Clinical trial NCT04077411: Approaches and Decisions for Acute Pediatric TBI Trial
Official title: Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Severe Traumatic Brain Injury
Keywords: Severe Traumatic Brain Injury
TBI
Intracranial hypertension
Cerebrospinal fluid
Hypersmolar therapies
Prophylactic hyperventilation
Metabolism
Neuropsychology
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2019-09-04
Enrollment: 1000
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Children with severe traumatic brain injury (TBI)

Brief summary: Approaches and Decisions in Acute Pediatric TBI Trial (ADAPT) is an international research study designed to evaluate the impact of interventions on the outcomes of children with severe traumatic brain injury.

Pediatric traumatic brain injury (TBI) is the leading killer of children, resulting in more than 7000 deaths and $2 billion in acute care costs each year. Despite this large burden of disease, advances in the field have been limited due to weak evidenced-based guidelines and the limitations of randomized, controlled trials (RCTs) to demonstrate efficacy of single treatment strategies due to wide treatment variability. ADAPT is a practical study design in a novel approach - an observational cohort study designed to evaluate the association of 6 aspects of pediatric TBI care with outcomes using statistical modeling to correct for confounding variables. Completion of this study will provide compelling evidence to change clinical practices, provide evidence for new Level II recommendations for future guidelines and lead to improved research protocols that would limit variability in TBI treatments - helping children immediately through better clinical practices and ultimately through more effective investigation.

Detailed description: Traumatic brain injury (TBI) is the leading cause of death in children in the US. According to the CDC, 7440 children died of TBI in 2005, but this likely underestimates the full burden of the disease. Based on the current best estimates for severe pediatric TBI (20% mortality, 50.6% unfavorable 6 mo outcome, mean age 9 y), each year 37,200 children suffer a severe TBI with up to 1.3 million life-years potentially adversely affected.

Incremental improvement in outcomes could make enormous differences for the health of children, but such advances have remained elusive. Dozens of injury mechanisms have been identified after experimental TBI, yet no mitigating treatments have been translated into clinical practice. Randomized controlled trials (RCTs) of therapies, from steroids to novel pharmaceutical agents to hypothermia, have failed for adult and pediatric TBI victims. Single-center experiences have contributed to understanding, yet these largely remain insufficiently powerful to change practice. Recently, evidenced-based guidelines for 15 aspects of pediatric TBI were published that provide no level I and only 4 Level II recommendations - with such recommendations indicating therapies that "must be done" or "should be considered" based on the literature, respectively. Disappointingly, 3 of these recommendations advised against specific interventions (hypothermia, steroids and immune-enhanced diets) - emphasizing the uncertainty of the effectiveness of many commonly used therapies that leads to wide variations in clinical practice. Unsurprisingly, significant variations of clinical outcomes and basic treatment strategies for TBI have been observed. The IMPACT study merged data from over 9000 adults with TBI from 11 trials and demonstrated significant variations in outcomes from clinical sites. Similar variations in outcomes in children with TBI can be found using various administrative databases, with mortality rates varying between 12.2% - 34.4% in 11 US states. There are also variations in strategies within an international consortium and a recently completed RCT - with marked variations in strategies for first-line intracranial hypertension treatments, prevention of common secondary insults and metabolic support after pediatric TBI.

The paucity of data to create robust guidelines, the failure of RCTs that tested a wide-variety of putative mechanisms and variations in outcomes and in clinical practices argues that the current understanding of contemporary therapies is inadequate. Because neither retrospective analyses from available databases nor self-reported variations in practices can determine optimal therapeutic strategies for these contemporaneous strategies, a new approach is urgently needed.

ADAPT is a large, prospective, observational cohort study using an international consortium including sites from the US, EU and UK. Children with severe TBI \[Glasgow coma scale (GCS) score ≤ 8 with intracranial pressure (ICP) monitoring, n = 1000, \>32 sites\] will be studied. The local standard of care at each site will be used and extensive data collection over the first 7 days after TBI will be performed to interrogate the effectiveness of strategies for intracranial hypertension, mitigation of specific secondary insults and metabolism.

Several statistical approaches, often used in comparative effectiveness research (CER) to control for measured confounding effects, will test the following aims:

Specific Aim 1: Compare the effectiveness of first-line intracranial hypertension strategies on outcome. Intracranial hypertension management is a mainstay of TBI care yet evidence for utilization the first-line therapies of cerebrospinal fluid (CSF) diversion and use of hyperosmolar solutions, is incomplete.

Aim 1a: Determine the effect of CSF diversion strategies (continuous drainage, intermittent drainage and none) on outcome. Aim 1b: Determine the effect of hyperosmolar therapies (hypertonic saline, mannitol) on outcome.

Specific Aim 2: Compare the effectiveness of strategies that mitigate specific secondary insults on outcome. Prophylactic hyperventilation (HV) and hypoxia may worsen outcome after TBI but have been inadequately studied.

Aim 2a: Determine the effect of prophylactic HV (CO2 \< 30 mm Hg) on outcome.

Aim 2b: Determine the effect of hypoxia detection with brain tissue oxygen monitoring (PbO2) on outcome.

