Conditions: Concussion, Brain Traumatic Brain Injury
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 23
Healthy volunteers: no

Brief summary:
Concussions are the leading form of mild traumatic brain injury. Management of concussions and mild traumatic brain injury is a high priority medical focus, social concern, and research topic. Currently, there are no FDA approved treatments for acute concussion. The current standard of care is rest followed by gradual return to normal activity. The purpose of this study is to show improvement in the way patients feel or function after a concussion.

OXE-103 is a protein hormone produced in the laboratory which identical to the hormone ghrelin that is secreted by the stomach. This study will investigate the use of this hormone as treatment for symptoms of acute concussion. The goal of this study is to show improvement in the way study participants feel or function after concussion.

An OXE-103 (ghrelin) agonist is already FDA approved for another condition, but not for concussion. For concussion, it is considered investigational.

This study will examine, if ghrelin is taken every day for two weeks, if the brain will heal faster and help improve or resolve symptoms. The study will also include a placebo arm and a non-treatment group (for those who wish to participate but do not want to receive any treatment). The OXE-103 and placebo will be self-administered through injections using needles.

Detailed description:
All consenting participants will be screened for eligibility.

The study does not include randomization and all enrolling subjects will be offered treatment with OXE-103. Enrolling subjects will also have the option to choose participation in a non-treatment control group if they do not want treatment.

Consenting participants must be willing to commit to the following:

* give themselves subcutaneous injections twice a day (for the treatment groups)
* attend several study visits, which require both in-person and phone-only visits
* complete various questionnaires and testing
* have blood drawn
* have ECG's performed
* undergo a pregnancy test (if of childbearing potential) and use contraception while on study (for the treatment groups)
* tell the study team about any side effects they might experience from the study drug during study participation

Total participation will last about 7 weeks, which includes screening, 14 days of taking the study drug, and 4 weeks of follow-up. Participation for the non-treatment group will last the same amount of time.

Arms:
arm 1: Placebo (40ug/kg) will be self-administered twice daily for 14 days.

ONLY THE PART B (ACUTE) SUBJECTS WILL BE RANDOMIZED AND MAY RECEIVE PLACEBO. arm 2: OXE-103 (40ug/kg) will be self-administered twice daily for 14 days.

PART A (POST-ACUTE) SUBJECTS WILL BE OFFERED EXPERIMENTAL TREATMENT WITHOUT RANDOMIZATION.

PART B (ACUTE) SUBJECTS WILL BE DOUBLE-BLIND RANDOMIZED TO EXPERIMENTAL OR PLACEBO TREATMENT.

Interventions: intervention 1: Ghrelin (OXE-103) intervention 2: Placebo
Intervention descriptions: intervention 1: 40ug/kg twice daily by self-injection intervention 2: 40ug/kg twice daily by self-injection

Protocol document:
Prot_000.pdf: 
Protocol v.1.7 
Ghrelin (OXE--103) for Acute Concussion Management 
NCT04558346 
March 28, 2021 
 
 


Protocol v.1.7 
2 
 
Summary of Changes and Rationale  
The List of Changes table below lists modifications to the current protocol (as per amendment 
1.6). 
List of Changes – Amendment 1.7 
Page(s) 
Modification(s) 
1-2 
Intro – Summary of the Changes and Rationale of modifications 
 
 
12 
 
 
12 
 
 
10-11 
Proposed Clinical Trial 
• For Part B change start of treatment criteria from 24 hours from time of 
injury to within 24 hours of presentation to Trauma Unit.  
• Modify Part A to an open-label treatment arm (OXE-103) compared to a 
non-treatment concurrent control arm. Maintain Part B randomized and 
blinded, OXE-103 versus placebo. 
• Added flowsheets depicting Day 1 study activities for both Parts A & B 
(including the two arms of Part A: open-label treatment and non-
treatment concurrent control). 
 
13 
 
 
 
 
 
 
 
13 
Specific Aim 1 
• The Part A open-label treatment arm will enroll up to 30 participants but 
will stop recruiting when Part A has 20 participants who complete the 
study. 
• The Part A non-treatment concurrent control arm will enroll a minimum of 
20 participants who complete the study but may continue to recruit 
beyond 20 while the open-label arm is still recruiting.  
Specific Aims 1-4 
• Corrects use of terms Day 14 to Day 15 and Day 45 to Day 44.  This 
reflects the visits as listed on the Schedule of Events. 
 
 
14 
 
15 
 
 
 
 
 
 
 
16 
Inclusion/Exclusion 
• Increase the upper limit for age to 60-years-old from 55-years-old. 
• The seven-day screening period for Part A has been removed.  Part A 
participation, including study drug treatment, now begins on Day 1. The 
removed screening period occurred from Days -7 to 1.   
For clarity there is no screening period for the Part B acute study; 
participation already begins on Day 1.   
• Removes gamma-glutamyl transferase lab exclusion criteria, because 
this lab is not available as part of the UKHS standard chemistry panel. 
• Allows for procedures/labs performed prior to study participation as part 
of subject’s normal care to be used for study. 
 
 
15 
 
Study Procedures 
• Restatement of change for Part A from randomization to OXE-103 or 
placebo to open-label treatment with OXE-103 and a non-treatment 


Protocol v.1.7 
3 
 
 
15-16 
 
 
 
 
 
 
17 
 
17 
 
 
16 
 
 
16 
 
17 
concurrent control arm. 
• Revision of recruitment goals for Part A.  Previously it was 40 for Part A 
and 40 for Part B, with a maximum of 50 subjects in each Part.  Now, 
Part A is revised to have a target of 30 for the treatment Arm (Arm 1) and 
20 for the non-treatment Arm (Arm 2), with opportunities for additional 
Arm 2 enrollment.  The maximum for Part A Arm 1and Part B combined 
is 80 subjects.    
• Modified the visit schedule language to allow for the Part A Arm 2 non-
treatment subjects’ schedule.  
• Study visits for the Part A non-treatment concurrent control group not 
requiring correlative lab draws or study equipment return may be 
conducted via telemedicine at the discretion of the Principal Investigator.  
• Removal of the seven-day screening period and adjusted language to 
reflect that activities for both Parts start on Day 1. 
• Removal of required abstinence from other mTBI treatments and 
therapies during study participation. 
• Removal of safety monitoring language for Part A non-treatment Arm. 
 
18 
Cardiovascular and Respiratory Risk - ECG recording will not be collected for 
the Part A non-treatment concurrent control arm. 
 
19 
Laboratory & Endocrine Risks  
• 
Laboratory testing for safety will not be required for participants in the 
Part A non-treatment concurrent control arm, however, correlative lab 
collection for this arm will occur on Days 1 and 15.  
• 
Removal of gamma-glutamyl transferase lab language (lab not available 
as part of the UKHS standard chemistry panel. 
 
18 
Contraception and Women of Childbearing Potential – Adds language to 
allow for serum pregnancy testing.  Due to laboratory testing limitations, this 
change was required. 
 
23-25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
24 
Schedule of Events 
• 
Study table has been modified to eliminate the Part A  screening period, 
add relevant evaluations to Day 1, and to separate out Part A Arms to 
clarify that safety monitoring activities will not be done on Part A non-
treatment Arm 2 (includes adverse event recording, lab testing, and 
ECG’s). 
• 
Adds reference that both serum and urine pregnancy tests are allowed. 
• 
Adds clarification to footnote language regarding assessments and 
questionnaires done on Days 1 and 8 are to be done prior to dispensing 
drug.  This allows for dosing of drug by subjects prior to study visit on 
Day 8. 
• 
Clarifies that clinically significant abnormal labs will be repeated until 
normalized to allow for lab values that may present as abnormal but not 
clinically significant. 
• 
Adds reference to remote or in-person clinic visits for the Part A Arm 2 
non-treatment group for visits Days 8 and 21. 


Protocol v.1.7 
4 
• 
Clarifies that correlative labs collected includes biomarkers. 
 
 
19 
19 
 
 
20 
Outcomes & Study Tools 
• 
Removal of screening period language for Part A. 
• 
Added for clarity that language applies to both acute and sub-acute 
concussions. 
• 
Corrects visit dates for BrainCheck testing to match what was previously 
listed in the Schedule of Events. 
21 
Statistical Analysis—Removes reference to baseline visit for emphasis that 
there is not a screening period. 
 
 


Protocol v.1.7 
5 
 Ghrelin (OXE--103) for acute concussion management 
 
HSC #: 145983 
 
Site Investigators: Michael Rippee (PI), Jeff Radel (Co-I), Suzanne Hunt (Co-I), David Smith 
(Co-I), Robert Winfield (Co-I) 
 
Summary:  
 
Ghrelin is a naturally occurring hormonal peptide with extensive preclinical and clinical 
safety data to supporting the safety of OXE-103 for studies in patients with concussion/m 
TBI.  In addition, Ghrelin has been shown in many preclinical and clinical studies to 
potentially target many different areas of concussive injury including energy regulation, 
inflammation, and axonal connectivity.  There have been no clinical studies looking at 
ghrelin as treatment for acute concussion.  If there are indeed benefits, the societal 
impact could be huge. 
 
Overview 
Management of concussions and mild traumatic brain injury is a high priority medical focus, 
social concern, and research topic.  Currently, there are no FDA approved treatments for acute 
concussion.  Current standard of care starts with cognitive rest followed by a gradual return to 
normal activity as symptoms abate.  We will investigate use of the hormone ghrelin (OXE-103) 
as treatment for symptoms of acute concussion.  Our initial goal is to show improvement in the 
way patients feel or function via assessment of post-concussion related symptoms.  We expect 
the findings from this pilot to support larger Phase II studies of efficacy for symptom 
management, and potential treatment of underlying neurologic injury. 
 
Oxeia Biopharma Inc. will donate the drug supply for this study. The clinical safety, product 
characterization and manufacturing information presented herein has been extracted from an 
open FDA IND on OXE-103. The open IND will be cross referenced for regulatory submissions 
prepared for this study. 
 
A. Background & Rationale 
 
Introduction: 
Concussions are the leading form of mild traumatic brain injury.  The CDC reported the U.S. 
population sustains 1.7 million concussions annually and although underreported by as much as 
80% the annual rate of concussion has more than doubled in the past decade [1]. There are 
currently no evidence-based treatments for concussion.  The current standard of care is 
cognitive rest followed by gradual return to normal activity.  Treatment is based on symptom 
management, which has varying efficacy, while waiting for the underlying injury to repair itself. 
 
Pharmacology and Mechanism of Action:  
At the neuronal level, a concussion causes a well-established neurometabolic cascade.  Brain 
injury results in a massive efflux of potassium out of the neuron and an influx of calcium into the 
neuron.  At the same time, there is a depolarization event that results in release of glutamate.  
This glutamate then causes toxicity to surrounding neurons.  Meanwhile the injured neuron tries 
to achieve homeostasis by pumping calcium out of the cell and co-transporting potassium into 
the cell.  These events result in expenditure of energy--glucose in the form of ATP.  This results 


Protocol v.1.7 
6 
in an energy crisis.  Mitochondrial respiration is disrupted and formation of ATP is impaired.  
This leads to oxidative stress (Reactive Oxygen Species--ROS) and inflammation.  The direct 
injury also causes disrupted axonal transport, swelling, and reduces neuronal connectivity [2].  
 
