BOOST3: Brain Oxygen Optimization in Severe TBI, Phase 3

Sponsor

University of Michigan (Other)

Overall Status

Recruiting

CT.gov ID

NCT03754114

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH), University of Washington (Other), University of Pennsylvania (Other), University of Pittsburgh (Other), Medical University of South Carolina (Other)

1,094

Enrollment

Locations

Arms

46.1

Anticipated Duration (Months)

31.3

Patients Per Site

0.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

BOOST3 is a randomized clinical trial to determine the comparative effectiveness of two strategies for monitoring and treating patients with traumatic brain injury (TBI) in the intensive care unit (ICU). The study will determine the safety and efficacy of a strategy guided by treatment goals based on both intracranial pressure (ICP) and brain tissue oxygen (PbtO2) as compared to a strategy guided by treatment goals based on ICP monitoring alone. Both of these alternative strategies are used in standard care. It is unknown if one is more effective than the other. In both strategies the monitoring and goals help doctors adjust treatments including the kinds and doses of medications and the amount of intravenous fluids given, ventilator (breathing machine) settings, need for blood transfusions, and other medical care. The results of this study will help doctors discover if one of these methods is more safe and effective.

Condition or Disease	Intervention/Treatment	Phase
Brain Injuries, Traumatic	Other: ICP + PbtO2 guided management strategy Other: ICP guided management strategy	N/A

Detailed Description

When a person has a TBI, their injured brain can swell over a period of hours or days. If the brain swells too much, the pressure in the skull increases and becomes dangerous, causing further injury to the brain. To try to prevent this, doctors usually insert a device, an ICP monitor, into the brain through a hole in the skull of people with severe TBI. An ICP monitor measures the pressure inside the skull. Most doctors agree that it is important to measure and prevent high ICP. Patients with injured brains also suffer additional injury to the brain if the amount of oxygen in the brain gets too low. Some doctors also insert a second device, a PbtO2 monitor, in the brain through the same or a second hole in the skull to measure brain tissue oxygen. A PbtO2 monitor measures how much oxygen is in a small area of the brain near the tip of the monitor. Other doctors think this is unnecessary and unhelpful. Both monitoring devices are approved by the US Food and Drug Administration (FDA) and Health Canada for patients with TBI. Both are commonly used. The ICP and PbtO2 goals guided by these monitors are used to help doctors adjust their treatment choices. Treatments include kinds and doses of medications and the amount of intravenous fluids given, ventilator (breathing machine) settings, need for blood transfusions, and other medical care. Each of these treatment decisions is intended to improve outcomes. However, each treatment decision also involves potential risks. Different treatment decisions may result in different risks. This study will also help doctors better understand these risks. This study is funded by the National Institutes of Health because it answers questions important to the care of patients with TBI.

This study is a two-arm, single-blind, randomized, controlled, phase III, multi-center trial of ICU monitoring and treatment strategies for patients with severe TBI. It will compare the efficacy of ICU care guided by PbtO2 and ICP monitoring versus monitoring of ICP alone in the first 5 days after injury. Only subjects who have severe TBI and require invasive monitoring, according to Brain Trauma Foundation (BTF) and American College of Surgeons-Trauma Quality Improvement (ACS TQIP) guidelines, will be enrolled. All participants in this study will have both ICP monitors and PbtO2 monitors. Half of the participants will be randomized to an arm that includes treatment informed by PbtO2 and ICP, and half will be randomized to an arm that treats only ICP.

The PbtO2 values of those in the ICP only arm will be masked, so that the treating physicians will not be guided by PbtO2 information. Participants in the PbtO2 and ICP arm will have PbtO2 monitored and low measurements treated. Treatments to address physiological goals in both arms will follow a clinical standardization plan. Participants will be followed for 6 months and occurrence of serious adverse events or death will be recorded. Participants will have a follow-up interview to assess their level of recovery approximately 6 months post injury.

To reduce the likelihood of imbalance of important prognostic factors between groups, a covariate-adjusted randomization scheme will be used in this study. Adjustment variables are clinical site and probability of a poor outcome as defined by the IMPACT core model.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1094 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

The outcomes assessors will be blinded to the treatment assignment of the participant.

Primary Purpose:

Treatment

Official Title:

Brain Oxygen Optimization in Severe TBI (BOOST3): A Comparative Effectiveness Study to Test the Efficacy of a Prescribed Treatment Protocol Based on Monitoring the Partial Pressure of Brain Tissue Oxygen.

