An Outpatient Study Of The Efficacy, Safety, And Tolerability Of PF-02545920 In The Adjunctive Treatment Of Sub-Optimally Controlled Symptoms of Schizophrenia

Study Overview
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Brief Summary
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This study aims to evaluate whether PF-02545920 is safe and effective in the treatment of sub-optimally controlled symptoms of schizophrenia during a 12-week outpatient treatment period. The study will use the Positive and Negative Syndrome Scale (PANSS) to measure change in symptoms for PF-02545920 from baseline compared to placebo.

Official Title
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A 12-week , Randomized, Phase 2, Double-blind, Parallel-group Study Of Two Dose Levels Of Pf-02545920 Compared To Placebo In The Adjunctive Treatment Of Outpatients With Sub-optimally Controlled Symptoms Of Schizophrenia

Conditions
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Schizophrenia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Psychiatrically stable subjects with schizophrenia who have had a suboptimal response to current treatment 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 with schizophrenia that have not responded at all to current treatment. Pregnant or nursing females, and females of child bearing potential.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-02545920 (5mg)<br> | Drug: PF-02545920<br>* PF-02545920 2 mg BID x 7 days, then 5 mg BID until the Week 12 visit<br>* Other names: 5 mg BID;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo BID until the Week 12 visit<br>|
| Experimental: PF-02545920 (15mg)<br> | Drug: PF-02545920<br>* PF-02545920 5 mg BID x 7 days, then 10 mg BID x 7 days, then 15 mg BID until the Week 12 visit<br>* Other names: 15 mg BID;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Syndrome Scale (PANSS) Total Score at Baseline | The Positive and Negative Syndrome Scale (PANSS) assesses the positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS Total Score and ranges from 30 to 210; higher score indicates greater severity. | Baseline | 
| Change From Baseline to Week 12 in PANSS Total Score | The PANSS assesses the positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS Total Score and ranges from 30 to 210; higher score indicates greater severity. | Baseline, Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 12 in Personal and Social Performance Scale (PSP) Total Score | The Personal and Social Performance Scale (PSP) is a validated clinician-related scale that measured personal and social functioning in the domains of: socially useful activities (eg, work and study), personal and social relationships, self-care, disturbing and aggressive behaviors. Information from the participant and the informant were utilized in determining the rating. A PSP total score was determined from the 4 domains (score range 0-100). A score between 71 and 100 indicates a mild degree of difficulty; a score between 31 and 70 indicates a moderate degree of dysfunction, and a participant with a score of 30 or less has functioning so poor he or she requires intensive supervision. | Baseline, Week 12 | 
| Change From Baseline to Week 12 in PANSS Positive, Negative, and General Subscales | The PANSS includes 3 scales and 30 items: 7 items that make up the Positive Scale (eg, delusions, conceptual disorganization, hallucinatory behavior); 7 items that make up the Negative Scale (eg, blunted affect, emotional withdrawal, poor rapport, passive/apathetic social withdrawal); and 16 items that make up the General Psychopathology Scale (eg, somatic concern, anxiety, guilt feelings, mannerisms and posturing, motor retardation, uncooperativeness, disorientation, poor impulse control, preoccupation). Individual items are scored with values ranging from 1 to 7. Total Negative and Positive Subscale scores each range from 7 to 49; higher score indicates greater severity. Total General Psychopathology Subscale score range from 16 to 112; higher score indicates greater severity. | Baseline, Week 12 | 
| Change From Baseline to Week 12 in PANSS-Derived Marder Factor Scores | The subscales based on Marder factors are: negative symptoms, positive symptoms, disorganized thoughts factor, uncontrolled hostility/excitement factor, and anxiety/depression factor. The symptoms are rated on a 7-point scale, with a range of 7 to 49 for negative symptoms, 8 to 56 for positive symptoms, 7 to 49 for disorganized thoughts and 4 to 28 for uncontrolled hostility/excitement and anxiety/depression. Higher scores indicate higher severity of symptoms. | Baseline, Week 12 | 
| Change From Baseline to Week 12 in Clinical Global Impression of Severity (CGI-S) | CGI-S: 7-point clinician-rated scale to assess severity of participant's current illness state; range: 1 (normal - not ill at all) to 7 (among the most extremely ill patients). Higher score = more affected. Change: score at observation minus score at baseline. | Baseline, Week 12 | 
| Clinical Global Impression - Improvement (CGI-I) Total Score at Week 12 | CGI-I: 7-point clinician-rated scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved), 2 (much improved), or 3 (minimally improved) on the scale. Higher score = more affected. | Week 12 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations Due to Adverse Events (AEs) | An AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs comprised both SAEs and non-SAEs. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent adverse events (TEAEs) were defined as newly occurring AEs or those worsening after first dose. | Baseline up to 7-10 days after last dose of study drug (follow-up) | 
