A Study To Examine The Safety, Tolerability And Pharmacokinetics Of PF-02545920 In Psychiatrically Stable Subjects With Schizophrenia

Study Overview
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Brief Summary
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To evaluate the safety and tolerability of multiple doses of PF 02545920 administered orally to psychiatrically stable subjects with schizophrenia receiving background antipsychotic +/- other adjunctive medication.

Official Title
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A Randomized, Double-blind, Placebo Controlled, Sponsor Open, Phase 1b Study To Examine The Adjunctive Safety, Tolerability And Pharmacokinetics Of Pf-02545920 In Psychiatrically Stable Subjects With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: PF-02545920
* Drug: PF-02545920
* Drug: PF-02545920
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Psychiatrically stable subjects with schizophrenia. Evidence of stable schizophrenia symptomatology greater than or equal to 3 months. Subjects must be on a stable medication treatment regimen greater than or equal to 2 months, including concomitant psychotropic medications. Exclusion Criteria: History of seizures or of a condition with risk of seizures. Subjects who have had electroconvulsive therapy within the 6 months prior to randomization. Pregnant or nursing females, and females of child bearing potential.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-02545920<br> | Drug: PF-02545920<br>* 15 mg (2 mg X 2d, 5 mg X 2d, 8 mg X 3 d, then 15 mg) Q12h<br>* Other names: Cohort 1;Drug: PF-02545920<br>* 15 mg (5 mg X 2d, 10 mg X 2d, then 15 mg) Q12h<br>* Other names: Cohort 2;Drug: PF-02545920<br>* 15 mg (5 mg BID for 7 days 10 mg BID for 7 days, then 15 mg BID for 4 days) Q12h<br>* Other names: Cohort 3;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo Q12h<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Abbreviated Extrapyramidal Symptom Rating Scale (ESRS-A) Scores (Cohorts 1 and 2) at Day 10 | ESRS-A is a clinician rated scale consisting of 24 items to assess severity of extrapyramidal symptoms for following parameters: parkinsonism (10 items), dystonia (6 items), dyskinesia (6 items) and akathisia (2 items). Each item was scored on a 6-point scale (0=absent, 1=minimal, 2=mild, 3=moderate, 4=severe, 5=extreme). Additionally, 4 Clinical Global Impression of Severity (CGI-S) items were assessed on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=extremely ill): CGI-S parkinsonism; CGI-S dystonia; CGI-S dyskinesia; CGI-S akathisia. | Day 0 (Baseline) up to Day 10 | 
| Change From Baseline in ESRS-A Scores (Cohort 3) at Day 18 | ESRS-A is a clinician rated scale consisting of 24 items to assess severity of extrapyramidal symptoms for following parameters: parkinsonism (10 items), dystonia (6 items), dyskinesia (6 items) and akathisia (2 items). Each item is scored on a 6-point Likert scale (0=absent, 1=minimal, 2=mild, 3=moderate, 4=severe, 5=extreme). Additionally, 4 CGI-S items were assessed on a 7-point scale (1=normal, not ill at all; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=extremely ill): CGI-S parkinsonism; CGI-S dystonia; CGI-S dyskinesia; CGI-S akathisia. | Day 0 (Baseline) up to Day 18 | 
| Number of Participants With Response to Columbia-Suicide Severity Rating Scale (C-SSRS) (Cohorts 1 and 2) at Baseline (Day 0) | Data relevant to the assessment of suicidality was mapped to the Columbia-Classification Algorithm of Suicide Assessment (C-CASA) event codes. C-SSRS assessed whether participant experienced following: completed suicide (Event code 1), suicide attempt (Event code 2) (Response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (Event code 3) (Yes on aborted attempt, interrupted attempt, preparatory acts or behavior), suicidal ideation (Event code 4) (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act/some intent to act without specific plan or with specific plan and intent), self-injurious behavior, no suicidal intent (Event code 7) (Yes on Has participant engaged in non-suicidal self-injurious behavior). Number of participants with Yes response for above mentioned categories were assessed. | Day 0 (Baseline) | 
| Number of Participants With Response to C-SSRS (Cohorts 1 and 2) at Day 11 | Data relevant to the assessment of suicidality was mapped to the C-CASA event codes. C-SSRS assessed whether participant experienced following: completed suicide (Event code 1), Suicide attempt (Event code 2) (Response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (Event code 3) (Yes on aborted attempt, interrupted attempt, preparatory acts or behavior), suicidal ideation (Event code 4) (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act/some intent to act without specific plan or with specific plan and intent), self-injurious behavior, no suicidal intent (Event code 7) (Yes on Has participant engaged in non-suicidal self-injurious behavior). Number of participants with Yes response for above mentioned categories were assessed. | Day 11 | 
