Phase 1-2 Study of Hyperbaric Treatment of Traumatic Brain Injury
Phase: PHASE1
Conditions: Traumatic Brain Injury
Sponsor: Barry Miskin, MD

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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STUDY PROTOCOL 
 
 
Hyperbaric Oxygen Therapy for Traumatic Brain injury 
 
 
PROTOCOL TITLE:                              Hyperbaric Oxygen Therapy for Traumatic                        
                                                                 Brain Injury  
 
         PROTOCOL NUMBER: 
JMC-TBI-001 
 
VERSION NUMBER: 
910 
 
VERSION DATE: 
February 21, 2018 
 
     
SPONSORED BY: 
Jupiter Medical Center 
 
 
1210 S. Old Dixie Hwy 
 
 
Jupiter, FL  33458 
 
PRINCIPAL INVESTIGATOR: 
Barry  Miskin, M.D. 
 
 
 
 
1002 S. Old Dixie Hwy, Suite 304 
 
Jupiter, FL  33458 
 
 
SUB INVESTIGATOR: 
Lee Fox, MD  
 
 
1210 S. Old Dixie Hwy 
 
 
Jupiter, FL  33458 
 
 
SITE ADDRESS: 
Jupiter Medical Center 
 
 
1210 S. Old Dixie Hwy 
 
 
Jupiter, FL  33458 
 
 
 
 
 
 
 
 
 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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INVESTIGATOR STATEMENT OF COMPLIANCE AND SIGNATURE: 
I confirm that I have read  this study protocol Study Number JMC-TBI-001, Version 10 – dated 
February 21, 2018   ---- including appendices and agree to the performance of the study according to this 
protocol. I will perform the study in accordance with the procedures described in the protocol and 
potential later amendments, and will try to contribute to the study in such a way that the targeted time 
schedule will be fulfilled. 
By my professional education and experience, I am licensed to practice medicine and qualified to 
execute this clinical study in patients. 
I will provide training and all necessary information including copies of the study protocol to the staff 
involved in the performance of the study. I will keep them informed about the general status of the 
study, including the development and report of any new information learned about the investigated 
treatment which may influence willingness of participants to participate/continue to participate in the 
study, and will verify that all tasks are fulfilled thoroughly and in a timely manner. 
I will perform the study according to the ICH-GCP Guidelines, the Declaration of Helsinki, national 
laws and regulations, and according to accepted moral, ethical and scientific standards within clinical 
research. 
I confirm that my facilities (equipment, etc.) are adequate to conduct the study according to the 
requirements of the study protocol. 
A patient will not be enrolled in the study without first providing his/her written informed consent. Only 
the versions of the Informed Consent that have been reviewed and approved by the local Institutional 
Review Board (IRB) will be used. 
I, or one of the sub-Investigators delegated by me, will review each case report form and confirm the 
correctness of entries by signature. 
I agree to regular monitor visits and to audits/inspections by contracted monitor company and/or by 
local and national authorities. I will provide original data (e.g., medical records, Imaging) to the 
monitors and/or auditors/inspectors to allow Source Data Verification. I, sub-Investigators, study 
coordinators delegated by me, will cooperate in data clarification procedures. 
All patients’ data will be treated as confidential; patient data will only be transferred in pseudonymous 
ways. All research data will be property of Jupiter Medical Center. 
Investigator Name and Address:  ____________________________________________________ 
                                      ____________________________________________________________ 
                                      ____________________________________________________________ 
Position:  
 
_____________________________________________________________ 
Signature: ____________________________________________ Date: _____________________ 
 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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The information contained in this document is confidential proprietary information of Jupiter Medical Center. 
Table of Contents: 
 
