A Study of LY2140023 in Schizophrenia Patients With Prominent Negative Symptoms

• Sponsor: Denovo Biopharma LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01052103
• Collaborator: (none)
• Enrollment: 167
• Locations: 9
• Arms: 2
• Duration (Months): 29
• Patients Per Site: 18.6
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether LY2140023, when added to standard-of-care antipsychotic treatment, will improve negative symptoms.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: LY2140023; Drug: Placebo; Drug: Standard of Care	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 167 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A 17-Week, Phase 2, Multicenter, Randomized, Double-Blind Study of Treatment With LY2140023 Combined With Standard of Care (SOC) Compared to Placebo With SOC in the Treatment of Patients With Prominent Negative Symptoms of Schizophrenia
• Study Start Date: Jan 1, 2010
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY2140023	Drug: LY2140023; 40 milligrams (mg), oral tablets, twice daily: 20 mg in the morning, 20 mg in the evening, for 16 or 17 weeks. The dose may be adjusted to a minimum of 20 mg or a maximum of 80 mg.; Drug: Standard of Care; United States (U.S.) label prescribed dose of one of the following Standard of Care Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine); Other Names: Zyprexa LY170053
Placebo Comparator: Placebo	Drug: Placebo; Placebo oral tablets, twice daily: in the morning and in the evening, for 16 or 17 weeks.; Drug: Standard of Care; United States (U.S.) label prescribed dose of one of the following Standard of Care Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine); Other Names: Zyprexa LY170053

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the 16-Item Negative Symptoms Assessment (NSA-16) [Baseline, randomization treatment Week 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 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.

Secondary Outcome Measures

1. Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score [Baseline, randomization treatment Week 16]

   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.

2. Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale [Baseline, randomization treatment Week 16]

   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.

3. Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) Overall Composite T-Score [Baseline, randomization treatment Week 16]

   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.

4. Change From Baseline in University of California at San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) Total Score [Baseline, randomization treatment Week 16]

   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.

5. Change From Baseline in Barnes-Akathisia Scale (BAS) Global Score [Baseline, randomization treatment Week 16]

   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.

6. Change From Baseline in Simpson Angus Scale (SAS) Total Score [Baseline, randomization treatment Week 16]

   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.

7. Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score [Baseline, randomization treatment Week 16]

   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.

8. Number of Participants With Incidence of Epileptiform Activity Outside of Normal Range in Electroencephalograms (EEGs) [Baseline to randomization treatment Week 16]

   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.

9. Number of Participants With Incidence of Potentially Clinically Significant Changes in Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) Electrocardiograms (ECGs) [Baseline to randomization treatment Week 16]

   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.

10. Percentage of Participants With a Worsening of Neurological Symptoms From Baseline to Endpoint on the Neurological Examination [Baseline to randomization treatment Week 16]

    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)].

11. Change From Baseline in Standing Blood Pressure (BP) [Baseline, randomization treatment Week 16]

    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.

12. Change From Baseline in Standing Pulse Rate [Baseline, randomization treatment Week 16]

    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.

13. Change From Baseline in Weight [Baseline, randomization treatment Week 16]

    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.

14. Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - General [Baseline to randomization treatment Week 16]

    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.

15. Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - Fasting Cholesterol [Baseline to randomization treatment Week 16]

    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.

16. Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - Fasting Triglycerides [Baseline to randomization treatment Week 16]

    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.

17. Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - Fasting Glucose [Baseline to randomization treatment Week 16]

    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.

18. Percentage of Participants With Incidence of Potentially Clinically Significant Change of Columbia-Suicide Severity Rating Scale (C-SSRS) [Baseline to randomization treatment Week 16]

    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.

19. Change From Baseline to Endpoint in Personal and Social Performance (PSP) Scale [Baseline, randomization treatment Week 16]

    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.

20. Time to Discontinuation From the Study Due to Any Reason [First dose to randomization treatment Week 16]

    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.

21. Schizophrenia Resource Use Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits [Baseline to randomization treatment Week 16]

    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).

