided to the DSMB for consideration with 
the safety summaries in the evaluation of the overall risk/benefit of the study treatment. 
 
Under the condition that the proportional odds model assumption holds, the statistical power to 
reject the null hypothesis of equal six-month GOS is shown below under a variety of scenarios 
(Table 3). 
 
Conditional power is the estimate of the power to observe a difference in treatment groups 
different from that observed at the interim analysis.  The conditional power is calculated based 
upon the observed critical value and measure of the completion of the trial.  Methods for this 
calculation have been proposed by Lan, DeMets and Halperin and Lan, Simon and Halperin. 
Table 3 
Futility Analysis: Power to Reject Null hypothesis under Various Scenarios 
 
1    A common odds ratio of 1.27, 1.5 and 2.33 is equivalent to a 5%, 10% and 20% effect size respectively. 
2    Interim analysis is based on the assessment of 400 completed subjects (200 in each arm). 
3    Final analysis is based on total study recruitment at 1180 treated subjects with 590 in each arm.  This sample size 
is calculated based on the defined baseline outcome distribution (31% Good Recovery, 21% Moderate Disability, 
19% Severe Disability and 29% Vegetative State/Death) to detect a common odds ratio of 1.5 of improvement in 
outcome with 90% power and 1% significance level (2-sided). 
Common odds ratio1 
Power at interim and final analysis 
Placebo 
BHR-100 
Interim analysis2 
Final analysis3 
1.0 
1.27 
1.54% 
39.36% 
1.0 
1.50 
10.93% 
90.66% 
1.0 
2.33 
88.49% 
99.99% 


 
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In the event that the final primary efficacy analysis does not show statistical significance at the 
study-wise 1% significance level (i.e. the final analysis p-value is not less than 0.0098) a final 
adjusted p-value will be calculated and the result considered statistically significant at the 5% 
level if the adjusted p-value is less than 0.05.  The adjusted p-value will be calculated using 
EAST (Cytel Statistical Software, Cambridge, MA) or other appropriate statistical software 
package to adjust for the interim analysis.   
8 
DATA REVIEW 
8.1 
Data Handling and Transfer 
For this study PRA International provides full Data Management services, including the 
development of the Data Management Plan (DMP) which outlines all Data Management 
activities to be undertaken.  The DMP is a living document that evolves over the course of a trial 
and consists of the following documents: 
 Data Management Process Summary, 
 Annotated CRF, 
 Data Management Quality Control Plan, 
 Critical Variable List, 
 Data Edit Specifications, 
 Dictionary Coding Conventions, 
 SAE/AE Reconciliation Plan, 
 Electronic Clinical Data Handling Instructions, and 
 Database Conversion Specifications. 
For this study, PRA International defines and maintains the study database.  The database will be 
provided to the PRA International Analysis and Reporting group in SAS dataset format.   
Assessments will be conducted at the central bioanalytical laboratory for blood levels of 
progesterone. 
8.2 
Data Screening 
Beyond the data screening built into the PRA DMP, programming of analysis datasets, tables, 
figures, and listings will be ongoing during the data management of the study. During this 
process potential data issues will be communicated to Data Management.  Before the data are 
considered clean (as defined by PRA Data Management processes), blinded tables, figures, and 
listings will be run (using a dummy randomization) and distributed to the study team for review.  
Any data values requiring investigation or correction will be identified at that point, and protocol 
deviations will be reviewed and documented.  Once all data issues have been resolved, the 
database will be locked, treatment codes unblinded, and the final run of outputs will take place. 
Furthermore, during the conduct of the study, an independent DSMB will meet to conduct safety 
reviews of the data, at approximately 100-subject intervals.  The duties, operational procedures, 
and frequency of meetings/teleconferences are described in the DSMB Charter.  At each 
meeting, the DSMB can recommend early trial termination or study modification in response to 
safety concerns. 


 
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The DSMB can request additional, unplanned, unblinded analysis of primary outcome data in 
case of major safety issues from the safety analysis.  Therefore, the DSMB will be able to 
monitor the study in its completeness by analyzing the overall risk/benefit of the trial results as 
necessitated by safety concerns that may arise.   
9 
STATISTICAL METHODS 
All analyses and reporting of study results will be conducted using SAS V9.1.3  In addition 
EAST will be used to adjust for the interim analysis.   
All variables will be presented using appropriate descriptive statistics according to the variable 
nature: 
 Continuous variables: number of non-missing observations, mean, standard deviation , 
minimum, first quartile (Q1), median, third quartile (Q3), maximum, 
 Categorical variables: number of non-missing observations, absolute and relative 
frequency (n and percentages (%)), 
 Time-to-event variables: number of non-missing observations, number and percentage of 
censored observations, first quartile, median (and 95% CI), third quartile, and 
Kaplan-Meier survival curves. 
The behavior over time of continuous variables will be analyzed by presenting descriptive 
statistics for each time point and the difference compared to baseline (actual values and change 
from baseline).  The behavior over time of categorical data will be analyzed by presenting the 
descriptive statistics for each time point and the shift compared to baseline.   
The decimal places for summary statistics and percentages will be as follows: 
 Precision of data + 2 decimal places (dp) for standard deviations, 
 Precision of data + 1 dp for means, medians and quartiles, 
 Same precision as data for minimum and maximum, 
 1 dp for percentages except when the percentage is 100% in which case no dp would be 
presented, and 
The primary and confirmatory efficacy analyses will be 2-sided and conducted at a 1% 
significance level.  All secondary efficacy tests will be 2-sided and conducted at a 5% 
significance level. 
The randomization will be stratified by region.  This variable will be included as a covariate in 
the primary and secondary GOS efficacy analyses. 
Secondary efficacy analyses will be conducted in ranked order as listed in Section 9.5.2 with the 
understanding that no confirmatory claims can be based on variables that have a rank lower than 
or equal to that variable whose null hypothesis was the first that could not be rejected at the 
p<0.05 significance level. 
All exploratory analyses will be considered supportive in nature, and therefore no adjustment 
will be made for multiple testing of exploratory variables. 
All data will be included in subject data listings for all subjects in the mITT population. 


 
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9.1 
Subject Disposition 
An enrollment summary will be presented overall and by site, showing the first date of consent, 
the date of the last subject randomized, duration (in days) (calculated as end date – start date +1), 
and number of subjects randomized and completed endpoint.   
 
The number and percentage of subjects randomized in total, by site, by country and by region 
will be summarized for each treatment group and overall for the mITT population. 
 
The number and percentage of subjects in each study population (mITT (randomized and treated 
with i.v. study drug), randomized but not treated, PP, Safety, Study Completers, Endpoint 
Completers (includes deaths prior to Month 6), and Early Terminations) and the reasons for early 
termination will be summarized by treatment group and overall for mITT subjects.   
 
Subjects remaining in the study by time will also be summarized.   
 
These details will also be listed. 
9.2 
Protocol Deviations and Violations 
Subjects with protocol violations that result in exclusion from the PP population will be listed. 
9.3 
Treatments 
9.3.1 Extent of Study Drug Exposure 
The number of subjects in each of the following categories will be summarized for each 
treatment group and overall for the safety population: 
 Who initiated study drug within 8 hours of injury, 
 Who were treated for at least 96 hours, 
 Who prematurely discontinued study drug (with the corresponding reason for 
discontinuation). 
Duration of study drug exposure and total dose will also be summarized for the safety 
population.  The duration of study drug exposure (in hours) will be summarized as both a 
continuous and categorical variable by treatment group and overall.  Total dose (in mg/kg) will 
also be summarized as a continuous variable.  Total dose received in milligrams will be adjusted 
by a subject’s weight entered into IWRS at the time of randomization.   
Continuous and categorical summaries of time since injury to study drug initiation will be 
presented. 
Counts and percentages of subjects with any infusion rate modifications or interruptions, and the 
reasons for infusion rate modifications and interruptions, will be summarized by treatment group 
and overall for the safety population. 
The percentage compliance with study medication will be summarized by treatment group and 
overall for the safety population as a continuous variable.  See Section 5 for further details. 


 
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9.3.2 Concomitant Medications, Concomitant Procedures and Surgical Therapy 
Prior medications are defined as medications with a start date before the first initiation of study 
medication.  Concomitant medications are defined as medications which: 
 
Started after the initiation of study medication,  
 
Had a stop date on or after the first administration of study medication, or 
 
Are ongoing on Day 15.   
It is possible for a medication to be both prior and concomitant.  It should be noted that 
medications administered to or taken by the subject during the study will only be recorded from 
the time of informed consent through to Day 15 of the study. 
Medications with partial start dates will be determined as prior and/or concomitant medications 
by using available non-missing information.  Medications with completely missing start dates 
(i.e. missing information for medication start day, month, and year) will be assumed to be 
concomitant.  If just the day is missing, and the month and year are the same as the month and 
year of study drug administration, the medication will be considered concomitant.  If the day and 
month are missing and the year is present, and is the same as the year of study drug 
administration, the medication will be considered concomitant.   
Medications will be coded using the WHO (World Health Organization) Drug Dictionary March 
2010 version international thesaurus with no updates, adding WHO-DD preferred term for use in 
the relevant tabulation.  Counts and percentages for prior and concomitant medications will be 
summarized by preferred term, treatment group and overall for the mITT population.   
The number and percentage of subjects with intracranial and extracranial surgery will be 
summarized by surgery type, actual surgical procedure (for example, craniofacial surgery), 
treatment group and overall for the mITT Population.  
9.4 
Demographic and Baseline Characteristics 
Demographic variables (age, sex, ethnicity and race), pregnancy testing, and baseline 
characteristics (geographical region, GCS motor score, pupillary response, presence of hypoxia, 
presence of hypotension, classification of CT scan, presence of traumatic subarachnoid 
hemorrhage) will be summarized for each treatment group and overall. 
The cause of TBI and type of injuries (face, chest, abdomen, extremities, spine, head injury 
alone) will be summarized by treatment group and overall.  
Medical histories will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 13.0 with no updates.  The number and percentage of subjects reporting any medical 
history will be displayed together with the number and percentage of subjects having at least one 
medical history within each system organ class (SOC) and preferred term. 
9.5 
Efficacy Analyses 
9.5.1 Primary Efficacy Analysis 
The primary efficacy variable is GOS evaluated at 6 months post injury.  The primary analysis 
will be based on imputation of missing data as described in Section 5. 
 


 
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9.5.1.1 
Proportional Odds Model 
The primary efficacy variable of GOS at 6 months post injury will be compared between 
treatment groups using a POM.  For the purposes of this analysis the first two categories of the 
GOS will be combined (vegetative state and dead).  A POM will be fitted including the effect of 
treatment, geographic region (North America, Europe, Asia, and South America), age, GCS 
motor score, pupil response, and CT classification.  With 4 categories in the response variable, 
GOS at 6 months following injury, the POM simultaneously fits 3 (number of categories – 1) 
binary logistic regression models as follows. 
 
If Y = response = GOS at 6 months following injury. 
 
Model 1 
Y1 = 0 (not event),  
if Y = vegetative state or dead 
Y1 = 1 (event),  
if Y = severe disability, moderate disability, good recovery 
 
Model 2 
Y2 = 0 (not event),  
if Y = vegetative state or dead, severe disability 
Y2 = 1 (event),  
if Y = moderate disability, good recovery 
 
Model 3 
Y3 = 0 (not event),  
if Y = vegetative state or dead, severe disability, moderate disability 
Y3 = 1 (event),  
if Y =good recovery 
 
The dichotomous logistic regression models for YJ (J=1, 2, 3) can be expressed as follows: 
 
ln (PJ/(1 – PJ)) = αJ + β1X1 + β2X2 + β3X3 + β4X4 + β5X5 + β6X6, 
 
where 
 ln is the natural logarithm, 
 PJ = Probability of an ‘event’ (for example, good recovery) = Probability that YJ = 1, 
 PJ/(1 – PJ) = odds of an ‘event’,  
 X1 = treatment group,  
 β1 = effect of treatment,  
 X2 = region,  
 β2 = effect of region,  
 X3 = age,  
 β3 = effect of age,  
 X4 = GCS motor score,  
 β4 = effect of GCS motor score,  
 X5 = pupil response,  
 β5 = effect of pupil response, and  
 X6 = CT classification,  
 β6 = effect of CT classification. 
 


 
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With a POM, it is assumed that the effect of the explanatory variables, such as treatment, are 
identical for all possible dichotomies of the response variable, that is, β1, etc. are the same for 
each model. 
 
The fact that the effects of the explanatory variables (e.g. treatment (β1), etc.) are the same for 
each model is referred to as the proportional odds assumption and needs to hold for this 
methodology to be appropriate.  This assumption will be tested using the Score Test.  A 
non-significant result (p-value > 0.05) supports the assumption of proportional odds.  As the 
Score Test is known to be anti-conservative, additional graphical methods will be used to assess 
the proportional odds assumption in greater detail, if the Score Test is statistically significant.   
 
The proportional odds assumption for an ordinal response implies that the curves on the various 
cumulative logits are parallel.  This assumption can be assessed visually for a given predictor 
(e.g. region) by plotting it against the empirical logits.  
 
For the 4 levels of the GOS there will be 3 cumulative logits which can be expressed as: 
 
Logit1 = log[ p1/(1-p1) ] = log[ p1/(p2+p3+p4) ] ,  
Logit2 = log[ (p1+p2)/(1-(p1+p2)) ] = log[ (p1+p2)/(p3+p4) ] ,  
Logit3 = log[ (p1+p2+ p3)/(1-(p1+p2+ p3)) ] = log[ (p1+p2+ p3)/(p4) ]  
where pi = P(Y=i), where Y (response, GOS at 6 months) = i and i=1, 2, 3 or 4. 
By using the observed counts, yi , in the study data empirical logits can be computed for use in 
plots as follows: 
EmpLogit 1 = log[ (y1)/(y2+y3+y4) ] 
where yi=number of subjects with Y (response, GOS at 6 months) = i and i=1, 2, 3 or 4. 
The empirical logits can then be calculated for each category of the predictor and plotted.  If the 
resulting plotted lines are roughly parallel this can be considered a visual confirmation of the 
proportional odds assumption.  
See Appendix 3 (Model Checking Figures) for plot specification details. 
  
Provided that the proportional odds assumption is not rejected, the POM will then be used to test 
the null hypothesis that the odds of being “higher” or “lower” on the outcome variable, GOS at 6 
months following injury, across the entire range of the outcome, adjusted for region, age, GCS 
motor score, pupil response, and CT classification (as defined in Section 4.3) is the same in both 
treatment groups, i.e. 
 
Null Hypothesis: 
H0 : β1 = 0 
Alternative Hypothesis: 
H1 : β1 ≠ 0 
 


 
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If the p-value from the test of the null hypothesis of 1 = 0 is less than 0.0003 (at the interim) or 
0.0098 (at the final analysis), it will be concluded that BHR-100 is statistically significantly 
different from placebo with respect to the GOS at 6 months following injury.  The odds of some 
degree of improvement in the GOS at 6 months will be modeled and the corresponding common 
odds ratio for treatment, 
1

e
, can then be interpreted to determine the direction of the treatment 
difference as follows.  With the placebo group being considered as the reference category, if the 
odds ratio (ORBHR-100/placebo) is greater than 1, the odds of some improvement in the GOS at 6 
months is greater in the BHR-100 treatment group compared to placebo. 
 
In the event that the primary efficacy analysis does not show statistical significance at the 
study-wise 1% significance level, please refer to section 9.5.1.4 for further details on how the 
statistical significance of the primary efficacy analysis should be interpreted.   
 
The POM will be fitted in SAS® using the PROC LOGISTIC procedure. 
 
Goodness of fit of the model will be assessed using the Deviance and Pearson tests (add SCALE 
= NONE AGGREGATE to the MODEL statement of PROC LOGISTIC) to compare the fitted 
model with the saturated model.  If these tests are not statistically significant it implies that the 
model fits the data adequately. 
 
The score test for the proportional odds assumption and individual p-values associated with the 
tests of effects (treatment, geographic region, age, GCS motor score, pupil response, and CT 
classification) will be summarized for the POM of GOS at 6 months post injury. 
 
The odds ratios and associated 95% CIs for the levels of the effects relative to a reference 
category will be presented for all factors and covariates included in the POM of GOS at 6 
months post injury. 
 
In addition to the results of the hypothesis tests from the statistical modeling, the number of 
non-missing observations, absolute and relative frequency (n and percentages), will be provided 
by treatment group for the GOS categories at 6 months post injury. 
 
The analyses above will be repeated for the straight observed case analysis (no imputation of 6-
month GOS or covariates) in the mITT population, the straight observed case analysis in the PP 
population (no imputation of 6-month GOS or covariates), and the analysis of imputed missing 
values in the mITT population for US subjects only. 
 
 
In addition to the above POM for the primary analysis, the individual binary logistic regression 
models will be fitted for each possible dichotomization of the GOS at 6 months, as outlined 
above under model 1, 2 and 3.  This will be done using missing value imputation for the mITT 
population. This will allow an assessment of the odds ratio for treatment within each possible 
dichotomization and a further assessment of the proportional odds assumption.  If the parameter 
estimates obtained under each dichotomized model are similar then the proportional odds 
assumption would seem sensible.  


 
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A bar chart illustrating the percentage of responses in each GOS category for each treatment 
group will be produced for the GOS at 6 months for the mITT (observed values and missing 
values imputed)  and PP populations (observed values). 
 
9.5.1.2 
Alternate Primary Efficacy Analysis (Sliding Dichotomy) 
If the proportional odds assumption cannot be justified, a sliding dichotomy of the GOS outcome 
at 6 months following injury, following categorization of subjects into different prognosis groups 
(worst, intermediate, and best) based on baseline prognostic factors, will be the primary efficacy 
analysis.  The primary sliding dichotomy analysis will be based on imputation of missing data 
(covariates and 6-month GOS assessments). 
For each subject a baseline prognostic risk score (BPRS) will be calculated as a weighted linear 
function of baseline prognostic factors of age, age squared, GCS motor score, Marshall CT 
classification, pupillary reactivity, presence of hypoxia, presence of hypotension, and presence of 
traumatic subarachnoid hemorrhage.  The weighting of the BPRS factors will be based on the 
prognostic model developed in Hukkelhoven et al (2005).  The BPRS will be sorted from lowest 
to highest, noting that higher BPRS represent a worse prognosis, and split into tertiles which will 
represent best, intermediate and worst prognosis.   
For the cohort predicted to have the worst outcome, the outcome of severe disability or better is 
considered a “favorable outcome,” while for the cohort predicted to have the best outcome, only 
the outcome of good recovery is considered a “favorable outcome.”  For the middle cohort there 
is no difference from the dichotomized model, so that the outcomes of moderate disability and 
good recovery are pooled to define “favorable outcome.” 
The hypothesis that the proportion of favorable responses observed in each treatment group is the 
same will be tested using the Cochran-Mantel Haenszel (CMH) Chi-Square test, adjusted for 
region.   
Null Hypothesis: 
H0: p1 = p2 
Alternative Hypothesis: 
H1: p1 ≠ p2 
where p1 = proportion of favorable responses in the BHR-100 treated group and p2 = proportion 
of favorable responses in the placebo treated group.  The Mantel-Haenszel estimate of the 
common odds ratio and corresponding 95% CI will also be presented.   
If the p-value from the test of the null hypothesis of p1 = p2 is less than 0.0003 (at the interim) or 
0.0098 (at the final analysis), it will be concluded that there is a statistically significantly 
difference in the proportion of favorable responses between the 2 treatment groups.     
In addition to the formal inference testing discussed above, the difference in proportion of 
favorable outcomes and associated 2-sided 95% confidence interval between the BHR-100 and 
placebo treatment groups will be calculated. 
In addition to the primary analysis that tests whether the overall proportion of favourable 
responses is the same in each treatment group, the CMH test results and odds ratios by baseline 
prognosis grouping (best, intermediate, worse) will also be presented.  The Breslow-Day test will 
be computed to test whether the odds ratios are different across the prognostic groups.  A 
significant test result will not affect the validity of the overall test of a difference between 
treatment groups, but will aid in the interpretation of the results. 


 
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The analyses above will be repeated for the straight observed case analysis (no imputation of 6-
month GOS or covariates) in the mITT population, the observed case analysis in the PP 
population, and the analysis of imputed missing values in the mITT population for US subjects 
only. 
 
9.5.1.3 
Sensitivity Analysis (Dichotomized Model) 
The GOS at 6 months post injury will be dichotomized into Good Recovery, Moderate Disability 
versus Severe Disability, Vegetative Status/Dead.  As a supportive analysis, the binary outcome 
will be analyzed using logistic regression analysis.  The logistic regression model will be fitted 
including the effect of treatment, geographic region (North America, Europe, Asia, and South 
America), age, GCS motor score, pupil response, and CT classification.   
 
If Y = response = GOS at 6 months following injury. 
 
Model 
Y1 = 0 (not event),  
if Y = vegetative state or dead, severe disability 
Y1 = 1 (event),  
if Y = moderate disability, good recovery 
 
The dichotomous logistic regression model can be expressed as follows: 
 
ln (P/(1 – P)) = αJ + β1X1 + β2X2 + β3X3 + β4X4 + β5X5 + β6X6, 
 
where 
 ln is the natural logarithm, 
 P = Probability of an ‘event’ (moderate disability, good recovery) = Probability that Y = 
1, 
 P/(1 – P) = odds of an ‘event’,  
 X1 = treatment group,  
 β1 = effect of treatment,  
 X2 = region,  
 β2 = effect of region,  
 X3 = age,  
 β3 = effect of age,  
 X4 = GCS motor score,  
 β4 = effect of GCS motor score,  
 X5 = pupil response,  
 β5 = effect of pupil response, and  
 X6 = CT classification,  
 β6 = effect of CT classification. 
 
The logistic regression model will be used to test the null hypothesis that the odds of an ‘event’, 
i.e. observing a response of moderate disability or good recovery on the outcome variable, GOS 
at 6 months following injury, adjusted for region, age, GCS motor score, pupil response, and CT 
classification is the same in both treatment groups, i.e. 


 
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Null Hypothesis: 
H0 : β1 = 0 
Alternative Hypothesis: 
H1 : β1 ≠ 0 
 
If the p-value from the test of the null hypothesis of 1 = 0 is less than 0.05, it will be concluded 
that BHR-100 is statistically significantly different from placebo with respect to the GOS at 6 
months following injury.  The odds of an ‘event’ (moderate disability or good recovery) in the 
GOS at 6 months will be modeled and the corresponding common odds ratio for treatment, 
1

e
, 
can then be interpreted to determine the direction of the treatment difference as follows.  With 
the placebo group being considered as the reference category, if the odds ratio (ORBHR-100/placebo) 
is greater than 1, the odds of a favorable outcome in the GOS at 6 months is greater in the BHR-
100 treatment group compared to placebo.   
 
The logistic regression analysis will be fitted in SAS® using the PROC LOGISTIC procedure. 
 
Goodness of fit of the model will be assessed as outlined above for the Proportional Odds Model. 
 
The individual p-values associated with the tests of effects (treatment, geographic region, age, 
GCS motor score, pupil response, and CT classification) will be summarized for the Logistic 
Regression Model of GOS at 6 months post injury. 
 
The odds ratios and associated 95% CIs for the levels of effects relative to a reference category 
will be presented for all factors and covariates included in the Logistic Regression Model of 
GOS at 6 months post injury. 
 
In addition to the results of the hypothesis tests from the statistical modeling, the number of 
non-missing observations, absolute and relative frequency (n and percentages), will be provided 
by treatment group for the dichotomized GOS categories at 6 months post injury. 
 
The primary dichotomized analysis will be based on missing values of 6-month GOS and 
covariates imputed.  It will also be repeated for the straight observed case analysis (no 
imputation of 6-month GOS or covariates) in the mITT population and the straight observed case 
analysis in the PP population. 
 
A bar chart illustrating the percentage of responses in each of the dichotomized categories for 
each treatment group will be produced for the GOS at 6 months (observed values and missing 
values imputed) for the mITT population. 
 
9.5.1.4 
Interpretation of Statistical Significance of Primary Efficacy Analysis 
In the event that the primary efficacy analysis does not show statistical significance at the 
study-wise 1% significance level, i.e. the final analysis p-value is not less than 0.0098, a final 
adjusted p-value will be calculated and the result considered statistically significant at the 5% 
level if the adjusted p-value is less than 0.05.  The adjusted p-value will be calculated using 
EAST (Cytel Statistical Software, Cambridge, MA) or other appropriate statistical software 


 
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package to adjust for the interim analysis using the pre-specified boundaries discussed above and 
in section 7. 
 
9.5.1.5 
Handling of Missing Data 
Please refer to section 5 for further details on the handling of missing data. 
 
9.5.1.6 
Exploratory Analysis 
An exploratory analysis will be conducted to assess each of the following covariates of interest: 
treatment (BHR-100 vs. placebo), region (North America vs. Europe vs. Asia vs. South 
America), age, race (white vs. non-white), GCS motor score (1-2 vs. 3 vs. 4 vs. 5-6), pupil 
response (bilateral vs. unilateral/no reactive pupils/not testable), CT classification (I/II vs. III vs. 
IV vs. V/VI), presence of hypoxia (yes/suspected vs. no/unknown), presence of hypotension 
(yes/suspected vs. no/unknown), presence of traumatic subarachnoid hemorrhage (yes vs. no), 
gender (male vs. female), and time to first dose of study medication from TBI (0-4 vs. 4-6 vs. 4-8 
vs. >8 hours), for inclusion into an expanded model.  Each covariate, along with the 
corresponding interaction with treatment term, will be included in a simple model with 
treatment.  A backward selection model will be fit beginning with all covariates.  Factor by 
treatment interactions will be included in the backward elimination model if the p-value<0.10 in 
the corresponding simple model.   A significance level of 0.05 may be too stringent and may 
exclude important variables from the model, so a significance level of 0.1 will be used for the 
backward selection process.  If the interaction term is significant, an exploratory subgroup 
analysis will be performed for the corresponding covariate.  
 
This analysis will be conducted for the  POM based on imputation of missing data.  Missing 
covariates will not be imputed for the exploratory analysis. 
9.5.2 Secondary Variables 
Secondary efficacy parameters will be ranked as follows: 
1) GOS-E at Month 6, 
2) Mortality at Month 6 in mITT population (comparison of incidence of death), 
3) GOS at Month 3, 
4) GOS-E at Month 3, 
5) Mortality at Month 1 in mTT population (comparison of incidence of death), 
6) SF-36 mental composite score at Month 6,  
7) SF-36 physical composite score at Month 6 
8) SF-36 mental composite score at Month 3, and 
9) SF-36 physical composite score at Month 3. 
No confirmatory claims can be based on variables that have a rank lower than or equal to the 
variable whose null hypothesis was the first that could not be rejected  at the p<0.05 significance 
level. 
 


 
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9.5.2.1 
Mortality at Month 1, Month 6 
These efficacy variables are obtained by collecting the survival status from the date of injury 
(Day 1 of the study) until Day 30 (Month 1) and Day 180 (Month 6) respectively as lost to 
follow-up, consent withdrawn, alive, dead or other.  Every effort will be made to ascertain the 
survival status of subjects with status other than dead or alive, but in the absence of further 
information these observations will be omitted from the analysis.  The 1-month mortality rate 
will be defined as the proportion of subjects at risk in the mITT population (subjects for whom 
the survival status at Day 30 is known) who died on or before Study Day 30.  Similarly, the 6-
month mortality rate will be defined as the proportion of subjects at risk in the mITT population 
who died on or before Study Day 180.   
The hypothesis that the mortality rate observed in each treatment group is the same will be tested 
using the Fisher’s Exact test.   
Null Hypothesis: 
H0: p1 = p2 
Alternative Hypothesis: 
H1: p1 ≠ p2 
where p1 = proportion of deaths in the BHR-100 treated group and p2 = proportion of deaths in 
the placebo treated group. 
A 2-sided, 5% significance level will be used to test the null hypothesis.  If rejected (p < 0.05), it 
will be concluded that there is a statistically significant difference in the proportion of deaths 
between the 2 treatment groups. 
In addition to the formal inference testing discussed above, 2-sided 95% confidence intervals for 
the difference in the proportion of deaths between BHR-100 and placebo treatment groups will 
be calculated.  
Summaries of mortality at Months 1 and 6 will be presented for both the mITT and PP 
populations. 
The mortality rate for each treatment group will also be plotted on a bar chart for mortality at 1 
and 6 months for the mITT population. 
 
9.5.2.2 
GOS at Month 3 
The GOS at Month 3 will be analyzed using the POM in the same way as the primary efficacy 
analysis of GOS at Month 6 outlined above for the observed values.   
 
