DASH After TBI Study: Decreasing Adrenergic or Sympathetic Hyperactivity After Traumatic Brain Injury

• Sponsor: Vanderbilt University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01322048
• Collaborator: Vanderbilt Institute for Clinical and Translational Research (CTSA) (Other), Eastern Association for the Surgery of Trauma (EAST) (Other)
• Enrollment: 48
• Location: 1
• Arms: 2
• Duration (Months): 64
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The investigators intend to determine the effect of adrenergic blockade on 1) short-term physiology, behavior, and cognition and 2) long-term neuropsychological outcomes after severe Traumatic Brain Injury (TBI).

The primary hypothesis is that adrenergic blockade after severe TBI will be associated with increased ventilator-free days.

Condition or Disease	Intervention/Treatment	Phase
Brain Injuries; Craniocerebral Trauma; Trauma, Nervous System; Traumatic Brain Injury	Drug: IV Propranolol and Per Tube Clonidine; Drug: Placebo	Phase 2

Detailed Description

Severe traumatic brain injury (TBI) is associated with sympathetic hyperactivity resulting in catecholamine excess, abnormal heart rate variability, agitation and sympathetic storms, deep white matter changes, and poor neuropsychological outcomes. Notably, persistent sympathetic hyperactivity after TBI results in higher days of mechanical ventilation and longer intensive care unit (ICU) length of stay (LOS). While there are data describing limited portions of this response, the full spectrum of sympathetic hyperactivity after severe TBI has not been systemically described or methodically intervened upon.

We will perform a double-blinded, randomized, placebo-controlled pilot trial in a 100 patient cohort in which one group will receive centrally acting sympatholytic drugs, propranolol and clonidine, and the other group, placebo, within 48 hours of severe TBI. The length of therapy will be 7 days.

The primary question studied is whether ventilator-free days will be increased after therapy.

Secondary endpoints include plasma and urine catecholamine levels, heart rate and blood pressure variability, responses to autonomic cold pressor testing, assessments of coma, sedation, and agitation, sedative requirements, analgesic use, antipsychotic medication use, coma-free days, ventilator-free days, Intensive Care Unit (ICU) length of stay, and survival. Also, neuropsychological outcomes will be measured at ICU discharge, 3 months, and 12 months.

Interim Analysis: At approximately 50% targeted accrual, n=46 randomized subjects, an interim analysis will be performed with A Priori (planned) futility and efficacy rules, which are DSMB and IRB approved.

Study Design

• Study Type: Interventional
• Actual Enrollment: 48 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: DASH After TBI Study: Decreasing Adrenergic or Sympathetic Hyperactivity After Severe Traumatic Brain Injury, A Pilot Randomized Clinical Trial Using Propranolol and Clonidine
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Jan 1, 2015
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Adrenergic Blockade Propranolol and Clonidine	Drug: IV Propranolol and Per Tube Clonidine; 1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days
Placebo Comparator: Placebo Placebo	Drug: Placebo; Placebo IV q6h and Per Tube q12, both for 7 days

Outcome Measures

Primary Outcome Measures

1. Ventilator-free Days [Baseline to day 28]

Secondary Outcome Measures

1. Plasma Norepinephrine Levels [Post-treatment (t=Day 8)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years to 64 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age: 16 years to 64 years

• Glasgow Coma Scale score less than or equal to 8 (Severe TBI) with injury on CT

• Screen within 24 hours of injury

Exclusion Criteria:

• Pre-existing heart disease (i.e. coronary heart disease)

• Pre-existing cardiac dysrhythmia

• Allergy to study drugs

• Penetrating brain injury

• Pre-existing brain dysfunction (i.e. prior severe TBI, debilitating stroke)

• Impending brain herniation (i.e. loss of bilateral corneal reflexes)

• Craniectomy or craniotomy

• Spinal cord injury

• Myocardial injury

• Severe liver disease

• Current use of beta-blockers and/or alpha-2-agonist

• Withdrawal of care expected in 24 hours

• Prisoners

• Pregnant women

• Unable to follow-up through final visit

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37212

Sponsors and Collaborators

• Vanderbilt University
• Vanderbilt Institute for Clinical and Translational Research (CTSA)
• Eastern Association for the Surgery of Trauma (EAST)

Investigators

• Principal Investigator: Mayur B Patel, MD, MPH, Vanderbilt University Medical Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Vanderbilt Multidisciplinary Traumatic Brain Injury Clinic (MTBIC)

Publications

None provided.