22. Schizophrenia Resource Use Module (S-RUM) - Number of Sessions With a Psychiatrist [Baseline to randomization treatment Week 16]

    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.

23. Change From Baseline to Endpoint in the EuroQol Questionnaire-5 Dimension (EQ-5D) Visual Analog Scale (VAS) Health State Score [Baseline, randomization treatment Week 16]

    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.

24. Change From Baseline to Endpoint in the Subjective Well-Being Under Neuroleptic Treatment-Short Form (SWN-SF) Total Score [Baseline, randomization treatment Week 16]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Clinical diagnosis of schizophrenia

• Participants must have been receiving monotherapy treatment for at least 3 months prior to study entry with one of 4 atypical antipsychotic medications (aripiprazole, olanzapine, risperidone, quetiapine)

• Disease symptoms must meet a certain range as assessed by the clinician

• Participants must have evidence of prominent negative symptoms of schizophrenia (for example blunted affect, emotional withdrawal, or motor retardation)

• 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 informed consent

Exclusion Criteria:

• Participants who are actively suicidal

• Participants who are pregnant or nursing

• Participants who have had electroconvulsive therapy (ECT) within 3 months of screening or who will have ECT at any time during the study

• 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 with Parkinson's disease, psychosis related to dementia or related disorders

• Participants with known Human Immunodeficiency Virus positive (HIV+) status

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Garden Grove	California	United States	92845
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Chicago	Illinois	United States	60640
3	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Hoffman Estates	Illinois	United States	60169
4	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	New York	New York	United States	10035
5	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Jerusalem		Israel	91060
6	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Parma		Italy	43100
7	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Torino		Italy	10126
8	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Barcelona		Spain	08036
9	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Zamora		Spain	49021

Sponsors and Collaborators

• Denovo Biopharma LLC

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Denovo Biopharma LLC
• ClinicalTrials.gov Identifier: NCT01052103
• Other Study ID Numbers: 13261; H8Y-MC-HBCO
• First Posted: Jan 20, 2010
• Last Update Posted: Sep 22, 2021
• Last Verified: Jul 1, 2012

• Additional relevant MeSH terms: Schizophrenia; Olanzapine

Study Results

Participant Flow

Pre-assignment Detail	This study consisted of a 1-week placebo lead-in period and a 16-week randomization treatment period.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Period Title: Overall Study
STARTED	84	83
Received at Least 1 Dose of Study Drug	82	82
COMPLETED	50	60
NOT COMPLETED	34	23

Baseline Characteristics

Arm/Group Title	LY2140023 + SOC	Placebo + SOC	Total
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.	Total of all reporting groups
Overall Participants	82	82	164
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.7 (11.22)	42.8 (10.23)	43.3 (10.71)
Sex: Female, Male (Count of Participants)
Female	19 23.2%	18 22%	37 22.6%
Male	63 76.8%	64 78%	127 77.4%
Race/Ethnicity, Customized (participants) [Number]
Asian	0 0%	1 1.2%	1 0.6%
Black or African American	41 50%	43 52.4%	84 51.2%
Multiple	0 0%	2 2.4%	2 1.2%
White	41 50%	35 42.7%	76 46.3%
Missing	0 0%	1 1.2%	1 0.6%
Region of Enrollment (participants) [Number]
United States	58 70.7%	61 74.4%	119 72.6%
Spain	9 11%	7 8.5%	16 9.8%
Israel	11 13.4%	9 11%	20 12.2%
Italy	2 2.4%	2 2.4%	4 2.4%
Puerto Rico	2 2.4%	3 3.7%	5 3%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the 16-Item Negative Symptoms Assessment (NSA-16)
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	81	82
Least Squares Mean (Standard Error) [units on a scale]	-2.7 (1.2)	-3.6 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.732
	Comments	One-sided p-value.
	Method	Type 3 Tests
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	1.0
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.6
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023, orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	81	82
Least Squares Mean (Standard Error) [units on a scale]	-4.4 (1.62)	-6.6 (1.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.846
	Comments	One-sided p-value.
	Method	Type 3 Tests
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	2.2
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.10
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Clinical Global Impression Severity (CGI-S) Scale
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023, orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Least Squares Mean (Standard Error) [units on a scale]	-0.4 (0.1)	-0.3 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.201
	Comments	One-sided p-value.
	Method	Type 3 Tests
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	-0.1
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline in Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery (MCCB) Overall Composite T-Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	58	56
Least Squares Mean (Standard Error) [units on a scale]	3.2 (1.0)	1.8 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.136
	Comments	One-sided p-value.
	Method	Type 3 Tests
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	1.4
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.3
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in University of California at San Diego Performance-Based Skills Assessment-Brief Version (UPSA-B) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	62	65
Least Squares Mean (Standard Error) [units on a scale]	6.5 (1.9)	4.9 (1.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.739
	Comments	One-sided p-value.
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	1.5
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.4
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Barnes-Akathisia Scale (BAS) Global Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Least Squares Mean (Standard Error) [units on a scale]	-0.1 (0.0)	0.0 (0.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.190
	Comments
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	-0.1
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.1
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Simpson Angus Scale (SAS) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Least Squares Mean (Standard Error) [units on a scale]	-0.2 (0.2)	-0.1 (0.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.702
	Comments
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	-0.1
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Abnormal Involuntary Movement Scale (AIMS) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Least Squares Mean (Standard Error) [units on a scale]	0.0 (0.2)	0.1 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.851
	Comments
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	0.0
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.2
	Estimation Comments

9. Secondary Outcome

Title	Number of Participants With Incidence of Epileptiform Activity Outside of Normal Range in Electroencephalograms (EEGs)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	80	82
Number [participants]	1 1.2%	0 0%

10. Secondary Outcome

Title	Number of Participants With Incidence of Potentially Clinically Significant Changes in Corrected (for Rate) Cardiac QT Interval Using Fridericia's Formula (QTcF) Electrocardiograms (ECGs)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	81	82
Number [participants]	3 3.7%	1 1.2%

11. Secondary Outcome

Title	Percentage of Participants With a Worsening of Neurological Symptoms From Baseline to Endpoint on the Neurological Examination
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Tremor	11.0 13.4%	12.2 14.9%
Nystagmus	2.4 2.9%	2.4 2.9%
Increased Reflexes	3.7 4.5%	4.9 6%
Decreased Reflexes	7.3 8.9%	8.5 10.4%
Abnormal Finger-Nose Test	1.2 1.5%	3.7 4.5%
Romberg's Sign	1.2 1.5%	0.0 0%
Abnormal Gait	2.4 2.9%	2.4 2.9%
Decreased Muscle Strength	3.7 4.5%	4.9 6%
Myoclonus Jerks	4.9 6%	2.4 2.9%

12. Secondary Outcome

Title	Change From Baseline in Standing Blood Pressure (BP)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Standing Systolic BP	-2.0 (1.6)	-2.0 (1.6)
Standing Diastolic BP	1.4 (1.1)	-2.4 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.999
	Comments	P-value is for standing systolic BP.
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -4.3 to 4.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	P-value is for standing diastolic BP.
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; 1.0 to 6.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Change From Baseline in Standing Pulse Rate
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Least Squares Mean (Standard Error) [beats per minute (bpm)]	-2.3 (1.7)	-1.8 (1.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.818
	Comments
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -5.0 to 3.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Change From Baseline in Weight
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	81	81
Least Squares Mean (Standard Error) [kilograms (kg)]	-1.25 (0.56)	-0.81 (0.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.571
	Comments
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -1.98 to 1.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - General
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
ALT	4 4.9%	5 6.1%
AST	1 1.2%	3 3.7%
Total bilirubin	2 2.4%	0 0%
Hy's rule	0 0%	0 0%
Eosinophil counts	0 0%	0 0%
Blood creatine phosphokinase	7 8.5%	7 8.5%

