Schizophrenia
Conditions
Brief summary
This study is to evaluate the safety and efficacy of the study drug compared to placebo in the treatment of cognitive impairment in men with schizophrenia.
Interventions
DRUGMK5757
This is a 2 period, cross-over study. In each of the two treatment periods, each patient will receive the following: Days 1 and 28 MK5757 25 mg capsules three times a day (tid). Days 2 through 14 and Days 29 through 42 MK5757 50 mg capsules tid. Study drug is taken 3 times daily. Each treatment period is 14 days
DRUGComparator: Placebo
This is a 2 period, cross-over study. In each of the two treatment periods, each patient will receive the following: Days 1 and 28 MK5757 one placebo capsules three times a day (tid). Days 2 through 14 and Days 29 through 42 two MK5757 placebo capsules tid. Study drug is taken 3 times daily. Each treatment period is 14 days.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
21 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* Patient is male between 21 and 55 years of age * Duration of the illness must be longer than 1 year * Patient's current antipsychotic medication regimen must be stable * Patient is negative for selected drugs of abuse at Screening * Must be in a stable living arrangement for at least 3 months prior to screening (not a homeless shelter)
Exclusion criteria
* Patient has mental retardation * Undergone Electroconvulsive Therapy (ECT) treatment within 6 months prior to screening * Has suicidal attempts or ideation within the last 12 months * Patient has a history of alcohol/drug dependence within 1 year or alcohol/drug abuse within 12 months of starting the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in the Composite Score From the Brief Assessment of Cognition in Schizophrenia (BACS) Battery After 2 Weeks of Treatment | Baseline and Week 2 | The Brief Assessment of Cognition in Schizophrenia (BACS) was used to evaluate cognitive impairment, as measured by the mean change from baseline after 2 weeks of treatment in the composite score. The BACS composite score was calculated by averaging scores from the BACS subtests, including Verbal Memory, Digit Sequencing, Token Motor, Symbol Coding, Verbal Fluency (Semantic Fluency and Letter Fluency) and Tower of London. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -111.5 and 111.5, respectively. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline After 2 Weeks of Treatment in the CogState Composite Score | Baseline and week 2 | CogState Schizophrenia Battery was used to evaluate cognitive impairment, as measured by the mean change from baseline after 2 weeks of treatment in the composite score. The composite score was comprised of 4 modules from the CogState Schizophrenia Battery: Identification Task, Detection Task, One Card Learning Task and Groton Maze Learning Task. Composite score was calculated by averaging all available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at 2 weeks of treatment for the endpoint are -347.5 and 347.5, respectively. |
| Mean Change From Baseline After 2 Weeks of Treatment in the Executive Functioning Composite Score | Baseline and Week 2 | The Executive Functioning Composite Score was comprised of the following tests: Groton Maze Learning Task from the CogState Schizophrenia Battery and Tower of London, Semantic Fluency and Letter Fluency tests from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -253.4 and 253.4, respectively. |
| Mean Change From Baseline After 2 Weeks of Treatment in the Episodic Memory Composite Score | Baseline and Week 2 | The Episodic Memory Composite Score was comprised of the following tests: Continuous Paired Associate Learning Task and One Card Learning Task from the CogState Schizophrenia Battery and the Verbal Memory test from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -207.06 and 207.06, respectively. |
| Mean Change From Baseline After 2 Weeks of Treatment in the Working Memory Composite Score | Baseline and Week 2 | The Working Memory Composite Score was comprised of the following tests: Two-Back Memory Task from the CogState Schizophrenia Battery and the Digit Sequencing test from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -27.06 and 27.06, respectively. |
| Mean Change From Baseline After 2 Weeks of Treatment in the Attention/Processing Speed Composite Score | Baseline and Week 2 | The Attention/Processing Speed Composite Score was comprised of the following tests: Identification Task and the Detection Task from the CogState Schizophrenia Battery and the Symbol Coding test from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -287.15 and 287.15, respectively. |
Participant flow
Recruitment details
First Patient Evaluated: 14-Oct-2008, Last Patient Last Visit: 18-Jun-2009; 6 sites (2 United States, 4 Russia). In total, enrollment lasted approximately 8 months.
