Clinical trial NCT03348930
Conditions: Obsessive-Compulsive Disorder
Sponsor: University of Chicago
Start date: 2018-03-20; Completion date: 2020-12-14
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The proposed study will consist of a 5-week double-blind cross-over study trial of tolcapone in 20 people (ages 18-65). The study will be divided into an initial 2 week phase and a second 2 week phase, with one of the 2 week phases consisting of active treatment with tolcapone, and the other 2 week phase consisting of inactive placebo treatment. There will be a one-week wash-out phase between the 2-week treatment phases. Participants will be randomized to receive either tolcapone or placebo during the first 2 week phase on a 1:1 basis. This blinding will be maintained by the IDS pharmacy at the University of Chicago.

Detailed description:
The goal of the proposed study is to evaluate the efficacy and safety of tolcapone in adults with obsessive compulsive disorder (OCD). The hypothesis to be tested is that tolcapone will be more effective and well tolerated in adults with OCD compared to placebo. The proposed study will provide needed data on the treatment of a disabling disorder where current treatments are often ineffective.

The primary aim of this application is to conduct a randomized placebo-controlled pharmacotherapy trial using tolcapone in 20 participants with OCD. The study will consist of two phases: a 2 week active treatment phase with tolcapone, a one-week wash-out phase, and a 2 week placebo phase. The subjects will be randomized to either receive tolcapone or placebo treatment in the first 2 weeks, and the other during the remaining 2 week phase.

This will be one of few studies assessing the use of pharmacotherapy for the treatment of OCD in adults. Assessing the efficacy and safety of tolcapone will help inform clinicians about additional treatment options for adults suffering from this disorder.

Arms: arm 1: Each subject will have a 4 week treatment phase with Tolcapone arm 2: 4 week placebo phase before or after Tolcapone phase depending on randomization.
Interventions: intervention 1: Tolcapone 200 MG
Intervention descriptions: intervention 1: All eligible study subjects will go through a 2-week treatment phase during which they will begin tolcapone at 100mg twice a day.

Protocol documents:
Prot_SAP_001.pdf: 
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Tolcapone Treatment of Obsessive Compulsive Disorder:  
A Double-Blind, Placebo-Controlled, Cross-Over Pilot Study  
 
NCT03348930 
Version Date: 26AUG2020 
 
Jon E. Grant, M.D. 
 
University of Chicago 
 
 
 
 
 
 
 
 
 
 
 


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Project Goals 
 
The goal of the proposed study is to evaluate the efficacy and safety of tolcapone in 
adults with obsessive compulsive disorder (OCD).  The hypothesis to be tested is that tolcapone 
will be more effective and well tolerated in adults with OCD compared to placebo. The proposed 
study will provide needed data on the treatment of a disabling disorder where current treatments 
are often ineffective. 
Specific Aims 
The primary aim of this application is to conduct a randomized placebo-controlled 
pharmacotherapy trial using tolcapone in 20 participants with OCD. The study will consist of 
two phases: a 2 week active treatment phase with tolcapone, a one-week wash-out phase, and a 2 
week placebo phase. The subjects will be randomized to either receive tolcapone or placebo 
treatment in the first 2 weeks, and the other during the remaining 2 week phase. 
This will be one of few studies assessing the use of pharmacotherapy for the treatment of 
OCD in adults. Assessing the efficacy and safety of tolcapone will help inform clinicians about 
additional treatment options for adults suffering from this disorder. 
Several brain structures and functions have been implicated in OCD. Studies have 
consistently shown hyperactivity in the orbitofrontal cortex and caudate (1-2). Other key 
implicated regions (suggesting abnormalities in functional or structural connections) include the 
anterior cingulate cortex, thalamus, amygdala, and parietal cortex (3-5). Neuropsychological 
studies involving patients with OCD have shown deficits in cognitive abilities that are linked to 
the functioning of the frontal lobe and its related frontosubcortical structures, such as executive 
functioning, impulsivity in motor function, and cognitive inflexibility (i.e., not changing 
behavior on the basis of new information) (6-7). 
If OCD is untreated, the course is usually chronic, often with waxing and waning 
symptoms. Without treatment, remission rates among adults are low (approximately 20%) (8). 
With appropriate treatment (serotonin reuptake inhibitors [SRIs]), patients report substantially 
higher rates of symptom response and remission (9). However, only approximately one-third of 
patients with OCD receive appropriate pharmacotherapy, and fewer than 10% receive evidence-
based psychotherapy (10). In addition, even with appropriate treatment, approximately 30-35% 
of people with OCD fail to find any relief from SRIs (11), and thus more treatment options are 
needed.  
In the frontal lobes, low levels of dopamine reuptake transporters and Catechol-O-
methyltransferase (COMT) are responsible for the regulation of synaptic dopamine and its 
inactivation (12).  The COMT effect on prefrontal cortical efficiency has been robust (i.e. 
significant by meta-analysis; see 13), although associations with behavior have been less 
convincing. Tolcapone, a COMT inhibitor, has shown benefit in improving executive 


