SIREN/BOOST3 Overview
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This document provides details about the BOOST3 clinical trial being conducted by the SIREN Clinical Coordinating Center. The trial aims to determine if a treatment protocol informed by brain tissue oxygen (PbtO2) monitoring improves outcomes for patients with severe traumatic brain injury, compared to a protocol using only intracranial pressure monitoring. The Phase 3 trial plans to enroll over 1000 patients at approximately 45 sites. It provides information on the study design, inclusion/exclusion criteria, treatment protocols, and progress to date enrolling sites and investigators.
SIREN/BOOST3 Overview
- 1. William Barsan, MD Principal Investigator (MPI) SIREN Clinical Coordinating Center
- 2. Funded in 2017 ALIAS 2 RAMPART ATACH 2 ProTECT POINT SHINE ESETT
- 3. Specific aims 1. diligently recruit, efficiently perform, and widely disseminate the most scientifically and clinically important trials in emergency patient care 2. create a culture of clinical trials that is collaborative, multidisciplinary, diverse and inclusive through leadership, openness, and engagement 3. transform the emergency research enterprise through innovative design, patient stakeholder engagement, better operational strategies
- 4. Multiple PI Leadership Plan - CCC • Bill Barsan • Robert Silbergleit • Clif Callaway
- 5. Multiple PI Leadership Plan - DCC • Yuko Palesch • Valerie Durkalski
- 6. SIREN Grant Awards Massachusetts General Hospital Temple University University of Pittsburgh Wayne State University University of Cincinnati Emory University Medical College of Wisconsin University of Minnesota University of Washington Oregon Health Sciences University University of California Los Angeles Coordinating Centers University of Michigan Medical University of South Carolina
- 7. Scope of Portfolio Late learning phase or confirmatory phase trials Patient oriented outcomes Controlled efficacy to registry based RCT Appropriately sized for our scalable network Primary focus on neurological, cardiac, lung and blood (NINDS/NHLBI) Secondary focus on other IC portfolios, and health services
- 8. Current Trials • HOBIT—Hyperbaric Oxygen Brain Injury Trial • Use of HBO in patients with severe TBI (GCS 3-8) • Late phase 2 trial with 200 patients at 13 sites • 7 enrolling sites currently • First patient enrolled July 30, 2018 • 18 enrollments to date • 6 more sites to open by July 2019 • BOOST3—Outcomes of severe TBI patients comparing use of brain tissue oxygen with ICP monitoring vs ICP monitoring alone
- 9. Trials in the Pipeline • ICECAP • Duration of hypothermia after OOH cardiac arrest • Recently reviewed at NHLBI study section • HATTRIC • What is the optimal dose of tPA for massive/submassive PE • U34 planning grant approved for funding
- 10. QUESTIONS?
- 11. Brain Oxygen Optimization in Severe TBI-Phase 3 (BOOST- 3) William Barsan, MD, Contact PI, CCC SIREN Ramon Diaz-Arrastia, MD, PhD, Scientific PI Lori Shutter, MD, Clinical PI Sharon Yeatts, PhD, Statistical PI, DCC SIREN
- 12. Brain Tissue Oxygen Monitors • FDA-approved November, 2000 • Measures PbtO2 in mm3 region around tip of catheter • No Class I data that it improves outcome • Variable penetrance of utilization in NICU
- 13. Rationale for PbtO2 monitoring • Episodes of low PbtO2 are common after TBI • Van den Brink et al1 (2000) • 101 patients monitored average 86 hours • 57% had values < 15 mm Hg • 42% had values < 10 mm Hg • 22% had values < 5 mm Hg • Longhi et al2 (2007) • Episodes PbtO2 10 - 19 mm Hg in 23% of time • Median duration 50 minutes • Episodes PbtO2 < 10 mm Hg 11% of the time • Median duration 39 minutes 1. van den Brink WA, et al, Neurosurgery 2000; 46:868-878. 2. Longhi L, et al, Intensive Care Med 2007; 33(12):2136-2142.