Eligibility criteria: Inclusion Criteria:

* Admission to a study site for treatment of severe traumatic brain injury
* ICP monitor placed as part of the child's standard care
* Glasgow Coma Scale (GCS) ≤ 8 after resuscitation
* Age 0 - 18 y

Exclusion Criteria:

* 1. ICP Monitor placed at another hospital
* 2. Diagnosis of pregnancy in clinical subject

Primary outcomes:
measure: Glasgow Outcome Score - Extended Pediatrics
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: La Jolla
country: United States
facility: University of California, San Diego / Rady's Children's Hospital
state: California
city: Los Angeles
country: United States
facility: Children's Hospital of Los Angeles
state: California
city: Los Angeles
country: United States
facility: UCLA Mattel Children's Hospital
state: California
city: West Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Denver
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Miami
country: United States
facility: Miami Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Iowa City
country: United States
facility: University of Iowa Children's Hospita
state: Iowa
city: Baltimore
country: United States
facility: John Hopkins Children's Center of Baltimore
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston Children's Hospital / Harvard University
state: Massachusetts
city: Detroit
country: United States
facility: Wayne State University in Detroit / Children's Hospital of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University - St. Louis
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Charlotte
country: United States
facility: Carolinas Medical Center Levine Children's Hospital
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati / Cincinnati Children's Hospital Medical Center
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Hershey
country: United States
facility: Penn State University - Hershey
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: University of Tennessee / Le Bonheur Children's Hospita
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern / Children's Medical Center at Dallas
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital (Baylor College of Medicine)
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Hospital
state: Utah
city: Richmond
country: United States
facility: Children's Hospital of Richmond at VCU
state: Virginia
city: Seattle
country: United States
facility: University of Washington - Seattle
state: Washington
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
city: Brisbane
country: Australia
facility: Children's Health Queensland Hospital and Health Service
city: Melbourne
country: Australia
facility: Royal Children's Hospital
city: Perth
country: Australia
facility: Princess Margaret Hospital
city: New Delhi
country: India
facility: All India Institute of Medical Sciences
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center Children's Hospital
city: Auckland
country: New Zealand
facility: Starship Children's Hospital
city: Cape Town
country: South Africa
facility: University of Cape Town
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospita
city: Bristol
country: United Kingdom
facility: University Hospitals Bristol
city: Cambridge
country: United Kingdom
facility: Addenbrookes Hospital
city: Leeds
country: United Kingdom
facility: Leeds Teaching Hospital
city: Liverpool
country: United Kingdom
facility: Alder Hey Children's
city: London
country: United Kingdom
facility: King's College Hospital
city: London
country: United Kingdom
facility: Great Ormond Street
city: Newcastle upon Tyne
country: United Kingdom
facility: Newcastle upon Tyne Hospital
city: Southampton
country: United Kingdom
facility: University Hospital Southampton
city: Victoria
country: United Kingdom
facility: Royal Manchester Children's Hospital
Study officials:
affiliation: University of Pittsburgh Medical Center
name: Michael J Bell, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Stephen R Wisniewski, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Sarnaik A, Ferguson NM, O'Meara AMI, Agrawal S, Deep A, Buttram S, Bell MJ, Wisniewski SR, Luther JF, Hartman AL, Vavilala MS; Investigators of the ADAPT Trial. Age and Mortality in Pediatric Severe Traumatic Brain Injury: Results from an International Study. Neurocrit Care. 2018 Jun;28(3):302-313. doi: 10.1007/s12028-017-0480-x.
citation: Bell MJ, Adelson PD, Wisniewski SR; Investigators of the ADAPT Study,. Challenges and opportunities for pediatric severe TBI-review of the evidence and exploring a way forward. Childs Nerv Syst. 2017 Oct;33(10):1663-1667. doi: 10.1007/s00381-017-3530-y. Epub 2017 Sep 6.
citation: Miller Ferguson N, Sarnaik A, Miles D, Shafi N, Peters MJ, Truemper E, Vavilala MS, Bell MJ, Wisniewski SR, Luther JF, Hartman AL, Kochanek PM; Investigators of the Approaches and Decisions in Acute Pediatric Traumatic Brain Injury (ADAPT) Trial. Abusive Head Trauma and Mortality-An Analysis From an International Comparative Effectiveness Study of Children With Severe Traumatic Brain Injury. Crit Care Med. 2017 Aug;45(8):1398-1407. doi: 10.1097/CCM.0000000000002378.
citation: Larsen GY, Schober M, Fabio A, Wisniewski SR, Grant MJ, Shafi N, Bennett TD, Hirtz D, Bell MJ. Structure, Process, and Culture Differences of Pediatric Trauma Centers Participating in an International Comparative Effectiveness Study of Children with Severe Traumatic Brain Injury. Neurocrit Care. 2016 Jun;24(3):353-60. doi: 10.1007/s12028-015-0218-6.
citation: Surtees TL, Kumar I, Garton HJL, Rivas-Rodriguez F, Parmar H, McCaffery H, Riebe-Rodgers J, Shellhaas RA. Levetiracetam Prophylaxis for Children Admitted With Traumatic Brain Injury. Pediatr Neurol. 2022 Jan;126:114-119. doi: 10.1016/j.pediatrneurol.2021.10.009. Epub 2021 Oct 19.