A Clinical Trial to Determine the Safety and Efficacy of Hope Biosciences Autologous Mesenchymal Stem Cell Therapy for the Treatment of Traumatic Brain Injury and Hypoxic-Ischemic Encephalopathy
Phase: PHASE1
Conditions: Traumatic Brain Injury
Sponsor: Hope Biosciences LLC

A Clinical Trial to Determine the Safety and Efficacy of 
Hope Biosciences Autologous Mesenchymal Stem Cell 
Therapy for the Treatment of Traumatic Brain Injury 
and / or Hypoxic-Ischemic Encephalopathy
Protocol V8 
June 14th, 2023 
Principal Investigator: 
Charles S. Cox, Jr., M.D. 
The George and Cynthia Mitchell Distinguished Chair in Neurosciences 
Director, Children’s Program in Regenerative Medicine 
Professor, Department of Pediatric Surgery 
UTHealth McGovern Medical School at Houston 
Charles.S.Cox@uth.tmc.edu 
Phone: 713.500.7300     FAX: 713.500.7296    Pager: 713.327.1927 
Study Sponsor:  Hope Biosciences 
IRB NUMBER: HSC-MS-19-0685
IRB APPROVAL DATE: 07/31/2023

Hope Bio Protocol V8     
Document Date: 14 JUN 2023 
Title: 
A Clinical Trial to Determine the Safety and Efficacy of Hope Biosciences 
Autologous Mesenchymal Stem Cell Therapy for the Treatment of Traumatic 
Brain Injury and / or Hypoxic-Ischemic Encephalopathy 
Principal 
Charles S. Cox, Jr., MD 
Investigator: 
The George and Cynthia Mitchell Distinguished Chair in Neurosciences 
Director, Children’s Program in Regenerative Medicine 
Professor, Departments of Surgery and Pediatric Surgery 
UTHealth, McGovern Medical School at Houston  
Co-Investigators: 
Sean Savitz, M.D. Professor, Neurology 
UTHealth, McGovern Medical School at Houston 
Alan Prossin, MD.  Assistant Professor, Psychiatry  
UTHealth, McGovern Medical School at Houston 
Jenifer Juranek, PhD.  Associate Professor in Pediatric Research 
UTHealth, McGovern Medical School at Houston  
Biostatistician: 
Claudia Pedroza, PhD.  Assistant Professor 
UTHealth, McGovern Medical School at Houston 
Research 
Jacob Schriner, MD, Research Fellow, Department of Pediatric Surgery 
Residents: 
UTHealth, McGovern Medical School at Houston  
Study Coordinators: Steven C. Kosmach, MSN, RN, CCRC 
Clinical Trial Program Manager, Department of Pediatric Surgery 
UTHealth, McGovern Medical School at Houston  
Carmon Duron, MHA, RN 
Senior Research Nurse, Department of Pediatric Surgery 
UTHealth, McGovern Medical School at Houston  
Julia Ruiz 
Research Coordinator II, Department of Pediatric Surgery 
UTHealth, McGovern Medical School at Houston 
IRB NUMBER: HSC-MS-19-0685
IRB APPROVAL DATE: 07/31/2023

Hope Bio Protocol V8     
Document Date: 14 JUN 2023 
SYNOPSIS 
Protocol Title 
A Clinical Trial to Determine the Safety and Efficacy of Hope Biosciences Autologous 
Mesenchymal Stem Cell Therapy for the Treatment of Traumatic Brain Injury and / or 
Hypoxic-Ischemic Encephalopathy 
Clinical Phase 
Phase 1/2a 
IND # 
19204 
NCT # 
NCT04063215 
Study Site 
UTHealth Clinical Research Unit at Memorial Hermann Hospital-TMC 
Houston Methodist Research Institute 
Study 
Population 
Patients (18-55 years of age) with severe, chronic, neurological injury as defined by a history 
of traumatic brain injury or hypoxic-ischemic encephalopathy. 
Primary 
Objective: 
Determine the safety of HB-adMSCs as determined by infusional toxicity of the cell product. 
Secondary 
Objectives: 
Obtain treatment effect estimates of HB-adMSC infusion on global gray and/or white matter as 
well as structural integrity of GM and WM regions of interest in the corpus callosum and 
corticospinal tracts as measured by fractional anisotropy (FA) and mean diffusivity (MD) in 
specific regions known to correlate with specific neurocognitive deficits in patients after 
neurological injury.    
Exploratory 
Objective: 
Investigate if HB-adMSC infusion reduces the neuroinflammatory response to injury. 
Study Design 
Non-Randomized, Phase 1/2a study of three infusions of autologous HB-adMSCs (2 x 108 total 
cells per dose) administered over a 6wk. period with 14 day intervals between infusions. 
Sample Size 
A maximum of 24 patients. 
Inclusion 
Criteria 
1.
Adults between 18 and 55 years of age.
2.
Documented functional neurological damage to the central nervous system from closed
head trauma unlikely to improve with present standard of care approaches.
3.
A Glasgow Outcome Scale-Extended (GOS-E) score >2 and ≤ 6.
4.
Onset or diagnosis of the injury or disease process greater than 6 months.
5.
Ability to obtain consent from the subject or their legally authorized representative (LAR).
6.
Ability to communicate in English or Spanish (required for validated neurocognitive
outcome testing).