OXE-103 is a 28 amino-acid polypeptide hormone produced semi-synthetically and is identical 
to endogenous ghrelin secreted by the stomach.  It is also secreted by the hypothalamus and 
possibly other brain regions [3].  Ghrelin binds to the growth hormone secretagogue receptor 
(GHSR-1a) and is the only known peripherally-produced orexigenic hormone.  The amino acid 
sequences of ghrelins are well conserved across species, indicative of its biological importance. 
The physiological and pharmacological effects of ghrelin are thought to be diverse, pleiotropic 
and complex, including growth hormone secretion, appetite stimulation, regulation of energy 
balance, acceleration of gastric emptying, stimulation of gastrointestinal motility, 
neuroprotection, and regulation of the immune system, as well as regulation of the 
cardiovascular system [4].  Of direct relevance to this study, ghrelin directly impacts the 
neurometabolic cascade by increasing glucose availability, increasing mitochondrial ATP, and 
decreasing ROS by uncoupling protein 2 (UCP-2) pathway.  It increases axonal potentiation and 
synaptic number thereby increasing axonal connectivity [5]. Recent nonclinical studies of ghrelin 
as a neuroprotective intervention in several central nervous system models report increased 
mitochondrial respiration and synaptic density; and reduced ROS, inflammation, and tau protein 
phosphorylation.  
 
Ghrelin activates the AMPK pathway.  AMPK turns on ATP producing pathways and increases 
mitochondrial biogenesis.  The binding of ghrelin to the GHSR-1 receptor increases 
mitochondrial membrane protein UCP-2 expression. UCP-2 directly “uncouples” oxidative 
phosphorylation thereby decreasing ROS generation, and increases mitochondrial generation 
and respiration [5]. Ghrelin increases mitochondrial respiration and decreases ROS [4]. 
 
UCP2 and GHSR-1 knockout model studies have separately reported UCP2 overexpression as 
neuroprotective [6], and enhanced mitochondrial respiration and reduction in reactive oxygen 
species after ghrelin administration to be UCP-2 dependent [5]. Furthermore, ghrelin directly 
increases the synaptic density of the hippocampus [5], which is particularly sensitive to volume 
loss after concussion/mTBI in an athletic population [7]. Improved memory and neurocognition 
are also observed with ghrelin treatment [8]. Taken together, ghrelin’s effects are specifically 
relevant to limiting post concussive metabolic impairment and its consequential neurotoxicity.  
 
An observational human study has also identified a positive correlation between acute serum 
ghrelin levels and measures of improved neurocognitive function after concussion. In the study, 
118 patients presenting to a large research hospital were included based on concussion 
diagnosis and followed for 90 days. All patients underwent blood collection at Day 0, 1 and 2 
following enrollment and serum samples were retained for subsequent analysis. Neurocognitive 
testing including memory, reaction time, visual tracking and attention was conducted. Day 90 
neurocognitive scores were used to distinguish patients into better and worse performing 
cohorts. Out of eight endogenous hormones analyzed, only ghrelin was shown to be an 
independent predictor of three-month cognitive outcome. Patients with higher endogenous 
ghrelin levels were less likely to have cognitive impairment compared to those patients with 
lower endogenous ghrelin levels based on ROC analysis (AUC = 0.904, p < 0.001) [5].  
 
These clinical and nonclinical reports of ghrelin’s effects support its potential as a novel 
neuroprotective treatment when administered following acute concussion/mTBI.  
The neuroprotective effects of ghrelin were recently observed in TBI mice models using a 
controlled weight drop apparatus. Acute intraperitoneal (IP) ghrelin administration (10 μg ghrelin 


Protocol v.1.7 
7 
per dose), twice on the day of injury result in significantly higher UCP-2 levels, less loss of brain 
volume 7 days following injury (p<0.05), significantly less apoptosis in the neurocortex and 
hippocampus, decreased invasion of inflammatory cells, and, significantly, with respect to 
potential beneficial effects in clinical trials, improved motor function up to 7 days after injury 
(p<0.001) [9, 10]. Furthermore, the neuroprotective action of ghrelin in TBI is dependent on 
binding to the GHSR-1 receptor [11].  
 
In a mouse model of TBI using a controlled cortical impactor with standardized settings for 
milder injury [12], subcutaneous ghrelin administration (10 μg ghrelin per dose) at 10 minutes 
and one hour after injury significantly reduced ROS. Animals (n = 5 per group, 3 groups) were 
sacrificed 24 hours after injury and whole brain ROS was assessed by a flow cytometer 
oxidative burst assay. Treatment with ghrelin significantly decreased oxidative burst as 
compared to sham and vehicle treated groups (p<0.05). HOCL formation (myeloperoxidase 
staining) and neutrophil infiltration (Gr-1 staining) in the hippocampus were also notably reduced 
versus sham and vehicle treated groups [13].  
 
OXE-103 neuroprotective activity has been demonstrated in commonly used animal model for 
ALS (transgenic mice that overexpress the mutant human superoxide dismutase 1 [SOD1] gene 
(SOD1G93A mice) [14, 15]. In this model, the number of motor neurons was assessed after 7 
weeks of OXE-103 treatment (50 μg/day, SC infusion) from 10 weeks of age. The number of 
motor neurons in sections of the spinal cord was significantly higher in the OXE-103 treated 
group when compared with the vehicle treated group, indicating that OXE-103 protected against 
degeneration of motor neurons in the spinal cord of SOD1G93A mice. 
 
GLP Safety and Toxicology: Extensive preclinical GLP toxicology and safety studies have 
been conducted by Daiichi Sankyo. Single dose repeat dose (13, 26, and 39 weeks), 
genotoxicity, reproductive toxicology and developmental toxicology studies have been 
conducted across rats, monkeys, and rabbits (see Appendix 1). 
 
Clinical Safety: 
The safety, tolerability and pharmacokinetics of OXE-103 has been evaluated in 9 clinical 
studies, with IV and SC routes of administration. This includes 6 studies with OXE-103 
administered as either an IV bolus or IV infusion and 4 studies using SC injection.  The 
safety of OXE-103 administered SC has been evaluated with doses up to 80 µg/kg/day in 
205 subjects and the safety of IV administered OXE-103 has been evaluated with doses up 
to 8 µg/kg/day in 139 subjects. OXE-103 has been reported to be well tolerated in higher 
doses and for longer durations, relative to the dose and duration of OXE-103 in the proposed 
clinical trial. The observations made in clinical trials conducted thus far support the proposed 
dose of 40 µg/kg bid for 14 days in this clinical study. All clinical trial information is included 
in the open IND at the FDA (see Appendix 1). 
 
Drug Interactions: 
No significant drug interactions with agents used in neurologic intensive care units have been 
identified for OXE-103. 
 
P1 Data, Pharmacodynamics, Pharmacokinetics, Dose Selection: 
A Phase 1 safety and PK study in 50 healthy male and female volunteers has been conducted 
via both intravenous and subcutaneous routes of administration at several doses. 
Pharmacodynamic markers included Growth Hormone (GH), ACTH, cortisol, prolactin, glucose, 
and insulin. Ghrelin was shown to have a benign safety profile for both routes of administration. 


Protocol v.1.7 
8 
Exposure increased in a dose-related manner for IV and SC dosing. The most direct PD marker, 
GH, was dose related and demonstrated maximal levels between 20-45ug/kg which indicated 
saturation of ghrelin receptors. These data inform dosing levels that are metabolically active and 
are supported by preclinical dosing levels from neurometabolic as well as neurogenic models. 
 
Safety Concern 
Safety Data 
ECG 
Investigator’s Brochure 
4.1.2.2 Effects on the Cardiovascular and Respiratory Systems:  
Continuous IV infusion of OXE103 (up to 1000 µg/kg/hr) in 
conscious, unrestrained monkeys resulted in a transient increase 
and then decrease in blood pressure in 1 of the 4 monkeys 
evaluated. None of the animals had changes in heart rate, ECG 
parameters, respiratory rate, arterial blood pH, blood gas tensions, 
hemoglobin oxygen saturation, body temperature or clinical signs. 
Table 5.9 Summary of Safety Results from Phase 2 studies with SC 
Treatment of OXE103:  
12-lead ECGs:  
no clinically meaningful changes in ECG in Study ASBI303 (n=6), 
ASBI304 (n=17), and ASBI307 (n=151) 
Complete blood count, 
metabolic panel, coagulation 
panel 
Investigator’s Brochure 
 
Table 8.8 Summary Tables For Clinical Studies:  
Japan Phase 1 NA 1401 (n=42):  
No SAEs reported. The TEAEs, regardless of causality, occurring in >1 
subject from any individual treatment group or from combining the 
OXE103 treatment groups were clinical TEAEs of feeling hot, hot 
flush, and sweaty; chemistry and urine laboratory TEAEs included 
bilirubin total increased, creatinine decreased, HDL C decreased, 
LDH decreased, indirect bilirubin increased, urate increased, protein 
total decreased, urine WBC increased, and urine ketone body 
present; complete blood count TEAEs included lymphocyte 
percentage decreased, neutrophil percentage increased, WBC count 
decreased, and WBC count increased. Single IV administration of 
OXE103 up to 8.0 µg/kg was generally well tolerated. 
 


Protocol v.1.7 
9 
Safety Concern 
Safety Data 
5.4.2.9:   
Clinical Laboratory Evaluations: 
In ASBI 303(n=6), there were no laboratory abnormalities 
reported as TEAEs.  
In ASBI 304 (n = 17), the hematology, serum chemistry, 
urinalysis, and coagulation results were unremarkable. 
Table 5.9 Summary of Safety Results from Phase 2 studies with SC 
Treatment of OXE103  
Assessment of laboratory tests (hematology, chemistry, urinalysis, 
and coagulation): There were no clinically meaningful changes from 
baseline at any visit in the active treatment groups compared to 
placebo for any of the hematology, chemistry, urinalysis. Study 
ASBI303 (n=6), ASBI304 (n=17), and ASBI307 (n=151) 
Pregnancy in females of 
childbearing potential 
OXE-103 is a polypeptide composed of 28 amino acid residues 
produced semi-synthetically and is structurally identical to the 
human endogenous ghrelin.  According to data derived from 
reproductive toxicity studies summarized in the OXE-103 
Investigator’s Brochure:  
Section 1.4 Nonclinical Toxicology (paragraph 5) 
No effects were observed on fertility in rats, on reproductive function 
in parental rats and maternal rabbits, or on embryo-fetal 
development in rats or rabbits by IV administration. In addition, no 
effects were observed on maternal rabbits and on embryo-fetal 
development in rabbits by SC administration. In an IV-dose study on 
pre- and postnatal development including maternal function in rats, 
a tendency to increase in body weights of live newborns was noted 
at 300 μg/kg/day or more as pharmacological effects of OXE103. 
 
The complete toxicology reports can be found under Oxeia’s existing 
IND (120694). 
Other labs related to ghrelin 
(including possibly growth 
hormone, insulin, ICF-1, ACTH, 
cortisol and prolactin) 
Investigator’s Brochure: 
5.3 Clinical Pharmacology:  
Serial blood samples were obtained for pharmacokinetic and 
pharmacodynamic evaluations of ghrelin, desacyl-ghrelin, growth 
hormone (GH) and insulin growth factor-1 (IGF-1) in 6 of the 9 studies 


Protocol v.1.7 
10
Safety Concern 
Safety Data 
(ASBI 301 (n=6), ASBI 303 (n=6), ASBI 304 (n=17), NA 1401(n=42), NA 
1501(n=12) and NA 1502 (n=6). 
 
Additional data from studies referenced in 5.3 above: 
In addition to the data referenced above, serum samples for GH and 
IGF-1 was also assessed in ASBI 307 n=142. Additional PD markers not 
mentioned above were also assayed across the 9 studies include: 
prolactin n=72, ACTH n=72, cortisol n=214, catecholamines n=89, 
insulin n=89, glucose n=225, A1C n=159, FSH n=12, LH n=12, CRP 
n=165, NT-proBNP n=6, IL-6 n=159, IL-1B n=17, TNF n=159. 
 
GH consistently increased proportional to the dose of OXE103; IGF-1, 
prolactin, and ACTH either showed increases which returned to 
baseline within 3 hours of dosing or showed no difference to placebo; 
the remaining PD markers showed no changes attributed to 
administration of OXE103. 
 
The conclusions across the 9 studies were that no safety issues related 
to these biomarkers and the administration of OXE103 was observed. 
 