1. Introduction……………………..……………………………………………………………………4 
2. Research Objectives and 
Hypothesis……………………………………………………………………………………………4 
3. Study 
Population……………………………………………………………………………………………4 
4. Study Design and Research 
Methods………………………………………………………………………………………………5 
          Table 4.1: Assessment 
Schedule………………………………………………………………………………………….6 
5. Eligibility…………………………………………………………………………………………….7 
5.1 Inclusion…………………………………………………………………………………….7 
5.2 Exclusion……………………………………………………………………………………7 
Table 5.1: Prohibited 
Medications…………………………………………………………………………………8 
6. Human Subject 
Protections……………………………………………………………………………………………9 
7. Consent 
Process……………………………………………………………………………………………….9 
8. Evaluation of Benefits, Risks and 
Discomforts………………………………………………………….................................................9 
8.1 Benefits……………………………………………………………………………………..9 
8.2 Risks………………………………………………………………………………………..9 
9. How HBO Treatment is 
Administered……………………………………………………………………………………….10 
10. Contraindications to HBO 
Treatment…………………………………………………………………………………………..,11 
11. Early Study 
Termination………………………………………………………………………………………,,,,11 
12. Compensation……………………………………………………………………………………,,, ,11 
13. Efficacy 
Assessment…………………………………………………………………………………………,11 
14. Safety 
Assessment…………………………………………………………………………………………,12 
15. Statistical 
Analysis……………………………………………………………………………………………..12 
16. Expected 
Outcomes……………………………………………………………………………………………13 
17. References.…………………………………………………………………………………………. 14 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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18. ECOG Performance 
Status…………………………………………………………………………………………………15 
19. Appendix 
1……………………………………………………………………………………………………,,,. 
20. Appendix 
2……………………………………………………………………………………………………… 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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1. Introduction: 
Traumatic Brain Injury (TBI) is a painful, disabling disease of the brain. Several studies have reported 
improvement in behavioral and cognitive symptoms of TBI using pharmacological therapies such as the 
use of stimulant medications as well as amantadine. In addition, cognitive rehabilitation techniques are 
commonly used in most TBI clinical centers with some degree of effectiveness (Arciniegas, Anderson, 
Topkoff, & McAllister, 2005). Recently, animal and human studies (Harch et al 2012, Harch et al 2007, 
and Golden et al 2002) have shown promising results in the treatment of TBI with hyperbaric oxygen 
(HBO). Ischemia has been implicated as a major factor in symptoms of TBI.  The lack of oxygenation of 
the brain cells causes a shift from aerobic metabolism to anaerobic metabolism.  This results in acidosis 
and depletion of cellular energy. The damage from the event propagates to manifest in a myriad of 
symptoms attributed to TBI (Centers 2011). Penumbra (an area of moderately ischemic brain tissue 
surrounding an area of more severe ischemia) results from traumatic brain injury. This is an area of brain 
that has cells that are dormant.  They are not getting enough oxygen. Hyperbaric Oxygen Therapy is 
able to transport oxygen to this area and stimulate the cells to function again, resulting in improvement 
of traumatically damaged brain tissue. 
 
The use of HBO to treat disease is not new; at 2.0 to 3.0 atmospheres absolute (ATA), it is approved by 
Medicare for15 diagnoses (Centers 2006). A lower-pressure protocol of HBOT (1.5 ATA) has been 
under investigation beginning around 1989 (Golden et al, 2002; Harch and Neubauer, 1999, 2004a; 
Harch et al, 1994, 1996a; Neubauer et al, 1994) The use of HBO for treatment of various wounds and 
diabetic foot ulcers is thought to be the same process as treating TBI. HBO treatment of diabetic foot 
ulcers and wounds stimulates healing by oxygenating an area that was not accessible to oxygen prior and 
prevented healing.  This is the same mechanism that HBO uses to heal the brain in TBI. Recent studies 
using low pressure HBO for TBI at Louisiana State University as well as University of California, 
Irvine, University of North Dakota, and Georgetown University Medical Center have shown 
encouraging results (Harch et al 2012). 
 
Oxygen toxicity, with the most severe manifestation being seizure, is possible in all HBOT studies. Lin 
et al, in 2008, reported a 9% seizure rate at 2.0 ATA. At doses less than 2.0 ATA, toxicity has been 
noted only with prolonged treatment (Harch 2002). 
 
 
 
2. Research Objectives and Hypothesis 
 
This study is designed to test the hypothesis that patients with TBI treated with HBO will show 
improvement in function and an increased blood flow as evidenced by single-photon emission 
computerized tomography (SPECT) scan. Improvement is evidenced by increase in number of pixels on 
SPECT Scan and increased brain metabolism. Improvement may also be identified via cognitive 
assessments administered by Jupiter Medical Center Research Department. 
 
3. Study Population: 
100 male or female patients over the age of 18 years old that have experienced a TBI at least one 
year old from Visit 1A. 
 
