A Study in Schizophrenic Patients

Study Overview
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Brief Summary
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This study is designed to compare 3 doses of LY2140023 for the treatment of schizophrenia as assessed at endpoint (up to 7 weeks) using the Clinical Utility Index (CUI), a measure of efficacy, safety, and tolerability.

Official Title
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A Multicenter, Double-Blind, Placebo-Controlled Study of 3 Doses of LY2140023 in 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; APA 2000) (Disorganized, 295.10; Catatonic, 295.20; Paranoid 295.30; or Undifferentiated, 295.90) and confirmed by the Structured Clinical Interview for DSM-IV-TR (SCID) Non pregnant female participants who agree to use acceptable birth control At entry to the study must be considered moderately ill in the opinion of the investigator 1 year history of Schizophrenia prior to entering the study At study entry participants 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 based on the investigator's clinical judgment. Participants who have never taken antipsychotic treatment may enter the study even without a history of hospitalization At study entry participants 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. Participants 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 participants must have experienced an exacerbation of illness within the 4 weeks prior to entering the study, leading to an intensification of psychiatric care in the opinion of the investigator. If exacerbation occurs in participants who are presently hospitalized, the participants must not have been hospitalized longer than 60 days at entry of the study Exclusion Criteria: Participated in any clinical trial with any pharmacological treatment intervention for which they received a study-related medication in the 6 months prior to visit 1 Previously completed or withdrawn from this study, or any other study investigating LY2140023 or any predecessor molecules with glutamatergic activity Have any known history of receiving treatment with clozapine at any dose, as determined at baseline Have received treatment with a depot formulation of an antipsychotic medication within the 6 months prior entering the study Participants who are currently suicidal Females who are pregnant, nursing, or who intend to become pregnant within 30 days of completing the study Participants with uncorrected narrow-angle glaucoma, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, untreated thyroid condition or other serious or unstable illnesses Have a history of one or more seizures, except for those who experienced a single simple febrile seizure between ages 6 months and 5 years Participants are excluded if their biological father, mother, brother, sister, or child has a history of idiopathic epilepsy Within 1 year of study enrollment, participants have a history of central nervous system infection, uncontrolled migraine, transient ischemic attack (TIA), or head trauma with loss of consciousness or a post-concussive Participants are excluded if they have a lifetime history of any of the following: head trauma, stroke, or central nervous system (CNS) infection with persistent neurological deficit (focal or diffuse); brain surgery; an electroencephalogram with paroxysmal (epileptiform) activity, or brain structural lesion, including developmental abnormalities, as determined by examination or previous neuroimaging studies that are consistent with a diagnosable neurological disease or syndrome Electroconvulsive therapy (ECT) within 3 months of entering the study or who will have ECT at any time during the study Leukopenia Medical history of Human Immunodeficiency Virus positive (HIV+) status Higher than normal blood prolactin levels Certain electrocardiogram results

Ages Eligible for Study
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Minimum Age: 20 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 10 milligrams (mg) LY2140023<br> | Drug: LY2140023<br>* Administered orally, twice daily for up to 7 weeks of treatment<br>|
| Experimental: 80 mg LY2140023<br> | Drug: LY2140023<br>* Administered orally, twice daily for up to 7 weeks of treatment<br>|
| Experimental: 160 mg LY2140023<br> | Drug: LY2140023<br>* Administered orally, twice daily for up to 7 weeks of treatment<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Administered orally, twice daily for up to 7 weeks of treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Utility Index (CUI) | CUI measures the efficacy (response), tolerability (time on treatment) and safety [incidence of adverse events (AEs)] by quantifying these 3 attributes and provides a single metric for overall treatment outcome. Each component is given a score ranging from 0 to 5. The CUI Total Score is the sum of the 3 items and ranges from 0 to 15. The greater the CUI Total Score, the more effective the treatment. If a participant experiences a drug-related seizure/death, the safety component is given a score of 0 resulting in an overall CUI Total Score of 0. Analysis of variance (ANOVA) was used to calculate Least Squares (LS) mean and standard error. LS mean values were controlled for treatment, gender and pooled investigators. | Baseline through Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 6 Endpoint in the Positive and Negative Syndrome Scale (PANSS) Total Score, Positive Score, Negative Score, and Psychopathology Subscale | The PANSS consists of 30 items and 3 subscales designed to measure severity of psychopathology in schizophrenia. The PANSS Positive Subscale and the PANSS Negative Subscale each contain 7 items, and the remaining 16 items make up the PANSS General Psychopathology Subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). The PANSS Total Score is the sum of the 30 items (range from 30 to 210). The PANSS Positive Subscale and PANSS Negative Subscale scores each range from 7 to 49. The PANSS General Psychopathology Subscale score ranges from 16 to 112. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and 95% confidence interval. LS mean values were controlled for baseline, treatment, gender, pooled investigator, visit, treatment*visit and baseline*visit. | Baseline, Week 6 | 
| Change From Baseline to Week 6 Endpoint in the Clinical Global Impression-Severity Scale (CGI-S) | The CGI-S instrument is used to record the severity of mental illness at the time of assessment. The score ranges from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicate greater severity of illness. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and 95% confidence interval. LS mean values were controlled for baseline, treatment, gender, pooled investigator, visit, treatment*visit and baseline*visit. | Baseline, Week 6 | 
| Change From Baseline to Week 6 Endpoint in the 16-item Negative Symptoms Assessment (NSA-16) | The NSA-16 scale is used to help clinicians rate behaviors (not psychopathology) commonly associated with negative symptoms of schizophrenia. The scale rates participants on 16 anchors. Each item (anchor) is rated from 1 (better) to 6 (worse). The NSA-16 Total Score is the sum of the 16 specific items and ranges from 16 to 96. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and 95% confidence interval. LS mean values were controlled for baseline, treatment, gender, pooled investigator, visit, treatment*visit and baseline*visit. | Baseline, Week 6 | 
| The Number of Participants With Treatment-Emergent Suicidal Ideation and Behavior Based on the Columbia Suicide Severity Rating Scale (C-SSRS) | Columbia Suicide Rating Scale (C-SSRS) captures occurrence, severity, and frequency of suicide-related thoughts and behaviors. Suicidal ideation: a yes answer to any one of 5 suicidal ideation questions: wish to be dead, and 4 different categories of active suicidal ideation. Suicidal behavior: a yes answer to any of 5 suicidal behavior questions: preparatory acts or behavior, aborted attempt, interrupted attempt, non-fatal suicide attempt, and completed suicide. The number of participants with statistically significant changes of the C-SSRS was the number of participants with a treatment-emergent suicidal ideation and behavior (an increase in suicidal behavior or ideation over lead-in baseline.) | Baseline up to Week 6 | 
| Percentage of Participants Who Discontinued (Rate of Discontinuation) | Rate of discontinuation was calculated as the number of participants who discontinued from study due to any reason divided by the total number of participants who received study drug, then multiplied by 100. | Baseline through Week 6 |