5.4.2.1 Overall safety Evaluation: 
glucose tolerance testing was done in studies ASBI 304 (n=17) and 
ASBI 307 (n= 151) since it has been reported that ghrelin can suppress 
insulin release and cause insulin resistance [Garin et al. 2013]. No 
obvious relationship was observed between 2-hour postload value 
from OGTT (mmol/L; Day 8) and predicted AUCss (pg·h/mL; Day 85) 
of OXE103. 
 
 
Appendix 1: Tabular Summaries of OXE103 NonClinical 
Studies:  
GH Secretion, Non-GLP, Study PBC 79-44 (n=4M): OXE103 
did not significantly increase plasma prolactin and ACTH 
concentrations 


Protocol v.1.7 
11
Safety Concern 
Safety Data 
 Published Studies  
There is extensive published literature on over 100 clinical studies 
administering ghrelin via intravenous infusion or bolus. The patient 
populations in these studies include:  Healthy, 
obese, gastrectomy, cancer, hypopituitarism, metabolic  
syndrome/diabetes, anorexia nervosa/ bulimia nervosa,  
pulmonary disease, gastroparesis, hyperthyroid, renal disease,  heart 
failure, cushing’s syndrome, PCOS, functional dyspepsia, acromegaly, 
hyperparathyroid, osteoarthritis, and major depression disorder. 
Garin et.al 2013 (reference supplied upon request). 
 
These studies support the benign safety profile of OXE103 and are 
consistent with data generated in the Phase 1 and Phase 2 clinical 
studies.  
 
 
 


Protocol v.1.7 
12
PART A: POST-ACUTE DAY 1 
 
Subjects are presented with study drug (OXE-103) treatment.  If they decline, they will be 
offered participation in non-treatment control Arm.  If subjects choose treatment and fail screening, 
they may be offered non-treatment control Arm option. 
PART A ARM 1 = OXE-103 treatment 
PART A ARM 2 = Non-treatment concurrent control 
 
PI presents study drug participation to subject
Accepts
Informed 
Consent
Screening:
-review inclusion/exclusion
-PCSS (score must be >or= 20)
-labs: CBC, CMP, urine or serum pregnancy, correlative
-ECG
Screen Fail
Offered Non-Treatment 
Concurrent Control participation
Proceed to Study Assessments:
-medical history
-prior medications/therapy history
-physical exam
-neurological exam
-concomitant medications
-demographics
-body weight
-vital signs
-QOLIBRI, PGAS VAS, PHQ-9, BrainCheck
Proceed to Study Assessments:
-medical history
-prior medications/therapy history
-physical exam
-neurological exam
-concomitant medications
-demographics
-body weight
-vital signs
-QOLIBRI, PGAS VAS, PHQ-9, BrainCheck
Proceed with 
Randomization
Train subcutaneous 
injection
Administer Day 1 first dose
Declines
Offered Non-Treatment 
Concurrent Control participation
Informed 
Consent
Screening:
-review inclusion/exclusion
-PCSS (score must be >or= 20)
Proceed to Study Assessments:
-medical history
-prior medications/therapy history
-physical exam
-neurological exam
-concomitant medications
-demographics
-body weight
-vital signs
-PCSS, QOLIBRI, PGAS VAS, PHQ-9, BrainCheck
Proceed with Study Lab Draw:
-correlative lab


Protocol v.1.7 
13
PART B: ACUTE DAY 1 
 
Subjects choosing to participate in study are randomized to receive study drug (OXE-103) or 
placebo. 
PART B ARM 1 = OXE-103 
PART B ARM 2 = Placebo 
 
 
 
Informed Consent
Screening:
-review inclusion/exclusion
-PCSS (score must be >or= 20)
-labs: CBC, CMP, urine or serum pregnancy, correlative
-ECG
Screen Fail
Proceed to Study Assessments:
-medical history
-prior medications/therapy history
-physical exam
-neurological exam
-concomitant medications
-demographics
-body weight
-vital signs
-QOLIBRI, PGAS VAS, PHQ-9, BrainCheck
Proceed with Randomization
Train subcutaneous injection
Administer Day 1 first dose


Protocol v.1.7 
14
 
 
 
Regulatory: 
Oxeia’s license through Daiichi Sankyo includes cross-reference to an open IND at the FDA. In 
November 2017 Oxeia submitted a pre-IND briefing package for a proposed Phase 2 study. The 
FDA response supported moving into Phase 2. This study will be conducted under an 
investigator sponsored IND cross referencing the existing open FDA IND.   
 
Manufacturing, Partnerships, Current GMP Drug Supply: 
The company maintains access to clinical grade drug supply manufactured by Daiichi Sankyo, 
Ltd. for subcutaneous injection. Multiple lots have been produced and are available for clinical 
study use.  The drug product is manufactured in compliance with good manufacturing practice. 
It is supplied in a 5 mL clear, borosilicate glass vial with a butyl-rubber closure (fluoro-resin film 
laminated), as a sterile lyophilized white powder or cake equivalent to 14 mg of OXE-103 as the 
active ingredient and sucrose (inactive ingredient). Matching placebo and diluent product is also 
available.   
 
OXE-103 drug product, placebo, and diluent should be stored refrigerated between 2°C to 8°C 
(35.6°F to 46.4°F). Reconstituted OXE-103 for SC administration 14 mg (in 5 mL multi-use vials) 
is stable for up to 14 days at 10°C or for up to 3 days when stored at 25°C/1000 Lux. The 
reconstituted drug product (and placebo) should be stored refrigerated at 2°C to 8°C (35.6°F to 
46.4°F). 
 
Upon request from the study team, Oxeia Biopharmaceuticals will coordinate shipment of all 
necessary study drug product, placebo, and diluent to the study team.  Shipments will include all 
appropriate certificates of quality, as may be necessary for any FDA-related audits and 
submissions. 
 
 
 
Proposed Clinical Trial  
We propose a pilot study to treat 1) Sub-acute concussion with OXE-103 in Part A and 2) Acute 
concussion management with OXE-103 within 24 hours of presentation to the Trauma Unit in 
Part B.  For Part A, we will recruit subjects from the University of Kansas Health System Center 
for Concussion Management (CCM) clinics which include Neurology, Sports Medicine, and 
Neurosurgery/PM&R.  For Part B, we will recruit subjects from the University of Kansas Health 
System Trauma Unit.  In Part A we will compare an open-label treatment arm (OXE-103) to a 
non-treatment concurrent control arm.  Part B will be randomized double blind 1:1 to treatment 
with OXE-103 and placebo.  We will compare these using self-report symptom scoring, quality 
of life questionnaires, computerized cognitive testing assessing executive function, memory and 
processing speed, and accelerometer-based balance scoring.  The exploratory nature of this 
study is not powered to yield statistically significant outcomes, but will allow detection of trends 
within subjects and between groups, will support comparison with standard tests of 
neurocognitive functions, and will provide sample size estimates for future studies of people with 
persistent concussion related symptoms. 
 
This study is highly relevant clinically and uniquely suited to being conducted at the CCM.  It will 
be the first to test ghrelin as therapy for sub-acute concussion. 


Protocol v.1.7 
15
 
Specific Aims: 
 
1. Describe the change in symptom burden in sub-acute (Part A) and acute (Part B) 
concussion for the two groups. This aim defines our primary objective.  In Part A we will 
enroll a maximum of 30 subjects in the open-label treatment Arm (OXE-103) but will stop 
recruiting when that arm has 20 participants who have completed study requirements.  All 
Part A participants must be diagnosed with a concussion and experience persistent 
concussion symptoms  28 days post injury. The Part A non-treatment concurrent control 
Arm will enroll a minimum 20 participants who complete the study requirements, but may 
continue to recruit more than 20 participants while the Part A open-label treatment Arm is 
still recruiting.  In Part B we will enroll a maximum of 50 subjects but will stop recruiting after 
each arm (OXE-103 Arm and placebo Arm) has 20 participants who have completed the 
study requirements. In Part A subjects will receive OXE-103 open-label and in Part B we will 
randomize 1:1 to placebo versus OXE-103.  The Post-Concussion Symptom Score 
questionnaire (PCSS) will be used as an overall measure of symptom burden. The number 
of symptoms and severity at each time point are also measures of interest. In addition, 
subjects will be asked to identify and rank the 4 most bothersome symptoms. We 
hypothesize that changes in these most bothersome symptoms may have a higher 
correlation to improvement in quality of life. A visual comparison of change in the two groups 
will be made. We will consider a change of 20% to be clinically meaningful.  Our primary aim 
will describe the change in symptoms between day 1 and day 15. 
 
2. Describe the change in quality of life between the two groups.  This aim defines one of 
our secondary objectives.   To assess this, we will administer the Quality of Life after Brain 
Injury scale (QOLIBRI) and a Patient Global Assessment of Status (PGAS). A change of 
20% will be considered clinically meaningful.  Our primary objective with this aim will assess 
the change between days 1 and 15. 
 
3. Describe the correlation between the change in symptom burden and quality of life.  
This is an exploratory aim.  We hypothesize that improvement in symptom burden will 
correlate with improvement in quality of life measures.  This may be more evident in the 
correlation between the change in the 4 most bother symptoms and quality of life measures.  
This aim will describe this correlation between days 1 and 15. 
 
4. Describe changes between symptom burden and quality of life at different time 
points.  This is an exploratory aim.  We will collect data at days 21 and 44 to allow for 
comparisons at later time points.  This may be used to describe changes in these 
measurements at time points after administration of OXE-103.  It is hypothesized that the 
effects of OXE-103 are long standing and therefore worsening after administration should 
not occur.  We will have data to compare day 15 to days 21 and 44. 


Protocol v.1.7 
16
5. Describe changes in cognitive performance between the two groups.  This aim defines 
one of our secondary objectives.  Improvement in cognitive functioning could correlate with 
underlying improvement in neuronal function.  We will assess cognitive function with 
BrainCheck, a digital assessment tool, at specified intervals.  This tool is administered via 
iPad and can be administered in clinic with supervision by trial personnel as well as at home 
by the subject. 
 
Benefits/Risks of research 
Benefits: Currently rest is the initial treatment for concussion.  Therapies that can be prescribed 
later (there is no consensus as to when to start these—tends to range from a couple of weeks 
post-injury to a couple of months) include physical/vestibular therapy (but this takes time and 
may provoke symptoms initially), and symptomatic treatment of symptoms with medications.  
The effectiveness of these drugs to provide potential treatment of underlying neurometabolic 
changes versus purely symptomatic relief is unknown. Further, each medication comes with 
potential for adverse events.  Providing a safe treatment that is effective at reducing symptoms, 
increasing quality of life, and potentially providing treatment for underlying neurometabolic 
dysfunction would be innovative and change the current paradigm of concussion care. 
 
Risks: Previous studies have shown that OXE-103 is quite safe.  This study will help to confirm 
that safety profile in this clinical population.  Long term use of ghrelin can lead to increased 
appetite, weight gain, and adiposity [16].  However, we will mitigate that risk by using OXE-103 
for a short period and we will obtain weight measurements at regular intervals during drug 
treatment. 
 
Inclusion/Exclusion: 
Subjects will be both men and women, ages 18-60 years old, with a concussion resulting from a 
direct or indirect blow, rotation, or whiplash injury to the head or body.  For the purposes of this 
study, we will define diagnosis of concussion/mTBI as those who have met the criteria set forth 
in this classification schema [23]: 
 
 
*GCS=Glasgow Coma Scale; PTA=Post-Traumatic Amnesia; LOC=Loss of Consciousness 
 
However, as noted by the American Congress of Rehabilitation Medicine’s statement on the 
definition of mTBI, “Due to the lack of medical emergency, or the realities of certain medical 
systems, some patients may not have the above factors medically documented in the acute 
stage. In such cases, it is appropriate to consider symptomatology that, when linked to a 
traumatic head injury, can suggest the existence of a mild traumatic brain injury [24].  When 
available, the study team will use medical records to confirm a patient’s injury as an mTBI 
according to the schema above, however, if no records exist or are obtainable, clinical history 
and symptomatology will be used to confirm the diagnosis.  


