A Study of LY2140023 in Patients With Schizophrenia

Study Overview
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Brief Summary
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The purpose of this study is to determine whether at least 1 dose level of LY2140023 given to acutely ill patients with schizophrenia will demonstrate significantly greater efficacy as compared to placebo.

Detailed Description
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The primary objective of this study was to test the hypothesis that at least 1 dose level of LY2140023, given orally to patients with schizophrenia at doses of 80 mg twice daily (BID), 40 mg BID, or 10 mg BID, would demonstrate significantly greater efficacy than placebo at Visit 9, as measured by the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score. This was a multicenter, randomized, double-blind, parallel, fixed-dose, Phase 3 study in patients with schizophrenia. The study consisted of 3 periods: a screening and antipsychotic taper phase, a 7-day placebo lead-in phase that was blinded to investigators and patients, and a 6-week active treatment phase. Eligible patients were those for whom a modification of antipsychotic medication was acutely indicated, in the opinion of the investigator. To be included in the study, patients must have experienced an exacerbation of their illness within the 2 weeks prior to study entry, leading to an intensification of the level of psychiatric care.

Official Title
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A Phase 3, Multicenter, Double-Blind, Placebo-Controlled Study of 3 Doses of LY2140023 Monohydrate in the Acute Treatment of Patients With DSM-IV-TR Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: LY2140023
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of schizophrenia as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR); and confirmed by the Structured Clinical Interview for DSM-IV-TR (SCID) Non pregnant female patients who agree to use acceptable birth control Participants must be considered moderately ill in the opinion of the investigator Patients in whom a modification of antipsychotic medication or initiation of antipsychotic medication is acutely indicated in the opinion of the investigator Willing to participate in a minimum of 2 weeks of inpatient hospitalization One year history of Schizophrenia prior to entering the study At study entry patients with a history of antipsychotic treatment must have a lifetime history of at least one hospitalization for the treatment of schizophrenia, not including the hospitalization required for study. Patients who have never taken antipsychotic treatment may enter the study even without a history of hospitalization. At study entry patients with a history of antipsychotic treatment must have a history of at least one episode of illness exacerbation requiring an intensification of treatment intervention or care in the last 2 years, not including the present episode of illness. Patients who have never taken antipsychotic treatment may enter the study without a past history of illness exacerbation and intensification of treatment in the last 2 years. At study entry patients must have experienced an exacerbation of illness within the 2 weeks prior to entering the study, leading to an intensification of psychiatric care in the opinion of the investigator. If exacerbation occurs in patients who are presently hospitalized, the patient must not have been hospitalized longer than 60 days at entry of the study. Patients must be considered reliable and have a level of understanding sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures Exclusion Criteria: Patients who have a history of inadequate clinical response to antipsychotic treatment for schizophrenia Diagnosis of substance dependence or substance abuse within 6 month of study entry Diagnosis of substance-induced psychosis within 7 days of study entry Currently enrolled in, or discontinued within 6 months from a clinical trial involving an investigational product or unapproved use of a drug or device Participated in any clinical trial with any pharmacological treatment intervention for which they received a study-related medication in the 6 months prior to study entry Previously completed or withdrawn from this study, or any other study investigating LY2140023 or any predecessor molecules with glutamatergic activity Treatment with clozapine at doses greater than 200 mg daily within 12 months prior to entering the study, or who have received any clozapine at all during the month before study entry Patients currently receiving treatment (within 1 dosing interval, minimum of 4 weeks, prior entering the study) with a depot formulation of an antipsychotic medication Patients who are currently suicidal Females who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study Patients with uncorrected narrow-angle glaucoma, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, uncontrolled thyroid condition or other serious or unstable illnesses Have a history of one or more seizures Electroconvulsive therapy (ECT) within 3 months of entering the study or who will have ECT at any time during the study History of low white blood cell count Medical history of Human Immunodeficiency Virus positive (HIV+) status. Higher than normal blood prolactin levels Abnormal electrocardiogram results