Exclusion 
Criteria 
1. Known history of:
a) intellectual deficiency or psychiatric conditions likely to invalidate our ability to assess
changes in cognition or behavior,
b) recently treated infection,
c) renal disease or altered renal function (screening eGFR > 60 mL/min/1.73m2),
d) hepatic disease or altered liver function (screening SGPT > 150 U/L or
T. Bilirubin >1.3 mg/dL),
e) cancer,
f) immunosuppression (screening WBC < 3, 000 cells/ml),
g) HIV+,
h) chemical or ETOH dependency that in the opinion of the investigator would preclude
participation in the study,
i) acute or chronic lung disease requiring significant medication, oxygen supplementation,
or mechanical ventilation,
j) bleeding disorders including immune-mediated heparin-induced thrombocytopenia,
k) known sensitivity to heparin, Lovenox, and pork products,
l) individuals with mechanical prosthetic heart valves.
....m) individuals who have received a stem cell treatment. 
2. Normal brain CT/MRI exam.
3. Spinal deformity, spinal surgery (including repeated epidural or spinal punctures), or
complete spinal cord injury diagnosed by CT/MR or clinical exam.  
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Hope Bio Protocol V8     
Document Date: 14 JUN 2023 
4. Diagnosed with a genetic or metabolic disorder related to the neurologic condition.
5. Other acute or chronic medical conditions that, in the opinion of the investigator, may
increase the risks associated with study participation.
6. For women of child bearing potential, a positive pregnancy test at the screening visit or, for
both women and men, unwillingness to comply with acceptable methods of birth control
during the study.
7. Concurrent participation in an interventional drug or device study.
8. Inability to undergo the diagnostic tests (PET/DT-MRI) or unwilling/unable to cooperate
with the diagnostic tests and outcome assessments.
9. Unwilling or unable to return for follow-up study visits.
10. Individuals planning to receive a vaccination two weeks before the brain imaging visits or
planning to receive a vaccination two weeks before or after a stem cell infusion visit.
Safety 
Monitoring  
and Follow-Up 
Subjects will be monitored and assessed for infusion related toxicity for the first 4hr. after the 
infusion and by telephone 24hr. after each infusion.  Safety assessments will be conducted at 
the study follow-up clinic visits 6 and 12 months, and 2 years (telephone call) after the last HB-
adMSC infusion, or more frequently if infusion related adverse events are suspected. 
Statistical 
Analyses 
The data will be analyzed using general linear mixed models (GLMMs) to estimate differences 
across time points (pre- and post-treatment).    
Stopping Rules 
The stopping rules listed below will trigger cessation of enrollment and potential study closure 
pending a comprehensive DSMB safety review. 
1. Any infusion related death.
2. An infusion related, sustained (over 3 minutes) episode of hypoxia (SaO2 of less than 80%)
or the new requirement for mechanical ventilation.
3. Grade 4-5 CNS cerebrovascular ischemia event or Grade 4-5 seizure event as defined in
the NCI CTCAE v4.0 occurring within 48 to 72 hours of the infusion.
4. Any Grade 4-5 Adverse Event as defined in the NCI CTCAE v4.0 and determined to be
temporally related to the HB-adMSC infusion by the Medical Safety Monitor and/or DSMB.
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ABBREVIATIONS 
adMSCs–Adipose Derived Mesenchymal Stem Cells 
ADL-Activities of Daily Living 
AE-Adverse Event 
ANAM-Automated Neuropsychological Assessment Metrics 
ARDS-Adult Respiratory Distress Syndrome 
CAT-Calibrated Automated Thrombogram 
CBC-Complete Blood Count 
CCI-Controlled Cortical Impact 
CD142-Tissue Factor or Platelet Tissue Factor 
CFU-Colony Forming Unit 
CGMP-Current Good Manufacturing Practices 
CFR-Code of Federal Register 
CMP-Complete Metabolic Panel 
CNS-Central Nervous System 
CRF-Case Report Form 
CRO-Contract Research Organization 
CRU-Clinical Research Unit 
CSF-Cerebral Spinal Fluid 
CTCAE-Common Terminology Criteria for Adverse Events 
CXR-Chest X-Ray 
DSMB-Data Safety Monitoring Board 
DTI-Diffusion Tensor Imaging 
DVT-Deep Vein Thrombosis 
EMR-Electronic Medical Record 
ESC-Embryonic Stem Cells 
ETOH-Ethanol/Alcohol 
F-Fibroblast 
FA-Fractional Anisotropy 
FDA-Food and Drug Administration 
GCP-Good Clinical Practice 
GCS-Glasgow Coma Scale 
GLMM-Generalized Linear Mixed Model 
GM-Gray Matter 
GOAT-Galveston Orientation and Amnesia Test 
GOS-E-Glasgow Outcome Scale - Extended 
HB-adMSC’s–Hope Biosciences’ Autologous Adipose-Derived Mesenchymal Stem Cells 
HIPAA-Health Insurance Protection and Portability Act 
HMRI-Houston Methodist Research Institute 
HPA-Hypothalamo-Pituitary-Adrenocortical 
HTLV- Human T-Lymphotrophic Virus 
IDO-Indoleamine 2,3-dioxygenase 
IND-Investigational New Drug 
INR-International Normalized Ratio 
iPS Cells-Induced Pluripotent Stem Cells 
IV-Intravenous
IRB-Institutional Review Board
LAR-Legally Authorized Representative
LPS-Lipo-Polysaccharide
MAPC-Multipotent Adult Progenitor Cells
MD-Mean Diffusivity
MHH-Memorial Hermann Hospital
MNC-Mononuclear Cells
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MSC-Mesenchymal Stem Cell 
MSM-Medical Safety Monitor 
MRI-Magnetic Resonance Imaging 
NCI-CTCAE-National Cancer Institute-Common Terminology Criteria for Adverse Events 
NIDRR-National Institute on Disability and Rehabilitation Research 
NIH-National Institutes of Health 
NINDS-National Institute of Neurological Disorders and Stroke 
NSC-Neural Stem Cells 
PBS-Phosphate Buffered Saline 
PCP-Primary Care Provider 
PE- Pulmonary Embolism 
PET-Positron Emitting Radionuclide 
PI-Principal Investigator 
PMN-Polymorphonuclear Leukocytes 
PT-Prothrombin Time 
PTT-Partial Thromboplastin Time 
QA-Quality Assurance 
QC-Quality Control 
SAE-Serious Adverse Events 
SQ-Subcutaneous 
TBI-Traumatic Brain Injury 
TSPO-Translocator Protein 
VFT- Verbal Fluency Test 
VOI-Volume of Interest 
VTE-Venous Thromboembolism 
WBC-White Blood Count 
WM-White Matter 
WOCBP-Women of Childbearing Potential 
IRB NUMBER: HSC-MS-19-0685
IRB APPROVAL DATE: 07/31/2023

Hope Bio Protocol V8     
Document Date: 14 JUN 2023 
A Clinical Trial to Determine the Safety and Efficacy of Hope 
Biosciences Autologous Mesenchymal Stem Cell Therapy for the Treatment 
of Traumatic Brain Injury and / or Hypoxic-Ischemic Encephalopathy 
1. STUDY OBJECTIVES
The global objective of this study is to establish the safety and investigate the potential treatment 
effect of an intravenous infusion of HB-adMSC on brain structure, neurocognitive/functional 
outcomes, and neuro inflammation after traumatic brain injury and/or hypoxic-ischemic 
encephalopathy in adults. 