9.5.2.3 
GOS-E at Month 3 and Month 6 
The GOS-E at Month 3 and Month 6 will be analyzed using the POM, similar to the primary 
efficacy analysis of the GOS at Month 6 described above.  The GOS-E is an 8-point scale with 
the following categories: 
 
 Dead (D), 
 Vegetative state (VS),  
 Lower severe disability(SD LL), 
 Upper severe disability (SD UL), 
 Lower moderate disability (MD LL), 


 
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 Upper moderate disability (MD UL), 
 Lower good recovery (GR LL), 
 Upper good recovery (GR UL). 
For the POM analysis, the first 2 categories will be combined (vegetative state and dead).  With 
7 categories in the response variable, the POM simultaneously fits 6 binary logistic regression 
models.  If the proportional odds assumption cannot be justified, the GOS-E at Month 6 will be 
analyzed using the SD as described in Section 9.5.1.2.  For each subject, a BPRS will be 
calculated as described in Section 9.5.1.2.  Subjects will be sorted from lowest to highest based 
on BPRS, and split into 6 equal groups representing different prognosis groups.  The first 
prognosis group, representing the lowest BPRS and therefore the best prognosis, will be Group 
1.  The definition of a favorable or unfavorable outcome for each group will be defined as in 
Table 4. 
Table 4 
Sliding Dichotomy Groupings for GOS-E 
Group 
Unfavorable Outcome 
Favorable Outcome 
1 
D+VS+SD+MD+GR LL 
GR UL 
2 
D+VS+SD+MD 
GR 
3 
D+VS+SD+MD LL 
MD UL+GR 
4 
D+VS+SD 
MD+GR 
5 
D+VS+SD LL 
SD UL+MD+GR 
6 
D+VS 
SD+MD+GR 
D= Dead, VS=Vegetative state, SD=Severe Disability, MD=Moderate Disability, GR=Good Recovery, SD 
LL=Lower severe disability, SD UL=Upper severe disability, MD LL=Lower moderate disability, MD UL=Upper 
moderate disability, GR LL=Lower good recovery, GR UL=Upper good recovery  
The hypothesis that the proportion of favorable responses observed in each treatment group is the 
same will be tested using the CMH test as described above. 
The analyses of the GOS-E at Month 3 and Month 6 will be done for the straight observed case 
analysis only. 
 
9.5.2.4 
Quality of Life: SF-36 
During the conduct of the study, the SF-36 health survey will be administered at Months 3 and 6 
to assess quality of life with respect to health status.  Since a baseline SF-36 is not assessed prior 
to study treatment, the analyses of the SF-36 will compare mean SF-36 scores at Month 3 and 6 
between treatment groups.   
The SF-36 consists of 36 questions that are grouped into eight scaled scores.  These scores are 
the weighted sums of the questions in their section.  Each scale is directly transformed into a 0-
100 scale on the assumption that each question carries equal weight. 


 
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For each scale, a simple mean imputation of missing data with a restriction to cases where the 
subject has completed at least 50% of the items of that scale (the “half-scale” rule) will be used. 
The eight sections are as follows: 
 
Vitality,  
 
Physical functioning,  
 
Bodily pain,  
 
General health perceptions, 
 
Physical role functioning,  
 
Emotional role functioning,  
 
Social role functioning, and 
 
Mental health.  
Summary statistics for the 8 scales and the physical and mental composite summary scores will 
be presented for each treatment group. 
In addition to summarizing the data, the physical and mental composite summary scores at 
Month 3 and 6 will be analyzed using an analysis of covariance (ANCOVA) model including 
treatment group.  
 
The null hypothesis that the mean physical and mental summary scores are the same for both 
treatment groups (BHR-100 and placebo) will be tested against the 2-sided alternative hypothesis 
that the mean physical and mental summary scores are different in each treatment group, at the 
0.05 significance level. 
 
The least square means for the treatment groups, difference in least square means between the 
treatment groups, effect size calculated as the absolute difference in least square means between 
BHR-100 and placebo divided by the root mean square, and p-value for difference between 
treatment groups will be presented. 
 
A 2-sided, 5% significance level will be used to test the null hypothesis.  If rejected at the 5% 
level (p < 0.05), it will be concluded that there is a statistically significant difference in the 
relevant summary score between the 2 treatment groups.  The magnitude of the summary 
statistics will be examined to determine the direction of the treatment difference. 
 
Diagnostic residual plots will be evaluated to test for violations of normality. If the 
normality assumption for the model is not met, the null hypothesis that the mean physical and 
mental summary scores are the same in each treatment group will be tested using the 2-sided 
Wilcoxon Rank-Sum test, an unstratified non-parametric test, which can be obtained from the 
NPAR1WAY procedure in SAS®.  
9.5.3 Exploratory Variables 
9.5.3.1 
Time to Death 
The actual time to death will be analyzed for the mITT population.     
If a subject does not die during the conduct of the study, they will be censored at their Month 6 
GOS assessment or end of study date, whichever comes first.  


 
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The LIFETEST procedure in SAS® will be used to produce Kaplan-Meier plots and estimates of 
25th, 50th, and 75th quartiles and corresponding 95% confidence limits of the median time to 
death.  The 2 treatment groups will be compared using a 2-sided log-rank test.  Examination of 
the point estimates will indicate the direction of the treatment difference.  The cumulative 
percent mortality based on the Kaplan-Meier survival probability estimates will be plotted for 
each treatment group. 
The time to death (in days) will be further analyzed using a Cox proportional hazard model.   
The comparison of the treatment effect on the time to death will be based on the hazard ratio 
(HR) from the Cox regression model using the PHREG procedure in SAS.  Estimates of HR 
and 95% confidence limits will be presented.  The model will include the same terms as the 
primary efficacy analysis, namely treatment, region, age, GCS motor score, pupil response, and 
CT classification.   
The Cox proportional hazards model is a standard model used in failure time analysis.  
Compared to parametric analyses, its assumptions are fairly unspecified and will therefore yield 
robust estimates of the treatment effect.  The model will be applied using the Efron approach for 
handling ties, since this approach is known to give a reasonable approximation of the exact 
likelihood in the presence of ties and is computationally faster when large amounts of data are 
being analyzed.   
 
9.5.3.2 
Comparison of CT scans at admission and Day 6 
A CT scan will be performed before randomization (Day 1) and once again at Day 6 ± 1 day 
post-injury to assess the progression of lesion volume and brain edema.  The findings by the 
Central Reader will be classified in accordance with the Marshall classification: 
 Diffuse injury I - no visible pathology (CT class I), 
 Diffuse injury II (CT class II), 
 Diffuse injury III – swelling (CT class III), 
 Diffuse injury IV – shift (CT class IV), 
 Evacuated mass lesion (CT class V), 
 Non-evacuated mass lesion (CT class VI). 
A shift summary of CT classification from Baseline to Day 6 will be presented by treatment 
group. 
9.5.3.3 
ICP 
Intracranial Pressure (ICP) will be collected for Days 1 – 6 of the study, at the investigators’ 
discretion. 
Descriptive summary statistics, categorical summaries (maximum daily ICP: 0 to <15, ≥15 to 
<25, ≥25 to <40 and ≥40 mmHg and maximum daily ICP: 0 to ≤20, >20 mmHg), and the 
number of subjects with maximum daily ICP ≥25 and maximum daily ICP >20 mmHg (cutpoints 
of particular interest) will be presented for the maximum ICP by treatment group and study day 
for the mITT population. 
 


 
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9.5.3.4 
CPP 
CPP is computed based upon simultaneously recorded ICP and blood pressure measurements, 
see Section 5 for formula.  Summary statistics for the highest and lowest daily CPP values will 
be presented for each treatment group by Study Day.   
CPP measurements in the following potentially clinically relevant categories will be presented 
for each treatment group: less than 50 mmHg, 50-<60 mmHg, 60-<70 mmHg and greater than or 
equal to 70 mmHg.  The number and percentage of subjects within the various categories by 
Study Day will be summarized by treatment group.   
Summary statistics will also be presented for the percentage of subjects with CPP measurements 
within the above specified categories at any time during treatment, where on-treatment will 
include all scheduled and unscheduled CPP measurements after the initiation of study 
medication. 
 
9.5.3.5 
TIL 
TIL will be monitored during Study Days 1 – 6 (inclusive) while ICP is being monitored (i.e. up 
to 6 days).   
Each of the unique treatments given on a study day used for ICP management will have a score 
of 1, and the maximum score (sum of the individual items) per assessment period (study day) is 
10.  It is assumed that there will be a stepwise progression of therapy (from sedation to surgical 
decompression).  However, in the event that the most aggressive therapies are used, i.e. the 
subject has barbiturate administration or surgical decompression, this will result in a TIL score of 
10 regardless of which of the other therapies have been administered. 
The number of non-missing observations, absolute and relative frequency (n and percentage) of 
the subjects having at least one occurrence of the individual therapies (surgical decompression, 
barbiturate induced coma, hypothermia for ICP reduction, hyperventilation, pressor 
administration, hypertonic saline, mannitol, ventricular drainage, paralysis induction, and 
sedation) will be summarized for each treatment group.  The most aggressive therapy received 
during Days 1-6, expressed as the highest stepwise level of the TIL, will also be summarized.  
Furthermore, the daily TIL score will be summarized as a continuous variable by  Study Day and 
treatment group. 
9.6 
Safety Analyses 
9.6.1 Adverse Events 
For this study, it is intended to limit the collection of AEs to the window in which events are 
considered treatment-emergent.  Treatment-emergent adverse events (TEAEs) are defined as 
events that start on or after the first dose of study medication and up to 15 days and 6 months 
after the initiation of study treatment, for AEs and SAEs respectively.   
Partial start dates of AEs will be imputed in order to determine whether or not the AE is TE.  If 
just the day is missing, and any date of dose administered is within the month of the AE, the AE 
will be treated as TE.  If the month is missing and the year is present, and any date of dose 
administered is within the year of the AE, the AE will be treated as TE.  If the year is missing, 


 
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the AE will be treated as TE.  For the imputation, the day will be set to the first date of that 
month, or the first dose date, if the first dose date is within that month.  Alternatively, if the 
month is missing the month will be set to January, or the first dose date, if the first dose date is 
within that year. 
AEs will be coded using the MedDRA international thesaurus version 13.0 with no updates, 
adding system organ class (SOC) and preferred term.  The AE summaries will be presented for 
TEAEs only.  The total number of subjects reporting at least one AE and the number of AEs will 
be summarized by treatment group.  The initial summary will also provide a breakdown of 
events that: 
 Are treatment-related, 
 Are serious, 
 Are treatment-related and serious, 
 Resulted in the study drug being prematurely discontinued, 
 Are treatment-related and resulted in the study drug being prematurely discontinued,  
 Resulted in death, and 
 Are treatment-related and resulted in death. 
Additionally, the overall summary of AEs will be summarized by treatment group for the 
subgroups of interest: gender, race group (white vs. non-white vs. not allowed to obtain),  and 
age group (≤45 years vs. >45 years). 
The number and percentage of subjects with at least one TEAE and the number of TEAEs will 
be presented by SOC, preferred term, and treatment group for the following summaries: 
 
All AEs, 
 
All AEs by gender, 
 
All AEs by race group, 
 
All AEs by age group, 
 
Treatment-related AEs, 
 
All AEs, by maximum severity, 
 
Treatment-related AEs, by maximum severity, 
 
All AEs, by maximum relationship, 
 
All AEs that resulted in the study drug being prematurely discontinued, and 
 
Treatment-related AEs that resulted in the study drug being prematurely discontinued.  
Additionally, the following AEs of special interest will be presented by treatment group: serious 
thromboembolic events such as thrombotic myocardial infarction, pulmonary embolism, deep 
vein thrombosis, ischemic stroke; allergic reactions; marked liver function abnormalities; serious 
infections such as pneumonia, sepsis, meningitis.  Preferred terms for each AE of special interest 
will be identified by medical review prior to unblinding for the primary analysis.  Preferred terms 
related to the following events will also be grouped to ensure similar events that are coded to 
different terms using MedDRA are summarized together: electrolyte imbalance, anemia, infusion 
site reactions, thrombocyte disorders, and seizures.  These events will also be listed. 


 
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9.6.2 Neuroworsening 
See Section 5 for definition of neuroworsening.  The incidence of any episode of 
neuroworsening occurring ≤ Day 6 and ≤Day 15 will be summarized.   
Details of all neuroworsening events will also be listed. 
9.6.3 Deaths and Serious Adverse Events 
The number and percentage of subjects with at least one SAE and the number of events will be 
presented by SOC, preferred term and treatment group for the following summaries: 
 
All SAEs, and 
 
Treatment-related SAEs. 
The primary cause of death as recorded on the death report will be summarized by treatment 
group and overall for the mITT population. 
9.6.4 Laboratory Data 
Laboratory data (coagulation, hematology, serum chemistry and urinalysis) will be collected at 
baseline, end of study treatment (Day 6), and Day 15 of the study. 
The status of clinically significant (non AE) abnormalities (resolved, ongoing, or lost to follow-
up) will be summarized for Day 15 by laboratory parameter and treatment group in the safety 
population. 
Clinically significant (non-AE) abnormal lab results (coagulation, hematology, serum chemistry, 
and urinalysis) will be listed. 
Coagulation, hematology, and serum chemistry laboratory assessments will also be summarized 
descriptively for baseline, Day 6, and Day 15.  The change from baseline will be summarized for 
Day 6 and Day 15.  All lab parameters will be summarized in standard SI units.   
All lab results from Baseline, Day 6, and Day 15 will be listed. 
9.6.5 Vital Signs 
Vital signs will be collected for Days 1 – 6 of the study. 
Descriptive summary statistics will be presented for the highest and lowest measurements by 
study day for each vital sign parameter:  pulse rate (per minute), respiration rate (per minute), 
systolic and diastolic blood pressure (mm Hg), and temperature (°C).  A descriptive summary of 
weight (kg) will also be presented.  These tables will include the absolute values and the change 
from baseline.  See Section 5 for the definition of baseline. 
9.6.6 Physical Examinations, ECGs, and Other Observations Related to Safety 
The number and percentage of subjects with normal or abnormal physical examination findings 
will be presented by visit, body system (e.g. skin, HEENT, etc.) and treatment group. 
Post-baseline physical examination abnormalities will be listed to provide details of the noted 
abnormalities. 
ECGs will be performed at Day 1 prior to the initiation of study treatment and at Day 6 


 
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(post-infusion). 
Abnormal rhythm, conduction, and QRS complex findings will be summarized by study day and 
treatment group for the safety population.  Subjects with abnormal and clinically significant, 
abnormal post-baseline results will be listed.   
 
9.6.6.1 
Arterial Blood Gases 
Arterial blood gases (PaO2, PaCO2, HCO3, pH, SaO2 and FiO2) will be recorded before 
randomization (Day 1 pre-dose) and once daily during Days 1 – 6.   
Descriptive summary statistic tables will be presented for the worst daily ABG parameters by 
treatment group and measurement day.  These tables will include the absolute values and the 
change from baseline.  The worst value will be calculated as the lowest value of the day for 
PaO2, HCO3, pH, SaO2, and FiO2 and the highest value of the day for PaCO2.  See Section 5 for 
the definition of baseline and guidance on how to handle repeat observations at a given visit. 
9.6.7 Progesterone Levels  
A descriptive summary of Day 2 progesterone levels will be presented by treatment group. 
10 VALIDATION 
PRA Analysis and Reporting seeks to ensure the quality of the results provided for the study in 
the form of tables, figures, and listings (TFLs), and the derived datasets used in their creation, 
through the following processes: 
 Derived datasets will be independently reprogrammed by a second programmer. The 
separate datasets produced by the two programmers must match 100%. 
 Tables will be independently reprogrammed by a second programmer for numeric results. 
Statisticians will be involved in the process of programming and validating tables that 
include inferential statistical results. 
 Figures will be checked for consistency against corresponding tables and listings, or 
independently reprogrammed if there are no corresponding tables or listings. 
 Listings will be checked for consistency against corresponding tables, figures, and 
derived datasets. 
The entire set of TFLs will be checked for completeness and consistency prior to its delivery to 
the sponsor by the lead analysis programmer, the lead statistician, and a senior level statistician, 
or above, who is not a member of the project team. 
The PRA validation process will be repeated any time TFLs are redelivered using different data. 
Execution of this validation process will be documented through the study Table of Programs 
that will be provided to the sponsor at study conclusion. 
11 REFERENCES 
Agresti A.  An introduction to Categorical Data Analysis.  Wiley Series.  1996. 
Allison P.  Logistic Regression using the SAS System.  Cary, NC: SAS Institute Inc.; 1999. 
CPMP/EWP/2863/99 (Points to Consider on Adjustment for Baseline Covariates). 


 
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Ellenberg SS, Fleming TR, De Mets DL.  Data Monitoring Committees in Clinical Trials A 
Practical Perspective.  John Wiley & Sons; 2002. 
Gardner M, Altman D.  Statistics with Confidence – Confidence intervals and statistical 
guidelines.  London: BMJ; 1989. 
Hukkelhoven CWPM, Steyerberg EW, Habbema JDF, et al.  Predicting outcome after traumatic 
brain injury: development and validation of a prognostic score based on admission 
characteristics.  Journal of Neurotrauma 2005: 22: 1025 – 1039. 
ICH Guideline E9.  
Lee Y J, Quan H.  P-values after repeated significance testing: a simple approximation method 
Statistics in Medicine 1993: 12: 675-84.  
Lu, Juan.  Unpublished data from IMPACT database.  2011. 
Maas AI R, Murray G, Henney H, et al.  Efficacy and safety of dexanabinol in severe traumatic 
brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol. 
2006; 5: 38-45. 
Mccullagh P, Nelder JA.  Generalized Linear Models.  1st ed. London: Chapman and Hall; 1983. 
Proschan MA, Lan KKG, Wittes JT.  Statistical monitoring of clinical trials: a unified approach. 
New York, NY: Springer; 2006.  
Walker G.  Common Statistical Methods for Clinical Research.  Cary, NC: SAS Institute Inc.;  
2002. 
Whitehead J.  The Design and Analysis of Sequential Clinical Trials.  Statistics in Practice.  
1997. 


 
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APPENDIX 1 
GLOSSARY OF ABBREVIATIONS 
 
ABG 
Arterial Blood Gases 
ABIC 
American Brain Injury Consortium 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BHR-100 
BHR Pharma, LLC’s proprietary formulation of intravenous 
progesterone 
BP 
Blood Pressure  
BPRS 
Baseline Prognostic Risk Score 
BTF 
Brain Trauma Foundation 
CI 
Confidence Interval 
CMH 
Cochran-Mantel Haenszel 
CPP 
Cerebral Perfusion Pressure 
CRF 
Case Report Form (paper or other media) 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
DMAP 
Data Monitoring and Analysis Plan 
DMP 
Data Management Plan 
DP 
Decimal Places 
DSMB 
Data Safety Monitoring Board 
EBIC 
European Brain Injury Consortium 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
FiO2 
Fraction of Inspired Oxygen 
GCS 
Glasgow Coma Scale 
GOS 
Glasgow Outcome Scale 
GOS-E 
Extended Glasgow Outcome Scale 
HCO3 
Bicarbonate 
HR 
Hazard Ratio 
ICH 
International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 


 
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ICP 
Intracranial Pressure 
ICU 
Intensive Care Unit 
IMPACT 
International Mission for Prognosis and Analysis of Clinical 
Trials in TBI 
ITT 
Intent-to-treat 
i.v. 
Intravenous 
IWRS 
Interactive Web-based Randomization System 
LOCF 
Last Observation Carried Forward 
MAP 
Mean Arterial Pressure 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-to-treat 
OR 
Odds Ratio 
PaO2 
Partial Pressure of Oxygen 
PaCO2 
Partial Pressure of Carbon Dioxide 
POM 
Proportional Odds Model 
PP 
Per Protocol 
Q1 
First Quartile 
Q3 
Third Quartile 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SaO2 
Saturation of Oxygen, arterial blood 
SD 
Sliding Dichotomy 
SF-36 
Short Form 36 Health Survey 
SOC 
System Organ Class 
TBI 
Traumatic Brain Injury 
TEAE 
Treatment-Emergent Adverse Events 
TFL 
Tables, Figures and Listings 
TIL 
Therapy Intensity Level 
WHO-DD 
World Health Organization-Drug Dictionary 
 
 
 


 
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APPENDIX 2 LIST OF POST-TEXT TABLES, FIGURES, LISTINGS, AND 
SUPPORTIVE SAS OUTPUT APPENDICES 
Tables 
Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.1.1.1 
Summary of Investigational Sites’ Enrollment Duration (mITT 
Population) 
 
X 
Table 14.1.1.2 
Summary of Enrollment by Region, Country and Site (mITT 
Population) 
 
X 
Table 14.1.1.3 
Summary of Subject Disposition (Randomized Subjects) 
 
X 
Table 14.1.1.4 
Summary of Subject Status by Time (mITT Population) 
 
 
Table 14.1.1.5 
Country Codes per ISO 
 
 
Table 14.1.2.1 
Summary of Study Drug Exposure and Time From Injury (Safety 
Population) 
 
X 
Table 14.1.2.2 
Drug Administration Summary (Safety Population) 
 
 
Table 14.1.2.3 
Summary of Study Drug Compliance Rate (Safety Population) 
 
 
Table 14.1.3.1 
Prior and Concomitant Medications by WHO Drug Dictionary 
Preferred Term (mITT Population) 
 
 
Table 14.1.3.2 
Surgical Therapy (mITT Population) 
 
 
Table 14.1.4.1 
Demographic Characteristics (mITT Population) 
 
X 
Table 14.1.4.2 
Pregnancy Testing (mITT Population) 
 
X 
Table 14.1.4.3 
Baseline Characteristics (mITT Population) 
 
X 
Table 14.1.4.4 
Summary of Injury (mITT Population) 
 
 
Table 14.1.5 
Summary of Medical History by System Organ Class and Preferred 
Term (Safety Population) 
 
 
Table 14.2.1.1 
Summary of Glasgow Outcome Scale at 6 Months Post Injury –  
Missing Values Imputed (mITT Population) 
 
X 
Table 14.2.1.2 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury – 
Proportional Odds Model - Missing Values Imputed (mITT 
Population) 
 
X 
Table 14.2.1.3 
ORs and 95% CIs of Glasgow Outcome Scale at 6 Months Post 
Injury – Proportional Odds Model - Missing Values Imputed (mITT 
Population) 
 
X 
Table 14.2.1.4 
Summary of Glasgow Outcome Scale at 6 Months Post Injury –  
Observed Values (mITT Population) 
14.2.1.1 
X 
Table 14.2.1.5 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury –  
Proportional Odds Model - Observed Values (mITT Population) 
14.2.1.2 
X 


 
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Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.2.1.6 
ORs and 95% CIs of Glasgow Outcome Scale at 6 Months Post 
Injury – Proportional Odds Model  - Observed Values (mITT 
Population) 
14.2.1.3 
X 
Table 14.2.1.7 
Summary of Glasgow Outcome Scale at 6 Months Post Injury – 
Observed Values (PP Population) 
14.2.1.1 
 
Table 14.2.1.8 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury –  
Proportional Odds Model  - Observed Values (PP Population) 
14.2.1.2 
 
Table 14.2.1.9 
ORs and 95% CIs of Glasgow Outcome Scale at 6 Months Post 
Injury  – Proportional Odds Model  - Observed Values (PP 
Population) 
14.2.1.3 
 
Table 14.2.1.10 
Summary of Glasgow Outcome Scale at 6 Months Post Injury for US 
Only –  Missing Values Imputed (mITT Population) 
14.2.1.1 
 
Table 14.2.1.11 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury for US 
Only – Proportional Odds Model - Missing Values Imputed (mITT 
Population) 
14.2.1.2 
 
Table 14.2.1.12 
ORs and 95% CIs of Glasgow Outcome Scale at 6 Months Post 
Injury for US Only – Proportional Odds Model - Missing Values 
Imputed (mITT Population) 
14.2.1.3 
 
Table 14.2.1.13 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury – 
Proportional Odds Model - Missing Values Imputed (Unadjusted 
Analysis) (mITT Population) 
14.2.1.2 
 
Table 14.2.1.14 
ORs and 95% CIs of Glasgow Outcome Scale at 6 Months Post 
Injury – Proportional Odds Model - Missing Values Imputed 
(Unadjusted Analysis) (mITT Population) 
14.2.1.3 
 
Table 14.2.2.1 
Summary of Sliding Dichotomy (Dichotomization) – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.2.2 
Summary and Analysis of Sliding Dichotomy at 6 Months Post 
Injury  – Missing Values Imputed (mITT Population) 
 
 
Table 14.2.2.3 
ORs and 95% CIs for Sliding Dichotomy at 6 Months Post Injury  – 
Missing Values Imputed (mITT Population) 
 
 
Table 14.2.2.4 
Summary of Sliding Dichotomy (Dichotomization) at 6 Months Post 
Injury  – Observed Values (mITT Population) 
14.2.2.1 
 
Table 14.2.2.5 
Summary and Analysis of Sliding Dichotomy at 6 Months Post 
Injury  – Observed Values (mITT Population) 
14.2.2.2 
 
Table 14.2.2.6 
ORs and 95% CIs for Sliding Dichotomy at 6 Months Post Injury  – 
Observed Values (mITT Population) 
14.2.2.3 
 
Table 14.2.2.7 
Summary of Sliding Dichotomy (Dichotomization) at 6 Months Post 
Injury  – Observed Values (PP Population) 
14.2.2.1 
 
Table 14.2.2.8 
Summary and Analysis of Sliding Dichotomy at 6 Months Post 
Injury  – Observed Values (PP Population) 
14.2.2.2 
 
Table 14.2.2.9 
ORs and 95% CIs for Sliding Dichotomy at 6 Months Post Injury  – 
Observed Values (PP Population) 
14.2.2.3 
 


 
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Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.2.2.10 
Summary of Sliding Dichotomy (Dichotomization) at 6 Months Post 
Injury for US Only – Missing Values Imputed (mITT Population) 
14.2.2.1 
 
Table 14.2.2.11 
Summary and Analysis of Sliding Dichotomy at 6 Months Post 
Injury  for US Only – Missing Values Imputed (mITT Population) 
14.2.2.2 
 
Table 14.2.2.12 
ORs and 95% CIs for Sliding Dichotomy at 6 Months Post Injury for 
US Only – Missing Values Imputed (mITT Population) 
14.2.2.3 
 
Table 14.2.3.1 
Summary of Dichotomized Glasgow Outcome Scale at 6 Months 
Post Injury – Missing Values Imputed (mITT Population) 
 
X 
Table 14.2.3.2 
Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome 
Scale at 6 Months Post Injury – Missing Values Imputed (mITT 
Population) 
 
 
Table 14.2.3.3 
ORs and 95% CIs for Dichotomized (GR, MD vs. SD, V/D) Glasgow 
Outcome Scale at 6 Months Post Injury  – Missing Values Imputed 
(mITT Population) 
 
 
Table 14.2.3.4 
Summary of Dichotomized Glasgow Outcome Scale at 6 Months 
Post Injury – Observed Values (mITT Population) 
14.2.3.1 
 
Table 14.2.3.5 
Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome 
Scale at 6 Months Post Injury  – Observed Values (mITT Population) 
14.2.3.2 
 
Table 14.2.3.6 
ORs and 95% CIs for Dichotomized (GR, MD vs. SD, V/D) Glasgow 
Outcome Scale at 6 Months Post Injury  – Observed Values (mITT 
Population) 
14.2.3.3 
 
Table 14.2.3.7 
Summary of Dichotomized Glasgow Outcome Scale at 6 Months 
Post Injury – Observed Values (PP Population) 
14.2.3.1 
 
Table 14.2.3.8 
Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome 
Scale at 6 Months Post Injury – Observed Values (PP Population) 
14.2.3.2 
 
Table 14.2.3.9 
ORs and 95% CIs for Dichotomized (GR, MD vs. SD, V/D) Glasgow 
Outcome Scale at 6 Months Post Injury – Observed Values (PP 
Population) 
14.2.3.3 
 
Table 14.2.3.10 
Analysis of Dichotomized (GR vs. MD, SD, V/D) Glasgow Outcome 
Scale at 6 Months Post Injury – Missing Values Imputed (mITT 
Population) 
14.2.3.2 
 
Table 14.2.3.11 
ORs and 95% CIs for Dichotomized (GR vs. MD, SD, V/D) Glasgow 
Outcome Scale at 6 Months Post Injury – Missing Values Imputed 
(mITT Population) 
14.2.3.3 
 
Table 14.2.3.12 
Analysis of Dichotomized (GR, MD, SD vs. V/D) Glasgow Outcome 
Scale at 6 Months Post Injury – Missing Values Imputed (mITT 
Population) 
14.2.3.2 
 
Table 14.2.3.13 
ORs and 95% CIs for Dichotomized (GR, MD, SD vs. V/D) Glasgow 
Outcome Scale at 6 Months Post Injury – Missing Values Imputed 
(mITT Population) 
14.2.3.3 
 
Table 14.2.4.1 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury – 
Exploratory Analysis – Missing Values Imputed (mITT Population) 
 
 


 
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Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.2.4.2 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by 
Region – Exploratory Analysis – Missing Values Imputed (mITT 
Population) 
 
 
Table 14.2.4.3 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Region – Exploratory Analysis – Missing Values Imputed 
(mITT Population) 
 
 
Table 14.2.4.4 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by Age 
Group – Exploratory Analysis – Missing Values Imputed (mITT 
Population) 
 
 
Table 14.2.4.5 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Age Group – Exploratory Analysis – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.4.6 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by Race 
Group – Exploratory Analysis – Missing Values Imputed (mITT 
Population) 
 
 
Table 14.2.4.7 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Race Group – Exploratory Analysis – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.4.8 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by GCS 
Motor Score – Exploratory Analysis – Missing Values Imputed 
(mITT Population) 
 
 
Table 14.2.4.9 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by GCS Motor Score – Exploratory Analysis – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.4.10 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by 
Pupil Response – Exploratory Analysis – Missing Values Imputed 
(mITT Population) 
 
 
Table 14.2.4.11 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Pupil Response – Exploratory Analysis – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.4.12 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by CT 
Classification – Exploratory Analysis – Missing Values Imputed 
(mITT Population) 
 
