Remediation of Impaired Self-Regulation in Patients With Mild TBI

NCT02260570 | Completed Early Phase 1 Results DMC FDA Drug

• 2 other identifiers: D0825-I1I01RX000825-01
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 1

Brief Summary

The ability to regulate impulses enables us to plan for the future, to maintain focus in the face of distractions (i.e. to encode memories), and to manage emotions. This self regulation can be compromised in individuals who have a history of mild traumatic brain injury and co-occurring disorders. In this study the investigators are using functional MRI scanning to understand how memory and self regulation are expressed in the brains of people with a history of mild traumatic brain injury. The investigators are also testing whether the medication tolcapone may improve memory and self regulation.

Conditions

Mild Traumatic Brain Injury

Keywords

concussion; MRI; memory; tolcapone; post-traumatic stress disorder

Outcome Measures

Primary Outcomes (2)

• Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI.

  Functional MRI measures blood flow changes. Blood Oxygen Level Dependent (BOLD) signals provide an indirect unitless measure of brain activity typically described as a percentage. However, because fMRI data sets are large (\> 10,000 comparisons), analysis packages present results as F statistics or similar measures for individual voxels across the brain. Thus, no single mean or median value describes the 3-way interaction between drug (tolcapone minus placebo), stimulus emotion (neutral versus anxious), and CAPS-score with degrees of freedom = \[1,1,60\]. Because each subject serves as his/her own control, drug results are also intrinsically paired -- i.e. data are presented for participants as tolcapone minus placebo results within subject. The data values below represent the number of above-threshold, neighboring voxels in the largest clusters of voxels in the brain for the patient group as a whole, not separately for each participant.

  Approximately 60-240 minutes following tolcapone/placebo administration

• Performance on Cognitive Testing

  Tasks to assess cognition were performed while subjects are scanned. Signal detection theory (SDT) assesses the ability of subjects to accurately recall working memory memoranda. In SDT, the sensitivity index d' results from subtracting the normalized false alarm rate from the normalized hit rate; thus, higher values of d' indicate better working memory performance. Here we evaluate the interaction with respect to d' between drug condition (tolcapone minus placebo) and Post-Traumatic Stress Disorder severity as measured by the total score on the \*Clinician Administered PTSD Scale\*, or CAPS. Total CAPS scores range from 0 to 80, with higher scores indicating greater PTSD severity. Because each subject serves as his/her own control, drug results for behavior are intrinsically paired -- i.e. data are presented for participants as tolcapone minus placebo results, as prespecified in the statistical analysis plan.

  Approximately 60-240 minutes following tolcapone/placebo administration

Study Arms (2)

Functional MRI Arm 1: Tolcapone first, then placebo

EXPERIMENTAL

This cognitive science study consists of a single "arm" in which all subjects receive both tolcapone and placebo in randomized, double-blind, counterbalanced, crossover fashion. Subjects have been divided into two arms based on the order in which they received the drug intervention. Because baseline dopamine levels can vary substantially between individuals, this grouping by sequence rather than by drug condition retains the within-subject information necessary for subsequent analyses.

Drug: Tolcapone; Drug: Placebo

Functional MRI Arm 2: Placebo first, then tolcapone

EXPERIMENTAL

This cognitive science study consists of a single "arm" in which all subjects receive both tolcapone and placebo in randomized, double-blind, counterbalanced, crossover fashion. Subjects have been divided into two arms based on the order in which they received the drug intervention. Because baseline dopamine levels can vary substantially between individuals, this grouping by sequence rather than by drug condition retains the within-subject information necessary for subsequent analyses.

