Trial Outcomes & Findings for Clinical Trial of Tolcapone for Cognition in Schizophrenia (NCT NCT00044083)
NCT ID: NCT00044083
Last Updated: 2018-09-27
Results Overview
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.
TERMINATED
PHASE2
210 participants
At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)
2018-09-27
Participant Flow
Patients with schizophrenia were recruited through families, physicians and community organizations. Healthy volunteers were recruited through the NIH Normal Volunteers Office. Subjects first participated in Protocol # 95-M-0150 to obtain genotype data. If eligible after the study, they were invited to participate in the Tolcapone protocol.
Participant milestones
| Measure |
Placebo First Then Tolcapone
Placebo one week first:
Tolcapone 200 mg second:
|
Tolcapone First, Then Placebo
Tolcapone one week:
Placebo one week second:
|
|---|---|---|
|
First Intervention (One Week)- HV's
STARTED
|
74
|
73
|
|
First Intervention (One Week)- HV's
COMPLETED
|
64
|
66
|
|
First Intervention (One Week)- HV's
NOT COMPLETED
|
10
|
7
|
|
Second Intervention (One Week) HV's
STARTED
|
64
|
66
|
|
Second Intervention (One Week) HV's
COMPLETED
|
64
|
66
|
|
Second Intervention (One Week) HV's
NOT COMPLETED
|
0
|
0
|
|
First Intervention (One Week) Patients
STARTED
|
31
|
32
|
|
First Intervention (One Week) Patients
COMPLETED
|
30
|
30
|
|
First Intervention (One Week) Patients
NOT COMPLETED
|
1
|
2
|
|
Second Intervention (One Week) Patients
STARTED
|
30
|
30
|
|
Second Intervention (One Week) Patients
COMPLETED
|
30
|
29
|
|
Second Intervention (One Week) Patients
NOT COMPLETED
|
0
|
1
|
Reasons for withdrawal
| Measure |
Placebo First Then Tolcapone
Placebo one week first:
Tolcapone 200 mg second:
|
Tolcapone First, Then Placebo
Tolcapone one week:
Placebo one week second:
|
|---|---|---|
|
First Intervention (One Week)- HV's
Adverse Event
|
1
|
0
|
|
First Intervention (One Week)- HV's
Not follow directions
|
2
|
2
|
|
First Intervention (One Week)- HV's
Withdrawal by Subject
|
5
|
3
|
|
First Intervention (One Week)- HV's
Pregnancy
|
1
|
0
|
|
First Intervention (One Week)- HV's
Used illegal drugs
|
1
|
0
|
|
First Intervention (One Week)- HV's
Abnormal MRI
|
0
|
1
|
|
First Intervention (One Week)- HV's
Drank while on protocol
|
0
|
1
|
|
First Intervention (One Week) Patients
Not follow directions
|
0
|
2
|
|
First Intervention (One Week) Patients
Used illegal drug
|
1
|
0
|
|
Second Intervention (One Week) Patients
Withdrawal by Subject
|
0
|
1
|
Baseline Characteristics
Clinical Trial of Tolcapone for Cognition in Schizophrenia
Baseline characteristics by cohort
| Measure |
Healthy Volunteers
n=130 Participants
Tolcapone 200 mg 1 week:Wash Out 1 week:Placebo 1 week: (or vice versa)
|
Patients
n=59 Participants
Tolcapone 200 mg 1 week:Wash Out 1 week:Placebo 1 week: (or vice versa)
|
Total
n=189 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
130 Participants
n=99 Participants
|
59 Participants
n=107 Participants
|
189 Participants
n=206 Participants
|
|
Age, Categorical
>=65 years
|
0 Participants
n=99 Participants
|
0 Participants
n=107 Participants
|
0 Participants
n=206 Participants
|
|
Age, Continuous
|
34.5 years
STANDARD_DEVIATION 9.1 • n=99 Participants
|
26.9 years
STANDARD_DEVIATION 6.8 • n=107 Participants
|
32.1 years
STANDARD_DEVIATION 9.1 • n=206 Participants
|
|
Sex: Female, Male
Female
|
59 Participants
n=99 Participants
|
18 Participants
n=107 Participants
|
77 Participants
n=206 Participants
|
|
Sex: Female, Male
Male
|
71 Participants
n=99 Participants
|
41 Participants
n=107 Participants
|
112 Participants
n=206 Participants
|
|
Region of Enrollment
United States
|
130 participants
n=99 Participants
|
59 participants
n=107 Participants
|
189 participants
n=206 Participants
|
PRIMARY outcome
Timeframe: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)Population: 147 HV's recruited, 8 left after signing consents, 8 excluded for other reasons, 57 excluded for excessive motion, inferior quality or not completion. 63 patients recruited, 4 removed for different reasons, 26 excluded from image analyses for not completing the second phase of the study, excessive motion or bad image quality.