 
Table 14.2.4.13 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by CT Classification – Exploratory Analysis – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.4.14 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by 
Presence of Hypoxia– Exploratory Analysis – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.4.15 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Presence of Hypoxia – Exploratory Analysis – Missing 
Values Imputed (mITT Population) 
 
 


 
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Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.2.4.16 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by 
Presence of Hypotension– Exploratory Analysis – Missing Values 
Imputed (mITT Population) 
 
 
Table 14.2.4.17 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Presence of Hypotension – Exploratory Analysis – Missing 
Values Imputed (mITT Population) 
 
 
Table 14.2.4.18 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by 
Presence of Traumatic Subarachnoid Hemorrhage– Exploratory 
Analysis – Missing Values Imputed (mITT Population) 
 
 
Table 14.2.4.19 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Presence of Traumatic Subarachnoid Hemorrhage – 
Exploratory Analysis – Missing Values Imputed (mITT Population) 
 
 
Table 14.2.4.20 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by 
Gender – Exploratory Analysis – Missing Values Imputed (mITT 
Population) 
 
 
Table 14.2.4.21 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Gender – Exploratory Analysis – Missing Values Imputed 
(mITT Population) 
 
 
Table 14.2.4.22 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury by 
Time to First Dose – Exploratory Analysis – Missing Values Imputed 
(mITT Population) 
 
 
Table 14.2.4.23 
ORs and 95% CIs for Glasgow Outcome Scale at 6 Months Post 
Injury by Time to First Dose – Exploratory Analysis – Missing 
Values Imputed (mITT Population) 
 
 
Table 14.2.5.1 
Summary and Analysis of Mortality at Month 6 (mITT Population) 
 
X 
Table 14.2.5.2 
Summary and Analysis of Mortality at Month 1 (mITT Population) 
14.2.5.1 
X 
Table 14.2.5.3 
Summary and Analysis of Mortality at Month 6 (PP Population) 
14.2.5.1 
X 
Table 14.2.5.4 
Summary and Analysis of Mortality at Month 1 (PP Population) 
14.2.5.1 
X 
Table 14.2.5.5 
Summary and Kaplan-Meier Analysis of Time to Death (days) (mITT 
Population) 
 
 
Table 14.2.5.6 
Summary of Cox Proportional Hazards Analysis of Time to Death 
(days) (mITT Population) 
 
 
Table 14.2.6.1 
Summary of Glasgow Outcome Scale at 3 Months Post Injury – 
Observed Values (mITT Population) 
14.2.1.1 
 
Table 14.2.6.2 
Analysis of Glasgow Outcome Scale at 3 Months Post Injury – 
Proportional Odds Model - Observed Values (mITT Population) 
14.2.1.2 
 
Table 14.2.6.3 
ORs and CIs of Glasgow Outcome Scale at 3 Months Post Injury – 
Proportional Odds Model - Observed Values (mITT Population) 
14.2.1.3 
 
Table 14.2.7.1 
Summary of Glasgow Outcome Scale - Extended at 6 Months Post 
Injury – Observed Values (mITT Population) 
14.2.1.1 
 


 
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Protocol No. BHR-100-301 
 
 
Page 43 of 213 
Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.2.7.2 
Analysis of Glasgow Outcome Scale – Extended at 6 Months Post 
Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
14.2.1.2 
 
Table 14.2.7.3 
ORs and CIs of Glasgow Outcome Scale - Extended at 6 Months Post 
Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
14.2.1.3 
 
Table 14.2.7.4 
Summary of Sliding Dichotomy (Dichotomization) – Glasgow 
Outcome Scale – Extended at 6 Months Post Injury  – Observed 
Values (mITT Population) 
 
 
Table 14.2.7.5 
Summary and Analysis of Sliding Dichotomy – Glasgow Outcome 
Scale – Extended at 6 Months Post Injury  – Observed Values (mITT 
Population) 
 
 
Table 14.2.7.6 
ORs and 95% CIs for Sliding Dichotomy – Glasgow Outcome Scale 
– Extended at 6 Months Post Injury  – Observed Values (mITT 
Population) 
 
 
Table 14.2.7.7 
Summary of Glasgow Outcome Scale - Extended at 3 Months Post 
Injury – Observed Values (mITT Population) 
 
 
Table 14.2.7.8 
Analysis of Glasgow Outcome Scale – Extended at 3 Months Post 
Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
 
 
Table 14.2.7.9 
ORs and CIs of Glasgow Outcome Scale - Extended at 3 Months Post 
Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
 
 
Table 14.2.8.1 
Summary of SF-36 by Visit (mITT Population) 
 
 
Table 14.2.8.2 
Analysis of SF-36 by Visit (mITT Population) 
 
 
Table 14.2.9 
Shift Summary of CT Classification (mITT Population) 
 
 
Table 14.2.10 
Summary of Maximum Intracranial Pressure by Visit (mITT 
Population) 
 
 
Table 14.2.11.1 
Summary of Cerebral Perfusion Pressure by Visit (mITT Population) 
 
 
Table 14.2.11.2 
Potentially Clinically Important On-Treatment Cerebral Perfusion 
Pressure (mITT Population) 
 
 
Table 14.2.12.1 
Summary of Therapy Intensity Level by Visit (mITT Population) 
 
 
Table 14.2.12.2 
Summary of Individual TIL Therapies (mITT Population) 
 
 
Table 14.2.12.3 
Summary of Maximum Therapy Intensity Level (mITT Population) 
 
 
Table 14.3.1.1 
Overall Summary of Treatment Emergent Adverse Events (Safety 
Population) 
 
X 
Table 14.3.1.2 
Overall Summary of Treatment Emergent Adverse Events by Gender 
(Safety Population) 
 
 
Table 14.3.1.3 
Overall Summary of Treatment Emergent Adverse Events by Race 
Group (Safety Population) 
14.3.1.2 
 


 
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Protocol No. BHR-100-301 
 
 
Page 44 of 213 
Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.3.1.4 
Overall Summary of Treatment Emergent Adverse Events by Age 
Group (Safety Population) 
14.3.1.2 
 
Table 14.3.1.5 
Treatment Emergent Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 
 
X 
Table 14.3.1.6 
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Gender (Safety Population) 
 
 
Table 14.3.1.7 
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Race Group (Safety Population) 
 
 
Table 14.3.1.8 
Treatment Emergent Adverse Events by System Organ Class, 
Preferred Term, and Age Group (Safety Population) 
 
 
Table 14.3.1.9 
Treatment-Related Treatment Emergent Adverse Events by System 
Organ Class and Preferred Term (Safety Population) 
14.3.1.5 
X 
Table 14.3.1.10 
Treatment Emergent Adverse Events by Maximum Severity, System 
Organ Class and Preferred Term (Safety Population) 
 
 
Table 14.3.1.11 
Treatment-Related Treatment Emergent Adverse Events by 
Maximum Severity, System Organ Class and Preferred Term (Safety 
Population) 
14.3.1.9 
 
Table 14.3.1.12 
Treatment Emergent Adverse Events by Maximum Relationship, 
System Organ Class and Preferred Term (Safety Population) 
 
 
Table 14.3.1.13 
Treatment Emergent Adverse Events Leading to Premature 
Discontinuation of Study Drug by System Organ Class and Preferred 
Term (Safety Population) 
14.3.1.5 
 
Table 14.3.1.14 
Treatment-Related Treatment Emergent Adverse Events Leading to 
Premature Discontinuation of Study Drug by System Organ Class 
and Preferred Term (Safety Population) 
14.3.1.5 
 
Table 14.3.1.15 
Treatment Emergent Adverse Events of Special Interest (Safety 
Population) 
 
X 
Table 14.3.1.16 
List of Adverse Events of Special Interest (Safety Population) 
 
X 
Table 14.3.2.1 
Serious Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
14.3.1.5 
X 
Table 14.3.2.2 
Treatment-Related Serious Adverse Events by System Organ Class 
and Preferred Term (Safety Population) 
14.3.1.5 
X 
Table 14.3.2.3 
Primary Cause of Death (mITT Population) 
 
X 
Table 14.3.4.1 
Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory 
Test Results: Coagulation (Safety Population) 
 
X 
Table 14.3.4.2 
Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory 
Test Results: Hematology  (Safety Population) 
14.3.4.1 
X 
Table 14.3.4.3 
Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory 
Test Results: Serum Chemistry (Safety Population) 
14.3.4.1 
 


 
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Protocol No. BHR-100-301 
 
 
Page 45 of 213 
Output 
Title 
Use  
Table  
Shell 
DSMB* 
Table 14.3.4.4 
Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory 
Test Results: Urinalysis (Safety Population) 
 
 
Table 14.3.4.5 
List of Post-Baseline Abnormal, Clinically Significant (non-AE) 
Laboratory Test Results: Coagulation (Safety Population) 
14.3.4.9 
X 
Table 14.3.4.6 
List of Post-Baseline Abnormal, Clinically Significant (non-AE) 
Laboratory Test Results: Hematology (Safety Population) 
 
X 
Table 14.3.4.7 
List of Post-Baseline Abnormal, Clinically Significant (non-AE) 
Laboratory Test Results: Serum Chemistry (Safety Population) 
14.3.4.9 
X 
Table 14.3.4.8 
List of Post-Baseline Abnormal, Clinically Significant (non-AE) 
Laboratory Test Results: Urinalysis (Safety Population) 
14.3.4.9 
X 
Table 14.3.4.9 
Summary of Coagulation Laboratory Test Results (Safety 
Population) 
 
 
Table 14.3.4.10 
Summary of Hematology Laboratory Test Results (Safety 
Population) 
14.3.4.12 
 
Table 14.3.4.11 
Summary of Serum Chemistry Laboratory Test Results (Safety 
Population) 
14.3.4.12 
 
Table 14.3.5 
Summary of Incidence of Neuroworsening (Safety Population) 
 
 
Table 14.3.6.1 
Summary of Vital Signs Corresponding to Lowest Measurement 
(Safety Population) 
 
X 
Table 14.3.6.2 
Summary of Vital Signs Corresponding to Highest Measurement 
(Safety Population) 
14.3.5.1 
X 
Table 14.3.6.3 
Summary of Vital Signs by Visit – Weight (kg) (Safety Population) 
 
 
Table 14.3.7.1 
Summary of Physical Examination by Visit (Safety Population) 
 
 
Table 14.3.7.2 
List of Physical Examination Abnormalities Post-Baseline (Safety 
Population) 
 
 
Table 14.3.8.1 
Post-Baseline Abnormal ECG Results (Safety Population) 
 
X 
Table 14.3.8.2 
List of Post-Baseline Abnormal ECG Results – Part 1 and Part 2 
(Safety Population) 
 
X 
Table 14.3.9 
Summary of Worst Arterial Blood Gas (ABG) Results by Visit 
(Safety Population) 
 
X 
14.3.10 
Summary of Day 2 Progesterone Levels (Safety Population) 
 
 
* Tables produced for DSMB 
Figures 
Figure 
Title 
DSMB* 
Figure 14.2.1.1 
Glasgow Outcome Scale distribution at 6 Months Post Injury – Missing 
Values Imputed (mITT Population) 
X 


 
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Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 46 of 213 
Figure 
Title 
DSMB* 
Figure 14.2.1.2 
Glasgow Outcome Scale distribution at 6 Months Post Injury – Observed 
Values (mITT Population) 
X 
Figure 14.2.1.3 
Glasgow Outcome Scale distribution at 6 Months Post Injury – Observed 
Values (PP Population) 
 
Figure 14.2.2.1 
Dichotomized Glasgow Outcome Scale at 6 Months Post Injury – Missing 
Values Imputed (mITT Population) 
 
Figure 14.2.2.2 
Dichotomized Glasgow Outcome Scale at 6 Months Post Injury – 
Observed Values (mITT Population) 
 
Figure 14.2.3.1 
Mortality at 6 Months (mITT Population) 
X 
Figure 14.2.3.2 
Mortality at 1 Month (mITT Population) 
X 
Figure 14.2.3.3 
Time to Death (mITT Population) 
 
* Figures produced for DSMB 
Data Listings 
Listing 
Title 
DSMB* 
Listing 16.2.1.1 
Study Completion/Discontinuation Details 
 
Listing 16.2.1.2 
Eligibility/Randomization 
 
Listing 16.2.1.3 
Exclusions from Per Protocol Population 
 
Listing 16.2.3.1 
Subject General Information 
X 
Listing 16.2.3.2 
Informed Consent 
 
Listing 16.2.4.1 
Demographic Characteristics 
X 
Listing 16.2.4.2 
Baseline Characteristics 
X 
Listing 16.2.4.3 
Pre-injury Narrative – Baseline Status – Parts 1, 2 and 3 
 
Listing 16.2.4.4 
Glasgow Coma Scale 
 
Listing 16.2.4.5 
Medical History 
 
Listing 16.2.4.6 
Prior, and Concomitant Medications 
 
Listing 16.2.4.7 
Concomitant Procedures 
 
Listing 16.2.4.8 
Surgical Therapy 
 
Listing 16.2.4.9 
Study Admission 
 
Listing 16.2.4.10 
Subject Transfer 
 
Listing 16.2.4.11 
Facility Transfer 
 
Listing 16.2.4.12 
Intubation 
 
Listing 16.2.4.13 
Daily Fluid 
 
Listing 16.2.5.1 
Study Drug Administration Parts 1 and 2 
X 
Listing 16.2.5.2 
End of Treatment 
X 


 
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Protocol No. BHR-100-301 
 
 
Page 47 of 213 
Listing 
Title 
DSMB* 
Listing 16.2.6.1.1 
Glasgow Outcome Scale, Questions 
X 
Listing 16.2.6.1.2 
Glasgow Outcome Scale, Explanation of Categories 
X 
Listing 16.2.6.1.3 
Glasgow Outcome Scale – Extended, Explanation of Categories 
 
Listing 16.2.6.1.4 
Glasgow Outcome Scale – Part 1  
X 
Listing 16.2.6.1.5 
Glasgow Outcome Scale, Glasgow Outcome Scale-Extended Narrative – 
Parts 1-6 
X 
Listing 16.2.6.1.6 
Primary Efficacy, Covariates, and Subgroup Variables (Observed Values) 
X 
Listing 16.2.6.1.7 
Primary Efficacy, Covariates, and Subgroup Variables (Missing Values 
Imputed) 
X 
Listing 16.2.6.2 
Sliding Dichotomy 
 
Listing 16.2.6.3 
Mortality 
X 
Listing 16.2.6.4.1 
SF-36, Explanation of Categories 
 
Listing 16.2.6.4.2 
SF-36 (Individual Questions) - Parts 1, 2 and 3 
 
Listing 16.2.6.4.3 
SF-36 (Scales and Summary Scores) - Parts 1 and 2 
 
Listing 16.2.6.5.1 
CT Scan and Classification - Parts 1, 2 and 3 
 
Listing 16.2.6.5.2 
CT Scan Comparison - Parts 1, 2 and 3 
 
Listing 16.2.6.6.1 
Intracranial Pressure 
 
Listing 16.2.6.6.2 
Intracranial Pressure Monitoring 
 
Listing 16.2.6.7 
Cerebral Perfusion Pressure 
 
Listing 16.2.6.8.1 
Therapy Intensity Level Parts 1 and 2 
 
Listing 16.2.7 
Adverse Events  
X 
Listing 16.2.8.1.1 
Laboratory (Coagulation) Results 
 
Listing 16.2.8.1.2 
Laboratory (Hematology) Results 
 
Listing 16.2.8.1.3 
Laboratory (Serum Chemistry) Results 
 
Listing 16.2.8.1.4 
Laboratory (Urinalysis) Results 
 
Listing 16.2.8.1.5 
Laboratory (Pregnancy Test) Results 
 
Listing 16.2.8.2 
Vital Signs 
X 
Listing 16.2.8.3 
Physical Examinations 
 
Listing 16.2.8.4 
12-Lead Electrocardiogram (ECG) Parts 1 and 2  
 
Listing 16.2.8.5 
Arterial Blood Gas  
X 
Listing 16.2.8.6 
Neuroworsening Parts 1 and 2 
 
* Listings produced for DSMB 
Note: Listings generated for all mITT subjects. 


 
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Protocol No. BHR-100-301 
 
 
Page 48 of 213 
Statistical Output 
Appendix 
Title 
Appendix 14.2.1.2 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury – Missing Values 
Imputed (mITT Population)* 
The above appendix will include the SAS output details relating to Table 14.2.1.2 and 14.2.1.3 (Analysis, 
ORs and CIs). 
Appendix 14.2.1.5 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury – Observed Values 
(mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.1.5 and 14.2.1.6 (Analysis, 
ORs and CIs). 
Appendix 14.2.1.8 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury – Observed Values 
(PP Population) 
The above appendix will include the SAS output details relating to Table 14.2.1.8 and 14.2.1.9 (Analysis, 
ORs and CIs). 
Appendix 14.2.1.11 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury for US Only – 
Missing Values Imputed (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.1.11 and 14.2.1.12 (Analysis, 
ORs and CIs). 
Appendix 14.2.1.13 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury– Missing Values 
Imputed (Unadjusted Analysis) (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.1.13 and 14.2.1.14 (Analysis, 
ORs and CIs). 
Appendix 14.2.2.2 
Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury  – Missing 
Values Imputed (mITT Population) 
Appendix 14.2.2.5 
Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury – 
Observed Values (mITT Population) 
Appendix 14.2.2.8 
Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury – 
Observed Values (PP Population) 
Appendix 14.2.2.11 
Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury for US 
Only – Missing Values Imputed (mITT Population) 
Appendix 14.2.3.2 
Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale at 6 
Months Post Injury – Missing Values Imputed (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.3.2 and 14.2.3.3 (Analysis, 
ORs and CIs). 
Appendix 14.2.3.5 
Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale at 6 
Months Post Injury – Observed Values (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.3.5 and 14.2.3.6 (Analysis, 
ORs and CIs). 
Appendix 14.2.3.8 
Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale at 6 
Months Post Injury – Observed Values (PP Population) 
The above appendix will include the SAS output details relating to Table 14.2.3.8 and 14.2.3.9 (Analysis, 
ORs and CIs). 


 
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Protocol No. BHR-100-301 
 
 
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Appendix 
Title 
Appendix 14.2.3.10 
Analysis of Dichotomized (GR vs. MD, SD, V/D) Glasgow Outcome Scale at 6 
Months Post Injury – Missing Values Imputed (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.3.10 and 14.2.3.11 (Analysis, 
ORs and CIs). 
Appendix 14.2.3.12 
Analysis of Dichotomized (GR, MD, SD vs. V/D) Glasgow Outcome Scale at 6 
Months Post Injury – Observed Values (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.3.12 and 14.2.3.13 (Analysis, 
ORs and CIs). 
Appendix 14.2.4.1 
Analysis of Glasgow Outcome Scale at 6 Months Post Injury – Exploratory 
Analysis – Missing Values Imputed (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.4.1 (Analysis, ORs and CIs). 
Appendix 14.2.5.1 
Summary and Analysis of Mortality at Month 6 (mITT Population) 
Appendix 14.2.5.2 
Summary and Analysis of Mortality at Month 1 (mITT Population) 
Appendix 14.2.5.3 
Summary and Analysis of Mortality at Month 6 (PP Population) 
Appendix 14.2.5.4 
Summary and Analysis of Mortality at Month 1 (PP Population) 
Appendix 14.2.5.5 
Summary and Kaplan-Meier Analysis of Time to Death (days) (mITT 
Population) 
Appendix 14.2.5.6 
Summary and Cox Proportional Hazards Analysis of Time to Death (days) 
(mITT Population) 
Appendix 14.2.6.2 
Analysis of Glasgow Outcome Scale at 3 months post injury – Observed Values 
(mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.6.2 and 14.2.6.3 (Analysis, 
ORs and CIs). 
Appendix 14.2.7.2 
Analysis of Glasgow Outcome Scale - Extended at 6 Months Post Injury – 
Observed Values (mITT Population) 
The above appendix will include the SAS output details relating to Table 14.2.7.2 and 14.2.7.3 (Analysis, 
ORs and CIs). 
Appendix 14.2.7.5 
Summary and Analysis of Sliding Dichotomy – Glasgow Outcome Scale – 
Extended at 6 Months Post Injury – Observed Values (mITT Population) 
Appendix 14.2.7.8 
Analysis of Glasgow Outcome Scale - Extended at 3 Months Post Injury – 
Observed Values (mITT Population) 
Appendix 14.2.8.2 
Analysis of SF-36 by Visit (mITT Population) 
 


 
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Protocol No. BHR-100-301 
 
 
Page 50 of 213 
Model Checking Figures 
 
Figure 14.2.1.1.1 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months [Treatment Group] – Missing 
Values Imputed (mITT Population) 
Figure 14.2.1.1.2 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months [Region] – Missing Values 
Imputed (mITT Population) 
Figure 14.2.1.1.3 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months [Age] –  Missing Values Imputed 
(mITT Population) 
Figure 14.2.1.1.4 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months [GCS Motor Score] – Missing 
Values Imputed (mITT Population) 
Figure 14.2.1.1.5 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months [Pupil Response] – Missing 
Values Imputed (mITT Population) 
Figure 14.2.1.1.6 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months [CT Classification] – Missing 
Values Imputed (mITT Population) 
 


 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 51 of 213 
 
 
Figure 
14.2.1.1.1 
Title 1 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months – Missing Values Imputed 
[Treatment Group] (mITT Population) 
Title 2 
Predictor = Treatment Group 
Type of 
graph 
Line graph 
y-axis 
Empirical Cumulative Logit 
y-axis (label) Empirical  Cumulative Logit 
x-axis 
Treatment Group 
x-axis (label) Treatment Group 
Legend (if 
applicable) 
A legend should be included to identify each empirical cumulative logit 
1 = EmpLogit1 = log[(y1)/( y2+ y3+ y4)] , 2 = EmpLogit2 = log[(y1+ y2)/(y3+ y4)] 
and 3 = EmpLogit3 = log[(y1+ y2+ y3)/(y4)] 
And treatment group: BHR-100 and Placebo 
Footnote 1 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY 
xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.1. 
 


 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 52 of 213 
 
Figure 
14.2.1.1.2 
Title 1 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months Missing Values Imputed [Region] 
(mITT Population) 
Title 2 
Predictor = Region 
Type of 
graph 
Line graph 
y-axis 
Empirical Cumulative Logit 
y-axis (label) Empirical  Cumulative Logit 
x-axis 
Region 
x-axis (label) Region 
Legend (if 
applicable) 
A legend should be included to identify each empirical cumulative logit 
1 = EmpLogit1 = log[(y1)/( y2+ y3+ y4)] , 2 = EmpLogit2 = log[(y1+ y2)/(y3+ y4)] 
and 3 = EmpLogit3 = log[(y1+ y2+ y3)/(y4)] 
And region: North America, Europe, Asia and South America 
Footnote 1 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY 
xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.1. 
 


 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 53 of 213 
 
Figure 
14.2.1.1.3 
Title 1 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months Missing Values Imputed [Age] 
(mITT Population) 
Title 2 
Predictor = Age 
Type of 
graph 
Line graph 
y-axis 
Empirical Cumulative Logit 
y-axis (label) Empirical  Cumulative Logit 
x-axis 
Age 
x-axis (label) Age 
Legend (if 
applicable) 
A legend should be included to identify each empirical cumulative logit 
1 = EmpLogit1 = log[(y1)/( y2+ y3+ y4)] , 2 = EmpLogit2 = log[(y1+ y2)/(y3+ y4)] 
and 3 = EmpLogit3 = log[(y1+ y2+ y3)/(y4)] 
Footnote 1 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY 
xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.1. 
 


 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 54 of 213 
 
Figure 
14.2.1.1.4 
Title 1 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months Missing Values Imputed [GCS 
Motor Score] (mITT Population) 
Title 2 
Predictor = GCS motor score 
Type of 
graph 
Line graph 
y-axis 
Empirical Cumulative Logit 
y-axis (label) Empirical  Cumulative Logit 
x-axis 
GCS motor score 
x-axis (label) GCS motor score 
Legend (if 
applicable) 
A legend should be included to identify each empirical cumulative logit 
1 = EmpLogit1 = log[(y1)/( y2+ y3+ y4)] , 2 = EmpLogit2 = log[(y1+ y2)/(y3+ y4)] 
and 3 = EmpLogit3 = log[(y1+ y2+ y3)/(y4)] 
And GCS motor score:  ≤2 versus >2. 
Footnote 1 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY 
xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.1. 
 


 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 55 of 213 
 
Figure 
14.2.1.1.5 
Title 1 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months Missing Values Imputed [Pupil 
Response] (mITT Population) 
Title 2 
Predictor = Pupil Response 
Type of 
graph 
Line graph 
y-axis 
Empirical Cumulative Logit 
y-axis (label) Empirical  Cumulative Logit 
x-axis 
Pupil Response 
x-axis (label) Pupil Response 
Legend (if 
applicable) 
A legend should be included to identify each empirical cumulative logit 
1 = EmpLogit1 = log[(y1)/( y2+ y3+ y4)] , 2 = EmpLogit2 = log[(y1+ y2)/(y3+ y4)] 
and 3 = EmpLogit3 = log[(y1+ y2+ y3)/(y4)] 
And Pupil Response:  bilateral, unilateral, no reactive pupils, or not testable 
Footnote 1 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY 
xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.1. 
 


 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
Protocol No. BHR-100-301 
 
 
Page 56 of 213 
 
Figure 
14.2.1.1.6 
Title 1 
Graphical Assessment of Proportional Odds Assumption for Proportional Odds 
Model of Glasgow Outcome Scale at 6 months Missing Values Imputed [CT 
Classification] (mITT Population) 
Title 2 
Predictor = CT Classification 
Type of 
graph 
Line graph 
y-axis 
Empirical Cumulative Logit 
y-axis (label) Empirical  Cumulative Logit 
x-axis 
CT Classification 
x-axis (label) CT Classification 
Legend (if 
applicable) 
A legend should be included to identify each empirical cumulative logit 
1 = EmpLogit1 = log[(y1)/( y2+ y3+ y4)] , 2 = EmpLogit2 = log[(y1+ y2)/(y3+ y4)] 
and 3 = EmpLogit3 = log[(y1+ y2+ y3)/(y4)] 
And CT Classification:  Marshall’s CT Classification II, III, IV, evacuated and 
non-evacuated mass lesion 
Footnote 1 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY 
xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.1. 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 57 of 213 
 
APPENDIX 3 SHELLS FOR POST-TEXT TABLES, FIGURES, AND LISTINGS 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 58 of 213 
 
Table 14.1.1.1 Summary of Investigational Sites’ Enrollment Duration (mITT Population) 
 
 
 
 
 
 
 
 
 
 
Study 
Number of Subjects 
Region/Country1/ 
Site 
Principal 
Investigator 
Start Date2 
End Date2 
Duration 
(days)3 
Randomized 
Completed 
Endpoint4 
 
 
 
 
 
 
 
All Sites (N=xxx) 
 
DDMONYYYY 
DDMONYYYY 
xx 
   xx 
   xx 
 
 
 
 
 
 
 
Region 1/Country AR/ 
 
 
 
 
 
 
  01 
xxxxxxxxxxxx 
DDMONYYYY 
DDMONYYYY 
xx 
   xx 
   xx 
  02 
xxxxxxxxxxxx 
DDMONYYYY 
DDMONYYYY 
xx 
   xx 
   xx 
  03 
xxxxxxxxxxxx 
DDMONYYYY 
DDMONYYYY 
xx 
   xx 
   xx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 See Table 14.1.1.6 for 2-letter country codes. 
2 Start Date and End Date are the date of the first consent and the last subject randomization at a specific site, respectively. 
3 Duration (days) = End Date – Start Date + 1. 
4 Subjects are endpoint completers if they provide a GOS assessment at Month 6 or die before Month 6. 
 
Source: Listing 16.2.3.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 59 of 213 
 
 
Table 14.1.1.2 Summary of Enrollment by Region, Country, and Site (mITT Population) 
 
Region1/Country2/Site 
 
Statistic 
BHR-100 
(N=xx) 
n (%) 
Placebo 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
All Sites 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Region 
 
 
 
 
  North America 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Europe 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Asia 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  South America 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Country 
 
 
 
 
  AR 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  AU 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  BE 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
… 
 
 
 
 
 
 
 
 
 
Region/Site 
 
 
 
 
  North America 
  n (%) 
 
 
 
    01 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
    02 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  … 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Europe 
 
 
 
 
    01 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
    02 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
…  
 
 
 
 
 
1 North America=United States, Europe=Austria, Belgium, Czech Republic, Finland, France, Germany, Hungary, Israel, Italy, 
Netherlands, Romania, Russia, Spain, and United Kingdom, Asia=China, Malaysia, Singapore, Taiwan, and Thailand, South 
America=Argentina. 
2 See Table 14.1.1.6 for 2-letter country codes. 
Note: Percentages are based on the number of subjects in each treatment group and overall in the population of interest. 
 