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functioning and the efficiency of cortical information processing in healthy volunteers (14). 
Therefore, we hypothesized that tolcapone would decrease OCD symptoms and augment 
prefrontal dependent neural circuitry via improvement in executive functioning. 
The proposed study will allow us to investigate baseline cognitive aspects of adults with 
OCD and examine the impact of drug treatment on tasks of cognitive dysfunction. We will 
examine the effects of tolcapone versus placebo in adults with OCD. By targeting deficits in 
cognitive deficits, tolcapone may offer a unique mechanism to address OCD symptoms. We 
hypothesize that tolcapone will be more effective than placebo in reducing OCD symptoms.   
 
Background and Significance 
 
The hallmark of OCD is the presence of obsessions, compulsions, or both.  Obsessions 
are repetitive and persistent thoughts (e.g., of contamination), images (e.g., of violent scenes), or 
urges (e.g., to stab someone). Obsessions are intrusive, unwanted thoughts that cause distress or 
anxiety. The person attempts to ignore or suppress these obsessions with another thought or 
action (i.e., a compulsion). Compulsions (or rituals) are repetitive behaviors (e.g., washing) or 
mental acts (e.g., counting) that the person feels driven to perform in response to an obsession. 
Compulsions are meant to neutralize or reduce the person's discomfort or to prevent a dreaded 
event.  
Tolcapone, a catechol-O-methyl-transferase (COMT) inhibitor, is currently approved by 
the FDA for the treatment of Parkinson’s disease. Tolcapone’s mechanism of action is unlike any 
pharmacological agent currently available. The methylation enzyme COMT regulates dopamine 
levels in the prefrontal cortex.  Lower dopaminergic activity in the prefrontal cortex may be 
considered as a common biological substrate of a predisposition to be unable to inhibit and stop 
behaviors. In the frontal cortex, optimal dopamine modulation of prefrontal cortical networks 
appears to be necessary for a variety of cognitive functions, including planning, attention, and 
response flexibility (15-16). Studies of naturally occurring COMT isozymes with differential 
enzymatic activity have shown that the higher cortical dopamine levels associated with reduced 
COMT activity results in improved frontal cortical cognitive performance (17-19). Preclinical 
and clinical research has demonstrated that tolcapone improves improves executive functioning 
in normal controls (20). Cortical control is felt to be the basis for top-down control of motivated 
behaviors (21-22). As the only CNS penetrant COMT inhibitor, tolcapone offers a unique 
mechanism to address cognitive deficits associated with OCD. Tolcapone has shown benefit in 
improving executive functioning, the efficiency of cortical information processing in healthy 
controls (23). A COMT inhibitor, such as tolcapone, should increase prefrontal cortical 
dopamine, enhance prefrontal efficiency, and improve executive functioning and cognitive 
flexibility; this in turn should improve cognitive control. Tolcapone may therefore offer promise 
for the treatment of individuals with OCD. 


