Clinical trial NCT03348930: Tolcapone in Obsessive Compulsive Disorder
Official title: Tolcapone Treatment of Obsessive Compulsive Disorder: A Double-Blind, Placebo-Controlled, Cross-Over Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Obsessive-Compulsive Disorder
Lead sponsor: University of Chicago
Sponsor class: OTHER
First posted: 2017-11-21
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Eligibility criteria: 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;
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);
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)

Primary outcomes:
measure: Yale Brown Obsessive Compulsive Scale (Y-BOCS)
timeFrame: 2 weeks (start of study to washout period OR two weeks following washout period)
Secondary outcomes:
measure: Clinical Global Impression- Severity and Improvement (CGI)
timeFrame: 2 weeks (start of study to washout period OR two weeks following washout period)
measure: Sheehan Disability Scale (SDS)
timeFrame: 2 weeks (start of study to washout period OR two weeks following washout period)
measure: Hamilton Anxiety Rating Scale (HAM-A)
timeFrame: 2 weeks (start of study to washout period OR two weeks following washout period)
measure: Hamilton Depression Rating Scale (HAM-D)
timeFrame: 2 weeks (start of study to washout period OR two weeks following washout period)
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
Study officials:
affiliation: University of Chicago
name: Jon E Grant, JD,MD,MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Grant JE. Clinical practice: Obsessive-compulsive disorder. N Engl J Med. 2014 Aug 14;371(7):646-53. doi: 10.1056/NEJMcp1402176.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Blum K, Chen TJ, Meshkin B, Waite RL, Downs BW, Blum SH, Mengucci JF, Arcuri V, Braverman ER, Palomo T. Manipulation of catechol-O-methyl-transferase (COMT) activity to influence the attenuation of substance seeking behavior, a subtype of Reward Deficiency Syndrome (RDS), is dependent upon gene polymorphisms: a hypothesis. Med Hypotheses. 2007;69(5):1054-60. doi: 10.1016/j.mehy.2006.12.062. Epub 2007 Apr 30.
citation: Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, Hergueta T, Baker R, Dunbar GC. The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry. 1998;59 Suppl 20:22-33;quiz 34-57.
citation: Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, Heninger GR, Charney DS. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989 Nov;46(11):1006-11. doi: 10.1001/archpsyc.1989.01810110048007.
citation: Olanow CW, Watkins PB. Tolcapone: an efficacy and safety review (2007). Clin Neuropharmacol. 2007 Sep-Oct;30(5):287-94. doi: 10.1097/wnf.0b013e318038d2b6.
citation: HAMILTON M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960 Feb;23(1):56-62. doi: 10.1136/jnnp.23.1.56. No abstract available.
citation: HAMILTON M. The assessment of anxiety states by rating. Br J Med Psychol. 1959;32(1):50-5. doi: 10.1111/j.2044-8341.1959.tb00467.x. No abstract available.
citation: Sheehan DV. (1983). The Anxiety Disease. New York: Scribner's.
citation: 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.