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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Tolcapone | Experimental | Each subject will have a 4 week treatment phase with Tolcapone |
|
| Placebo | Placebo Comparator | 4 week placebo phase before or after Tolcapone phase depending on randomization. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Tolcapone 200 MG | Drug | All eligible study subjects will go through a 2-week treatment phase during which they will begin tolcapone at 100mg twice a day. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Yale Brown Obsessive Compulsive Scale (Y-BOCS) | The entire study for the subject will last 5 weeks. Every 2 weeks and after the one week washout period the subject will take the YBOCS. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses severity of OCD symptoms. The YBOCS scale ranges from 0 to 40, with 0 being no symptoms and 40 being severe. | 2 weeks (start of study to washout period OR two weeks following washout period) |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical Global Impression- Severity and Improvement (CGI) | The entire study for the subject will last 5 weeks. Every two weeks and after the one week washout period the subject will complete the CGI. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses overall disorder severity on a scale from 1 to 7 with 1 being "not at all" and 7 being "among the most severe cases" |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Jon E Grant, JD,MD,MPH | University of Chicago | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Chicago | Chicago | Illinois | 60637 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 10986728 | Background | Saxena S, Rauch SL. Functional neuroimaging and the neuroanatomy of obsessive-compulsive disorder. Psychiatr Clin North Am. 2000 Sep;23(3):563-86. doi: 10.1016/s0193-953x(05)70181-7. | |
| 3493749 | Background | Baxter LR Jr, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM, Selin CE. Local cerebral glucose metabolic rates in obsessive-compulsive disorder. A comparison with rates in unipolar depression and in normal controls. Arch Gen Psychiatry. 1987 Mar;44(3):211-8. doi: 10.1001/archpsyc.1987.01800150017003. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Tolcapone, Then Placebo | Each subject will have a 2 week active treatment phase first with Tolcapone (100mg, twice a day), followed by a one-week washout period, followed by a 2 week treatment phase with a Tolcapone-matched placebo tablet. |
| FG001 | Placebo, Then Tolcapone | Each subject will have a 2 week active treatment phase first with a Tolcapone-matched placebo, followed by a one-week washout period, followed by a 2 week active treatment phase with Tolcapone (100mg, twice a day). |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (2 Weeks) |
| |||||||||||||
| Washout (1 Week) |
| |||||||||||||
| Second Intervention (2 Weeks) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Tolcapone/Placebo | Each subject will have a 4 week treatment phase with Tolcapone and a 4 week placebo phase before or after Tolcapone phase depending on randomization. Tolcapone 200 MG: All eligible study subjects will go through a 2-week treatment phase during which they will begin tolcapone at 100mg twice a day. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| 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 | Yale Brown Obsessive Compulsive Scale (Y-BOCS) | The entire study for the subject will last 5 weeks. Every 2 weeks and after the one week washout period the subject will take the YBOCS. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses severity of OCD symptoms. The YBOCS scale ranges from 0 to 40, with 0 being no symptoms and 40 being severe. | All participants who received at least one dose of each intervention and completed all study visits were included in the efficacy analysis. | Posted | Mean | Standard Deviation | mean change in YBOCS score | 2 weeks (start of study to washout period OR two weeks following washout period) |
|
Adverse event data were collected through study completion, as necessary over the period of 5 week (the length of the trial).
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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 | Tolcapone | Subjects received 100mg of tolcapone twice a day for two weeks either starting after the baseline visit, or starting after the 1-week washout period. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Mild Headache | General disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Jon Grant | University of Chicago | 7738341325 | jgrant4@bsd.uchicago.edu |
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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 | Aug 26, 2020 | Nov 15, 2021 | Prot_SAP_001.pdf |
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| ID | Term |
|---|---|
| D009771 | Obsessive-Compulsive Disorder |
| ID | Term |
|---|---|
| D001008 | Anxiety Disorders |
| D001523 | Mental Disorders |
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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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|
| 2 weeks (start of study to washout period OR two weeks following washout period) |
