Clinical Trial of Tolcapone for Cognition in Schizophrenia

Tracking Information
First Submitted Date ICMJE	August 16, 2002
First Posted Date ICMJE	August 19, 2002
Last Update Posted Date	September 1, 2016
Study Start Date ICMJE	August 2002
Actual Primary Completion Date	December 2015 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: April 23, 2010)	Genetic differences in working memory testing or fMRI activation1
Original Primary Outcome Measures ICMJE	Not Provided
Change History	Complete list of historical versions of study NCT00044083 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: April 1, 2008)	Panss, Ham-A, POMS, Blood draws for drug levels and liver enzymes
Original Secondary Outcome Measures ICMJE	Not Provided
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Clinical Trial of Tolcapone for Cognition in Schizophrenia
Official Title ICMJE	Randomized, Double-Blinded, Placebo Controlled Study of the Effects of Tolcapone and Entacapone on Cognitive Function in Patients With Schizophrenia and Normal Controls Based on COMT Genotype
Brief Summary	This study will evaluate whether Tolcapone improves cognition in healthy volunteers as well as patients with schizophrenia. Talcapone is a drug that has been FDA approved for Attention Deficit Disorder and allegedly increase the amount of the neurotransmitter dopamine in the frontal cortex of the brain.
Detailed Description	Psychopharmacological modulation of the catecholaminergic system can enhance some aspects of cognitive function. For example, COMT inhibitors can slightly improve working memory/executive function. Differences in the response between individuals might be related to a number of factors, including variations in the genes. The recent finding that a polymorphism in the catechol-o-methyl-transferase (COMT) gene, which produces a 4 fold change in enzyme activity, accounts for 4 percent of the variance in performance of working memory tasks in humans suggest that COMT genotype may predict response to COMT inhibitors. In the present investigation our goal is to examine, in normal controls and patients with schizophrenia, the effect of a centrally acting (tolcapone) and of a peripherally acting (entacapone) COMT inhibitor on cognitive function. We predict that both normal controls and patients with schizophrenia with the val/val genotype will have a significant, though transient, improvement in working memory in subjects treated with tolcapone but not in those treated with entacapone. Furthermore, in conjunction with other NIMH imaging protocols, we would like to examine the neurophysiological correlates related to working memory. We predict, in tolcapone treated subjects, improved measures in prefrontal 'efficiency' in subjects and patients specifically with the val/val genotype. The present protocol will provide new insights on the importance of this genetic polymorphism in the regulation of aminergic-controlled cognitive function in normal individuals. Furthermore, this protocol will test whether COMT inhibitors offer a new treatment-based on genotype - for cognitive impairment in schizophrenia. No IND is required for the present study.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Double
Condition ICMJE	Schizophrenia
Intervention ICMJE	Drug: Tolcapone; Tolcapone 200 mg tid: Placebo 1 week-Wash Out 1 week-Drug 1 week (or vice versa)
Study Arms	Not Provided
Publications *	Aksoy S, Klener J, Weinshilboum RM. Catechol O-methyltransferase pharmacogenetics: photoaffinity labelling and western blot analysis of human liver samples. Pharmacogenetics. 1993 Apr;3(2):116-22.; Andreasen NC, Arndt S, Cizadlo T, O'Leary DS, Watkins GL, Ponto LL, Hichwa RD. Sample size and statistical power in [15O]H2O studies of human cognition. J Cereb Blood Flow Metab. 1996 Sep;16(5):804-16.; Arnsten AF. Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997;11(2):151-62. Review.; Magalona SC, Rasetti R, Chen J, Chen Q, Gold I, Decot H, Callicott JH, Berman KF, Apud JA, Weinberger DR, Mattay VS. Effect of tolcapone on brain activity during a variable attentional control task: a double-blind, placebo-controlled, counter-balanced trial in healthy volunteers. CNS Drugs. 2013 Aug;27(8):663-73. doi: 10.1007/s40263-013-0082-x.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: June 21, 2016)	213
Original Enrollment ICMJE; (submitted: June 23, 2005)	180
Actual Study Completion Date	December 2015
Actual Primary Completion Date	December 2015 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	INCLUSION CRITERIA: Prior participation under NIH protocol number 95-M-0150, or new normal volunteers or schizophrenic patients that meet criteria for NIH protocol number 95-M-0150. No Axis I or Axis II diagnosis in normal volunteers. Age range: 18-50 years. EXCLUSION CRITERIA: Normal volunteers with an Axis I or Axis II disorder obtained either from prior SCID interview in Protocol 95-M-0150 or through a screening interview will be excluded.; Subjects with a history of cardiovascular disease, liver disease and other medical illnesses, and untreated or uncontrolled hypertension will be excluded. An electrocardiogram, blood pressure, pulse rate and metabolic panel including LFTs will be checked on all subjects prior to participation in the study. Individuals with persistent tardive dyskinesia or abnormal LFTs, or individuals with significant history of alcoholism or liver enzyme elevation will be excluded from the study.; Schizophrenic patients taking clozapine, a COMT inhibitor, any illicit drugs of abuse, or MAO inhibitors will be excluded.; Normal control subjects taking any medications other than occasional NSAI will be excluded.; Pregnant women. Women of childbearing potential will undergo a urine pregnancy test the day the study initiates and screened by history for the possibility of pregnancy.
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 50 Years (Adult)
Accepts Healthy Volunteers	Yes
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00044083
Other Study ID Numbers ICMJE	020239; 02-M-0239
Has Data Monitoring Committee	Not Provided
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Not Provided
Responsible Party	National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
Study Sponsor ICMJE	National Institute of Mental Health (NIMH)
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Jose A Apud, M.D. National Institute of Mental Health (NIMH)
PRS Account	National Institutes of Health Clinical Center (CC)
Verification Date	June 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP