A Safety Study Comparing LY2140023 to Atypical Antipsychotic Standard Treatment in Schizophrenic Patients

EEG scoring by a central neurologist is done by the following definitions: E0=Normal; E1(within normal)=fewer than 3 focal abnormalities or non-epileptiform abnormalities; E2(questionably epileptiform)=3-10 focal discharges and/or 1-10 multifocal or generalized discharges; E3=(clearly epileptiform)= Sharp/slow complex, runs of epileptiform abnormalities, greater than 10 total epileptiform discharges; and E4= seizure. Decreased= maximum (max) post-baseline (PB) EEG grading< baseline EEG grading; Increased= max PB EEG grading> baseline EEG grading; Same=no change from baseline to max PB result.

A potentially clinically significant QT interval (high) is defined as a value meeting the criteria of (> 450 millisecond [ms]) at anytime during the active treatment phase, provided it does not meet the criteria at baseline.

(analysis for Study Period III only)

An increase in score from baseline was considered a treatment-emergent change, unless stated otherwise. Tremor: 0 (absent) - 3 (interferes with motor function); Nystagmus: 0 (absent) - 3 (present on forward gaze); Reflexes: 0 (absent) - 4 (clonic) with normal being a score 2, decrease or increase in score was considered change. Finger-nose and gait tests: 0 (normal) - 1(abnormal); Romberg's sign: (0) absent - (1) present; Muscular strength: 0 (no contraction)-5 (full/normal resistance), decrease in score was considered change; Myoclonic jerks: 0 (absent) - 3 (frequent).

Least Square (LS) Mean of change from baseline in BP is from a mixed model repeated measures (MMRM) model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.

LS Mean of change from baseline in weight is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline weight and baseline-by-visit interaction.

LS Mean of change from baseline in pulse rate is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline value and baseline-by-visit interaction.

Treatment-emergent changes in lab results on fasting glucose were analyzed using the American Diabetes Association (ADA 2001) and National Cholesterol Education Program (NCEP ATP III) guidelines. Glucose Normal to High is <100 milligram/deciliter (mg/dL) at baseline and ≥126mg/dL post-baseline.

Treatment-emergent changes in lab results on lipids level were analyzed using the American Diabetes Association (ADA 2001) and National Cholesterol Education Program (NCEP ATP III) guidelines. Total cholesterol Normal to High is <200 mg/dL at baseline and ≥240 mg/dL post-baseline. Low-density lipoprotein (LDL) cholesterol Normal to High is <100 mg/dL at baseline and ≥160 mg/dL post-baseline. High-density lipoprotein (HDL) cholesterol Normal to Low is ≥40 mg/dL at baseline and <40 mg/dL post-baseline. Triglycerides Normal to High is <150 mg/dL at baseline and ≥200 mg/dL post-baseline.

Columbia Suicide Rating Scale (C-SSRS): scale capturing occurrence, severity, and frequency of suicide-related thoughts and behaviors. Number of participants with suicidal behaviors and ideations are provided. 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. Suicidal ideation: a "yes" answer to any one of 5 suicidal ideation questions, which includes wish to be dead, and 4 different categories of active suicidal ideation. There are no scores on a scale reported, rather, number of patients who reported "yes" as described above.

Assesses the positive and negative symptoms and general psychopathology associated with schizophrenia. The scale consists of 30 items. Each item is rated on a scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210. LS Mean of change from baseline is from a mixed model repeated measures (MMRM) model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline score and baseline-by-visit interaction. Higher PANSS scores mean worse symptoms.

The CGI-S scale measures severity of illness at the time of assessment compared with start of treatment. Scores range from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). LS Mean of change from baseline is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline score and baseline-by-visit interaction. Higher CGI-S score means worse symptoms.

The NSA-16 is used to rate behaviors (not psychopathology) associated with negative symptoms of schizophrenia and rates patients on 16 "anchors", each of which is rated 1 to 6. The total score is their sum and ranges from 16 to 96. Higher scores indicate greater severity of illness. LS Mean of change from baseline is from a MMRM model which includes treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline score and baseline-by-visit interaction.

The MCCB assesses cognitive function in 7 domains important in schizophrenia. The MCCB overall composite score is calculated by summing age- and gender-corrected T-scores of all the domains and then standardizing the sum to a T-score, where the mean is 50 and a standard deviation is 10. A higher score indicates better performance. LS Mean of change from baseline is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline score and baseline-by-visit interaction.

The MADRS is a rating scale for severity of depressive mood symptoms. The MADRS has a 10-item checklist. Items are rated on a scale of 0-6, for a total score range of 0 (low severity of depressive symptoms) to 60 (high severity of depressive symptoms). LS Mean of changes from baseline is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline score and baseline-by-visit interaction. Higher MADRS scores mean worse symptoms.