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The current pilot study examines the tolerability and efficacy of tolcapone in the 
treatment of OCD in adults. We hypothesize that tolcapone will reduce the severity of symptoms 
related to OCD and improve patients’ overall functioning. 
Methodology 
 
The proposed study will consist of a 5-week double-blind cross-over study trial of 
tolcapone in 20 people (ages 18-65). The study will be divided into an initial 2 week phase and a 
second 2 week phase, with one of the 2 week phases consisting of active treatment with 
tolcapone, and the other 2 week phase consisting of inactive placebo treatment. There will be a 
one-week wash-out phase between the 2-week treatment phases. Participants will be randomized 
to receive either tolcapone or placebo during the first 2 week phase on a 1:1 basis. This blinding 
will be maintained by the IDS pharmacy at the University of Chicago. 
 
Based on a recent single dose tolcapone study for OCD, we should not need longer than 
two weeks to see an effect (unpublished data). Tolcapone is not an SSRI, so we don’t anticipate 
it taking as long as an SSRI to see an effect. In a study using tolcpone for gambling disorder, 
effects were shown within the first two weeks of taking the drug (Grant et al., 2013). We do not 
have enough data to know what the effect size will be. It will likely be underpowered, but 20 
active vs. 20 placebo should be sufficient to detect a signal. This will provide data for a future 
well-powered study. 
Subjects:  
Inclusion criteria:  
1) Males and females age 18-65;  
2) Diagnosis of current OCD based on DSM-5 criteria and confirmed using the clinician-
administered Structured Clinical Interview for DSM-5 (SCID);  
3) Able and willing to provide written consent for participation. 
 
Exclusion criteria:  
1) Unstable medical illness, including liver disease, as determined by the investigator and liver 
function test; 
2) History of seizures;  
3) Clinically significant suicidality (defined by the Columbia Suicide Severity Rating Scale);  
4) Baseline score of ≥17 on the Hamilton Depression Rating Scale (17-item HDRS); 


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5) Lifetime history of bipolar disorder type I or II, schizophrenia, autism, any psychotic disorder, 
or any substance use disorder;  
6) Initiation of psychotherapy or behavior therapy within 3 months prior to study baseline;  
7) Previous treatment with tolcapone; 
 
8) Any history of psychiatric hospitalization in the past year; 
9) Currently pregnant (confirmed by urine pregnancy test) 
 
Data Handling and Record Keeping 
All subject data will be maintained by the study personnel under the supervision of the 
principal investigator.  All subjects will be seen in the Department of Psychiatry at the University 
of Chicago Medical Center at 5841 South Maryland Avenue. Patient binders will be kept in a 
locked room only accessible to research staff.   
Finance and Insurance 
All research will be paid for by the internal departmental funds of the Department of 
Psychiatry at the University of Chicago. In the event that this research activity results in an 
injury, treatment will be available, including first aid, emergency treatment and follow-up care as 
needed. Care for such injuries will be billed in the ordinary manner to the subjects’ insurance 
company.  If the subject believes that they have suffered a research related injury, they will be 
instructed to inform the principal investigator immediately. 
Compensation 
The study will consist of 4 visits. For participating in the study, participants will receive 
$25 per visit to be paid in the form of a check at the completion of the study. Parking vouchers 
will also be provided for subjects as-needed. 
Time Line  
Recruitment for the proposed study will begin as soon as study drug is available. It is 
anticipated that all subjects would be entered into the study within approximately 12 months, and 
that the study would be completed within 15 months of initiation. 
Study Design 
 
The study is a 5-week, double-blind, placebo-controlled, pilot study of the safety and 
efficacy of tolcapone for adults with OCD. All eligible study subjects will go through a 2-week 
treatment phase during which they will begin tolcapone at 100mg twice a day. Subjects will be 


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given a matching placebo during the 2-week placebo phase. Subjects will be seen for scheduled 
study visits every two weeks during the 2-week blinded phases. Subjects will be randomized to 
either receive either the active or placebo condition during the first 2-week phase, and the 
remaining condition during the second 2-week phase. Study timeline is outlined below.  
 