Protocol v.1.7 
17
 
In Part A, subjects must be consented  28 days post injury.  In Part B, subjects must be 
consented, randomized, and start treatment within 24 hours of presentation to the Trauma Unit.  
 
Subjects in both Part A and B will have a symptom severity score of  20 at the time of 
randomization in order to reduce the expected degree (number and severity) of spontaneous 
symptom resolution prior to study completion.   
 
Subjects with pre-existing neurologic conditions other than mTBI (including cognitive 
dysfunction) will be excluded.   
Subjects with concurrent long bone fractures or orbital fractures will be excluded.  
Subjects receiving, or planning to receive, a continuous ketamine infusion while enrolled in 
study will be excluded. 
Subjects with these known endocrinological abnormalities at baseline will be excluded from 
study: diabetes mellitus, excess or deficiency of growth hormone, cortisol, or prolactin.  
Exclusion from study for any other endocrinological abnormalities or diagnoses existing at 
baseline are ultimately up to the discretion of the study physician. 
Significant abnormalities in serum creatinine (>2.5 mg/dL), or alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) >3 times the upper limit of normal, or bilirubin (>2.5 mg/dL) 
will exclude subjects from participation.   
Subjects with any abnormal findings noted on imaging, such as hemorrhage, will be 
excluded from the study.  Subjects who meet criteria for moderate or severe TBI will also be 
excluded. 
Subjects who are known to be pregnant will be excluded.  Subjects who do not agree to 
double-barrier contraception or abstinence (for female subjects of child-bearing potential or 
male subjects who are sexually active with a female of child-bearing potential) until the day 
following last dose (total of at least 5 half-lives) will be excluded. 
In Part A subjects receiving other concomitant medications, physical therapy, or other 
treatments related to their current mTBI will be eligible if they meet the inclusion criteria. 
Subjects (or household members) who are not able to inject themselves or the subject will be 
excluded.  Ultimately study subject participation will be at the discretion of the study physician. 
 
For both Part A and Part B, subjects are not allowed to be concurrently enrolled in another 
therapeutic intervention clinical trial while participating in this study.  Any subjects currently 
enrolled in such a separate therapeutic intervention clinical trial, for any condition, will be 
excluded from participating in this study.  For clarification, this does not include observational 
clinical trials or registries.  
 
Procedures and labs performed as part of the subject’s normal medical care (not for study) 
within one day prior to consent may be allowed to be used for study.  This includes items such 
as CBC, CMP, ECG, and pregnancy testing. 
 
Study Procedures: 
General study design: 


Protocol v.1.7 
18
We propose an open-label design for the sub-acute Part A. Arm 1 will receive OXE-103 and 
Arm 2 will be a non-treatment concurrent control. Both Arms of Part A will each have a target of 
20 subjects who will complete the study requirements. In Arm 1 (open-label treatment) an 
additional 10 subjects may be enrolled to replace any subjects that do not complete the study 
requirements. In the event that Arm 2 (non-treatment control) has reached its minimum target of 
20 completed subjects and Arm 1 (open-label treatment) is still recruiting, then Arm 2 may 
continue to enroll subjects until Arm 1 reaches its target enrollment. 
  
In Part B the design will be randomized, double-blinded, and placebo-controlled with Arm 1 
receiving OXE-103 and Arm 2 receiving placebo. The enrollment target will be 20 subjects 
receiving OXE-103 and 20 subjects receiving placebo. Up to 50 subjects may by enrolled in 
Arms 1 and 2 combined to allow for replacement of subjects who may not complete the study 
requirements.   
 
In Part A Arm 1 and Part B both Arms 1 & 2, the maximum enrollment will be 80 subjects. For 
the Part A Arm 2 (non-treatment concurrent control) the minimum target enrollment will be 20 
subjects, but there will be no maximum number.  
 
We will randomize using the REDCap database.  The database will be set up to share 
randomization allocation only with the statistician and Investigational Pharmacy.  All subjects will 
be consented and either begin treatment within 24 hours of presentation to the Trauma Unit (for 
Part B) or 28 days post-injury (for Part A).  For Part A, starting on Day 1, the treatment cohort 
(Arm 1) will receive OXE-103 40ug/kg twice daily by self-injection and the non-treatment control 
group (Arm 2) will begin their monitoring.  For Part B, on Day 1 (within 24 hours of being 
admitted into the Trauma Unit) the treatment Arm will receive OXE-103 40ug/kg SC twice daily 
by self-injection and the placebo Arm will receive a placebo injection SC twice daily.  OXE-103 
and placebo will be maintained and dispensed by Investigational Pharmacy.  Subjects will 
receive an 8-day supply of syringes pre-loaded with OXE-103 or placebo.  Each cohort 
receiving OXE-103 or placebo will receive the 2nd set of syringes with OXE-103 or placebo at 
the Day 8 visit. Appropriate therapy that would be considered standard of care by the Principal 
Investigator or Co-Investigator will be administered or prescribed at any time during subjects’ 
study participation.  
 
Subject training 
Subjects will be provided with instructions for SC self-administration of OXE-103 and placebo. 
Subjects will be trained to inject themselves and need to demonstrate competency by self-
administering the first dose of the study drug at the study site. Alternatively, if a subject is 
accompanied by a reliable and willing household member, that individual will be trained to 
administer study drug to the subject and will be required to demonstrate competency at the 
study site. If neither self-administration nor administration by a household member is feasible 
the subject will be deemed ineligible to participate. Subjects will also be instructed on storage of 
the drug/placebo according to the parameters. A study team member will document the storage 
location for each subject enrolled.  Subjects will be asked to inject the first daily dose in the 
morning, after eating.  The second dose will occur in the evening, again after eating. The study 
team may provide  injection diaries to subjects in order to document dosing. 
 
Recruitment: 
Subject recruitment for Part A will take place among patients seen in Dr. Rippee’s Center for 
Concussion Management (CCM) clinic located at The University of Kansas Health System 
(TUKHS), Landon Center on Aging, Department of Neurology. Subject recruitment for Part B will 
take place among patients seen by the TUKHS Trauma team.   Patients meeting the study’s 


Protocol v.1.7 
19
inclusion/exclusion criteria will be invited  to participate in the study. If they are interested, a 
study team member will meet with the patient to discuss the study in more detail. Informed 
consent will be sought; when obtained, subjects will be screened for study risks and other 
exclusion criteria. Subjects enrolled in Part B of the study by the Trauma team will be followed 
after discharge from the hospital in Dr Rippee’s clinic; the remainder of their study visits will be 
completed with Dr. Rippee in his ambulatory clinic.  Part A Arm 1 (non-treatment control) study 
visits may be conducted via telemedicine at the discretion of the Principal Investigator, Dr 
Rippee, with the exception of Study Days 1 and 15 when correlative labs will need to be drawn, 
and Day 44 when study iPads will need to be returned to the study team. 
 
In the event that subjects are enrolled by the Trauma team into Part B while having an inpatient 
status at TUKHS, the study team, Investigational Pharmacy, and the medical team will work 
together to dispense, store, and administer the study medication.  The study team will continue 
to work with the Investigational Pharmacy and medical team, as appropriate, for the duration of 
the subject’s inpatient status while on study, as necessary to comply with this protocol.   
 
Attrition: This is a pilot study and no previous data exists as a basis to estimate attrition for this 
study. Any study participant who withdraws consent or is removed from Part A or Part B of the 
study during the 28-day trial period or does not successfully complete the protocol required 14 
days of dosing may be replaced to allow for 40 subjects who complete the protocol.  
 
Target Duration: The target duration of the treatment intervention with OXE-103 will be two 
weeks. The total involvement in the study including screening and follow up assessments will be 
8 weeks. 
 
Adverse Events: Oxeia, the supplier to the study team of the OXE-103 and placebo, performs 
and submits safety reports to the FDA under a separate IND.  As OXE-103 has already 
undergone safety testing and the safety profile is known, the adverse events associated with 
OXE-103 are included in an Investigator’s Brochure written by Oxeia Biopharmaceuticals.  For 
the purposes of this study, the study team will collect all adverse events reported by subjects 
including SAEs and TEAEs regardless of suspected causality, and in accordance with 
appropriate rules and regulations.  Study team will report any that are deemed by Investigator to 
be: 
• 
Unexpected AND related 
• 
Expected but occurring at an increased frequency or severity 
• 
Occurring in such a way that changes the risks/benefit ratio to study 
participants and warrants an update in consent form and/or protocol. 
• 
All SAE’s will be reported per applicable rules and regulations (IRB/FDA) 
 
Depression Screening:  The study team will administer the PHQ-9 questionnaire at specified 
timepoints to help identify any potential risk or need for intervention.  
 
Safety Monitoring:  Subjects participating in Part A Arm 2 (non-treatment control) will not require 
safety monitoring.  All other subjects participating in Part A Arm 1 and Part B Arms 1 & 2 will 
require safety monitoring. 
Vital signs including temperature, heart rate, and blood pressure will be obtained at all clinical 
visits.  Body weight, physical exam, and neurological exam will also occur at all clinical visits. 
 


Protocol v.1.7 
20
Dr. Richard Dubinsky, MD, MPH will serve as an independent medical monitor.  The study team 
will submit all adverse events reported to Dr. Dubinsky for review after 10 subjects are enrolled 
and again after 30 subjects are enrolled. 
 
 
Contraception and Women of Childbearing Potential: 
OXE-103 is a polypeptide composed of 28 amino acid residues produced semi-synthetically and 
is structurally identical to the human endogenous ghrelin.  According to data derived from 
reproductive toxicity studies summarized in the OXE-103 Investigator’s Brochure:  
Section 1.4 Nonclinical Toxicology (paragraph 5) 
No effects were observed on fertility in rats, on reproductive function in parental rats and 
maternal rabbits, or on embryo-fetal development in rats or rabbits by IV administration. In 
addition, no effects were observed on maternal rabbits and on embryo-fetal development in 
rabbits by SC administration. In an IV-dose study on pre- and postnatal development including 
maternal function in rats, a tendency to increase in body weights of live newborns was noted at 
300 μg/kg/day or more as pharmacological effects of OXE103. 
 
The complete toxicology reports can be found under Oxeia’s existing IND (120694). 
 
Given that ghrelin naturally exists within and is produced by the body, along with the 
reproductive toxicology study data, the study team will not exclude patients who may have 
childbearing potential.   However, all female participants will undergo a urine or serum 
pregnancy test at screening.  Any subjects who are pregnant will be excluded.  Further, all 
female subjects of child-bearing potential and male subjects sexually active with a female of 
child-bearing potential will be required to use double-barrier contraception or practice 
abstinence during the 14 day treatment period with ghrelin and for 24 hours after the final dose.  
The half life of ghrelin is 30 minutes, therefore this will be more than 5 half lives after the final 
dose. 
 
Cardiovascular and Respiratory Risks: 
Pre-clinical studies performed with OXE-103 showed that, continuous IV infusion of OXE-103 
(up to 1000 µg/kg/hr) in conscious, unrestrained monkeys resulted in a transient increase and 
then decrease in blood pressure in 1 of the 4 monkeys evaluated. None of the animals had 
changes in heart rate, ECG parameters, respiratory rate, arterial blood pH, blood gas tensions, 
hemoglobin oxygen saturation, body temperature or clinical signs. 
 
Additionally, results from the Phase 2 study as noted in Oxeia’s Investigator’s Brochure showed 
no clinically meaningful changes with regard to ECG and subcutaneous treatment with OXE-
103.  Results are summarized on Table 5.9 of the Investigator’s Brochure, which can be cross 
referenced under Oxeia’s existing IND (120694). 
 
