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

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)

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

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

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

Inclusion Age 16-65 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

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

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

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

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

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

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

What Will Happen in the ED? Screen Patient for Eligibility using inclusion/exclusion criteria *CT, blood alcohol level, pregnancy test Call Study Coordinator at 612-347-5710 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

What Will Happen in the ICU? Continue to Screen Patient for Eligibility using inclusion/exclusion criteria, if applicable Call Study Coordinator at 612-347-5710, 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

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)

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.

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.