Coma, Minimally Conscious State, Traumatic Brain Injury, Vegetative State
Conditions
Keywords
Randomized Clinical Trial, Auditory Stimulation
Brief summary
The purpose of the study is to determine whether familiar vocal stimulation, provided during coma recovery, improves outcomes for persons who are unconscious after severe TBI. The primary hypothesis is that unconscious persons who receive standard rehabilitation (SR) plus a high-dose of Familiar Voice stimulation (FVs) compared to unconscious persons who receive SR plus a sham stimulation (Sham Group) will demonstrate: 1. Significantly more neurobehavioral functioning post-intervention compared to pre-intervention. 2. Using Functional Magnetic Resonance Imaging (fMRI), significantly higher average measures of volumetric activity in the whole brain, middle temporal gyrus bilaterally, primary auditory area, bilateral pre-frontal cortex, hippocampus and/or the cerebellum post-intervention compared to pre-intervention.
Detailed description
Medical advances have improved the odds of surviving a severe traumatic brain injury (TBI) thereby increasing demands for rehabilitation. Medical rehabilitation management during coma recovery, however, has been hampered by a paucity of rigorous clinical trials examining rehabilitation effectiveness. This randomized clinical trial addresses this knowledge gap. The purpose of the study is to determine whether a high dose of familiar vocal stimulation (FVs) improves outcomes for persons who are unconscious after severe TBI. The research objectives are to: 1. Determine whether neural responses elicited with FVs improve neurobehavioral outcomes and/or elicit activations in expected regions. 2. Examine the relationship between neurobehavioral and neurophysiological responses to high doses of FVs during coma recovery. There are two study cohorts and each group receives standard rehabilitation. The experimental group will be exposed daily to 40 minutes of FVs for 6 weeks. The Sham Group (Control Group 2) will receive 40 minutes of sham treatment, or silence, daily for 6 weeks. The 40 minutes of FVs treatment will be provided in four 10 minute sessions. Each FV session will start with the subject hearing a familiar voice call the 'Subject's Own Name' aloud and then that same voice re-telling a memory or an event familiar to the subject. The person re-telling the event will be a person who experienced the event with the subject and who interacted with the subject on a daily basis for at least 1 year prior to injury.
Interventions
BEHAVIORALFamiliar Auditory Sensory Training
Patient is provided with customized recordings of stories told by people well known to the patient at least 1 year prior to injury. The stories represent specific events experienced by both the patient and the storyteller. Patients received FAST for 10 minutes 4 times per day, with at least 2 hours in between, for 6 week.
BEHAVIORALSham Auditory Sensory Training
The sham intervention is zero minutes of Familiar Auditory Sensory Training. Each day for 6 weeks 0 minutes of Familiar voice stimulation will be provided in 10 minute daily segments for 6 weeks. Each 10 minute recording is a digital recording of silence.
Sponsors
Shirley Ryan AbilityLab
Northwestern Memorial Hospital
Northwestern University Feinberg School of Medicine
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Severe brain injury of traumatic origin * Non-brain penetrating gun shot wound * Blunt trauma with subsequent closed head injuries such as diffuse axonal injury * 18 years of age or older * Unconscious for at least 28 days consecutively * Medically Stable * Does not have active seizures
Exclusion criteria
* History of brain injury * More than 1 year post injury * MRI is contraindicated (e.g., metal, titanium in brain) * Ventilator dependent * Cardiac contraindications * The definition of traumatic brain injury excludes: (a) Lacerations or contusions of the face, eye, ear or scalp and fractures of facial bones with-out loss of consciousness; (b) Primary cause of injury is blunt trauma (e.g., contusion from blow to head) without subsequent closed head injuries such as contra coup or diffuse axonal injury; (c) Brain-penetrating gun shot wound; (d) Primary BI due to anoxic, inflammatory, infectious, toxic metabolic encephalopathies; (e) Cancer, brain infarction (ischemic stroke), intracranial hemorrhage (hemorrhagic stroke) aneurysms and arterio-venous malformations.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| DOCS Neurobehavioral Measure (DOCS = Disorders of Consciousness Scale) Change | Baseline and immediately after treatment ends (6 weeks after Baseline) | The primary outcome, the DOCS, is a reliable, valid and precise measure of global neurobehavioral functioning shown to remain stable over six weeks.The DOCS-25 starts with a systematic observation followed by administration of 25 sensory stimuli. Best responses to each stimulus are rated on a scale of 0 to 2 and total raw scores range from 0 (worst) to 50 (best). The DOCS change was calculated as the value at endpoint (6 weeks after Baseline) minus the value at Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Coma Near Coma Scale | Baseline and after the 8th CNC assessment (4 weeks after Baseline) | The CNC scale measures arousal and awareness and test stimuli are administered to elicit a specified behavior. Presence/absence of this behavior is scored as 0, 2 or 4. Total raw scores range from 0 (consistently responsive) to 36 (extreme coma). The CNC change score was calculated as the 8th CNC measure minus the Baseline CNC measure. Since 2 CNC measurements were collected per week, the 8th CNC measure occurred in Week 4. To calculate the change, we used the eighth CNC measure because two patients (one per group) recovered full consciousness after the eighth CNC measure. In the second statistical analysis, all CNC measures were used to calculate the slope; this includes the Baseline CNC and CNC measures 2-8. Again, we used the first 8 CNC measures (instead of all 12 collected over 6 weeks of treatment) because two patients recovered full consciousness after the eighth CNC measure. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from a large urban community population and two acute rehabilitation hospitals. Community participants included patients not treated at the two acute rehabilitation hospitals. Acute rehabilitation programs included one U.S.