 
 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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4. Study Design and Research Methods 
 
Patients with TBI who have may have abnormal findings including hemorrhagic cortical contusions or 
petechial or foci of altered signal that represents white matter injury are candidates for inclusion in this 
trial. MRI, CT or SPECT scans showing changes consistent with TBI and or medical history of TBI as 
evidenced by medical records will be screened for treatment with HBO. Each recruited patient will 
undergo 5 times-a-week HBO treatments to 1.5 ATA (atmospheres absolute).  
 
Prior to study enrollment patients will be screened for eligibility by evaluating CT scan of head without 
contrast, MRI of brain or SPECT Scan, neurological evaluation from neurologist and history and 
physical from patient’s primary medical physician.  The neurological evaluation will determine whether 
patients have contraindications for HBO treatment and meet study criteria.  
 
After obtaining informed consent of patient, each patient will have a baseline SPECT scan, cognitive 
assessment, and physician evaluation prior to first treatment. The treatment regimen will be completed 
in 40 treatment increments. After 40, 80, and 120 treatments SPECT scan, cognitive testing and 
physician visit will be performed to document progress of the treatment. Cognitive assessment will 
include the Trail Making Test Parts A and B (See Appendix 1) performed by the research coordinator.  
Patients will be seen by Principal Investigator to assess level of disability at each interval; the United 
States Department of Veterans Affairs’ Evaluation of Cognitive Impairment and Subjective Symptoms 
(VAECI) (2012) tool (See Appendix 2) will be utilized during the physician’s evaluation as an objective 
measure of the patient’s level of disability. At the completion of study regimen, patient will again be 
seen by neurologist to assess level of function and cognitive status.  HBO treatments may be adjusted for 
patient comfort. If the SPECT scan, cognitive assessment and physician evaluation show improvement 
after 40 treatments, another 40 HBO treatments will be administered. Treatments will be discontinued 
after a 40 session interval if the SPECT scan, cognitive assessment and physician evaluation show no 
improvement. At this time, a neurology exam will also be performed. The patient will also have a 
SPECT scan and cognitive assessment follow up 3 months after final HBO treatment. See Assessment 
Schedule listed in Table: 4.1 
 
Because of the expected high variability on these measures for different TBI patients, the outcome of 
this study will be based on changes in the measures from baseline.  Thus each subject serves as his/her 
own control.  This has the further advantage of removing the need for a separate expensive and unethical 
control arm of this study in which healthy patients undergo the same regimen as the TBI patients, or TBI 
patients undergo a waiting period before starting TBI treatments.  Baseline assessments must be 
completed not more than one year before the initial Visit 1/ to the clinic.   
 
The primary endpoint will be improved cerebral blood flow on the SPECT scan. It is expected that most 
TBI will show signs of improvement within completion of 40 HBO treatments (Harch et al, 2012). The 
study treatment will be stopped at the patient's request, the physician's request, or if HBO cannot be 
continued due to medical or financial constraints. 
 
Secondary endpoints will include improvement scores on cognitive assessment and level of disability. 
 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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Table 4.1: Assessment Schedule: 
 
Visit: 
Baselin
e 
Baselin
e 
 
Post 40 
HBO 
Post 80 
HBO 
Post 120 
HBO 
3 Month 
Follow Up 
Visit No. 
1A 
1B 
 
2 
 
3 
 
4 
5 
Informed Consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Inclusion/Exclusion 
X 
X 
 
 
 
 
Pregnancy Test¹ 
 
X 
 
 
 
 
SPECT Scan 
X 
 
X 
X 
X 
X 
Physical Examination 
 
 
X 
 
 
 
 
Trail Making Test A and B 
 
X 
X 
X 
X 
X 
VA Cognitive Eval.² 
 
X 
X 
X 
X 
X 
Physician Review 
X 
X 
X 
X 
X 
X 
Neurologist Eval.³ 
 
 
 
 
X 
 
HBO treatment scheduled  
 
X 
X 
X 
 
 
 
 
 
 
1. To be completed by all women of childbearing potential at Baseline and again within 7 days of 
first HBO treatment. 
2. VA Cognitive Evaluation to be completed by Principal Investigator. 
3. Neurologist Evaluation to be completed after final 120 HBO treatments.  