Pre-assignment details
Patients in this cross-over study were randomly assigned to placebo or MK5757 for 2 weeks separated by a 2-week wash-out period. Women were not permitted to enroll into this study because safety, pharmacokinetic or pharmacodynamic properties of MK5757 in women have not been established.
Participants by arm
| Arm | Count |
|---|---|
| MK5757 / Placebo Patients were randomly assigned to two weeks of treatment with MK5757 during Treatment Period 1 followed by a 2-week washout followed by administration of placebo during Treatment Period 2.
Patients received one orally-administered three times a Day\[ter in die\] (tid) dose on the first day of each treatment period. Patients titrated to two orally-administered tid doses on the second day of each Treatment Period and had the option to down-dose to one tid dose for the remainder of that treatment period.
Patients who down-dosed during Treatment Period 1 titrated to the target dose of 50 mg tid (or the placebo equivalent) during Treatment Period 2, but were permitted to down-dose if necessary. A 14-day Washout Period separated each 14-day treatment period | 27 |
| Placebo / MK5757 Patients were randomly assigned to two weeks of treatment with placebo during Treatment Period 1 followed by a 2-week washout followed by administration of MK5757 during Treatment Period 2.
Patients received one orally-administered three times a Day\[ter in die\] (tid) dose on the first day of each treatment period. Patients titrated to two orally-administered tid doses on the second day of each Treatment Period and had the option to down-dose to one tid dose for the remainder of that treatment period.
Patients who down-dosed during Treatment Period 1 titrated to the target dose of 50 mg tid (or the placebo equivalent) during Treatment Period 2, but were permitted to down-dose if necessary. A 14-day Washout Period separated each 14-day treatment period | 27 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| First Intervention (Treatment Period 1) | Adverse Event | 2 | 1 |
| First Intervention (Treatment Period 1) | Physician Decision | 0 | 1 |
| First Intervention (Treatment Period 1) | Withdrawal by Subject | 0 | 1 |
| Second Intervention (Treatment Period 2) | Lost to Follow-up | 0 | 1 |
| Washout Period of Two Weeks | Withdrawal by Subject | 0 | 3 |
Baseline characteristics
| Characteristic | MK5757 / Placebo | Placebo / MK5757 | Total |
|---|---|---|---|
| Age, Continuous | 33.8 years STANDARD_DEVIATION 8.5 | 36.1 years STANDARD_DEVIATION 9.1 | 35.0 years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 0 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 27 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 6 participants | 7 participants | 13 participants |
| Race/Ethnicity, Customized Multi-Racial | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 20 participants | 20 participants | 40 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 27 Participants | 27 Participants | 54 Participants |
| Study Region Russia | 19 participants | 20 participants | 39 participants |
| Study Region United States | 8 participants | 7 participants | 15 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 15 / 48 | 8 / 52 |
| serious Total, serious adverse events | 0 / 48 | 1 / 52 |
Outcome results
Primary
Mean Change From Baseline in the Composite Score From the Brief Assessment of Cognition in Schizophrenia (BACS) Battery After 2 Weeks of Treatment
The Brief Assessment of Cognition in Schizophrenia (BACS) was used to evaluate cognitive impairment, as measured by the mean change from baseline after 2 weeks of treatment in the composite score. The BACS composite score was calculated by averaging scores from the BACS subtests, including Verbal Memory, Digit Sequencing, Token Motor, Symbol Coding, Verbal Fluency (Semantic Fluency and Letter Fluency) and Tower of London. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -111.5 and 111.5, respectively.
Time frame: Baseline and Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients which included randomized patients who received at least one dose of study treatment and had at least one measurement in any of the two treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK5757 | Mean Change From Baseline in the Composite Score From the Brief Assessment of Cognition in Schizophrenia (BACS) Battery After 2 Weeks of Treatment | 0.3 T-score based on normative data |
| Placebo | Mean Change From Baseline in the Composite Score From the Brief Assessment of Cognition in Schizophrenia (BACS) Battery After 2 Weeks of Treatment | 1.5 T-score based on normative data |
p-value: 0.277constrained Longitudinal Data Analysis
Secondary
Mean Change From Baseline After 2 Weeks of Treatment in the Attention/Processing Speed Composite Score
The Attention/Processing Speed Composite Score was comprised of the following tests: Identification Task and the Detection Task from the CogState Schizophrenia Battery and the Symbol Coding test from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -287.15 and 287.15, respectively.
