Schizophrenia
Conditions
Brief summary
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
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.
Interventions
DRUGLY2140023
Administered orally
DRUGAripiprazole
Administered orally
Sponsors
Denovo Biopharma LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 24 Weeks in Body Weight | Baseline, 24 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline up to 24 Weeks in Barnes Akathisia Scale (BAS) | Baseline, 24 weeks | 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. |
| Change From Baseline up to 24 Weeks in Simpson-Angus Scale (SAS) | Baseline, 24 weeks | 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. |
| Change From Baseline up to 24 Weeks in Abnormal Involuntary Movement Scale (AIMS) | Baseline, 24 weeks | 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. |
| Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | Baseline, 24 weeks | 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. |
| Change From Baseline up to 24 Weeks in EuroQol-5 Dimensions Questionnaire (EQ-5D) Visual Analog Scale (VAS) Health State Score | Baseline, 24 weeks | 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. |
| Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | Baseline to 24 weeks | 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. |
| Schizophrenia Resource Use Module (S-RUM) - Number of Sessions With a Psychiatrist | Baseline to 24 weeks | 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. |
| Percentage of Participants With Clinically Significant Weight Change | Baseline up to 24 weeks | Clinically significant change in body weight is defined as either an increase or decrease in weight of ≥7% from baseline. |
| Change From Baseline up to 24 Weeks in Personal and Social Performance (PSP) Score | Baseline, 24 weeks | 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. |
| Change From Baseline up to 24 Weeks in Clinical Global Impression-Severity Scale (CGI-S) | Baseline, 24 weeks | 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. |
| Change From Baseline up to 24 Weeks in 16-Item Negative Symptom Assessment (NSA-16) | Baseline, 24 weeks | 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. |
| Number of Participants With 30% or Greater Decrease in Positive and Negative Syndrome Scale (PANSS) Total Score | Baseline up to 24 weeks | 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. |
| Number of Participants With Suicidal Behaviors and Ideations Measured by Columbia Suicide Severity Rating Scale (C-SSRS) | Baseline to 24 weeks | 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). |
| Time to Discontinuation | Randomization up to 24 weeks | 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. |
| Change From Baseline up to 24 Weeks in Subjective Well-Being Under Neuroleptic Treatment Scale- Short Form (SWN-SF) Total Score | Baseline, 24 weeks | 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. |
Countries
Austria, Belgium, France, Germany, Poland, Puerto Rico, Romania, Spain, Sweden, United States
Participant flow
Pre-assignment details
This study consisted of a 24-week Double-Blind Active Treatment Phase and was followed by a 28-week Open-Label Active Treatment Phase. Modified intent-to-treat (mITT) is all randomized participants who received at least 1 dose of study drug, excluding participants from a Good Clinical Practice (GCP) noncompliant study site.
Participants by arm
| Arm | Count |
|---|---|
| LY2140023-DB 40 milligrams (mg) LY2140023 administered orally, twice daily for 24 weeks during the Double-Blind (DB) Phase. Dose was adjustable to 20 mg twice daily or 80 mg twice daily. | 511 |
| Aripiprazole-DB 15 mg aripiprazole administered orally, once daily for 24 weeks during the Double-Blind (DB) Phase. Dose was adjustable to 10 mg once daily or 30 mg once daily. | 161 |
| Total | 672 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-Blind Phase | Adverse Event | 78 | 15 |
| Double-Blind Phase | Death | 1 | 0 |
| Double-Blind Phase | Entry Criteria Not Met | 7 | 5 |
| Double-Blind Phase | Lack of Efficacy | 55 | 13 |
| Double-Blind Phase | Lost to Follow-up | 39 | 14 |
| Double-Blind Phase | Protocol Violation | 30 | 10 |
| Double-Blind Phase | Scheduling conflict | 8 | 3 |
| Double-Blind Phase | Sponsor Decision | 17 | 3 |
| Double-Blind Phase | Subject is moving or has moved | 8 | 1 |
| Double-Blind Phase | Withdrawal by Subject | 42 | 14 |
| Open-Label Phase | Adverse Event | 10 | 4 |
| Open-Label Phase | Entry Criteria Not Met | 1 | 0 |
| Open-Label Phase | Lack of Efficacy | 5 | 6 |
| Open-Label Phase | Lost to Follow-up | 10 | 1 |
| Open-Label Phase | Protocol Violation | 8 | 3 |
| Open-Label Phase | Scheduling conflict | 2 | 1 |
| Open-Label Phase | Sponsor Decision | 98 | 34 |
| Open-Label Phase | Subject is moving or has moved | 2 | 0 |
| Open-Label Phase | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | Total | LY2140023-DB | Aripiprazole-DB |
|---|---|---|---|
| Age, Continuous | 42.45 years STANDARD_DEVIATION 10.88 | 42.29 years STANDARD_DEVIATION 10.86 | 42.95 years STANDARD_DEVIATION 10.95 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 96 Participants | 73 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 576 Participants | 438 Participants | 138 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 6 Participants | 6 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 302 Participants | 238 Participants | 64 Participants |
| Race (NIH/OMB) More than one race | 9 Participants | 5 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 352 Participants | 259 Participants | 93 Participants |
