A Study of LY2140023 in Schizophrenia Patients With Prominent Negative Symptoms

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 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 Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline NSA-16 total score, and baseline NSA-16 total score\*visit.

Time frame: Baseline, randomization treatment Week 16

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.

The 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, 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 AIMS 1-7 total score is the total of items 1 through 7 of the AIMS, and ranges from 0 to 28. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline AIMS 1-7 total score, and baseline AIMS 1-7 total score\*visit.

Time frame: Baseline, randomization treatment Week 16

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.

The BAS is a 4-item instrument that evaluates akathisia associated with use of antipsychotic medications. Item 4 is the Global Clinical Assessment and is rated 0 to 5 (0 = absent, 5 = severe). The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline BAS global score, and baseline BAS global score\*visit.

Time frame: Baseline, randomization treatment Week 16

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.

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 Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline CGI-S score, and baseline CGI-S score\*visit.

Time frame: Baseline, randomization treatment Week 16

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.

MCCB is an instrument that contains 10 tests to measure cognitive performance in 7 cognitive domains: speed processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning and problem solving, and social cognition. The MCCB overall composite T-score combines the individual scores of the 10 tests and scores them on a normative scale to derive a T-score, where the mean is 50 and a standard deviation is 10 for the MCCB overall composite T-score. Higher scores indicate better cognition. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline MCCB overall composite T-score, and baseline MCCB overall composite T-score\*visit.

Time frame: Baseline, randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline MCCB overall composite T-score measurement.

The PANSS Scale consists of 30 items and is designed to measure the severity of psychopathology in schizophrenia. 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 and has a score ranging from 30 to 210. Higher scores indicate greater severity of illness. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline PANSS total score, and baseline PANSS total score\*visit.

Time frame: Baseline, randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline PANSS total score measurement.

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, with 0 meaning complete absence of the condition and 4 meaning the presence of the condition in extreme form. The 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 Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline SAS total score, and baseline SAS total score\*visit.

Time frame: Baseline, randomization treatment Week 16

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.

The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline standing BP, and baseline standing BP\*visit.

Time frame: Baseline, randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline standing BP measurement.

The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline standing pulse rate, and baseline standing pulse rate\*visit.

Time frame: Baseline, randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline standing pulse rate measurement.

The UPSA-B is a performance-based assessment of improvement in functional capacity. Participants are asked to role-play tasks in 2 areas of functioning: communication and finances. Raw scores for the 2 subscales are converted into an UPSA-B Total Score (range = 0-100) with higher scores indicating a greater level of functional capacity. Scores of 75 or higher are associated with independent living. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline UPSA-B total score, and baseline UPSA-B total score\*visit.

Time frame: Baseline, randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline UPSA-B total score measurement.

The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline weight, and baseline weight\*visit.

Time frame: Baseline, randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline weight measurement.

The PSP scale is a 100-point, 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. The higher scores indicate a higher level of functioning. The Mixed Model Repeated Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline PSP score, and baseline PSP score\*visit.

Time frame: Baseline, randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline PSP measurement.

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 Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline VAS health state score, and baseline VAS health state score\*visit.

Time frame: Baseline, randomization treatment Week 16

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.

The SWN-SF measures subjective well-being 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 Measure (MMRM) analysis was used to calculate Least Squares (LS) mean and standard error. LS mean values are controlled for visit, pooled investigative site, treatment, standard of care (SOC) type, baseline positive symptom stratum, treatment\*visit, baseline SWN-SF total score, and baseline SWN-SF total score\*visit.

Time frame: Baseline, randomization treatment Week 16

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.

Incidence of epileptiform activity outside of normal range in EEGs is based on the changes from normal (E0) or within normal range (E1) at baseline to questionably epileptiform (E2) or clearly epileptiform (E3) or seizure (E4) post-baseline. E0 = Normal; E1 (within normal range) = fewer than 3 focal abnormalities or non-epileptiform abnormalities; E2 (questionably epileptiform) = 3 to 10 focal discharges and/or 1 to 10 multifocal or generalized discharges; E3 (clearly epileptiform) = Sharp/slow complex, runs of epileptiform abnormalities, greater than 10 total epileptiform discharges; and E4 = seizure.

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline EEG measurement.

QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. QTcF is the QT interval corrected for heart rate using the Fridericia formula. A potentially clinically significant change in QTcF is defined as \>450 milliseconds (ms) for male and \>470 ms for female.

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline ECG QTcF measurement.

PCS change in laboratory values were defined as a laboratory value which reached a predefined alert level at any time post-baseline. PCS change in total cholesterol: Normal (N) to High (H) \<200 milligrams/deciliter (mg/dL) at baseline and ≥240 mg/dL post-baseline; Borderline (B) to H ≥200 mg/dL and \<240 mg/dL at baseline and ≥240 mg/dL post-baseline; N/B to H \<240 mg/dL at baseline and ≥240 mg/dL post-baseline; N to B/H \<200 mg/dL at baseline, ≥200 mg/dL post-baseline. PCS change in low-density lipoprotein (LDL) cholesterol: N to H \<100 mg/dL at baseline and ≥160 mg/dL post-baseline; B to H ≥100 mg/dL and \<160 mg/dL at baseline and ≥160 mg/dL post-baseline; N/B to H \<160 mg/dL at baseline and ≥160 mg/dL post-baseline; N to B/H \<100 mg/dL at baseline, ≥100 mg/dL post-baseline. PCS change in high-density lipoprotein (HDL) cholesterol: ≥40 mg/dL at baseline and \<40 mg/dL post-baseline.

