A Study of Neural Circuit Responses to Catechol-O-methyl Transferase (COMT) Inhibitors

• Sponsor: University of California, San Francisco (Other)
• Overall Status: Completed
• CT.gov ID: NCT01158950
• Collaborator: University of California, Berkeley (Other), United States Department of Defense (U.S. Fed)
• Enrollment: 26
• Locations: 2
• Arms: 2
• Actual Duration (Months): 105
• Patients Per Site: 13
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

In this study, we seek to understand the effects of tolcapone, an FDA-approved COMT inhibitor, on reward choice and response inhibition, two measures we have previously shown to be altered in subjects with alcoholism. We now plan to test the hypothesis that COMT regulation of cortical dopamine levels is critical for regulation financial choices. Specifically, we propose that the lower levels of cortical dopamine present in individuals with the val158val COMT genotype reduces the inhibitory effect of frontal cortical areas on impulsive choice; an idea that extends previous hypotheses about the negative consequences of decreased prefrontal dopamine levels on inhibitory control. Moreover, this hypothesis suggests that inhibiting COMT may slow the degradation of dopamine and thereby decrease impulsivity.

Condition or Disease	Intervention/Treatment	Phase
Impulsive Behavior	Drug: Tolcapone; Other: Placebo	N/A

Detailed Description

Drug consumption despite adverse consequences is a defining feature of human addiction (DSM-IV-TR, 2004). Impulsivity, a tendency to choose an immediate action despite delayed adverse consequences, is a major risk factor for tobacco, psychostimulant, opioid and alcohol abuse. In humans, impulsivity can be quantified by presenting subjects with a choice between a small immediate monetary reward or a larger but delayed reward. We recently found that the val158val allele for the enzyme catechol-O-methyltransferase (COMT), which is associated with more rapid cortical dopamine catabolism and thus lower cortical dopamine levels correlates with greater impulsivity and greater fMRI blood oxygen level dependent (BOLD) signal in dorsolateral prefrontal and posterior parietal cortices.

The first phase of the study will involve healthy controls. The second phase of the study will involve abstinent alcoholics matched for age, education, and gender. Subjects will range in age between 18 and 50 years old.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: A Randomized, Double-Blind Study of Neural Circuit Responses to COMT Inhibitors
• Actual Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Dec 1, 2018
• Actual Study Completion Date: Dec 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tolcapone Drug: Tolcapone 200mg (single dose) administered at study visit	Drug: Tolcapone; Drug: Tolcapone 200mg (single dose) administered at study visit; Other Names: Tasmar
Placebo Comparator: Placebo Drug: Placebo for tolcapone administered at study visit	Other: Placebo; Placebo (200mg) administered at study visit

Outcome Measures

Primary Outcome Measures

1. Correlation Between the Impulsive Choice Ratio and Baseline Impulsivity, as Measured With the Barratt Impulsiveness Scale [120 minutes after drug ingestion]

   The presented value represents a correlation. Subjects completed a delay discounting task while functional MRI images were obtained. In this task, subjects made hypothetical choices between a smaller amount of money available sooner, and a larger amount of money available later. Performance on the delay discounting task, as assessed by the impulsive choice ratio, was determined for both the tolcapone and placebo sessions, and the difference between them (tolcapone minus placebo) was calculated. This difference value was then correlated with baseline scores on the Barratt Impulsiveness Scale.

Other Outcome Measures

1. Correlation Between the Difference in ICR (Tolcapone Minus Placebo) and the Difference in Blood Oxygen Level Dependent (BOLD) Signal in the Brain (Tolcapone Minus Placebo) [120 minutes after drug ingestion]

   The presented value represents a correlation. The difference in performance on the delay discounting task was calculated as the change in ICR (tolcapone minus placebo). In addition, the difference in BOLD activity throughout the brain was determined (tolcapone minus placebo).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Age between 18 and 50 years.

• Subject is right-handed.

• If female, subject is non-lactating, not pregnant, and using a reliable contraception method (i.e. abstinence, intrauterine device (IUD), hormonal birth control or barrier method).

• Subject is able to read and speak English.