| Number of Participants With Response to C-SSRS (Cohorts 1 and 2) at Follow-up (Any Day Between Day 17 and 20) | Data relevant to the assessment of suicidality was mapped to the C-CASA event codes. C-SSRS assessed whether participant experienced following: completed suicide (Event code 1), Suicide attempt (Event code 2) (Response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (Event code 3) (Yes on aborted attempt, interrupted attempt, preparatory acts or behavior), suicidal ideation (Event code 4) (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act/some intent to act without specific plan or with specific plan and intent), self-injurious behavior, no suicidal intent (Event code 7) (Yes on Has participant engaged in non-suicidal self-injurious behavior). Number of participants with Yes response for above mentioned categories were assessed. | Follow-up (any day between Day 17 and 20) | 
| Number of Participants With Response to C-SSRS (Cohort 3) at Baseline (Day 0) | Data relevant to the assessment of suicidality was mapped to the C-CASA event codes. C-SSRS assessed whether participant experienced following: Completed suicide (Event code 1), Suicide attempt (Event code 2) (Response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (Event code 3) (Yes on aborted attempt, interrupted attempt, preparatory acts or behavior), suicidal ideation (Event code 4) (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act/some intent to act without specific plan or with specific plan and intent), self-injurious behavior, no suicidal intent (Event code 7) (Yes on Has participant engaged in non-suicidal self-injurious behavior). Number of participants with Yes response for above mentioned categories were assessed. | Day 0 (Baseline) | 
| Number of Participants With Response to C-SSRS (Cohort 3) at Day 19 | Data relevant to the assessment of suicidality was mapped to the C-CASA event codes. C-SSRS assessed whether participant experienced following: Completed suicide (Event code 1), Suicide attempt (Event code 2) (Response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (Event code 3) (Yes on aborted attempt, interrupted attempt, preparatory acts or behavior), suicidal ideation (Event code 4) (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act/some intent to act without specific plan or with specific plan and intent), self-injurious behavior, no suicidal intent (Event code 7) (Yes on Has participant engaged in non-suicidal self-injurious behavior). Number of participants with Yes response for above mentioned categories were assessed. | Day 19 | 
| Number of Participants With Response to C-SSRS (Cohort 3) at Follow-up (Any Day Between Day 26 and 29) | Data relevant to the assessment of suicidality was mapped to the C-CASA event codes. C-SSRS assessed whether participant experienced following: Completed suicide (Event code 1), Suicide attempt (Event code 2) (Response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (Event code 3) (Yes on aborted attempt, interrupted attempt, preparatory acts or behavior), suicidal ideation (Event code 4) (Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act/some intent to act without specific plan or with specific plan and intent), self-injurious behavior, no suicidal intent (Event code 7) (Yes on Has participant engaged in non-suicidal self-injurious behavior). Number of participants with Yes response for above mentioned categories were assessed. | Follow-up (any day between Day 26 and 29) | 
| Number of Participants With Changes Since Screening in Physical Examination (Cohorts 1 and 2) | A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems was performed at Screening. The limited or abbreviated physical examination was focused on general appearance, the respiratory and cardiovascular systems, as well as towards assessment of subject reported symptoms and performed at other time points than Screening. | Screening up to Follow-up (any day between Day 17 and 20) | 
| Number of Participants With Changes Since Screening in Physical Examination (Cohort 3) | A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems was performed at Screening. The limited or abbreviated physical examination was focused on general appearance, the respiratory and cardiovascular systems, as well as towards assessment of subject reported symptoms and performed at other time points than Screening. | Screening up to Follow-up (any day between Day 26 and 29) | 
| Number of Participants With Abnormal Neurological Examination Findings (Cohorts 1 and 2) | The neurological examination included observation for cerebellar (intention) tremor and for non-cerebellar tremors (eg, resting or positional), finger-nose, heel-shin, Romberg, tandem walking, positional and gaze-evoked nystagmus. | Day 0 up to Follow-up (any day between Day 17 and 20) | 
| Number of Participants With Abnormal Neurological Examination Findings (Cohort 3) | The neurological examination included observation for cerebellar (intention) tremor and for non-cerebellar tremors (eg, resting or positional), finger-nose, heel-shin, Romberg, tandem walking, positional and gaze-evoked nystagmus. | Day 0 up to Follow-up (any day between Day 26 and 29) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Cohorts 1 and 2) | An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to last subject visit that were absent before treatment or that worsened relative to pretreatment state. | The time receiving the first dose of PF-02545920 or placebo through the last Follow-up (any day between Day 17 and 20) | 
