NABIS:HIIR: Effects of Hypothermia Upon Outcomes After Acute Traumatic Brain Injury

• Sponsor: The University of Texas Health Science Center, Houston (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00178711
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS) (NIH)
• Enrollment: 232
• Locations: 5
• Arms: 2
• Duration (Months): 49
• Patients Per Site: 46.4
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

Induction of hypothermia to < 35˚C by < 2.5 hours after severe traumatic brain injury, reaching 33˚C by 4 hours after injury and maintained for 48 hours in patients aged 16-45 will result in an increased number of patients with good outcomes at six months after injury compared to patients randomized to normothermia.

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Device: Hypothermia	Phase 3

Detailed Description

NABIS:HIIR was a randomized clinical trial conducted in patients with severe brain injury, age 16-45. Patients were randomized to standard treatment at normothermia or to standard treatment with moderate hypothermia (32.5-34C for 48 hours). An intent to treat analysis was used with the primary outcome measure as the Glasgow Outcome Scale at six months after injury. GOS is dichotomized into good outcome (Good Recovery/Moderate Disability) and poor outcome (Severe Disability, Vegetative, Dead).

Study Design

• Study Type: Interventional
• Actual Enrollment: 232 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: National Acute Brain Injury Study: Hypothermia IIR
• Study Start Date: Nov 1, 2005
• Actual Primary Completion Date: Dec 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: hypothermia Induction and maintenance of moderate hypothermia to 33 degrees celsius achieved within 2.5 hours of injury and maintained for 48 hours.	Device: Hypothermia; Induction of moderate hypothermia to 33 degrees celsius, within 2.5 hours from time of injury and maintained for 48 hours; Other Names: moderate hypothermia
No Intervention: control treated at normothermia

Outcome Measures

Primary Outcome Measures

1. The Dichotomized Glasgow Outcome Scale [6 months with a window of plus or minus one month]

   The primary outcome measure was the Glasgow Outcome Scale measured in person six months after injury by examiners who were blinded to the patient's treatment group. Good recovery and moderate disability were designated as favorable outcomes; severe disability, a vegetative state, and death as poor outcomes.

Other Outcome Measures

1. Glasgow Outcome Scale - Extended [0-12 months]

2. Disability Rating Scale [assessed 0-12 months]

3. Neurobehavioral Rating Scale - Revised [0-12 months]

4. Neurological Outcome Scale for Traumatic Brain Injury [0-12 months]

5. Symbol Digit Modalities Test [0-12 months]

6. Rey Osterrieth Complex Figure [0-12 months]

7. Verbal Selective Reminding Test Trails B [0-12 months]

8. Grooved Pegboard [0-12 months]

9. Controlled Oral Word Association Test [0-12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Non-penetrating brain injury with post-resuscitation Glasgow Coma Score (GCS) < 8 (motor 1-5)

2. Estimated or known age > 16 and < 45 years old

3. Time of Injury within 2.5hrs of arrival at hospital

Exclusion Criteria:

1. GCS = 7 or 8 with a normal head Cat Scan (CT) scan or showing only mild Subarachnoid hemorrhage (SAH)or skull fracture or GCS > 9 post- randomization

2. GCS = 3 AND bilaterally non-reactive pupils

3. Abbreviated Injury Score (AIS) > 4 for any body area except head

4. Positive abdominal ultrasound or CT scan

5. Persistent hypotension (systolic blood pressure < 110mmHGg)

6. Persistent hypoxia (O2 Saturation < 94%)

7. Positive pregnancy test

8. Injured greater than 2.5 hours from hospital arrival

9. Pre-existing medical conditions, if known

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of St Louis : St. Louis University Hospital	St. Louis	Missouri	United States	63110
2	University of Pittsburgh : University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
3	University of Texas Health Science Center, Memorial Hermann Hospital	Houston	Texas	United States	77030
4	Charleston Area Medical Center	Charleston	West Virginia	United States	25304
5	University of Calgary Health Science Center : Foothills Medical Center	Calgary	Alberta	Canada	T2N4N1

Sponsors and Collaborators

• The University of Texas Health Science Center, Houston
• National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Guy L Clifton, MD, UTHSC-H

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Guy Clifton, Professor - Neurosurgery, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT00178711
• Other Study ID Numbers: 5U01NS043353-06; FDA-2014-109
• First Posted: Sep 15, 2005
• Last Update Posted: Sep 17, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Guy Clifton, Professor - Neurosurgery, The University of Texas Health Science Center, Houston: Traumatic Brain Injury; Hypothermia
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Hypothermia; Wounds and Injuries

Study Results

Participant Flow

Recruitment Details	Patients were enrolled in hospitals of University of Texas Health Science Center at Houston, University of Calgary, University of Pittsburgh, St. Louis University, Charleston Area Medical Center, and University of New Mexico.Enrollment occurred from December 2005 to June 2009 with follow-up from June 2006 through December 2009
Pre-assignment Detail	Enrollment criteria at the first eligibility assessment were ages 16-45, non-penetrating brain injury, and not responsive to instructions. 232 participants met these criteria and also had none of a first set of exclusion criteria. At the second eligibility assessment, 97 patients had none of a second set of exclusion criteria.