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: 80 milligrams (mg) LY2140023, BID<br>An 80-mg LY2140023 tablet administered orally, twice daily (BID) for 6 weeks. Prior to randomization, participants will complete a 1-week placebo lead-in period, during which time placebo tablets identical to LY2140023 are administered orally, BID. | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Experimental: 40 mg LY2140023, BID<br>A 40-mg LY2140023 tablet administered orally, BID for 6 weeks. Prior to randomization, participants will complete a 1-week placebo lead-in period, during which time, placebo tablets identical to LY2140023 are administered orally, BID. | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Experimental: 10 mg LY2140023, BID<br>A 10-mg LY2140023 tablet administered orally, BID for 6 weeks. Prior to randomization, participants will complete a 1-week placebo lead-in period, during which time, placebo tablets identical to LY2140023 are administered orally, BID. | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Placebo Comparator: Placebo<br>A placebo tablet administered orally, BID for 7 weeks. | Drug: Placebo<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score | The PANSS scale assessed participants (pts) for positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consisted of 30 items. Each item was rated from 1 (absence of symptoms) to 7 (symptoms extremely severe). The sum of the 30 items was defined as the PANSS total score and ranged from 30 to 210. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score in a Predefined Subpopulation of Schizophrenia Participants | The PANSS scale assessed participants for positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consisted of 30 items. Each item was rated from 1 (absence of symptoms) to 7 (symptoms extremely severe). The sum of the 30 items was defined as the PANSS total score and ranged from 30 to 210. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, and gender, as well as the continuous fixed covariates of baseline score, and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in the Personal and Social Performance (PSP) Score | The PSP scale was a 100-point, single item scale that assessed 4 domains of functioning (personal and social relationships, socially useful activities, self-care, and disturbing and aggressive behaviors). PSP scores ranged from 1 (risk of death) to 100 (excellent functioning) in all 4 domain areas. A higher score indicated a better health state. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in the Personal and Social Performance (PSP) Score in a Predefined Subpopulation | The PSP scale was a 100-point, single item scale that assessed 4 domains of functioning (personal and social relationships, socially useful activities, self-care, and disturbing and aggressive behaviors). PSP scores ranged from 1 (risk of death) to 100 (excellent functioning) in all 4 domain areas. A higher score indicated a better health state. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, and gender, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Total Score in Females | The PANSS scale assessed participants for positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consisted of 30 items. Each item was rated from 1 (absence of symptoms) to 7 (symptoms extremely severe). The sum of the 30 items was defined as the PANSS total score and ranged from 30 to 210. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in the Positive and Negative Syndrome Scale (PANSS) Subscores | PANSS subscales included the positive, negative, and general psychopathology subscales. PANSS positive and negative subscales assessed participants for 7 symptoms (positive or negative) associated with schizophrenia. Each item was rated from 1 (absence of symptoms) to 7 (symptoms extremely severe). Scores for both subscales ranged from 7 to 49. PANSS general psychopathology subscale assessed participants for 16 items of general psychopathology associated with schizophrenia. Each item was rated from 1 (absence of symptom) to 7 (symptom extremely severe). General psychopathology scores ranged from 16 to 112. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Percentage of Participants Who Are Responders | Response during the treatment period was defined as a ≥30% decrease from baseline in Positive and Negative Syndrome Scale (PANSS) total score. The PANSS scale assessed participants for positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consisted of 30 items. Each item was rated from 1 (absence of symptoms) to 7 (symptoms extremely severe). The sum of the 30 items was defined as the PANSS total score and ranged from 30 to 210. | Baseline, Week 6 | 
| Time to Response | Time to response is the number of days from randomization until a ≥30% decrease from lead-in baseline in Positive and Negative Syndrome Scale (PANSS) total score. Participants who did not have a response were censored. The PANSS scale assessed participants for positive symptoms, negative symptoms, and general psychopathology specifically associated with schizophrenia. The scale consisted of 30 items. Each item was rated from 1 (absence of symptoms) to 7 (symptoms extremely severe). The sum of the 30 items was defined as the PANSS total score and ranged from 30 to 210. | Baseline up to Week 6 | 
| Change From Baseline in the Clinical Global Impression-Severity (CGI-S) Scale | The CGI-S was a single item scale that measured severity of illness at the time of assessment. Scores ranged from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in the 16-Item Negative Symptoms Assessment (NSA-16) Total Score | The NSA-16 scale was used to help clinicians rate behaviors (not psychopathology) commonly associated with negative symptoms of schizophrenia. The scale contained 16 items and each item was rated from 1 (normal behavior) to 6 (extreme, abnormal behavior). The sum of the 16 items was defined as the NSA-16 total score and ranged from 16 to 96. Higher scores indicated a greater severity of illness. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline on the European Quality of Life-5 Dimension (EQ-5D) Questionnaire | The EQ-5D was a generic, multidimensional, health-related, quality-of-life instrument. The overall health state score was self-reported using a visual analogue scale (VAS) from 0 (worst imaginable health state) to 100 (best imaginable health state). The least squares (LS) mean was estimated using an analysis of covariance (ANCOVA) model that included terms for treatment, pooled investigative site, gender, baseline score and predefined subpopulation ('yes/no'). | Baseline, Week 6 | 