| Region of Enrollment Austria | 8 participants | 6 participants | 2 participants |
| Region of Enrollment Belgium | 16 participants | 13 participants | 3 participants |
| Region of Enrollment France | 27 participants | 21 participants | 6 participants |
| Region of Enrollment Germany | 35 participants | 26 participants | 9 participants |
| Region of Enrollment Poland | 27 participants | 20 participants | 7 participants |
| Region of Enrollment Puerto Rico | 33 participants | 27 participants | 6 participants |
| Region of Enrollment Romania | 27 participants | 21 participants | 6 participants |
| Region of Enrollment Spain | 25 participants | 19 participants | 6 participants |
| Region of Enrollment Sweden | 21 participants | 17 participants | 4 participants |
| Region of Enrollment United States | 453 participants | 341 participants | 112 participants |
| Sex: Female, Male Female | 240 Participants | 185 Participants | 55 Participants |
| Sex: Female, Male Male | 432 Participants | 326 Participants | 106 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 358 / 511 | 107 / 161 | 112 / 270 |
| serious Total, serious adverse events | 42 / 511 | 5 / 161 | 12 / 270 |
Outcome results
Primary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had baseline and at least one post-baseline weight measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline to 24 Weeks in Body Weight | -2.8 kilograms (kg) | Standard Error 0.4 |
| Aripiprazole-DB | Change From Baseline to 24 Weeks in Body Weight | 0.4 kilograms (kg) | Standard Error 0.6 |
p-value: <0.001Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline NSA-16 Total Score measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in 16-Item Negative Symptom Assessment (NSA-16) | -6.22 units on a scale | Standard Error 0.68 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in 16-Item Negative Symptom Assessment (NSA-16) | -6.37 units on a scale | Standard Error 1.03 |
p-value: 0.891Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline AIMS 1-7 Total Score measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in Abnormal Involuntary Movement Scale (AIMS) | -0.11 units on a scale | Standard Error 0.05 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Abnormal Involuntary Movement Scale (AIMS) | -0.10 units on a scale | Standard Error 0.07 |
p-value: 0.924Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline BAS global score measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in Barnes Akathisia Scale (BAS) | 0.00 units on a scale | Standard Error 0.03 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Barnes Akathisia Scale (BAS) | -0.04 units on a scale | Standard Error 0.04 |
p-value: 0.353Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline CGI-S measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in Clinical Global Impression-Severity Scale (CGI-S) | -0.51 units on a scale | Standard Error 0.05 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Clinical Global Impression-Severity Scale (CGI-S) | -0.69 units on a scale | Standard Error 0.08 |
p-value: 0.055Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline VAS health state measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in EuroQol-5 Dimensions Questionnaire (EQ-5D) Visual Analog Scale (VAS) Health State Score | 4.2 units on a scale | Standard Error 1.4 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in EuroQol-5 Dimensions Questionnaire (EQ-5D) Visual Analog Scale (VAS) Health State Score | 3.1 units on a scale | Standard Error 2 |
p-value: 0.601Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline PSP measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in Personal and Social Performance (PSP) Score | 5.9 units on a scale | Standard Error 0.7 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Personal and Social Performance (PSP) Score | 6.4 units on a scale | Standard Error 1.1 |
p-value: 0.679Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline PANSS measurement, excluding participants from the excluded study site.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS Total Score | -12.03 units on a scale | Standard Error 0.99 |
| LY2140023-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS Positive Score | -3.40 units on a scale | Standard Error 0.32 |
| LY2140023-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS Negative Score | -2.98 units on a scale | Standard Error 0.31 |
| LY2140023-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS General Psychopathology Score | -5.80 units on a scale | Standard Error 0.56 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS General Psychopathology Score | -7.85 units on a scale | Standard Error 0.89 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS Total Score | -15.58 units on a scale | Standard Error 1.58 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS Negative Score | -3.34 units on a scale | Standard Error 0.48 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Positive and Negative Syndrome Scale (PANSS) Total and Subscale Scores | PANSS Positive Score | -4.62 units on a scale | Standard Error 0.5 |
p-value: 0.045Type III Tests
p-value: 0.032Type III Tests
p-value: 0.509Type III Tests
p-value: 0.04Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline SAS total score measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in Simpson-Angus Scale (SAS) | -0.17 units on a scale | Standard Error 0.06 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Simpson-Angus Scale (SAS) | -0.20 units on a scale | Standard Error 0.08 |
p-value: 0.698Type III Tests
Secondary
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.