Arm/Group Title	Hypothermia	Control
Arm/Group Description	There were two sets of exclusion criteria-one in the field; the other after resuscitation in the ER. In the field, patients were excluded for suspected pregnancy, systolic blood pressure <110 mm Hg, diastolic blood pressure <60 mm Hg, sustained heart rate >120 beats per minute, or failure to be reached by study-affiliated personnel within 2.5 hours of injury. Those that did not have any of the first set of exclusion criteria were further assessed for the presence of Glasgow Coma Scale 3-8 without life-threatening associated injuries. The second set of exclusion criteria were GCS 3 with nonreactive pupils, GCS 7-8 with normal brain CT scan, inability to obtain an accurate GCS, Abbreviated Injury Severity Score >4 for organs other than brain4, systolic blood pressure <110 mm Hg or diastolic blood pressure <60 mm Hg, persistent hypoxia, (oxygen saturation < 94%), or positive pregnancy test.	45 patients who had none of the second set of exclusion criteria and who has been randomized to normothermia served as the control group
Period Title: Overall Study
STARTED	52	45
COMPLETED	52	45
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Hypothermia	Control	Total
Arm/Group Description	Induction and maintenance of moderate hypothermia to 33 degrees celsius achieved within 4 hours of injury and maintained for 48 hours. Hypothermia: Induction of moderate hypothermia to 33 degrees celsius, within 4 hours from time of injury and maintained for 48 hours	Treated at normothermia	Total of all reporting groups
Overall Participants	52	45	97
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26 (9)	31 (11)	28 (10)
Age (Count of Participants)
<=18 years	7 13.5%	6 13.3%	13 13.4%
Between 18 and 65 years	45 86.5%	38 84.4%	83 85.6%
>=65 years	0 0%	1 2.2%	1 1%
Sex: Female, Male (Count of Participants)
Female	12 23.1%	4 8.9%	16 16.5%
Male	40 76.9%	41 91.1%	81 83.5%

Outcome Measures

1. Primary Outcome

Title	The Dichotomized Glasgow Outcome Scale
Description	The primary outcome measure was the Glasgow Outcome Scale measured in person six months after injury by examiners who were blinded to the patient's treatment group. Good recovery and moderate disability were designated as favorable outcomes; severe disability, a vegetative state, and death as poor outcomes.
Time Frame	6 months with a window of plus or minus one month

Outcome Measure Data

Analysis Population Description

Intention to Treat

Arm/Group Title	Hypothermia	Control
Arm/Group Description	Induction and maintenance of moderate hypothermia to 33 degrees celsius achieved within 4 hours of injury and maintained for 48 hours. Hypothermia: Induction of moderate hypothermia to 33 degrees celsius, within 4 hours from time of injury and maintained for 48 hours	treated at normothermia
Measure Participants	52	45
Number [participants with a poor outcome]	31 59.6%	25 55.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hypothermia, Control
	Comments	The primary hypothesis was a two-sided test assessing whether the induction of hypothermia modified the percentage of subjects with poor outcomes at 6 months after injury. Percentages in each group were compared using a generalized linear model with a binomial distribution and log link function, logistic regression model with admission age and baseline GCS as covariates.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	=0.67
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.76 to 1.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Other Pre-specified Outcome

Title	Glasgow Outcome Scale - Extended
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Other Pre-specified Outcome

Title	Disability Rating Scale
Time Frame	assessed 0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Neurobehavioral Rating Scale - Revised
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Neurological Outcome Scale for Traumatic Brain Injury
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Symbol Digit Modalities Test
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Rey Osterrieth Complex Figure
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Other Pre-specified Outcome

Title	Verbal Selective Reminding Test Trails B
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Other Pre-specified Outcome

Title	Grooved Pegboard
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Other Pre-specified Outcome