All participants will have vital signs, including heart rate and blood pressure, monitored at each 
clinical visit.  Further, an ECG will be acquired at visits 1 through 4.  This will be acquired using 
AliveCor’s Kardiastation digital 6 lead ECG. Kardiastation is a Class II medical device cleared 
by the FDA for acquiring ECGs in the physician office.  Kardiastation uses a HIPPA compliant 
smartphone app and cloud based database for storage of ECGs. ECG parameters evaluated 
and captured in the study database will include RR, PR, QRS, and QT intervals as well as 
normal sinus rhythm. Any clinically significant ECG finding will be recorded as an AE. ECG 
recording will not be collected for subjects in the Non-Treatment concurrent control arm Part A 
(Part A Arm 2). 
 


Protocol v.1.7 
21
Laboratory and Endocrine Risks: 
The semi-synthetic human ghrelin to be used in the clinical study is identical to human 
physiologic ghrelin.  Under the original sponsor of the IND, this molecule was extensively 
characterized in both young adults and the older adult populations under 9 clinical studies and 
was found to be very safe.  The information is summarized in the table above.  Please note the 
additional PD biomarker marker data included that was not referenced in the Investigator 
Brochure.   The longest duration study of the completed studies was ASBI307 in which 151 
subjects were given one of two doses BID of OXE103 for 12 weeks at the same dose level as 
this study. The current study is substantially shorter at 14 days of treatment. 
Subjects will undergo laboratory testing at Day 1 with a complete metabolic profile (CMP), to 
include liver function and glucose, and complete blood count (CBC).  Significant abnormalities in 
serum creatinine (>2.5 mg/dL), or alanine aminotransferase or aspartate aminotransferase >3 
times the upper limit of normal, or bilirubin >2.5 mg/dL will exclude subjects from participation.  
Study team will collect CBC and CMP (with fasting glucose, fasting when possible) at visits 2 
through 4 to monitor for any changes during treatment.  If there are any clinically significant 
abnormal values that have not yet corrected, labs will be repeated at 7-day intervals until they 
normalize. Additional serum will be taken with each laboratory sample for correlative testing of 
sparse PK sampling and anti-ghrelin antibody and biomarker testing at study visits 1-5.  
Subjects enrolled in the Part A Arm 2 non-treatment control group will have these correlative lab 
samples taken at Days 1 and 15.  
Outcomes & Study Tools: 
Symptom reduction (AIM 1):  Our primary goal is to describe the change in number of symptoms 
and/or severity in acute and sub-acute concussion with treatment with OXE-103 using the 
PCSS at Days 1 and 15.  We will also collect data at Days 21 and 44 to potentially describe long 
term changes and potential lasting effect (AIM 4). 
 
Subjects will complete the PCSS at the following timepoints[17]:  upon signing consent (score 
must 20) (Day 1), as well as days 4, 8, 11, 15, 21 and 44. Subjects will be instructed to record 
their symptoms at the same time of day for each assessment timepoint.  There can be a two-
hour window either way. (e.g. 12PM +/- 2 hrs.).  The PCSS is a self-reported assessment of 22 
symptoms using a Likert-type scale ranging from 0-6, with 0 indicating no difficulty with the 
outlined symptom and ratings of 1-6 representing mild-to-severe difficulty with the symptom. 
The reliability and validity of the PCSS are well documented [18-20]  We will also ask subjects 
to rank their 4 most burdensome symptoms (4MBS) at Day 1 and we will analyze these 
separately.  As stated in the Specific Aims the purpose of this study is to collect data that would 
further refine clinical endpoints that could be used for larger Phase 2 studies and possibly lead 
to the establishment of pivotal endpoints for Phase 3 registration trials. The 22 symptom PCSS 
assessment is designed to cover the full spectrum of concussion related symptoms across 
cognitive, emotional and somatic domains. In that regard the PCSS is particularly useful for 
diagnosis and monitoring recovery of patients post injury. However, due to the number of 
symptoms across cognitive, emotive and somatic domains, resolution of several mild symptoms 
may result in a change in the overall symptom score with relatively minor clinical impact on the 
patient’s well-being. Pre-IND feedback already obtained from the FDA has noted that an 
effective therapy for concussion must impact the way a patient feels or functions. By including a 
specific analysis of the patient perceived 4MBS we are likely to be able to correlate symptom 
scores with improvement in the quality of life tools also being used in the study.  The completion 
of the PCSS will take an estimated 5 minutes. 
 


Protocol v.1.7 
22
Quality of Life (AIM 2):  A secondary goal is to examine change in quality of life with treatment of 
acute and sub-acute concussion.  We hypothesize that OXE-103 will reduce symptoms when 
comparing days 1 and 15 and therefore improve quality of life as assessed by 1) Quality of Life 
after Brain Injury scale (QOLIBRI) and 2) a PGAS.  
The QOLIBRI is a 37 item instrument specifically developed to assess health-related quality of 
life (HRQoL) of individuals after traumatic brain injury [21].  Since it was developed for TBI as a 
disease or condition-specific HRQoL instrument, it is expected to be more sensitive than generic 
quality of life tools. The QOLIBRI was developed by an international task force in two multi-
language studies involving over 2000 persons after TBI. Use of a TBI-specific assessment of 
HRQoL can detect the effects of interventions by measuring physical, psychological, daily life 
and psychosocial changes typical of TBI. An increase/decrease of 20% in QOLIBRI is judged to 
represent an improvement. 
In addition, a PGAS will be used in this study. The tool will utilize a visual analog scale (VAS) to 
simply assess the patient’s global assessment of their symptoms via the question “How would 
you rate the effect of your symptoms on how you feel or function today?”. Patients will be 
instructed to rate the effects of their symptoms from 0 to 10 (with 0 being no effect and 10 being 
worst effect). An increase/decrease of 20% in PGAS is considered to indicate improvement.   
The QOL measures will be obtained on day 1, 4, 8, 11, 15, 21, & 44.  The completion of these 
will take an estimated 15 minutes.  The PGAS VAS will be obtained at all visits. 
Cognitive testing (AIM 5):  A secondary outcome measure is to summarize change in cognitive 
function in the 2 groups.  We hypothesize that the mechanism of action of OXE-103 will allow an 
improvement in cognitive function. 
 
Subjects will complete computerized neurocognitive testing on an iPad using BrainCheck [22]  
BrainCheck is a validated digital assessment tool to aid in the diagnosis of mild cognitive 
decline. The tool measures a battery of 7 tests to measure cognition, reaction time, and 
balance.  BrainCheck is a Computerized Cognitive Assessment Aid, a device that provides an 
impression of a person’s current level of cognitive function. It is registered as a Class II medical 
device with the (FDA). (Registration number: 3014129043).  Neurocognitive tests use small 
tasks to directly measure specific aspects of brain function. BrainCheck has created a library of 
neurocognitive assessments that measure specific components of brain function, such as 
reaction time, attention, visual processing and memory. 
BrainCheck assessments include a coordination balance test measuring static and dynamic 
balance using the Ebbinghaus Illusion, a digit symbol substitution test for general cognitive 
performance, the Flanker test measuring visual attention, the Stroop Effect measuring reaction 
time, Trails A&B measuring visual attention and task switching and Recall tests to measure 
immediate and delayed memory. All scoring algorithms compare test results to a normative age 
matched dataset.  All these tests are simple video games that require no special skills and are 
expected to cause no distress. The total time to complete the battery of tests is estimated to be 
15 minutes.  BrainCheck will be conducted on Days 1, 4, 8, 11, 15, 21, and 44.  The iPads will 
be collected at the end of the subjects’ study participation in all study procedures requiring use 
of an iPad.  If a subject withdraws from the study, they will be asked to return the iPad to the 
study team. 
 
Electronic PHI data will be kept on Amazon (HIPAA compliant) servers.  The computers are all 
password protected.  Server access is limited to study team and IT representatives, including 
any Amazon server representatives.  Access to study specific data and communications relating 


Protocol v.1.7 
23
to the study will be limited to the PI and PI's staff, study personnel, responsible individuals from 
the study sponsor and appropriate regulatory agencies.  The research data will not be added to 
the subject's medical records. 
Amazon work servers (AWS) has an established information security organization managed by 
the AWS security team and is led by the AWS Chief Information Security Officer (CISO). 
 
AWS meets criteria for security, availability, and confidentiality in the American Institute of 
Certified Public Accountants (AICPA) TSP Section 100, Trust Services Principles and Criteria 
for security, availability, processing, integrity, confidentiality, and privacy. 
 
BrainCheck uses AWS HIPAA compliant services and holds third-party validations certifying 
that: 
- AWS complies with the ISO 27017 implementation guidance of cloud-specific information 
security controls that supplement the ISO 27002 guidance and the ISO 27001 standard. 
- AWS complies with the ISO 27001 internationally-recognized standard for security 
management best practices and comprehensive security controls following the ISO 27002 best 
practice guidance 
- AWS complies with the ISO 27018 implementation guidance of controls applicable to public 
cloud personally identifiable information (PII) protection that supplement the ISO 27002 
guidance and the ISO 27001 standard. 
 
Information that will be transmitted from the app is limited to subject code, survey responses, 
and timestamps of survey responses. No location data will be transmitted. The vendor will not 
be permitted to attempt to re-identify subjects. 
 
The iPads will be supplied by Oxeia Biopharmaceuticals.  
 
ECG monitoring will be conducted via AliveCor’s Kardiastation digital 6 lead ECG.  Kardiastation 
has multiple 510(k) Class II device approvals through the FDA. Kardiostation is a Class II 
medical device cleared by the FDA for acquiring ECGs in the physician office.  Kardiostation 
uses a HIPPA compliant smartphone app and cloud based database for storage of ECGs. ECG 
parameters evaluated and captured in the study database will include RR, PR, QRS, and QT 
intervals as well as normal sinus rhythm. Any clinically significant ECG findings will be recorded 
as an AE.  All ECGs will be kept for the Clinical Trials File. 
 
Statistical Analysis: 
This pilot study will describe changes observed within  Part A and Part B:  placebo versus OXE-
103. Since the study is exploratory, analysis will focus on descriptive comparative statistics and 
not on a prespecified statistically significant primary endpoint. Data will be used to enable power 
calculations and the definition of suitable clinical endpoints for further clinical development. Data 
from all Study Days 1, 4, 8, 11, 15, 21, and 44 will be analyzed. 
 
The primary objective will be to determine the proportion of subjects (responders) who 
experience a clinically meaningful benefit as defined by a reduction of 20% in both the number 
and severity of concussion related symptoms. Concussion related symptoms will be measured 
using the 22 symptom PCSS. Severity of each of the 22 symptoms is graded by the patient on a 
7-point Likert Scale. This scale has been used extensively to assess patients with 
concussion/mTBI[18, 19].  
 
In addition, in order to control for the effect of changes in clinically minor symptoms on the 
overall number and severity of the PCSS, data will also be analyzed based on change of the 


Protocol v.1.7 
24
4MBS for each subject. This type of analysis has been employed in evaluation of patient 
reported outcomes for migraine and is discussed in an FDA guidance document (Dodick et al. 
2018, Migraine 2018 FDA).  
FDA pre-IND guidance from the FDA on the clinical development of OXE-103 advised that “The 
outcome measure should be constructed in a way that ensures that a score change is 
indicative of a meaningful improvement in how a patient feels or functions that comes 
from a treatment effect specific to mild TBI.” In order to correlate changes in symptom 
number/severity to effect on quality of life, two quality assessment tools will be used including 
QOLIBRI and a PGAS. Improvements in these assessments will be compared to definition of 
Responder to assess meaningful clinical improvements in response to treatment with OXE-103. 
In addition, patient reported outcomes on the PCSS scale will be correlated with objective digital 
measures of cognition and balance/stability using BrainCheck a Class-II FDA device. 
Medical history and test results will be housed in a REDCap. 
 
Plans for Assuring Subjects’ Privacy and Confidentiality 
Signed consent forms and data forms will be stored in a designated file cabinet belonging to a 
member of the study team with limited access. Outcomes data will be entered into the 
aforementioned REDCap database and access will be restricted to staff members with approval. 
All analyzed data will be de-identified before submitting to the sponsor or scientific journals, etc. 
per HIPAA guidelines.  Each participant will be assigned a unique study number to allow 
tracking of information over time. Personally-identifying information will be removed from initial 
data once a study number has been assigned, and from subsequent data once new data has 
been matched to an existing study number. The identity of participants and their associated 
study numbers will be housed in the Velos system, which will only be accessible by study team 
members who have authorization to access. 
 