1.1 Primary Objectives: Determine the safety of HB-adMSC as determined by infusional 
toxicity of the cell product. 
Allogeneic MSCs have been used in numerous oncologic and non-oncologic clinical trials.  They 
have an excellent safety profile that has been described in numerous publications.  A recent meta-
analysis evaluated 1012 patients with a variety of clinical conditions, and found only transient fever 
as an adverse event. (Lalu, 2012)  However, other publications have raised an issue of a complement 
mediated induction of coagulation using human cells in vitro. (Moll, 2014)  We and others have 
confirmed these findings, and have noted a Tissue Factor mediated pro-coagulant response associated 
with various types of MSCs with a wide variability related to CD142 expression. (Mangum, 2017; 
Christy, 2017, George, 2018)  We propose evaluating the potential infusional toxicity of HB-adMSC 
in patients with sub-acute and chronic neurological injury.   
1.2 Secondary Objectives: Obtain treatment effect estimates of HB-adMSC infusion on global 
gray and/or white matter as well as structural integrity of GM and WM regions of interest in 
the corpus callosum and corticospinal tracts as measured by fractional anisotropy (FA) and 
mean diffusivity (MD) in specific regions known to correlate with specific neurocognitive 
deficits in patients after neurological injury.   
We propose to investigate changes (from enrollment to 6 months post infusion) in global measures of 
structural integrity in GM and WM using volumetric and DT-MRI based imaging according to the 
protocols described in the appendix/Investigator Brochure.  T1-weighted images will be reviewed for 
image quality prior to performing morphometric analyses.  Using Freesurfer v5.0.0 software 
(www.surfer.nmr.mgh.harvard.edu), each brain is skull-stripped and segmented into 3 classes of 
voxels: gray matter, white matter, and cerebrospinal fluid (Dale & Sereno, 1993; Dale et al., 1999). 
Subsequently, the cortex will be parcellated for individual gyri yielding morphometric measures of 
cortical thickness, volume, and surface area and measures of underlying white matter fractional 
anisotropy (FA) within each gyrus (Fischl & Dale, 2000).  
Further, we will measure white and gray matter regions of interest and will correlate the degree of 
injury/preservation with functional and neuropsychological outcome measures.  These measures have 
been validated in multiple studies and are recommended by a task force from NIH and NIDRR as 
common data elements for TBI outcome research (McCauley et al., in press) and for use in clinical 
trials in TBI (Bagiella, 2011).  These measures were also selected to assess relations with specific 
white and gray matter structures that are particularly vulnerable to disruption by TBI.  White matter: 
corpus callosum (processing speed), corticospinal tract (motor coordination).  Gray matter: frontal 
lobe (fluency, attention, working memory) and temporal lobe (declarative memory). 
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2. Documented functional neurological damage to the central nervous system from closed head
trauma that is unlikely to improve with present standard of care approaches.
3. A Glasgow Outcome Scale-Extended (GOS-E) score >2 and ≤6.
4. Onset or diagnosis of the injury or disease process greater than 6 months.
5. Ability to obtain consent from the subject or their legally authorized representative (LAR).
6. Ability to communicate in English or Spanish (required for validated neurocognitive outcome
testing),
3.2 Exclusion Criteria: 
1. Known history of:
a) intellectual deficiency or psychiatric conditions likely to invalidate our ability to assess
changes in cognition or behavior,
b) recently treated infection,
c) renal disease or altered renal function (screening eGFR > 60 mL/min/1.73m2),
d) hepatic disease or altered liver function (screening SGPT > 150 U/L or T. Bilirubin
>1.3 mg/dL),
e) cancer,
f) immunosuppression (screening WBC < 3, 000 cells/ml),
g) HIV+,
h) chemical or ETOH dependency that in the opinion of the investigator would preclude
participation in the study,
i) acute or chronic lung disease requiring significant medication/oxygen supplementation,
j) bleeding disorders including immune-mediated heparin-induced thrombocytopenia,
k) known sensitivity to heparin, Lovenox, and pork products,
l) individuals with mechanical prosthetic heart valves,
m) individuals who have received a stem cell treatment.
2. Normal brain CT/MRI exam.
3. Spinal deformity, spinal surgery (including repeated epidural or spinal punctures), or complete
spinal cord injury diagnosed by CT or MR imaging or by clinical findings.