| Change From Baseline on Schizophrenia Resource Utilization Module (S-RUM): Emergency Room (ER) Visits and Outpatient Visits | The S-RUM was a 31-item questionnaire to assess the participant's occupation (work and home), living arrangements, encounters with law enforcement, victimization, ER visits, and outpatient medical visits for a specified period of time. Item 1 asked about the number of ER or equivalent facility visits a participant had for psychiatric (psych) illness during the last year [baseline (BL) assessment] or since the last assessment (post-baseline assessment). Item 2 asked about the number of ER or equivalent facility visits a participant had for non-psychiatric (non-psych) illness or injury during the last year (BL assessment) or since the last assessment (post-BL assessment). Item 5 asked about the number of outpatient visits to other physicians (not psychiatrists or dentists) a participant had during the last year (BL assessment) or since the last assessment (post-BL assessment). | Baseline and Week (Wk) 6 | 
| Change From Baseline on Schizophrenia Resource Utilization Module (S-RUM): Sessions With a Psychiatrist | The S-RUM was a 31-item questionnaire to assess the participant's occupation (work and home), living arrangements, encounters with law enforcement, victimization, emergency room (ER) visits, and outpatient medical visits for a specified period of time. Item 4 asked about the number of sessions with a psychiatrist a participant had, that were not part of this study, during the last year (baseline assessment) or since the last assessment (post-baseline assessment). | Baseline and Week 6 | 
| Change From Baseline on Subjective Well-Being Under Neuroleptic Treatment Scale - Short Form (SWN-S) Total Score | The SWN-S was a self-rated scale that measured subjective well-being for the previous 7 days. The SWN-S consisted of 20 items each rated using a 6-point scale from 1 (not at all) to 6 (very much). The sum of the 20 items was defined as the SWN-S total score and ranged from 20 to 120, with higher scores indicating better subjective well-being. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in Barnes Akathisia Scale (BAS) Global Score | The BAS was a 4-item instrument that evaluated akathisia associated with the use of antipsychotic medications. Item 4 was the Global Clinical Assessment (global score) and was rated from 0 (absent) to 5 (severe). The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in Simpson-Angus Scale (SAS) Total Score | The SAS was used to measure Parkinsonian-type symptoms in participants exposed to antipsychotics. The scale consisted of 10 items and each item was rated on a 5-point scale from 0 (complete absence of the condition) to 4 (the presence of the condition in extreme form). The sum of the 10 items was defined as the SAS total score and ranged from 0 to 40. Higher scores indicated a greater severity of illness. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Change From Baseline in Abnormal Involuntary Movement Scales (AIMS) 1-7 Total Score | The AIMS was a 12-item scale designed to record the occurrence of abnormal involuntary (dyskinetic) movements. Items 1 to 10 were rated on a 5-point scale from 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 11 and 12 were 'yes/no' questions regarding the dental condition of a participant. The sum of Items 1 through 7 was defined as the AIMS 1-7 total score and ranged from 0 to 28. Higher scores indicated a greater severity of illness. The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 | 
| Percentage of Participants With a Change From Baseline in Suicidal Behaviors and Ideations Measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) | The C-SSRS captured the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. Suicidal behavior: a yes answer to any 1 of 5 suicidal behavior questions (preparatory acts or behavior, aborted attempt, interrupted attempt, actual attempt, and completed suicide). Suicidal ideation: a yes answer to any 1 of 5 suicidal ideation questions (wish to be dead, and 4 different categories of active suicidal ideation). The percentage of participants with treatment-emergent suicidal ideation or behavior (with a change from baseline in C-SSRS) was calculated as the number of participants with an increase in suicidal behavior or ideation over lead-in baseline, divided by the total number of participants multiplied by 100. | Baseline up to Week 6 | 
| Number of Participants Who Discontinued | The reasons for study discontinuation are located in the Participant Flow. | Randomization up to Week 6 | 
| Time to Discontinuation | The time to discontinuation, due to any reason, was defined as the total number of days between the randomization date and discontinuation date. Participants who completed the study period were censored. The time to discontinuation was analyzed using Kaplan-Meier estimated survival curves. | Randomization up to Week 6 | 
| Change From Baseline in Prolactin |  | Baseline, Week 6 | 
| Change From Baseline in Weight | The least squares (LS) mean was estimated using a mixed-effects model with repeated measures (MMRM) that included the fixed, categorical effects of treatment, pooled investigative site, visit, treatment-by-visit interaction, gender, and predefined subpopulation ('yes/no'), as well as the continuous, fixed covariates of baseline score and baseline score-by-visit interaction. | Baseline, Week 6 |