16. Secondary Outcome

Title	Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - Fasting Cholesterol
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023, orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	73	68
Total Cholesterol N to H (n=35, 42)	1 1.2%	0 0%
Total Cholesterol B to H (n=36, 25)	8 9.8%	7 8.5%
Total Cholesterol N/B to H (n=71, 67)	9 11%	7 8.5%
Total Cholesterol N to B/H (n=35, 42)	9 11%	9 11%
LDL Cholesterol N to H (n=22, 13)	0 0%	0 0%
LDL Cholesterol B to H (n=42, 55)	13 15.9%	13 15.9%
LDL Cholesterol N/B to H (n=64, 68)	13 15.9%	13 15.9%
LDL Cholesterol N to B/H (n=22, 13)	9 11%	2 2.4%
HDL Cholesterol N to Low (n=73, 66)	24 29.3%	24 29.3%

17. Secondary Outcome

Title	Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - Fasting Triglycerides
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023, orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	67	59
N to H (n=51, 45)	10 12.2%	7 8.5%
N/B to H (n=67, 59)	20 24.4%	13 15.9%
N to very H (n=51, 45)	0 0%	0 0%
B to H (n=16, 14)	10 12.2%	6 7.3%
B to very H (n=16, 14)	0 0%	0 0%
N/B to very H (n=67, 59)	0 0%	0 0%
N to B/H/very H (n=51, 45)	18 22%	17 20.7%

18. Secondary Outcome

Title	Number of Participants With Incidence of Potentially Clinically Significant (PCS) Change in Laboratory Values Any Time Post-Baseline - Fasting Glucose
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023, orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	74	76
Normal to High (n=39, 46)	2 2.4%	8 9.8%
Impaired to High (n=35, 30)	10 12.2%	5 6.1%
Normal/Impaired to High (n=74, 76)	12 14.6%	13 15.9%

19. Secondary Outcome

Title	Percentage of Participants With Incidence of Potentially Clinically Significant Change of Columbia-Suicide Severity Rating Scale (C-SSRS)
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Treatment-Emergent Suicidal Ideation	2.4 2.9%	4.9 6%
Treatment-Emergent Suicidal Behavior	0.0 0%	1.2 1.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.682
	Comments	P-value is for treatment-emergent suicidal ideation.
	Method	Fisher Exact
	Comments

20. Secondary Outcome

Title	Change From Baseline to Endpoint in Personal and Social Performance (PSP) Scale
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	75	77
Least Squares Mean (Standard Error) [units on a scale]	8.9 (1.3)	7.9 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.727
	Comments	One-sided p-value.
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	1.0
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.7
	Estimation Comments

21. Secondary Outcome

Title	Time to Discontinuation From the Study Due to Any Reason
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	82	82
Median (Full Range) [months]	NA	NA

22. Secondary Outcome

Title	Schizophrenia Resource Use Module (S-RUM) - Number of Emergency Room (ER) or Equivalent Facility Visits and Outpatient Medical Visits
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	80	80
ER/Facility (Psych) visits	0.6 (4.11)	0.2 (1.79)
ER/Facility (Non-Psych) visits	0.2 (0.43)	0.1 (0.56)
Outpatient (Non-Psych or Dentist) visits	0.7 (1.33)	1.2 (2.99)

23. Secondary Outcome

Title	Schizophrenia Resource Use Module (S-RUM) - Number of Sessions With a Psychiatrist
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	80	80
Mean (Standard Deviation) [sessions]	3.4 (17.49)	1.5 (2.76)

24. Secondary Outcome

Title	Change From Baseline to Endpoint in the EuroQol Questionnaire-5 Dimension (EQ-5D) Visual Analog Scale (VAS) Health State Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	74	77
Least Squares Mean (Standard Error) [units on a scale]	3.7 (2.6)	5.4 (2.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.305
	Comments	One-sided p-value.
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	-1.7
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.4
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline to Endpoint in the Subjective Well-Being Under Neuroleptic Treatment-Short Form (SWN-SF) Total Score
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	LY2140023 + SOC	Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).	1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
Measure Participants	73	75
Least Squares Mean (Standard Error) [units on a scale]	3.9 (2.0)	4.4 (1.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LY2140023 + SOC, Placebo + SOC
	Comments	Changes from baseline to all post-baseline visits were analyzed using a restricted maximum likelihood-based MMRM. Model terms included fixed class effects for visit, investigative site, treatment, SOC type, baseline positive symptom stratum, and treatment-by-visit interaction as well as the continuous, fixed covariates of baseline measurement and baseline-by-visit interaction.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.420
	Comments	One-sided p-value.
	Method	Type 3 Sums of Squares
	Comments
Method of Estimation	Estimation Parameter	LS Mean Differences
	Estimated Value	-0.5
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.5
	Estimation Comments