Source: Listing 16.2.4.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 60 of 213 
 
 
Table 14.1.1.3 Summary of Subject Disposition (Randomized Subjects) 
 
 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Subjects Who Were  
 
 
 
 
 
 
 
 
 
Randomized but Not Treated 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Modified Intention-to-Treat1 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Safety Population2 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Per Protocol3 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Study Completers4  
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Endpoint Completers5  
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Early Termination  
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Reason for Early Termination 
 
 
 
 
  Death 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Adverse Event(s) 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Withdrawal of Consent 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Protocol Violation   
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Lost to Follow-up 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Discretion of the Investigator 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Discretion of the Sponsor 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Other 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
1 Modified Intention-to-Treat (mITT) Population includes all subjects who were randomized and in whom treatment with i.v. study drug 
was initiated (analyzed according to randomized treatment). 
2 Safety Population includes all subjects who received any study medication (analyzed according to actual treatment received). 
3 Per Protocol Population includes all subjects in the mITT population who meet all inclusion/exclusion criteria, received at least 96 
hours of study medication treatment, and have a non-missing 6-month GOS score.  
4 Subjects are completers if they complete 6 months involvement in the study. 
5 Subjects who provide a GOS at 6 months, including deaths carried forward to 6 months. 
Note: Percentages are based on the number of subjects in each treatment group and overall in the population of interest. 
 
Source: Listings 16.2.1.1, 16.2.1.2, 16.2.3.1 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 61 of 213 
 
 
 
 
Table 14.1.1.4 Summary of Subject Status by Time (mITT Population) 
 
 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
  Study Completers  
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Early Termination  
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Subjects Remaining in Study 
 
 
 
 
     Day 1 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 2 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 3 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 4 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 5 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 6 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 15  
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 30 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 90 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
     Day 180 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Note: Subjects are completers if they completed a Month 6 visit. Early terminations include deaths. 
Note: Percentages are based on the number of subjects in each treatment group and overall in the population of interest. 
 
Source: Listing 16.2.1.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 62 of 213 
 
 
Table 14.1.1.5 Country Codes per ISO 
 
Code 
Country 
 
 
AR 
Argentina 
AT 
Austria 
BE 
Belgium 
CN 
China 
CZ 
Czech Republic 
DE 
Germany 
ES 
Spain 
FI 
Finland 
FR 
France 
GB 
United Kingdom 
HU 
Hungary 
IL 
Israel 
IT 
Italy 
MY 
Malaysia 
NL 
Netherlands 
RO 
Romania 
RU 
Russia 
SG 
Singapore 
TH 
Thailand 
TW 
Taiwan 
US 
United States  
Note: ISO=International Organization for Standardization. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 63 of 213 
 
 
Table 14.1.2.1 Summary of Study Drug Exposure and Time from Injury (Safety Population) 
 
 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Trt1 Initiated Within 8 Hours of Injury 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Treated for at Least 96 Hours 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Reason for Incomplete Drug 
Administration 
 
 
 
 
  Adverse Event 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Death 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  PI Decision 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Sponsor Decision 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Consent Withdrawn 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Other 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Length of Exposure (hours) 
 
 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
 
Min, Max 
xx , xx 
xx , xx 
xx , xx 
 
 
 
 
 
Length of Exposure: Categorized (hours) 
 
 
 
 
  >0-<=24 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  >24-<=48 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  >48-<=72 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  >72-<=96 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  >96-<=120 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  >120 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Note: Length of Exposure (in hours) = last dose date/time – first dose date/time – (sum of recorded durations of infusion rate 
interruptions). 
Note: Percentages are based on the number of subjects in each treatment group and overall in the population of interest. 
1 Trt = Treatment. 
2 Relative Dose is summarized for the subset of subjects who received drug for 114 to 126 hours (120 +/- 5%).   
 
Source: Listing 16.2.5.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 64 of 213 
 
Table 14.1.2.1 Summary of Study Drug Exposure and Time from Injury (Safety Population) 
 
 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Total Dose (mg/kg) 
 
 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
 
Min, Max 
xx , xx 
xx , xx 
xx , xx 
 
 
 
 
 
Relative Dose2 
 
 
 
 
  0 < Relative Dose <=80% 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  80% < Relative Dose <=100% 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  100% < Relative Dose <=120% 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Relative Dose > 120% 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Time Since Injury to Study Drug (hours) 
 
 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
xx.x 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
 
Min, Max 
xx , xx 
xx , xx 
xx , xx 
 
 
 
 
 
Time Since Injury to Study Drug: 
Categorized (hours) 
 
 
 
 
   0-<=4 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   >4-<=6 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   >6-<=8 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   >8-<=9 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   >9 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Note: Length of Exposure (in hours) = last dose date/time – first dose date/time – (sum of recorded durations of infusion rate 
interruptions). 
Note: Percentages are based on the number of subjects in each treatment group and overall in the population of interest. 
1 Trt = Treatment. 
2 Relative Dose is summarized for the subset of subjects who received drug for 114 to 126 hours (120 +/- 5%).   
 
 
Source: Listing 16.2.5.2. 
 
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Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 65 of 213 
 
Table 14.1.2.2 Drug Administration Summary (Safety Population) 
 
 
 
Question 
 
 
Response 
 
 
Statistic 
 
BHR-100 
(N=xx) 
n (%) 
 
Placebo 
(N=xx) 
n (%) 
 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
 
Infusion Rate Modified on Any Day 
Yes 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
No 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Reason for Modification 
Adverse Event 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
IV Access Problem 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Subcutaneous Infusion 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Inappropriate/Non-Consistent 
Infusion Rate 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Other 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Infusion Interrupted >30 Minutes on Any 
Day 
Yes 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
No 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Reason for Modification 
Adverse Event 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
IV Access Problem 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Subcutaneous Infusion 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Inappropriate/Non-Consistent 
Infusion Rate 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Other 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on the number of subjects in each treatment group and overall in the population of interest. 
 
Source: Listing 16.2.5.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 [Note to Programmer: Include loading dose and maintenance doses in same table.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 66 of 213 
 
 
 
 
Table 14.1.2.3 Summary of Study Drug Compliance Rate (Safety Population) 
 
 
 Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Overall Compliance (%) 
  n 
xx 
xx 
xx 
 
  Mean (SD) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
xx.xx (xx.xx) 
 
  Median 
xx.xx 
xx.xx 
xx.xx 
 
  Q1, Q3 
xx.xx , xx.xx 
xx.xx , xx.xx 
xx.xx , xx.xx 
 
  Min, Max 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
 
 
 
 
 
 
Note: Compliance rate is calculated by dividing the hours of study medication taken by the number of hours that should have been 
taken during the treatment period multiplied by 100. 
 
Source: Listing 16.2.5.1 and 16.2.5.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Programmer Note: See section 5 and 9.3.1 for details about compliance calculation] 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 67 of 213 
 
 
 
Table 14.1.3.1 Prior and Concomitant Medications by WHO Drug Dictionary Preferred Term (mITT Population) 
 
 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Any Prior or Concomitant 
Medication 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
  Preferred Term 1 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 2 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 3 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 4 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 5 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Note: Percentages are based on the number of subjects in each treatment group and total in the population of interest. 
Note: Subjects could have received more than one prior medication. 
Note: Prior medications are defined as medications with a stop date before the first administration of study medication.  
Concomitant medications are defined as medications with a start or stop date after the first administration of study medicat
ion or ongoing on Day 15. 
 
Source: Listing 16.2.4.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 68 of 213 
 
Table 14.1.3.2 Surgical Therapy (mITT Population) 
 
Characteristic 
 Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Type of Surgery 
  N 
xx 
xx 
xx 
  Intracranial 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Extracranial 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Intracracranial Surgery Type 
  N 
xx 
xx 
xx 
  Aneurysm (non trauma) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Acute Subdural Hematoma 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Contusion 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Craniofacial Surgery 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  CSF Shunt 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Chronic Subdural Hematoma 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Decompressive Craniectomy Injuries 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Depressed Skull Fracture 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Epidural Hematoma 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Intracerebral Hematoma 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Infection 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Optic Nerve Decompression 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Posterior Fossa Surgery 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Skull Base Fracture 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Ventriculostomy for CSG Drainage 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Debridement – Minimal for Penetrating Injuries 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Debridement – Extensive for Penetrating Injuries 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Foreign Body Removal 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Bone Flap Replacement 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Other  
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
   
      
       
       
 
Note: Percentages are based on the number of subjects with data in each treatment group and total in the population of interest. 
 
Source: Listing 16.2.4.8. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 69 of 213 
 
Table 14.1.3.2 Surgical Therapy (mITT Population) 
 
Characteristic 
 Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Extracranial Surgery Type 
  N 
xx 
xx 
xx 
  Maxillofacial 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Extremity Fracture Lower Limb (Internal Fixation) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Extremity Fracture Lower Limb (External Fixation) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Extremity Fracture Upper Limb (Internal Fixation) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Extremity Fracture Upper Limb (External Fixation) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Fasciotomy 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Laparotomy (Abdomen) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Pelvic Fracture (Internal Fixation) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Pelvic Fracture (External Fixation) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Placement of Chest Tube 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Placement of Gastric Tube (PEG) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Spinal Stabilization/Thoracic 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Spinal Stabilization/Lumbal 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Thoracotomy 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Tracheostomy 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Urinary Catheter 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Vascular (Operative) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Vascular (Endovascular Treatment) 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Wound Closure Graft 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Other 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
   
      
       
       
 
Note: Percentages are based on the number of subjects with data in each treatment group and total in the population of interest. 
 
Source: Listing 16.2.4.8. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 70 of 213 
 
Table 14.1.4.1 Demographic Characteristics (mITT Population) 
 
Characteristic 
 Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Age (years) 
  n 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx.x 
xx.x 
xx.x 
 
  Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
xx.x , xx.x 
 
  Min, Max 
xx , xx 
xx , xx 
xx , xx 
 
 
 
 
 
Sex 
  N 
xx 
xx 
xx 
  Male 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Female 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Ethnicity 
  N 
xx 
xx 
xx 
  Hispanic or Latino 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Not Hispanic or Latino 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Not Allowed to Obtain 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Race 
  N 
xx 
xx 
xx 
  White 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Black, African American or of African heritage 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Native Hawaiian or other Pacific Islander 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Asian 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  American Indian or Alaska Native 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Not Allowed to Obtain 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Other 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
   
      
       
       
 
Note: Percentages are based on the number of subjects with data in each treatment group and total in the population of 
interest. 
Note: Age (years) = (date of informed consent – date of birth + 1)/365.25. 
 
Source: Listing 16.2.4.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 71 of 213 
 
 
Table 14.1.4.2 Pregnancy Testing (mITT Population) 
 
Characteristic 
 Statistic 
 BHR-100 
(N=xx) 
 Placebo 
(N=xx) 
 Total 
(N=xx) 
 
 
 
 
 
Female1 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Female of Child-Bearing Potential2 
  N 
xx 
xx 
xx 
  Yes 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  No 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Missing 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Sample Collected for Pregnancy Test3 
  N 
xx 
xx 
xx 
  Yes 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  No 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Missing 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Pregnancy Test Result4 
  N 
xx 
xx 
xx 
  Positive 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Negative 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Missing 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
   
      
       
       
 
1 Percentages are calculated using the number of subjects with data as the numerator and the number of subjects in the mITT 
population as the denominator. 
2 Percentages are calculated using the number of subjects with data as the numerator and the number of female subjects as 
the denominator. 
3 Percentages are calculated using the number of subjects with data as the numerator and the number of female subjects of 
child-bearing potential as the denominator. 
4 Percentages are calculated using the number of subjects with data as the numerator and the number of samples collected 
for pregnancy testing as the denominator. 
 
Source: Listing 16.2.8.1.5. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 72 of 213 
 
Table 14.1.4.3 Baseline Characteristics (mITT Population) 
 
Characteristic 
 Statistic 
BHR-100 
(N=xx) 
n (%) 
Placebo 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
Region 
 
 
 
 
  North America 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Europe 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Asia 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  South America 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
GCS Motor score 
 
 
 
 
  1-2 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  3 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  4 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  5-6 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Pupillary Response 
 
 
 
 
  Bilateral 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Unilateral 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  No Reactive Pupils 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Not Testable 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Hypoxia1 
 
 
 
 
  Yes 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  No 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Suspected 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Unknown 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
   
      
       
       
 
Note: GCS=Glasgow Coma Score. 
Note: Percentages are based on the number of subjects with baseline data in each treatment group and overall. 
1  Hypoxia is defined as PaO2 < 60 mmHg. 
2  Hypotension is defined as systolic blood pressure < 90 mmHg. 
Source: Listing 16.2.6.1.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: The GCS motor score will come from the screening GCS, presence of hypoxia/hypotension comes from 
resuscitation CRF page, CT classification and presence of subarachnoid hemorrhage will come from the screening CT scan. 
Pupillary response will come from the assessment of right and left pupil reactivity.  If both right and left pupils react = 
bilateral, if either right or left pupil reacts = unilateral , if neither pupil reacts = no reactivel pupils, or the eyes 
are closed (i.e. untestable) = not testable.] 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 73 of 213 
 
Table 14.1.4.3 Baseline Characteristics (mITT Population) 
 
Characteristic 
 Statistic 
BHR-100 
(N=xx) 
n (%) 
Placebo 
(N=xx) 
n (%) 
Total 
(N=xx) 
n (%) 
 
 
 
 
 
Hypotension2 
 
 
 
 
  Yes 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  No 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Suspected 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Unknown 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Marshall CT Classification 
 
 
 
 
  I 
 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  II 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  III 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  IV 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Evacuated/Non-Evacuated Mass Lesion 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Traumatic Subarachnoid Hemorrhage 
 
 
 
 
  Yes 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  No 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
   
   
      
       
       
 
Note: GCS=Glasgow Coma Score. 
Note: Percentages are based on the number of subjects with baseline data in each treatment group and overall. 
1  Hypoxia is defined as PaO2 < 60 mmHg. 
2  Hypotension is defined as systolic blood pressure < 90 mmHg. 
 
Source: Listing 16.2.6.1.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: The GCS motor score will come from the screening GCS, presence of hypoxia/hypotension comes from 
resuscitation CRF page, CT classification and presence of subarachnoid hemorrhage will come from the screening CT scan. 
Pupillary response will come from the assessment of right and left pupil reactivity.  If both right and left pupils react = 
bilateral, if either right or left pupil reacts = unilateral , if neither pupil reacts = no reactivel pupils, or the eyes 
are closed (i.e. untestable) = not testable.] 
  


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 74 of 213 
 
 
Table 14.1.4.4 Summary of Injury (mITT Population) 
 
Characteristic 
 Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Cause of Traumatic Brain Injury 
  n 
xx 
xx 
xx 
  Motor Vehicle 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Motorcycle 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Fall 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Sports/Recreation 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Pedestrian 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Diving 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Assault 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Other 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on the number of subjects in each treatment group and total in the population of interest. 
 
Source: Listing 16.2.4.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 75 of 213 
 
Table 14.1.4.4 Summary of Injury (mITT Population) 
 
Characteristic 
 Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
 
 
 
 
Head Injury Alone 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Face 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Chest 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Abdomen 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Extremities 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Spine 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on the number of subjects in each treatment group and total in the population of interest. 
 
Source: Listing 16.2.4.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
[Note to Programmer: The summaries of Face, Chest, Abdomen, Extremities, and Spine injuries will include subjects who had a severe or 
critical exam result for the given injury.  Head injury alone summary will include subjects who did not have a severe or critical 
injury to one of the other body parts.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 76 of 213 
 
                             
 
 
 
Table 14.1.5 Summary of Medical History by System Organ Class and Preferred Term (Safety Population) 
 
 
 
 
 
System Organ Class 
  Preferred Term 
  Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Any Medical History 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
   
 
 
 
System Organ Class 1 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 1 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 2 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 3 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 4 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 5 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
System Organ Class 2 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 1 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 2 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 3 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 4 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Preferred Term 5 
  n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
   
Note: Percentages are based on the number of subjects in each treatment group and total in the population of interest. 
 
Source: Listing 16.2.4.5. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 77 of 213 
 
 
 
Table 14.2.1.1 Summary of Glasgow Outcome Scale at 6 Months Post Injury – Missing Values Imputed (mITT Population) 
 
 
 
 
 
Glasgow Outcome Scale 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Vegetative State/Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month  
GOS, the missing value is imputed based upon the primary proportional odds model.  Percentages are based on the number of  
non-missing GOS at the month 6 assessment in each treatment group in the population of interest. 
 
Source: Listing 16.2.6.1.4. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: For the “Observed Values” summaries, please add a Missing category to the table.] 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 78 of 213 
 
 
Table 14.2.1.2 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury – Proportional Odds Model - Missing Values Imputed (mITT 
Population) 
 
 
 
 
 
 
Characteristic 
 
DF2 
 
Chi-Square3 
 
P-Value3 
 
 
 
 
Score Test for Proportional Odds Assumption4 
xx 
xx.xxx 
x.xxx 
 
 
 
 
Treatment 
xx 
xx.xxx 
x.xxx 
Region 
xx 
xx.xxx 
x.xxx 
Age 
xx 
xx.xxx 
x.xxx 
GCS Motor Score 
xx 
xx.xxx 
x.xxx 
Pupil Response 
xx 
xx.xxx 
x.xxx 
CT Classification 
xx 
xx.xxx 
x.xxx 
 
 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month GOS,  
the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common level over  
all subjects. 
1 Response variable Glasgow Outcome Scale at 6 months post injury has 4 values (Good Recovery, Moderate Disability, Severe Disability and 
Vegetative State/Dead). 
2 DF=Degrees of Freedom. 
3 The score test is based on the Chi-Square test and the Type 3 analysis of effects are based on the Wald Chi-Square test from a Logistic 
Regression analysis (Proportional Odds Model).  The POM will model the odds of a favorable outcome/higher GOS category and will be fitted 
including treatment, geographic region (North America, Europe, Asia, and South America), age, GCS motor score (1-2, 3, 4, 5-6), pupil 
response (unilateral, bilateral, no reactive pupils/not testable), and CT classification (I/II, III, IV, V/VI). 
4 A non-significant result supports the proportional odds assumption. 
 
Source: Listing 16.2.6.1.4 and 16.2.6.1.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 79 of 213 
 
 
Table 14.2.1.3 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury – Proportional Odds Model – Missing Values Imputed (mITT 
Population) 
 
 
 
 
Effect3 
 
Odds Ratio 
 
95% CI2 
 
 
 
Treatment (BHR-100 vs. Placebo) 
x.xx 
(x.xx, x.xx) 
 
 
 
Region (North America vs. Europe) 
x.xx 
(x.xx, x.xx) 
Region (Asia vs. Europe) 
x.xx 
(x.xx, x.xx) 
Region (South America vs. Europe) 
x.xx 
(x.xx, x.xx) 
 
 
 
Age 
x.xx 
(x.xx, x.xx) 
 
 
 
GCS Motor Score (3 vs. 1/2) 
x.xx 
(x.xx, x.xx) 
GCS Motor Score (4 vs. 1/2) 
x.xx 
(x.xx, x.xx) 
GCS Motor Score (5/6 vs. 1/2) 
x.xx 
(x.xx, x.xx) 
 
 
 
Pupil Response (Bilateral vs. Unilateral/No Reactive Pupils/Not 
Testable) 
x.xx 
(x.xx, x.xx) 
 
 
 
CT Classification (I/II vs. V/VI) 
x.xx 
(x.xx, x.xx) 
CT Classification (III vs. V/VI) 
x.xx 
(x.xx, x.xx) 
CT Classification (IV vs. V/VI) 
x.xx 
(x.xx, x.xx) 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month GOS,  
the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common level  
over all subjects. 
1 OR=Odds Ratio. 
2 CI=Confidence Interval. 
3 The OR and CIs come from a Logistic Regression analysis (Proportional Odds Model).  The POM will model the odds of a favorable 
outcome/higher GOS category and will be fitted including treatment, geographic region (North America, Europe, Asia, and South America), 
age, GCS motor score (1-2, 3, 4, 5-6), pupil response (unilateral, bilateral, no reactive pupils/not testable), and CT classification 
(I/II, III, IV, V/VI). For factors, the last level is taken as the reference level.  For example, CT classification with 5 levels (II-
V/VI), level V/VI is taken as the reference level.  Marshall CT Score classification was used. 
 
Source: Listing 16.2.6.1.4 and 16.2.6.1.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 80 of 213 
Table 14.2.1.4 Summary of Glasgow Outcome Scale at 6 Months Post Injury – Observed Values (mITT Population) 
Table 14.2.1.5 Analysis of Glasgow Outcome Scale at 6 Months Post Injury – Proportional Odds Model - Observed Values (mITT Population) 
Table 14.2.1.6 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
 
 
Table 14.2.1.7 Summary of Glasgow Outcome Scale at 6 Months Post Injury – Observed Values (PP Population) 
Table 14.2.1.8 Analysis of Glasgow Outcome Scale at 6 Months Post Injury – Proportional Odds Model - Observed Values  (PP Population) 
Table 14.2.1.9 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury – Proportional Odds Model - Observed Values (PP 
Population) 
 
Table 14.2.1.10 Summary of Glasgow Outcome Scale at 6 Months Post Injury for US Only – Missing Values Imputed (mITT Population) 
Table 14.2.1.11 Analysis of Glasgow Outcome Scale at 6 Months Post Injury for US Only – Proportional Odds Model - Missing Values 
Imputed (mITT Population) 
Table 14.2.1.12 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury for US Only – Proportional Odds Model - Missing 
Values Imputed (mITT Population) 
 
Table 14.2.1.13 Analysis of Glasgow Outcome Scale at 6 Months Post Injury – Proportional Odds Model - Missing Values Imputed 
(Unadjusted Analysis) (mITT Population) 
Table 14.2.1.14 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury – Proportional Odds Model - Missing Values Imputed 
(Unadjusted Analysis) (mITT Population) 
 
Note: Tables 14.2.1.13 and 14.2.1.14 will only have a row for Treatment, as other covariates will not be included in the model. 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 81 of 213 
 
 
Table 14.2.2.1 Summary of Sliding Dichotomy (Dichotomization) at 6 Months Post Injury – Missing Values Imputed (mITT Population) 
 
 
 
 
 
 
 
Prognosis 
 
Characteristic 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
Best 
n 
n 
xx 
xx 
xx 
 
Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Vegetative State/Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Intermediate 
n 
n 
xx 
xx 
xx 
 
Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Vegetative State/Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Worst 
n 
n 
xx 
xx 
xx 
 
Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Vegetative State/Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Overall 
n 
n 
xx 
xx 
xx 
 
Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Vegetative State/Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month  
GOS, the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common  
level over all subjects. 
Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Source: Listing 16.2.6.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Is there a way to indicate with a different font or making the font bold the Glasgow Outcome Scale outcomes that 
respond to a favorable outcome, i.e. split the overall column into approximately 50:50 within each prognosis group?] 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 82 of 213 
 
Table 14.2.2.2 Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury – Missing Values Imputed (mITT Population) 
 
 
 
 
 
 
 
 
Prognosis 
 
Characteristic 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
P-Value1 
BHR-100 vs. Placebo 
Difference (95% CI)2 
BHR-100 - Placebo 
 
 
 
 
 
 
 
Overall 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
Best 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
Intermediate 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
Worst 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month GOS,  
the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common  
level over all subjects.  Percentages are based on the number of subjects in each treatment group in the population of interest. 
1 P-value is based on Cochran-Mantel Haenszel Chi-Square test adjusted for region. 
2 Difference is in proportion of favourable outcomes.  The confidence interval for the difference is the standard Wald asymptotic 
confidence interval based on the normal approximation to the binomial distribution. 
 
Source: Listing 16.2.6.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
Table 14.2.2.4 Summary of Sliding Dichotomy (Dichotomization) at 6 Months Post Injury – Observed Values (mITT Population) 
Table 14.2.2.5 Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury – Observed Values (mITT Population) 
Table 14.2.2.6 ORs1 and 95% CIs2 for Sliding Dichotomy at 6 Months Post Injury – Observed Values (mITT Population) 
 
 
Table 14.2.2.7 Summary of Sliding Dichotomy (Dichotomization) at 6 Months Post Injury – Observed Values (PP Population) 
Table 14.2.2.8 Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury – Observed Values (PP Population) 
Table 14.2.2.9 ORs1 and 95% CIs2 for Sliding Dichotomy at 6 Months Post Injury – Observed Values (PP Population) 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 83 of 213 
Table 14.2.2.10 Summary of Sliding Dichotomy (Dichotomization) at 6 Months Post Injury for US Only – Missing Values Imputed (mITT 
Population) 
Table 14.2.2.11 Summary and Analysis of Sliding Dichotomy at 6 Months Post Injury for US Only – Missing Values Imputed (mITT 
Population) 
Table 14.2.2.12 ORs1 and 95% CIs2 for Sliding Dichotomy at 6 Months Post Injury for US Only – Missing Values Imputed (mITT Population) 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 84 of 213 
 
 
 
 
Table 14.2.2.3 ORs1 and 95% CIs2 for Sliding Dichotomy at 6 Months Post Injury – Missing Values Imputed (mITT Population) 
 
 
 
 
 
 
 
 
Characteristic 
 
Prognosis 
 
p-value 
 
OR3 (95% CI) 
 
 
 
 
Breslow-Day Test for Homogeneity of Odds Ratios 
 
x.xxx 
 
 
 
 
 
Prognosis 
Overall 
 
x.xx (xx.x, xx.x) 
 
Best 
 
x.xx (xx.x, xx.x) 
 
Intermediate 
 
x.xx (xx.x, xx.x) 
 
Wost 
 
x.xx (xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month GOS,  
the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common level  
over all subjects.   
1 OR=Odds Ratio. 
2 CI=Confidence Interval. 
3  OR for BHR-100 vs. Placebo is based on Cochran-Mantel Haenszel Chi-Square test adjusted for region. 
 
Source: Listing 16.2.6.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 85 of 213 
 
 
Table 14.2.3.1 Summary of Dichotomized Glasgow Outcome Scale at 6 Months Post Injury – Missing Values Imputed (mITT Population) 
 
 
 
 
 
Glasgow Outcome Scale1 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
N 
n 
xx 
xx 
GR 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
MD, SD, V/D 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
N 
n 
xx 
xx 
GR, MD 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
SD, V/D 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
N 
n 
xx 
xx 
GR, MD, SD 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
V/D 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month GOS,  
the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common  
level over all subjects.  Percentages are based on the number of subjects with data at the month 6 assessment in each treatment group in 
the population of interest.   
1 GR=Good Recovery, MD=Moderate Disability, SD=Severe Disability, V/D=Vegetative State/Dead.  Vegetative state and dead categories are 
combined for analysis. 
 
Source: Listing 16.2.6.1.4. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 86 of 213 
 
 
Table 14.2.3.2 Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale1 at 6 Months Post Injury – Missing Values Imputed (mITT 
Population) 
 
 
 
 
 
 
Variable 
 
DF2 
 
Chi-Square3 
 
P-Value3 
 
 
 
 
 
 
 
 
Treatment 
xx 
xx.xxx 
x.xxx 
Region 
xx 
xx.xxx 
x.xxx 
Age 
xx 
xx.xxx 
x.xxx 
GCS Motor Score 
xx 
xx.xxx 
x.xxx 
Pupil Response 
xx 
xx.xxx 
x.xxx 
CT Classification 
xx 
xx.xxx 
x.xxx 
 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month GOS,  
the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common  
level over all subjects.   
1 Response variable Glasgow Outcome Scale at 6 months post injury has 2 values (Good Recovery, Moderate Disability vs. Severe Disability, 
Vegetative State/Dead). 
2 DF=Degrees of Freedom. 
3 The Type 3 analysis of effects are based on the Wald Chi-Square test from a Logistic Regression analysis.  The odds of a favorable 
outcome (GR, MD) will be modeled and will be fitted including treatment, geographic region (North America, Europe, Asia, and South 
America), age, GCS motor score (1-2, 3, 4, 5-6), pupil response (unilateral, bilateral, no reactive pupils/not testable), and CT 
classification (I/II, III, IV, V/VI).4  
 
Source: Listing 16.2.6.1.4 and 16.2.6.1.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 87 of 213 
 
Table 14.2.3.3 ORs1 and 95% CIs2 for Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale at 6 Months Post Injury – Missing Values 
Imputed (mITT Population) 
 
 
 
 
Effect3 
 
Odds Ratio 
 
95% CI2 
 
 
 
Treatment (BHR-100 vs. Placebo) 
x.xx 
(x.xx, x.xx) 
 
 
 
Region (North America vs. Europe) 
x.xx 
(x.xx, x.xx) 
Region (Asia vs. Europe) 
x.xx 
(x.xx, x.xx) 
Region (South America vs. Europe) 
x.xx 
(x.xx, x.xx) 
 
 
 
Age 
x.xx 
(x.xx, x.xx) 
 
 
 
GCS Motor Score (3 vs. 1/2) 
x.xx 
(x.xx, x.xx) 
GCS Motor Score (4 vs. 1/2) 
x.xx 
(x.xx, x.xx) 
GCS Motor Score (5/6 vs. 1/2) 
x.xx 
(x.xx, x.xx) 
 
 
 
Pupil Response (Bilateral vs. Unilateral/No Reactive Pupils/Not 
Testable) 
x.xx 
(x.xx, x.xx) 
 
 
 
CT Classification (I/II vs. V/VI) 
x.xx 
(x.xx, x.xx) 
CT Classification (III vs. V/VI) 
x.xx 
(x.xx, x.xx) 
CT Classification (IV vs. V/VI) 
x.xx 
(x.xx, x.xx) 
 
 
 
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month GOS,  
the missing value is imputed based upon the primary proportional odds model. Missing covariates are imputed as the most common  
level over all subjects.   
1 OR=Odds Ratio. 
2 CI=Confidence Interval. 
3 The OR and CIs come from a Logistic Regression analysis.  The odds of a favorable outcome (GR, MD) will be modeled and will be fitted 
including treatment, geographic region (North America, Europe, Asia, and South America), age, GCS motor score (1-2, 3, 4, 5-6), pupil 
response (unilateral, bilateral, no reactive pupils/not testable), and CT classification (I/II, III, IV, V/VI). 
For factors, the last level is taken as the reference level.  For example, CT classification with 4 levels (II-V/VI), level V/VI is taken 
as the reference level.  Marshall CT classification was used.   
 
