Mild Traumatic Brain InjuryEarly Phase 1NCT02260570

Remediation of Impaired Self-Regulation in Patients With Mild TBI

A Early Phase 1 study testing Tolcapone in people with Mild Traumatic Brain Injury, run by VA Office of Research and Development at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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Trial summary

Who is it for?: Ages 18 to 50 yearsHealthy volunteers can take part
Conditions the study is for: Mild Traumatic Brain Injury
What is being tested?: Tolcapone
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 55 participants
Where: 1 siteUnited States
Study dates: 1 Aug 2015to 30 Jun 2021
Phase: Early Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 50 years
All sexes
Healthy volunteers accepted
Adult

Who may be able to join

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

Who cannot join

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;

Show all 12Show fewer

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)

Trial locations and contacts

1 site in 1 country.

United States1 site

VA Northern California Health Care System, Mather, CA
Sacramento, California, 95655

Other trials in United States

About this study

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.

Read the detailed description

In this randomized, double-blind, placebo-controlled, crossover cognitive neuroscience study, the investigators are evaluating whether the catechol-O-methyltransferase (COMT) inhibitor tolcapone impacts memory and self regulation, as measured both behaviorally (via cognitive testing) and neurophysiologically (via functional MRI).

Conditions: Mild Traumatic Brain Injury
Being tested: Tolcapone, Placebo
Keywords: concussion, MRI, memory, tolcapone, post-traumatic stress disorder
Medical subject headings: Brain Concussion, Stress Disorders, Post-Traumatic

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

TolcaponeDrug
Also called Tasmar
COMT Inhibitor
PlaceboDrug
A pill that contains no active ingredient

Study groups in NCT02260570
Study group	Role	What they receive
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. Receives: 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. Receives: Drug: Tolcapone; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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.
Measured: 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.
Measured: Approximately 60-240 minutes following tolcapone/placebo administration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Aug 201530 Jun 2021

First posted9 Oct 2014 (estimated)
Study start1 Aug 2015
Primary completion30 Jun 2021
Study completion30 Jun 2021

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Mild Traumatic Brain InjuryStudies of the same condition, open and under way.
More trials run by VA Office of Research and DevelopmentThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Early Phase 1
Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
Model description: 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.
Masking: Double blind
Who is masked: Participant, Investigator
Enrolment: 55 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02260570
Sponsor's protocol ID: D0825-I
Other IDs: 1I01RX000825-01
Status last verified: Sep 2025
First submitted: 6 Oct 2014
Last updated: 22 Sep 2025
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: No

Publications

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.
PubMed 34253715

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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All Mild Traumatic Brain Injury trials

Study at a glance

From the registry record, last updated by the sponsor on 22 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Remediation of Impaired Self-Regulation in Patients With Mild TBI
ClinicalTrials.gov ID: NCT02260570
Acronym / sponsor ID: D0825-I
Conditions: Mild Traumatic Brain Injury
Keywords: concussion, MRI, memory, tolcapone, post-traumatic stress disorder
Phase: Early Phase 1
Study type: Interventional
Recruitment status: Completed
Enrolment: 55 participants (actual)
Lead sponsor: VA Office of Research and DevelopmentUS federal agency
Collaborators: University of California, Berkeley, University of California, San Francisco
Study start: 1 Aug 2015 (actual)
Primary completion: 30 Jun 2021 (actual)
Study completion: 30 Jun 2021 (actual)
First posted: 9 Oct 2014 (estimated)
Results: Posted 22 Sep 2025

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Basic science
Allocation: Randomised
Intervention model: Crossover
Masking: Double blind (participant, investigator)
Number of arms: 2
Model description: 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.

Arm	Type	Receives
Functional MRI Arm 1: Tolcapone first, then placebo	Experimental	Drug: Tolcapone, Drug: PlaceboThis 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.
Functional MRI Arm 2: Placebo first, then tolcapone	Experimental	Drug: Tolcapone, Drug: PlaceboThis 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.

