Brain Tissue Oxygen Monitoring in Traumatic Brain Injury (TBI)

Design and Outcomes

This study is a two-arm, single-blind, randomized, controlled, phase II, multi-center pilot
trial of the efficacy of pBrO2 monitoring, and is designed to obtain data required for a
definitive phase III study, such as efficacy of physiologic maneuvers aimed at normalizing
pBrO2. 182 patients with severe TBI who require ICP monitoring will be recruited into this
study at 4 clinical sites in the US (Univ. of Texas Southwestern/Parkland Memorial Hospital,
Univ. of Washington/Harborview Medical Center, Univ. of Miami/Jackson Memorial Hospital, and
Univ. of Pennsylvania/Hospital of the Univ. of Pennsylvania). All patients will have both
ICP monitors and pBrO2 monitors inserted through the same burr hole. Half of the patients
will be randomized to a treatment protocol based on both ICP and pBrO2 readings, while the
control group will be randomized to a treatment protocol based only on ICP readings. The
pBrO2monitors of the control arm will be masked, so that the treating physicians will be
unaware of the pBrO2 information. Patients will have telephone follow-up interview to assess
their level of recovery 6 months post injury, using the Glasgow Outcome Scale-Extended.

Interventions and Duration

Patients randomized to the control group will have pBrO2 implanted in a similar fashion as
patients in the treatment group, but after calibration of the device, the display will be
covered with opaque tape. Patients in the control will be treated with a protocol based on
ICP measures only. Patients in the treatment group (both ICP and pBrO2 measures are visible)
will be treated according to a protocol that incorporates both ICP and pBrO2 measures. The
treatment protocols are based on current standards of care, but are described in detail to
insure uniformity in treatments across the 4 study sites.

The probe will remain in place for a maximum or 5 days, until all values are normal for 48
hours, or sooner if a complication arises. If the patient has normal values, monitors will
be removed after 48 hours.

Objectives

Primary Objective: The prescribed treatment protocol, based on pBrO2 monitoring, results in
reduction of the fraction of time that brain oxygen levels are below the critical threshold
of 20 mm Hg in patients with severe traumatic brain injury.

Secondary Objectives:

- Safety hypotheses: Adverse events associated with pBrO2 monitoring are rare.

- Feasibility hypotheses: Episodes of decreased pBrO2 can be identified and treatment
protocol instituted comparably across 4 clinical sites, and protocol violations will be
low (<10%) and uniform across different clinical sites.

- Non-futility hypothesis: A relative risk of good outcome measured by the Glasgow
Outcome Scale-Extended 6 months after injury of 2.0 is consistent with the results of
this phase II study.

Inclusion Criteria:

1. Non-penetrating traumatic brain injury

2. Requirement for intracranial pressure monitoring according to Guidelines for the
Management of Severe TBI, as operationalized below:

- GCS 3-8 (measured off sedatives or paralytics) with abnormal CT scan. If patient
is intubated, motor GCS < 4 required.

- If CT scan normal, motor GCS < 4 (measured off sedatives or paralytics)

- Intoxication is not a reason for deferring ICP monitoring if above criteria are
met.

- If the patient has a witnessed seizure, wait 30 minutes to evaluate GCS.

3. Randomization and placement of monitors within 12 hours of injury.

4. Males and females Age 18-70 years, English or Spanish speaking patients.

Exclusion Criteria:

1. Specific clinical contraindications:

- GCS motor score > 4 with normal CT scan

- Bilaterally absent pupillary responses

2. Laboratory contraindications per safety considerations:

Coagulopathy that makes insertion of parenchymal monitors contraindicated (Platelets
< 50,000/mL, INR > 1.4) (Enrollment allowed if coagulopathy can be corrected before
12 hour post-injury deadline).

3. Pregnant females will be excluded. Blood test for pregnancy is a routine part of care
in ED's. However, if not done, a urine or blood test will be done as a safety
precaution after consent but prior to study treatment.

4. Monitoring with pBrO2 monitor prior to randomization.

5. Clinical, demographic and other characteristics that precludes appropriate diagnosis,
treatment or follow-up in the trial.

- Systemic sepsis at the time of screening

- Refractory hypotension (SBP < 70 mm Hg for > 30 minutes)

- Refractory systemic hypoxia (paO2 < 60 mm Hg on FiO2 < 0.5)

- Evidence of premorbid disabling conditions that interfere with outcome
assessment. These include diagnosis of Alzheimer's disease, Parkinson's disease,
multiple sclerosis, spinal cord injury with deficits, history of stroke, brain
tumors, chronic use of medication for disabling neurologic or psychiatric
disorder, or history of suicide attempt within the past year.

- Imminent death or current life-threatening disease

- Prisoner

- Individuals who hold religious beliefs against blood transfusion

- Previous TBI hospitalization greater than 1 day

- Patients who are unlikely to be available for follow-up interview, even by
telephone. for example, patients who are homeless, illegal aliens, or live in
foreign countries and those with whom future personal (including family) or
telephone contact is unlikely.

6. Active drug or alcohol use or dependence that, in the opinion of the stie
investigator, would interfere with follow-up.

7. Imminent death or current life-threatening disease

8. Inability or unwillingness of subject or legal guardian/representative to give
written informed consent

9. Participation in other observational or interventional clinical trials is allowed as
long as the PI of each study agree ahead of time to allow co-enrollment.