- 14. Rationale for PbtO2 monitoring • Low PbtO2 is associated with poor neurological outcome Study (First Author, # of patients evaluable) Hypoxia No Hypoxia Odds Ratio (95% C.I.) Unfavorable Outcome (n) Favorable Outcome (n) Unfavorable Outcome (n) Favorable Outcome (n) Van den Brink 2000 (n = 99) 29 14 24 32 3.8 (1.6 – 8.4) Bardt et al 1998 (n = 35) 18 5 3 9 10.8 (2.1 – 55.7) Chang et al 2009 (n = 25) 6 1 7 11 9.43 (1.1 – 95.9) 1. van den Brink WA, etr al Neurosurgery 2000; 46:868-878 2. Bardt TF, et al, Acta Neurochir 1998; Suppl. 71:153-156 3. Chang J, et al, Crit Care Med 2009;37:283-290
- 15. BOOST—Phase 2 study Primary and Secondary Objectives 1. Primary Objective: Treatment protocol informed by PbtO2 monitoring results in reduction of brain tissue hypoxia 2. Secondary Objectives: a. Safety hypotheses: Adverse events associated with PbtO2 monitoring are rare. b. Feasibility hypotheses: Episodes of decreased PbtO2 can be identified and treatment protocol instituted comparably across clinical sites, and protocol violations will be low and uniform across different clinical sites. c. Non-futility hypothesis: Relative Risk of good outcome measured by the GOS-E 6 months after injury of 2.0 is consistent with the results of this phase II study.
- 16. BOOST-2 Primary Outcome Okonkwo et al, Crit. Care Med 2017 Nov;45(11):1907-1914
- 18. BOOST-Phase 3 (BOOST3) • Approved by NINDS Council 9/2017 • Target enrollment 1094 • Sufficient to detect a 10% absolute improvement in good outcome • GOS-E Sliding Dichotomy • Planned 45 sites • Funded in August 2018 • $32M Direct and Indirect costs
- 19. Primary Objective To determine whether the prescribed treatment protocol, informed by PbtO2 monitoring, results in improved neurologic outcome measured by the Glasgow Outcome Scale-Extended (GOS-E) 6 months after injury compared to treatment based on intracranial pressure (ICP) monitoring only.
- 20. InclusionCriteria • 1. Non-penetrating traumatic brain injury (TBI) • 2. Requirement for intracranial pressure monitoring, based on BTF / ACS TQIP Guidelines for the Management of Severe TBI, as operationalized below: • GCS 3-8 (measured off paralytics) (In intubated patients, GCS Motor score < 6) • Evidence of intracranial trauma on CT scan (Marshall Score > 1) • If patient has a witnessed seizure, wait 30 min to evaluate GCS • 3. Able to place intracranial monitors and randomize within 6 hours of arrival at enrolling hospital, but no later than 12 hours from injury • 4. Males and females ages >14
- 21. Exclusion Criteria • 1. Bilaterally absent pupillary response in the absence of paralytic medication • 2. Contraindication to the placement of parenchymal monitors, such as uncorrectable coagulopathy • 3. Refractory hypotension (SBP < 90 mmHg for two consecutive readings at least 5 minutes apart any time prior to randomization) • 4. Refractory systemic hypoxia (SaO2 < 90% or FiO2 > 0.5 for two consecutive readings at least 5 minutes apart any time prior to randomization) • 5. PaO2/FiO2 ratio < 200 • 6. Pre-existing neurologic disease (e.g. TBI, stroke, or neurodegenerative disorder) with confounding residual neurologic deficits • 7. Inability to perform activities of daily living (ADL) without assistance prior to injury • 8. Known active drug or alcohol dependence that, in the opinion of site investigator, would interfere with physiological response to PbtO2 treatments • 9. Non-survivable injury (e.g. withdrawal of care prior to randomization, no intention for aggressive intervention, on hospice or DNR order etc.) • 10. Pregnancy • 11. Prisoner or ward of the state