Pre-assignment details
All patients with possible impairment in sound conduction were withdrawn prior to randomization. In total, 5 participants were withdrawn prior to randomization: 1 participant failed the auditory pathway screen, 2 participants recovered full consciousness, and 2 participants were placed in hospice by LAR. Therefore 16 participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| FAST high dose of familiar voice stimulation
Familiar Voice Stimulation High Dose: The High Dose intervention is 1,680 minutes of Familiar Vocal Stimulation (FVs) provided in 40 minute daily segments at least 2 hours apart and for 6 weeks. Four CDs with 10 minutes of FVs preceded by the familiar voice calling out the subject's name, will be played (1 at a time) each day for 6 weeks providing 1,680 minutes of FVs. | 8 |
| Sham sham auditory stimulation
Sham Auditory Stimulation: The sham intervention is zero minutes of Familiar Voice Stimulation. Each day for 6 weeks 0 minutes of Familiar voice stimulation will be provided in 10 minute daily segments for 6 weeks. Each 10 minute recording is a digital recording of silence. | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Unblinding | 0 | 1 |
Baseline characteristics
| Characteristic | FAST | Total | Sham |
|---|---|---|---|
| Age, Continuous | 35.6 years STANDARD_DEVIATION 11 | 35.1 years STANDARD_DEVIATION 11 | 34.4 years STANDARD_DEVIATION 12 |
| Education Achieved at Injury Bachelor Degree | 2 participants | 4 participants | 2 participants |
| Education Achieved at Injury Graduate or Professional Degree | 1 participants | 2 participants | 1 participants |
| Education Achieved at Injury High School Graduate or GED | 4 participants | 5 participants | 1 participants |
| Education Achieved at Injury Some College, No Degree | 1 participants | 4 participants | 3 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 3 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 12 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 12 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 8 | 0 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
DOCS Neurobehavioral Measure (DOCS = Disorders of Consciousness Scale) Change
The primary outcome, the DOCS, is a reliable, valid and precise measure of global neurobehavioral functioning shown to remain stable over six weeks.The DOCS-25 starts with a systematic observation followed by administration of 25 sensory stimuli. Best responses to each stimulus are rated on a scale of 0 to 2 and total raw scores range from 0 (worst) to 50 (best). The DOCS change was calculated as the value at endpoint (6 weeks after Baseline) minus the value at Baseline.
Time frame: Baseline and immediately after treatment ends (6 weeks after Baseline)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FAST | DOCS Neurobehavioral Measure (DOCS = Disorders of Consciousness Scale) Change | 13.5 units on a scale | Standard Deviation 8.2 |
| Sham | DOCS Neurobehavioral Measure (DOCS = Disorders of Consciousness Scale) Change | 18.9 units on a scale | Standard Deviation 15.6 |
Comparison: The planned sample of 15 per group provided 80% power for a one-sided t-test to detect be-tween group endpoint differences in DOCS averages equivalent to an effect size of .91 (9 units). Clinically, this assumes that the FAST protocol would facilitate progression from one clinical state to another (e.g., vegetative (VS) to minimally conscious (MCS) states). The hypothesized effect was based on average DOCS change for a severe TBI sample receiving three weeks of acute rehabilitation.p-value: 0.46595% CI: [-11.1, 21.9]t-test, 1 sided
Secondary
Coma Near Coma Scale
The CNC scale measures arousal and awareness and test stimuli are administered to elicit a specified behavior. Presence/absence of this behavior is scored as 0, 2 or 4. Total raw scores range from 0 (consistently responsive) to 36 (extreme coma). The CNC change score was calculated as the 8th CNC measure minus the Baseline CNC measure. Since 2 CNC measurements were collected per week, the 8th CNC measure occurred in Week 4. To calculate the change, we used the eighth CNC measure because two patients (one per group) recovered full consciousness after the eighth CNC measure. In the second statistical analysis, all CNC measures were used to calculate the slope; this includes the Baseline CNC and CNC measures 2-8. Again, we used the first 8 CNC measures (instead of all 12 collected over 6 weeks of treatment) because two patients recovered full consciousness after the eighth CNC measure.
Time frame: Baseline and after the 8th CNC assessment (4 weeks after Baseline)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FAST | Coma Near Coma Scale | 1.0 units on a scale | Standard Deviation 0.6 |
| Sham | Coma Near Coma Scale | 0.25 units on a scale | Standard Deviation 0.7 |
Comparison: Power was not calculated for the CNC because the effect size was not published.p-value: 0.04995% CI: [-1.51, -0.00493]t-test, 1 sided
p-value: 0.0022t-test, 1 sided