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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5. Eligibility 
 
5.1 Inclusion criteria: 
Patients eligible for inclusion in this study have to fulfill all of the following criteria: 
 All Stage TBI as demonstrated by loss of consciousness due to the injury that is at least 1 year 
old at the time of Visit 1. Minimum of 1 year old. TBI may include: external head injury, stroke, 
open head injury, hypoxic injury and diffuse axonal injury. 
 Male or female patients Age ≥18 years of age at Visit 1. 
 ECOG rating score 0-2  
   Women: Negative pregnancy test via urine specimen required at screening for all women of 
child bearing potential. If sexually active, women will take contraceptive measures for the 
duration of the treatments. Medically acceptable contraceptives include: 1) surgical sterilization 
(such as tubal ligation, hysterectomy, 2) approved hormonal contraceptives (such as birth 
control pills, patches, implants or injections), 3) barrier methods (such as a condom or 
diaphragm) used with a spermicide, or 4) an intrauterine device (IUD). 
   Women: Additional urine specimen for pregnancy testing is required for all women of child 
bearing potential within 7 days prior to first dose of HBO.  
 Subject is alert and oriented x3 to give legal, effective consent. 
 Written informed consent, approved by the Institutions Review Board must be obtained before 
any assessments are performed. 
    History of lung disease (e.g. bronchitis, asthma) requires chest x-ray prior to   inclusion in the 
study 
    Documentation of TBI with a CT Scan of head , MRI of brain or SPECT Scan, neurological 
evaluation by a neurologist and primary physician within 12 months of Visit 1. 
   Not taking prohibited medications 
 
5.2  Exclusion criteria: 
Patients fulfilling any of the following criteria are not eligible for inclusion of this study. 
 Untreated Pneumothorax 
 Anti-metabolites/chemotherapeutic agents (is used currently) 
 History of spontaneous pneumothorax 
 Seizure Disorder 
 Acute Upper Respiratory Infection 
 Acute High Fever 
 Acute Viral Infection 
 Participation in another experimental trial with active interventions 
 Women who are pregnant or lactating 
 History of Brain tumor (malignant or benign) 
 Brain infection 
 Dementia or Alzheimer’s Disease 
 History of malignancy (basal cell carcinoma and in situ squamous cell carcinoma of skin 
that has been completely excised with clear margins will be considered eligible). 
 No psychiatric disorders (e.g., bipolar disorder, schizophrenia, Major depressive disorder, 
etc.)  

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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Treated depressive disorders with documented stability for 12 months prior to Visit 1 will 
be considered eligible. 
 Any previous HBO treatment 
 Any concurrent disease that may interfere with efficacy of treatment in the opinion of the 
Investigator. 
 Currently taking any prohibited medications (See Table 5.1 below) 
 Active/Open Workers Compensation Case. 
 Active cardiac issues:  e.g. Aortic aneurysm, Unstable ventricular tachycardia, atrial 
fibrillation, etc.as  per PI discretion. 
 
Table 5.1: Prohibited Medications 
 
Prohibited Medication: 
Comments: 
Antiepileptic medications (e.g., Valproate, 
lamotrigine, carbamazeipine, phenytoin, 
levetiracetam, topiramate, etc.) 
Use of medication for indications other 
than seizure control with documentation 
will be considered eligible. 
Acetylcholinesterase inhibitors (e.g., 
donepezil, galantamine, rivastigmine, etc.) 
 Requires a wash out period of 5 half-lives 
prior to screening period 
Memantine 
Requires a wash out period of 5 half-lives 
prior to screening period 
Anti-metabolites (e.g., methotrexate, 
flurouracil, etc.) 
Requires a wash out period of 5 half-lives 
prior to screening period 
Chemotherapeutic agents  
Current use 
Amantadine 
 Requires a wash out period of 5 half-lives 
prior to screening period 
 
 The following are exclusions, if diagnosed in the past year, unless medically cleared by a 
physician: 
 History of thoracic surgery 
 Pneumothorax risk & CPR 
 Pulmonary lesions on X-ray or CT scan 
 Obstructive lung disease 
 Asthma 
 Congestive Heart Failure 
 Chronic Sinusitis 
 Sickle Cell Anemia 
 Reconstructive Ear Surgery 
 History of optic neuritis 
 Recent retinal repair 
 Congenital spherocytosis 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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 Severe confinement anxiety 
 Use of nicotine 
 
6. Human Subject Protections 
 
Adult subjects will be selected by the above criteria. Recruitment of patients will include word of 
mouth via community doctors, pamphlets and press release. All treatments will be at Jupiter Medical Center. 
 
