SchizophreniaPhase 2NCT00044083
Clinical Trial of Tolcapone for Cognition in Schizophrenia
A Phase 2 study testing Tolcapone in people with Schizophrenia, run by National Institute of Mental Health (NIMH) at 1 site in United States.
Trial 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. ... Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Schizophrenia
- What is being tested?
- Tolcapone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 210 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2002to Dec 2015
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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 (NCT00001486).
- No Axis I or Axis II diagnosis in normal volunteers.
- Age range: 18-50 years.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
Official title: 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
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.
...
Read the 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.
- Conditions
- Schizophrenia
- Being tested
- Placebo, Tolcapone
- Keywords
- Catecholamines, Dopamine, Clinical Trial, fMRI, PFC, Vitamin B2, Riboflavin, Tolcapone, Placebo, Normal Volunteers, Schizophrenia, Healthy Volunteers, HV
- Medical subject headings
- Schizophrenia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboOther
Placebo: One capsule 3 times a day from Day 1 to Day 7
TolcaponeDrug
Also called Tasmar
Tolcapone: One capsule 3 times a day from Day 1 to Day 7
| Study group | Role | What they receive |
|---|---|---|
| Placebo Arm | Placebo comparator | Placebo one week Receives: Other: Placebo |
| Tolcapone Arm | Active comparator | Tolcapone one week Receives: Drug: Tolcapone |
What is being measured
The primary outcome is the main question the study is designed to answer.
N-Back Task Performance
Working Memory was measured in HVs and patients with schizophrenia after a 7-day treatment with Tolcapone or placebo in a double-blind, cross-over fashion. The working memory was quantified by taking the number of trials entered correctly divided by the total number of trials multiplied by 100. Values range from 0 to 100. Zero indicates the poorest performance while 100 indicates perfect performance.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
N-Back Task Activation Diagnosis Effect
Activation beta values (N-Back vs. 0-Back) were extracted within the Main Effect of Diagnosis cluster around the peak (p < 0.05 uncorrected) from the contrast maps in the Placebo condition. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
N-Back Task Activation Drug Effect
Activation beta values (N-Back vs. 0-Back) extracted within the Main Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps across both groups. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
N-Back Task Activation in DLPFC in Patients With Schizophrenia
Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
N-Back Task Activation in Healthy Volunteers
Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
N-Back Task Activation Genotype Effect in Healthy Volunteers
Activation beta values (N-Back vs. 0-Back) extracted within the Effect of Genotype cluster around the peak (p < 0.05 uncorrected) in right and left DLPFC from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
N-Back Task Activation by Genotype in Patients With Schizophrenia
Activation beta values (N-Back vs. 0-Back) extracted from DLPFC from the contrast maps in Patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Secondary outcomes (1)
Positive and Negative Syndrome Scale
Rating Scales PANSS. The Positive Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The Negative Scale ranges for 7 to 49 with a higher score indicating greater severity of symptoms. The General Scale ranges from 16 to 112, the higher score indicating greater severity of symptoms.
Measured: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Aug 2002 (estimated)
- Study startAug 2002
- Primary completionDec 2015
- Study completionDec 2015
Why it stopped: Scientific Director request to use resources for other studies
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for SchizophreniaStudies of the same condition, open and under way.
- More trials run by National Institute of Mental Health (NIMH)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 210 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Institute of Mental Health (NIMH)
- Sponsor type
- US National Institutes of Health
- Responsible party
- Sponsor
- Investigators
- Jose A Apud, M.D., Principal investigator, National Institute of Mental Health (NIMH)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00044083
- Sponsor's protocol ID
- 020239
- Other IDs
- 02-M-0239, NCT00044083
- Status last verified
- Mar 2018
- First submitted
- 16 Aug 2002
- Last updated
- 27 Sep 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No: No plan to share data
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. doi: 10.1097/00008571-199304000-00008.