Adverse Events

Arm/Group Title	LY2140023 + SOC		Placebo + SOC
Arm/Group Description	1 week placebo lead-in period followed by 20 milligrams (mg) LY2140023 orally, twice daily for 16 weeks (40 mg/day) treatment period. The dose was allowed to adjust to a minimum of 20 mg/day or a maximum of 80 mg/day plus one of the following Standard of Care (SOC) Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling).		1 week placebo lead-in period followed by placebo orally, twice daily for 16 weeks (40 mg/day) plus one of the following SOC Antipsychotics (aripiprazole, olanzapine, risperidone, quetiapine) taken per label (United States labeling) during the treatment period.
All Cause Mortality
	LY2140023 + SOC		Placebo + SOC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LY2140023 + SOC		Placebo + SOC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/82 (9.8%)		4/82 (4.9%)
Hepatobiliary disorders
Cholangitis	1/82 (1.2%)	1	0/82 (0%)	0
Infections and infestations
Cellulitis	1/82 (1.2%)	1	0/82 (0%)	0
Nervous system disorders
Ischaemic stroke	0/82 (0%)	0	1/82 (1.2%)	1
Psychiatric disorders
Psychotic disorder	3/82 (3.7%)	3	1/82 (1.2%)	1
Schizophrenia	3/82 (3.7%)	3	1/82 (1.2%)	1
Suicidal ideation	0/82 (0%)	0	1/82 (1.2%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/82 (0%)	0	1/82 (1.2%)	1
Other (Not Including Serious) Adverse Events
	LY2140023 + SOC		Placebo + SOC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	54/82 (65.9%)		51/82 (62.2%)
Gastrointestinal disorders
Abdominal discomfort	3/82 (3.7%)	3	0/82 (0%)	0
Diarrhoea	5/82 (6.1%)	5	2/82 (2.4%)	3
Dry mouth	2/82 (2.4%)	2	9/82 (11%)	9
Nausea	11/82 (13.4%)	12	4/82 (4.9%)	4
Toothache	1/82 (1.2%)	1	3/82 (3.7%)	3
Vomiting	10/82 (12.2%)	13	2/82 (2.4%)	7
General disorders
Fatigue	1/82 (1.2%)	1	4/82 (4.9%)	4
Pain	3/82 (3.7%)	3	0/82 (0%)	0
Infections and infestations
Nasopharyngitis	3/82 (3.7%)	3	4/82 (4.9%)	4
Upper respiratory tract infection	1/82 (1.2%)	1	3/82 (3.7%)	5
Vulvovaginal mycotic infection	1/19 (5.3%)	1	0/18 (0%)	0
Investigations
Blood creatine phosphokinase increased	6/82 (7.3%)	6	7/82 (8.5%)	7
Weight increased	3/82 (3.7%)	3	1/82 (1.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	2/82 (2.4%)	2	5/82 (6.1%)	5
Back pain	2/82 (2.4%)	2	3/82 (3.7%)	3
Nervous system disorders
Akathisia	1/82 (1.2%)	1	4/82 (4.9%)	5
Dizziness	3/82 (3.7%)	4	3/82 (3.7%)	3
Headache	11/82 (13.4%)	12	11/82 (13.4%)	12
Somnolence	0/82 (0%)	0	3/82 (3.7%)	3
Psychiatric disorders
Anxiety	3/82 (3.7%)	4	2/82 (2.4%)	2
Insomnia	3/82 (3.7%)	3	3/82 (3.7%)	4
Respiratory, thoracic and mediastinal disorders
Cough	0/82 (0%)	0	3/82 (3.7%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.