4. Diagnosed with a genetic or metabolic disorder related to the neurologic condition.
5. Other acute or chronic medical conditions that, in the opinion of the investigator, may increase
the risks associated with study participation.
6. For women of child bearing potential, a positive pregnancy test at the screening visit or, for both
women and men, unwillingness to comply with acceptable methods of birth control during
the study.
7. Concurrent participation in interventional drug or device study.
8. Inability to undergo the diagnostic tests (PET/DT-MRI) or unwilling/unable to cooperate with the
diagnostic tests and outcome assessments.
9. Unwilling or unable to return for the follow-up study visits.
10. Individuals planning to receive a vaccination two weeks before the brain imaging visits or
planning to receive a vaccination two weeks before or after a stem cell infusion visit.
The exclusion criteria are designed to prevent the enrollment of patients with chronic diseases or pre-
existing conditions that would influence the study outcome measures.  Also, patients with previous 
malignancy or immunosuppression are excluded as immunomodulation of the inflammatory response 
to injury is one of the putative mechanisms of action.  Spinal cord injury is an exclusion criterion due 
to the inability to perform many of the functional outcome measures.  Significant pulmonary disease 
is an exclusion criterion due to the potential for exacerbation of lung dysfunction with the intravenous 
cell infusion.  Lovenox administration for the prophylactic prevention of DVT/PE is contraindicated 
in individuals with known sensitivity to heparin and pork products, individuals with mechanical 
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prosthetic heart valves, individuals with spinal deformities, history of spinal cord injury or surgery.  
Vaccinations are known to produce a temporary systemic inflammatory response that may alter the 
brain PET scans and inflammatory biomarker results.  The effects of concomitant administrant of 
vaccines and stem cells are unknown. 
3.3 Selection and Pre-Screening of Subjects: 
Subjects will be recruited from the PI/Co-Investigator clinic population or by self-referral.  Potential 
subjects referred to the study will be contacted by telephone and screened using an IRB approved 
screening telephone script.  The study consent will be mailed to potentially eligible subjects wanting 
to proceed with the screening visit.  Potential subjects may also be identified from the PI/Co-
Investigator’s clinic population and approached in person during a routine clinic visit.  The research 
staff will screen potential subjects using standard of care medical record information and the 
inclusion/exclusion criteria listed above.   
Subjects may also be recruited from two IRB approved studies, HSC-MS-16-0283 or HSC-MS-15-
0744.  Potentially eligible subjects will be offered the opportunity of enrolling in the Hope Bio study 
during the end of study visit for the two protocols listed above.  The two studies share the same 
PET/DT-MRI imaging and analysis procedures as those listed in this protocol.  Subjects consenting 
to enroll in the Hope Bio study will not be required to repeat a brain PET/DT-MRI.  Their PET/DT-
MRI imaging data from HSC-MS-16-0283 or HSC-MS-15-0744 will be used for the Hope Bio study 
baseline imaging visit.   
During the first visit, the PI/Co-PI will review the study consent with the patient or their LAR.  The 
PI and/or Co-PI will meet with the patient and explain the purpose of the study, study procedures 
(including the adipose tissue extraction, cell infusions, and safety assessment procedures), follow-up 
visits, potential risks and benefits of the study, alternatives, and the voluntary nature of participation. 
Ample time will be given for the patient to ask questions and make a decision about participation.  If 
consent is obtained, a schedule of study events and a copy of the signed informed consent document 
will be provided to the patient.  The informed consent process will be documented in the subject’s 
medical record and will include the discussion points mentioned above.  A copy of the signed 
informed consent will be placed in the medical record.  If consent is not obtained from the patient, 
data collection will cease and the subject deemed a screening failure.  A screening log will be 
maintained to track enrollment information and reasons for screened but ineligible subjects. 
Subjects meeting the initial pre-screening interview (either in person or by telephone) will be 
scheduled for the 1st study visit in the Clinical Research Unit (CRU) at Memorial Hermann Hospital 
and if eligible, continue on with the study procedures/visits presented in Table 1 below.   
3.4 Visit #1: Screening & Consent 
During this visit, and after consent has been obtained, the subject will undergo the following 
procedures: 
1. Medical history including current medications and vaccinations,
2. Physical and neurological exam,
3. Vital signs (Heart Rate, BP, Respirations, Temp., SpO2),
4. Blood samples for baseline clinical labs (CBC with diff., CMP, coagulation panel, renal function
panel, urine hCG if applicable), and neuroinflammatory biomarkers and TSPO genotype,
5. Chest x-ray (AP, single view).
6. Baseline neurocognitive assessments.
The screening visit is anticipated to take about 4hr. to complete.  The site PI/Co-PI will make the 
final determination on the subjects’ eligibility and complete the inclusion/exclusion CRF.  Ineligible 
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subjects will be notified by telephone and referred to their PCP for follow-up care if indicated.  
Subjects meeting study eligibility will be contacted by telephone to schedule the baseline imaging 
visit.  The baseline imaging visit will be completed within 10 days of the screening visit. 
Subjects entering the study from HSC-MS-16-0283 or HSC-MS-15-0744 will already be consented 
and will not have a blood sample drawn for their TSPO genotype. 
Subjects will also be referred to a physician with Hope Biosciences who will perform the adipose 
tissue extraction. The adipose tissue extraction and processing will be performed under Hope 
Biosciences IND #18388 CMC procedures.  Hope Biosciences’ SOP for the adipose tissue extraction 
is provided in Appendix 1.  If for any reason Hope Biosciences is unable to prepare the HB-AdMSC 
infusion (insufficient stem cells, contamination, etc.) the subject will be contacted and given the 
option to repeat the adipose tissue extraction or withdrawal from participation.   