Source: Listing 16.2.6.1.4 and 16.2.6.1.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 88 of 213 
 
 
 
Table 14.2.3.4 Summary of Dichotomized Glasgow Outcome Scale at 6 Months Post Injury – Observed Values (mITT Population) 
 
 
 
 
 
 
Glasgow Outcome Scale1 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
n 
n 
xx 
xx 
GR, MD 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
SD, V/D 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
1 GR=Good Recovery, MD=Moderate Disability, SD=Severe Disability, V/D=Vegetative/Dead.  Vegetative state and dead categories are 
combined. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Source: Listing 16.2.6.1.4. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
Note to Programmer: Missing value imputation ONLY done for GR, MD vs. SD, V/D dichotomization. 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 89 of 213 
Table 14.2.3.5 Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale1 at 6 Months Post Injury – Observed Values (mITT 
Population) 
Table 14.2.3.6 ORs1 and 95% CIs2 for Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale at 6 Months Post Injury – Observed Values 
(mITT Population) 
 
 
 
Table 14.2.3.7 Summary of Dichotomized Glasgow Outcome Scale at 6 Months Post Injury – Observed Values (PP Population) 
Table 14.2.3.8 Analysis of Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale1 at 6 Months Post Injury – Observed Values (PP 
Population) 
Table 14.2.3.9 ORs1 and 95% CIs2 for Dichotomized (GR, MD vs. SD, V/D) Glasgow Outcome Scale at 6 Months Post Injury – Observed Values 
(PP Population) 
 
 
Table 14.2.3.10 Analysis of Dichotomized (GR vs. MD, SD, V/D) Glasgow Outcome Scale1 at 6 Months Post Injury – Missing Values Imputed 
(mITT Population) 
Table 14.2.3.11 ORs1 and 95% CIs2 for Dichotomized (GR vs. MD, SD, V/D) Glasgow Outcome Scale at 6 Months Post Injury –Missing Values 
Imputed (mITT Population) 
 
Table 14.2.3.12 Analysis of Dichotomized (GR, MD, SD vs. V/D) Glasgow Outcome Scale1 at 6 Months Post Injury – Missing Values Imputed 
(mITT Population) 
Table 14.2.3.13 ORs1 and 95% CIs2 for Dichotomized (GR, MD, SD vs. V/D) Glasgow Outcome Scale at 6 Months Post Injury – Missing Values 
Imputed (mITT Population) 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 90 of 213 
 
 
 
 
Table 14.2.4.1 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury – Exploratory Analysis – Missing Values Imputed (mITT 
Population) – EXAMPLE SHELL* 
 
 
 
 
 
 
Effect 
 
DF4 
Wald 
Chi-Square5 
 
P-Value5 
Interaction Wald 
Chi-Square5 
Interaction with 
Treatment P-value 
 
 
 
 
 
 
Simple Model2 
 
 
 
 
 
  Treatment 
xx 
xx.xxx 
x.xxx 
xx.xxx 
 
  Region 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Age 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Race 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  GCS Motor Score 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Pupil Response 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  CT Classification 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Hypoxia 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Hypotension 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Subarachnoid Hemorrhage 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Gender 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
  Time to first dose 
xx 
xx.xxx 
x.xxx 
xx.xxx 
x.xxx 
 
 
 
 
 
 
Backward Elimination Model3 
 
 
 
 
 
  Treatment 
xx 
xx.xxx 
x.xxx 
 
 
  Region 
xx 
xx.xxx 
x.xxx 
 
 
  Age 
xx 
xx.xxx 
x.xxx 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Response variable Glasgow Outcome Scale at 6 months post injury has 4 values (Good Recovery, Moderate Disability, Severe Disability 
and Vegetative State/Dead). 
2 Each factor is included in a model with treatment and the factor by treatment interaction and run individually.  
3 The backward elimination model begins with all factors in the model. Factor by treatment interactions with p<0.10 in the simple model 
are included in the Backward Elimination Model. Factors must have a significance level of p<0.10 to remain in the model. Only the 
final model is shown. 
4 DF=Degrees of Freedom. 
5 The Type 3 analysis of effects are based on the Wald Chi-Square test. 
 
 
 
Source: Listing 16.2.6.1.4 and 16.2.6.1.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 91 of 213 
 
 
[* The above template is an example.  ONLY the final exploratory model will be presented, so not all the terms indicated above may be 
included.] 
If any of the interaction terms in the exploratory analysis are significant, the following subgroup analyses will be presented: 
 
 
Table 14.2.4.2 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Region – Proportional Odds Model - Missing Values Imputed 
(mITT Population) 
Table 14.2.4.3 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Region – Proportional Odds Model – Missing Values 
Imputed (mITT Population) 
 
Table 14.2.4.4 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Age Group – Proportional Odds Model - Missing Values 
Imputed (mITT Population) 
Table 14.2.4.5 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Age Group – Proportional Odds Model – Missing 
Values Imputed (mITT Population) 
 
Table 14.2.4.6 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Race Group – Proportional Odds Model - Missing Values 
Imputed (mITT Population) 
Table 14.2.4.7 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Race Group – Proportional Odds Model – Missing 
Values Imputed (mITT Population) 
 
Table 14.2.4.8 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by GCS Motor Score – Proportional Odds Model - Missing Values 
Imputed (mITT Population) 
Table 14.2.4.9 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by GCS Motor Score – Proportional Odds Model – 
Missing Values Imputed (mITT Population) 
 
Table 14.2.4.10 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Pupil Response – Proportional Odds Model - Missing Values 
Imputed (mITT Population) 
Table 14.2.4.11 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Pupil Response – Proportional Odds Model – 
Missing Values Imputed (mITT Population) 
 
Table 14.2.4.12 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by CT Classification – Proportional Odds Model - Missing 
Values Imputed (mITT Population) 
Table 14.2.4.13 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by CT Classification – Proportional Odds Model – 
Missing Values Imputed (mITT Population) 
 
Table 14.2.4.14 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Presence of Hypoxia – Proportional Odds Model - Missing 
Values Imputed (mITT Population) 
Table 14.2.4.15 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Presence of Hypoxia – Proportional Odds Model – 
Missing Values Imputed (mITT Population) 
 
Table 14.2.4.16 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Presence of Hypotension – Proportional Odds Model - 
Missing Values Imputed (mITT Population) 
Table 14.2.4.17 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Presence of Hypotension – Proportional Odds 
Model – Missing Values Imputed (mITT Population) 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 92 of 213 
Table 14.2.4.18 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Presence of Traumatic Subarachnoid Hemorrhage – 
Proportional Odds Model - Missing Values Imputed (mITT Population) 
Table 14.2.4.19 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Traumatic Subarachnoid Hemorrhage – Proportional 
Odds Model – Missing Values Imputed (mITT Population) 
 
 
 
Table 14.2.4.20 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Gender – Proportional Odds Model - Missing Values Imputed 
(mITT Population) 
Table 14.2.4.21 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Gender – Proportional Odds Model – Missing 
Values Imputed (mITT Population) 
 
Table 14.2.4.22 Analysis of Glasgow Outcome Scale1 at 6 Months Post Injury by Time to First Dose – Proportional Odds Model - Missing 
Values Imputed (mITT Population) 
Table 14.2.4.23 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 6 Months Post Injury by Time to First Dose – Proportional Odds Model – 
Missing Values Imputed (mITT Population) 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 93 of 213 
 
Table 14.2.5.1 Summary and Analysis of Mortality at Month 6 (mITT Population) 
 
 
 
 
 
 
 
Mortality 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
P-Value1 
BHR-100 vs. Placebo 
Difference (BHR-100 – 
Placebo) 
(95% CI2) 
 
 
 
 
 
 
N3 
n 
xx 
xx 
 
 
Lost to Follow-up 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Consent Withdrawn 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Alive 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Dead  
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
Other 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
N4 
n 
xx 
xx 
 
 
Alive 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
0.xxx 
x.xx (x.xx, x.xx) 
Dead  
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
1 P-value is based on Fishers Exact test.  Only subjects who were either alive or dead at Month 6 will be included in the analysis. 
2 2-sided 95% confidence interval for the difference in percentage of deaths between BHR-100 and placebo. 
3 Percentages are based on the number of subjects in the mITT population. 
4 Percentages are based on the number of subjects with status=alive or dead, Month 6 within the mITT Population. 
 
Source: Listing 16.2.6.3.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Add a missing category if not all mITT subjects provide details on Month 6 mortality.] 
 
Table 14.2.5.2 Summary and Analysis of Mortality at Month 1 (mITT Population) 
[Update the footnotes to reflect Month 1 timepoint.] 
 
Table 14.2.5.3 Summary and Analysis of Mortality at Month 6 (PP Population) 
Table 14.2.5.4 Summary and Analysis of Mortality at Month 1 (PP Population) 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 94 of 213 
 
 
 
 
 
Table 14.2.5.5 Summary and Kaplan-Meier Analysis of Time to Death1 (days) (mITT Population) 
 
 
 
 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
Kaplan-Meier Estimates 
Total Deaths 
xx 
xx 
 
Total Censored 
xx 
xx 
 
25th percentile 
xx 
xx 
 
Median (95% CI) 
xx (xx , xx) 
xx (xx , xx) 
 
75th percentile 
xx 
xx 
 
 
 
 
Treatment Difference from Placebo2 
 
p=0.xxx 
 
 
 
 
 
 
1 Time to Death (in days) = Date of death/date of last contact (for censored records) – date of TBI + 1.   
2 P-value is based on Log-Rank test. 
 
Source: Listing 16.2.6.3.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: The K-M estimates are those obtained from PROC LIFETEST.   
 
The log-rank test is fitted in SAS using the following syntax:  
PROC LIFETEST DATA=<dataset name>; 
     TIME WKS*CENS(1 – censoring indicator); 
     STRATA TREATMENT; 
RUN;] 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 95 of 213 
 
Table 14.2.5.6 Summary of Cox Proportional Hazards Analysis of Time to Death (days) (mITT Population) 
 
 
 
 
Factor/Covariate1 
Hazard Ratio1 
95% Confidence Limits 
P-value 
 
 
 
 
Treatment Group (BHR-100 vs. Placebo) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
 
 
 
 
Region (North America vs. Europe) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
Region (Asia vs. Europe) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
Region (South America vs. Europe) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
 
 
 
 
Age 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
 
 
 
 
GCS Motor Score (3 vs. 1/2) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
GCS Motor Score (4 vs. 1/2) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
GCS Motor Score (5/6 vs. 1/2) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
 
 
 
 
Pupil Response (Bilateral vs. Unilateral/No 
Reactive Pupils/Not Testable) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
 
 
 
 
CT Classification (I/II vs. V/VI) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
CT Classification (III vs. V/VI) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
CT Classification (IV vs. V/VI) 
x.xxx 
(x.xxx, x.xxx) 
0.xxx 
 
 
 
 
 
1 For factors the last level is taken as the reference level.  Marshall CT classification was used. 
 
Source: Listings 16.2.6.1.6 and 16.2.6.3.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Indicator variables or PROC TPHREG (which has a CLASS statement) will need to be created for the factors with 
more than 2 levels (Region, GCS motor score, Pupil Response and CT classification). 
 
proc tphreg data=<dataset>; 
 class treatment region gcs_motor pupil ct_class; 
 model time_to_death*censoring(0-censoring indicator)=treatment region age gcs_motor pupil ct_class/ties=efron; 
run; 
proc phreg data=<dataset>; 
 treatment gcs_motor pupil ct_class; 
 model time_to_death*censoring(0-censoring indicator)=treatment region1 4 region2 4 region3 4 age gcs_motor pupil1 3 pupil2 3 
ct class2 6 ct class3 6 ct class4 6 ct class5 6/ties=efron; NB. Underlined terms are indicator variables. 
run; 
NB. Using EFRON method for ties.] 
 
Table 14.2.6.1 Summary of Glasgow Outcome Scale at 3 Months Post Injury – Observed Values (mITT Population) 
Table 14.2.6.2 Analysis of Glasgow Outcome Scale at 3 Months Post Injury – Proportional Odds Model - Observed Values (mITT Population) 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 96 of 213 
Table 14.2.6.3 ORs1 and 95% CIs2 for Glasgow Outcome Scale at 3 Months Post Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 97 of 213 
 
 
Table 14.2.7.1 Summary of Glasgow Outcome Scale – Extended at 6 Months Post Injury – Observed Values (mITT Population) 
 
 
 
 
 
 
Glasgow Outcome Scale-Extended 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Vegetative State 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Lower Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Upper Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Lower Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Upper Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Lower Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Upper Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
Missing 
n 
xx 
xx 
 
 
 
 
Note:  Percentages are based on the number of non-missing GOS-E at the month 6 assessment in each treatment group within the 
population of interest. 
 
Source: Listings 16.2.6.1.4. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
Table 14.2.7.2 Analysis of Glasgow Outcome Scale – Extended at 6 Months Post Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
[See shell for 14.2.1.2.] 
 
Table 14.2.7.3 ORs and CIs of Glasgow Outcome Scale - Extended at 6 Months Post Injury – Proportional Odds Model - Observed Values 
(mITT Population) 
[See shell for 14.2.1.3.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 98 of 213 
 
Table 14.2.7.4 Summary of Sliding Dichotomy (Dichotomization) – Glasgow Outcome Scale – Extended at 6 Months Post Injury - Observed 
Values (mITT Population) 
 
 
 
 
 
 
 
Prognosis 
 
Characteristic 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Overall 
(N=xx) 
 
 
 
 
 
 
Group 1 (Best) 
n 
n 
xx 
xx 
xx 
 
Upper Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Lower Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Upper Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Lower Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Upper Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Lower Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Vegetative State/Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Group 2 
n 
n 
xx 
xx 
xx 
 
Upper Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Lower Good Recovery 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Upper Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Lower Moderate Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Upper Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Lower Severe Disability 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
Vegetative State/Dead 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
…  
 
 
 
 
 
 
 
 
 
 
 
Group 6 (Worst) 
 
 
 
 
 
 
 
 
 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Source: Listing 16.2.6.1.4. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Include all 6 prognosis groups and an overall summary.  Please make the font bold for the responses in each 
prognosis group that correspond to a favorable outcome (see SAP text above in Section 9.5.2.3.] 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 99 of 213 
 
Table 14.2.7.5 Summary and Analysis of Sliding Dichotomy – Glasgow Outcome Scale – Extended at 6 Months Post Injury - Observed Values 
(mITT Population) 
 
 
 
 
 
 
 
Prognosis 
 
Characteristic 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
P-Value1 
BHR-100 vs. Placebo 
Difference (95% CI)2 
BHR-100 - Placebo 
 
 
 
 
 
 
 
Overall 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
Group 1 (Best) 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
Group 2 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
Group 3 
n 
n 
xx 
xx 
0.xxx 
xx.x (xx.x, xx.x) 
 
Favorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
Unfavorable 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
…  
 
 
 
 
 
 
 
 
 
 
 
 
 
Note:  Percentages are based on the number of subjects in each treatment group in the population of interest. 
1 P-value is based on Cochran-Mantel Haenszel Chi-Square test adjusted for region. 
2 Difference is in proportion of favourable outcomes.  The confidence interval for the difference is the standard Wald asymptotic confidence  
interval based on the normal approximation to the binomial distribution. 
Source: Listing 16.2.6.1.4. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 100 of 213 
 
Table 14.2.7.6 ORs1 and 95% CIs2 for Sliding Dichotomy – Glasgow Outcome Scale – Extended at 6 Months Post Injury - Observed Values 
(mITT Population) 
 
 
 
 
 
 
Characteristic 
 
Prognosis 
 
p-value 
 
OR3 (95% CI) 
 
 
 
 
Breslow-Day Test for Homogeneity of Odds Ratios 
 
x.xxx 
 
 
 
 
 
Prognosis 
Overall 
 
x.xx (xx.x, xx.x) 
 
Group 1 (Best) 
 
x.xx (xx.x, xx.x) 
 
Group 2 
 
x.xx (xx.x, xx.x) 
 
Group 3 
 
x.xx (xx.x, xx.x) 
 
Group 4 
 
x.xx (xx.x, xx.x) 
 
Group 5 
 
x.xx (xx.x, xx.x) 
 
Group 6 (Worst) 
 
x.xx (xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
1 OR=Odds Ratio. 
2 CI=Confidence Interval. 
3  OR for BHR-100 vs. Placebo is based on Cochran-Mantel Haenszel Chi-Square test adjusted for region. 
 
Source: Listing 16.2.6.1.4. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 
Table 14.2.7.7 Summary of Glasgow Outcome Scale – Extended at 3 Months Post Injury – Observed Values (mITT Population) 
Table 14.2.7.8 Analysis of Glasgow Outcome Scale – Extended at 3 Months Post Injury – Proportional Odds Model - Observed Values (mITT 
Population) 
[See shell for 14.2.1.2.] 
 
Table 14.2.7.9 ORs and CIs of Glasgow Outcome Scale - Extended at 3 Months Post Injury – Proportional Odds Model - Observed Values 
(mITT Population) 
[See shell for 14.2.1.3.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 101 of 213 
 
Table 14.2.8.1 Summary of SF-361 by Visit (mITT Population) 
 
 
 
 
Scale                  
  Visit                           
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
Vitality 
 
 
 
  Month 3 
  n 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx.x 
xx.x 
 
  Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
  Min, Max 
xx , xx 
xx , xx 
 
 
 
 
  Month 6 
  n 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx.x 
xx.x 
 
  Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
  Min, Max 
xx , xx 
xx , xx 
Physical Functioning 
 
 
 
  Month 3 
  n 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx.x 
xx.x 
 
  Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
  Min, Max 
xx , xx 
xx , xx 
 
 
 
 
  Month 6 
  n 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx.x 
xx.x 
 
  Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
  Min, Max 
xx , xx 
xx , xx 
… 
 
 
 
 
 
 
 
 
1 SF-36=Short Form (36) Health Survey. 
 
Source: Listing 16.2.6.4.3. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Month 3 and Month 6 for vitality, physical functioning, bodily pain, general health perceptions, 
physical role functioning, emotional role functioning, social role functioning, and mental health & physical and mental composite 
summary scores.] 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 102 of 213 
 
Table 14.2.8.2 Analysis of SF-36 by Visit (mITT Population) 
 
Summary Scores 
Visit 
Comparison 
LS Mean 
Difference in LS Mean 
BHR-100 – Placebo  
(95% CI)1 
Effect 
Size1 
P-Value1  
BHR-100 
Placebo 
 
 
 
 
 
 
 
 
Physical Composite 
Month 3 
BHR-100 vs. 
Placebo 
xx.x 
xx.x 
xx.x (xx.x, xx.x) 
x.xxx 
0.xxx 
 
Month 6 
BHR-100 vs. 
Placebo 
xx.x 
xx.x 
xx.x (xx.x, xx.x) 
x.xxx 
0.xxx 
 
 
 
 
 
 
 
 
Mental Composite 
Month 3 
BHR-100 vs. 
Placebo 
xx.x 
xx.x 
xx.x (xx.x, xx.x) 
x.xxx 
0.xxx 
 
Month 6 
BHR-100 vs. 
Placebo 
xx.x 
xx.x 
xx.x (xx.x, xx.x) 
x.xxx 
0.xxx 
 
 
 
 
 
 
 
 
 
1 LS Mean, Effect Size and P-Value are based on type III sum of squares from an ANCOVA model for the SF-36 composite  
summary scores at Month 3 and Month 6, including treatment group.  
The SF-36 scores are calculated so that a higher score indicates better health. 
A positive difference in LS Mean (BHR-100 – Placebo) indicates a positive effect of BHR-100 over placebo. 
 
Source: Listing 16.2.6.4.3. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 103 of 213 
 
Table 14.2.9 Shift Summary of CT1 Classification (mITT Population) 
 
Treatment 
Group 
Baseline2 
Day 62 
 
I 
 
II 
 
III 
 
IV 
Evacuated 
Mass Lesion 
Non-Evacuated 
Mass Lesion 
Missing 
Dead 
 
 
 
 
 
 
 
 
 
 
BHR-100 
(N=xx) 
I 
xx (xx.x %) 
xx (xx.x %) xx (xx.x %) xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x 
%) 
 
II 
xx (xx.x %) 
xx (xx.x %) xx (xx.x %) xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x 
%) 
 
III 
xx (xx.x %) 
xx (xx.x %) xx (xx.x %) xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x 
%) 
 
IV 
xx (xx.x %) 
xx (xx.x %) xx (xx.x %) xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x 
%) 
 
Evacuated 
Mass Lesion 
xx (xx.x %) 
xx (xx.x %) xx (xx.x %) xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x 
%) 
 
Non-
Evacuated 
Mass Lesion 
xx (xx.x %) 
xx (xx.x %) xx (xx.x %) xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x 
%) 
 
Missing 
xx (xx.x %) 
xx (xx.x %) xx (xx.x %) xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x 
%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
1 CT=Computed Tomography. 
2 The Baseline scan was obtained pre-randomization. The second CT was obtained post-infusion on Day 6 +/- 1 day (Post-Injury). 
CT scans were assessed and compared by the Central Reader, and classified as follows: I=Diffuse Injury No Visible Pathologic Change, 
II=Diffuse Injury – Cisterns present, III=Diffuse Injury with Swelling, IV=Diffuse Injury with Shift, V=Evacuated Mass Lesion and VI=Non-
Evacuated Mass Lesion. 
 
Source: Listing 16.2.6.5.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x   
 
[Note to Programmer: Repeat for Placebo.] 
  


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 104 of 213 
 
Table 14.2.10  Summary of Maximum Intracranial Pressure by Visit (mITT Population) 
 
 
 
 
 
 
Visit1 
 
Characteristic2 
 
Statistic 
 BHR-100 
(N=xx) 
 Placebo 
(N=xx) 
 
 
 
 
 
Baseline 
Missing ICP 
n 
xx  
xx  
 
 
 
 
 
 
Maximum ICP (continuous) 
n 
xx 
xx 
   
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
 
Min, Max 
xx , xx 
xx , xx 
 
 
 
 
 
 
Maximum ICP (categorical) 
 
 
 
 
     0 to < 15 mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x) 
 
  >=15 to < 25 mmHg  
n (%) 
xx (xx.x %) 
xx (xx.x) 
 
  >=25 to < 40 mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x) 
 
  >=40 mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x) 
 
 
 
 
 
 
Maximum ICP (categorical) 
 
 
 
 
     0 to <= 20 mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x) 
 
     >20 mmHg  
n (%) 
xx (xx.x %) 
xx (xx.x) 
 
 
 
 
 
 
 
 
 
 
 
Maximum ICP >= 25mmHg 
 
 
 
 
  Yes 
n (%) 
xx (xx.xx %) 
xx (xx.xx %) 
 
  No 
n (%) 
xx (xx.xx %) 
xx (xx.xx %) 
 
 
 
 
 
 
Maximum ICP > 20mmHg 
 
 
 
 
  Yes 
n (%) 
xx (xx.xx %) 
xx (xx.xx %) 
 
  No 
n (%) 
xx (xx.xx %) 
xx (xx.xx %) 
…  
 
 
 
 
 
1 The baseline value is defined as the last measurement taken prior to first administration of study drug. 
2 ICP=Intracranial Pressure. 
Note: Percentages are calculated using the number of subjects with data as the numerator and the number of subjects with a non-
missing ICP result as the denominator. 
 
Source: Listing 16.2.6.6.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Day 1-6 (scheduled visits only).] 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 105 of 213 
Table 14.2.11.1 Summary of Cerebral Perfusion Pressure by Visit (mITT Population) 
 
 
 
 
 
 
Visit1  
 
Characteristic2 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
Baseline 
Missing CPP 
n 
xx 
xx 
 
 
 
 
 
 
Lowest CPP (continuous) 
n 
xx 
xx 
  
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
 
Min, Max 
xx , xx 
xx , xx 
 
 
 
 
 
 
Lowest CPP (categorical) 
n 
xx 
xx 
 
  < 50mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  >=50 – <60mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  >=60 - <70mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  >=70mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Highest CPP (continuous) 
n 
xx 
xx 
  
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
 
Min, Max 
xx , xx 
xx , xx 
 
 
 
 
 
 
Highest CPP (categorical) 
n 
xx 
xx 
 
  < 50mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  >=50 – <60mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  >=60 - <70mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
… 
  >=70mmHg 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
1 The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1). 
2 CPP=Cerebral Perfusion Pressure. 
 
Source: Listing 16.2.6.7. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Day 1-6.  ] 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 106 of 213 
 
Table 14.2.11.2 Potentially Clinically Important On-Treatment1 Cerebral Perfusion Pressure (mITT Population) 
 
 
 
 
 
 
Characteristic2 
 
Response 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
Subjects with any On-treatment CPP 
Measurement  
 
n 
xx 
xx 
 
 
 
 
 
Any CPP value < 50mmHg 
Yes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
No 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Any CPP value >=50 – <60mmHg 
Yes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
No 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Any CPP value >=60 - <70mmHg 
Yes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
No 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
Any CPP value >=70mmHg 
Yes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
No 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
1 On-treatment includes all scheduled and unscheduled CPP measurements taken during Days 1-6 after initiation of study medication. 
2 CPP=Cerebral Perfusion Pressure. 
 
Source: Listing 16.2.6.7. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 107 of 213 
 
Table 14.2.12.1 Summary of Therapy Intensity Level by Visit (mITT Population) 
 
 
 
 
 
Visit1 
  Characteristic2 
 
Response 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
Baseline 
 
n 
xx 
xx 
  TIL (continuous)    
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
 
Min, Max 
xx , xx 
xx , xx 
 
 
 
 
 
 
 
 
 
 
Day 1 
 
n 
xx 
xx 
  TIL (continuous)    
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median 
xx.x 
xx.x 
 
 
Q1, Q3 
xx.x , xx.x 
xx.x , xx.x 
 
 
Min, Max 
xx , xx 
xx , xx 
… 
 
 
 
 
 
 
 
 
 
 
1 The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1). 
2 TIL=Therapy Intensity Level.  TIL is recorded for up to 6 days while ICP is being monitored.  Each of the listed treatments will 
have a score of 1 with a maximum score of 10 per subject. 
 
Source: Listing 16.2.6.8.1. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Day 2-6.] 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 108 of 213 
 
Table 14.2.12.2 Summary of Individual TIL Therapies (mITT Population) 
 
 
 
 
 
 
Therapy 
 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
  Surgical Decompression   
 
 
xx (xx.x %) 
xx (xx.x %) 
  Barbiturate Induced Coma   
 
 
xx (xx.x %) 
xx (xx.x %) 
  Hypothermia  
 
 
xx (xx.x %) 
xx (xx.x %) 
  Hyperventilation  (pCO2<30) 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Pressor Administration (to keep CPP>60) 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Hypertonic Saline 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Mannitol 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Ventricular Drainage 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Paralysis Induction 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Sedation 
 
 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects may have received multiple therapies, and therefore may be counted in multiple rows. 
Source: Listing 16.2.6.8.1. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 109 of 213 
 
Table 14.2.12.3 Summary of Maximum Therapy Intensity Level (mITT Population) 
 
 
 
 
 
   
Therapy 
 
Response 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
  Surgical Decompression   
 
 
xx (xx.x %) 
xx (xx.x %) 
  Barbiturate Induced Coma   
 
 
xx (xx.x %) 
xx (xx.x %) 
  Hypothermia  
 
 
xx (xx.x %) 
xx (xx.x %) 
  Hyperventilation  (pCO2<30) 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Pressor Administration (to keep CPP>60) 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Hypertonic Saline 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Mannitol 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Ventricular Drainage 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Paralysis Induction 
 
 
xx (xx.x %) 
xx (xx.x %) 
  Sedation 
 
 
xx (xx.x %) 
xx (xx.x %) 
  No Intervention 
 
 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
Note: Subjects are summarized according to the maximum therapy received on Days 1-6. 
 
