Cognitive Impairments Associated With Schizophrenia
Conditions
Brief summary
This is a Phase II, randomized, double-blind, placebo-controlled, cross-over POC study of stable patients with Schizophrenia or Schizoaffective disorder. The primary objective of this study is to test the efficacy of treatment with one of two does of a glycine transporter inhibitor (GlyT1I) combined with cognitive remediation to enhavce cognitive function. Subjects will be randomized to one of two doses of the glycine transporter inhibitor (GlyT1I) and placebo twice daily in addition to their antipsychotic medication for 2 treatment periods, each lasting a minimum of 5 weeks. Treatment periods will be separated by a washout period lasting approximately 3 weeks.
Interventions
DRUGPF-03463275
DRUGPlacebo
Sponsors
National Center for Advancing Translational Sciences (NCATS)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 1\) Males or females 21 to 65 years of age (inclusive). * 2\) Diagnosis of Schizophrenia or Schizoaffective Disorder * 3\) Able to provide written informed consent. * 4\) Only CYP2D6 extensive metabolizers.
Exclusion criteria
* 1\) No ongoing acute medical issues * 2\) Clinically significant ECG abnormality * 3\) Blood donation within eight weeks of the start of the study * 4\) Current treatment with Clozapine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Change from baseline in cognitive measures at approximately 5 weeks. Mean scores were calculated per time point for each arm. | To test the efficacy of PF-03463275 on cognitive test performance specifically, the MCCB composite score was used. The MCCB consists of 10 tests and provides standard scores and percentiles for each of seven cognitive domains and an overall composite score. Domains assessed include: speed of processing, attention/vigilance, working memory (verbal and visual), verbal learning, visual learning, reasoning and problem solving, and social cognition. The MCCB overall composite score is presented as a T-score. The range of T-scores is between 0 to 100 with a mean of 50 and standard deviation of 10. Higher scores indicate better overall cognitive functioning. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Change from Baseline at approximately 1 week | To determine whether PF-03463275 impacts symptom domain scores and visual event related potentials (ERPs), analogous to long-term potentiation (LTP) with PF-03463275 treatment. A more positive value reflects a better outcome - there is no established range to report. A Z-score of 0 indicates the mean score. A positive z-score indicates the mean is higher than average. |
Countries
United States
Participant flow
Pre-assignment details
Subjects will be randomized to one of two doses of PF-03463275 and placebo twice daily for 2 treatment periods each lasting approx 5 weeks. Treatment periods will be separated by a washout period lasting approx 3 weeks. The 4 possible study arms are as follows: A) Pd 1: Active dose 60mg PF-03463275 then Pd 2: Placebo B) Pd 1: Active dose 40mg PF-03463275 then Pd 2: Placebo C) Pd 1: Placebo then Pd 2: Active dose 60mg PF-03463275 D) Pd 1: Placebo 40mg PF-03463275 then Pd 2: Placebo.
Participants by arm
| Arm | Count |
|---|---|
| PF-03463275 Active Dose #1 Subjects randomized to this arm will receive the following: Period 1) Active dose 60mg PF-03463275, then Period 2) Placebo. | 23 |
| PF-03463275 Active Dose #2 Subjects randomized to this arm will receive the following: Period 1) Active dose 40mg PF-03463275, then Period 2) Placebo. | 23 |
| Placebo, Active Dose #1 Subjects randomized to this arm will receive the following: Period 1) Placebo, then Period 2) Active dose 60mg PF-03463275. | 12 |
| Placebo, Active Dose #2 Subjects randomized to this arm will receive the following: Period 1) Placebo, then Period 2) Active dose 40mg PF-03463275. | 13 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 1 of Study | Physician Decision | 2 | 0 | 0 | 1 |
| Period 1 of Study | Withdrawal by Subject | 4 | 2 | 1 | 2 |
| Period 2 of Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Period 2 of Study | Physician Decision | 2 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo, Active Dose #2 | Total | PF-03463275 Active Dose #1 | PF-03463275 Active Dose #2 | Placebo, Active Dose #1 |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 71 Participants | 23 Participants | 23 Participants | 12 Participants |
| Age, Continuous | 39.77 years | 46.9 years | 45.4 years | 49.6 years | 50.92 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 9 Participants | 2 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 62 Participants | 21 Participants | 21 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 41 Participants | 16 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 25 Participants | 6 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Female | 5 Participants | 15 Participants | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 8 Participants | 56 Participants | 21 Participants | 20 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 33 | 0 / 63 | 0 / 59 |
| other Total, other adverse events | 13 / 34 | 13 / 33 | 9 / 63 | 7 / 59 |
| serious Total, serious adverse events | 0 / 34 | 2 / 33 | 0 / 63 | 0 / 59 |
Outcome results
Primary
Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB)
To test the efficacy of PF-03463275 on cognitive test performance specifically, the MCCB composite score was used. The MCCB consists of 10 tests and provides standard scores and percentiles for each of seven cognitive domains and an overall composite score. Domains assessed include: speed of processing, attention/vigilance, working memory (verbal and visual), verbal learning, visual learning, reasoning and problem solving, and social cognition. The MCCB overall composite score is presented as a T-score. The range of T-scores is between 0 to 100 with a mean of 50 and standard deviation of 10. Higher scores indicate better overall cognitive functioning.