7. Consent Process 
 
The Principal Investigator or designee will fully explain the purpose and potential risks and benefits of 
the study to the subject prior to enrollment and address any questions posed by the subject. The 
subject will receive a copy of the signed consent document. The original signed consent will be 
retained by Jupiter Medical Center’s Research Department for each subject. The investigators will 
explain to each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, and any discomfort it may entail. Each subject will 
be informed that participation in the study is voluntary and that he/she may withdraw from the study 
at any time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. If the consent form is amended throughout the duration of the 
subject’s treatment, the subject who are currently active at the time of the change will be informed of 
the changes and asked to sign the amended consent form. A copy will be given and the original will be 
retained with the previous signed consent. 
 
8. Evaluation of Benefits, Risks and Discomforts 
 
8.1  Benefits:  
Decrease in symptoms, improved cerebral blood flow, neurologic improvement in patients with 
TBI 
 
       8.2  Risks:  
Under proper supervision, the risks of HBO treatment are very minimal. The most common side effect is 
ear pain, and patients are monitored closely for this. Rarely, less likely but serious, oxygen toxicity, 
pulmonary barotrauma, and vision change can be experienced. 
  
The following list of potential side effects is reviewed with each patient prior to beginning 
therapy. 
 
 Otic Barotrauma (pain in the ears or sinuses). Some patients may experience pain in their ears 
or sinuses. If they are not able to equalize their ears or sinuses, the pressurization will be slowed 
or halted and suitable remedies will be applied. 
 Serous Otitis. Fluid in the ears sometimes accumulates as a result of breathing high 
concentrations of oxygen. It may occasionally feel like having a "pillow over the ear." This 
disappears after hyperbaric treatment ceases and often can be eased with decongestants. 
 Oxygen Toxicity. The risk of oxygen toxicity is minimized by never exposing patients to greater 
pressure or longer times than are known to be safe for the body and its organs. The risk is less 
than one in 10,000 treatments. 

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 Visual Changes (blurring, worsening of near-sightedness [myopia], temporary improvement in 
far-sightedness [presbyopia]). After 20 or more treatments, especially for those over 40 years 
old, some patients may experience a change in vision. This is usually temporary and in the 
majority of patients, vision returns to its pre-treatment level about six weeks after the cessation 
of therapy. It is not advisable to get a new prescription for glasses or contacts until at least eight 
weeks after ending hyperbaric oxygen therapy. 
 Maturing or Ripening Cataracts. Individuals with cataracts have occasionally had a maturing 
or ripening of cataracts. This is not reversible and may need surgical treatment. 
 Cerebral Air Embolism and Pneumothorax. Whenever there is a rapid change in ambient 
pressure, there is the possibility of rupture of the lungs with escape of air into the arteries or into 
the chest cavity outside the lungs. This can only occur if the normal passage of air out of the 
lungs is blocked during decompression.  Only slow decompressions are used in HBO treatment 
to obviate this possibility. It is important for patients to breathe normally during treatment and 
not hold their breath. This is less likely, but serious. 
 Fatigue. Some people may subjectively feel fatigue following hyperbaric treatment, but this is 
not a consistent finding. 
 Risk of Fire. With the use of oxygen in any form there is always an increased risk of fire. 
However, strict precautions have been taken to prevent this and all applicable codes have been 
complied with. There has never been a fire involving a hyperbaric chamber at Jupiter Medical 
Center. 
 
9. How HBO Treatment Administered 
 
Before going into the monoplace chamber, the patient is required to remove all clothing and put on a 
100% cotton gown. Once they are lying comfortably on the transfer gurney, it will be slid into the clear 
sided chamber. After the door closes, the gentle "hiss" of the incoming oxygen used to pressurize the 
chamber will be heard. 
 
As pressure develops in the chamber, the patient will notice the chamber warming slightly. They will 
also feel fullness in their ears and should begin ear clearing procedures. When compression is complete, 
the need for ear clearing ceases. The patient may now rest, watch TV, view a video tape or listen to 
music. The patient will be in the HBO chamber for approximately 60 minutes at 1.5 ATA. Allowance of 
additional time in the chamber will be needed to account for compression and decompression.  
 
During decompression, the chamber becomes cooler and the patient will feel a slight popping sensation 
in their ears as they adjust to the changing pressure. There is no need to clear the ears during 
decompression.  No oxygen mask is required in this chamber because the entire chamber is filled with 
USP medical grade oxygen. 
 