Source: Listing 16.2.6.8.1. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 110 of 213 
 
 
Table 14.3.1.1 Overall Summary of Treatment Emergent Adverse Events (Safety Population) 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Adverse Event Category 
 
# (%) Subj 
# AEs 
# (%) Subj 
# AEs 
 
 
 
 
 
Any 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Serious AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related Serious AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any AE Leading to Premature Discontinuation of Study Drug 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE Leading to Premature Discontinuation of Study Drug 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any AE Which Resulted in Death 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE Which Resulted in Death 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
 
Note: Treatment-emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: For each category, subjects are included only once, even if they experienced multiple events in that category. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: An event is considered related to study medication if it has a relationship other than not related. 
An event is considered serious, if “Is this a serious adverse event (SAE)”=Yes, an event leads to premature discontinuation of study 
drug if action taken with study drug due to the AE is drug withdrawn and an event which resulted in death has “If SAE is Yes, Results 
in death?”=Yes.] 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 111 of 213 
 
Table 14.3.1.2 Overall Summary of Treatment Emergent Adverse Events by Gender (Safety Population) 
Gender: Male 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Adverse Event Category 
 
# (%) Subj 
# AEs 
# (%) Subj 
# AEs 
 
 
 
 
 
Any 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Serious AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related Serious AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any AE Leading to Premature Discontinuation of Study Drug 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE Leading to Premature Discontinuation of Study Drug 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any AE Which Resulted in Death 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE Which Resulted in Death 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
 
Note: Treatment-emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: For each category, subjects are included only once, even if they experienced multiple events in that category. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: An event is considered related to study medication if it has a relationship other than not related. 
An event is considered serious, if “Is this a serious adverse event (SAE)”=Yes, an event leads to premature discontinuation of study 
drug if action taken with study drug due to the AE is drug withdrawn and an event which resulted in death has “If SAE is Yes, Results 
in death?”=Yes.] 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 112 of 213 
 
Table 14.3.1.2 Overall Summary of Treatment Emergent Adverse Events by Gender (Safety Population) 
Gender: Female 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Adverse Event Category 
 
# (%) Subj 
# AEs 
# (%) Subj 
# AEs 
 
 
 
 
 
Any 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Serious AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related Serious AE 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any AE Leading to Premature Discontinuation of Study Drug 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE Leading to Premature Discontinuation of Study Drug 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any AE Which Resulted in Death 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
Any Treatment-Related AE Which Resulted in Death 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
 
Note: Treatment-emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: For each category, subjects are included only once, even if they experienced multiple events in that category. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: An event is considered related to study medication if it has a relationship other than not related. 
An event is considered serious, if “Is this a serious adverse event (SAE)”=Yes, an event leads to premature discontinuation of study 
drug if action taken with study drug due to the AE is drug withdrawn and an event which resulted in death has “If SAE is Yes, Results 
in death?”=Yes.] 
 
Table 14.3.1.3 Overall Summary of Treatment Emergent Adverse Events by Race Group(Safety Population) 
 [Repeat the table for each Race group: white, non-white, not allowed to obtain] 
Table 14.3.1.4 Overall Summary of Treatment Emergent Adverse Events by Age Group (Safety Population) 
 [Repeat the table for each Age group: ≤45 years, >45 years] 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 113 of 213 
 
 
 
 
 
Table 14.3.1.5 Treatment Emergent Adverse Events by System Organ Class and Preferred Term (Safety Population) 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
System Organ Class 
  Preferred Term 
 
# (%) Subj 
# AEs 
 
# (%) Subj 
# AEs 
 
 
 
 
 
Any Adverse Event 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
System Organ Class 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 4 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 5 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
System Organ Class 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 4 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 5 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
System Organ Class 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 4 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 5 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
 
Note: Treatment-emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: Adverse events are coded by MedDRA Version 13.0. 
Note: For each system organ class and preferred term, subjects are included only once, even if they experienced multiple events 
in that system organ class or preferred term. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Sort in decreasing order of frequency in the BHR-100 column by SOC and by preferred term within SOC.] 
 
 
Table 14.3.1.9 Treatment-Related Treatment Emergent Adverse Events by System Organ Class and Preferred Term (Safety Population) 
[Repeat above table for treatment-related AEs.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 114 of 213 
 
Table 14.3.1.6 Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and Gender (Safety Population) 
Gender=Male 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Subgroup 
  System Organ Class 
    Preferred Term 
 
# (%) Subj 
# AEs 
 
# (%) Subj 
# AEs 
 
 
 
 
 
  Any Adverse Event 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
  System Organ Class 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 4 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 5 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
  System Organ Class 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 4 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 5 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
  System Organ Class 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 3 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 4 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
    Preferred Term 5 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
 
Note: Treatment-emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: Adverse events are coded by MedDRA Version 13.0. 
Note: For each system organ class and preferred term, subjects are included only once, even if they experienced multiple events 
in that system organ class or preferred term. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Gender=Female.  Sort in decreasing order of frequency in the BHR-100 column by SOC and by 
preferred term within SOC.] 
 
 
Table 14.3.1.7 Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and Race Group (Safety Population) 
[Repeat above table for race groups White, Non-white, and Not allowed to obtain.] 
Table 14.3.1.8 Treatment Emergent Adverse Events by System Organ Class, Preferred Term, and Age Group (Safety Population) 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 115 of 213 
[Repeat above table for age groups ≤45 years and >45 years.] 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 116 of 213 
 
 
Table 14.3.1.10 Treatment Emergent Adverse Events by Maximum Severity, System Organ Class and Preferred Term (Safety Population) 
 
 
 
 
 
 
 
 
BHR-100 (N=xx) 
Placebo (N=xx) 
System Organ Class 
 Preferred Term 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
Mild 
n (%) 
Moderate 
n (%) 
Severe 
n (%) 
 
 
 
 
 
 
 
All Adverse Events 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 
 
 
 
 
 
 
System Organ Class 1 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 1 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 2 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 3 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 4 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 5 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 
 
 
 
 
 
 
System Organ Class 2 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 1 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 2 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 3 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 4 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 Preferred Term 5 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 xx (xx.x%) 
 
 
 
 
 
 
 
 
Note: Treatment-Emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: Adverse Events are coded by MedDRA Version 13.0. 
Note: For each system organ class and preferred term, subjects are included only once, even if they experienced multiple events in 
that system organ class or preferred term. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
Note: If the severity of an Adverse Event is missing, then it is considered to be severe. 
 
Source: Listing 16.2.7. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Each subject is counted only once in the particular AE class, under the highest intensity they 
experienced for that class of AE.] 
 
Table 14.3.1.11 Treatment-Related Treatment Emergent Adverse Events by Maximum Severity, System Organ Class and Preferred Term (Safety 
Population) 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 117 of 213 
 
Table 14.3.1.12 Treatment Emergent Adverse Events by Maximum Relationship and System Organ Class and Preferred Term (Safety 
Population) 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 (N=xx) 
Placebo (N=xx) 
System Organ Class 
 Preferred Term 
Not Related 
n (%) 
Possibly 
n (%) 
Probably 
n (%) 
Related 
n (%) 
Not Related 
n (%) 
Possibly 
n (%) 
Probably 
n (%) 
Related 
n (%) 
 
 
 
 
 
 
 
 
 
All Adverse Events 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 1 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 2 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 3 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 4 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 5 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 1 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 2 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 3 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 4 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 Preferred Term 5 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
Note: Treatment-Emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: Adverse Events are coded by MedDRA Version 13.0. 
Note: For each system organ class and preferred term, subjects are included only once, even if they experienced multiple events in 
that system organ class or preferred term. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
Note: If the relationship of an Adverse Event is missing, then it is considered to be related to study medication. 
 
Source: Listing 16.2.7. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Each subject is counted only once in the particular AE class, under the most related category they experienced 
for that class of AE.  If the AE relationship to study medication is missing, then it is considered to be related.] 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 118 of 213 
Table 14.3.1.13 Treatment Emergent Adverse Events Leading to Premature Discontinuation of Study Drug by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.14 Treatment-Related Treatment Emergent Adverse Events Leading to Premature Discontinuation of Study Drug by System Organ 
Class and Preferred Term (Safety Population) 
[Use shell for Table 14.3.1.7, change footnotes accordingly.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 119 of 213 
 
 
Table 14.3.1.15 Treatment Emergent Adverse Events of Special Interest (Safety Population) 
 
   
 
 
 
 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
AE of Special Interest 
  Preferred Term 
 
# (%) Subj 
# AEs 
 
# (%) Subj 
# AEs 
 
 
 
 
 
Any Adverse Event of Special Interest 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
   
 
   
 
Serious Thromboembolic Events 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 1 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  Preferred Term 2 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
  …  
 
 
 
 
 
 
 
 
 
Thrombotic Myocardial Infarction 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Pulmonary Embolism 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Deep Vein Thrombosis 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Ischemic Stroke 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Allergic Reactions 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Marked Liver Function Abnormalities 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Serious Infections 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Pneumonia 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Pneumonia Streptococcal 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Sepsis 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
Meningitis 
xx (xx.x %) 
xx 
xx (xx.x %) 
xx 
 
 
 
 
 
 
Note: Treatment-emergent adverse events are defined as events that start on or after the first dose of study medication. 
Note: Adverse events are coded by MedDRA Version 13.0. 
Note: For each preferred term, subjects are included only once, even if they experienced multiple events in that preferred term. 
Note: Percentages are based on the number of subjects in each treatment group in the population of interest. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Sort in decreasing order of frequency in the BHR-100 column by preferred term.  Need to identify the MedDRA 
preferred terms that relate to these events of special interest (see page 28 of protocol for events of special interest details).] 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 120 of 213 
 
Table 14.3.1.16 List of Adverse Events of Special Interest (Safety Population) 
 
Treat
-ment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Adverse Event/ 
Preferred Term/ 
SOC 
Start Date/ 
Day2 
Stop Date 
Length of 
Exposure 
(days)3 
Duration4 
 
Intensity 
Relation-
ship/ 
Outcome 
Action Taken 
with Study 
Drug 
Serious?/ 
Treatment 
Emergent?5 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-
100 
xx-xxx 
M/10/W 
xxxxxxxxxxxxxxx / 
xxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxx 
DDMONYYYY/ 
xx 
 
DDMONYYYY 
xx 
xx 
Mild, 
Moderate, 
Severe 
Not 
Related, 
Possibly 
Related, 
Probably 
Related,  
Related/Re
covered/re
solved, 
Recovering
/Resolving
, … 
 Dose not 
changed, drug 
withdrawn, … 
 
Yes/ 
   Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 Day is relative to the start date of study medication, event start date – administration start date + 1 if event start date if on or after the 
date of the start of study medication administration or event start date – administration start date if event date if before the date of the start 
of study medication administration. 
3 Length of exposure is based on administration start date and administration end date during the study (end date – start date + 1). 
4 Duration = AE end date – AE start date + 1. 
5 Treatment emergent adverse events are defined as events that start on or after the first dose of study medication. 
Events of special interest are defined as one of the following dictionary defined terms: Serious Thromboembolic Events, Thrombotic Myocardial 
Infarction, Pulmonary Embolism, Deep Vein Thrombosis, Ischemic Stroke, Allergic Reactions, Marked Liver Function Abnormalities, Serious Infections, 
Pneumonia, Pneumonia Streptococcal, Sepsis, or Meningitis. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 121 of 213 
Table 14.3.2.1 Serious Adverse Events by System Organ Class and Preferred Term (Safety Population) 
Table 14.3.2.2 Treatment-Related Serious Adverse Events by System Organ Class and Preferred Term (Safety Population) 
[Use shell for Table 14.3.1.7, change footnotes accordingly.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 122 of 213 
 
Table 14.3.2.3 Primary Cause of Death (mITT Population) 
 
 
 
Statistic 
 BHR-100 
(N=xx) 
 Placebo 
(N=xx) 
 Total 
(N=xx) 
 
 
 
 
 
Any Death 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Increased Intracranial Pressure 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Increase in Hematoma Size 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  New Hematoma/Re-accumulation 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Cerebral Edema 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Herniation 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Cerebral Infarct 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Cerebral Vasospasm 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Meningitis 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Extracranial Injury 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Myocardial Infarction 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Pulmonary Embolus 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Multiple Organ Failure 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Pneumonia 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Adult Respiratory Distress Syndrome 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Sepsis 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Unknown/Undetermined 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
  Other 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 123 of 213 
 
 
 
Table 14.3.4.1 Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory Test Results: Coagulation (Safety Population) 
 
Outcome 
BHR-100 
Placebo 
Day 6 
n (%) 
Day 15 
n (%) 
Day 6 
n (%) 
Day 15 
n (%) 
 
 
 
 
 
Number of Abnormal, Clinically Significant (non-AE) 
lab results 
xx 
xx 
xx 
xx 
 
 
 
 
 
Resolved 
 
xx (xx.x %) 
 
xx (xx.x %) 
Ongoing  
 
xx (xx.x %) 
 
xx (xx.x %) 
Lost to Follow-up 
 
xx (xx.x %) 
 
xx (xx.x %) 
Missing 
 
xx (xx.x %) 
 
xx (xx.x %) 
 
 
 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
[Note to Programmer: If there are no results with a Missing outcome, do not include the Missing row.] 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 124 of 213 
 
Table 14.3.4.2 Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory Test Results: Hematology (Safety Population) 
 
Parameter 
  Outcome 
BHR-100 
Placebo 
Day 6 
n (%) 
Day 15 
n (%) 
Day 6 
n (%) 
Day 15 
n (%) 
 
 
 
 
 
White blood cell count 
 
 
 
 
 
 
 
 
 
  Number of Abnormal, Clinically Significant (non- 
  AE) lab results 
xx 
xx 
xx 
xx 
 
 
 
 
 
  Resolved 
 
xx (xx.x %) 
 
xx (xx.x %) 
  Ongoing  
 
xx (xx.x %) 
 
xx (xx.x %) 
  Lost to Follow-up 
 
xx (xx.x %) 
 
xx (xx.x %) 
  Missing 
 
xx (xx.x %) 
 
xx (xx.x %) 
 
 
 
 
 
…  
 
 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
[Note to Programmer: Repeat for remaining hematology lab tests: Differential WBC, Red blood cell count (RBC), Hemoglobin, Hematocrit, 
Reticulocyte count, and Platelets.  If there are no results with a Missing outcome, do not include the Missing row.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 125 of 213 
 
 
Table 14.3.4.3 Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory Test Results: Serum Chemistry (Safety Population) 
(Use Table 14.3.4.2 shell, Subset off details for serum chemistry lab tests: AST, ALT, Alkaline Phosphatase, GGT, Total Protein, Total 
Cholesterol, Triglycerides, Glucose, Sodium, Potassium, Chloride) 
 
Table 14.3.4.4 Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory Test Results: Urinalysis (Safety Population) 
(Use Table 14.3.4.2 shell, Subset off details for all urinalysis tests) 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 126 of 213 
Table 14.3.4.5 List of Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory Test Results: Coagulation (Safety 
Population) 
(Produce for INR) 
[Use shell below for Table 14.3.4.6] 
 
Table 14.3.4.6 List of Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory Test Results: Hematology (Safety 
Population) 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Test Name 
Visit 
Sample 
Date 
Result 
(Unit) 
Range 
Flag2 
Reference Range 
 
 
 
 
Low 
 
 
High 
 
 
Outcome 
 
Other, 
specify 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
Hemoglobin 
Screening 
DDMONYYYY 
xx.x g/L 
L 
xx.x 
xx.x 
Ongoing 
 
 
 
 
 
UN 
DDMONYYYY 
xx.x g/L 
L 
xx.x 
xx.x 
Resolved 
 
 
 
 
 
Day 6 
DDMONYYYY 
xx.x g/L 
L 
xx.x 
xx.x 
Ongoing 
 
 
 
 
 
Day 15 
DDMONYYYY 
xx.x g/L 
L 
xx.x 
xx.x 
Other 
xxxxxxxxxx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 N = Normal, L = Low, H = High. 
UN = Unscheduled. 
 
[Note to Programmer: Produce for clinically significant abnormalities only.  Produce for Hemoglobin, Hematocrit, RBC, Reticulocyte 
Count, Platelet Count, WBC, Neutrophils, Lymphocytes, Monocytes, Eosinophils, Basophils.] 
 
 
 
Table 14.3.4.7 List of Post-Baseline Abnormal, Clinically Significant (non-AE) Laboratory Tests: Serum Chemistry (Safety 
Population) 
(Produce for Sodium, Potassium, Chloride, Total Cholesterol, Triglycerides, ALT, AST, GGT, Alkaline Phosphatase, Total Protein, 
Glucose.) 
Table 14.3.4.8 List of Post-Baseline Abnormal, Clinically Signficant (non-AE) Laboratory Tests: Urinalysis (Safety Population) 
(Produce for pH, Specific Gravity, Protein, Glucose, Blood, WBC, RBC, Casts, Epithelial Cells, Bacteria.) 
[Use shell for table 14.3.4.6] 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 127 of 213 
 
Table 14.3.4.9 Summary of Coagulation Laboratory Test Results (Safety Population) 
 
 
 
 
 
 
Parameter/Visit 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Actual Value 
Change from 
Baseline 
Actual Value 
Change from 
Baseline 
 
 
 
 
 
 
INR (ratio) 
 
 
 
 
 
 
 
 
 
 
 
     Baseline 
n 
  xx 
 
  xx 
 
 
Mean (SD) 
  xx.x (xx.xx) 
 
  xx.x (xx.xx) 
 
 
Median 
  xx.x 
 
  xx.x 
 
 
Min, Max 
  xx , xx 
 
  xx , xx 
 
 
Q1, Q3 
  xx , xx 
 
  xx , xx 
 
 
 
 
 
 
 
     Day 6 
n 
  xx 
  xx 
  xx 
  xx 
 
Mean (SD) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
 
Median 
  xx.x 
  xx.x 
  xx.x 
  xx.x 
 
Min, Max 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
Q1, Q3 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
 
 
 
 
 
     Day 15 
n 
  xx 
  xx 
  xx 
  xx 
 
Mean (SD) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
 
Median 
  xx.x 
  xx.x 
  xx.x 
  xx.x 
 
Min, Max 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
Q1, Q3 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1). 
 
Source: Listing 16.2.8.1.1. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
Table 14.3.4.10 Summary of Hematology Laboratory Test Results (Safety Population) 
(Produce for Hemoglobin, Hematocrit, RBC, Reticulocyte Count, Platelets, WBC, Neutrophils, Lymphocytes, Monocytes, Eosinophils, 
and Basophils.  Sort parameters alphabetically.  Summarize parameters in standard SI units.) 
 
Table 14.3.4.11 Summary of Serum Chemistry Laboratory Test Results (Safety Population) 
(Produce for Sodium, Potassium, Chloride, Total Cholesterol, Triglycerides, ALT, AST, GGT, Alkaline phosphatase, Total Protein, 
Glucose.  Sort parameters alphabetically.  Summarize parameters in standard SI units.) 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 128 of 213 
 
Table 14.3.5 Summary of Incidence of Neuroworsening (Safety Population) 
 
 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
Subjects Experiencing Neuroworsening  
    Event ≤ Day 6  
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
Subjects Experiencing Neuroworsening 
    Event ≤ Day 15 
   n (%) 
xx (xx.x %) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
 
 
 
 
 
Note: Neuroworsening is defined as any one of the following: a decrease in GCS motor score ≥ 2 , development of pupillary 
abnormalities, any other neurological deterioration or progression of lesion on CT scan leading to a change in subject management. 
Note: Percentages are based on the number of subjects in each treatment group and overall in the population of interest. 
 
Source: Listing 16.2.8.6. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 129 of 213 
 
Table 14.3.6.1 Summary of Vital Signs Corresponding to Lowest Measurement by Visit (Safety Population) 
 
 
 
 
 
 
Variable/Visit 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Actual Value 
Change from 
Baseline 
Actual Value 
Change from 
Baseline 
 
 
 
 
 
 
Pulse (per min) 
 
 
 
 
 
 
 
 
 
 
 
     Baseline 
n 
  xx 
 
  xx 
 
 
Mean (SD) 
  xx.x (xx.xx) 
 
  xx.x (xx.xx) 
 
 
Median 
  xx.x 
 
  xx.x 
 
 
Min, Max 
  xx , xx 
 
  xx , xx 
 
 
Q1, Q3 
  xx , xx 
 
  xx , xx 
 
 
 
 
 
 
 
     Day 1 
N 
  xx 
  xx 
  xx 
  xx 
 
Mean (SD) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
 
Median 
  xx.x 
  xx.x 
  xx.x 
  xx.x 
 
Min, Max 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
Q1, Q3 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
 
 
 
 
 
     Day 2 
N 
  xx 
  xx 
  xx 
  xx 
 
Mean (SD) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
 
Median 
  xx.x 
  xx.x 
  xx.x 
  xx.x 
 
Min, Max 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
Q1, Q3 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1). 
 
Source: Listing 16.2.8.2. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Day 3-6.  Repeat for other vital sign parameters – respiration rate (bpm, breaths per minute), 
systolic pressure (mmHg), diastolic blood pressure (mmHg), and temperature (C).  The vital signs are reported which correspond 
to the lowest and highest measurements per study day.] 
 
Table 14.3.6.2 Summary of Vital Signs Corresponding to Highest Measurement by Visit (Safety Population) 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 130 of 213 
 
Table 14.3.6.3 Summary of Vital Signs by Visit – Weight (kg) (Safety Population) 
 
 
 
 
 
 
Variable/Visit 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
Actual Value 
Change from 
Baseline 
Actual Value 
Change from 
Baseline 
 
 
 
 
 
 
Weight (kg) 
 
 
 
 
 
 
 
 
 
 
 
     Baseline 
n 
  xx 
 
  xx 
 
 
Mean (SD) 
  xx.x (xx.xx) 
 
  xx.x (xx.xx) 
 
 
Median 
  xx.x 
 
  xx.x 
 
 
Min, Max 
  xx , xx 
 
  xx , xx 
 
 
Q1, Q3 
  xx , xx 
 
  xx , xx 
 
 
 
 
 
 
 
     Day 6 
N 
  xx 
  xx 
  xx 
  xx 
 
Mean (SD) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
  xx.x (xx.xx) 
 
Median 
  xx.x 
  xx.x 
  xx.x 
  xx.x 
 
Min, Max 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
Q1, Q3 
  xx , xx 
  xx , xx 
  xx , xx 
  xx , xx 
 
 
 
 
 
 
 
Note: The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1). 
 
Source: Listing 16.2.8.2. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 131 of 213 
 
 
Table 14.3.7.1 Summary of Physical Examination by Visit (Safety Population) 
 
 
 
 
 
Body System/ 
  Visit 
Characteristic 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
Skin 
 
N 
xx 
xx 
  Baseline 
Normal 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Not Done 
n  
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
N 
xx 
xx 
  Day 6 
Normal 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Not Done 
n  
xx (xx.x%) 
xx (xx.x%)  
 
 
 
 
 
HEENT 
 
N 
xx 
xx 
  Baseline 
Normal 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Not Done 
n  
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
N 
xx 
xx 
  Day 6 
Normal 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Not Done 
n  
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Respiratory 
 
N 
xx 
xx 
  Screening 
Normal 
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal  
n (%) 
xx (xx.x%) 
xx (xx.x%) 
 
Not Done 
n  
xx (xx.x%) 
xx (xx.x%) 
… 
 
 
 
 
 
 
 
 
 
 
Note: The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1).  For physical 
examination assessments this will be the screening visit. 
Note: Percentages are based on the number of subjects with data at the visit within the population of interest.   
 
Source: Listing 16.2.8.3. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Physical examination is only conducted at screening and Day 6 visit. 
Repeat for all Body systems: Skin, HEENT, Respiratory, Cardiovascular, Abdomen (including liver and kidneys), Neurological, 
Gastrointestinal, Genitourinary, Endocrine, Lymph Nodes.] 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 132 of 213 
 
 
Table 14.3.7.2 List of Physical Examination Abnormalities Post-Baseline (Safety Population) 
 
 
 
 
 
 
 
 
Treatment Group 
Subject No. 
Sex/Age/ 
Race1 
Body System 
Baseline2 
Visit3 
Describe Abnormality 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
(Skin, HEENT, 
Respiratory, 
Cardiovascular, 
Abdomen (including 
liver and kidneys), 
Neurological, 
Gastrointestinal, 
Genitourinary, 
Endocrine, Lymph 
Nodes.) 
 
Normal 
(Day 6, UN) 
xxxxxxxxxxxxxxxxxx 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1).  For physical 
examination assessments this will be the screening visit. 
3 UN = Unscheduled. 
 
[Note to Programmer: Only produce for records which record the physical examination post-baseline as abnormal.] 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 133 of 213 
 
14.3.8.1 Post-baseline Abnormal ECG Results (Safety Population) 
 
 
 
 
 
 
Visit1  
 
Characteristic2 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
Baseline 
Abnormal Rhythm 
n 
xx 
xx 
 
  Sinus Arrhythmia 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Atrial Fibrillation 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Atrial Flutter 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Premature Ventricular Contraction 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Other Arrhythmia 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Abnormal Rhythm – Clin Sig  
n 
xx 
xx 
 
  Yes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  No 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Abnormal Conduction 
n 
xx 
xx 
 
  LBBB 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  RBBB 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  AV Block 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  QT Prolongation 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Other 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Abnormal Conduction – Clin Sig  
n 
xx 
xx 
 
  Yes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  No 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
1 The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1). 
2 Clin Sig = Clinically Significant. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Baseline and Day 6.] 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 134 of 213 
 
14.3.8.1 Post-baseline Abnormal ECG Results (Safety Population) 
 
 
 
 
 
 
Visit1  
 
Characteristic2 
 
Statistic 
BHR-100 
(N=xx) 
Placebo 
(N=xx) 
 
 
 
 
 
Baseline 
Abnormal QRS Complex 
n 
xx 
xx 
 
  Non-specific ST Changes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Old MI 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Myocardial Ischemia 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Acute Myocardial Infarction 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
  Other 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
Abnormal QRS Complex – Clin Sig  
n 
xx 
xx 
 
  Yes 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
… 
  No 
n (%) 
xx (xx.x %) 
xx (xx.x %) 
 
 
 
 
 
 
1 The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1). 
2 Clin Sig = Clinically Significant. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for Screening and Day 6.] 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 135 of 213 
 
 
 
Table 14.3.8.2 List of Post-Baseline Abnormal ECG Results – Part 1 (Safety Population) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rhythm 
Conduction 
Treatment  
Group 
Subject 
No. 
Sex/Age/ 
Race1 
Visit2 Result 
Specify# 
Clin. 
Sig.3 
Result 
Specify# 
QTC Prolongation 
(ms)  
Clin. 
Sig.3 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
Day 6 
Abnormal Sinus Arrhythmia 
No 
Normal    
 
 
 
 
 
UN 
Abnormal Other: xxxxxxxxxxxxx 
Yes 
Abnormal QT 
Prolongation 
xxx 
No 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 UN = Unscheduled. 
3 Clin. Sig. = Clinically Significant. 
# If specify=other include details from the other specify comment here. 
 
[Note to Programmer: Only produce for records which record the ECG post-baseline as abnormal.] 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 136 of 213 
 
Table 14.3.8.2 List of Post-Baseline Abnormal ECG Results – Part 2 (Safety Population) 
 
 
 
 
 
 
 
 
 
 
 
 
QRS Complex 
 
Treatment  
Group 
Subject 
No. 
Sex/Age/ 
Race1 
Visit2 Result 
Specify# 
Clin. 
Sig.3 
Comments 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
Day 6 
Abnormal Non-specific ST Changes 
Yes 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
UN 
Normal 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 UN = Unscheduled. 
3 Clin. Sig. = Clinically Significant. 
# If specify=other include details from the other specify comment here. 
 
[Note to Programmer: Only produce for records which record the ECG post-baseline as abnormal.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 137 of 213 
 
14.3.9 Summary of Worst Arterial Blood Gas (ABG) Results by Visit (Safety Population) 
 
 
BHR-100  
(N = XXX) 
Placebo  
(N = XXX) 
ABG Parameter 
  Timepoint 
Value 
Change  
from Baseline 
Value 
Change  
From Baseline 
 
 
 
 
 
 PaO2 
 
 
 
 
  Baseline 
 
 
 
 
    n 
xx 
 
xx 
 
    Mean (std) 
xx.xx (xx.xxx) 
 
xx.xx (xx.xxx) 
 
    Median  
xx.x 
 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
    Min, Max 
xx.x, xx.x 
 
xx.x, xx.x 
 
 
 
 
 
 
  Day 1 
 
 
 
 
    n 
xx 
xx 
xx 
xx 
    Mean (std) 
xx.xx (xx.xxx) 
xx.xx (xx.xxx) 
xx.xx (xx.xxx) 
xx.xx (xx.xxx) 
    Median  
xx.x 
xx.x 
xx.x 
xx.x 
    Q1, Q3 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
    Min, Max 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
xx.x, xx.x 
 
 
 
 
 
  Day 2 
 
 
 
 
    n 
xx 
 
xx 
 
    Mean (std) 
xx.xx (xx.xxx) 
 
xx.xx (xx.xxx) 
 
    Median  
xx.x 
 
xx.x 
 
    Q1, Q3 
xx.x, xx.x 
 
xx.x, xx.x 
 
    Min, Max 
xx.x, xx.x 
 
xx.x, xx.x 
 
… 
 
 
 
 
 
 
 
 
 
 
Note: The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1).  Worst result 
is calculated as lowest value of the day for PaO2, HCO3, pH, SaO2, and FiO2 and the highest value of the day for PaCO2. 
 