Title	Controlled Oral Word Association Test
Time Frame	0-12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were reported from the time of the second eligibility assessment to the time of discharge from the acute-care hospital. Generally patients were discharged from the acute care hospital within 3 months of admission.
Arm/Group Title	Randomized to Hypothermia and Hypothermia Maintained		Randomized to Normothermia and Normothermia Maintained		Randomized to Hypothermia and Then Excluded		Randomized to Normothermia Then Excluded
Arm/Group Description	Induction and maintenance of moderate hypothermia and not excluded by second set of exclusion criteria		Induction and maintenance of normothermia and not excluded by second set of exclusion criteria		Induction and maintenance of moderate hypothermia before trauma evaluation in ED and then excluded by second set of criteria		Maintenance of normothermia before trauma evaluation in ED and then excluded by second set of criteria
All Cause Mortality
	Randomized to Hypothermia and Hypothermia Maintained		Randomized to Normothermia and Normothermia Maintained		Randomized to Hypothermia and Then Excluded		Randomized to Normothermia Then Excluded
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Randomized to Hypothermia and Hypothermia Maintained		Randomized to Normothermia and Normothermia Maintained		Randomized to Hypothermia and Then Excluded		Randomized to Normothermia Then Excluded
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/52 (57.7%)		20/45 (44.4%)		11/67 (16.4%)		5/68 (7.4%)
Cardiac disorders
Hypotension	1/52 (1.9%)	6	0/45 (0%)	0	1/67 (1.5%)	1	0/68 (0%)	0
Cardiac Arrest	1/52 (1.9%)	1	1/45 (2.2%)	1	1/67 (1.5%)	1	0/68 (0%)	0
General disorders
Hypothermia	1/52 (1.9%)	1	0/45 (0%)	0	0/67 (0%)	0	0/68 (0%)	0
Multiple Organ Dysfunction	1/52 (1.9%)	1	1/45 (2.2%)	1	1/67 (1.5%)	1	0/68 (0%)	0
Clinical Sepsis	0/52 (0%)	0	0/45 (0%)	0	1/67 (1.5%)	1	0/68 (0%)	0
Infections and infestations
Blood Stream Infection	0/52 (0%)	0	2/45 (4.4%)	2	3/67 (4.5%)	4	3/68 (4.4%)	3
Catheter Positive Culture	0/52 (0%)	0	1/45 (2.2%)	1	0/67 (0%)	0	0/68 (0%)	0
Nervous system disorders
Elevated Intracranial Pressure	14/52 (26.9%)	91	9/45 (20%)	20	4/67 (6%)	7	0/68 (0%)	0
Decreased Cerebral Perfusion Pressure	21/52 (40.4%)	46	13/45 (28.9%)	34	4/67 (6%)	15	0/68 (0%)	0
Subdural Hemorrhage	1/52 (1.9%)	1	1/45 (2.2%)	1	0/67 (0%)	0	0/68 (0%)	0
Intraparenchymal Hemorrhage	1/52 (1.9%)	1	0/45 (0%)	0	0/67 (0%)	0	0/68 (0%)	0
Tentorial Herniation	0/52 (0%)	0	1/45 (2.2%)	1	0/67 (0%)	0	1/68 (1.5%)	1
Epidural Hemorrhage	0/52 (0%)	0	0/45 (0%)	0	0/67 (0%)	0	1/68 (1.5%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	2/52 (3.8%)	2	0/45 (0%)	0	0/67 (0%)	0	0/68 (0%)	0
Acute Respiratory Distress Syndrome	2/52 (3.8%)	2	2/45 (4.4%)	2	1/67 (1.5%)	1	0/68 (0%)	0
Hypoxemia	1/52 (1.9%)	1	0/45 (0%)	0	0/67 (0%)	0	1/68 (1.5%)	1
Hemothorax	1/52 (1.9%)	1	0/45 (0%)	0	1/67 (1.5%)	1	0/68 (0%)	0
Pneumothorax	0/52 (0%)	0	1/45 (2.2%)	1	0/67 (0%)	0	0/68 (0%)	0
Other (Not Including Serious) Adverse Events
	Randomized to Hypothermia and Hypothermia Maintained		Randomized to Normothermia and Normothermia Maintained		Randomized to Hypothermia and Then Excluded		Randomized to Normothermia Then Excluded
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/52 (80.8%)		38/45 (84.4%)		22/67 (32.8%)		30/68 (44.1%)
General disorders
hypotension	7/52 (13.5%)	8	3/45 (6.7%)	7	6/67 (9%)	10	4/68 (5.9%)	21
Nervous system disorders
Elevated Intracranial Pressure	23/52 (44.2%)	244	18/45 (40%)	128	8/67 (11.9%)	82	7/68 (10.3%)	30
Decreased Cerebral Perfusion Pressure	3/52 (5.8%)	36	3/45 (6.7%)	20	5/67 (7.5%)	31	1/68 (1.5%)	1
Renal and urinary disorders
Urinary Tract Infection	3/52 (5.8%)	5	6/45 (13.3%)	6	5/67 (7.5%)	5	4/68 (5.9%)	4
Respiratory, thoracic and mediastinal disorders
Pneumonia	28/52 (53.8%)	29	28/45 (62.2%)	33	17/67 (25.4%)	20	17/68 (25%)	19
Pneumothorax	4/52 (7.7%)	4	4/45 (8.9%)	5	0/67 (0%)	0	2/68 (2.9%)	2
Skin and subcutaneous tissue disorders
Decubitus	4/52 (7.7%)	4	2/45 (4.4%)	2	4/67 (6%)	4	2/68 (2.9%)	2
Vascular disorders
Deep Vein Thrombosis	6/52 (11.5%)	6	6/45 (13.3%)	6	0/67 (0%)	0	2/68 (2.9%)	2

Limitations/Caveats

Early termination for futility.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.