| Number of Participants With Change From Baseline and Absolute Values in Vital Signs Meeting Categorical Summarization Criteria | Categorical summarization criteria in vital signs included: sitting, supine, and standing systolic blood pressure (SBP) of less than (<)90 millimeters of mercury (mm Hg) or change in sitting, supine and standing SBP of more than or equal to (>=)30 mm Hg; supine, sitting, and standing diastolic blood pressure (DBP) of <50 mm Hg or change in sitting, supine, and standing DBP of >=20 mm Hg; supine and sitting pulse rate of <40 or more than (>)120 beats per minute (bpm); and standing pulse rate of <40 or >140 bpm. | Screening up to 7-10 days after last dose of study drug (follow-up) | 
| Overall Number of Participants With Positive Responses to Categories on the Columbia Suicide Severity Rating Scale (C-SSRS) | C-SSRS assessed whether participant experienced the following: completed suicide (Category 1), suicide attempt (Category 2; response of Yes on actual attempt), preparatory acts toward imminent suicidal behavior (Category 3; Yes on preparatory acts or behavior), suicidal ideation (Category 4; Yes on wish to be dead, non-specific active suicidal thoughts, active suicidal ideation with methods without intent to act or some intent to act, without specific plan or with specific plan and intent), any suicidal behavior or ideation, self-injurious behavior (Category 7; Yes on Has subject engaged in non-suicidal self-injurious behavior). | Baseline up to 7-10 days after last dose of study drug | 
| Concentration of PF-02545920 and Its Metabolite, PF-01001252 | Pharmacokinetic (PK) samples were collected at varying times relative to drug dosing whenever participants could be scheduled for study visits (sparse PK sampling). Thus, because of the variable time between the last dose and the collection of the PK samples, typical summary PK analyses were not planned or described in the study protocol and are not available. The study protocol analysis section specified that the sparse sampled PK data might be pooled with PK data from previous PF-02545920 clinical studies, however the study results did not support conducting those analyses. | Days 14, 28, 42, 56, 70, 84/Early Termination | 
| Number of Participants With Electrocardiogram (ECG) Values Meeting Categorical Summarization Criteria | Criteria for ECG (12-lead) values meeting categorical summarization criteria were: the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization (PR interval >=300 milliseconds (msec) and increase from baseline >=25/50%; time from the beginning of the electrocardiogram Q wave to the end of the S wave corresponding to ventricular depolarization (QRS) interval >=140 msec and increase of >=50%; the beginning of the Q wave to the end of the T wave corresponding to electrical systole (QT) interval corrected using the Fridericia formula (QTcF) of 450 to <480 msec, 480 to <500 msec and >=500 msec, or an increase of 30 to <60 msec or >=60 msec. | Screening/Baseline up to Week 12 (or Early Termination) | 
| Number of Participants With Weight Change >=7% | The effects of PF-02545920 on body weight were evaluated. The number of participants with changes from baseline in body weight of >=7% were tabulated and summarized. | Screening up to Day 84 | 
| Number of Participants With New/Intensified Physical Examination Findings From Baseline by Body Site | A complete physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. | Baseline and Week 12 or Early Termination | 
| Number of Participants With Laboratory Test Abnormalities | Number of participants with laboratory test abnormalities without regard to baseline abnormality. Laboratory test parameters included hematology, liver function, renal function, lipids, electrolytes, hormones (prolactin), clinical chemistry, and urinalysis (dipstick and microscopy). | Screening up to Week 12/Early Termination and 7-10 days after last dose of study drug (hematology only) | 
| Number of Participants With Extrapyramidal Motor System (EPS) AEs | EPS AEs consisted of oromandibular dystonia, extrapyramidal disorder, akathisia, dyskinesia, and tremor. | Baseline up to 7-10 days after last dose of study drug (follow-up) | 
| Change From Baseline in Cholesterol, Triglycerides (TG), Low-Density Lipoprotein (LDL), and High-Density Lipoprotein (HDL) at Weeks 6 and 12 | Choleseterol, TG, glycosylated hemoglobin (HbA1c), LDL, HDL, insulin, and prolactin were a part of the laboratory tests done (metabolic tests). | Baseline; Weeks 6 and 12 | 
| Change From Baseline in Glycosylated Hemoglobin (HbA1c) at Weeks 6 and 12 | Choleseterol, TG, HbA1c, LDL, HDL, insulin, and prolactin were a part of the laboratory tests done (metabolic tests). | Baseline; Weeks 6 and 12 | 
| Change From Baseline in Insulin at Weeks 6 and 12 | Choleseterol, TG, HbA1c, LDL, HDL, insulin, and prolactin were a part of the laboratory tests done (metabolic tests). | Baseline; Weeks 6 and 12 | 
| Change From Baseline in Prolactin at Weeks 6 and 12 | Choleseterol, TG, HbA1c, LDL, HDL, insulin, and prolactin were a part of the laboratory tests done (metabolic tests). | Baseline; Weeks 6 and 12 | 
| Change From Baseline to Week 12 on the Extrapyramidal Symptom Rating Scale-Abbreviated (ESRS-A) | The ESRS-A is a 28-item instrument designed to facilitate standardized observations of parkinsonism, dystonia, dyskinesia, and akathisia. Ratings were determined through a combination of clinical interview and a motor examination. Scores were divided into individual domain scores and clinical global impression scores (CGI-S). Scores started from 0 (normal) to 6 (0 to 8 for CGI-S), with higher scores indicating greater severity. | Baseline, Week 12 | 
| Absolute Values of Movement Disorder Burden Score - Dystonia (MDBS-D) Over Active Treatment Period | The MDBS-D quantified the dystonia burden during the active treatment period. For an individual participant, MDBS-D took into account all treatment-emergent dystonia events and was defined as a combination of the severity of the AE due to dystonia, AE duration, prescribed concomitant medication, and the total number of days the study treatment was received. Scores for the MDBS-D ranged from 0 (no dystonia events) to 4.5, with higher scores indicating greater dystonia burden. | Active treatment period (Weeks 1 to 12/Early Termination) | 

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