Source: Listing 16.2.8.5. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Repeat for all ABG parameters: PaO2, PaCO2, HCO3, pH, SaO2 (%) and FiO2 (%) and all visits (Day1-6). 
Values should be the worst ABG result recorded that day.] 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 138 of 213 
 
Table 14.3.10 Summary of Day 2 Progesterone Levels (Safety Population) 
 
 
 
 
 
 
Parameter  
Statistic 
BHR-100 
(N = XXX) 
Placebo 
(N = XXX) 
 
 
 
 
Day 2 
 
 
 
 
 
 
 
     Baseline 
n 
xxx 
xxx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median 
xx.x 
xx.x 
 
Min, Max 
xx , xx 
xx , xx 
 
Q1, Q3 
xx , xx 
xx , xx 
 
 
 
 
 
 
 
 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 139 of 213 
 
 
Figure 
14.2.1.1 
Title 1 
Glasgow Outcome Scale distribution at 6 Months Post Injury – Missing Values Imputed (mITT Population) 
Title 2 
 
Type of graph 
Bar Chart 
y-axis 
% response 
y-axis (label) 
% response 
x-axis 
Glasgow Outcome Scale response 
x-axis (label) 
Glasgow Outcome Scale response 
Legend (if applicable) 
Treatment Group: BHR-100 and Placebo.  Different bar color for each treatment group. 
Glasgow Outcome Scale response: D/VS=Dead, Vegetative State, SD=Severe Disability, MD=Moderate 
Disability, GR=Good Recovery 
Footnote 1 
Note: Percentages are based on the number of GOS at the month 6 assessment in each treatment group in the 
population of interest, after imputation.  Missing values are first imputed by carrying forward the Month 3 
GOS assessment.  If a subject has neither the 3 nor the 6 month GOS, the missing value is imputed based 
upon the primary proportional odds model. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.1. 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 140 of 213 
 
Figure 
14.2.1.2 
Title 1 
Glasgow Outcome Scale distribution at 6 Months Post Injury – Observed Values  (mITT Population) 
Title 2 
 
Type of graph 
Bar Chart 
y-axis 
% response 
y-axis (label) 
% response 
x-axis 
Glasgow Outcome Scale response 
x-axis (label) 
Glasgow Outcome Scale response 
Legend (if applicable) 
Treatment Group: BHR-100 and Placebo.  Different bar color for each treatment group. 
Glasgow Outcome Scale response: D/VS=Dead, Vegetative State, SD=Severe Disability, MD=Moderate 
Disability, GR=Good Recovery 
Footnote 1 
Note: Percentages are based on the number of non-missing GOS at the month 6 assessment in each treatment 
group in the population of interest. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.4. 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 141 of 213 
 
Figure 
14.2.1.3 
Title 1 
Glasgow Outcome Scale distribution at 6 Months Post Injury – Observed Values (PP Population) 
Title 2 
 
Type of graph 
Bar Chart 
y-axis 
% response 
y-axis (label) 
% response 
x-axis 
Glasgow Outcome Scale response 
x-axis (label) 
Glasgow Outcome Scale response 
Legend (if applicable) 
Treatment Group: BHR-100 and Placebo.  Different bar color for each treatment group. 
Glasgow Outcome Scale response: D/VS=Dead, Vegetative State, SD=Severe Disability, MD=Moderate 
Disability, GR=Good Recovery 
Footnote 1 
Note: Percentages are based on the number of non-missing GOS at the month 6 assessment in each treatment 
group in the population of interest. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.1.7. 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 142 of 213 
 
Figure 
14.2.2.1 
Title 1 
Dichotomized Glasgow Outcome Scale at 6 Months Post Injury – Missing Values Imputed (mITT 
Population) 
Title 2 
 
Type of graph 
Bar Chart 
y-axis 
% response 
y-axis (label) 
% response 
x-axis 
Dichotomized Glasgow Outcome Scale response (favorable, unfavorable) 
x-axis (label) 
Dichotomized Glasgow Outcome Scale response (favorable, unfavorable) 
Legend (if applicable) 
 
Footnote 1 
Favorable response = GR,MD; Unfavorable response = SD, VS/D.  
Note: Missing values are first imputed by carrying forward the Month 3 GOS assessment.  If a subject has 
neither the 3 nor the 6 month GOS, the missing value is imputed based upon the primary proportional odds 
model. 
 
Additional 
information 
Corresponds to table 14.2.3.1. 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 143 of 213 
 
Figure 
14.2.2.2 
Title 1 
Dichotomized Glasgow Outcome Scale at 6 Months Post Injury – Observed Values  (mITT Population) 
Title 2 
 
Type of graph 
Bar Chart 
y-axis 
% response 
y-axis (label) 
% response 
x-axis 
Dichotomized Glasgow Outcome Scale response (favorable, unfavorable) 
x-axis (label) 
Dichotomized Glasgow Outcome Scale response (favorable, unfavorable) 
Legend (if applicable) 
 
Footnote 1 
Favorable response = GR,MD; Unfavorable response = SD, VS/D. 
Additional 
information 
Corresponds to table 14.2.3.4. 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 144 of 213 
 
Figure 
14.2.3.1 
Title 1 
Mortality at 6 months (mITT Population) 
Title 2 
 
Type of graph 
Bar Chart 
y-axis 
% mortality 
y-axis (label) 
% mortality 
x-axis 
Treatment Group 
x-axis (label) 
Treatment Group 
Legend (if 
applicable) 
Treatment Group: BHR-100 and Placebo.  Different bar color/pattern for each treatment group. 
 
Footnote 1 
Note: Fishers Exact test p=0.xxx.  Only subjects who were either alive or dead at Month 6 will be included in 
the analysis. 
Note: Percentages are based on the number of subjects with status=alive or dead at Month 6 within the mITT 
population. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.5.1. 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 145 of 213 
 
Figure 
14.2.3.2 
Title 1 
Mortality at 1 month (mITT Population) 
Title 2 
 
Type of graph 
Bar Chart 
y-axis 
% mortality 
y-axis (label) 
% mortality 
x-axis 
Treatment Group 
x-axis (label) 
Treatment Group 
Legend (if 
applicable) 
Treatment Group: BHR-100 and Placebo.  Different bar color/pattern for each treatment group. 
 
Footnote 1 
Note: Fishers Exact test p=0.xxx.  Only subjects who were either alive or dead at Month 1 will be included in 
the analysis. 
Note: Percentages are based on the number of subjects with status=alive or dead at Month 1 within the mITT 
population. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
Additional 
information 
Corresponds to table 14.2.5.2. 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 146 of 213 
 
Figure 
14.2.3.3 
Title 1 
Time to Death (mITT Population) 
Title 2 
 
Type of graph 
Line graph 
y-axis 
1 - Kaplan-Meier survival estimates x 100 
y-axis (label) 
Cumulative Percent Dead 
x-axis 
Time (0-6/7 months) 
x-axis (label) 
Time (in months) 
Legend (if 
applicable) 
BHR-100, Placebo (different line type for each treatment group) 
Footnote 1 
Time to death = (Date of death or date of last contact (if censored) – date of TBI + 1)/30.4. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
Additional 
information 
Censored observations should be identified. 
Output K-M survival estimates using OUTSURV on PROC LIFETEST statement or SURVIVAL statement.  
Then calculate 1-K-M survival estimates as want to calculate probability of death over time.  Then multiply 
by 100 to obtain the percentage. 
Figure will run from 0% (no deaths) to 100% (all subjects have died) as the x-axis of time progresses from the 
left to the right.  Figure corresponds with Table 14.2.5.5. 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 147 of 213 
LISTINGS 
 
 
 
 
Listing 16.2.1.1 Study Completion/Discontinuation Details 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Infusion  
Administration 
Start Date/Time 
Infusion 
Completion 
Date/Time 
Completion 
Status 
Reason for Early Termination 
(Specify) 
Date of Study 
Completion/ 
Early 
Termination 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx  
M/35/W 
 
DDMONYYYY/ 
XX:XX 
Completed 
(Death, Adverse Event(s), 
Withdrawal of Consent,  Protocol 
Violation, Lost to Follow-up, 
Discretion of the Investigator, 
Discretion of the Sponsor, 
other) 
(provide details when reason for 
termination is other) 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
F/33/B 
 
DDMONYYYY/ 
XX:XX 
Withdrew 
Other 
(xxxxxxxxxxxxxxxxxxxxxxxxxxxxx) 
 
DDMONYYYY 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other.  
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 148 of 213 
 
Listing 16.2.1.2 Eligibility/Randomization 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
 
 
 
Subject No. 
 
Sex/ 
Age/ 
Race1 
Date/Time of 
Written 
Informed 
Consent 
 
Subject met 
all entry 
criteria? 
 
 
Inclusion/Exclusion 
Criteria Not Met 
Subject 
Randomized? 
Date/Time of 
Randomization 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYYY/ 
XX:XX 
(Yes, No) 
Inclusion Criteria 1 
(Yes,No) 
DDMONYYYY/ 
XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other.  
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: All inc/exc criteria met comes from has the subject met all eligibility criteria? 
If date of randomization provided, subject is randomized set to Yes] 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 149 of 213 
 
Listing 16.2.1.3 Exclusions from Per Protocol Population 
 
 
 
 
 
 
 
 
 
 
 
Treatment Group 
 
 
 
Subject No. 
 
Sex/ 
Age/ 
Race1 
 
 
 
Violation Code 
 
 
 
Violation Description 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
xxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other.  
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Include violations with an NE (not evaluable) designation.] 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 150 of 213 
 
Listing 16.2.3.1 Subject General Information 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treat- 
ment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
 
 
 
 
mITT2 
 
 
 
 
Safety/ 
Act Tmt 
 
 
 
 
PP2 
Date or Date/Time 
Study 
Outcome 
Exit 
Day3 
 
 
Treatment 
Duration 
(hours)4 
Compliance 
Rate5 
Screened 
 
 
Informed 
Consent 
Random- 
ization 
First Dose  
Last 
Dose 
Study 
Exit 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-
100 
xx-xxx 
M/35/W Yes 
Yes 
Yes DDMONYYYY DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
DDMONYYYY Completed 182 
120 
xxx.x 
 
 
F/33/B Yes 
Yes 
Yes DDMONYYYY DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
DDMONYYYY Withdrew 
24 
121 
xxx.x 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, A = Asian, N = American 
Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other.  
2 mITT=Modified Intention-to-Treat, PP=Per Protocol. 
3 Exit day = exit date (date of completion/date of early termination) – date of randomization + 1. 
4 Treatment duration (hours) = (end of administration date/time – start of administration date/time + 1) – duration of any interruptions. 
5 Compliance rate is calculated by dividing the hours of study medication taken by the number of hours that should have been taken during the treatment 
period multiplied by 100. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: List for BHR-100 and Placebo.  Sort by subject number within treatment group.  This note relates to all listings.] 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 151 of 213 
 
Listing 16.2.3.2 Informed Consent 
 
 
 
Treatment 
Group 
 
 
 
Subject No. 
 
Sex/ 
Age/ 
Race1 
Date/Time 
of Written 
Informed 
Consent 
Did Subject Sign Informed Consent when he/she regained consciousness? 
 
 
Response 
If Yes, Date  
Subject Signed  
Informed Consent 
If No or N/A, Specify 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYYY/ 
XX:XX 
(yes, no, N/A) 
DDMONYYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other.  
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 152 of 213 
 
 
 
 
Listing 16.2.4.1 Demographic Characteristics 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Date 
of 
Birth 
Date of 
Screening 
Visit 
Age 
(years)1 
Sex 
Ethnicity2 
Race3 
If other, Specify 
Weight 
(kg) 
Region/Country4/Site 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
DDMONYYYY 
DDMONYYYY 
xx 
(Male, 
Female) 
(HL, NHL, 
NAL) 
(W, B, P, A,  
N, Z, O) 
 
(xxxxxxxxxxxxxxxx) 
xx.x 
xxxxxx/xx/xxxxxx 
 
(Region is North 
America, Europe, or 
Asia and South 
America) 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Age is defined as (date of informed consent – date of birth + 1)/365.25. 
2 HL= Hispanic or Latino, NHL=Not Hispanic or Latino, NAL=Not Allowed to Obtain.   
3 W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, A = Asian, N = American 
Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other.  
4 This is the two letter country code: US=United States, AT=Austria, BE=Belgium, CZ=Czech Republic, FI=Finland, FR=France, 
DE=Germany, HU=Hungary, IL=Israel,IT=Italy, NL=Netherlands, RO=Romania, RU=Russia, GB=United Kingdom, ES=Spain, CN=China,  
MY=Malaysia, TW=Taiwan, Province of China,  SG=Singapore, TH=Thailand, AR=Argentina. 
 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Weight is obtained from IWRS upload.] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 153 of 213 
 
 
 
Listing 16.2.4.2 Baseline Characteristics 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Date of 
Screening 
Visit 
Date/Time 
of Injury 
Start 
Date/Time 
of Study 
Medication 
Injury to 
medication 
intake 
(hours)2 
Cause of TBI3 
(If Other, Specify) 
Exam 
Status4 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYYY DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
7 
Motor Vehicle 
Head 
Critical 
 
 
xx-xxx 
F/33/W 
DDMONYYYY DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
8.5* 
Other 
(xxxxxxxxxxxxxxxxxx) 
Abdomen 
Serious 
 
 
 
 
 
 
 
 
 
 
 
 
xx-xxx 
F/39/B 
DDMONYYYY DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
7 
(Motor 
Vehicle, 
Motorcycle,  
Fall, 
Sports/ 
Recreation,  
Pedestrian,  
Diving, 
Assault, 
Other) 
 
(Head, Face, 
Chest, 
Abdomen, 
Extremities, 
Spine) 
(None, 
Minor, 
Moderate, 
Serious, 
Severe, 
Critical) 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or 
Other Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 Injury to medication intake (hours) = start date/time of study medication – date/time of injury.  A star (*) will be added to 
indicate that the intake of study medication was greater than 8 hours after injury. 
3 TBI=Traumatic Brain Injury. 
4 None=no treatment, moderate=requires only outpatient treatment, serious=requires non-ICU hospital admission, 
severe=requires ICU observation and/or basic treatment, critical=requires intubation, mechanical ventilation or 
vasopressors for blood. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 154 of 213 
 
 
Listing 16.2.4.3 Pre-Injury Narrative – Baseline Status – Part 1 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
 
Interview 
Date/Time 
 
 
Occupational Status 
 
 
Social Skills 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 155 of 213 
 
Listing 16.2.4.3 Pre-Injury Narrative – Baseline Status – Part 2 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
 
Interview 
Date/Time 
 
 
Activities of Daily Living 
 
 
Mode of Transportation 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 156 of 213 
 
Listing 16.2.4.3 Pre-Injury Narrative – Baseline Status – Part 3 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
 
Interview 
Date/Time 
 
 
General 
 
 
Source of Information 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
(Patient alone,  
Relative/Friend/Caretaker Alone,  
Patient plus Relative/Friend/Caretaker, 
Medical Personnel) 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 157 of 213 
 
Listing 16.2.4.4 Glasgow Coma Scale 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Study Day 
Date/ 
Time of 
Assessment 
Stop  
Date/ 
Time 
Not 
Done? 
Eye Opening2 
(none due to 
severe facial 
swelling/damage) 
Verbal 
Response3 
(none due 
to 
intubation) 
Motor  
Response4 
GCS 
Score 
Assessed By? 
If Other, 
Specify 
Did 
Neurological 
Worsening 
Occur? 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W (Screening 
Post-
Resuscitation, 
Day 1, Day 2, 
Day 3, Day 4, 
Day 5, Day 6 
Day 15) 
DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
(yes, 
no) 
(SPON,  
SPEECH,  
PAIN,  
NONE) 
 
(no, yes) 
(O,  
C,  
INAPP, 
INCOMP,  
NONE) 
 
(yes, no) 
(OC,  
LP,  
WNF,  
ABF,  
ABE,  
NONE) 
xx 
(Neurosurgeon, 
ER Physician, 
Intensivist, 
Other 
(specify)) 
(yes, no) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, N = American Indian or Alaska 
Native, O = Other. 
2 SPON=Spontaneous, SPEECH=In response to speech, PAIN=In response to pain, NONE=None. 
3 O=Oriented, C=Confused, INAPP=Inappropriate words, INCOM=Incomprehensible sounds, NONE=None. 
4 OC=Obeys Commands, LP=Localizes Pain, WNF=Withdrawal/Normal flexion, ABF=Abnormal flexion, ABE=Abnormal Extension, NONE=None. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 158 of 213 
 
Listing 16.2.4.5 Medical History 
 
Treatment 
Group 
Subject No. 
Sex/ 
Age/ 
Race1 
Date of 
Diagnosis 
System 
Diagnosis or 
Abnormality 
Diagnosis 
Active? 
End Date 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYYY 
(Skin, HEENT, 
Respiratory, 
…) 
xxxxxxxxxxxxxx 
(Yes, No) 
(DDMONYYYY, or 
missing if 
diagnosis is 
active) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
gram: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 159 of 213 
 
Listing 16.2.4.6 Prior and Concomitant Medications 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Preferred Drug Name/ 
Medication Name 
Dose Per 
Frequency Units 
Frequency Route 
Start Date 
 
 
Ongoing? Stop Date 
Indication 
P/ 
C2 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W xxxxxxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxxxxxxx 
xx 
(mg, g, 
…, Other) 
(Day, 
Week, 
Month, As 
needed, 
One time) 
(PO, 
SC, 
IM, 
IV, … 
Other) 
DDMONYYYY 
(Yes, 
No) 
DDMONYYYY 
 
(Stop date 
will be 
missing if 
medication 
ongoing.) 
xxxxxxxxxxxx C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific 
Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 P=Prior Medication, C=Concomitant Medication, P&C=Prior and Concomitant Medication. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 160 of 213 
 
Listing 16.2.4.7 Concomitant Procedures 
 
Treatment Group 
Subject No. 
Sex/ 
Age/ 
Race1 
Procedure Date 
Procedure 
Indication/Reason 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYYY 
 xxxxxxxxxxxxxxxxxx 
xxxxxxxxxxxxxxxxx 
 
 
 
Procedure Date 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 161 of 213 
 
Listing 16.2.4.8 Surgical Therapy 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Date of Surgery 
Type of Surgery 
Specify 
Repeat 
Procedure? 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYYY 
(Intracranial Surgery, 
Extracranial Surgery) 
((Aneurysm…) if Intracranial Surgery, 
(Maxillofacial …) if Extracranial 
Surgery, or Specify if Other) 
 
(xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx) 
(Yes, No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 162 of 213 
 
Listing 16.2.4.9 Study Admission 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Was Subject Transferred from 
Another Facility? 
Admission to  
First Facility  
Date/Time 
Admission at  
Study Center 
Date/Time 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
(yes, no) 
DDMONYYYY/ XX:XX 
DDMONYYYY/ XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 163 of 213 
 
Listing 16.2.4.10 Subject Transfer 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Initial  
Site 
Number 
Initial 
Subject  
Number 
New 
Site 
Number 
New 
Subject 
Number 
Date Subject 
First Seen at 
New Site 
Type of Visit 
(Specify) 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
xx 
xx-xxx 
xx 
xx-xxx 
DDMONYYYY 
(Day, 15, Day 30, Day 90, 
Day 180, Other) 
 
(xxxxxxxxxxxxxxxxxxxxxxxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 164 of 213 
 
Listing 16.2.4.11 Facility Transfer 
 
 
 
 
Subject Discharged/Transferred From 
Subject Discharged/Transferred to/Admitted To 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
 Specify 
Date 
Specify 
Date 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
(ICU, General Ward, 
Nursing Home/Long-Term 
Care, Other ICU, Other 
Hospital, Rehabilitation 
Unit, Home, Other) 
 
(xxxxxxxxxxxxxxxxxxxxxxx) 
DDMONYYYY 
(ICU, General Ward, Nursing 
Home/Long-Term Care, Other ICU, 
Other Hospital, Rehabilitation 
Unit, Home, Other) 
 
(xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx) 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or 
Other Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 165 of 213 
 
 
Listing 16.2.4.12 Intubation 
 
 
 
 
 
Treatment Group 
Subject No. 
Sex/ 
Age/ 
Race1 
Date/Time of Intubation 
Date/Time of Extubation 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
DDMONYYYY/ 
XX:XX 
 
 
DDMONYYYY/ 
XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 166 of 213 
 
Listing 16.2.4.13 Daily Fluid 
 
 
 
 
 
 
 
 
Treatment Group 
Subject No. 
Sex/ 
Age/ 
Race1 
Visit 
Collection  
Period Start 
Date/Time 
Collection  
Period Stop  
Date/Time 
Total Fluid 
Administered 
(ml) 
Total Fluid 
Excreted 
(ml) 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
Day 1 
DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
xxxxx.x 
xxxxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 167 of 213 
 
Listing 16.2.5.1 Study Drug Administration – Part 1 
 
 
Treat-
ment 
Group 
 
 
Subject 
No. 
 
Sex/ 
Age/ 
Race1 
Dose/ 
Day/ 
Bottle/ 
Record 
 
 
Start Date/ 
Time 
 
 
Stop Date/ 
Time 
 
 
 
Route 
 
Infusion 
Rate 
(ml/hr) 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
(Loading, 
Maintenance)/1
/1/1 
DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
(Central line, 
Peripheral 
line) 
xxxxx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 168 of 213 
 
Listing 16.2.5.1 Study Drug Administration – Part 2 
 
 
 
 
 
 
Infusion Rate 
Infusion Rate Interrupted 
 
Treat-
ment 
Group 
 
 
Subject 
No. 
 
Sex/ 
Age/ 
Race1 
Dose/ 
Day/ 
Bottle/ 
Record 
 
 
Modified? 
 
 
Reason 
If Other, Specify 
 
For more 
than 30 
mins? 
 
 
Reason 
If Other, specify 
 
 
 
Duration (mins) 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/
W 
(Loading, 
Maintenan
ce)/1/1/1 
(Yes, No) 
(Adverse Event, I.V. access 
problem, …, Other) 
 
(xxxxxxxxxxxxxxxxxxxxxxxxxx) 
(Yes, No) 
(Adverse Event, 
I.V. access 
problem, …, Other) 
 
(xxxxxxxxxxxxxxxxx) 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 169 of 213 
 
  
Listing 16.2.5.2 End of Treatment  
 
 
 
 
 
 
Treat-
ment 
Group 
 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Did the Subject 
Complete 5 Days 
of Treatment? 
Date/Time 
Infusion 
Completed 
If No, Reason for Discon- 
tinuation of Study Drug 
(If Other, Specify) 
Treatment 
Duration 
(hours)2 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
(Yes, No) 
DDMONYYYY 
(Adverse Event, Death, PI Decision,  
Sponsor Decision, Consent Withdrawn, Other) 
 
(xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx) 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, O = Other. 
2 Duration of study drug exposure (in hours) = date:hour of last study medication administered – date:hour of first study medication 
administered + 1 – sum of recorded durations of infusion rate interruptions. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 170 of 213 
 
 
 
 
Listing 16.2.6.1.1 Glasgow Outcome Scale, Questions 
 
Question 
Details and Possible Responses 
 
 
1 
Has the subject resumed pre-injury occupational status?  Yes/No. 
 
 
 
[If subject resumed pre-injury occupational status is "Yes"] Check one box on the 
right A, B, C or D, that is most specific to the subject : 
 
A: Subject has resumed pre-injury employment: (e.g. executive or skilled laborer that has returned to the same level of 
responsibility at the same number of hours worked each week at the same performance level equivalent to that of their pre-
injury status, with or without the use of compensatory mechanisms.) 
B: Subject could have resumed pre-injury occupational status, but currently has a reduction in performance level due to 
outlying circumstances that are not brain related: (e.g. previous work place out of business so they are unemployed and job 
hunting or a physical injury such as leg amputation that prevents them from returning to work - these are not "Brain Related 
Injuries" and should not be rated as a No for these types of reasons.) 
C: Subject has resumed academic pursuits: (e.g. a student has resumed the same number of hours/classes at the same performance 
level equivalent to that of their pre-injury abilities - independently, without the need for special accommodations such as 
tutors, if they were not necessary prior to the injury.) 
D: Subject has resumed household responsibilities: (e.g. a subject that was previously a housewife, househusband, unemployed 
and/or volunteer that has returned to the same level of responsibility, same number of hours involved at the same performance 
level equivalent to that of pre-injury.) 
 
 
2 
Has the subject resumed at least half as often as the pre-injury level of social activities?  Yes/No. 
 
 
3 
Has the subject resumed pre-injury level of independence in activities of daily living?  Yes/No. 
 
 
4 
Is the subject able to be left alone at home and is able to care for her/himself at the same level of pre-injury?  Yes/No. 
 
 
5 
Has the subject resumed independence in transportation?  Yes/No. 
 
 
6 
Does the subject respond to verbal communication and/or obey commands?  Yes/No. 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 171 of 213 
 
Listing 16.2.6.1.2 Glasgow Outcome Scale, Explanation of Categories 
 
Rating 
Explanation 
 
 
Good Recovery 
If you answered YES to ALL questions (1-6). 
 
 
Moderate Disability 
If you answered NO to questions 1 and 2 and YES to 3, 4, 5 & 6. 
 
 
Severe Disability 
If you answered NO to questions 3, 4, or 5 and YES to 6. 
 
 
Vegetative State 
If you answered NO to Question 6. 
 
 
Dead 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 172 of 213 
 
 
Listing 16.2.6.1.3 Glasgow Outcome Scale – Extended, Explanation of Categories 
 
GOS-E 
Rating 
Explanation 
 
 
Upper 
Good 
Return to normal life and NO current problems relating to the injury that affect daily life (dizziness, headache, and 
sensitivity to noise or light, slowness, memory failure, concentration problems). 
 
Lower 
Good 
Return to normal life BUT current problems relating to the injury that affect daily life (dizziness, headache, and 
sensitivity to noise or light, slowness, memory failure, concentration problems). 
Social Activities: Resumed at least half as often as pre-injury. 
Disruption or Strain: Occasional (less than once per week). 
 
Upper 
Moderate 
Work capacity: Reduced 
Social Activities: Resumed less than half as often as pre-injury 
Disruption or Strain: Frequent (once a week or more but tolerable) 
 
Lower 
Moderate 
Work capacity: Unable to work or only able to work in sheltered workshop 
Social Activities: Unable or rarely able to participate 
Disruption or Strain: Constant (daily and intolerable) 
 
Upper 
Severe 
Care: Does not require someone to be around at home most of the time (for at least 8 hours during the day, if necessary) 
Travel: Unable to travel locally without assistance 
Shopping: Unable to shop without assistance 
 
Lower 
Severe 
Care: Requires frequent help of someone to be around at home most of the time 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 173 of 213 
 
Listing 16.2.6.1.4 Glasgow Outcome Scale  
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Month 
 
Interview 
Date 
 
Source of 
Information 
Q1 
Q2 
Q3 
Q4 
Q5 
 
 
Q6 
GOS Rating 
GOS – 
Extended 
Rating 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (3,6) DDMONYYY 
(Patient Alone, 
Relative/Friend/ 
Caretaker Alone, 
…) 
(Yes: 
(A,B,C,D) 
or No) 
(Yes, 
No) 
(Yes, 
No) 
(Yes, 
No) 
(Yes, 
No) 
(Yes, 
No) 
(Good 
Recovery, 
Moderate 
Disability, 
Severe 
Disability, 
Vegetative 
State, 
Dead) 
(Upper 
Good, 
Lower 
Good, 
Upper 
Moderate, 
Lower 
Moderate, 
Upper 
Severe, 
Lower 
Severe) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
[Note to Programmer: Dead is not an option on the GOS CRF page.  This information can be read from the mortality or date of death 
details (for premature terminations due to death).  This information should be combined for the derived datasets.] 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 174 of 213 
 
Listing 16.2.6.1.5 Glasgow Outcome Scale, Glasgow Outcome Scale-Extended Narrative – Part 1 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Month 
 
Interview 
Date 
 
 
Occupational Status 
Summarize Subjects  
Work Capacity 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (3,6) DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
(Returned to normal level, 
Reduced, Only able to work 
in sheltered work shop or 
unable to work) 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or 
Other Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 175 of 213 
 
Listing 16.2.6.1.5 Glasgow Outcome Scale, Glasgow Outcome Scale-Extended Narrative – Part 2 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Month 
 
Interview 
Date 
 
 
Social Skills 
Has the subject resumed pre-
injury level of social 
activities? 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (3,6) DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
(At least half as often, 
Less than half as often, 
Unable to or rarely 
participate) 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or 
Other Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 176 of 213 
 
Listing 16.2.6.1.5 Glasgow Outcome Scale, Glasgow Outcome Scale-Extended Narrative – Part 3 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Month 
 
Interview 
Date 
 
 
Disruption or Strain 
Summarize the subject’s 
extent of disruption or 
strain: 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (3,6) DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
(Occasional (less than once 
per week), Frequent (once 
per week or more but 
tolerable), Constant (daily 
and intolerable)) 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or 
Other Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 177 of 213 
 
Listing 16.2.6.1.5 Glasgow Outcome Scale, Glasgow Outcome Scale-Extended Narrative – Part 4 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Month 
 
Interview 
Date 
 
 
Activities of Daily Living 
Are the family able to leave 
subject home alone for >= 8 
hours/day, if necessary? 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (3,6) DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
(yes, no) 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or 
Other Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 178 of 213 
 
Listing 16.2.6.1.5 Glasgow Outcome Scale, Glasgow Outcome Scale-Extended Narrative – Part 5 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Month 
 
Interview 
Date 
 
 
Mode of Transportation 
 
Is subject able to drive or use public 
transport without assistance? 
Is subject able to 
shop without 
assistance? 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (3,6) DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxx (yes, no) 
(yes, no) 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific 
Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 179 of 213 
 
Listing 16.2.6.1.5 Glasgow Outcome Scale, Glasgow Outcome Scale-Extended Narrative – Part 6 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Month 
 
Interview 
Date 
 
 
General 
Are there any problems e.g. 
dizziness, that affect daily 
life after the head injury? 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (3,6) DDMONYYY 
xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 
(yes, no) 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or 
Other Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 180 of 213 
 
 
Listing 16.2.6.1.6 Primary Efficacy, Covariates, and Subgroup Variables (Observed Values) 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
GOS Rating 
at Month 6 
Region 
GCS 
Motor 
Score 
Pupil 
Response 
CT 
Classification 
Time to 
First 
Dose 
Relative 
to TBI  
(Hours) 
Baseline 
Hypoxia 
Baseline 
Hypo- 
tension 
Traumatic 
Sub- 
arachnoid 
Hemorrhage 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W (Good 
Recovery, 
Moderate 
Disability, 
Severe 
Disability, 
Vegetative 
State) 
(North 
America, 
Europe, 
Asia and 
South 
America) 
(1-2, 
3, 4, 
5-6) 
(Bilateral, 
Unilateral, 
No Reactive 
Pupils, Not 
Testable) 
(II, III, IV, 
evacuated/ 
non-evacuated 
mass lesion) 
(0-<=4, 
>4-<=8, 
>8) 
(Yes, 
No) 
(Yes, 
No) 
(Yes, No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other 
Pacific Islander, A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
Repeat this shell for 
Listing 16.2.6.1.7 Primary Efficacy, Covariates, and Subgroup Variables (Missing Values Imputed) 
Add 
Note:Missing values are first imputed by carrying forward the Month 3 GOS assessment. If a subject has neither the 3 nor the 6 month G
OS, the missing value is imputed based upon the primary proportional odds model.  Missing covariates are imputed as the most common 
level over all subjects.  


