A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study to Investigate the Efficacy and Safety of Progesterone in Patients With Severe Traumatic Brain Injury
Phase: PHASE3
Conditions: Brain Injuries
Sponsor: BHR Pharma, LLC



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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
Subjects who do not complete the study for any reason will not be replaced.

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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.

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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.

Progesterone in Patients with Severe Traumatic Brain Injury
BHR Pharma, LLC
Page 47 of 53
Amendment 3
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).
139(4), 286-294.
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.

Progesterone in Patients with Severe Traumatic Brain Injury
BHR Pharma, LLC
Page 48 of 53
Amendment 3
November 15, 2011
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,
S287-292.
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
(Methodological), 42, 109–142.
McHorney, C.A., Ware, J.E., Jr, & Raczek, A.E. (1993). The MOS 36-Item Short-Form
Health Survey (SF-36): II. Psychometric and clinical tests of validity in measuring physical
and mental health constructs. Med. Care.,31, 247-263.
Murray, G.D., Barer, D., Choi, S., et al. (2005). Design and analysis of phase III trials with
ordered outcome scales: the concept of the sliding dichotomy. J. Neurotrauma., 22(5), 511-
517.
O’Brien, P.C., Fleming, T.R. (1979). A multiple testing procedure for clinical trials.
Biometrics, 35, 549-556.
Pettus, E.H., Wright, D.W., Stein, D.G., and Hoffman, S.W. (2005). Progesterone treatment
inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res., 1049,
112-9.
Roof, R.L., Duvdevani R., and Stein, D.G. (1993). Gender influences outcome of brain
injury: Progesterone plays a protective role. Brain Res., 607, 333-336.
Roof, R.L., Duvdevani R., Heyburn, J.W., and Stein, D.G. (1996). Progesterone rapidly
decreases brain edema: treatment delayed up to 24 hours is still effective. Exp. Neurol., 138,
246-251.
Roof, R.L., Duvdevani, R., Braswell, L., and Stein, D.G. (1994). Progesterone facilitates
cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury
in male rats. Exp. Neurol., 129, 64-69.
Roof, R.L., Hall, E.D. (2000). Gender differences in acute CNS trauma and stroke:
neuroprotective effects of estrogen and progesterone. J. Neurotrauma, 17(5), 367-388.
Roof, R.L., Hoffman, S.W., Stein, D.G. (1997). Progesterone protects against lipid
peroxidation following traumatic brain injury in rats. Mol. Chem. Neuropathol., 31(1), 1-
11.
Sayeed, I., Wali, B., Stein, D.G. (2007). Progesterone inhibits ischemic brain injury in a rat
model of permanent middle cerebral artery occlusion. Restor. Neurol. Neurosci., 25(2), 151-
159.

Progesterone in Patients with Severe Traumatic Brain Injury
BHR Pharma, LLC
Page 49 of 53
Amendment 3
November 15, 2011
Shear, D.A., Galani, R., Hoffman, S.W., and Stein, D.G. (2002). Progesterone protects
against necrotic damage and behavioral abnormalities caused by traumatic brain injury.
Exp. Neurol., 178, 59-67.
Stein, D.G. (2005). The case for progesterone. Ann. N. Y. Acad. Sci., 1052, 152-169.
Stein, D.G. (2008). Progesterone exerts neuroprotective effects after brain injury. Brain Res.
Rev., 57, 386-397.
Tagliaferri, F., Compagnone, C., Korsic, M., Servadei, F., & Kraus, J. (2006). A systematic
review of brain injury epidemiology in Europe. Acta Neurochirurgica, 148(3), 255-268.
Teasdale, G., and Jennett, B. (1974). Assessment of coma and impaired consciousness. A
practical scale. Lancet, 2(7872), 81-84.
Teasdale, G.M., Pettigrew, L.E., Wilson, J.T., Murray, G., Jennett, B. (1998). Analyzing
outcome of treatment of severe head injury: a review and update on advancing the use of
the Glasgow Outcome Scale. J. Neurotrauma, 15(8), 587-597.
VanLandingham, J.W., Cekic, M., Cutler, S., Hoffman, S.W., and Stein, D.G. (2007).
Neurosteroids reduce inflammation after TBI through CD55 induction. Neurosci Lett.,
425(2), 94-98.
Ware, J.E., Jr, and Sherbourne, C.D. (1992). The MOS 36-item short-form health survey
(SF-36). I. Conceptual framework and item selection. Med. Care. 30, 473-483.
Whitehead, J. (1993). Sample size calculations for ordered categorical data. Statistics in
Medicine, 12, 2257-2271.
Wilson, J.T., Pettigrew, L.E., Teasdale, G.M. (1998). Structured interviews for the Glasgow
Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. J.
Neurotrauma, 15(8), 573-585.
Wright, D.W., Bauer, M.E., Hoffman, S.W., and Stein, D.G. (2001). Serum progesterone
levels correlate with decreased cerebral edema after traumatic brain injury in male rats. J.
Neurotrauma, 18, 901-909.
Wright, D.W., Kellermann, A.L., Hertzberg, V.S., Clark, P.L., Frankel, M., Goldstein, F.C.,
et al. (2007). ProTECT: A randomized clinical trial of progesterone for acute traumatic
brain injury. Ann. Emerg. Med., 49,391-402.
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
infusion in patients with acute moderate to server traumatic brain injury. J. Clin.
Pharmacol., 45,640-648.

Progesterone in Patients with Severe Traumatic Brain Injury
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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,
64(5), 1313-1319.
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
randomized controlled trial. Crit. Care., 12, R61.
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