| Sheehan Disability Scale (SDS) | The entire study for the subject will last 5 weeks. Every two weeks and after the one week washout period the subject will complete the SDS. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses the level of disability from obsessive compulsive disorder (or target disorder). The SDS is a brief, 5-item self-report tool that assesses functional impairment in work/school, social life, and family life. Work/school scores range from 0 to 10, Social life scores range from 0 to 10, Family life/home responsibilities scores range from 0 to 10). Total scores are calculated by adding the scores for work/school, social life, and family life. Total scores range from a minimum of 0 to a maximum of 30 (0 unimpaired, 30 highly impaired). | 2 weeks (start of study to washout period OR two weeks following washout period) |
| Hamilton Anxiety Rating Scale (HAM-A) | Every study visit, the subject will complete the HAM-A. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses level of anxiety. Higher scores indicate higher levels of anxiety, with 0 being no symptoms of anxiety and 30 being severe anxiety. | 2 weeks (start of study to washout period OR two weeks following washout period) |
| Hamilton Depression Rating Scale (HAM-D) | The entire study for the subject will last 5 weeks. The HAM-D will be administered at every study visit. The change in scores from baseline to after the end of the 2-week active treatment period will be assessed and the change in scores from baseline to the end of the 2-week placebo period. The scale itself assesses level of depression. The minimum score is 0 and indicates no depressive symptoms, while the highest possible score is 50. Higher total scores indicate high levels of depression. Higher scores indicate a worse outcome. Higher total scored (14-50) indicate higher levels of depression, while a score between 0-7 is considered normal. | 2 weeks (start of study to washout period OR two weeks following washout period) |
| 22138231 | Background | Milad MR, Rauch SL. Obsessive-compulsive disorder: beyond segregated cortico-striatal pathways. Trends Cogn Sci. 2012 Jan;16(1):43-51. doi: 10.1016/j.tics.2011.11.003. Epub 2011 Dec 2. |
| 11144344 | Background | Graybiel AM, Rauch SL. Toward a neurobiology of obsessive-compulsive disorder. Neuron. 2000 Nov;28(2):343-7. doi: 10.1016/s0896-6273(00)00113-6. No abstract available. |
| 24177038 | Background | Piras F, Piras F, Caltagirone C, Spalletta G. Brain circuitries of obsessive compulsive disorder: a systematic review and meta-analysis of diffusion tensor imaging studies. Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 2):2856-77. doi: 10.1016/j.neubiorev.2013.10.008. Epub 2013 Oct 28. |
| 17855376 | Background | Menzies L, Achard S, Chamberlain SR, Fineberg N, Chen CH, del Campo N, Sahakian BJ, Robbins TW, Bullmore E. Neurocognitive endophenotypes of obsessive-compulsive disorder. Brain. 2007 Dec;130(Pt 12):3223-36. doi: 10.1093/brain/awm205. Epub 2007 Sep 13. |
| 18635808 | Background | Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, del Campo N, Aitken M, Craig K, Owen AM, Bullmore ET, Robbins TW, Sahakian BJ. Orbitofrontal dysfunction in patients with obsessive-compulsive disorder and their unaffected relatives. Science. 2008 Jul 18;321(5887):421-2. doi: 10.1126/science.1154433. |
| 10025435 | Background | Skoog G, Skoog I. A 40-year follow-up of patients with obsessive-compulsive disorder [see commetns]. Arch Gen Psychiatry. 1999 Feb;56(2):121-7. doi: 10.1001/archpsyc.56.2.121. |
| 17196050 | Background | Mancebo MC, Eisen JL, Pinto A, Greenberg BD, Dyck IR, Rasmussen SA. The brown longitudinal obsessive compulsive study: treatments received and patient impressions of improvement. J Clin Psychiatry. 2006 Nov;67(11):1713-20. doi: 10.4088/jcp.v67n1107. |
| 16848654 | Background | Blanco C, Olfson M, Stein DJ, Simpson HB, Gameroff MJ, Narrow WH. Treatment of obsessive-compulsive disorder by U.S. psychiatrists. J Clin Psychiatry. 2006 Jun;67(6):946-51. doi: 10.4088/jcp.v67n0611. |
| 25119610 | Background | Grant JE. Clinical practice: Obsessive-compulsive disorder. N Engl J Med. 2014 Aug 14;371(7):646-53. doi: 10.1056/NEJMcp1402176. |
| 15190105 | Background | Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ. Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci. 2004 Jun 9;24(23):5331-5. doi: 10.1523/JNEUROSCI.1124-04.2004. |
| 19417742 | Background | Mier D, Kirsch P, Meyer-Lindenberg A. Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis. Mol Psychiatry. 2010 Sep;15(9):918-27. doi: 10.1038/mp.2009.36. Epub 2009 May 5. |
| 17063156 | Background | Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF, Goldberg TE, Weinberger DR. Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology. 2007 May;32(5):1011-20. doi: 10.1038/sj.npp.1301227. Epub 2006 Oct 25. |
| 2392679 | Background | Servan-Schreiber D, Printz H, Cohen JD. A network model of catecholamine effects: gain, signal-to-noise ratio, and behavior. Science. 1990 Aug 24;249(4971):892-5. doi: 10.1126/science.2392679. |
| 15381316 | Background | Seamans JK, Yang CR. The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol. 2004 Sep;74(1):1-58. doi: 10.1016/j.pneurobio.2004.05.006. |
| 11925305 | Background | Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry. 2002 Apr;159(4):652-4. doi: 10.1176/appi.ajp.159.4.652. |
| 18037454 | Background | Roussos P, Giakoumaki SG, Pavlakis S, Bitsios P. Planning, decision-making and the COMT rs4818 polymorphism in healthy males. Neuropsychologia. 2008 Jan 31;46(2):757-63. doi: 10.1016/j.neuropsychologia.2007.10.009. Epub 2007 Oct 22. |
| 21521027 | Background | Bitsios P, Roussos P. Tolcapone, COMT polymorphisms and pharmacogenomic treatment of schizophrenia. Pharmacogenomics. 2011 Apr;12(4):559-66. doi: 10.2217/pgs.10.206. |