All efficacy and safety assessments will be performed at each visit.  Subjects who are not 
compliant with their use of study medication (i.e. failing to take medication for three or more 
consecutive days) will be discontinued from the study.  Patients who experience a clinically 
significant adverse event will also be discontinued from the study. Liver diseases will be 
assessed at the time of subject entry and at the last visit. Subjects will have their blood drawn at 
baseline and again at the time of study completion to test for liver function.  
 
Due to the pandemic of COVID19, study participants can perform their baseline and follow-up 
visits online using encrypted Zoom instead of in person visits. All inventories will be assessed. 
Blood samples, however, will be at the discretion of the study PI. In cases where they are 
considered medically necessary, the participant can have them drawn locally and submitted to 
the study team. 
 
Screening Assessments  
 
1. Demographic data and clinical characteristics will be recorded for each subject (baseline 
visit). 
2. Formal screening psychiatric interview for each subject including the Mini International 
Neuropsychiatric Inventory (24) (baseline visit). 
3. Symptom severity at baseline and follow-up visits will be examined using reliable and valid 
scales: 
a. Yale Brown Obsessive Compulsive Scale (YBOCS) (25) (each visit) 
b. Clinical Global Impression severity and improvement scales (26) (each visit) 
c. Sheehan Disability Scale (27) (baseline and final visit) 
d. Hamilton Anxiety Rating Scale (HAM-A) (28) (each visit) 
e. Hamilton Depression Rating Scale (HAM-D) (29) (each visit) 
 
 
Yale Brown Obsessive Compulsive Scale (YBOCS) (25). The YBOCS is a reliable and valid 10-
item clinician administered scale assessing urge, behavior, and total severity scores. 
 
Clinical Global Impression- Severity and Improvement (CGI) (26). The CGI consists of a 
reliable and valid 7-item Likert scale used to assess severity and improvement in clinical 


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symptoms. The CGI severity scale was used at each visit and ranges from 1 = “not ill at all” to 7 
= “among the most extremely ill.”  The CGI Improvement scale was used at each follow-up visit 
and ranges from 1 = “very much improved” to 7 = “very much worse.”  
 
Sheehan Disability Scale (SDS) (27). The SDS is a three-item, reliable and valid self-report scale 
that assesses functioning in three areas of life: work, social or leisure activities, and home and 
family life. Scores on the SDS range from 0 to 30.  
 
Hamilton Anxiety Rating Scale (HAM-A) (28). The HAM-A is a reliable and valid, clinician-
administered, 14-item scale that provides an overall measure of global anxiety. 
 
 
 
Hamilton Depression Rating Scale (HAM-D) (29).The HAM-D is a valid and reliable, 17-item, 
clinician-administered rating scale assessing severity of depressive symptoms.  
 
Cognitive Assessments: In addition, subjects will undergo cognitive assessments at baseline. 
Assessments of cognitive control will be comprised of several valid paradigms (Table 1). These 
tasks are designed to probe dissociable neural circuitry and cognitive processes likely to be 
implicated in the pathophysiology of OCD. Task order will be chosen arbitrarily and will be 
applied consistently across subjects, to minimize possible confounding factors of differences in 
task order across participants. 
 
Table 1.Neurocognitive Tasks 
Task 
Target Cognitive Process 
MOT 
Training Task. 
Intra-dimensional/Extra-dimensional 
Set Shift Task (ID/ED task)  
Intra- and extra-dimensional thinking ability. Assesses 
cognitive flexibility. 
Stop-Signal Task of Inhibitory 
Control  
Motor impulsivity and response inhibition. 
Tower of London Task  
Problem solving and logic task. 
Cambridge Gamble Task 
Decision making and risk adjustment. 


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RVP 
Visual processing abilities. 
SWM 
Spatial working memory abilities. 
 