Follow-up 
Subjects will be recruited from the CCM. These patients will continue with their standard care at 
the CCM upon completion of or removal from the study.  
 
Study findings will be summarized and reported within the University of Kansas Medical Center 
(KUMC) and TUKHS (student research forum, seminars), in the community (aggregate data 
discussed in education or in-service forums), and professionally (conference proceedings, 
journal publications). 
 
Record Retention Issues 
The study team will retain any research and data records for 5 years in accordance with 
institution and federal requirements, as applicable.  Records will be maintained in a secure 
method, with restricted or limited access to only authorized individuals.  Records will be kept in 
a locked file cabinet inside a locked office. 


Protocol v.1.7 
25
Part  A Study Design - Schedule of events 
Arm 1 (OXE-103) 
 
Assessment 
 
Day 
 
1 
4 
8 
+/-1 
11 
15 
21  
+/-1 
44  
+/-3 
Clinic Visit 
1 
 
2 
 
3 
4 
5 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Body Weight 
X 
 
X 
 
X 
 
X 
Vital signs (temperature, 
heart rate, blood pressure) 
X 
 
X 
 
X 
 
X 
Medical History, including 
current TBI injury, mental 
health diagnoses, and 
neurologic conditions 
(including any cognitive 
dysfunction) 
X 
 
 
 
 
 
 
Adverse Effects 
X 
X 
X 
X 
X 
X 
X 
Prior Medications/Therapy 
Hx 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
 
X 
X 
X 
Neurological Examination 
X 
 
X 
 
X 
X 
X 
Concomitant Medications 
X 
 
X 
 
X 
X 
X 
ECG 
X 
 
X 
 
X 
X 
 
Labs: serum/urine 
pregnancy test 
X 
 
 
 
 
 
 
Labs: CMP & CBC1 
X 
 
X 
 
X 
X 
 
Labs: PK sampling,  
anti-ghrelin anti-body and 
biomarker 
X 
 
X 
 
X 
X 
 
Train subcutaneous injection  X 
 
 
 
 
 
 
PCSS 
X 
X 
X 
X 
X 
X 
X 
Ipad Neurocog and balance 
(BrainCheck) 
X 
X 
X 
X 
X 
X 
X 
QOL - QOLIBRI 
X 
X 
X 
X 
X 
X 
X 
QOL - PGAS VAS 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 
X 
 
X 
 
X 
 
X 
Administer OXE-103 
40ug/kg OR placebo  
SC BID ** 
X  
Study Days 1-14   
 
 
Phone Only (no in-person 
required) 
 
X 
 
X 
 
 
 
 
1If there are any clinically significant abnormal values that have not yet 
corrected at Day 15, labs will be repeated at 7-day intervals until they 
normalize. 
**Assessments and questionnaires performed and collected on Day 1 & 8 
will be completed prior to dispensing of OXE-103. 
 


Protocol v.1.7 
26
Part  A Study Design - Schedule of events 
Arm 2 (Non-treatment concurrent control group) 
 
Assessment 
 
Day 
 
1 
4 
8 
+/-1 
11 
15 
21  
+/-1 
44  
+/-3 
Clinic Visit 
1 
 
 
 
2 
 
3 
Remote Testing Only (No 
Visit) 
 
X 
 
X 
 
 
 
Remote Visit OR Clinic 
Visit 
 
 
X 
 
 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Body Weight 
X 
 
 
 
X 
 
X 
Vital signs (temperature, 
heart rate, blood pressure) 
X 
 
 
 
X 
 
X 
Medical History, including 
current TBI injury, mental 
health diagnoses, and 
neurologic conditions 
(including any cognitive 
dysfunction) 
X 
 
 
 
 
 
 
Prior Medications/Therapy 
Hx 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
 
X 
Neurological Examination 
X 
 
 
 
X 
 
X 
Concomitant Medications 
X 
 
 
 
X 
 
X 
Labs: PK sampling,  
anti-ghrelin anti-body and 
biomarker 
X 
 
 
 
X 
 
X 
PCSS 
X 
X 
X 
X 
X 
X 
X 
Ipad Neurocog and balance 
(BrainCheck) 
X 
X 
X 
X 
X 
X 
X 
QOL - QOLIBRI 
X 
X 
X 
X 
X 
X 
X 
QOL - PGAS VAS 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 
X 
 
X 
 
X 
 
X 
 
 
 


Protocol v.1.7 
27
Part B Study Design - Schedule of events 
Arms 1 (OXE-103) and 2 (placebo) 
 
Assessment 
 
Day 
 
1 
4 
8 
+/-1 
11 
15 
21  
+/-1 
44  
+/-3 
Clinic Visit 
1 
 
2 
 
3 
4 
5 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/ Exclusion Criteria 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Body Weight 
X 
 
X 
 
X 
 
X 
Vital signs (temperature, 
heart rate, blood pressure) 
X 
 
X 
 
X 
 
X 
Medical History, including 
current TBI injury, mental 
health diagnoses, and 
neurologic conditions 
(including any cognitive 
dysfunction) 
X 
 
 
 
 
 
 
Adverse Effects 
X 
X 
X 
X 
X 
X 
X 
Prior Medications/Therapy 
Hx 
X 
 
 
 
 
 
 
Physical Examination 
X 
 
X 
 
X 
X 
X 
Neurological Examination 
X 
 
X 
 
X 
X 
X 
Concomitant Medications 
X 
 
X 
 
X 
X 
X 
ECG 
X 
 
X 
 
X 
X 
 
Labs: serum/urine 
pregnancy test 
X 
 
 
 
 
 
 
Labs: CMP & CBC1 
X 
 
X 
 
X 
X 
 
Labs: PK sampling, 
anti-ghrelin anti-body and 
biomarker 
X 
 
X 
 
X 
X 
X 
Train subcutaneous injection 
X 
 
 
 
 
 
 
PCSS 
X 
X 
X 
X 
X 
X 
X 
Ipad Neurocog and balance 
(BrainCheck) 
X 
X 
X 
X 
X 
X 
X 
QOL – QOLIBRI 
X 
X 
X 
X 
X 
X 
X 
QOL – PGAS VAS 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 
X 
 
X 
 
X 
 
X 
Administer OXE-103 
40ug/kg OR placebo  
SC BID** 
X  
Study Days 1-14   
 
 
Phone Only (no in-person 
required) 
 
X 
 
X 
 
 
 
 
1If there are any clinically significant abnormal values that have not yet 
corrected at Day 15, labs will be repeated at 7-day intervals until they 
normalize. 
**Assessments and questionnaires performed and collected on Day 1 & 8 
will be completed prior to dispensing of OXE-103. 


Protocol v.1.7 
28
References 
 
 
1. 
CDC, TBI Data an Statistics. https://www.cdc.gov/TraumaticBrainInjury/data/index.html. 
2. 
Giza, C.C. and D.A. Hovda, The new neurometabolic cascade of concussion. Neurosurgery, 2014. 
75 Suppl 4: p. S24-33. 
3. 
Klok, M.D., S. Jakobsdottir, and M.L. Drent, The role of leptin and ghrelin in the regulation of 
food intake and body weight in humans: a review. Obes Rev, 2007. 8(1): p. 21-34. 
4. 
Gahete, M.D., et al., Ghrelin gene products, receptors, and GOAT enzyme: biological and 
pathophysiological insight. J Endocrinol, 2014. 220(1): p. R1-24. 
5. 
Andrews, Z.B., et al., UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free 
radicals. Nature, 2008. 454(7206): p. 846-51. 
6. 
Liu, Y., et al., Both ischemic preconditioning and ghrelin administration protect hippocampus 
from ischemia/reperfusion and upregulate uncoupling protein-2. BMC Physiol, 2009. 9: p. 17. 
7. 
Singh, R., et al., Relationship of collegiate football experience and concussion with hippocampal 
volume and cognitive outcomes. JAMA, 2014. 311(18): p. 1883-8. 
8. 
Diano, S., et al., Ghrelin controls hippocampal spine synapse density and memory performance. 
Nat Neurosci, 2006. 9(3): p. 381-8. 
9. 
Lopez, N.E., et al., Ghrelin decreases motor deficits after traumatic brain injury. J Surg Res, 2014. 
187(1): p. 230-6. 
10. 
Lee, J., et al., Altering leukocyte recruitment following traumatic brain injury with ghrelin 
therapy. J Trauma Acute Care Surg, 2014. 77(5): p. 709-715. 
11. 
Qi, L., et al., Ghrelin protects rats against traumatic brain injury and hemorrhagic shock through 
upregulation of UCP2. Ann Surg, 2014. 260(1): p. 169-78. 
12. 
Washington, P.M., et al., The effect of injury severity on behavior: a phenotypic study of 
cognitive and emotional deficits after mild, moderate, and severe controlled cortical impact 
injury in mice. J Neurotrauma, 2012. 29(13): p. 2283-96. 
13. 
Bansal, V., The Use of Exogenous Ghrelin as a Treatment for Mild Traumaic Brain Injury. 2016. 
14. 
Kong J, X.Z., Massive Mitochondrial Degeneration in Motor Neurons Triggers the Onset of 
Amyotrophic Lateral Sclerosis in Mice Expressing a Mutant SOD1. J Neurosci, 1998. 18(9): p. 
3241-3250. 
15. 
Ludolph AC, B.C., Blaugrund E, Chio A, Greensmith L, Loeffler JP, Mead R, Niessen HG, Petri S, 
Pradat PF, Robberecht W, Ruegg M, Schwalenstöcker B, Stiller D,  van den Berg L, Vieira F, von 
Horsten S., Guidelines for preclinical animal research in ALS/MND: A consensus meeting. 
Amyotroph Lateral Scler, 2010(11): p. 38-45. 
16. 
Muller, T.D., et al., Ghrelin. Mol Metab, 2015. 4(6): p. 437-60. 
17. 
Post Concussion Symptom Scale (PCSS). Available from: 
https://hawaiiconcussion.com/downloads/Post-Concussion-Symptom-Scale.pdf. 
18. 
Meehan, W.P., 3rd, et al., Early symptom burden predicts recovery after sport-related 
concussion. Neurology, 2014. 83(24): p. 2204-10. 
19. 
Meehan, W.P., 3rd, et al., Symptom severity predicts prolonged recovery after sport-related 
concussion, but age and amnesia do not. J Pediatr, 2013. 163(3): p. 721-5. 
20. 
Luoto, T.M., et al., Sport concussion assessment tool 2 in a civilian trauma sample with mild 
traumatic brain injury. J Neurotrauma, 2014. 31(8): p. 728-38. 
21. 
Qolibri. Quality of Life Assessment for TBI. Available from: http://qolibrinet.com. 
22. 
Yang, S., et al., Diagnostic accuracy of tablet-based software for the detection of concussion. 
PLoS One, 2017. 12(7): p. e0179352. 


Protocol v.1.7 
29
23. 
Severity of Traumatic Brain Injuiry. Available from: 
http://www.medicalclinicsofnyc.com/traumatic-brain-injury/. 
24. 
American Congress of Rehabilitation Medicine, Definition of mild traumatic brain injury. J Head 
Trauma Rehabil, 1993. 8(3): p. 86-7. 
Appendix 1 
 
A. Toxicology 
Nonclinical toxicity studies of OXE103 (SUN11031) have been conducted by SC and IV 
administration to mice, rats, rabbits and monkeys. Single dose toxicity studies were 
conducted in rats (SC and IV) and monkeys (IV) and repeat-dose toxicity studies were 
conducted in rats, rabbits and monkeys following either SC or IV administration. No deaths 
or moribund sacrifice were reported following SC (26-week administration in rats with doses 
up to 20,000 µg/kg and 39 week administration in monkeys with doses up to 5000 µg/kg) or 
IV (4- and 13-week administration in rats with doses up to 100,000 and 25,000 µg/kg, 
respectively, and 4- and 13-week administration in monkeys with doses up to 30,000 and 
3000 µg/kg, respectively) administration. The monkey is considered to be the most sensitive 
species. 
 