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had normal or borderline cholesterol level at baseline and at least one post-baseline cholesterol measurement. Number represents number of participants with an incidence of potentially clinically significant (PCS) change in laboratory values

PCS change in laboratory values were defined as a laboratory value which reached a predefined alert level at any time post-baseline. PCS change for Normal to High: \<100 milligrams/deciliter (mg/dL) at baseline and ≥126 mg/dL post-baseline; Impaired to High ≥100 mg/dL and \<126 mg/dL at baseline and ≥126 mg/dL any time post-baseline; Normal/Impaired to High \<126 mg/dL at baseline and ≥126 mg/dL any time post-baseline.

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had normal or impaired glucose level at baseline and at least 1 post-baseline glucose measurement. Number represents number of participants with an incidence of potentially clinically significant (PCS) change in laboratory values

PCS change in laboratory values were defined as a laboratory value which reached a predefined alert level at any time post-baseline. PCS change for Normal (N) to High (H) \<150 milligrams/deciliter (mg/dL) at baseline and ≥200 mg/dL post-baseline; N/Borderline (B) to H \<200 mg/dL at baseline and ≥200 mg/dL post-baseline; N to very H \<150 mg/dL at baseline and ≥500 mg/dL post-baseline; B to H \>150 and \<200 mg/dL at baseline and ≥200 mg/dL post-baseline; B to very H \>150 and \<200 mg/dL at baseline and ≥500 mg/dL post-baseline; N/B to very H \<200 mg/dL at baseline and ≥500 mg/dL post-baseline; N to B/H/very H \<150 mg/dL at baseline and ≥150 mg/dL post-baseline.

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had normal or borderline triglycerides level at baseline and at least one post-baseline triglycerides measurement. Number represents number of participants with an incidence of potentially clinically significant (PCS) change in laboratory values

PCS change in laboratory values were defined as a laboratory value which reached a predefined alert level at any time post-baseline. PCS change in liver function: alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥2\* the upper limit of normal (ULN) or total bilirubin ≥1.5\*ULN any time post-baseline regardless of the baseline value. Hy's rule: ALT ≥3\*ULN, total bilirubin ≥1.5\*ULN and alkaline phosphatase \<2\*ULN at the same time any time post-baseline regardless of the baseline value. PCS change in eosinophil counts: \>1.5\*10³ cells/microliter any time post-baseline regardless of the baseline value. PCS change in blood creatine phosphokinase: ≥5\*ULN any time post-baseline regardless of the baseline value.

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug and had at least one post-baseline laboratory measurement.

Neurological change from baseline was assessed using a 17-item neurological examination and defined as treatment-emergent tremor \[increased score on any Item 1- 5; each ranged from 0 (absent) to 3 (interferes with motor function)\], nystagmus \[increased score for Item 6 or 7; each ranged 0 (absent) to 3 (present on forward gaze)\], increased reflexes \[increased score and absolute score \>2 on any Item 8-11; each ranged 0 (absent) to 4 (clonic)\], decreased reflexes \[decreased score and absolute score \<2 on any Item 8-11; each ranged 0 (absent) to 4 (clonic)\], abnormal finger-nose test (Item 12; normal to abnormal), Romberg's sign (Item 13; absent to present), abnormal gait (Item 14; normal to abnormal), decreased muscle strength \[decreased score for Item 15 or 16; each ranged 0 (no muscle contraction) to 5 (full and normal power against resistance)\], myoclonic jerks \[increased score for Item 17; ranged from 0 (absent) to 3 (frequent and across several body regions)\].

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug, had a baseline and at least one post-baseline neurological examination.

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. Percentage of participants with incidence of potentially clinically significant change of the C-SSRS was calculated as the number of participants with an increase in suicidal behavior or ideation over baseline, divided by the total number of participants multiplied by 100.

Time frame: Baseline to randomization treatment Week 16

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.

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).

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug and had S-RUM assessment.

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.

Time frame: Baseline to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug and had S-RUM assessment.

The time to discontinuation due to any reason was defined as the total number of days between the date of first dose and discontinuation date. The time to discontinuation was analyzed using Kaplan-Meier estimated survival curves. Participants who completed the study were considered censored. Less than 50% of participants discontinued from study at randomization treatment Week 16 endpoint, therefore median values were not calculated.

Time frame: First dose to randomization treatment Week 16

Population: All randomized participants who received at least one dose of study drug. Participants who completed the study were considered censored: 50 for LY2140023 + SOC group and 60 for placebo + SOC group.