Time frame: Baseline and Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients which included randomized patients who received at least one dose of study treatment and had at least one measurement in any of the two treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK5757 | Mean Change From Baseline After 2 Weeks of Treatment in the Attention/Processing Speed Composite Score | -0.2 T-score based on normative data |
| Placebo | Mean Change From Baseline After 2 Weeks of Treatment in the Attention/Processing Speed Composite Score | -1.3 T-score based on normative data |
p-value: 0.686constrained Longitudinal Data Analysis
Secondary
Mean Change From Baseline After 2 Weeks of Treatment in the CogState Composite Score
CogState Schizophrenia Battery was used to evaluate cognitive impairment, as measured by the mean change from baseline after 2 weeks of treatment in the composite score. The composite score was comprised of 4 modules from the CogState Schizophrenia Battery: Identification Task, Detection Task, One Card Learning Task and Groton Maze Learning Task. Composite score was calculated by averaging all available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at 2 weeks of treatment for the endpoint are -347.5 and 347.5, respectively.
Time frame: Baseline and week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients which included randomized patients who received at least one dose of study treatment and had at least one measurement in any of the two treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK5757 | Mean Change From Baseline After 2 Weeks of Treatment in the CogState Composite Score | 0.3 T-score based on normative data |
| Placebo | Mean Change From Baseline After 2 Weeks of Treatment in the CogState Composite Score | -0.5 T-score based on normative data |
p-value: 0.686constrained Longitudinal Data Analysis
Secondary
Mean Change From Baseline After 2 Weeks of Treatment in the Episodic Memory Composite Score
The Episodic Memory Composite Score was comprised of the following tests: Continuous Paired Associate Learning Task and One Card Learning Task from the CogState Schizophrenia Battery and the Verbal Memory test from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -207.06 and 207.06, respectively.
Time frame: Baseline and Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients which included randomized patients who received at least one dose of study treatment and had at least one measurement in any of the two treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK5757 | Mean Change From Baseline After 2 Weeks of Treatment in the Episodic Memory Composite Score | 0.1 T-score based on normative data |
| Placebo | Mean Change From Baseline After 2 Weeks of Treatment in the Episodic Memory Composite Score | 0.8 T-score based on normative data |
p-value: 0.686constrained Longitudinal Data Analysis
Secondary
Mean Change From Baseline After 2 Weeks of Treatment in the Executive Functioning Composite Score
The Executive Functioning Composite Score was comprised of the following tests: Groton Maze Learning Task from the CogState Schizophrenia Battery and Tower of London, Semantic Fluency and Letter Fluency tests from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -253.4 and 253.4, respectively.
Time frame: Baseline and Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients which included randomized patients who received at least one dose of study treatment and had at least one measurement in any of the two treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK5757 | Mean Change From Baseline After 2 Weeks of Treatment in the Executive Functioning Composite Score | 0.9 T-score based on normative data |
| Placebo | Mean Change From Baseline After 2 Weeks of Treatment in the Executive Functioning Composite Score | 1.0 T-score based on normative data |
p-value: 0.933constrained Longitudinal Data Analysis
Secondary
Mean Change From Baseline After 2 Weeks of Treatment in the Working Memory Composite Score
The Working Memory Composite Score was comprised of the following tests: Two-Back Memory Task from the CogState Schizophrenia Battery and the Digit Sequencing test from the BACS. The composite score was calculated by averaging all of the available standardized tests scores for the specified tests. The possible minimum and maximum scores for change from baseline at two weeks of treatment for the endpoint are -27.06 and 27.06, respectively.
Time frame: Baseline and Week 2
Population: Full Analysis Set (FAS): The FAS population was a subset of all randomized patients which included randomized patients who received at least one dose of study treatment and had at least one measurement in any of the two treatment periods.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| MK5757 | Mean Change From Baseline After 2 Weeks of Treatment in the Working Memory Composite Score | -1.7 T-score based on normative data |
| Placebo | Mean Change From Baseline After 2 Weeks of Treatment in the Working Memory Composite Score | -0.1 T-score based on normative data |
p-value: 0.686Wilcoxon (Mann-Whitney)