A Study of Safety and Tolerability in Subjects With Schizophrenia

Study Overview
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Brief Summary
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This is an inpatient, open-label, multiple-dose, multicenter study to evaluate the safety and tolerability of LY2140023 given at doses expected to reflect multiples of the anticipated therapeutic exposure under clinical investigation. In the event of poor tolerability in Part A of this study Part B may be conducted to explore higher doses using titration. Participants in both Parts A and B will participate in a 9 day wash-out period of current medication (Study Days 1-9); participants coming into the study on aripiprazole will remain on their current therapy throughout.

Detailed Description
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The primary objective of this study was to evaluate the safety and tolerability of escalating doses of LY2140023 in subjects with schizophrenia. The secondary objectives of this study were: to characterize the pharmacokinetic (PK) parameters of LY2140023 and its active moiety - LY404039 in subjects with schizophrenia to explore higher doses of LY2140023 in subjects with schizophrenia for use in further regulatory studies to compare safety of LY2140023 to aripiprazole (ARP) to access changes in pharmacodynamic (PD) measures (Clinical Global Impression-Severity Scale [CGI-S], Extrapyramidal Symptoms [EPS], and Brief Psychiatric Rating Scale [BPRS]) This was an inpatient, open-label, multiple-dose, multi-center study to evaluate the safety and tolerability of LY2140023 given at doses expected to reflect multiples of the anticipated maximum therapeutic exposure under investigation.

Official Title
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Safety and Tolerability of Multiple Ascending Doses of LY2140023 in Subjects With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: LY2140023
* Drug: Aripiprazole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of schizophrenic disorder Female participants who test negative for pregnancy at screening and agree to use a reliable method of birth control for the duration of the study and for at least 3 months after the last LY2140023 dose or are postmenopausal Not have been hospitalized for psychiatric illness for at least 12 weeks prior to Day 1 of washout period and have a Clinical Global Impression -Severity (CGI-S) scale score of <4 Be willing and able as determined by the investigator to be hospitalized from the beginning of the washout period to the end of the study In the opinion of the investigator, the participant can be washed out of their Standard of Care (SOC) therapy (other than aripiprazole for the aripiprazole participants) for the duration of the study without detrimental effect to the participant's mental health (CGI-S <4 after completion of the washout period) 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 Be able to understand the nature of the study and have given their own informed consent Have clinical laboratory test results within normal reference range for the population or investigator site, or results with acceptable deviations that are judged to be not clinically significant by the investigator Have venous access sufficient to allow blood sampling Clinically acceptable sitting blood pressure and pulse rate, as determined by the investigator Participants on Aripiprazole prior to study entry must: On a stable dose of aripiprazole within the approved range in product labeling (less than or equal to 30 milligrams [mg]/day) for at least 60 days prior to Day 1 and with no anticipation of changes to dose, regimen (except as required for this study) or treatment within the next 1 month Exclusion Criteria: Currently enrolled in, or discontinued within the 30 days prior to screening from, a clinical trial involving an investigational drug or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have known allergies to LY2140023, LY404039, aripiprazole, or related compounds Participants with moderate to severe renal impairment as defined by creatinine clearance (CrCl) <60 milliliters (mL)/minute (min) Have previously completed this study or have discontinued from any study investigating LY2140023 after having received at least 1 dose of LY2140023 Participants for whom treatment with LY2140023 or aripiprazole as specified in this protocol, is relatively or absolutely clinically contraindicated Participants who have received treatment with clozapine Participants who have a diagnosis of schizophrenia who are taking either thioridazine or thiothixene Participants receiving treatment with depot antipsychotic medication within 12 weeks, prior to screening Participants who are taking any of medications that are specifically excluded Participants who have answered 'yes' to either Question 4 (Active Suicidal Ideation with Some Intent to Act, Without Specific Plan) or Question 5 (Active Suicidal Ideation with Specific Plan and Intent) on the Suicidal Ideation portion of the Columbia suicide severity rating scale (C-SSRS), or answer yes to any of the suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, preparatory act or behavior) on the Suicidal Behavior portion of the C-SSRS; and the ideation or behavior occurred within the past 3 months Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition (Text