A staggered infusion visit plan for the 1st four subjects is included in Appendix 3  
3.5 Visit #2: Baseline Imaging  
The baseline PET/DT-MRI imaging will be conducted at the Houston Methodist Research Institute 
(HMRI).  The second study visit is expected to take about 5 hours to complete. 
Subjects will undergo the following procedures; 
1. Interval H&P update,
2. A pregnancy test will be repeated for female subjects of child bearing potential (if applicable),
3. Vital signs (Heart Rate, BP, Resp., Temp., SpO2),
4. PET/DT-MRI
Subjects and their care providers will receive instructions on administering SQ Lovenox (40mg once 
a day) for 7 days beginning the day before each infusion visit.  Subjects will be asks to record the 
Lovenox injections on a log and return the form at the next study visit.  A reminder call will be made 
to subjects the day before beginning each round of Lovenox.  SQ Lovenox will not be required for 
subjects already taking an anticoagulant. 
Subjects recruited from HSC-MS-16-0283 or HSC-MS-15-0744 will not be required to repeat the 
brain PET/DT-MRI for baseline imaging data. 
3.6 Visits #3 thru 5: HB-adMSC Infusions 
The infusion visits will be conducted in the CRU.  Subjects will receive a total of 3 infusions (2 x 108 
total cells per dose) administered over a 6 week period with 14 day intervals between infusions (+/- 3 
days).  The volume of each infusion will be 250mL infused over a 1hr. period (+/- 5 min.) at a rate of 
4-5mL per minute.
At each infusion visit, the subject will undergo the following study procedures: 
1. Interval H&P update (detailed neuro exam if indicated from interview and physical exam, current
medications and recent vaccinations),
2. Confirmation the subject started prophylactic Lovenox injections and review of the Lovenox
medication logs at follow-up visits,
3. A pregnancy test will be repeated for female subjects of child bearing potential (if applicable),
4. Vital signs (Heart Rate, BP, Resp., Temp., SpO2),
5. Insertion of a peripheral IV line,
6. Blood sample for clinical labs (CBC with diff., CMP, coagulation and renal function panels),
7. Benadryl and Solumedrol will be given as pre-meds before the infusion.  The dose for both drugs
will be 25mg for subjects <100kg. or 50mg for subjects ≥100kg.
8. A “time out” verification of patient/consent/procedure/cell product will be performed,
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9. The HB-adMSC infusion will be given by through the peripheral IV,
10. The subject will then be monitored for a minimum of 4hr.
Vital signs will be continuously monitored during the infusion and recorded at 15 minute intervals.  
Vital signs will be recorded at the end of the infusion and then every 15 minutes x 4 (1st hour), and 
then every 30 minutes x 4 (next 2 hours), and then every hour until discharge from the CRU, or more 
frequently if clinically indicated.  A chest x-ray may be obtained if clinically indicated to assess 
pulmonary AE/SAE’s.  The subject will be contacted by telephone 24hr. after each infusion visit to 
determine if adverse events have occurred.  Each infusion visit is expected to take around 6 hours to 
complete. 
3.7 Visit #6: Six Months Post-Infusion 
Safety and outcome assessments will be conducted in the CRU and at the HMRI 6 months from the 
last HB-adMSC infusion.  The visit will include: 
1. Interval H&P update,
2. Vital signs (Heart Rate, BP, Resp., Temp., SpO2),
3. Blood sample for clinical labs (CBC with diff., CMP, coagulation and renal function panels) and
neuro-inflammatory biomarkers,
4. A pregnancy test will be repeated for female subjects of child bearing potential (if applicable),
5. PET/DT-MRI,
6. Neurocognitive/functional outcome assessments.
The visit is expected to take about 8 hours and may require two days to complete the assessments and 
brain imaging. 
3.8 Visits #7: One Year Post-Infusion 
The one year post-infusion visit will be conducted in the CRU and is expected to take about 2 hours 
to complete.  The visit will include:  
1. Interval H&P update,
2. Physical and neurological exam,
3. Vital signs (Heart Rate, BP, Resp., Temp., SpO2),
4. Blood sample for clinical labs (CBC with diff., CMP, coagulation and renal function panels)
& neuro-inflammatory biomarkers,
5. A pregnancy test will be repeated for female subjects of child bearing potential (if applicable),
6. Chest x-ray (AP, single view),
7. Neurocognitive/functional outcome assessments.
3.9 Two Years Post-Infusion Telephone Call (End of Study) 
The final safety and outcome assessment will be conducted by telephone two years after the last HB-
adMSC infusion.  The brief telephone interview will include an assessment of the subjects’ health 
and adverse events or hospitalizations since the last study visit. 
3.10 Participant Satisfaction Survey 
Subjects or their care provider will be invited to complete an anonymous satisfaction survey in 
REDCap.  The survey results will be used for the development of future clinical research studies 
requiring community based participatory research (CBPR) activities with the goal of improving 
research recruitment and retention. 
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Table 1a: Study Procedures 
 
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Table 1b: Study Procedures for Subjects Recruited from HSC-MS-16-0283 or HSC-MS-15-0744 
 
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4. RISKS
4.1 Respiratory Risks: 
A concern exists regarding the intravenous infusion of large, adherent cells in a concentrated manner into a 
patient with a dysregulated systemic inflammatory response syndrome.  A potential risk is amplification 
instead of diminution of the post-trauma pro-inflammatory response that typically manifest as exacerbation 
of respiratory failure or ARDS.  Alternatively, the infusion could initiate a VTE event with subsequent 
cardiopulmonary sequelae of respiratory failure and/or right heart strain/failure.  Infused cells will be 
evaluated for CD142 expression (cell number and intensity) and evaluated via in vitro thromboelastography 
for pro-coagulant activity.  We plan to monitor oxygen saturation, and respiratory rate/work of breathing 
for the first 4 hours post-infusion.  Chest x-rays will be obtained at baseline and the final study visit or more 
frequently if clinically indicated.  We will re-examine the patient for VTE events (clinical exam, oxygen 
saturation) at each follow-up visit. 