 
10. Contraindications to HBO Treatment 
 
Two contraindications to HBO treatment are an untreated tension pneumothorax (an accumulation of air 
or gas in the pleural cavity of the lungs) and certain chemotherapy agents. Chest X-rays will be 
performed prior to initial treatment. 
 
There are several conditions in which caution must be observed. It is important that the hyperbaric 
physician is aware of the following conditions prior to beginning treatment: 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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Chronic sinusitis  
History of thorax surgery 
Congenital spherocytosis  
Pulmonary lesions in routine X-ray or CT scan 
Emphysema with C02 retention  
 
 
Seizure disorders 
History of optic neuritis 
 
 
 
Sickle cell anemia 
History of reconstructive ear surgery  
 
 
History of spontaneous pneumothorax 
 
 
 
11.  Early Study Termination 
The Investigator must promote compliance to treatment schedule by instructing the subject to complete 
each HBO treatment exactly as designed in the protocol by stating that compliance is necessary for the 
validity of the study. The subject must also be instructed to contact the Investigator if he/she is unable to 
complete a treatment for any reason. If a subject cannot complete a treatment due to an adverse event, 
the Investigator will determine whether the subject should continue or be terminated from the trial. If a 
subject misses more than 5 consecutive treatments, the Investigator will determine whether or not to 
terminate the subject from the trial. 
 
12. Compensation 
 
There will be no compensation given to participants in this study. 
 
 
13. Efficacy Assessment 
 
Monitored by SPECT scan, Trail Making Test Part A and B (See in Appendix 1), Evaluation of 
Cognitive Impairment (4.124a - Schedule of ratings - neurological conditions and convulsive disorders, 
United States Department of Veteran Affairs, 2012) completed by the Principal Investigator (See 
Appendix 2). 
 
14. Safety Assessment (including recording adverse events) 
The investigator will assess for adverse events at each treatment. 
Serious adverse events (SAE) are to be reported to FDA utilizing MEDWatch form FDA 3500A.  
 
An SAE is defined as death or a life threatening event, permanent impairment or an event that requires 
medical or surgical intervention to preclude impairment. 
 
All adverse events (AE) will be recorded by Jupiter Medical Center’s Research Department. All AEs 
will be documented using CTCAE v4 criteria with grade and attribution. Any SAE will be reported to 
the IRB as requested/required. 
 
An independent Clinical Research Organization (CRO) will monitor all data, regulatory documents, and 
compliance with AE reporting throughout the study.  In addition, interim analyses will be performed 
after 25% accrual has been reached. 
 
 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
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15. Statistical Analysis 
 
Statistics will be documented to identify improvement.   
 
The Trail Making Test (TMT) uses an objective scoring method based on time that offers validity to 
cognitive performance status. “Results for both TMT A and B are reported as the number of seconds 
required to complete the task; therefore, higher scores reveal greater impairment” (Trail Making Test 
(TMT) Parts A & B (See Appendix 1)).   
 
The Veterans Administration Evaluation of Cognitive Impairment and Other Residuals of TBI will also 
be used to determine extent of improvement (4.124a - Schedule of ratings - neurological conditions and 
convulsive disorders, United States Department of Veteran Affairs, 2012 (See Appendix 2)).  
 
SPECT CT blood flow analysis will be performed consistently on the same machine and interpreted by 
the same investigator or designee to increase objectivity. An increase in the number of pixels on the 
SPECT scan will indicate improved blood flow to the brain. 
 
The objective measure will be the Trail Marking Test.  We will compute the fraction of patients who 
show improvement on the Trail Marking Test.  If a sample of patients were taken without treatment we 
would expect about half to improve on the TMT and about half to get worse.  For the treated patients we 
will test the hypothesis that the population fraction improving is larger than 0.5 against the alternative 
that is it 0.5 (a one-sided test).  The binomial distribution will be used to perform the test and obtain 
confidence intervals.  Other measures will be summarized by the average and confidence intervals for 
the change from baseline using appropriate t-distributions. 
 
 
16.   Expected Outcomes 
 
Improved (increase number of pixels on SPECT scan) blood flow to brain, improved (cognitive 
assessment score) cognitive function, improvement in symptoms and Evaluation of Cognitive 
Impairment score. 
 