In the 26-week toxicity study (0; 3000; 7000; 20,000 µg/kg/day) evaluating OXE103 
(SUN11031) SC administration in rats, no animals in any group died and the 3000 µg/kg/day 
dose in males was well tolerated, with no toxic signs observed. An increase in urinary β2- 
microglobulin (β2-MG) and a decrease in serum albumin, albumin ratio and albumin/globulin 
(A/G) were noted in females at 3000 µg/kg or more, an increase in urinary β2-MG in males 
and a decrease in serum total protein in females at 7000 µg/kg or more, and an increase in 
urinary albumin, decreases in albumin ratio and A/G in serum in males at 20,000 µg/kg. 
These were slight toxicological changes. The NOAEL was determined to be 3000 µg/kg/day 
for males and less than 3000 µg/kg/day for females. 
 
In the 39-week toxicity study (0; 300; 1000; 5000 µg/kg/day) evaluating OXE103 
(SUN11031) SC administration in monkeys, no animals died, and doses up to 1000 
µg/kg/day were well tolerated with no toxic signs observed. Local irritation was observed at 
the injection site and considered to be related to the dosing procedure and the vehicle (0.03 
mol/L acetic acid buffer [pH 4.0] containing 10% sucrose and 1% benzyl alcohol). Antibody 
titers were below the lower limit of detection. However, incidences and/or grades of 
inflammation of the subcutaneous tissue and regeneration of the cutaneous muscle fiber 
were slightly greater in the 5000 μg/kg group than in the vehicle control group. The NOAEL 
was determined to be 1000 μg/kg/day. 
 
Male and female rats treated with OXE103 (SUN11031) by SC administration for 13 weeks 
developed anti OXE103 antibody at the end of the dosing period which did not differ from 
control rats at the end of the recovery period. 
 
No effects were observed on fertility in rats, on reproductive function in parental rats and 
maternal rabbits, or on embryo-fetal development in rats or rabbits by IV administration. In 
addition, no effects were observed on maternal rabbits and on embryo-fetal development in 
rabbits by SC administration. In an IV-dose study on pre- and postnatal development 
including maternal function in rats, a tendency to increase in body weights of live newborns 


Protocol v.1.7 
30
was noted at 300 μg/kg/day or more as pharmacological effects of OXE103 (SUN11031). 
 
OXE103 (SUN11031) was not judged to be genotoxic. Although some results suggest that 
OXE103 may promote proliferation of selected cell types under experimental conditions, 
there is no clear evidence of tumor promoting potential in vivo. 
 
In monkeys, a dose of 1000 µg/kg is approximately 4 fold higher than a clinical dose of 40 
µg/kg twice daily based on body surface area. This may also be expressed as a systemic 
equivalent total daily exposure of approximately 28- and 12 fold for maximum plasma 
concentration (Cmax) and area under the plasma concentration time curve (AUC), 
respectively. 
B. Clinical Overview 
Safety, tolerability and pharmacokinetics of, SUN11031 (alternatively OXE103) has been 
evaluated in 9 clinical studies with the SC and IV routes of administration: 
 
• 4 phase 1 clinical studies in healthy volunteers: 
- 
3 in Japan (NA 1401, NA 1501, and NA 1502 – all IV administration) and 
- 
1 in the US (ASBI 301 – SC and IV administration). 
• 4 phase 2 clinical studies: 
- 
1 study in subjects with eating disorders conducted in Japan (NA 2601 – IV 
administration), 
- 
1 study in subjects with cachexia associated with CHF conducted in Poland (ASBI 
303 – SC administration), 
- 
1 study in subjects with cachexia associated with COPD conducted in the US (ASBI 
304 – SC administration), and 
- 
1 multinational study in subjects with cachexia associated with COPD (ASBI 307 – 
SC administration). 
• 1 phase 3 clinical study: 
- 
in subjects with eating disorders in Japan (NA 3801 – IV administration). 
 
SUN11031 has been administered as either an IV bolus or IV infusion in 6 clinical studies 
(NA 1401, NA 1501, NA1502, ASBI 301, NA 2601, and NA 3801) and as an SC injection in 4 
clinical studies (ASBI 301, ASBI 303, ASBI 304, and ASBI 307).  
 
Subcutaneous injections of SUN11031 at doses up to 45.5 µg/kg once daily and 22.7 µg/kg 
bid for up to 7 days, have been administered to healthy subjects. Subcutaneous doses of 
SUN11031 10 µg/kg bid have been administered to subjects with cachexia associated with 
CHF (ASBI 303; 6 subjects; up to 14 days) and up to 20 µg/kg bid have been administered to 
subjects with cachexia associated with COPD (ASBI 304 [during which 9 subjects were 
administered 10 µg/kg bid and 8 subjects were administered 20 µg/kg bid] for up to 21 days 
and ASBI 307 [during which a total of 75 and 76 subjects were administered 20 and 40 µg/kg 
bid SUN11031, respectively]) for up to 3 months. 
 
 


Protocol v.1.7 
31
 
 

SAP_001.pdf: 
1 
 
  
 
STATISTICAL ANALYSIS PLAN 
 
Ghrelin (OXE--103) for Acute Concussion Management 
NCT04558346 
 
Version History: 
Version 1.0, November 30, 2020 
 
 
 


2 
 
Table of Contents 
List of Abbreviations ..................................................................................................................................... 3 
1. 
Introduction .......................................................................................................................................... 4 
2. 
Study Design.......................................................................................................................................... 4 
3. 
Study Objectives ................................................................................................................................... 4 
4. 
Sample Size ........................................................................................................................................... 5 
5. 
Outcome Measures ............................................................................................................................... 5 
5.1 Primary Efficacy Outcome Measures .................................................................................................. 5 
5.2 Secondary Efficacy Outcome Measures .............................................................................................. 6 
5.3 Exploratory Efficacy Outcome Measures ............................................................................................ 6 
5.4 Safety Outcome Measures .................................................................................................................. 6 
6. 
Statistical Methods ............................................................................................................................... 6 
6.1 General Methods ................................................................................................................................ 6 
6.2 Analysis Sets ........................................................................................................................................ 7 
6.3 Subject Accountability ........................................................................................................................ 7 
6.4 Entrance Criteria Violations and Other Protocol Deviations .............................................................. 7 
6.5 Demographic and Baseline Characteristics ......................................................................................... 8 
6.6 Study Drug Exposure ........................................................................................................................... 8 
6.7 Prior and Concomitant Medications ................................................................................................... 8 
6.8 Efficacy Analysis .................................................................................................................................. 8 
6.9 Safety Analysis .................................................................................................................................... 9 
6.10 Missing Data Handling ...................................................................................................................... 9 
6.11 Visit Windows ................................................................................................................................... 9 
6.12 Subgroup Analyses ............................................................................................................................ 9 
6.13 Adjustment for Covariates ................................................................................................................ 9 
6.14 Interim Analyses.............................................................................................................................. 10 
6.15 Statistical Software ......................................................................................................................... 10 
6.16 References ...................................................................................................................................... 10 
 
 
 
 


3 
 
List of Abbreviations 
 
4MBS 
4 most bothersome symptoms (on the PCSS) 
AE 
Adverse event 
 
 
CCM 
Center for Concussion Management 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAE 
AE leading to study drug discontinuation 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration (United States) 
ICD-10-CM 
International Classification of Diseases, Tenth Revision, Clinical Modification 
IND 
Investigational new drug 
ITT 
Intent-to-treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCSS 
Post-Concussion Symptom Score questionnaire  
PGAS 
Patient Global Assessment of Status 
PHQ-9 
Patient Health Questionnaire 
 
 
PP 
Per protocol 
PT 
Preferred term 
QOLIBRI 
Quality of Life after Brain Injury questionnaire 
ROC 
Receiver operating characteristic 
SAE 
Serious AE 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SOC 
System-organ class 
TE 
Treatment-emergent 
UU 
Unanticipated or unexpected 
VAS 
Visual analog scale 
 
 
 


4 
 
1. Introduction 
This statistical analysis plan (SAP) provides details on the study design, outcome measures and data 
analyses planned for the exploratory study of ghrelin (OXE-103) in subacute and acute concussion 
management that is being conducted at the University of Kansas Health System Center for Concussion 
Management (CCM).  The outcome measures and data analyses specified in this SAP supersede any 
specified in the study protocol, if differences exist. 
Any deviations from this plan will be documented in the clinical study report, and will include timing of 
changes in relation to unblinding of the study. 
Pharmacokinetic, anti-ghrelin antibody and/or biomarker samples may be collected for future use and 
any data analysis will be the subject of a separate SAP. 
2. Study Design 
This subacute and acute concussion management study will be conducted as a randomized, single 
center, double-blind, placebo-controlled, parallel group design in two distinct parts.  In Part A, subjects 
will be recruited from the University of Kansas Health System CCM clinics which include Neurology, 
Sports Medicine, and Neurosurgery/Physical Medicine and Rehabilitation.  Subjects who provide written 
informed consent and satisfy enrollment criteria at the end of a 7-day screening period will be 
randomized in a 1:1 manner to either the OXE-103 or placebo treatment groups.  In Part B, subjects will 
be recruited from the emergency department and enrolled within 24 hours of injury.  Treatments will be 
self-administered subcutaneously twice daily during a 14-day treatment period; the OXE-103 group will 
receive 40 µg/kg with each dose.  
For Part A, clinic visits will be conducted at the start of Screening (Day -7), Randomization (Day 1), Day 8, 
End of Treatment (Day 15), 1 week after the end of treatment (Day 21) and End of Study (Day 44).  
Phone contacts will be done during Screening (Day -3) and during treatment (Days 4 and 11).  Part B 
subjects will follow the same schedule except that there will be no screening visit or phone contact. 
Outcomes for the investigation of the effect of OXE-103 will be based on self-reported symptom scoring, 
quality of life questionnaires, computerized cognitive testing assessing executive function, memory and 
processing speed, and accelerometer-based balance scoring.  Safety assessments will include collection 
of adverse events, clinical laboratory samples, electrocardiograms (ECGs), vital signs including body 
weights, suicide screening and physical/neurological examination findings. 
3. Study Objectives 
The primary objective of this study is to describe the change in symptom burden of subacute or acute 
concussion for the two treatment groups in each part, as measured by the change from baseline to Day 
15 in the Post-Concussion Symptom Score questionnaire (PCSS) total score, total number of symptoms 
and total score for the 4 most bothersome symptoms (4MBS, as identified on Day 1).  Improvements of 
≥20% will be considered clinically meaningful. 