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 181 of 213 
 
 
Listing 16.2.6.2 Sliding Dichotomy 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Visit 
Prognosis Group 
GOS Group 
(4-level) 
GOS Group 
(2-level) 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Month 6 
(Best, 
Intermediate, 
Worst) 
(Good Recovery, Moderate Disability, Severe 
Disability, Vegetative State/Dead) 
(Favorable, 
Unfavorable) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 182 of 213 
 
Listing 16.2.6.3 Mortality 
 
 
Treatment  
Group 
 
Subject  
No. 
Sex/  
Age/ 
Race1 
 
Visit 
 
Status 
(If Other, Specify) 
 
 
Patient Residence 
Date of Death or  
Date of Last  
Contact 
Time to Death 
or Last Contact 
(days)2 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Month 1 
(Lost to Follow-up, 
Consent Withdrawn, 
Alive, Dead, Other 
[specify]) 
(At Home, Hospital, 
Rehab Unit, Nursing 
Home/Long-Term Care, 
Other[Specify]) 
DDMONYYY 
XX* 
 
 
 
 
 
 
 
 
 
 
 
Month 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 If subject has not died, they will be censored on their last date of contact for the Kaplan-Meier survival analysis. 
* Indicates that time to death or last contact is censored. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
  


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 183 of 213 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 184 of 213 
 
Listing 16.2.6.4.1  SF-36, Explanation of Categories 
 
Question 
Explanation 
 
 
1. In general, would you say your health is: 
1=Excellent, 2=Very Good, 3=Good, 4=Fair, 5=Poor. 
 
 
2. Compared to one year ago, how would you rate your health in 
general now? 
1=Much better now than one year ago, 2=Somewhat better now than one 
year ago, 3=About the same as one year ago, 4=Somewhat worse now than 
one year ago, 5=Much worse now than one year ago. 
 
 
3. The following questions are about activities you might do 
during a typical day. Does your health now limit you in these 
activities? If so, how much? 
 
  a. Vigorous activities 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  b. Moderate activities 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  c. Lifting or carrying groceries 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  d. Climbing several flights of stairs 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  e. Climbing one flight of stairs 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  f. Bending, kneeling, or stooping 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  g. Walking more than one mile 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  h. Walking several hundred yards 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  i. Walking one hundred yards 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
  j. Bathing or dressing yourself 
1=Yes, limited a lot, 2=Yes, limited a little, 3=No, not limited at all 
   
 
4. During the past 4 weeks, have you had any of the following 
problems with your work or other regular daily activities as a 
result of your physical health?  
 
  a.  
1=All of the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, 5=None of the time 
  b.  
1=All of the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, 5=None of the time 
  c.  
1=All of the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, 5=None of the time 
  d.  
1=All of the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, 5=None of the time 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 185 of 213 
 
Listing 16.2.6.4.1  SF-36, Explanation of Categories 
 
Question 
Explanation 
 
 
5. During the past 4 weeks, how much of the time have you had 
any of the following problems with your work or other regular 
daily activities as a result of any emotional problems (such as 
feeling depressed or anxious)? 
 
  a. Cut down on the amount of time spent on work or other 
activities. 
1=All of the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, 5=None of the time 
  b. Accomplished less than you would like 
1=All of the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, 5=None of the time 
  c. Did work or other activities less carefully than usual 
1=All of the time, 2=Most of the time, 3=Some of the time, 4=A little 
of the time, 5=None of the time 
 
 
6. During the past 4 weeks, to what extent has your physical 
health or emotional problems interfered with your normal social 
activities with family, friends, neighbors, or groups? 
1=Not at all, 2=Slightly, 3=Moderately, 4=Quite a bit, 5=Extremely 
 
 
7. How much bodily pain have you had during the past 4 weeks? 
1=None, 2=Very mild, 3=Mild, 4=Moderate, 5=Severe, 6=Very severe 
 
 
8. During the past 4 weeks, how much did pain interfere with 
your normal work (including both work outside the home and 
housework)? 
1=Not at all, 2=Slightly, 3=Moderately, 4=Quite a bit, 5=Extremely 
 
 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 186 of 213 
 
Listing 16.2.6.4.1  SF-36, Explanation of Categories 
 
Question 
Explanation 
 
 
9. These questions are about how you feel and how things have 
been with you during the past 4 weeks. For each question, 
please give the one answer that comes closest to the way you 
have been feeling. How much of the time during the past 4 
weeks... 
 
  a. Did you feel full of life? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  b. Have you been very nervous? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  c. Have you felt so down in the dumps that nothing could 
     cheer you up? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  d. Have you felt calm and peaceful? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  e. Did you have a lot of energy? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  f. Have you felt downhearted and depressed? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  g. Did you feel worn out? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  h. Have you been happy? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
  i. Did you feel tired? 
1 = All of the time, 2 = Most of the time, 3 = Some of the time, 4 = A 
little of the time, 5 = None of the time 
 
 
10. During the past 4 weeks, how much of the time has your 
physical health or emotional problems interfered with your 
social activities (like visiting friends, relatives, etc.)? 
 
 
 
11. How TRUE or FALSE is each of the following statements for 
you? 
 
  a. I seem to get sick a little easier than other people 
1 = Definitely true, 2 = Mostly true, 3 = Don't know, 4 = Mostly false, 
5 = Definitely false 
  b. I am as healthy as anybody I know 
1 = Definitely true, 2 = Mostly true, 3 = Don't know, 4 = Mostly false, 
5 = Definitely false 
  c. I expect my health to get worse 
1 = Definitely true, 2 = Mostly true, 3 = Don't know, 4 = Mostly false, 
5 = Definitely false 
  d. My health is excellent 
1 = Definitely true, 2 = Mostly true, 3 = Don't know, 4 = Mostly false, 
5 = Definitely false 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 187 of 213 
 
Listing 16.2.6.4.2 SF-36 (Individual Questions) – Part 1 
 
 
 
 
 
 
Q1 
Q2 
Q3 
 
Treatment  
Group 
 
Subject  
No. 
Sex/  
Age/ 
Race1 
Visit 
Interview  
Date 
 
 
a 
b 
c 
d 
e 
f 
g 
h 
i 
j 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/39/W 
Month 3 
DDMONYYYY 
(1-5) 
(1-5) 
(1-3) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 188 of 213 
 
 
 
Listing 16.2.6.4.2 SF-36 (Individual Questions) – Part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q4 
Q5 
Q6 
Q7 
Q8 
Treatment  
Group 
Subject  
No. 
Sex/  
Age/ 
Race1 
Visit 
Interview  
Date 
a 
b 
c 
d 
a 
b 
 
 
c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/39/W 
Month 3 
DDMONYYYY 
(1-5) 
(1-5) 
(1-5) 
(1-5) 
(1-5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 189 of 213 
 
 
Listing 16.2.6.4.2 SF-36 (Individual Questions) – Part 3 
 
 
 
 
 
 
 
 
 
 
 
 
 
Q9 
Q10 
Q11 
 
Treatment  
Group 
 
Subject  
No. 
Sex/  
Age/ 
Race1 
Visit 
Interview  
Date 
a 
b 
c 
d 
e 
f 
g 
h 
i 
 
a 
b 
c 
d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/39/W 
Month 3 
DDMONYYYY 
(1-5) 
(1-5) 
(1-5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 190 of 213 
 
 
Listing 16.2.6.4.3 SF-36 (Scales and Summary Scores)  – Part 1 
 
Treatment 
Group 
Subject No. 
Sex/  
Age/ 
Race1 
Visit 
Interview 
Date 
Vitality 
Physical 
Functioning 
Bodily 
Pain 
General 
Health 
Perceptions 
Physical Role 
Functioning 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Month 3 
DDMONYYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 191 of 213 
 
Listing 16.2.6.4.3 SF-36 (Scales and Summary Scores) – Part 2 
 
Treatment Group Subject No. 
Sex/ 
Age/ 
Race1 
Visit 
Interview 
Date 
Emotional 
Role 
Functioning 
Social Role 
Functioning 
Mental 
Health 
Physical 
Composite 
Mental 
Composite 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Month 3 
DDMONYYYY 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Month 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 192 of 213 
 
Listing 16.2.6.5.1 CT Scan and Classification – Part 1 
 
Treatment  
Group 
Subject  
No. 
Sex/  
Age/ 
Race1 
Visit/ 
Date/ 
Time 
 
 
 
Admission CT 
Scan / If No, 
Study Day 
Number of 
Parenchymal 
Hemorrhage 
Lesions 
Subarachnoid 
Hemorrhage/ 
If Yes, 
Specify 
Basal 
Cisterns 
Midline 
Shift 
Size 
(mm) 
Total 
Volume 
of 
Largest 
Lesion 
(ml) 
 
 
 
Parenchymal 
Hemorrhage/ If 
Yes, ≥ 25 ml? 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W Screen- 
Ing 
DDMONYYYY/ 
XX:XX 
(Yes, No) / x 
 
xx 
(Yes, No)/ 
(Basal,  
Convexity) 
(Present, 
Compressed, 
Absent) 
xx 
xxxx.xx 
(Yes,No)/ 
(Yes,No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
DDMONYYYY/ 
XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 193 of 213 
 
Listing 16.2.6.5.1 CT Scan and Classification – Part 2 
 
Treatment  
Group 
Subject  
No. 
Sex/  
Age/ 
Race1 
Visit/ 
Date/ 
Time 
Cerebral 
Contusion 
/ If Yes, 
≥ 25 ml? 
Subdural 
Hemorrhage/ 
If Yes, ≥ 
25 ml? 
Epidural 
Hemorrhage/ 
If Yes, ≥ 
25 ml? 
Intraventricular 
Hemorrhage/ If 
Yes, ≥ 25 ml? 
Small Slit 
Ventricles 
Cerebral 
Edema 
Pneumocephalus 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W Screen- 
Ing 
DDMONYYYY/ 
XX:XX 
(Yes,No)/ 
(Yes,No) 
(Yes,No)/ 
(Yes,No) 
(Yes,No)/ 
(Yes,No) 
(Yes,No)/ 
(Yes,No) 
(Yes, No) 
(Yes, 
No) 
(Yes, No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
DDMONYYYY/ 
XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 194 of 213 
 
Listing 16.2.6.5.1 CT Scan and Classification – Part 3 
 
Treatment  
Group 
Subject  
No. 
Sex/  
Age/ 
Race1 
Visit/ 
Date/ 
Time 
Other 
Intracranial 
Findings/ 
Specify 
Skull 
Fracture, 
Depressed 
Skull 
Fracture, 
Basilar 
Skull Fracture, 
Other / Specify 
Evacuated Mass or 
Plans to Evacuate 
CT 
Classification 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W Screen- 
Ing 
DDMONYYYY/ 
XX:XX 
(Yes,No)/ 
xxxxxxxx 
(Yes, No) 
(Yes, No) 
(Yes, No) / 
xxxxxxxxxx 
(Yes, No) 
(1,2 … 6) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
DDMONYYYY/ 
XX:XX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 195 of 213 
 
Listing 16.2.6.5.2 CT Scan Comparison – Part 1 
 
Treatment  
Group 
Subject  
No. 
Sex/  
Age/ 
Race1 
Date of 
Comparison2 
 
Parenchymal 
Hemorrhage 
Cerebral 
Contusion 
Subdural 
Hematoma 
Epidural 
Hematoma 
Subarachnoid 
Hematoma 
Intraventricular 
Hemorrhage 
Progressive 
Intracranial 
Pathology (PIP) 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W DDMONYYYY 
(Not Applicable, Improved, Worsened, New Findings, No Change) 
(Not 
Applicable, 
Same, Worsened, 
Improved) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 CT scans will be compared to the screening CT scan. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 196 of 213 
 
Listing 16.2.6.5.2 CT Scan Comparison – Part 2 
 
Treatment  
Group 
Subject  
No. 
Sex/  
Age/ 
Race1 
Date of  
Comparison2 
 
 
Small Slit  
Ventricles 
Cerebral  
Edema 
Midline  
Shift 
Pneumo- 
cephalus 
Other  
Intracranial  
Findings 
(specify) 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W 
DDMONYYYY 
(Not Applicable, Improved, Worsened,  
New Findings, No Change) 
(Not Applicable, Improved, 
Worsened, New Findings, No 
Change) 
(xxxxxxxxxxxxxxxxxxxxxxxx) 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/31/W 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 CT scans will be compared to the screening CT scan. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 197 of 213 
 
Listing 16.2.6.5.2 CT Scan Comparison – Part 3 
 
Treatment  
Group 
Subject  
No. 
Sex/  
Age/ 
Race1 
Date of  
Comparison2 
 
Skull Fracture, 
Depressed 
Skull Fracture, 
Basilar 
Skull Fracture, 
Other 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W 
DDMONYYYY 
(Not Applicable, Improved, Worsened,  
New Findings, No Change) 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/31/W 
DDMONYYYY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 CT scans will be compared to the screening CT scan. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 198 of 213 
 
 
Listing 16.2.6.6.1 Intracranial Pressure 
 
Treatment Group 
Subject No. 
Sex/  
Age/ 
Race1 
Visit 
Date 
Time 
 
 
Value 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Screening 
DDMONYYYY 
xx.xx 
xxx  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 199 of 213 
 
 
Listing 16.2.6.6.2 Intracranial Pressure Monitoring 
 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/  
Age/ 
Race1 
Date/Time 
ICP 
Monitor 
Placed 
Device Used 
(If Other, Specify) 
End 
Date/Time 
ICP 
Monitoring 
Reason for Ending  
ICP Monitoring 
(If Other, Specify) 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
DDMONYYYY/ 
XX:XX 
(Ventriculostomy, 
Intraparenchymal, Epidural, 
Subdural, Other) 
DDMONYYYY/ 
XX:XX 
(Clinically no longer required, 
Monitor/catheter failure, Patient 
considered unsalvageable, Patient 
died, Other) 
 
 
 
 
 
 
(xxxxxxxxxxxxxxxx) 
 
(xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 200 of 213 
 
Listing 16.2.6.7 Cerebral Perfusion Pressure 
 
Treatment Group 
Subject No. 
Sex/  
Age/ 
Race1 
Visit 
Date 
ICP 
(mmHg) 
 
Highest/ 
Lowest 
ICP? 
 
Pulse 
Rate 
(bpm) 
Systolic 
Blood 
Pressure 
(mmHg) 
Diastolic 
Blood 
Pressure 
(mmHg) 
CPP 
(mmHg) 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Screen- 
ing 
DDMONYYYY 
xxx 
(H, L) 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 201 of 213 
 
 
 
Listing 16.2.6.8.1 Therapy Intensity Level – Part 1 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Visit 
Date/ 
Time/ 
ICP2 
Sedation 
Paralysis 
Induction 
Ventricular 
Drainage 
Mannitol 
Hypertonic 
Saline 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Screening DDMONYYYY/ 
XX:XX/ 
(H, L, UNK) 
(Yes, No) 
(Yes, No) 
(Yes, No) 
(Yes, No) 
(Yes, No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 Was TIL recorded at highest (H), lowest (L) or unknown (UNK) ICP value.  The therapies taken each study day through to day 6 can 
continue to be monitored after the ICP monitor is removed.  For such cases the ICP measurement would be unknown. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 202 of 213 
 
Listing 16.2.6.8.1 Therapy Intensity Level – Part 2 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Visit 
Date/ 
Time/ 
ICP2 
Pressor 
Administration 
Hyper-
ventilation 
Hypothermia 
for ICP 
Reduction 
Barbiturate 
Induced 
Coma 
Surgical 
Decompression 
TIL 
Score 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Screening DDMONYYYY/ 
XX:XX/ 
(H, L, UNK) 
(Yes, No) 
(Yes, No) 
(Yes, No) 
(Yes, No) 
(Yes, No) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 Was TIL recorded at highest (H), lowest (L) or unknown (UNK) ICP value.  The therapies taken each study day through to day 6 can 
continue to be monitored after the ICP monitor is removed.  For such cases the ICP measurement would be unknown. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 203 of 213 
 
 
Listing 16.2.7 Adverse Events  
 
 
 
 
 
 
 
 
 
Treatment  
Group 
 
Subject  
No. 
Sex/  
Age/  
Race1 
Adverse Event/ 
Preferred Term/ 
SOC 
Start Date/ 
Stop Date/ 
Day2 / 
Duration3/ 
Length of 
Exposure 
(hours)4 
Intensity/ 
Relationship/ 
Outcome5 
 
 
Action 
Taken 
with Study 
Drug6 
 
 
Treatment 
for 
AE? 
(specify)7 
Serious?/ 
(Reason for 
Seriousness8 
)/ 
Treatment 
Emergent?9 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W 
xxxxxxxxxxxxxxx/ 
Xxxxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxx 
DDMONYYYY/ 
DDMONYYYY/ 
xx 
 
x/ 
x.xx 
xxxxxxxx/ 
x/ 
x 
x 
xxx/ 
(x) 
xxx (xxx)/ 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 Day is relative to the start date of study medication, event start date – administration start date + 1 if event start date is on or 
after the date of the start of study medication administration or event start date – administration start date if event date is 
before the date of the start of study medication administration. 
3 Length of exposure is based on administration start date and administration end date during the study (end date – start date + 1). 
4 Duration = AE end date – AE start date + 1. 
5 Relationship: 1=Not related, 2=Possibly related, 3=Probably related, 4=Related.   
  Outcome: 1=Recovered/resolved, 2=Recovering/resolving, 3=Not recovered/not resolved, 4=Recovered/resolved with sequelae,    
  5=Fatal, 6=Unknown. 
6 1=Dose not changed, 2=Drug withdrawn, 3=Drug interrupted, 4=Dose reduced, 5=Dose increased, 6=Unknown, 7=Not applicable. 
7 1=none, 2=Change in therapy intensity level, 3=procedure/surgery, 4=other (specify). 
8 1=Results in death, 2=Life threatening, 3=Results in persistent or significant disability/incapacity, 4=Requires or prolongs 
hospitalization, 5=Congenital abnormality/birth defect, 6=Other medically important event. 
9 Treatment-emergent adverse events are defined as events that start on or after the first dose of study medication and up to 15 days 
and 6 months after the initiation of study treatment, for adverse events and serious adverse events respectively. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 204 of 213 
 
 
Listing 16.2.8.1.1 Laboratory (Coagulation) Results 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Test Name 
Visit 
Sample 
Date/ 
Time 
Result 
(Unit) 
Change 
from 
Baseline 
Range 
Flag2 
Reference Range 
 
 
 
Low 
 
High 
 
Clin Sig? 
Is this 
an AE? 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W INR 
Screening DDMONYYYY/ 
XX:XX 
xx.x g/L 
xx.x 
L 
xx.x 
xx.x 
(Yes, No) 
(Yes, 
No) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 6 
DDMONYYYY/ 
XX:XX 
xx.x g/L 
xx.x 
L 
xx.x 
xx.x 
 
 
 
 
 
 
Day 15 
DDMONYYYY/ 
XX:XX 
xx.x g/L 
xx.x 
L 
xx.x 
xx.x 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: The baseline value is defined as the last measurement taken prior to first administration of study drug (Day 1).  For 
laboratory assessments this will be the screening visit. 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
2 N = Normal, L = Low, H = High. 
 
 
 
[Note to Programmer: Do not include unscheduled results in this listing.] 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 205 of 213 
 
Listing 16.2.8.1.2 Laboratory (Hematology) Results  
 (Produce for Hemoglobin, Hematocrit, RBC, Reticulocyte Count, Platelet Count, WBC, Neutrophils, Lymphocytes, Monocytes, 
Eosinophils, Basophils) 
Listing 16.2.8.1.3 Laboratory (Serum Chemistry) Results  
 (Produce for Sodium, Potassium, Chloride, Cholesterol, total, Triglycerides, ALT, AST, GGT, Alkaline Phosphatase, Total 
Protein, Glucose) 
Listing 16.2.8.1.4 Laboratory (Urinalysis) Results 
 (Produce for pH, Specific Gravity, Protein, Glucose, Blood, WBC, RBC, Casts, Epithelial Cells, Bacteria) 
[Use shell for Listing 16.2.8.1.1] 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 206 of 213 
 
 
Listing 16.2.8.1.5 Laboratory (Pregnancy Test) Results 
 
 
 
 
 
 
 
 
 
 
 
 
If, Yes 
Treatment 
Group 
Subject No. 
Sex/  
Age/  
Race1 
Is Subject 
Female of 
Child-bearing 
Potential? 
Was Sample 
Collected for 
Pregnancy Test? 
Pregnancy  
Test Type 
Date of  
Collection 
Pregnancy Test 
Result 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/35/W 
(yes, no) 
(yes, no) 
(Serum, Urine) 
DDMONYYYY 
(Positive, 
Negative) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black, African American or of African Heritage, P = Native Hawaiian or Other Pacific Islander, 
A = Asian, N = American Indian or Alaska Native, Z=Not Allowed to Obtain, O = Other. 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 207 of 213 
 
Listing 16.2.8.2 Vital Signs 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Visit 
Date/Time 
Pulse 
Rate 
(bpm) 
Resp 
Rate  
(bpm) 
SBP 
(mmHg) 
DBP 
(mmHg) 
Temp 
(°C) 
Weight 
(kg) 
Right 
Pupil2 
Left 
Pupil2 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Screen-
ing 
DDMONYYYY/ 
XX:XX 
xxx 
xx 
xxx 
xxx 
xx.x 
xx 
(R, 
NR, 
UN) 
(R, 
NR, 
UN) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
2 R=Reacts, NR=No Reaction, UN=Eyes Closed/Untestable. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 208 of 213 
 
Listing 16.2.8.3 Physical Examinations 
 
Treatment 
Group 
Subject No. 
Sex/ 
Age/ 
Race1 
Visit 
Date Exam 
Performed 
Body System 
Status 
Abnormalities 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W 
Screen- 
ing 
DDMONYYYY 
Skin 
Normal 
 
 
 
 
 
 
HEENT 
Abnormal 
xxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
Respiratory 
Not Done 
 
 
 
 
 
 
Cardiovascular 
Not Done 
 
 
 
 
 
 
Abdomen 
Normal 
 
 
 
 
 
 
Musculoskeletal 
Normal 
 
 
 
 
 
 
Neurological 
Normal 
 
 
 
 
 
 
Gastrointestinal 
Normal 
 
 
 
 
 
 
Genitourinary 
Normal 
 
 
 
 
 
 
Endocrine 
 
 
 
 
 
... 
... 
Lymph Nodes 
... 
... 
 
 
 
 
 
. . . 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 209 of 213 
 
Listing 16.2.8.4 12-Lead Electrocardiogram (ECG) – Part 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rhythm 
Conduction 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
 
 
Visit 
Heart 
Rate 
bpm) 
 
 
Result 
 
 
Specify 
 
Clin 
Sig 
 
 
Result 
 
 
Specify 
 
Clin 
Sig 
QT 
Prolongation 
Interval 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xxx-
xxxx 
 
M/30/W 
Screening 
xx 
(Normal, 
Abnormal) 
(Sinus 
Arrhythmia, …, 
Other Arrhythmia 
[xxxxxxx]) 
(Yes, 
No) 
(Normal, 
Abnormal) 
(LBBB, …, 
Other 
[xxxxxx]) 
(Yes, 
No) 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 210 of 213 
 
Listing 16.2.8.4 12-Lead Electrocardiogram (ECG) – Part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Visit 
QRS Complex 
Comments 
Result 
Specify 
Clin Sig 
 
 
 
 
 
 
 
 
BHR-100 
xxx-xxxx 
 M/30/W 
Screening 
(Normal, 
Abnormal) 
(Non-specific ST changes, …, 
other [xxxxx]) 
(Yes, 
No) 
xxxxxxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 211 of 213 
 
 
Listing 16.2.8.5 Arterial Blood Gas  
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Visit 
Date/ 
Time 
Line 
pH 
PaCO2 
(mmHg) 
HCO3 
(mmol/L) 
 
 
SaO2 (%) 
 
PaO2 
(mmHg) 
FiO2 (%) 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
 M/30/W 
Screening DDMONYYYY/ 
XX:XX 
(1.1, 
2.2, 
3.3, 
4.4, 
5.5, 
6.6) 
x.xx 
xxx.x* 
xxx.x 
xxx.x 
xxx.x 
xx.xx* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, 
N = American Indian or Alaska Native, O = Other. 
* Indicates the worst value of the day for a given parameter. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 
 
 
 
 
 
 
 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 212 of 213 
 
Listing 16.2.8.6 Neuroworsening – Part 1 
 
 
 
 
 
Neuroworsening? 
Prior Neurologic Worsening 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Visit 
Start 
Date/ 
Time 
Stop  
Date/ 
Time 
Contin- 
uing? 
Eye Opening2 
(none due to 
severe facial 
swelling/damage) 
Verbal 
Response3 
(none due 
to 
intubation) 
Motor  
Response4 
Right  
Pupil  
React-
ivity5 
Left  
Pupil  
React-
ivity5 
ICP(mmHg)/ 
SBP (mmHg)/ 
DBP (mmHg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W Day 1 DDMONYYYY/ 
XX:XX 
DDMONYYYY/ 
XX:XX 
(yes, 
no) 
 
If no, a 
stop 
date 
should 
be 
provided 
in the 
previous 
column. 
(SPON,  
SPEECH,  
PAIN,  
NONE) 
 
(no, yes) 
(O,  
C,  
INAPP, 
INCOMP,  
NONE) 
 
(yes, no) 
(OC,  
LP,  
WNF,  
ABF,  
ABE,  
NONE) 
(R, 
NR, 
UN) 
(R, 
NR, 
UN) 
xxx/ 
xxx/ 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, N = American Indian or 
Alaska Native, O = Other. 
2 SPON=Spontaneous, SPEECH=In response to speech, PAIN=In response to pain, NONE=None. 
3 O=Oriented, C=Confused, INAPP=Inappropriate words, INCOM=Incomprehensible sounds, NONE=None. 
4 OC=Obeys Commands, LP=Localizes Pain, WNF=Withdrawal/Normal flexion, ABF=Abnormal flexion, ABE=Abnormal Extension, NONE=None. 
5 R=Reacts, NR=No Reaction, UN=Untestable. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x 
 


 
 
Statistical Analysis Plan 
Version Date: 2.0  April 19, 2014 
 
Protocol No. BHR-100-301 
 
Page 213 of 213 
 
 
Listing 16.2.8.6 Neuroworsening – Part 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At Time of Neurologic Worsening 
 
Treatment 
Group 
Subject 
No. 
Sex/ 
Age/ 
Race1 
Start 
Date/ 
Time 
Eye Opening2 
(none due to 
severe facial 
swelling/damage) 
Verbal 
Response3 
(none due 
to 
intubation) 
Motor  
Response4 
Right  
Pupil  
React-
ivity 
Left  
Pupil  
React-
ivity 
ICP(mmHg)/ 
SBP (mmHg)/ 
DBP (mmHg) 
Primary Reason  
for Deterioration 
(If Other, Specify) 
 
 
 
 
 
 
 
 
 
 
 
BHR-100 
xx-xxx 
M/30/W DDMONYYYY/ 
XX:XX 
(SPON,  
SPEECH,  
PAIN,  
NONE) 
 
(no, yes) 
(O,  
C,  
INAPP, 
INCOMP,  
NONE) 
 
(yes, no) 
(OC,  
LP,  
WNF,  
ABF,  
ABE,  
NONE) 
(R, 
NR, 
UN) 
(R, 
NR, 
UN) 
xxx/ 
xxx/ 
xxx 
(Increased 
Intracranial Volume, 
Cerebral Ischemia, 
Seizures, Systemic 
Complication, Other 
[xxxxxxxxxxxxxxxxx]) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 M = Male, F = Female; W = White, B = Black or African American, P = Native Hawaiian or Other Pacific Islander, A = Asian, N = American 
Indian or Alaska Native, O = Other. 
2 SPON=Spontaneous, SPEECH=In response to speech, PAIN=In response to pain, NONE=None. 
3 O=Oriented, C=Confused, INAPP=Inappropriate words, INCOM=Incomprehensible sounds, NONE=None. 
4 OC=Obeys Commands, LP=Localizes Pain, WNF=Withdrawal/Normal flexion, ABF=Abnormal flexion, ABE=Abnormal Extension, NONE=None. 
5 R=Reacts, NR=No Reaction, UN=Untestable. 
 
Program: xxxxxxx.sas, Output: xxxxxxx.rtf, Generated on: DDMONYYYY xx:xx, Page x of x