Actual Study Start Date :

Aug 28, 2019

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: ICP only ICP guided management strategy: Care in the ICU of research participants randomized to this arm will be guided by a monitoring and treatment strategy in which doctors try to prevent high intracranial pressure (ICP) caused by a swollen brain. This strategy is one of two alternative strategies that is currently used in standard care of patients with traumatic brain injury.	Other: ICP guided management strategy In this management strategy, the physiological goal is to avoid ICP from exceeding 22 mm Hg. ICP and PbtO2 are monitored using devices inserted into the brain through a hole in the skull, but PbtO2 is not used to guide care. These devices are approved by the US Food and Drug Administration (FDA) and Health Canada, and are routinely used in patients with severe TBI. Doctors adjust their treatment choices to try to achieve this ICP goal. Treatments include kinds and doses of medications and the amount of intravenous fluids given, ventilator (breathing machine) settings, need for blood transfusions, and other medical care. This management strategy is used to guide care for 5 days in this research study.
Active Comparator: ICP + PbtO2 ICP + PbtO2 guided management strategy: Care in the ICU of research participants randomized to this arm will be guided by a monitoring and treatment strategy in which doctors try to prevent high intracranial pressure (ICP), and also try to prevent low PbtO2 (brain tissue oxygen levels). This strategy is one of two alternative strategies that is currently used in standard care of patients with traumatic brain injury.	Other: ICP + PbtO2 guided management strategy In this management strategy, the physiological goal is to avoid ICP from exceeding 22 mm Hg and to avoid PbtO2 dropping below 20 mm Hg. ICP and PbtO2 are monitored using devices inserted into the brain through a hole in the skull. These devices are approved by the US Food and Drug Administration (FDA) and Health Canada for patients with severe TBI. The devices are used in standard care at hospitals participating in this research study. Doctors adjust their treatment choices to try to achieve these ICP and PbtO2 goals. Treatments include kinds and doses of medications and the amount of intravenous fluids given, ventilator (breathing machine) settings, need for blood transfusions, and other medical care. This management strategy is used to guide care for 5 days in this research study.

Arm

Intervention/Treatment

Active Comparator: ICP only

ICP guided management strategy: Care in the ICU of research participants randomized to this arm will be guided by a monitoring and treatment strategy in which doctors try to prevent high intracranial pressure (ICP) caused by a swollen brain. This strategy is one of two alternative strategies that is currently used in standard care of patients with traumatic brain injury.

Other: ICP guided management strategy

In this management strategy, the physiological goal is to avoid ICP from exceeding 22 mm Hg. ICP and PbtO2 are monitored using devices inserted into the brain through a hole in the skull, but PbtO2 is not used to guide care. These devices are approved by the US Food and Drug Administration (FDA) and Health Canada, and are routinely used in patients with severe TBI. Doctors adjust their treatment choices to try to achieve this ICP goal. Treatments include kinds and doses of medications and the amount of intravenous fluids given, ventilator (breathing machine) settings, need for blood transfusions, and other medical care. This management strategy is used to guide care for 5 days in this research study.

Active Comparator: ICP + PbtO2

ICP + PbtO2 guided management strategy: Care in the ICU of research participants randomized to this arm will be guided by a monitoring and treatment strategy in which doctors try to prevent high intracranial pressure (ICP), and also try to prevent low PbtO2 (brain tissue oxygen levels). This strategy is one of two alternative strategies that is currently used in standard care of patients with traumatic brain injury.

Other: ICP + PbtO2 guided management strategy

In this management strategy, the physiological goal is to avoid ICP from exceeding 22 mm Hg and to avoid PbtO2 dropping below 20 mm Hg. ICP and PbtO2 are monitored using devices inserted into the brain through a hole in the skull. These devices are approved by the US Food and Drug Administration (FDA) and Health Canada for patients with severe TBI. The devices are used in standard care at hospitals participating in this research study. Doctors adjust their treatment choices to try to achieve these ICP and PbtO2 goals. Treatments include kinds and doses of medications and the amount of intravenous fluids given, ventilator (breathing machine) settings, need for blood transfusions, and other medical care. This management strategy is used to guide care for 5 days in this research study.

Outcome Measures

Primary Outcome Measures

Glasgow Outcome Scale-Extended (GOS-E) [6 months]
The Glasgow Outcome Scale-Extended (GOS-E) is a global scale for functional outcome, in which higher scores indicate better outcomes. The GOS-E rates patient status into one of eight categories. A GOS-E score of 1 indicates death, 2 indicates a vegetative state, 3 or 4 indicates severe disability, 5 or 6 indicates moderate disability, and 7 or 8 indicates good recovery. The categories of severe disability, moderate disability and good recovery are subdivided into a lower and upper category. All injury related disabilities are assessed.

