ADAPT: Approaches and Decisions for Acute Pediatric TBI Trial

Sponsor

University of Pittsburgh (Other)

Overall Status

Completed

CT.gov ID

NCT04077411

Collaborator

National Institute of Neurological Disorders and Stroke (NINDS) (NIH)

1,000

Enrollment

Locations

54.2

Actual Duration (Months)

20.8

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Severe Traumatic Brain Injury	Other: Observational

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.

Study Design

Study Type:

Observational

Actual Enrollment :

1000 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Approaches and Decisions for Acute Pediatric TBI (ADAPT) Trial

Actual Study Start Date :

Feb 20, 2014

Actual Primary Completion Date :

Sep 26, 2016

Actual Study Completion Date :

Aug 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Children with severe TBI Children with severe Traumatic Brain Injury	Other: Observational This is an observational study with no interventions.

Arm

Intervention/Treatment

Children with severe TBI

Children with severe Traumatic Brain Injury

Other: Observational

This is an observational study with no interventions.

Outcome Measures

Primary Outcome Measures

Glasgow Outcome Score - Extended Pediatrics [6 months]
Physician-rated assessment of functional outcome. Problems in functioning should have deteriorated from premorbid level. The categories are: 8 - Death 7 - Vegetative State (VS) 6 - Lower Severe Disability (Lower SD) 5 - Upper Severe Disability (Upper SD) 4 - Lower Moderate Disability (Lower MD) 3 - Upper Moderate Disability (Upper MD) 2 - Lower Good Recovery (Lower GR) 1 - Upper Good Recovery (Upper GR)

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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
1. Diagnosis of pregnancy in clinical subject

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Alabama	Birmingham	Alabama	United States	35294
2	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
3	University of California, San Diego / Rady's Children's Hospital	La Jolla	California	United States	92093
4	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027
5	UCLA Mattel Children's Hospital	Los Angeles	California	United States	90095
6	UC Davis Medical Center	West Sacramento	California	United States	95798
7	Children's Hospital Colorado	Denver	Colorado	United States	80045
8	Children's National Medical Center	Washington	District of Columbia	United States	20010
9	Miami Children's Hospital	Miami	Florida	United States	33155
10	Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30322
11	University of Iowa Children's Hospita	Iowa City	Iowa	United States	52252
12	John Hopkins Children's Center of Baltimore	Baltimore	Maryland	United States	21287
13	Massachusetts General Hospital	Boston	Massachusetts	United States	02241
14	Boston Children's Hospital / Harvard University	Boston	Massachusetts	United States	414413
15	Wayne State University in Detroit / Children's Hospital of Michigan	Detroit	Michigan	United States	13201
16	Washington University - St. Louis	Saint Louis	Missouri	United States	63112
17	University of Nebraska Medical Center	Omaha	Nebraska	United States	68198
18	Carolinas Medical Center Levine Children's Hospital	Charlotte	North Carolina	United States	28260
19	University of Cincinnati / Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
20	Nationwide Children's Hospital	Columbus	Ohio	United States	43271
21	Penn State University - Hershey	Hershey	Pennsylvania	United States	17033
22	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19178
23	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15213
24	University of Tennessee / Le Bonheur Children's Hospita	Memphis	Tennessee	United States	38163
25	UT Southwestern / Children's Medical Center at Dallas	Dallas	Texas	United States	75284
26	Texas Children's Hospital (Baylor College of Medicine)	Houston	Texas	United States	77030
27	Primary Children's Hospital	Salt Lake City	Utah	United States	84113
28	Children's Hospital of Richmond at VCU	Richmond	Virginia	United States	23298
29	University of Washington - Seattle	Seattle	Washington	United States	98185
30	University of Wisconsin - Madison	Madison	Wisconsin	United States	53715
31	Children's Health Queensland Hospital and Health Service	Brisbane		Australia
32	Royal Children's Hospital	Melbourne		Australia
33	Princess Margaret Hospital	Perth		Australia	6008
34	All India Institute of Medical Sciences	New Delhi		India	110029
35	Erasmus Medical Center Children's Hospital	Rotterdam		Netherlands	3015 GJ
36	Starship Children's Hospital	Auckland		New Zealand
37	University of Cape Town	Cape Town		South Africa
38	Hospital Vall d'Hebron	Barcelona		Spain
39	Birmingham Children's Hospita	Birmingham		United Kingdom	6NH
40	University Hospitals Bristol	Bristol		United Kingdom
41	Addenbrookes Hospital	Cambridge		United Kingdom	CB2 0QQ
42	Leeds Teaching Hospital	Leeds		United Kingdom	LS 7TF
43	Alder Hey Children's	Liverpool		United Kingdom	L12 2AP
44	King's College Hospital	London		United Kingdom	SE5 9NY
45	Great Ormond Street	London		United Kingdom	WC1N 1EH
46	Newcastle upon Tyne Hospital	Newcastle upon Tyne		United Kingdom	NE7 7DN
47	University Hospital Southampton	Southampton		United Kingdom	SO16 6YD
48	Royal Manchester Children's Hospital	Victoria		United Kingdom	3052

Sponsors and Collaborators

University of Pittsburgh
National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

Principal Investigator: Michael J Bell, MD, University of Pittsburgh Medical Center
Principal Investigator: Stephen R Wisniewski, PhD, University of Pittsburgh