Brain Tissue Oxygen Monitoring in Traumatic Brain Injury (TBI)
Condition: Severe Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries
Study type: Interventional
Phase: Phase 2

Summary: 
      Traumatic brain injury (TBI) is a major cause of death and disability, with an estimated cost
      of 45 billion dollars a year in the United States alone. Every year, approximately 1.4
      million sustain a TBI, of which 50,000 people die, and another 235,000 are hospitalized and
      survive the injury. As a result, 80,000-90,000 people experience permanent disability
      associated with TBI. This project is designed to determine whether a device designed to
      measure brain tissue oxygenation and thus detect brain ischemia while it is still potentially
      treatable shows promise in reducing the duration of brain ischemia, and to obtain information
      required to conduct a definitive clinical trial of efficacy.

      A recently approved device makes it feasible to directly and continuously monitor the partial
      pressure of oxygen in brain tissue (pBrO2). Several observational studies indicate that
      episodes of low pBrO2 are common and are associated with a poor outcome, and that medical
      interventions are effective in improving pBrO2 in clinical practice. However, as there have
      been no randomized controlled trials carried out to determine whether pBrO2 monitoring
      results in improved outcome after severe TBI, use of this technology has not so far been
      widely adopted in neurosurgical intensive care units (ICUs). This study is the first
      randomized, controlled clinical trial of pBrO2 monitoring, and is designed to obtain data
      required for a definitive phase III study, such as efficacy of physiologic maneuvers aimed at
      treating pBrO2, and feasibility of standardizing a complex intensive care unit management
      protocol across multiple clinical sites.

      Patients with severe TBI will be monitored with Intracranial pressure monitoring (ICP) and
      pBrO2 monitoring, and will be randomized to therapy based on ICP along (control group) or
      therapy based on ICP in addition to pBrO2 values (treatment group). 182 participants will be
      enrolled at four clinical sites, the University of Texas Southwestern Medical Center/Parkland
      Memorial Hospital, the University of Washington/Harborview Medical Center, the University of
      Miami/Jackson Memorial Hospital, and the University of Pennsylvania/Hospital of the
      University of Pennsylvania. Functional outcome will be assessed at 6-months after injury.
    

Detailed description: 
      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.
    

Intervention name(s): Management protocol based on pBrO2 and ICP values.; Management protocol based on ICP values only.
Intervention type(s): Device; Device
Intervention description(s): For patients who experience falls in pBrO2 below 20 mm Hg, a hierarchical treatment algorithm will be instituted, adapted from published recommendations49. In principle, episodes requiring therapy will fall into one of 4 scenarios (scenario A, B, C, and D, defined in figure 7), which will require different management strategies. The treatment protocol depends on which type of episode is being treated. Treatment is triggered by abnormalities in either ICP (> 20 mm Hg) or pBrO2 (< 20 mm Hg) are noted. Elevations in ICP above 20 mm Hg or decline in pBrO2 below 20 mm Hg for more than 5 minutes will trigger a treatment intervention. Treatment is directed to an episode. Patients may start in one type of episode and move to another. Therapy will depend on which type of episode they are in at any given time.; For the patients randomized to ICP treatment alone, only Scenario A and Scenario B episodes are relevant.
Other intervention name(s): Licox; Camino; Camino
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: Hypoxia; Ischemia; Intracranial hypertension; Neurocritical care