• Responsible Party: Mayur Patel, Assistant Professor of Surgery and Neurosurgery, Vanderbilt University
• ClinicalTrials.gov Identifier: NCT01322048
• Other Study ID Numbers: 110429
• First Posted: Mar 24, 2011
• Last Update Posted: Aug 17, 2017
• Last Verified: Jul 1, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mayur Patel, Assistant Professor of Surgery and Neurosurgery, Vanderbilt University: Sympathetic Hyperactivity; Traumatic Brain Injury; Agitation; Severe TBI; TBI; Catecholamines; Heart rate variability; Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Cognitive Impairment
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Hyperkinesis; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Propranolol; Clonidine

Study Results

Participant Flow

Pre-assignment Detail	One subject was enrolled but was not randomized/assigned to either arm, due to a late withdrawal of care decision.

Arm/Group Title	Adrenergic Blockade	Placebo
Arm/Group Description	Propranolol and Clonidine IV Propranolol and Per Tube Clonidine: 1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days	Placebo Placebo: Placebo IV q6h and Per Tube q12, both for 7 days
Period Title: Overall Study
STARTED	21	26
COMPLETED	21	26
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Adrenergic Blockade	Placebo	Total
Arm/Group Description	Propranolol and Clonidine IV Propranolol and Per Tube Clonidine: 1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days	Placebo Placebo: Placebo IV q6h and Per Tube q12, both for 7 days	Total of all reporting groups
Overall Participants	21	26	47
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	24	27.5	25
Sex: Female, Male (Count of Participants)
Female	5 23.8%	1 3.8%	6 12.8%
Male	16 76.2%	25 96.2%	41 87.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	21 100%	26 100%	47 100%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 9.5%	2 7.7%	4 8.5%
White	19 90.5%	24 92.3%	43 91.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	21 100%	26 100%	47 100%

Outcome Measures

1. Primary Outcome

Title	Ventilator-free Days
Time Frame	Baseline to day 28

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Adrenergic Blockade	Placebo
Arm/Group Description	Propranolol and Clonidine IV Propranolol and Per Tube Clonidine: 1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days	Placebo Placebo: Placebo IV q6h and Per Tube q12, both for 7 days
Measure Participants	21	26
Median (Inter-Quartile Range) [days]	16.2	18.05

2. Secondary Outcome

Title	Plasma Norepinephrine Levels
Time Frame	Post-treatment (t=Day 8)

Outcome Measure Data

Analysis Population Description

Of those surviving treatment period

Arm/Group Title	Adrenergic Blockade	Placebo
Arm/Group Description	Propranolol and Clonidine IV Propranolol and Per Tube Clonidine: 1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days	Placebo Placebo: Placebo IV q6h and Per Tube q12, both for 7 days
Measure Participants	21	25
Median (Inter-Quartile Range) [pg/mL]	962	714

Adverse Events

Arm/Group Title	Adrenergic Blockade		Placebo
Arm/Group Description	Propranolol and Clonidine IV Propranolol and Per Tube Clonidine: 1 mg IV q6h Propranolol and 0.1 mg Per Tube Clonidine, both for 7 days		Placebo Placebo: Placebo IV q6h and Per Tube q12, both for 7 days
All Cause Mortality
	Adrenergic Blockade		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/21 (23.8%)		8/26 (30.8%)
Serious Adverse Events
	Adrenergic Blockade		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Adrenergic Blockade		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/21 (0%)		0/26 (0%)

Limitations/Caveats

[Not Specified]

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.