A Study of Safety and Tolerability in Subjects With Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Intervention: LY2140023; Aripiprazole
Intervention description: Administered orally; Administered orally
Intervention MeSH terms: Aripiprazole
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 75.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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