Secondary Outcome Measures

Survival [At discharge from hospital, an average of 19 days]
Survival at discharge from hospital
Total Brain Hypoxia Exposure [Inclusive of up to 5 days of study intervention]
The cumulative area on the time versus brain tissue oxygenation (PbtO2) curve in which PbtO2 is less than 20 mmHg.
Cognition: Rey Auditory Verbal Learning Test [6 months]
A measure of verbal learning and memory.
Cognition: Trail Making Test Part A+B [6 months]
A measure of attention, visual-motor tracking and executive functioning.
Emotional Health: Rivermead Post-Concussion Symptom Questionnaire [6 months]
A measure of the presence and severity of post-concussion somatic, cognitive, and emotional symptoms.
Emotional Health: Brief Symptom Inventory 18 [6 months]
A measure of psychological distress and psychiatric disorders.
Emotional Health: Satisfaction with Life Scale [6 months]
A measure of global cognitive judgments of one's life satisfaction.
Functional Status Exam [6 months]
Change in the activities of every day life as a function of a sudden event or illness

Eligibility Criteria

Criteria

Ages Eligible for Study:

14 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Non-penetrating traumatic brain injury
Glasgow Coma Scale (GCS) 3-8 measured off paralytics
Glasgow Coma Scale motor score < 6 if endotracheally intubated
Evidence of intracranial trauma on CT scan
Able to place intracranial probes and randomize within 6 hours of arrival at enrolling hospital
Able to place intracranial probes and randomize within 12 hours from injury
Age greater than or equal to 14 years

Exclusion Criteria:

Non-survivable injury
Bilaterally absent pupillary response in the absence of paralytic medication
Contraindication to the placement of intracranial probes
Treatment of brain tissue oxygen values prior to randomization
Planned use of devices which may unblind treating physicians to brain tissue hypoxia
Systemic sepsis at screening
Refractory hypotension
Refractory systemic hypoxia
PaO2/FiO2 ratio < 200
Known pre-existing neurologic disease with confounding residual neurological deficits
Known inability to perform activities of daily living (ADL) without assistance prior to injury
Known active drug or alcohol dependence that, in the opinion of site investigator, would interfere with physiological response to brain tissue oxygen treatments
Pregnancy
Prisoner
On EFIC Opt-Out list as indicated by a bracelet or medical alert

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ronald Reagan UCLA Medical Center	Los Angeles	California	United States	90095-7436
2	Stanford University Medical Center	Palo Alto	California	United States	94305
3	UC Davis Medical Center	Sacramento	California	United States	95817
4	San Francisco General Hospital	San Francisco	California	United States	94143
5	University of Colorado Hospital	Aurora	Colorado	United States	80045
6	Yale New Haven Hospital	New Haven	Connecticut	United States	06510
7	UF Health Shands Hospital	Gainesville	Florida	United States	32608
8	University of Chicago Medical Center	Chicago	Illinois	United States	60637
9	Maine Medical Center	Portland	Maine	United States	04102
10	Massachusetts General Hospital	Boston	Massachusetts	United States	02128
11	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
12	UMASS Memorial Medical Center	Worcester	Massachusetts	United States	01655
13	Detroit Receiving Hospital	Detroit	Michigan	United States	48201
14	Henry Ford Hospital	Detroit	Michigan	United States	48201
15	Regions Hospital	Saint Paul	Minnesota	United States	55101
16	Cooper University Hospital	Camden	New Jersey	United States	08103
17	University of New Mexico Hospital	Albuquerque	New Mexico	United States	87131
18	North Shore University Hospital	Manhasset	New York	United States	11030
19	Strong Memorial Hospital	Rochester	New York	United States	14642
20	University of North Carolina Medical Center	Chapel Hill	North Carolina	United States	27514
21	Duke University Hospital	Durham	North Carolina	United States	27710
22	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
23	OSU Wexner Medical Center	Columbus	Ohio	United States	43210
24	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
25	Oregon Health & Science University Hospital	Portland	Oregon	United States	97239
26	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania	United States	19104
27	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
28	UPMC Presbyterian Hospital	Pittsburgh	Pennsylvania	United States	15212
29	Memorial Hermann Hospital	Houston	Texas	United States	77024
30	Ben Taub General Hospital	Houston	Texas	United States	77030
31	University of Utah Healthcare	Salt Lake City	Utah	United States	84132
32	Harborview Medical Center	Seattle	Washington	United States	98104
33	WVU Healthcare Ruby Memorial Hospital	Morgantown	West Virginia	United States	26506
34	Froedtert Hospital	Milwaukee	Wisconsin	United States	53226
35	CIUSSS-NIM Hopital du Sacre - Coeur de Montreal	Montréal		Canada	H4J 1C5

Sponsors and Collaborators

University of Michigan
National Institute of Neurological Disorders and Stroke (NINDS)
University of Washington
University of Pennsylvania
University of Pittsburgh
Medical University of South Carolina

Investigators

Principal Investigator: Lori Shutter, MD, University of Pittsburgh, Pittsburgh, PA 15260
Principal Investigator: Ramon Diaz-Arrastia, MD, PhD, University of Pennsylvania, Philadelphia, PA 19104
Principal Investigator: William Barsan, MD, University of Michigan, Ann Arbor, MI 48109
Principal Investigator: Sharon Yeatts, PhD, Medical University of South Carolina, Charleston, SC 29425