• Subject is a high school graduate.

• Subject is able and willing to provide written and informed consent.

• Subject is able to understand and follow the instructions of the investigator, and understand all ratings scales.

• Subject is in good health.

Exclusion Criteria:

• Using cocaine, stimulants (other than THC, nicotine, & caffeine)amphetamines, hallucinogens, "ecstasy", opiates, sedatives, pain pills, sleeping pills or other psychoactive drugs within two weeks of the start of the study OR more than 10 times in the last year.

• Has a current dependence on, or addiction to any psychoactive drug (except nicotine or caffeine) including alcohol.

• Clinically significant medical or psychiatric illness requiring treatment as determined by screening blood tests, medical history, and physical exam performed or reviewed by the study physician.

• Subject has a history of major alcohol related complications within the proceeding 2 years (liver failure/cirrhosis, pancreatitis, esophageal varices, etc.)

• Liver function test ≥ 3 times normal upper limit.

• BAC level > 0.05% at the beginning of screening visit (within margin of error of detection).

• Has a neurological dysfunction or psychiatric disorder.

• Has severe low blood pressure.

• Has uncontrolled high blood pressure.

• Regular use of any of the drugs on the tolcapone or entacapone contraindications list OR within 2 weeks of drug administration.

• Regular use of SSRIs.

• Has an allergy or intolerance to tolcapone or entacapone.

• Subject has received an investigational drug within 30 days of screening visit.

• Subject is considered unsuitable for the study in the opinion of the investigator or study physician for any other reason.

MRI Exclusion Criteria:

• The subject has metal (metal plates, pins, wires or screws, artificial limb, joint replacement or anything that might have been inserted during an operation) in his/her body.

• Subject has a pacemaker, defibrillator, stent, or any metal implants related to heart/blood flow problems.

• Subject has worked with metals (ie. metallurgy, metal shaving, welding, soldering, etc).

• Subject has been wounded with anything metal (bullet, shrapnel or metal filling).

• Has ever gotten a piece of metal in the eye.

• Has tattoos done with ink containing metal or permanent eyeliner.

• Wears color contact lenses.

• Has a hearing problem or hearing aid, cochlear implant or past ear surgery.

• Has any irremovable dental bridges, dental plates, metal caps or any other non-removable metal in the mouth.

• The subject is claustrophobic.

• The subject is pregnant. (women only)

• Has a IUD. (women only)

• Significantly overweight.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, Berkeley	Berkeley	California	United States	94704
2	UCSF: Ernest Gallo Clinic and Research Center	Emeryville	California	United States	94591

Sponsors and Collaborators

• University of California, San Francisco
• University of California, Berkeley
• United States Department of Defense

Investigators

• Principal Investigator: Howard Fields, MD, PhD, UCSF: Ernest Gallo Clinic and Research Center
• Study Director: Jennifer Mitchell, PhD, UCSF: Ernest Gallo Clinic and Research

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 4, 2012

More Information

Publications

None provided.

• Responsible Party: University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT01158950
• Other Study ID Numbers: 2009-12-461; W81XWH-10-1-0231
• First Posted: Jul 8, 2010
• Last Update Posted: Nov 20, 2020
• Last Verified: Nov 1, 2020

• Additional relevant MeSH terms: Impulsive Behavior; Tolcapone

Study Results

Participant Flow

Pre-assignment Detail	Subjects were screened for inclusion / exclusion criteria.

Arm/Group Title	Tolcapone First, Then Placebo	Placebo First, Then Tolcapone
Arm/Group Description	Tolcapone 200mg (single dose) then Placebo (single dose) administered at study visit, followed by crossover to other drug at next visit	Placebo (single dose) then Tolcapone 200mg (single dose) tadministered at study visit, followed by crossover to other drug at next visit
Period Title: 1st Intervention (1 Day)
STARTED	13	13
Data Collected	12	11
COMPLETED	12	11
NOT COMPLETED	1	2
Period Title: 1st Intervention (1 Day)
STARTED	12	11
COMPLETED	12	11
NOT COMPLETED	0	0
Period Title: 1st Intervention (1 Day)
STARTED	12	11
COMPLETED	12	11
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All study participants receiving either Tolcapone 200mg (single dose) or Placebo (single dose) administered at study visit, followed by crossover to other drug at next visit - all participants were randomized to receive all interventions.
Overall Participants	23
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	23 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.1 (6.3)
Sex: Female, Male (Count of Participants)
Female	13 56.5%
Male	10 43.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 21.7%
Not Hispanic or Latino	18 78.3%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4.3%
White	20 87%
More than one race	1 4.3%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	23 100%
Barratt Impulsiveness Scale (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	58.6 (9.1)