PubMed 8518836Andreasen 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. doi: 10.1097/00004647-199609000-00005.
PubMed 8784225Arnsten AF. Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997;11(2):151-62. doi: 10.1177/026988119701100208.
PubMed 9208378Magalona 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.
PubMed 23794107
Study at a glance
From the registry record, last updated by the sponsor on 27 Sep 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT00044083
- Acronym / sponsor ID
- 020239
- Conditions
- Schizophrenia
- Keywords
- Catecholamines, Dopamine, Clinical Trial, fMRI, PFC, Vitamin B2, Riboflavin, Tolcapone
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Scientific Director request to use resources for other studies
- Enrolment
- 210 participants (actual)
- Lead sponsor
- National Institute of Mental Health (NIMH)US National Institutes of Health
- Study start
- Aug 2002
- Primary completion
- Dec 2015 (actual)
- Study completion
- Dec 2015 (actual)
- First posted
- 19 Aug 2002 (estimated)
- Results
- Posted 17 Jul 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Placebo Arm | Placebo comparator | Other: PlaceboPlacebo one week |
| Tolcapone Arm | Active comparator | Drug: TolcaponeTolcapone one week |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
Key exclusion criteria (5 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PlaceboPlacebo: One capsule 3 times a day from Day 1 to Day 7 | Other | Placebo Arm |
| TolcaponeAlso: TasmarTolcapone: One capsule 3 times a day from Day 1 to Day 7 | Drug | Tolcapone Arm |
Primary outcome
N-Back Task Performance
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Working Memory was measured in HVs and patients with schizophrenia after a 7-day treatment with Tolcapone or placebo in a double-blind, cross-over fashion. The working memory was quantified by taking the number of trials entered correctly divided by the total number of trials multiplied by 100. Values range from 0 to 100. Zero indicates the poorest performance while 100 indicates perfect performance.
N-Back Task Activation Diagnosis Effect
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Activation beta values (N-Back vs. 0-Back) were extracted within the Main Effect of Diagnosis cluster around the peak (p < 0.05 uncorrected) from the contrast maps in the Placebo condition. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation Drug Effect
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Activation beta values (N-Back vs. 0-Back) extracted within the Main Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps across both groups. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation in DLPFC in Patients With Schizophrenia
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation in Healthy Volunteers
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Activation Beta values (N-Back vs. 0-Back) extracted within the Effect of Drug cluster around the peak (p < 0.05 uncorrected) from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation Genotype Effect in Healthy Volunteers
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Activation beta values (N-Back vs. 0-Back) extracted within the Effect of Genotype cluster around the peak (p < 0.05 uncorrected) in right and left DLPFC from the contrast maps in Healthy Volunteers. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
N-Back Task Activation by Genotype in Patients With Schizophrenia
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Activation beta values (N-Back vs. 0-Back) extracted from DLPFC from the contrast maps in Patients with schizophrenia. Lower beta values reflect more efficient processing in the DLPFC when performing working memory tasks.
1 secondary outcome
Positive and Negative Syndrome Scale
Time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Sep 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 8518836Aksoy 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. doi: 10.1097/00008571-199304000-00008.
- Background: PubMed 8784225Andreasen 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. doi: 10.1097/00004647-199609000-00005.
- Background: PubMed 9208378Arnsten AF. Catecholamine regulation of the prefrontal cortex. J Psychopharmacol. 1997;11(2):151-62. doi: 10.1177/026988119701100208.
- Derived from this study: PubMed 23794107Magalona 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.
- NIH Clinical Center Detailed Web PageLink provided by the sponsor.
- Individual participant dataSharing planned: No. No plan to share data
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jose A Apud, M.D. principal investigator
National Institute of Mental Health (NIMH)
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Tolcapone in people with Schizophrenia, run by National Institute of Mental Health (NIMH) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 27 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Jul 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
N-Back Task Performance (time frame: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00044083, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Sep 2018.