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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=74 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=74 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
n=33 Participants
Placebo Days 1-7, Patient
|
Patients on Tolcapone
n=33 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
N-Back Task Performance
|
86.10 % of Correct Trials
Standard Error 1.13
|
85.50 % of Correct Trials
Standard Error 1.10
|
76.21 % of Correct Trials
Standard Error 2.31
|
80.94 % of Correct Trials
Standard Error 1.90
|
—
|
—
|
PRIMARY outcome
Timeframe: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)Population: 74 Healthy Volunteers and 33 Patients with Schizophrenia
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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=74 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=33 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
Placebo Days 1-7, Patient
|
Patients on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
N-Back Task Activation Diagnosis Effect
Right DLPFC
|
0.15 beta value
Standard Error 0.02
|
0.20 beta value
Standard Error 0.03
|
—
|
—
|
—
|
—
|
|
N-Back Task Activation Diagnosis Effect
Left DLPFC
|
0.18 beta value
Standard Error 0.02
|
0.23 beta value
Standard Error 0.03
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)Population: 74 Healthy Volunteers and 33 Patients with Schizophrenia
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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=74 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=74 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
n=33 Participants
Placebo Days 1-7, Patient
|
Patients on Tolcapone
n=33 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
N-Back Task Activation Drug Effect
Right DLPFC
|
0.09 beta value
Standard Error 0.03
|
0.11 beta value
Standard Error 0.02
|
0.12 beta value
Standard Error 0.04
|
0.07 beta value
Standard Error 0.03
|
—
|
—
|
|
N-Back Task Activation Drug Effect
Left DLPFC
|
0.27 beta value
Standard Error 0.04
|
0.25 beta value
Standard Error 0.04
|
0.23 beta value
Standard Error 0.05
|
0.09 beta value
Standard Error 0.06
|
—
|
—
|
PRIMARY outcome
Timeframe: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)Population: 33 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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=33 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=33 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
Placebo Days 1-7, Patient
|
Patients on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
N-Back Task Activation in DLPFC in Patients With Schizophrenia
Right DLPFC
|
0.26 beta value
Standard Error 0.02
|
0.24 beta value
Standard Error 0.018
|
—
|
—
|
—
|
—
|
|
N-Back Task Activation in DLPFC in Patients With Schizophrenia
Left DLPFC
|
0.25 beta value
Standard Error 0.02
|
0.23 beta value
Standard Error 0.02
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)Population: 74 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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=74 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=74 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
Placebo Days 1-7, Patient
|
Patients on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
N-Back Task Activation in Healthy Volunteers
Right DLPFC
|
0.09 beta value
Standard Error 0.03
|
0.11 beta value
Standard Error 0.02
|
—
|
—
|
—
|
—
|
|
N-Back Task Activation in Healthy Volunteers
Left DLPFC
|
0.38 beta value
Standard Error 0.03
|
0.36 beta value
Standard Error 0.03
|
—
|
—
|
—
|
—
|
PRIMARY outcome
Timeframe: 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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=24 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=29 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
n=21 Participants
Placebo Days 1-7, Patient
|
Patients on Tolcapone
n=24 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
n=29 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
n=21 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
N-Back Task Activation Genotype Effect in Healthy Volunteers
Right DLPFC
|
0.22 beta value
Standard Error 0.03
|
0.23 beta value
Standard Error 0.03
|
0.14 beta value
Standard Error 0.04
|
0.22 beta value
Standard Error 0.03
|
0.25 beta value
Standard Error 0.03
|
0.15 beta value
Standard Error 0.04
|
|
N-Back Task Activation Genotype Effect in Healthy Volunteers
Left DLPFC
|
0.14 beta value
Standard Error 0.03
|
0.19 beta value
Standard Error 0.03
|
0.10 beta value
Standard Error 0.03
|
0.14 beta value
Standard Error 0.03
|
0.18 beta value
Standard Error 0.03
|
0.09 beta value
Standard Error 0.04
|
PRIMARY outcome
Timeframe: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)Population: 33 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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=9 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=13 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
n=11 Participants
Placebo Days 1-7, Patient
|
Patients on Tolcapone
n=9 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
n=13 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
n=11 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
N-Back Task Activation by Genotype in Patients With Schizophrenia
right DLPFC
|
0.33 beta value
Standard Error 0.05
|
0.23 beta value
Standard Error 0.03
|
0.24 beta value
Standard Error 0.04
|
0.25 beta value
Standard Error 0.05
|
0.20 beta value
Standard Error 0.03
|
0.22 beta value
Standard Error 0.03
|
|
N-Back Task Activation by Genotype in Patients With Schizophrenia
left DLPFC
|
0.28 beta value
Standard Error 0.04
|
0.24 beta value
Standard Error 0.03
|
0.21 beta value
Standard Error 0.04
|
0.18 beta value
Standard Error 0.05
|
0.26 beta value
Standard Error 0.04
|
0.17 beta value
Standard Error 0.04
|
SECONDARY outcome
Timeframe: At end of treatment period (at 7th day for first intervention and at 21st day for second intervention)Population: There were 74 Healthy Volunteers and 33 Patients with Schizophrenia
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.