 
 
 
 
 
 
 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
Version #10:  Dated: February 21, 2018                                                                           Page 14 of 15 
 
The information contained in this document is confidential proprietary information of Jupiter Medical Center. 
17. References 
 
Arciniegas, D. B., Anderson, C. A., Topkoff, J., & McAllister, T. W. (2005). Mild traumatic brain 
injury: a neuropsychiatric approach to diagnosis, evaluation, and treatment. Neuropsychiatric Disease 
and Treatment, 1(4), 311. 
Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, Facts 
for Physicians about Mild Traumatic Brain Injury (2011, CS109152)  
Centers for Medicare and Medicaid Services. National Coverage Determination (NCD) Hyperbaric 
Oxygen Therapy (20.29) National Coverage Determination Manual, Publication Number 100-3, 
effective date 6/19/2006. 
Golden, Z. L., Neubauer, R., Golden, C. J., Greene, L., Marsh, J., and Mleko, A. (2002). Improvement 
in cerebral metabolism in chronic brain injury after hyperbaric oxygen therapy. International Journal of 
Neuroscience, 112(2), 119-131.. 
Harch, P. G., Andrews, S. R., Fogarty, E. F., Amen, D., Pezzullo, J. C., Lucarini, J., and Van Meter, K. 
W. (2012). A phase I study of low-pressure hyperbaric oxygen therapy for blast-induced post-
concussion syndrome and post-traumatic stress disorder. Journal of Neurotrauma, 29(1), 168-185. 
Harch, P. G., Kriedt, C., Van Meter, K. W., and Sutherland, R. J. (2007). Hyperbaric oxygen therapy 
improves spatial learning and memory in a rat model of chronic traumatic brain injury. Brain Research, 
1174, 120-129. 
Harch, P.G. and Neubauer, R.A. (2004a) Hyperbaric Oxygen Therapy in Global Cerebral 
Ischemia/Anoxia and Coma, in: Chapter 18, Textbook of Hyperbaric Medicine, 4th revised ed. K.K. Jain 
(ed.) Hogrefe and Huber Publishers: Seattle, pps. 223-261 
Lin, J. W., Tsai, J. T., Lee, L. M., Lin, C. M., Hung, C. C., Hung, K. S., & Chiu, W. T. (2008). Effect of 
hyperbaric oxygen on patients with traumatic brain injury. Reconstructive Neurosurgery, 145-149. 
Neubauer, R. A., Gottlieb, S. F., and Pevsner, N. H. (1994). Hyperbaric oxygen for treatment of closed 
head injury. Southern Medical Journal, 87, 933-933. 
Trail Making Test (TMT) Parts A & B. (PDF Document). Retrieved from 
http://doa.alaska.gov/dmv/akol/pdfs/uiowa_trailmaking.pdf  
United States Department of Veteran Affairs. (2012). 4.124a - Schedule of ratings - neurological 
conditions and convulsive disorders [Data file].  Retrieved from 
http://www.benefits.va.gov/warms/bookc.asp 

Ct just at baseline. Neuro at each check point. syhoneurologist should be administering the cognitive exam. Don't think we need inter nal med. 
Version # 10                                                                                               Page 15 of 15 
The information contained in this document is confidential proprietary information of Jupiter 
Medical Center. 
 
 
ECOG Performance Status* 
 
 
 
These scales and criteria are used by doctors and researchers to assess how a patient's disease 
is progressing, assess how the disease affects the dally living abilities of the patient, and 
determine appropriate treatment and prognosis. They are indicated for health care professionals 
to access. 
 
Grade 0 = Fully active, able to carry on all pre-disease performance without restriction 
 
Grade 1= Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g. light housekeeping, office work 
 
Grade 2 =Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
 
Grade 3 =Capable of only limited self-care, confined to bed or chair more than 
 
50% of waking hours 
  
Grade 4 = Complete disabled. Cannot carry on any self-care. Totally confined to bed or chair 
 
Grade 5 = Dead 
 
*As published in AM. J. Clin. Oncol.: 
  
Oken, M.M., Creech, R.H., Tormey, D.C., Horton,1., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am 
1Clin Oneal 
5:649-655, 1982. 
 
The ECOG Performance Status is in the public domain therefore available for public use. To 
duplicate the scale, please cite the reference above and credit the Eastern Cooperative 
Oncology Group, Robert Comis, M.D. Group Chair.