Efficacy Assessments 
 
The primary outcome measure will be the Yale Brown Obsessive Compulsive Scale 
(YBOCS). The YBOCS is a reliable and valid scale that is frequently used in research to assess 
symptom severity. 
Secondary efficacy measures include 
 The Clinical Global Impression-Improvement and Severity scales (CGI) 
 Sheehan Disability Scale (SDS) 
 Hamilton Anxiety Rating Scale (HAM-A) 
 Hamilton Depression Rating Scale (HAM-D). 
 
 
Safety Assessments 
Safety assessments (sitting blood pressure, heart rate, adverse effects, and concomitant 
medications) will be documented at each visit.  
Suicidality will be assessed using the Columbia Suicide Severity Rating Scale.  This scale 
will be performed at every visit. Subjects who endorse suicidal thoughts at any time during the 
study will be removed from the study and appropriate clinical intervention (e.g. hospitalization) 
will be arranged.  
Liver diseases will be assessed at the time of subject entry and during the final study 
visit. Subjects will undergo a blood draw by venipuncture. One 8ml sample will be collected for 
liver function testing. This procedure will be repeated at the time of study completion, during the 
subject’s final visit.  
The investigator will record use of concomitant medications in terms of daily dosage, 
start and stop dates, and reason for use. Adverse events will be recorded at each study visit and 
as they become known to the study staff. Medication compliance will be ascertained through 
weekly pill count of investigational medication.  
Risks and Benefits 
Risks 
Tolcapone has been associated with hepatic failure in some individuals and carries a 
Black Box warning of hepatotoxicity from the FDA. Given the tolcapone dose of 200mg/day 


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used in this study is far lower than the 600mg/day dose used in Parkinson’s disease and the dose 
associated with hepatotoxicity, and the fact that participant is only taking the medication for 2 
weeks, we feel that the risk of hepatotoxicity is very low.  Hepatotoxicity associated with 
tolcapone has been documented when the medication has been used continuously for at least 16 
weeks at total daily doses of 600mg/day and liver function tests were not monitored (30).  
Patients will also be assessed for clinical signs of hepatic dysfunction (persistent nausea, 
fatigue, lethargy, anorexia, jaundice, dark urine, and pruritus).  
Other common adverse events associated with tolcapone (nausea, diarrhea, orthostatic 
hypotension, somnolence, confusion, hallucinations, and rhabdomyolysis are possible, although 
these have been reported at the dosage used for Parkinson’s disease (300-600mg/day) and not the 
lower dose proposed for this study.  
 
Benefits 
 
Potential benefits include a possible direct medical benefit. Specifically, the study drug 
may help curb the severity of symptoms related to OCD, but there can be no guarantee that this 
will be the case.  As current options may provide little benefit for many people with OCD, the 
current study could offer significant advancement in possible treatments for this disorder. 
Data Analysis 
Demographic and baseline visit characteristics for tolcapone and placebo groups will be 
compared using chi-square and analysis of variance to determine if group differences existed at 
ranodmization. Given the crossover design, both the placebo and the active tolcapone groups will 
contain an N of 20. Primary and secondary measures will be examined using repeated-measures 
ANOVA modeling analyses (PROC MIXED, SAS/STAT Software for Windows, Version8.2, 
SAS Institute Inc., Cary, NC, USA). The baseline value of the measure being analyzed will be 
used as a covariate. A time trend (linear) will be included in all models. The difference in the 
overall level of posttreatment values, the main effect for treatment, will be the test of primary 
interest. Analyses will be performed on all available data as well as for the completers. All 
available post-randomization data will be first analyzed and a secondary, supportive analysis of 
completers will be performed. All comparison tests will be two-tailed and an alpha level of .05 
will be used to determine statistical significance given the exploratory nature of the study.  
Ethical Considerations 
 
This study will be conducted according to US and international standards of Good 
Clinical Practice (FDA regulations 21 CFR 312 for IND studies and FDA guidance E6) for all 
studies.  Applicable government regulations and University of Chicago research policies and 
procedures will also be followed. This protocol and any amendments will be submitted to the 


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University of Chicago Institutional Review Board (IRB) for formal approval to conduct the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the investigator. 
 
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