Outcome measures
| Measure |
Healthy Volunteer on Placebo
n=74 Participants
Placebo Days 1-7, Healthy voluntee
|
Healthy Volunteer Tolcapone
n=74 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Patient on Placebo
n=33 Participants
Placebo Days 1-7, Patient
|
Patients on Tolcapone
n=33 Participants
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid
|
Healthy Volunteer COMT Val/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Val/Met Genotype
|
Healthy Volunteer COMT Met/Met Genotype on Tolcapone
Day 1: Tolcapone 100 mg tid, Days 2-7: Tolcapone 200 mg tid Healthy Volunteer COMT Met/Met Genotype
|
|---|---|---|---|---|---|---|
|
Positive and Negative Syndrome Scale
Positive Subscale
|
7.01 units on a scale
Standard Deviation 0.01
|
7.02 units on a scale
Standard Deviation 0.03
|
12.15 units on a scale
Standard Deviation 0.51
|
12 units on a scale
Standard Deviation 0.54
|
—
|
—
|
|
Positive and Negative Syndrome Scale
Negative Subscale
|
7.36 units on a scale
Standard Deviation 0.14
|
7.27 units on a scale
Standard Deviation 0.13
|
16.51 units on a scale
Standard Deviation 1.00
|
15.88 units on a scale
Standard Deviation 1.02
|
—
|
—
|
|
Positive and Negative Syndrome Scale
General Psychopathology
|
16.36 units on a scale
Standard Deviation 0.10
|
16.33 units on a scale
Standard Deviation 0.09
|
27.12 units on a scale
Standard Deviation 0.78
|
26.24 units on a scale
Standard Deviation 0.84
|
—
|
—
|
Adverse Events
Healthy Volunteers on Placebo
Healthy Volunteers on Tolcapone
Patients on Placebo
Patients on Tolcapone
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Healthy Volunteers on Placebo
n=131 participants at risk
Placebo Days 1-7, Healthy Volunteers
|
Healthy Volunteers on Tolcapone
n=131 participants at risk
Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7.
|
Patients on Placebo
n=59 participants at risk
Placebo Days 1-7, Patients
|
Patients on Tolcapone
n=60 participants at risk
Tolcapone 100 mg TID on Day 1, 200 mg TID Days 2-7
|
|---|---|---|---|---|
|
Gastrointestinal disorders
Nausea
|
6.1%
8/131 • Day 1 to Day 21
|
12.2%
16/131 • Day 1 to Day 21
|
13.6%
8/59 • Day 1 to Day 21
|
8.3%
5/60 • Day 1 to Day 21
|
|
Nervous system disorders
Sleep Problems
|
6.1%
8/131 • Day 1 to Day 21
|
7.6%
10/131 • Day 1 to Day 21
|
10.2%
6/59 • Day 1 to Day 21
|
28.3%
17/60 • Day 1 to Day 21
|
|
General disorders
Appetite Problems
|
4.6%
6/131 • Day 1 to Day 21
|
6.1%
8/131 • Day 1 to Day 21
|
10.2%
6/59 • Day 1 to Day 21
|
8.3%
5/60 • Day 1 to Day 21
|
|
Gastrointestinal disorders
Diarrhea
|
3.8%
5/131 • Day 1 to Day 21
|
6.9%
9/131 • Day 1 to Day 21
|
6.8%
4/59 • Day 1 to Day 21
|
11.7%
7/60 • Day 1 to Day 21
|
|
Musculoskeletal and connective tissue disorders
Stiffness
|
1.5%
2/131 • Day 1 to Day 21
|
4.6%
6/131 • Day 1 to Day 21
|
10.2%
6/59 • Day 1 to Day 21
|
18.3%
11/60 • Day 1 to Day 21
|
|
Psychiatric disorders
Halluciantions
|
0.00%
0/131 • Day 1 to Day 21
|
0.00%
0/131 • Day 1 to Day 21
|
16.9%
10/59 • Day 1 to Day 21
|
15.0%
9/60 • Day 1 to Day 21
|
Additional Information
Jose A. Apud
Office of the Clinical Director-NIMH-NIH-HHS
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place