Time frame: Change from baseline in cognitive measures at approximately 5 weeks. Mean scores were calculated per time point for each arm.
Population: The 3 arms that subjects can be randomized to are: A) Period 1: Active 60mg PF-03463275 then Period 2: Placebo; B) Period 1: Active 40mg PF-03463275 then Period 2: Placebo; C) Period 1: Placebo then Period 2: Active 60mg or 40mg PF-03463275. The following completed both period 1 and period 2 of the study: A) 15 subjects; B) 21 subjects; and C) 18 subjects (11 randomized to period 1-placebo/period 2-60mg PF-03463275; and 8 randomized to period 1-placebo/period 2-40mg PF-03463275).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03463275 Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 2 | 29.39 score on scale | Standard Deviation 12.68 |
| PF-03463275 Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 1 | 29.25 score on scale | Standard Deviation 12.38 |
| PF-03463275 Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 1 | 28.15 score on scale | Standard Deviation 13.54 |
| PF-03463275 Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 2 | 31.84 score on scale | Standard Deviation 13.36 |
| PF-03463275 Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 1 | 26.33 score on scale | Standard Deviation 14.96 |
| PF-03463275 Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 1 | 25.22 score on scale | Standard Deviation 13.86 |
| PF-03463275 Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 2 | 27.11 score on scale | Standard Deviation 12.46 |
| PF-03463275 Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 2 | 28.21 score on scale | Standard Deviation 11.49 |
| Placebo, Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 1 | 31.71 score on scale | Standard Deviation 17.24 |
| Placebo, Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 2 | 32.86 score on scale | Standard Deviation 18.52 |
| Placebo, Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 1 | 30.86 score on scale | Standard Deviation 17.45 |
| Placebo, Active Dose #1 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 2 | 34.29 score on scale | Standard Deviation 18.88 |
| Placebo, Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 1 | 30.11 score on scale | Standard Deviation 14.75 |
| Placebo, Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 2 | 31.8 score on scale | Standard Deviation 16.5 |
| Placebo, Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Post-Dose Period 2 | 32.2 score on scale | Standard Deviation 16.01 |
| Placebo, Active Dose #2 | Change in Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) | Pre-Dose Period 1 | 28.3 score on scale | Standard Deviation 17.7 |
Secondary
Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275
To determine whether PF-03463275 impacts symptom domain scores and visual event related potentials (ERPs), analogous to long-term potentiation (LTP) with PF-03463275 treatment. A more positive value reflects a better outcome - there is no established range to report. A Z-score of 0 indicates the mean score. A positive z-score indicates the mean is higher than average.
Time frame: Change from Baseline at approximately 1 week
Population: Noncompleters and unusable data of completers led to differences between the total number of participants and the sample for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-03463275 Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 1 | -0.544 Mean LTP Standard (z) Score +1 SE | Standard Error 0.281 |
| PF-03463275 Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 2 | -0.129 Mean LTP Standard (z) Score +1 SE | Standard Error 0.15 |
| PF-03463275 Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 2 | -0.008 Mean LTP Standard (z) Score +1 SE | Standard Error 0.323 |
| PF-03463275 Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 1 | -0.169 Mean LTP Standard (z) Score +1 SE | Standard Error 0.221 |
| PF-03463275 Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 1 | 0.084 Mean LTP Standard (z) Score +1 SE | Standard Error 0.224 |
| PF-03463275 Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 1 | -0.013 Mean LTP Standard (z) Score +1 SE | Standard Error 0.188 |
| PF-03463275 Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 2 | 0.594 Mean LTP Standard (z) Score +1 SE | Standard Error 0.316 |
| PF-03463275 Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 2 | 0.473 Mean LTP Standard (z) Score +1 SE | Standard Error 0.182 |
| Placebo, Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 2 | -0.614 Mean LTP Standard (z) Score +1 SE | Standard Error 0.398 |
| Placebo, Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 1 | -0.629 Mean LTP Standard (z) Score +1 SE | Standard Error 0.267 |
| Placebo, Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 2 | -0.674 Mean LTP Standard (z) Score +1 SE | Standard Error 0.313 |
| Placebo, Active Dose #1 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 1 | 0.228 Mean LTP Standard (z) Score +1 SE | Standard Error 0.221 |
| Placebo, Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 2 | 0.915 Mean LTP Standard (z) Score +1 SE | Standard Error 0.421 |
| Placebo, Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 1 | -0.111 Mean LTP Standard (z) Score +1 SE | Standard Error 0.456 |
| Placebo, Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Post-Dose Period 1 | 0.606 Mean LTP Standard (z) Score +1 SE | Standard Error 0.3 |
| Placebo, Active Dose #2 | Alteration in Symptom Domain Scores and Event Related Potentials (ERPs) With PF-03463275 | Pre-Dose Period 2 | 0.127 Mean LTP Standard (z) Score +1 SE | Standard Error 0.443 |