4.2 Hepatic Risks: 
The reticuloendothelial system can sequester immature blood elements, theoretically resulting in hepatic 
injury.  An acute elevation of the AST/ALT hepatic enzymes > 900 U/dl post-infusion will be considered 
an infusion related adverse event.  This level is based upon the organ system scoring definitions for 
moderate hepatic failure and corresponds to the CTCAE v4.03 Grade 4 adverse event.  It is unlikely that 
"end vessel" microthrombosis would occur in the liver due to the dual blood supply of the liver and the 
lung is the first pass organ.  A comprehensive metabolic panel including AST/ALT will be drawn at each 
follow-up visit.    
4.3 Neurologic Complications: 
The patient's acute neurologic status will be evaluated at each study visit.  A grade 4-5 CNS 
cerebrovascular ischemia event or Grade 4-5 seizure event as defined in the CTCAE v4.03 occurring 
within 4 hours of HB-adMSC infusion will be considered an infusion related adverse event.  Other changes 
temporally related to HB-adMSC infusion (those events occurring within 48 to 72 hours of infusion) will 
be considered associated with the protocol and recorded as an adverse event.   
4.4 Coagulation Cascade: 
A coagulation panel will be obtained to include PT, PTT, (INR), FSP/D-Dimer, PLT thrombo-
elastography, CAT, and CD142.  Patients will also be monitored for the development of venous thrombo-
embolic events (see pulmonary monitoring above) as well as for the development of clinical deep vein 
thrombosis (limb swelling, tenderness, discoloration).  To minimize the risk of DVT or PE, prophylactic 
Lovenox SQ injections (40 mg once a day) will be given for 7 days beginning the day before each infusion 
visit.  Lovenox will not be administered to subjects already taking an anticoagulant. 
4.5 Pregnancy: 
Studies to assess the reproductive and developmental toxicity of HB-adMSC’s have not been conducted at 
this time.  Women of child bearing potential (WOCBP) and men (if their sexual partners are WOCBP) 
must use an effective form of birth control throughout the study period.  Highly effective birth control 
methods include sexual abstinence, surgical sterilization (hysterectomy, tubal ligation, vasectomy, etc.), 
hormonal contraceptives associated with inhibition of ovulation, intrauterine device, or intrauterine 
hormone –releasing system.  Post-menopausal is defined as having no periods for at least 12 months 
without another medical cause. 
5. OUTCOME EVALUATIONS
5.1 MRI Evaluations: 
5.1.1 MRI Acquisition and Analysis: 
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The primary goal of acquiring whole brain MRI data is twofold: 1) to quantitatively assess macro- and 
micro-structural properties of GM and WM regions at two time points after injury using state-of-the-art 
neuroimaging acquisition/analysis methods 2) to investigate macro- and micro-structural correlates of 
behavior in terms of cognitive performance and underlying neuropathology in a hypothesis-driven 
manner.  To accomplish these objectives, the MRI data needs to be collected using two different, yet 
complementary modalities of MRI: high-resolution anatomical MRI (aMRI) and diffusion tensor 
imaging (DTI).  The following MRI acquisition sequences will be used: 
Table 2: MRI Acquisition Sequences 
FOV 
[mm] 
Matrix 
Slice 
thickness 
No of slices 
(TR 
[msec]) 
No of 
Directions 
B0 
TE 
[ms] 
(TI 
[ms]) 
Coil 
DTI 
240 
(phase: 
A/P) 
128x192x1 , 100 % 
phase (reconstructed 
to 256) 
 ky_dir=2 
ky_dir=0 
3 mm 
36-40
(13,000)
32 
1000 
80 
(N/A) 
8 Ch 
Head 
(asset) 
3D 
FSPGR 
240 
(phase: L/R) 
224x352x1 75%phase 
(reconstructed to 512) 
1 mm 
128 
 (9.5) 
N/A 
N/A 
3.9 
(450) 
B0 
fieldmap 
FSPGR 
256x256x2 (nex) 
Also, set rhrcctrl to 3 
1 mm 
Same as 
Anatomical 
scans 
(50, angle 
30 degrees, 
BW 16kHz 
N/A 
N/A 
10 ms 
and 
15 ms 
BOLD 
220 
(phase:A/P) 
64x64x1 (epiRT) 
 3mm 
30 (cover 
whole 
head) 
N/A 
N/A 
35 
The details of analysis of the imaging data go beyond the space limitations of the synopsis section but are 
described in more detail in the Investigator Brochure. 
5.1.2 [11C]ER-176 PET Imaging: 
Upon meeting inclusion/exclusion criteria, subjects will be scheduled for a PET/DT-MRI scan.  All female 
subjects will be given a urine pregnancy test prior to each PET scan.  The results of this test will be kept as 
part of their confidential research record.  A positive screen will disqualify them from participation in the 
study.  Following their PET/DT-MRI scan, subjects will be contacted within 24-48 hours by a licensed study 
clinician to ascertain the presence/absence of unforeseen complications.  Clinical complications will trigger 
an appropriate medical intervention and/or referral.  
For the PET scan we will be using the tracer/label [11C]ER-176.  This tracer binds to proteins in the brain 
that we believe are involved in regulating the neuroinflammatory response to injury.  PET scans may include 
an affective challenge presented to the patient during the PET scanning period (e.g. induction of mood, 
affective pain, etc.).  Subjects will then be asked to lay quietly without movement on a cot with their head 
located within the PET "camera".  To permit tracer injection and withdrawal of blood samples, an IV will be 
inserted into a vein in both arms.  [11C]ER-176 will be injected into subjects’ vein during PET scanning by 
qualified and hospital approved/designated personnel.  At various points throughout the scan, subjects’ 
blood pressure, heart rate, breathing rate and blood oxygen saturation may be recorded.  If any of the MRI or 
PET data is compromised, subjects may be asked to repeat either the whole procedure or the portion 
compromised.  However, subjects have no obligation to honor this request.  Subjects will be compensated 
for their time. 