Revision) (DSM-IV-TR) diagnosis of substance dependence or substance abuse (except nicotine and caffeine) within the 6 months prior to admission Diagnosis of substance-induced psychosis by DSM-IV-TR criteria within 7 days of admission (or at any time during the dosing period) Have a history of one or more seizures except for either of the following 2 situations: a single simple febrile seizure between ages 6 months and 5 years or a single seizure with an identifiable etiology, which has been completely resolved Have a screening electroencephalogram (EEG) with paroxysmal (epileptiform) activity, for example, one that demonstrates 3 or more focal sharp or spike waves, any sharp and slow wave complex, or any epileptiform discharge that is rhythmic, sustained, or generalized, or as locally defined Participants who have had electroconvulsive therapy (ECT) within 3 months of observation period or who are expected to have ECT at any time during the live phase of this study A diagnosis of Parkinson's disease, dementia-related psychosis, or related disorders Participant with untreated hyperthyroidism or hypothyroidism needing a thyroid hormone supplement who have not been on a stable dose of medication for at least 2 months prior to screening Have leukopenia or history of leukopenia during the participant's lifetime Participants with alanine aminotransferase (ALT/SGPT) or aspartate aminotransferase (AST/SGOT) values >2 times the upper limit of normal (ULN) of the performing laboratory, or total bilirubin values >1.5 times the ULN of the performing laboratory at screening Participants with corrected QT interval (Bazett's); QTcB >450 milliseconds (msec) (male) or >470 msec (female) at admission Have acute, serious or unstable medical conditions, including (but not limited to) inadequately controlled diabetes (hemoglobin A1c [HgbA1c] >8%), severe hypertriglyceridemia (fasting triglycerides greater than or equal to 500 milligrams/deciliter (mg/dL) or 5.65 micromoles/liter [umol/L]), hepatic insufficiency (specifically any degree of jaundice), recent cerebrovascular accidents, seizure disorders, serious acute systemic infection or immunology disease, unstable cardiovascular disorders (including ischemic heart disease), renal, gastroenterologic, respiratory, endocrinologic, neurologic, or hematologic diseases Prolactin level of >200 nanograms/milliliter (ng/mL) (200 micrograms/liter [ug/L], or 4228 milli international units/liter [mIU/L]) at screening with the exception of participants treated with risperidone. Participants treated with risperidone are excluded if the prolactin level is >300 ng/mL (300 ug/L, or 6342 mIU/L) at screening Participants with known medical history of Human Immunodeficiency Virus positive (HIV+) status Test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody. Participants with positive Hepatitis B core antibody test and negative HBsAg may be included in the study if ALT/SGPT and AST/SGOT levels are less than 2 times the ULN and total bilirubin does not exceed the ULN of the central laboratory

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Aripiprazole<br>Part A: Continue current prescribed dosing regimen -- Study Day 1 to discharge (Study Day 21). Part B: Continue current prescribed dosing regimen (≤ 30 milligrams [mg]/day ) -- Study Day 1 to discharge (Study Day 23, 25 or 28 based on adaptive design) | Drug: Aripiprazole<br>* Administered orally<br>* Other names: Abilify;|
| Experimental: Part A: 160 mg LY2140023<br>Administered orally, twice daily (BID) for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16) | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Experimental: Part A: 240 mg LY2140023<br>Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16) | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Experimental: Part A: 320 mg LY2140023<br>Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16) | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Experimental: Part A: 400 mg LY2140023<br>Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16) | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Experimental: Part A: 480 mg LY2140023<br>Administered orally BID for 6 days (Study Days 10-15) and as a single morning dose on the 7th day (Study Day 16) | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|
| Experimental: Part B: LY2140023<br>If doses up to or equal to 400 mg BID are not tolerated, Part B of the study may be started. The dose of LY2140023 will be titrated in the same participant from highest dose that was tolerated in Part A, with the intention to reach a dose of 480 mg LY2140023. | Drug: LY2140023<br>* Administered orally<br>* Other names: pomaglumetad methionil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Events (Physical Assessments and Clinical Lab Tests) | Participants with at least 1 postdose (Day 10 through the end of study visit [Day 21]) treatment emergent adverse event (TEAE) were counted by dose cohort. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline up to Day 21 for Part A | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Pharmacokinetics, Maximum Concentration (Cmax) |  | Pre-dose and post-dose on Day 10 and Day 16 | 
| Part B: Pharmacokinetics, Maximum Concentration (Cmax) | Part B (dose titration as defined in Part B of study) was not conducted because the objective of the study was met in part A.; therefore, no data are available for analysis of this secondary outcome | Pre-dose and post-dose on Days 12, 15, 18, 21, and 24 | 