Drug: Tolcapone; Drug: Placebo

Interventions

Tolcapone DRUG

COMT Inhibitor

Also known as: Tasmar

Functional MRI Arm 1: Tolcapone first, then placebo; Functional MRI Arm 2: Placebo first, then tolcapone

Placebo DRUG

A pill that contains no active ingredient

Functional MRI Arm 1: Tolcapone first, then placebo; Functional MRI Arm 2: Placebo first, then tolcapone

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Veteran ages 18-50 and in general good health;
• Able to read English at a 6th grade level;
• Able to provide written informed consent;
• Normal or corrected to normal visual acuity;
• Stable doses of all medications (2 weeks or greater);
• History of mild traumatic brain injury greater than 6 months prior to participation

You may not qualify if:

• Contraindications to magnetic resonance imaging (MRI) scanning;
• Inability to complete basic fMRI requirements;
• History of brain surgery or penetrating brain injury;
• Uncontrolled blood pressure (low or high);
• Contraindications to tolcapone use;
• Use of medications or drugs with dopamine-related actions within 30 days;
• Active substance abuse or dependence;
• Clinically severe medical illness requiring treatment;
• History of psychiatric hospitalization (past 1 year) or suicide attempt (past 5 years);
• Seizures greater than 4 weeks after traumatic brain injury (TBI) event or seizures requiring active treatment;
• History of brain tumor, stroke, Alzheimer's disease, aneurysm rupture, or multiple sclerosis;
• History of schizophrenia, attention deficit hyperactivity disorder (ADHD) or psychiatric diagnosis EXCEPT depression or post-traumatic stress disorder (PTSD)

Sponsors & Collaborators

• VA Office of Research and Development: lead
• University of California, Berkeley: collaborator
• University of California, San Francisco: collaborator

Study Sites (1)

VA Northern California Health Care System, Mather, CA

Sacramento, California, 95655, United States

Location

Related Publications (1)

• Westphal AJ, Ballard ME, Rodriguez N, Vega TA, D'Esposito M, Kayser AS. Working memory, cortical dopamine tone, and frontoparietal brain recruitment in post-traumatic stress disorder: a randomized controlled trial. Transl Psychiatry. 2021 Jul 12;11(1):389. doi: 10.1038/s41398-021-01512-6.

  PMID: 34253715 RESULT

Related Links

• Reference + link to the published open-access manuscript

MeSH Terms

Conditions

Brain Concussion; Stress Disorders, Post-Traumatic

Interventions

Tolcapone

Condition Hierarchy (Ancestors)

Brain Injuries, Traumatic; Brain Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds and Injuries; Wounds, Nonpenetrating; Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Benzophenones; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Nitrophenols; Phenols; Ketones; Nitro Compounds

Limitations and Caveats

For additional details, including results discussion, please see the primary resulting open-access publication: Westphal AJ, Ballard ME, Rodriguez N, Vega TA, D'Esposito M, Kayser AS. Enhancing prefrontal dopamine tone improves working memory and recruits frontoparietal brain regions in individuals with post-traumatic stress disorder. Translational Psychiatry, 11(1): 389. This reference is also included in the References module of the Protocol section for this ClinitalTrials.gov record.

Results Point of Contact

• Title: Andrew Kayser, MD PhD
• Organization: Department of Veterans Affairs

Andrew.Kayser@va.gov

925-372-2000

Study Officials

• Andrew S Kayser, MD PhD

  VA Northern California Health Care System, Mather, CA

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: FED
• Responsible Party: SPONSOR

Model Details: In this study, subjects received either tolcapone or placebo in randomized, double-blind, counterbalanced fashion. The study is a single arm study in which all subjects receive both tolcapone and placebo, but to comply with clinical trial reporting requirements, it is listed here as a two arm study: one arm for subjects who received tolcapone first, and one arm for subjects who received placebo first. Because baseline dopamine levels can vary substantially between individuals, this grouping by sequence rather than by drug condition retains the within-subject information necessary for subsequent analyses. The alternative (grouping by tolcapone or placebo) loses this within-subject information.

Study Record Dates

• First Submitted: October 6, 2014
• First Posted: October 9, 2014
• Study Start: August 1, 2015
• Primary Completion: June 30, 2021
• Study Completion: June 30, 2021
• Last Updated: September 22, 2025
• Results First Posted: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)