| Number of Participants With TEAEs (Cohort 3) | An AE was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent were events between first dose of study drug and up to last subject visit that were absent before treatment or that worsened relative to pretreatment state. | The time receiving the first dose of PF-02545920/placebo through the last Follow-up (any day between Day 26 and 29) | 
| Number of Participants With Abnormal Clinical Laboratory Measurements (Cohorts 1 and 2) | The total number of participants with laboratory test abnormalities without regard to baseline abnormality was assessed. | Day 0 (Baseline) up to Follow-up (any day between Day 17 and 20) | 
| Number of Participants With Abnormal Clinical Laboratory Measurements (Cohort 3) | The total number of participants with laboratory test abnormalities without regard to baseline abnormality was assessed. | Day 0 (Baseline) up to Follow-up (any day between Day 26 and 29) | 
| Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern (Cohorts 1 and 2) | Vital signs included blood pressure (BP; supine and standing) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: systolic >=30 millimeters of mercury (mm Hg) change from baseline in same posture, systolic <90 mm Hg; diastolic >=20 mm Hg change from baseline in same posture, diastolic <50 mm Hg; 2), pulse rate (supine/sitting): <40 or greater than (>) 120 beats per minute (bpm); Standing: <40 or >140 bpm. | Day 0 (Baseline) up to Follow-up (any day between Day 17 and 20) | 
| Number of Participants With Vital Signs Data Meeting Criteria of Potential Clinical Concern (Cohort 3) | Vital signs included BP (supine and standing) and pulse rate. Vital signs criteria of potential clinical concern were 1), BP: systolic >=30 mm Hg change from baseline in same posture, systolic <90 mm Hg; diastolic >=20 mm Hg change from baseline in same posture, diastolic <50 mm Hg; 2), pulse rate (supine/sitting): <40 or >120 bpm; Standing: <40 or >140 bpm. | Day 0 (Baseline) up to Follow-up (any day between Day 26 and 29) | 
| Number of Participants With Electrocardiogram (ECG) Data Meeting Criteria of Potential Clinical Concern (Cohorts 1 and 2) | 12-lead ECG (triplicate) was performed on Day 0 and 12-lead ECG (singlet) was performed at other time points as specified in timeframe. ECG criteria of potential clinical concern were 1), PR interval: >=300 milliseconds (msec); >=25% increase when baseline was greater than (>) 200 msec; or increase >=50% when baseline was less than or equal to (<=) 200 msec; 2), QRS interval: >=140 msec; >=50% increase from baseline; 3), corrected QT interval (QTc interval): >=500 msec, QTc interval using Fridericia's formula (QTcF interval): absolute value >=450 - <480 msec(borderline), >=480 msec (prolonged); absolute change 30 - <60 (borderline), >=60 msec (prolonged). | Day 0 (Baseline) up to Day 10 | 
| Number of Participants With ECG Data Meeting Criteria of Potential Clinical Concern (Cohort 3) | 12-lead ECG (triplicate)was performed on Day 0 and 12-lead ECG (singlet) was performed at other time points as specified in timeframe. ECG criteria of potential clinical concern were 1), PR interval: >=300 msec; >=25% increase when baseline >200 msec; or increase >=50% when baseline <=200 msec; 2), QRS interval: >=140 msec; >=50% increase from baseline; 3), QTc interval: >=500 msec, QTcF interval: absolute value >=450 - <480 msec (borderline), >=480 msec (prolonged); absolute change 30 - <60 (borderline), >=60 msec (prolonged). | Screening up to Day 18 | 
| Sparse Pharmacokinetic (PK) Sampling for Population PK Analysis: PF-02545920 Concentration at 0 Hour (Predose) on Day 10 (Cohorts 1 and 2) |  | 0 hour (predose) on Day 10 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 25 Minutes (Post Dose) on Day 10 (Cohorts 1 and 2) |  | 25 minutes (post dose) on Day 10 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 1 Hour 30 Minutes (Post Dose) on Day 10 (Cohorts 1 and 2) |  | 1 hour 30 minutes (post dose) on Day 10 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 5 Hours (Post Dose) on Day 10 (Cohorts 1 and 2) |  | 5 hours (post dose) on Day 10 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 24 Hours (Post Dose) on Day 10 (Cohorts 1 and 2) |  | 24 hours (post dose) on Day 10 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 0 Hour (Predose) on Day 18 (Cohort 3) |  | 0 hour (predose) on Day 18 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 25 Minutes (Post Dose) on Day 18 (Cohort 3) |  | 25 minutes (post dose) Day 18 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 1 Hour 30 Minutes (Post Dose) on Day 18 (Cohort 3) |  | 1 hour 30 minutes (post dose) on Day 18 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 5 Hours (Post Dose) on Day 18 (Cohort 3) |  | 5 hours (post dose) on Day 18 | 
| Sparse PK Sampling for Population PK Analysis: PF-02545920 Concentration at 24 Hours (Post Dose) on Day 18 (Cohort 3) |  | 24 hours (post dose) on Day 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-02545920, safety, schizophrenia