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5.1.3 Post PET Scanning:  
Immediately following completion of PET scanning, subjects will remain in the PET suite and be observed 
by staff qualified to determine the presence of adverse effects/sequelae to the PET scanning procedure.  
Subjects will meet with study personnel (office, phone, video chat, etc.) to complete neuro/psychometric 
measures and to determine the presence of unforeseen/untoward study complications. 
5.2 Neurocognitive and Functional Outcomes Evaluations: 
Neuropsychological outcome testing will be overseen by Dr. Linda Ewing-Cobbs.  The battery 
includes core NIH common data elements for moderate/severe TBI outcomes, recommended measures 
from the NIH toolbox, and TBI Quality of Life patient-reported outcomes. 
Table 3: 
Hope Bio Study – Testing Timeline 
Baseline - Visit 1 
Screening 
6 Month - Visit 6 
6mo post-infusion 
12 Month - Visit 7 
12mo post-infusion 
Caregiver Interview 
Glasgow Outcome Scale - Extended (GOS-E) 
Self-Reports 
Galveston Orientation and Amnesia Test (GOAT) 
TBI Quality of Life Questionnaires (TBI-QOL SF) 
Brief Symptom Inventory 18 (BSI 18) 
Neuropsychological Assessments 
NIH Toolbox – Motor: 9-hole Pegboard Dexterity Test 
NIH Toolbox – Cognition: Flanker Inhibitory Control and Attention Test 
NIH Toolbox – Cognition: List Sorting Working Memory Test 
NIH Toolbox – Cognition: Picture Vocabulary Test (Baseline and 12M) 
NIH Toolbox – Cognition: Dimensional Change Card Sort Test 
NIH Toolbox – Cognition: Pattern Comparison Processing Speed Test 
Rey Auditory Verbal Learning Test (RAVLT) 
D-KEFS: Verbal Fluency (VF)
Wechsler Adult Intelligence Scale - IV: Coding (WAIS IV – CD) 
Wechsler Adult Intelligence Scale – IV: Symbol Search (WAIS IV – SS) 
5.3 Cytokines and Pro/Anti-Inflammatory Marker Evaluation: 
Plasma cytokines, IL-1α, IL-4, TNFα, IL-6, IL-10 and albumin will be measured via a bead-based, 
flow cytometric ELISA for the cytokines, and BCG immunochemical analysis for albumin 
concentration.  Samples will be obtained at the baseline imaging visit #2, and at the 6 and 12 month 
follow-up visits.  This approach is based on findings that cytokine markers may be a useful biological 
effect marker for Phase 2 and 3 trials. 
6. SAFETY MONITORING AND REPORTING PLAN
The study will be conducted according to Good Clinical Practice (GCP) guidelines, the Declaration of 
Helsinki, US 21 Code of Federal Regulations (CFR) Part 50 – Protection of Human Subjects, and Part 
56 – Institutional Review Boards.  An independent Medical Safety Monitor (MSM), monitors from an 
Independent Contract Research Organization (CRO) and a Data Safety Monitoring Board (DSMB) will 
provide study oversight. 
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7. SUBJECT WITHDRAWAL
7.1 Description of Subject Completion 
Subjects are considered to have completed the study if they completed three HB-adMSC fusions and 
the follow-up study visits at 6 and 12 months and the two year post-infusion telephone interview. 
7.2 Withdrawal of Individual Subjects 
The research team will make every reasonable effort to keep each subject in the study through the two 
year end of study telephone interview.  If a subject withdraws from the study, the reason for 
withdrawal will be documented in the study records.  Possible reasons for withdrawal include: adverse 
experiences, protocol non-compliance, lost to follow-up, at the discretion of investigator, the DSMB, 
the study sponsor, or other regulatory agencies.  Study data and biological samples collected up to the 
point of withdrawal will remain in the study database for analysis. 
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7.3 Withdrawal of Subject from the Study Following Adverse Events 
The Pl will determine if an adverse event (AE) is of sufficient severity to require stopping subject 
participation.  The subject (or LAR) may also voluntarily withdrawal from the study due to what 
he/she perceives as an intolerable AE.  If the withdrawal from the study is due to an AE, the subject 
will be offered appropriate care under medical supervision until the symptoms of the AE resolve or the 
subject's condition becomes stable.  Subsequent review by the MSM, DSMB, IRB or the study sponsor 
may also result in the suspension of further enrollment. 
8. STATISTICAL ANALYSIS PLAN
8.1 Sample Size and Power 
A total of 24 patients will be enrolled in the study.  We do not provide a power analysis for any 
outcomes since no formal hypothesis testing will be conducted.  Instead, we will calculate estimates of 
treatment effect and 95% confidence intervals for all measures.  We will also calculate probabilities of 
treatment benefit using Bayesian analyses and conservative neutral priors.  Given that this is a Phase 
1/2a study, there are no prior studies from which we could derive informative priors.  Therefore our 
approach will be to use neutral priors meaning that a priori they will be centered at a null treatment 
effect.  However, we will restrict the prior range (ie, 95% prior credible interval) to exclude large 
treatment effects that are almost never observed in human clinical studies.   
