1. HOBIT Hyperbaric Oxygen Brain Injury Treatment Trial: A Multicenter Phase II Adaptive Clinical Trial
Gaylan Rockswold, MD, PhD, Principal Investigator
Thomas Bergman, MD, Site Principal Investigator

2. Overview
HOBIT Trial: A Multicenter, Randomized, Prospective Phase II Adaptive Clinical Trial Evaluating the Most Effective Hyperbaric Oxygen Treatment Paradigm for Severe Traumatic Brain Injury
This trial will enroll 200 subjects over 3 1/2 years.
This trial is supported and sponsored by the SIREN Network which is funded by the National Institutes of Neurologic Disease and Stroke (NINDS)

3. Need for this Trial
Preclinical and clinical investigations indicate that hyperbaric oxygen (HBO₂) has a positive impact on reducing brain injury and improving outcomes in severe TBI.
By markedly increasing oxygen (O₂) delivery to the traumatized brain, HBO₂ can reverse the lack of O₂ that precipitates cellular energy failure and subsequent brain cell death.
Outcome from severe TBI has been flat lined for several decades

4. POTENTIAL MECHANISMS FOR HBO2 EFFICACY
Pre-clinical findings
-Depressed mitochondrial function following injury is restored
-ATP production is improved
-Ischemia induced brain cell loss is attenuated
-Neural apoptosis is reduced
-Cognitive deficits are markedly attenuated
-Intracranial hypertension is reduced

5. HOBIT Objectives
Objective 1​: (Signal of efficacy) whether there is a >50% probability of hyperoxia treatment demonstrating improvement in the rate of good neurological outcome versus control in a subsequent confirmatory trial.
Objective 2​: (Dose selection) To select, the combination of treatment parameters (pressure +/- intervening normobaric hyperoxia [NBH]) that is most likely to demonstrate improvement in the rate of good neurological outcome versus control in a subsequent confirmatory trial.
Probability of success of the trial
Find the most effective parameters

6. Inclusion
Age years
Severe TBI, defined as an index GCS (iGCS) of 3 to 8 (if intubated, motor score<6) in the absence of paralytic medication
For patients with a GCS of 7 or 8 or motor score = 5, Marshall computerized tomography (CT) score >1
For patients with an alcohol level >200 mg/dl, Marshall computerized tomography (CT) score >1
Requires abnormal CT scan in patients with GCS of 7 or 8

7. Inclusion Written, informed consent from LAR
For patients not requiring a craniotomy/craniectomy or any other major surgical procedure, the first HBO treatment can be initiated within 8 hours of arrival at​ enrolling hospital
For patients requiring a craniotomy/craniectomy or major surgical procedure, the first HBO can be initiated within 14 hours of arrival at​ enrolling hospital

8. Exclusion
First hyperbaric oxygen treatment cannot be initiated within 24 hours of injury
GCS of 3 with mid-position and non-reactive pupils bilaterally (4 mm) in the absence of paralytic medication
Penetrating head injury
Pregnant
Prisoner or ward of state
Acute spinal cord injury with neurologic deficits
Contraindication to ICP monitor placement

9. Exclusion Pulmonary dysfunction
Coma suspected to be due to primarily non-TBI causes
Non-survivable injury
Concern for inability to follow-up at 6 months
Inability to perform activities of daily living (ADL)
Implantable device/drug that is incompatible with HBO treatment

10. TREATMENT ARMS
Arm
Control (1.0 ATA)
260
416
540
592
620
776
952 1.
1.5 ATA 2.
2 ATA 3.
NBH (100% FiO2 at 1.0 ATA) 4.
2.5 ATA 5.
1.5 ATA+NBH
1.5, 2, 2.5 for 60 mins
3 arms followed by 3 hours NBH
NBH group= control for pressure 6.
2 ATA+NBH 7.
2.5 ATA+NBH 8.
Treatments will occur twice a day for 5 daysts given BID x 5 days
Investigator Meeting
February 2018

11. PRIMARY ENDPOINT
The treatment groups will be compared with respect to the proportion of subjects with favorable outcome at 6 months post randomization utilizing the injury severity adjusted GOS-E

12. SECONDARY ENDPOINTS
To analyze the level and duration of intracranial hypertension (> 22 mmHg) in HBO2-treated versus control groups
To analyze the therapeutic intensity level scores for controlling intracranial pressure in HBO2-treated subjects compared to controls
At sites utilizing Licox brain tissue partial pressure of oxygen (PO2) monitoring,
analyze the level and duration of brain tissue hypoxia (brain tissue PO2 < 20
mmHg) in HBO2-treated groups versus control
To compare the type and rate of serious adverse events (SAEs) between hyperoxia treatment arms and control
Does HBO treatment reduce intracranial hypertention
Look at TILS to see how much treatment keeps ICP under control
Peak PbtO2 levels during HBO2 treatments will be correlated with outcome at 6
months

13. What Will Happen in the ED?
Screen Patient for Eligibility using inclusion/exclusion criteria
*CT, blood alcohol level, pregnancy test
Call Study Coordinator at
Indicate if patient has an implantable device, study team will verify compatibility with HBO treatment at 2.5 ATA prior to enrollment.
Help coordinator identify/locate LAR for informed consent Patient will be randomized

14. What Will Happen in the ICU?
Continue to Screen Patient for Eligibility using inclusion/exclusion criteria, if applicable
Call Study Coordinator at , if not already done
Order HBO treatments (per randomization performed by the study team)
Prepare for initial transport to the HBO chamber (1st dive will occur w/in 8 OR 14 hours from ED arrival)
*Study coordinator help establish the schedule for the remaining dives and be on site for each dive

15. ICU Initial Prep for HBO: The Checklist
Remove all clothing. Jewelry, medication/patches
Perform bilateral myringotomies
Change IV tubing to HBO compatible tubing
Obtain CXR if significant changes occur in ventilatory/oxygenation status or invasive procedure performed
Make sure ETT tube is secure and note marking at lips
Correct any abnormalities in VS and ICP
Check blood glucose within 1 hour of transport to chamber (>100)

16. ICU Initial Prep for HBO
Cover / protect any sharp objects that cannot be removed, such as fixators
Cover open wound with dry dressings. Make sure wound/chest tube dressings are not saturated with petroleum/glycerin. Remove dressings containing alcohol.
Bring all IV medications and solutions (scheduled and PRN) for next 4- 6 hours.
Hep-lock non-essential IV ports. Note: monoplace chamber only has 6 ports and cannot piggyback.

17. 30 Minutes Prior to Transport to HBO
Confirm that Lung Sounds with ventiliation equal and bilateral. Suction as needed.
Notify HBO team of estimated time of transport to chamber
Sedate and paralyze patient for transport to HBO department (Bring extra meds)
Confirm that Monitors, IV pumps, pressure lines, Resuscitation bag, and transport ventilator are all ready for transport.
Move patient onto HBO2 gurney when transport team arrives
Elevate head of the bed to 30 degrees for HBO2 treatment.