A Comparison Study of LY2140023 and Aripiprazole in Schizophrenia Patients

Study Overview
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Brief Summary
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The purpose of this study is to determine whether weight gain will be significantly less in LY2140023 than aripiprazole in patients with schizophrenia.

Detailed Description
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The primary objective of this study was to test the hypothesis that mean weight gain, as assessed by change from baseline, would be statistically significantly less for flexibly dosed LY2140023 (20, 40, or 80 mg twice daily [BID]) than for flexibly dosed aripiprazole (10, 15, or 30 mg/day) in patients with schizophrenia after 24 weeks of double-blind treatment. This was a multicenter, randomized, double-blind, Phase 3 study to assess the safety and efficacy of LY2140023 (flexibly dosed between 20 and 80 mg BID) in patients with schizophrenia. An active control, aripiprazole (flexibly dosed between 10 and 30 mg/day), was included for comparison.

Official Title
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A Phase 3, Multicenter, Double-Blind Comparison of LY2140023 and Aripiprazole in Patients With DSM-IV-TR Schizophrenia Followed by Open-Label Treatment With LY2140023

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: LY2140023
* Drug: Aripiprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of schizophrenia Female participants of childbearing age must test negative for pregnancy at screening and agree to use single, effective, medically acceptable method of birth control Participants must require initiation of or modification to current antipsychotic treatment as outpatients Participants must be considered reliable, have a level of understanding sufficient to perform all tests and examinations required by the protocol, and be willing to perform all study procedures Participants must be able to understand the nature of the study and have given their own informed consent Exclusion Criteria: Have been on treatment with aripiprazole in the past 2 months or are aripiprazole nonresponders Participants who are pregnant, nursing, or intend to become pregnant within 30 days of completing the study Hospitalized within 2 weeks of screening or have been hospitalized for an exacerbation of symptoms of schizophrenia with a discharge date in the past 2 months Participants who are actively suicidal Participants with uncorrected narrow-angle glaucoma, history of or current seizure disorder, uncontrolled diabetes, certain diseases of the liver, renal insufficiency, uncontrolled thyroid condition or other serious or unstable illnesses Participants who have had electroconvulsive therapy (ECT) within 3 months prior to screening or will have ECT at any time during the study Participants with known medical history of Human Immunodeficiency Virus positive (HIV+) status Test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody Participants with a corrected QT interval (Bazett's; QTcB)>450 milliseconds (msec) (male) or >470 msec (female) at screening Participants who have a history of inadequate clinical response to antipsychotic treatment for schizophrenia Participants who have received treatment with any depot formulation of an antipsychotic medication within 1 dosing interval, minimum of 4 weeks, prior to screening Are currently enrolled in, or discontinued within the last 60 days from, a clinical trial involving an investigational product or unapproved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have any other psychiatric diagnoses in addition to schizophrenia Have previously completed or withdrawn from this study, or any other study investigating LY2140023 or any predecessor molecules with glutamatergic activity Participants who have received an adequate treatment trial, in the opinion of the investigator, with clozapine at doses greater than 200 milligrams (mg) daily within 12 months prior to screening, or who have received any clozapine at all during the month before screening Diagnosis of substance-induced psychosis within 7 days of screening (or at any time during the study)