8.2 Statistical Analyses 
Volumetric, DT-MRI, neuropsychological, and functional outcome measures will be analyzed using 
general linear mixed models (GLMMs) to estimate differences across time points (pre- and post-
treatment).  We will examine all variables to determine that they are relatively symmetric and 
unimodal and examine residuals from each model to ensure reasonable adherence to model 
assumptions.  The models will include time of assessment (pre- or post-treatment), and age (at study 
entry) as covariates and a random effect for subject to account for within subject correlation.  
Dependent variables will be the volume of whole brain gray matter, white matter, and CSF.  Each 
dependent variable will be evaluated separately.  Estimated differences at 6 months post treatment 
compared to pre-treatment will be reported along with 95% confidence intervals for all outcomes.  We 
will also calculate probabilities of treatment benefit or clinically important effects. 
8.2.1 Volumetric Analysis and Neurocognitive Outcomes 
For volumetric analyses and neurocognitive outcomes, we will use the global test procedure 
recommended by Bagiella et al (Bagiella, 2010).  This procedure allows analysis of multiple outcome 
measures in the assessment of intervention effects while controlling Type I error and maximizing 
power.  To examine brain-behavior relations, we will first examine the distribution of variables to 
determine whether assumptions are met for Pearson or Spearman correlation approaches.  To evaluate 
strength of brain-behavior relations, outcome scores will be correlated with specific macrostructural 
and microstructural metrics from the DTI.  For global outcome, the GOS-EC score will be correlated 
with gray and white matter volumes and corpus callosum FA.  For neurocognitive outcomes, the 
accompanying table shows the expected relations between outcomes and gray and white matter 
microstructural metrics.  We expect positive correlation of dependent variables with FA and white and 
gray matter volume and negative correlation of dependent variables with MD. 
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Table 4: 
8.2.2 Cytokine and Pro/Anti-Inflammatory Marker Analysis 
For inflammatory cytokines, time course data will be analyzed using a GLMM to test differences 
across time between pre- and post-treatment.  The dependent variables will be the neuroinflammatory 
biomarkers with time (to model the trajectory) and GOSE (3-4 or 5-8) as covariates and a random 
subject effect (to account for within subject correlation).  Point estimates of pre- and post-treatment 
differences will be reported along with 95% confidence interval 
8.2.3 PET Imaging Analysis 
PET imaging analysis: Following completion of PET scanning, two main types of PET analyses will 
be completed:  
8.2.3.1 Volume of Interest Analysis:  
A hypothesis-driven VOI analysis where selected brain regions are examined will be conducted. 
Advantage of narrow search within regions involved in regulating the pain experience (e.g., anterior 
cingulate, insular cortex, nucleus accumbens, thalamus, amygdala, periaqueductal gray).  Predefined 
VOIs obtained from data of previous studies are applied to image data and transferred to [11C]ER-176 
maps.  
8.2.3.2 Statistical Parametric Mapping:  
In these types of analyses, statistical parametric maps are obtained using whole brain image subtraction 
routines.  Differences between volunteer groups (and covariances with phenotypic data) will be 
compared using the general linear model on a voxel by voxel basis within SPM8 and Matlab software 
with correction for multiple comparisons.  Resulting Z-maps of statistical significance are mapped onto 
stereotactic space using volunteers’ anatomically standardized T1-weighted MRIs.  Only gray matter 
pixels and regions with specific binding will be included in the statistical parametric analyses (voxels 
with BPND values > 0.2).  To compensate for small residual anatomic variation between subjects and 
to improve signal to noise ratio, a 3D Gaussian filter (FWHM 6 mm) will be applied to each scan.  For 
Expected Relations of Neurocognitive Outcomes with Gray and White Matter 
Microstructure from Diffusion Tensor Imaging 
Neuropsychological Outcome 
Microstructure:  
Gray Matter MD 
Microstructure:  
White Matter FA 
Processing Speed 
WAIS-IV Coding 
Corpus callosum 
Fine Motor 
9-hole Pegboard Dexterity Test
Corticospinal 
Verbal 
D-KEFS Verbal Fluency
NIH Picture Vocabulary Test
Arcuate/superior 
longitudinal fasciculus 
Working Memory 
NIH List Sorting Working Memory 
Test 
Dorsolateral prefrontal 
cortex 
Declarative Memory 
Rey Auditory Verbal Learning Test 
Lateral temporal 
cortex, hippocampus 
Attention 
NIH Flanker Inhibitory Control and 
Attention Test 
Dorsolateral & 
ventrolateral prefrontal 
cortex 
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each subtraction analysis, one- or two-sample t-statistic values will be calculated for each voxel using a 
pooled smoothed variance across voxels.  Areas of significant differences will be detected with a 
statistical threshold set to control for a Type-I error rate at p = 0.05 for multiple comparisons, 
estimated using the Euler characteristic based on the number of voxels in the grey matter and image 
smoothness.  This threshold typically corresponds to z=4.3 to 4.6, lower for large size regions after 
cluster volume correction is applied.  Plans for implementing corrections based on false discovery rate 
(FDR) are underway.  The standard Euler characteristic method controls for Family-wise Type-I error, 
the chance of any false positives.  FDR is the proportion of false positives among suprathreshold 
voxels.  The FDR is a more lenient measure of false positives than Family-wise Error and hence more 
powerful, while offering a principled way to control false positives.  After significant statistical effects 
are obtained in SPM, regional data is extracted into SPSS, plotted to assess for outliers, and used in 
additional analyses (i.e. correlations with dependent variables).  Data is tested for normality (uniformly 
encountered) and if not obtained, equivalent non-parametric analyses will be used.  
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IRB NUMBER: HSC-MS-19-0685
IRB APPROVAL DATE: 07/31/2023

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Document Date: 14 JUN 2023 
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IRB NUMBER: HSC-MS-19-0685
IRB APPROVAL DATE: 07/31/2023