Cannabinoids and Traumatic Brain Injury: A Randomized, Placebo Controlled Trial

Study Overview
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Brief Summary
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This is a double-blind, placebo-controlled, parallel group study designed to assess the tolerability and efficacy of fsCBD and bsCBD, compared to a placebo control, to improve cognition and traumatic brain injury-related symptoms. If eligible for the study, subjects will be randomized to receive one of the conditions for 12 weeks.

Detailed Description
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To better understand the effects of hemp-derived CBD with and without a small amount of THC, we propose a Phase II randomized clinical trial (RCT) to examine the safety, tolerability, and clinical effects of Full Spectrum CBD (fsCBD, contains less than 0.3% THC) vs. Broad Spectrum CBD (bsCBD, does not contain THC), vs. a matching placebo in a population of patients with traumatic brain injury. This is a double-blind, placebo-controlled, parallel group study designed to assess the tolerability and efficacy of fsCBD and bsCBD, compared to a placebo control, to improve cognition and TBI-related symptoms such as anxiety, pain, depression, and sleep. If eligible for the study, subjects will be randomized to receive one of the conditions for 12 weeks. The initial Week 0 / Baseline visit will take place at the University of Colorado Anschutz Medical Campus. There will be in-person visits at Weeks 1, 6, and 12. Participants will be contacted remotely each remaining week during the 12-week period.

Official Title
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Cannabinoids and Traumatic Brain Injury: A Randomized, Placebo Controlled Trial

Conditions
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Brain Injuries, Traumatic

Intervention / Treatment
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* Drug: Cannabidiol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide valid informed consent 18-60 years old Current or history of TBI as identified by the Ohio Identification Method TBI severity is mild or moderate based on the VA/DoD Classification of TBI Severity TBI event must have resulted in hospital evaluation (emergency department or other hospital-based assessment) within 24 hours of injury, excepting cases in which the TBI was acquired in a military deployment context in which hospital services were not immediately available Ongoing neuropsychiatric symptoms (i.e., depressive, anxiety, pain, cognitive complaints, or sleep complaints) that are plausibly associated with TBI and not better accounted for by co-occuring medical or psychological health conditions Not currently in another treatment study for TBI-related symptoms or co-occuring medical or psychological health conditions Co-occurring treatments must be stable in type, dose, and frequency for the four weeks preceding study enrollment and participants must commit to making no changes in these co-occurring treatments during the study Exclusion Criteria: Currently incarcerated, paroled, or on probation Participant has retained an attorney in relation to the TBI Pregnant at the time of study enrollment or unwilling to commit to the use of barrier contraception throughout the duration of the study Vision, hearing, or communication impairments that preclude valid completion of study assessments History of autism spectrum disorders, intellectual disability, and/or serious neurological or central nervous system disease that would be expected to affect cognition (e.g., epilepsy, tumors, multiple sclerosis) Evidence of poor effort (TOMMe < 8) on neuropsychological testing Current or lifetime diagnosis of a schizophrenia spectrum disorder or other serious mental illness (e.g., bipolar disorder) as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022) Meets criteria for major depressive episode as defined by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022) and with a Beck Depression Inventory-2 score > 13; Current suicidal ideation, as indicated by Beck Depression Inventory-2 item #9 score > 0, Patient Health Questionnaire-9 item #9 score > 0, or verbal or written report of current suicidal ideation by the participant to any study team member History of significant systemic illness or unstable medical condition Alcohol or substance use disorder, based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revised (DSM-5-TR, APA 2022), in the six months preceding study enrollment; Reported use of other drugs (cocaine, opiates, methamphetamine, MDMA) in the past 60 days or test positive on a urine test for those drugs of abuse at baseline; Daily nicotine user; Report using cannabis more than once per week over the last 12 months; Report current use of CBD for medical reasons or TBI symptoms Liver function enzymes (AST, ALT) that are greater than 2x normal

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Full Spectrum Cannabidiol<br>Full Spectrum Cannabidiol (<0.3% THC) Oral softgel capsule, 210mg/day | Drug: Cannabidiol<br>* The current study will directly test the hypothesis that a moderate dose of CBD leads to improvements in cognition, TBI-related symptoms, pain, sleep, depression, anxiety, and peripheral markers of inflammation and oxidative stress.<br>* Other names: CBD;|
| Active Comparator: Broad Spectrum Cannabidiol<br>Broad Spectrum Cannabidiol (0.0% THC) Oral softgel capsule, 210mg/day | Drug: Cannabidiol<br>* The current study will directly test the hypothesis that a moderate dose of CBD leads to improvements in cognition, TBI-related symptoms, pain, sleep, depression, anxiety, and peripheral markers of inflammation and oxidative stress.<br>* Other names: CBD;|
| Placebo Comparator: Hemp Seed Oil<br>Placebo Oral softgel capsule, 210mg/day | Drug: Placebo<br>* Placebo arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cognition | The effects of study treatment (CBD or placebo) on attention, processing speed, working memory, long-term memory recall, and executive function will be assessed using the Trail Making Test; the Wechsler Adult Intelligence Scale-IV (WAIS-IV) Digit Span, Symbol Search, Coding, Letter-Number Sequencing; and HVLT delayed recall, to create domain scores used to inform an aggregate measure of cognition. | Week 0 to Week 12 | 
| Change in Neuropsychiatric Symptoms | The effects of study treatment (CBD or placebo) on neuropsychiatric symptoms associated with TBI will be assessed by the Neurobehavioral Symptom Inventory (NSI) | Week 0 to Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Depression | The Beck Depression Inventory II (BDI-II) will be used to measure depressive symptoms throughout the study. | Week 0 to Week 12 | 
| Change in Pain Intensity | PROMIS Pain Intensity 1a - A single-item measure of pain intensity. Average pain in the last 7 days is recorded on a scale of 1 - 10, with higher scores indicating higher pain levels. | Week 0 to 12 | 
| Change in Sleep Disturbance | PROMIS SF v10 Sleep Disturbance 4a - a 4-item measure assessing subjective sleep quality. | Week 0 to Week 6, Week 0 to Week 12 | 
| Change in Anxiety | PROMIS Anxiety SF - An 8-item measure to rate subjective anxiety symptoms. Possible scores range from 1 - 5 with higher scores indicating worse anxiety symptoms. | Week 0 to 12 | 
| Change in Biomarkers of Inflammation | Circulating levels of cytokine proteins before and after will be measured using immunoassay before and after treatment | Week 0 to Week 6, Week 0 to Week 12 | 
| Change in Biomarkers of Oxidative Stress | Circulating levels of cytokine proteins before and after will be measured using immunoassay before and after treatment | Week 0 to Week 12 | 
| Change in Quality of Life | The Short Form 36 will be used to measure quality of life. | Week 0 to Week 12 |