5 
 
The secondary objectives are to: 
• 
Describe the change in quality of life for the two groups in each part as measured by the change 
from baseline to Day 15 in the Quality of Life after Brain Injury (QOLIBRI) total score and Patient 
Global Assessment of Status Visual Analog Scale (PGAS VAS).  
• 
Describe changes in cognitive performance for the two groups in each part as measured by the 
change from baseline to Day 15 in the BrainCheck composite score. 
Exploratory objectives of the study are to: 
• 
Describe the correlation between the change in symptom burden and quality of life during the 
treatment period for each group in each part.   
• 
Describe changes in symptom burden and quality of life at different time points for the two groups 
in each part.   
4. Sample Size 
The exploratory nature of this study is such that it is not powered to yield statistically significant 
outcomes, but will allow detection of trends within subjects and between groups within each part, will 
support comparison with standard tests of neurocognitive functions, and will provide sample size 
estimates for future studies of individuals with acute or persistent concussion related symptoms. 
The study will enroll a maximum of 50 subjects in each part, but may stop recruiting if each group has at 
least 20 participants who have completed the study.   
5. Outcome Measures 
5.1 Primary Efficacy Outcome Measures 
• 
PCSS severity responder as defined by  ≥20% improvement over baseline at Day 15 in the severity 
score 
• 
PCSS symptom responder as defined by ≥20% improvement over baseline at Day 15 in the number 
of symptoms 
• 
PCSS 4MBS responder as defined by ≥20% improvement over baseline at Day 15 in the 4MBS 
severity score 
• 
Change from baseline in PCSS severity score at each post-baseline assessment (Days 4, 8, 11, 15, 21 
and 44) 
• 
Change from baseline in PCSS number of symptoms at each post-baseline assessment (Days 4, 8, 11, 
15, 21 and 44) 
• 
Change from baseline in PCSS 4MBS severity score at each post-baseline assessment (Days 4, 8, 11, 
15, 21 and 44) 


6 
 
5.2 Secondary Efficacy Outcome Measures 
• 
Change from baseline in QOLIBRI total score at each post-baseline assessment (Days 4, 8, 11, 15, 21 
and 44) 
• 
Change from baseline in PGAS VAS at each post-baseline assessment (Days 4, 8, 11, 15, 21 and 44) 
• 
Change from baseline in BrainCheck composite score at each post-baseline assessment (Days 4, 8, 
11, 15, 21 and 44) 
5.3 Exploratory Efficacy Outcome Measures 
The exploratory study objectives may be assessed by examining responder rates on days other than the 
assessments done at the end of treatment (Day 15) or by examining relationships between primary and 
secondary outcomes.  Therefore, there are no additional efficacy outcome measures to define. 
5.4 Safety Outcome Measures 
Any laboratory, vital sign or ECG result meeting Common Terminology Criteria for Adverse Events 
(CTCAE), version 5.0, will be included in adverse event (AE) reports.  Any unexpected findings on physical 
or neurological examinations will also be included in AE reports. 
• 
Occurrence of any AEs commonly reported for OXE-103, CTCAE Grade 1 (mild) only. 
• 
Occurrence of any unanticipated or unexpected (UU) treatment-emergent (TE) AE, UU serious AE 
(TE-SAE), UU AE leading to study drug discontinuation (TE-DAE), UU TE-AE related to study drug and 
UU TE-AE classified as Grade 2 or higher according to CTCAE, version 5.0. [Note that any AE 
commonly reported for OXE-103 that has CTCAE Grade 2 (moderate) or higher will be included 
among the UU TE-AEs.] 
• 
  
• 
Change from baseline in clinical laboratory parameters at each post-baseline assessment (Days 8, 15 
and 21) 
• 
Change from baseline in vital signs (including body weight) at each post-baseline assessment (Days 
8, 15 and 44) 
• 
Change from baseline in ECG intervals at each post-baseline assessment (Days 8, 15, 21) 
• 
Change from baseline in Patient Health Questionnaire (PHQ)-9 total score at each post-baseline 
assessment (Days 8, 15 and 44) 
6. Statistical Methods 
6.1 General Methods 
This pilot study will describe changes observed in the two treatment groups, placebo versus OXE-103, 
separately for each part. Since the study is exploratory, analyses will focus on descriptive comparative 
statistics and not on a pre-specified statistically significant primary endpoint. Data will be used to enable 
power calculations and the definition of suitable clinical endpoints for further clinical development. Data 
from baseline and on Study Days 4, 8, 11, 15, 21, and 44 will be analyzed. Note that day definitions in 
this study will follow the Clinical Data Interchange Standards Consortium in that there is no Day 0; 


7 
 
assessments performed prior to randomization will be done on Days -7 and -3 (Part A only) and 
randomization is considered Day 1.  
For all evaluations of changes from baseline, baseline is defined as the last reported value before the 
first dose of study drug.  In most instances, this will be the value recorded on Day 1. 
For the evaluation of safety, a treatment-emergent finding is any result that is newly reported after the 
first dose of study drug.  This may include an existing condition which worsens in severity after the start 
of treatment. 
Continuous variables such as total score or change from baseline will be summarized by the number of 
observations, mean, standard deviation, median, minimum and maximum value.  Graphs of changes 
from baseline over time will present the means and 95% confidence intervals. 
Binary or categorical variables will be summarized by the number of observations in each category along 
with the percent of observations. 
To aid in interpretation of the importance of relationships, correlation coefficients (Pearson and 
Spearman) will be reported with p-values.  
6.2 Analysis Sets 
The intent-to-treat (ITT) analysis set is defined as all randomized subjects.  This analysis set will be used 
for demographics and baseline characteristics, entrance criteria violations and other protocol deviations, 
study drug exposure and prior/concomitant medications summaries. 
Since this is an exploratory study being conducted for the purpose of signal detection, the per protocol 
(PP) analysis set will be used for all efficacy summaries.  This set is defined as all patients who completed 
at least 10 doses) of treatment, had a Day 8 PCSS assessment and no major protocol deviations. 
The safety analysis set is defined as all subjects who received at least one dose of study drug.  This 
analysis set will be used for all safety summaries, and subjects will be included in the treatment group 
which represents the treatment actually administered. If there are no errors in dosing (ie, each subject 
received the treatment to which he/she was randomized), it is anticipated that the safety analysis set 
will be the same as the ITT analysis set because it is expected that all randomized subjects will be dosed.   
6.3 Subject Accountability 
The number of subjects screened will be summarized along with the reasons for screen failure.  The 
number (%) of subjects randomized, treated, completing treatment, completing study and in each 
analysis set will be summarized by treatment group.  Reasons for not completing treatment and/or 
study will also be summarized by treatment group. 
6.4 Entrance Criteria Violations and Other Protocol Deviations 
The number (%) of subjects randomized in violation of each entrance criterion (if any) will be 
summarized by treatment group.  In addition, the number (%) of subjects for whom a pre-specified 
protocol deviation was observed will be summarized by treatment group.  


8 
 
6.5 Demographic and Baseline Characteristics 
Age at randomization, sex, race, ethnicity and days since injury will be summarized with appropriate 
statistics for each treatment group.  Days since injury will be calculated as randomization date – injury 
date.  Age and days since injury will also be summarized categorically (Age: 18-25, 26-35, 36-45 and 46-
55 years; Days since injury: ≤7, 8-14, 15-21, 22-28, >28 days). 
Medical history/concurrent conditions will be summarized for each treatment group by International 
Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnoses obtained from 
BioPortal [1,2].  In this summary, a subject may be counted only once for each distinct diagnosis. 
6.6 Study Drug Exposure 
The total number of doses self-administered by each subject will be summarized as both a continuous 
and categorical (≤7, 8-14, 15-21, 22-28 doses) variable and presented for each treatment group. 
 
6.7 Prior and Concomitant Medications 
A prior medication is defined as any medication reported in use by the patient prior to randomization.  A 
concomitant medication is defined as any medication either in use at randomization which was allowed 
to be continued during the treatment period, or, one that is started post-randomization and prior to the 
end of study.  One medication report may be identified as both a prior and a concomitant medication. 
Prior and concomitant medications will be summarized for each treatment group by generic name as 
determined by RxNORM ontology in BioPortal.  In these summaries, a subject may be counted only once 
for each unique medication. 
6.8 Efficacy Analysis 
As described previously, binary variables (responders) and continuous variables (values and changes 
from baseline) will be summarized with appropriate descriptive statistics for each treatment group and 
each visit (as needed).  Changes from baseline over time will also be presented graphically with means 
(95% confidence intervals) with both treatment groups presented on the same figure. 
To evaluate the appropriateness of the current responder definitions, a Receiver Operating 
Characteristic (ROC) analysis will be performed for each response outcome measure.  The current 
definitions indicate that a ≥20% improvement over baseline is required for a subject to be considered a 
responder. In the ROC analysis, the percent improvement will be varied from 5% to 95% to determine 
which percentage is best for distinguishing OXE-103 treated subjects from placebo subjects. If data 
suggest an early treatment response, the ROC analysis may be performed for a time point earlier than 
Day 15. 
FDA pre-IND guidance from the FDA on the clinical development of OXE-103 advised that “The outcome 
measure should be constructed in a way that ensures that a score change is indicative of a meaningful 
improvement in how a patient feels or functions that comes from a treatment effect specific to mild 
TBI.”   Pearson and Spearman correlation coefficients (and p-values) will be calculated to examine 


9 
 
relationships between the PCSS changes and changes in the quality of life measures (QOLIBRI total score 
and PGAS VAS).  
Relationships between PCSS changes and changes in cognition and balance (BrainCheck composite 
measure) will also be examined using correlation coefficients.  
6.9 Safety Analysis 
AEs commonly reported for OXE-103 will be summarized for each treatment group, by study day of 
assessment and will include an ‘At any time’ category. 
An  overview of UU AEs will provide the number (%) of subjects in each treatment group with any TE-AE, 
TE-SAE, TE-DAE, TE-AE related to study drug,, and TE-AE classified as Grade 2 or higher according to 
CTCAE, version 5.0.  Additionally, TE-AEs, related TE-AEs and Grade 2 or higher TE-AEs will be 
summarized for each treatment group by Medical Dictionary for Regulatory Activities (MedDRA) system-
organ class (SOC) and preferred term (PT) as obtained from CTCAE, version 5.0.  In these summaries, a 
subject may be counted only once for each PT and SOC.  Details for any TE-SAEs or TE-DAEs will be 
provided in individual subject data listings. 
  Clinical laboratory test, vital sign (including body weight), ECG and PHQ-9 values and changes from 
baseline will be summarized with appropriate descriptive statistics for each treatment group and each 
visit. 
6.10 Missing Data Handling 
For responder analyses, the last available post-baseline value will be used for patients who do not have 
an assessment on Day 15.  No other data will be imputed. 
6.11 Visit Windows 
Assessments during the treatment period (Days 4 to 15) that are not obtained on the scheduled day will 
be assigned to the nearest scheduled day.  For example, a PCSS assessment performed on Day 12 will be 
assigned to Day 11 for the purposes of ‘by visit’ summaries, unless the assessment was inadvertently 
obtained in addition to the Day 11 assessment. 
Assessments after the end of treatment that are not obtained within the scheduled window will be 
assigned to the nearest scheduled day (Day 21 or 44).   For example, if the QOLIBRI assessment was not 
obtained until Day 25, it would still be assigned to Day 21 for the purposes of ‘by visit’ summaries. 
6.12 Subgroup Analyses 
No subgroup analyses are currently planned for this exploratory study. 
6.13 Adjustment for Covariates 
No statistical modeling is planned for this exploratory study, therefore, there will be no adjustment for 
covariates. 


10 
 
6.14 Interim Analyses 
There are no plans for any unblinded interim analyses.  Unblinding will occur after the last subject has 
completed or discontinued from each part of the study, and the study database for that part has been 
cleaned and locked. 
It is anticipated that blinded data review will occur during to study in order to ensure that assumptions 
which served as the basis for planned analyses are appropriate. 
6.15 Statistical Software 
Data analysis will be conducted using Statistical Analysis System (SAS), 
Version 9.4.6.16 References 
 [1] The National Center for Biomedical Ontology was founded as one of the National Centers for 
Biomedical Computing, supported by the NHGRI, the NHLBI, and the NIH Common Fund under grant 
U54-HG004028. Musen MA, Noy NF, Shah NH, Whetzel PL, Chute CG, Story MA, Smith B; NCBO team. 
The National Center for Biomedical Ontology. J Am Med Inform Assoc. 2012 Mar-Apr;19(2):190-5. Epub 
2011 Nov 10. 
[2] Whetzel PL, Noy NF, Shah NH, Alexander PR, Nyulas C, Tudorache T, Musen MA. BioPortal: enhanced 
functionality via new Web services from the National Center for Biomedical Ontology to access and use 
ontologies in software applications. Nucleic Acids Res. 2011 Jul;39(Web Server issue):W541-5. Epub 
2011 Jun 14.