Outcome Measures

1. Primary Outcome

Title	Correlation Between the Impulsive Choice Ratio and Baseline Impulsivity, as Measured With the Barratt Impulsiveness Scale
Description	The presented value represents a correlation. Subjects completed a delay discounting task while functional MRI images were obtained. In this task, subjects made hypothetical choices between a smaller amount of money available sooner, and a larger amount of money available later. Performance on the delay discounting task, as assessed by the impulsive choice ratio, was determined for both the tolcapone and placebo sessions, and the difference between them (tolcapone minus placebo) was calculated. This difference value was then correlated with baseline scores on the Barratt Impulsiveness Scale.
Time Frame	120 minutes after drug ingestion

Outcome Measure Data

Analysis Population Description

The outcome for this study was the correlation between the baseline BIS score and the difference in ICR (tolcapone minus placebo). As such, one Arm/Group is presented below.

Arm/Group Title	Functional MRI Arm (Tolcapone and Placebo)
Arm/Group Description	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 is a medication in the class of catechol-O-methyltransferase (COMT) inhibitors. A placebo is a tablet or capsule that looks like the study medication (in this case, tolcapone) but does not contain any active ingredients.
Measure Participants	23
Number [Correlation coefficient]	-0.45

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Functional MRI Arm (Tolcapone and Placebo)
	Comments	The comparison group represents the difference in ICR and the baseline impulsiveness scale.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments	The threshold for statistical significance was set to p < 0.05.
	Method	Fisher transformation
	Comments

2. Other Pre-specified Outcome

Title	Correlation Between the Difference in ICR (Tolcapone Minus Placebo) and the Difference in Blood Oxygen Level Dependent (BOLD) Signal in the Brain (Tolcapone Minus Placebo)
Description	The presented value represents a correlation. The difference in performance on the delay discounting task was calculated as the change in ICR (tolcapone minus placebo). In addition, the difference in BOLD activity throughout the brain was determined (tolcapone minus placebo).
Time Frame	120 minutes after drug ingestion

Outcome Measure Data

Analysis Population Description

The outcome for this study was the correlation between the difference in the ICR and the difference in BOLD activity (tolcapone minus placebo). As such, one Arm / Group is presented below.

Arm/Group Title	Functional MRI Arm (Tolcapone and Placebo)
Arm/Group Description	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 is a medication in the class of catechol-O-methyltransferase (COMT) inhibitors. A placebo is a tablet or capsule that looks like the study medication (in this case, tolcapone) but does not contain any active ingredients.
Measure Participants	23
Number [Correlation coefficient]	-0.50

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Functional MRI Arm (Tolcapone and Placebo)
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	< 0.05
	Comments	The threshold is set to p < 0.05, corrected for multiple comparisons.
	Method	Fisher transformation
	Comments	Statistical tests are computed across multiple subregions (voxels) within each area. Thus, the correlation coefficient above is a summary score.

Adverse Events

Time Frame	4 weeks
Arm/Group Title	Tolcapone		Placebo
Arm/Group Description	Tolcapone 200mg (single dose)		Placebo (single dose)
All Cause Mortality
	Tolcapone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/26 (0%)
Serious Adverse Events
	Tolcapone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	Tolcapone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/26 (0%)		0/26 (0%)

Limitations/Caveats

Funding constrained the number of participants. Describing the thousands of statistical tests in neuroimaging studies is not possible within this reduced format. Please see the open access pdf of Kayser et al, JNeurocience 2012.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.