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY2140023<br>Double Blind Phase: 40 milligrams (mg) administered orally, given twice daily for 24 weeks. Dose may be adjusted to a minimum of 20 mg or a maximum of 80 mg. Open Label Phase: 40 mg administered orally, given twice daily for an additional 28 weeks. | Drug: LY2140023<br>* Administered orally<br>|
| Active Comparator: Aripiprazole<br>Double Blind Phase: 15 mg administered orally, given once daily for 24 weeks. Dose can be adjusted to a minimum of 10 mg or a maximum of 30 mg. Open Label Phase: LY2140023, 40 mg administered orally, given twice daily for an additional 28 weeks. | Drug: LY2140023<br>* Administered orally<br>Drug: Aripiprazole<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 to 24 Weeks in Body Weight | Mixed model repeated measures (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigator, visit, prior olanzapine use, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinically Significant Weight Change | Clinically significant change in body weight is defined as either an increase or decrease in weight of ≥7% from baseline. | Baseline up to 24 weeks | 
| Change From Baseline up to 24 Weeks in Barnes Akathisia Scale (BAS) | The BAS is a 4-item instrument that evaluates akathisia associated with use of antipsychotic medications. Item 4 Global Clinical Assessment of Akathisia is rated on a 6- point scale, with scores range from 0 (no symptoms) to 5 (increased severity of symptoms); Only Item 4 was analyzed and presented. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline up to 24 Weeks in Simpson-Angus Scale (SAS) | The SAS is used to measure Parkinsonian-type symptoms in participants exposed to antipsychotics. SAS consists of 10 items, each rated on a 5-point scale: 0 (complete absence of the condition) to 4 (presence of the condition in extreme form). The SAS Total Score is obtained by adding the ten items, and ranges from 0 to 40. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment by-visit-interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline up to 24 Weeks in Abnormal Involuntary Movement Scale (AIMS) | AIMS is a 12-item scale designed to record the occurrence of dyskinetic movements. Items 1 to 10 are rated on a 5- point scale: 0 (no dyskinetic movements) to 4 (severe dyskinetic movements). Items 11 and 12 are yes/no questions regarding the dental condition of a participant. The AIMS 1-7 Total Score is the sum of Items 1 through 7 of the AIMS, and ranges from 0 to 28. Higher scores indicate greater severity of illness. Only AIMS 1-7 Total Score was analyzed and presented. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | The PANSS consists of 30 items and 3 subscales and is 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, with scores 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 adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline up to 24 Weeks in EuroQol-5 Dimensions Questionnaire (EQ-5D) Visual Analog Scale (VAS) Health State Score | The EQ-5D is a generic, multidimensional, health-related, quality-of-life instrument that contains 2 parts: a health status profile and a visual analog scale (VAS) to rate global health-related quality of life. VAS health state scores range from 0 (worst imaginable health state) to 100 (best imaginable health state). The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | The S-RUM is 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 asks about the number of ER or equivalent facility visits a participant had for psychiatric (psych) illness. Item 2 asks about the number of ER or equivalent facility visits a participant had for non-psychiatric (non-psych) illness or injury. Item 5 asks about the number of outpatient visits to other physicians (not psychiatrists or dentists). Analysis of variance (ANOVA) was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for pooled investigator, gender and treatment. | Baseline to 24 weeks | 
| Schizophrenia Resource Use Module (S-RUM) - Number of Sessions With a Psychiatrist | The S-RUM is 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 asks about the number of sessions with a psychiatrist a participant had. Analysis of variance (ANOVA) was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for pooled investigator, gender and treatment. | Baseline to 24 weeks | 
| Change From Baseline up to 24 Weeks in Subjective Well-Being Under Neuroleptic Treatment Scale- Short Form (SWN-SF) Total Score | The SWN-SF measures subjective well-being of the participant for the previous 7 days. The 20-item scale covers 5 health domains (subscales; 4 items each): emotional regulation, self-control, mental functioning, social integration, and physical functioning. Individual scores range from 1 (not at all) to 6 (very much). Each of the 5 subscale scores range from 4 to 24. SWN-SF Total Scores range from 20 to 120. Higher scores indicate greater well-being. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline up to 24 Weeks in Personal and Social Performance (PSP) Score | The PSP scale is a 100-point (minimum 1, maximum 100), single item, clinician-rated scale to assess a participant's overall functioning, including personal and social relationships, socially useful activities, self-care, and disturbing and aggressive behaviors. Higher scores indicate a higher level of functioning. The Mixed Model Repeated Measures (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline up to 24 Weeks in 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 standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Change From Baseline up to 24 Weeks in 16-Item Negative Symptom 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 standard error. LS mean values were adjusted for baseline, treatment, gender, pooled investigative site, visit, predefined subpopulation, treatment-by-visit interaction and baseline-by-visit interaction. | Baseline, 24 weeks | 
| Number of Participants With 30% or Greater Decrease in Positive and Negative Syndrome Scale (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 (absence of symptoms) 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 scores indicate greater severity of illness. Data presented are the number of participants with 30% or greater decrease from baseline in PANSS Total score. | Baseline up to 24 weeks | 
| Number of Participants With Suicidal Behaviors and Ideations Measured by 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, actual attempt, and completed suicide. Data presented are the number of participants with treatment-emergent suicidal ideation or behavior during the treatment period (with a change from lead-in baseline in C-SSRS). | Baseline to 24 weeks | 
| Time to Discontinuation | The time to discontinuation due to any reason was defined as the total number of days between randomization and discontinuation date. The time to discontinuation was analyzed using Kaplan-Meier estimated survival curves. Participants who completed the study were considered censored. | Randomization up to 24 weeks |