Time frame: Baseline, 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline SWN-SF Total Score measurement, excluding participants from the excluded study site.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Change From Baseline up to 24 Weeks in Subjective Well-Being Under Neuroleptic Treatment Scale- Short Form (SWN-SF) Total Score | 4.6 units on a scale | Standard Error 1 |
| Aripiprazole-DB | Change From Baseline up to 24 Weeks in Subjective Well-Being Under Neuroleptic Treatment Scale- Short Form (SWN-SF) Total Score | 5.3 units on a scale | Standard Error 1.5 |
p-value: 0.63Type III Tests
Secondary
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.
Time frame: Baseline up to 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline PANSS measurement, excluding participants from the excluded study site. Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LY2140023-DB | Number of Participants With 30% or Greater Decrease in Positive and Negative Syndrome Scale (PANSS) Total Score | 133 participants |
| Aripiprazole-DB | Number of Participants With 30% or Greater Decrease in Positive and Negative Syndrome Scale (PANSS) Total Score | 49 participants |
Secondary
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).
Time frame: Baseline to 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline C-SSRS measurement, excluding participants from the excluded study site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2140023-DB | Number of Participants With Suicidal Behaviors and Ideations Measured by Columbia Suicide Severity Rating Scale (C-SSRS) | Treatment-Emergent Suicidal Ideation | 46 participants |
| LY2140023-DB | Number of Participants With Suicidal Behaviors and Ideations Measured by Columbia Suicide Severity Rating Scale (C-SSRS) | Treatment-Emergent Suicidal Behavior | 7 participants |
| Aripiprazole-DB | Number of Participants With Suicidal Behaviors and Ideations Measured by Columbia Suicide Severity Rating Scale (C-SSRS) | Treatment-Emergent Suicidal Ideation | 7 participants |
| Aripiprazole-DB | Number of Participants With Suicidal Behaviors and Ideations Measured by Columbia Suicide Severity Rating Scale (C-SSRS) | Treatment-Emergent Suicidal Behavior | 0 participants |
p-value: 0.064Fisher Exact
p-value: 0.205Fisher Exact
Secondary
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.
Time frame: Baseline up to 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline weight measurement, excluding participants from the excluded study site.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LY2140023-DB | Percentage of Participants With Clinically Significant Weight Change | ≥7% Increase | 4.1 percentage of participants |
| LY2140023-DB | Percentage of Participants With Clinically Significant Weight Change | ≥7% Decrease | 13.1 percentage of participants |
| Aripiprazole-DB | Percentage of Participants With Clinically Significant Weight Change | ≥7% Increase | 7.1 percentage of participants |
| Aripiprazole-DB | Percentage of Participants With Clinically Significant Weight Change | ≥7% Decrease | 3.2 percentage of participants |
p-value: 0.11Cochran-Mantel-Haenszel
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
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.
Time frame: Baseline to 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug and had S-RUM assessment, excluding participants from the excluded study site. Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| LY2140023-DB | Schizophrenia Resource Use Module (S-RUM) - Number of Sessions With a Psychiatrist | 0.39 sessions | Standard Error 0.07 |
| Aripiprazole-DB | Schizophrenia Resource Use Module (S-RUM) - Number of Sessions With a Psychiatrist | 0.41 sessions | Standard Error 0.11 |
p-value: 0.892Type III Tests
Secondary
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.
Time frame: Baseline to 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug and had S-RUM assessment, excluding participants from the excluded study site. Last observation carried forward (LOCF) principle was used.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| LY2140023-DB | Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | ER/Facility (Psych) visits | 0.06 visits | Standard Error 0.01 |
| LY2140023-DB | Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | ER/Facility (Non-Psych) visits | 0.06 visits | Standard Error 0.01 |
| LY2140023-DB | Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | Outpatient (Non-Psych or Dentist) visits | 0.28 visits | Standard Error 0.04 |
| Aripiprazole-DB | Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | ER/Facility (Psych) visits | 0.04 visits | Standard Error 0.02 |
| Aripiprazole-DB | Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | ER/Facility (Non-Psych) visits | 0.02 visits | Standard Error 0.02 |
| Aripiprazole-DB | Schizophrenia Resource Utilization Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits | Outpatient (Non-Psych or Dentist) visits | 0.30 visits | Standard Error 0.06 |
p-value: 0.322Type III Tests
p-value: 0.099Type III Tests
p-value: 0.787Type III Tests
Secondary
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.
Time frame: Randomization up to 24 weeks
Population: Modified intent-to-treat (mITT) population: All randomized participants who received at least one dose of study drug, excluding participants from the excluded study site. Participants who completed the study were considered censored: 229 for LY2140023 group and 84 for Aripiprazole group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| LY2140023-DB | Time to Discontinuation | 140 days |
| Aripiprazole-DB | Time to Discontinuation | 169 days |