- 22. Types of events ICP < 22 ICP > 22 PbtO2 > 20 Type A No interventions directed at PbtO2 or ICP needed Type B Interventions directed at lowering ICP PbtO2 < 20 Type C Interventions directed at increasing pBtO2 Type D Interventions directed at lowering ICP and increasing pBtO2
- 23. Isolated ICP increase Isolated PbtO2 drop ICP increase + PbtO2 drop TIER 1 • Adjust head of the bed to lower ICP • Ensure Temperature < 38 oC. • Adjust pharmacologic analgesia and sedation: Titrate to effect. • CSF drainage (if EVD available) Titrate to effect. • Standard dose Mannitol (0.25 – 1.0 g/kg), to be administered as bolus infusion. • Hypertonic saline. Titrate to ICP control and maintain serum Na+ 155-160). TIER 1 • Adjust head of the bed to improve brain oxygen level • Ensure Temperature < 38 oC. • Increase CPP to 70 mm Hg with fluid bolus. • Optimize hemodynamics. • Increase PaO2 by increasing FiO2 to 60%. • Increase PaO2 by adjusting PEEP • Add EEG monitoring • Consider adding AED’s, either Dilantin or Keppra, for 1 week only. TIER 1 • Adjust head of the bed to lower ICP • Ensure Temperature < 38 oC. • Pharmacologic analgesia and sedation • CSF drainage (if EVD available). • Increase CPP up to a maximum >70 mm Hg with fluid bolus. • Standard dose Mannitol, to be administered as bolus infusion. (0.25 – 0.5 mg/kg). • Hypertonic saline • Adjust ventilator parameters to increase paO2 by increasing FiO2 to 60%. • Increase FiO2 by increasing PEEP. • Consider EEG monitoring • Consider AED’s, either Dilantin or Keppra, for 1 week only. TIER 2 • Adjust ventilatory rate to lower paCO2 to 32 – 35 mm Hg. • High dose Mannitol > 1 g/kg. • Repeat CT to determine if increased size of intracranial mass lesions. • Treat surgically remediable lesions with craniotomy according to guidelines. • Adjust temperature to 35 – 37o C, using active cooling measures. TIER 2 • Adjust ventilator parameters to increase paO2. by increasing FiO2 to 100%. • Increase paO2 by adjusting PEEP • Increase CPP up to a maximum of 70 mmHg with vasopressors. • Adjust ventilatory rate to increase paCO2 to 45 – 50 mm Hg. • Transfuse pRBCs to reach Hgb > 10 g/dL. • Decrease ICP to < 10 mm Hg. • CSF drainage. • Increased sedation. TIER 2. • High dose Mannitol 1 g/kg, or frequent boluses standard dose Mannitol • Increase CPP up to maximum of 70 mm Hg with vasopressors. • Adjust ventilator parameters to increase paO2 by increasing FiO2 to 100%. • Increase FiO2 by increasing PEEP • Transfuse to Hgb > 10 g/dL. • Repeat CT to determine if increased size of intracranial mass lesions. • Treat surgically remediable lesions with craniotomy according to guidelines • Induced hypothermia to 35 - 37o C, using active cooling measures. TIER 3 (Tier 3 therapies are optional). • Pentobarbital coma, according to local protocol. • Decompressive craniectomy. • Adjust temperature to 32 – 34.5o C, using active cooling measures. • Neuromuscular paralysis TIER 3. (Tier 3 therapies are optional). • Pentobarbital coma: • Decompressive craniectomy. • Induced hypothermia. hypothermia to 32 – 34.5o C. • Neuromuscular paralysis
- 24. BOOST3 Progress to Date • Site recruitment • All sites experienced with PbtO2 monitoring • Initial sites—47 • Backup sites—10 • > 20 sites have already completed milestone 1 • EFIC • EFIC plan approved by CIRB • Sites are beginning EFIC activities • Investigators meeting • March 19-20 in Atlanta • First enrollment anticipated by May 2019
- 25. QUESTIONS?