The UPSA-B is a performance-based assessment of improvement in functional capacity. Patients are asked to role-play tasks in 2 areas of functioning: communication and finances. Scores are assigned for each of the 2 subscales and a provided formulae is used to calculated an UPSA-B Total Score (range = 0-100). The higher score indicates a better performance. LS mean of change from baseline is from a MMRM model which includes the effects of treatment, gender, investigator site, visit, treatment-by-visit interaction, baseline score and baseline score by-visit interaction.

Response is defined as reduction ≥ 30% from baseline on PANSS Total Score (Each PANSS item transformed to a 0-6 scale first). 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 an original scale from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30 to 210. Higher scores indicate greater severity of illness. (Analysis for Study Period III only)

Remission is defined as endpoint score of mild or better (≤3) for each of the following PANSS items: delusions, conceptual disorganization, hallucinatory behavior, social withdrawal, blunted affect, lack of spontaneity and flow of conversation, mannerisms and posturing, and unusual thought content. PANSS assesses the positive and negative symptoms and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated from 1 (symptom not present) to 7 (extremely severe). The sum of the 30 items is the PANSS total score and ranges 30 - 210. (Analysis for Study Period III only)

Relapse is defined as an increase in at least one PANSS positive item to a score>5 and an absolute increase of ≥2 points on that item post randomization , or hospitalization for any psychiatric condition, or active suicidal ideation or suicidal behavior as captured by the C-SSRS. PANSS assesses the positive and negative symptoms and general psychopathology specifically associated with schizophrenia. The scale consists of 30 items. Each item is rated from 1 (symptom not present) to 7 (symptoms extremely severe). The sum of the 30 items is defined as the PANSS total score and ranges from 30-210.

Measures subjective well-being for previous 7 days. 20 items covering 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). Subscale scores range from 4 to 24. Total score ranges from 20 to 120. LS mean of change from baseline is from a MMRM model which includes the effects of treatment, gender, investigator site, visit, treatment-by-visit interaction, baseline score and baseline score by-visit interaction.

The Personal and Social Performance (PSP) scale is a 100-point, single-item, clinician-rated scale to assess 4 domains of functioning, including personal and social relationships, socially useful activities, self care, and disturbing and aggressive behaviors. Score ranges from 1-100. The higher score indicates a better health state. LS Mean of changes from baseline is from a MMRM model which includes the effects of treatment, gender, investigator site, visit, treatment-by-visit interaction, baseline score and baseline score by-visit interaction.

The EQ-5D is a quality-of-life (QoL) instrument with 2 parts: a health status profile and a visual analog scale (VAS). The profile rates patients' health state in 5 domains and each of them ranges 1-3. The outcomes on the 5 domains are mapped to an index with range 0-1. The higher score indicates a better health state. The VAS is used to indicate the patient's health status with range 0=worst and 100=best. LS means are from a MMRM model with the effects of treatment, gender, investigator site, visit, treatment-by-visit interaction, baseline score and baseline score by-visit interaction.

Change in number of psychiatric visits between the 6 months prior to the active treatment phase and psychiatric visits reported during the active treatment phase was summarized. Treatment groups were compared on change using the analysis of covariance (ANCOVA) model. The model has baseline as a covariate, and investigative site, gender, and treatment as fixed effects. (Analysis for Study Period III only)

The BAS rates drug induced akathisia symptoms. Akathisia is rated on a 4-point scale, with 0 being no akathisia and 3 being severe akathisia. A global clinical assessment of akathisia is then scored on a 6-point scale, with 0 being no evidence of akathisia and 5 being severe akathisia. LS mean of change from baseline in BAS global score is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline and baseline-by-visit interaction.

The SAS is used to measure Parkinsonian type symptoms in patients exposed to antipsychotics. The scale consists of 10 items each rated on a 5-point scale, with 0 meaning complete absence of the condition and 4 meaning the presence of the condition in extreme form. The range of possible total score is 0-40. LS Mean of change from baseline in the SAS total score is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline and baseline-by-visit interaction.

The AIMS is a 12-item scale designed to record the occurrence of dyskinetic movements. Items 1 to 10 are rated 0 - 4, with 0 being no dyskinetic movements and 4 being severe dyskinetic movements. Items 11 and 12 are yes/no questions regarding the dental condition of a subject. The total score is the sum of items 1-7 and ranges from 0-28. LS means of change from baseline in the AIMS total score is from a MMRM model which includes the effects of treatment, gender, investigative site, visit, treatment-by-visit interaction, baseline and baseline-by-visit interaction.