| Part A: Pharmacokinetics, Area Under the Concentration - Time Curve (AUC) | The Day 10 parameter is area under the concentration versus time curve from time zero to infinity (AUC[0-inf]) post-single dose of LY2140023. The Day 16 parameter is area under the concentration versus time curve in a dosing interval (AUC[0-tau]) post-repeated daily doses of LY2140023. | Pre-dose and post-dose on Day 10 and Day 16 | 
| Part B: Pharmacokinetics, Area Under the Concentration - Time Curve (AUC) | Part B of this study was not conducted; therefore, no data are available for analysis. | Pre-dose and post-dose on Days 12, 15, 18, 21, and 24 | 
| Percentage of Participants With Increased Severity From Baseline to Day 17 in Clinical Global Impression- Severity Scale (CGI-S) | Clinical Global Impression- Severity Scale (CGI-S) measures severity of illness at the time of assessment compared with start of treatment with scores ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). The classification includes 1 = Normal, not at all ill, 2 = Borderline mentally ill, 3 = Mildly ill, 4 = Moderately ill, 5 = Markedly ill, 6 = Severely ill, and 7 = Among the most extremely ill patients. Increases or higher scores indicate increasing severity (=worse outcome) Only incidences of selected shifts of increasing severity (an increase in numbers on a scale) were reported for participants. Part B of this study was not conducted; therefore, no data are available for analysis. | Baseline through Day 17 for Part A | 
| Percentage of Participants With Worsening Symptoms From Baseline to Day 17 in Brief Psychiatric Rating Scale (BPRS) | Brief Psychiatric Rating Scale (BPRS) is an 18-item clinician-administered scale used to assess the degree of severity of a participant's general psychopathological symptoms. Item scores ranged from 0 (not assessed) to 7 (extremely severe). Total Scores ranged from 0 to 126. Increases or higher scores indicate a worsening of symptoms. Only incidences of selected shifts of worsening symptoms (an increase in numbers on a scale within the 18-symptom construct) were reported for participants. Part B of this study was not conducted; therefore, no data are available for analysis. | Baseline through Day 17 for Part A | 
| Percentage of Participants With Worsening Severity From Baseline to Day 17 in Extrapyramidal Symptoms as Measured by the Abnormal Involuntary Movement Scale (AIMS) | The Abnormal Involuntary Movement Scale (AIMS) is a 14-item, clinician-rated scale to assess the severity of dyskinesias in patients taking neuroleptic drugs. Items 1 through 10 were rated using a 5-point (0-4) scale, items 11 through 14 were rated using a 2-point (no or yes) scale. The AIMS total score is the sum of items 1 through 10, and can range from 0-40. A higher score indicates a presence of more severe dyskinesias. Increases or higher scores indicate a worsening of symptoms. The classification includes 0 = None, 1 = Minimal, may be extreme normal, 2 = Mild, 3 = Moderate, and 4 - Severe. Only incidences of selected shifts of worsening severity (an increase in numbers on a scale within the 10-item construct) were reported for participants. Part B of this study was not conducted; therefore, no data are available for analysis. | Baseline through Day 17 for Part A | 
| Percentage of Participants With Increasing Impairment From Baseline to Day 17 in Extrapyramidal Symptoms as Measured by the Simpson-Angus Scale (SAS) | Simpson-Angus Scale (SAS) is used to measure Parkinsonian-type symptoms in participants exposed to antipsychotics. The scale consists of 10 items each rated on a 5-point scale, with 0 meaning complete absence of the condition and 4 meaning the presence of the condition in extreme form. The total score is obtained by adding the items. Increases or higher scores indicate a worsening of impairment. Only incidences of selected shifts of increasing impairment (an increase in numbers on a scale within the 10-symptom construct) were reported for participants. Part B of this study was not conducted; therefore, no data are available for analysis. | Baseline through Day 17 for Part A | 
| Percentage of Participants With Worsening Symptoms From Baseline to Day 17 in Extrapyramidal Symptoms as Measured by the Barnes Akathisia Scale (BAS) | Barnes Akathisia Rating Scale (BAS) evaluates observable, restless movements of drug-induced akathisia associated with use of antipsychotic medications, includes objective (1-item) and subjective component (2-items, awareness of movement and distress related to movement) plus Global Clinical Assessment for overall disorder. Components were rated on a 4-point scale for the objective (0 = normal and 3 = constantly restless) and subjective items ((0 = absence of inner restlessness and 3 = awareness of intense compulsion to move for one item; and 0 = no distress and 3 = severe for the other item) and scored on a 6-point scale for the Global Clinical Assessment (0 = absent and 5 = severe). Increases or higher scores indicate a worsening of symptoms. Only incidences of selected shifts of worsening symptoms (an increase in numbers on a scale within the components) were reported for participants. Part B of this study was not conducted; therefore, no data are available for analysis. | Baseline through Day 17 for Part A |