| 19699472 | Background | Roussos P, Giakoumaki SG, Bitsios P. Tolcapone effects on gating, working memory, and mood interact with the synonymous catechol-O-methyltransferase rs4818c/g polymorphism. Biol Psychiatry. 2009 Dec 1;66(11):997-1004. doi: 10.1016/j.biopsych.2009.07.008. Epub 2009 Aug 22. |
| 12538800 | Background | Forsberg M, Lehtonen M, Heikkinen M, Savolainen J, Jarvinen T, Mannisto PT. Pharmacokinetics and pharmacodynamics of entacapone and tolcapone after acute and repeated administration: a comparative study in the rat. J Pharmacol Exp Ther. 2003 Feb;304(2):498-506. doi: 10.1124/jpet.102.042846. |
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| Background | Sheehan DV. (1983). The Anxiety Disease. New York: Scribner's. |
| Background | Guy W (1976). ECDEU Assessment Manual for Psychopharmacology. US Dept Health, Education and Welfare publication (ADM) 76-338. Rockville, MD: National Institute of Mental Health, 218-222. |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
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| Any psychiatric comorbidity | Count of Participants | Participants |
|
| OG001 | Placebo | All eligible study subjects will go through a 2-week phase (either during the first two weeks or last two weeks of the study) during which they will begin the tolcapone-matched placebo twice a day. |
|
|
| Secondary | Clinical Global Impression- Severity and Improvement (CGI) | The entire study for the subject will last 5 weeks. Every two weeks and after the one week washout period the subject will complete the CGI. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses overall disorder severity on a scale from 1 to 7 with 1 being "not at all" and 7 being "among the most severe cases" | Participants who fully completed Visits 2 and 4. | Posted | Mean | Standard Deviation | score on a scale | 2 weeks (start of study to washout period OR two weeks following washout period) |
|
|
|
| Secondary | Sheehan Disability Scale (SDS) | The entire study for the subject will last 5 weeks. Every two weeks and after the one week washout period the subject will complete the SDS. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses the level of disability from obsessive compulsive disorder (or target disorder). The SDS is a brief, 5-item self-report tool that assesses functional impairment in work/school, social life, and family life. Work/school scores range from 0 to 10, Social life scores range from 0 to 10, Family life/home responsibilities scores range from 0 to 10). Total scores are calculated by adding the scores for work/school, social life, and family life. Total scores range from a minimum of 0 to a maximum of 30 (0 unimpaired, 30 highly impaired). | Subjects who completed all five weeks of the study except for one subjects who's SDS data was missing at all time points (no data to carry forward). | Posted | Mean | Standard Deviation | mean change in SDS score | 2 weeks (start of study to washout period OR two weeks following washout period) |
|
|
|
| Secondary | Hamilton Anxiety Rating Scale (HAM-A) | Every study visit, the subject will complete the HAM-A. The change in scores from baseline to after 5 weeks will be assessed. The scale itself assesses level of anxiety. Higher scores indicate higher levels of anxiety, with 0 being no symptoms of anxiety and 30 being severe anxiety. | Adults with OCD who completed the study. | Posted | Mean | Standard Deviation | mean change in HAM-A score | 2 weeks (start of study to washout period OR two weeks following washout period) |
|
|
|
| Secondary | Hamilton Depression Rating Scale (HAM-D) | The entire study for the subject will last 5 weeks. The HAM-D will be administered at every study visit. The change in scores from baseline to after the end of the 2-week active treatment period will be assessed and the change in scores from baseline to the end of the 2-week placebo period. The scale itself assesses level of depression. The minimum score is 0 and indicates no depressive symptoms, while the highest possible score is 50. Higher total scores indicate high levels of depression. Higher scores indicate a worse outcome. Higher total scored (14-50) indicate higher levels of depression, while a score between 0-7 is considered normal. | Adults with OCD who completed the 5-week study. | Posted | Mean | Standard Deviation | mean change in HAM-D score | 2 weeks (start of study to washout period OR two weeks following washout period) |
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| 0 |
| 20 |
| 0 |
| 20 |
| 3 |
| 20 |
| EG001 | Placebo | Subjects received tolcapone-matched placebo twice a day for two weeks either starting after the baseline visit, or starting after the 1-week washout period. | 0 | 20 | 0 | 20 | 5 | 20 |
| Increased frequency in bowel movements | Gastrointestinal disorders | Non-systematic Assessment |
|
| Blood in stool | Gastrointestinal disorders | Non-systematic Assessment | This was followed up and found to be haemorrhoids |
|
| Less frequent bowel movements | Gastrointestinal disorders | Non-systematic Assessment |
|
| Fatigue | General disorders | Non-systematic Assessment |
|
| Muscle aching | General disorders | Non-systematic Assessment |
|
| Joint stiffness | General disorders | Non-systematic Assessment |
|
| Sleep problems | General disorders | Non-systematic Assessment |
|
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| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D009596 | Nitrophenols |
| D010636 | Phenols |
| D007659 | Ketones |
| D009574 | Nitro Compounds |