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| ID | Type | Description | Link |
|---|---|---|---|
| 1I01RX000825-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| University of California, Berkeley | OTHER |
| University of California, San Francisco | OTHER |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 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. |
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| 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tolcapone | Drug | COMT Inhibitor |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Andrew S Kayser, MD PhD | VA Northern California Health Care System, Mather, CA | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VA Northern California Health Care System, Mather, CA | Sacramento | California | 95655 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34253715 | Result | 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. |
| Label | URL |
|---|---|
| Reference + link to the published open-access manuscript | View source |
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Subjects were screened based on inclusion and exclusion criteria. Only eligible subjects were assigned to a study arm. 55 subjects provided informed consent to participate in screening and study procedures, but after the screening visit, only 35 subjects were determined to be eligible to proceed to study arm assignment.
All subjects participated in a single-arm study in which all subjects received tolcapone and placebo in randomized, counterbalanced, crossover fashion. Because baseline dopamine levels can differ substantially between individuals, each subject serves as their own control. As a result, compiling data for a "tolcapone" arm and a "placebo" arm is not preferred, as such a grouping ignores the within-subject comparison. Instead, subjects are grouped "per sequence".
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| ID | Title | Description |
|---|---|---|
| FG000 | Functional MRI Arm 1: Tolcapone First, Then Placebo | 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. For reporting purposes, 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 retains the within-subject information necessary for subsequent analyses. Tolcapone: COMT Inhibitor Placebo: A pill that contains no active ingredient |
| FG001 | Functional MRI Arm 2: Placebo First, Then Tolcapone | 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. For reporting purposes, 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 retains the within-subject information necessary for subsequent analyses. Tolcapone: COMT Inhibitor Placebo: A pill that contains no active ingredient |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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The total number of subjects reflects the number who completed all study procedures.
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| ID | Title | Description |
|---|---|---|
| BG000 | Baseline Data for All Subjects | 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. Baseline information was obtained across the entire group, not per arm Tolcapone: COMT Inhibitor Placebo: A pill that contains no active ingredient |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | The mean and standard deviation reported for age reflect the total number of completed subjects. |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | 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. | Posted | Number | voxels |
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.
Adverse events were defined as per clinicaltrials.gov.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Functional MRI Arm 1: Tolcapone | 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. Tolcapone: a COMT Inhibitor |
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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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Andrew Kayser, MD PhD | Department of Veterans Affairs | 925-372-2000 | Andrew.Kayser@va.gov |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | May 1, 2018 | May 13, 2022 | Prot_SAP_000.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 2, 2019 | May 12, 2022 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D001924 | Brain Concussion |
| D013313 | Stress Disorders, Post-Traumatic |
| ID | Term |
|---|---|
| D000070642 | Brain Injuries, Traumatic |
| D001930 | Brain Injuries |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
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| ID | Term |
|---|---|
| D000077867 | Tolcapone |
| ID | Term |
|---|---|
| D001577 | Benzophenones |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
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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.
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| Placebo | Drug | A pill that contains no active ingredient |
|
| Mean |
| Standard Deviation |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) | The mean and standard deviation reported for the CAPS-5 reflect the total number of subjects who completed all study procedures. (CAPS-5 scores 0-68, where scores of 31-33 or higher suggest the need for PTSD treatment). | Mean | Standard Deviation | units on a scale |
|
| Approximately 60-240 minutes following tolcapone/placebo administration |
|
|
|
|
| Primary | 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. | 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. | Posted | Mean | Full Range | units on a scale | Approximately 60-240 minutes following tolcapone/placebo administration |
|
|
|
|
| 0 |
| 30 |
| 0 |
| 30 |
| 0 |
| 30 |
| EG001 | Functional MRI Arm 2: Placebo | 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. Placebo first: A pill that contains no active ingredient | 0 | 30 | 0 | 30 | 0 | 30 |
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| D009422 | Nervous System Diseases |
| D006259 | Craniocerebral Trauma |
| D020196 | Trauma, Nervous System |
| D016489 | Head Injuries, Closed |
| D014947 | Wounds and Injuries |
| D014949 | Wounds, Nonpenetrating |
| D040921 | Stress Disorders, Traumatic |
| D000068099 | Trauma and Stressor Related Disorders |
| D001523 | Mental Disorders |
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D009596 | Nitrophenols |
| D010636 | Phenols |
| D007659 | Ketones |
| D009574 | Nitro Compounds |