Who may qualify

Ages: 18 to 50 years
Sex: All
Healthy volunteers: Accepted
Age groups: Adult

Key inclusion criteria (6 listed)

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);

Key exclusion criteria (12 listed)

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;

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
TolcaponeAlso: TasmarCOMT Inhibitor	Drug	Functional MRI Arm 1: Tolcapone first, then placebo, Functional MRI Arm 2: Placebo first, then tolcapone
PlaceboA pill that contains no active ingredient	Drug	Functional MRI Arm 1: Tolcapone first, then placebo, Functional MRI Arm 2: Placebo first, then tolcapone

Primary outcome

Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI.
Time frame: Approximately 60-240 minutes following tolcapone/placebo administration
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.
Performance on Cognitive Testing
Time frame: Approximately 60-240 minutes following tolcapone/placebo administration
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.

Results and safety

Results posted to the registry on 22 Sep 2025, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Functional MRI Arm 1: Tolcapone First, Then Placebo	18	15
Functional MRI Arm 2: Placebo First, Then Tolcapone	17	15

Primary outcome: Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI.

Time frame: Approximately 60-240 minutes following tolcapone/placebo administration. Number. Unit: voxels

Measure	Tolcapone n = 30	Placebo n = 30
Value	270	111

Tolcapone vs Placebo: F value: 24.1, p <0.0001, ANOVA

Population analysed: Using the Analysis of Functional Neuroimaging (AFNI) package, we implemented a 3-way ANOVA for the interaction between drug (tolcapone minus placebo), stimulus emotion (neutral versus anxious), and CAPS score. In the summary analysis below, the number of suprathreshold voxels below represents 2.65mm3 isotropic voxels in the left frontal pole and right inferior gyrus, respectively. It is a count, not a mean, and the fMRI package does \*not\* provide bootstrapped ranges for suprathreshold voxels.

Primary outcome: Performance on Cognitive Testing

Time frame: Approximately 60-240 minutes following tolcapone/placebo administration. Mean (Full Range). Unit: units on a scale

Measure	Tolcapone n = 30	Placebo n = 30
Value	25.4 (0 to 68)	25.4 (0 to 68)

Tolcapone vs Placebo: F value: 6.23, p = 0.0184, ANOVA

Population analysed: The population of 30 subjects evaluated in this single arm study is described elsewhere in this record. Here we used a 2-way ANOVA to evaluate the interaction between drug (tolcapone minus placebo) and CAPS-score with respect to the working memory performance measure d', taken from signal detection theory and based upon the hit rate and false alarm rate.

Adverse events

Time frame: In this study, subjects were administered tolcapone and placebo once each on the two study days. Adverse event data were recorded for the two days in which subjects participated.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Functional MRI Arm 1: Tolcapone	0 of 30 (0%)	0 of 30 (0%)	0 of 30
Functional MRI Arm 2: Placebo	0 of 30 (0%)	0 of 30 (0%)	0 of 30

Limitations and caveats (from the sponsor): 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.

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 22 Sep 2025.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Results publication: PubMed 34253715Westphal 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.
Reference + link to the published open-access manuscriptLink provided by the sponsor.
Individual participant dataSharing planned: No

Related trials for Mild Traumatic Brain Injury

Enrolling by invitationPhase 1
Pilot Safety and Exploratory Efficacy of PSC-05 for the Treatment of Chronic Mild Traumatic Brain Injury
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Recruiting
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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Andrew S Kayser, MD PhD principal investigator

VA Northern California Health Care System, Mather, CA

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Tolcapone in people with Mild Traumatic Brain Injury, run by VA Office of Research and Development at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 22 Sep 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Blood Oxygen Level Dependent (BOLD) Brain Signal Measured Using Functional MRI. (time frame: Approximately 60-240 minutes following tolcapone/placebo administration). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02260570, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2025.