A Study of LY2140023 in Hepatically-Impaired Participants
Condition: Hepatic Insufficiency
MeSH terms: Hepatic Insufficiency; Liver Failure
Intervention: LY2140023
Phase: Phase 1
Study type: Interventional
Primary purpose: Basic Science
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      This study will explore how liver impairment affects blood levels of LY2140023 (a prodrug)
      and its active metabolite (LY404039).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male participants agree to use a reliable method of birth control during the study and
             for 3 months following the last dose of LY2140023

          -  Female participants of child-bearing potential 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 dose of LY2140023

          -  Female participants who are postmenopausal. Postmenopausal is defined as no menses for
             at least 1 year, or a plasma follicle stimulating hormone (FSH) value of greater than
             40 units per liter (IU/L), unless the participant is taking hormone replacement
             therapy

          -  Have a body mass index (BMI) between 19 and 40 kilograms per square meter (kg/m^2),
             inclusive at the time of screening

          -  Have clinical laboratory test results within the 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 sitting blood pressure and heart rate compatible with their disease state, as
             determined by the investigator

          -  Have venous access sufficient to allow for blood sampling as per the protocol

          -  Are reliable and willing to make themselves available for the duration of the study
             and are willing to follow study procedures

          -  Have given written informed consent approved by Lilly and the ethical review board
             (ERB) governing the site

          -  Control participants that have normal hepatic function, as determined by medical
             history and physical examination

          -  Hepatically-impaired participants that have stable hepatic impairment (for example,
             alcoholic, posthepatitis, biliary cirrhosis, or cryptogenic) classified as Child-Pugh
             class A, B, or C (mild, moderate, or severe impairment) who are considered acceptable
             for participation in the study by the investigator

        Exclusion Criteria:

          -  Are currently enrolled in, have completed or discontinued within the last 90 days from
             last dosing of an investigational product (other than the investigational product used
             in this study); or are 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, related compounds, or any components of
             the formulation

          -  Have previously discontinued after receiving at least 1 dose of LY2140023 or completed
             this study or any other study investigating LY2140023 and or LY404039

          -  Have an abnormality in the 12-lead electrocardiogram (ECG) that, in the opinion of the
             investigator, increases the risks associated with participating in the study

          -  Have a history or presence of cardiovascular, respiratory, renal, gastrointestinal,
             endocrine, hematological, or neurological disorders capable of significantly altering
             the absorption (except cholecystectomy), metabolism, or elimination of drugs; of
             constituting a risk when taking the study medication; or of interfering with the
             interpretation of data

          -  Have evidence of significant active neuropsychiatric disease (for example, manic
             depressive illness, schizophrenia, or depression)

          -  Participants who answer '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

          -  Have increased risk of seizures based on a history of:

               -  One or more seizures (except for a single simple febrile seizure [lacking
                  focality and lasting less than 15 minutes, not associated with a central nervous
                  system (CNS) infection or severe metabolic disturbance] as a child between ages 6
                  months to 5 years)

               -  Head trauma with loss of consciousness or a post-concussive syndrome within 1
                  year or lifetime history of head trauma with persistent neurological deficit
                  (focal or diffuse)

               -  CNS infection, uncontrolled migraine or transient ischemic attack (TIA) within 1
                  year; stroke with persistent neurological deficit (focal or diffuse).
                  Uncontrolled migraine is defined as migraine attacks that produce headache
                  lasting up to 72 hours and are often accompanied by associated symptoms (nausea,
                  photophobia, and phonophobia) that impair well-being and disrupt social
                  functioning. TIA is defined as "mini-stroke" caused by temporary disturbance of
                  blood supply to an area of the brain, which results in a sudden, brief decrease
                  in brain function

               -  CNS infection with persistent neurological deficit (focal or diffuse)

               -  Brain surgery

               -  Electroencephalogram (EEG) with paroxysmal (epileptiform) activity (isolated
                  spikes waves, repetitive bursts of sharp waves, paroxysmal activity, frank
                  seizures, spike-wave complexes, sharp-slow wave complexes, or as locally defined)

               -  Brain structural lesion, including developmental abnormalities, as determined by
                  examination or imaging studies (does not include hydrocephalus unless treated by
                  shunt or resulting in neurological deficits)

          -  Known substance dependence unless approved prescription medication such as opiates, or
             known regular use of drugs of abuse and/or show positive findings on urinary drug
             screening

          -  Show evidence of human immunodeficiency virus (HIV) infection and/or positive human
             HIV antibodies

          -  Women who are pregnant or intend to get pregnant during the study or within 3 months
             after the last dose of investigational product

          -  Women who are breast feeding or lactating

          -  Have donated blood of more than 500 milliliters (mL) within the last 3 months prior to
             the screening

          -  Are organ transplant participants or have taken immunosuppressants following any organ
             transplant

          -  Have shown signs of variceal bleeding during the last 2 months prior to screening
             (except for participants with severe hepatic impairment, detailed in exclusion
             criterion)

          -  Show evidence of irritable bowel syndrome or chronic diarrhea

          -  Have an average weekly alcohol intake that exceeds 21 units per week (males) and 14
             units per week (females), and are participants unwilling to stop alcohol consumption
             for 96 hours predose until after 48 hours post-dose (1 unit equals 12 ounces [oz] or
             360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits)

          -  Have a clinically significant abnormality in the neurological examination

          -  Participants judged prior to dosing to be at suicidal risk by the investigator

          -  Participants who are unwilling to refrain from smoking from midnight prior to dosing
             until 6 hours postdose or are unable to abide by the Clinical Research Unit (CRU)
             restrictions

          -  Are on total parenteral nutrition (TPN)

          -  Take oral anticoagulants for therapeutic use

          -  Exhibit any other condition, which, in the opinion of the investigator would preclude
             participation in the study

          -  Show evidence of pruritus or skin exfoliation

          -  Have an eosinophil count >1.5 x 10^9/liter (L)

          -  Have electrolyte imbalance alerts (clinically significant changes in calcium
             magnesium, or sodium)

          -  Control Participants:

               -  Have any medically significant history of neurologic disease, cancer, or cardiac,
                  respiratory, metabolic, hepatic, renal, gastrointestinal (except appendectomy),
                  dermatological, venereal, hematological disorder or disease

               -  Have creatinine clearance (CrCl) less than 80 milliliters per minute (mL/min), as
                  calculated by the Cockcroft-Gault equation:

        Men: [(140 - age) x (weight in kilograms [kg])] / [72 x (serum creatinine in mg/100 mL)];
        or [(140 - age) x (weight in kg)] / [0.81 x (serum creatinine in micromoles per liter
        [μmol/L])] Women in both of the above equations: (x 0.85)

          -  Show evidence of significant active neuropsychiatric disease in the opinion of the
             investigator

          -  Evidence of hepatitis B and/or positive hepatitis B surface antigen (HBsAg)

          -  Show evidence of hepatitis C and/or positive hepatitis C antibody

          -  Intend to use over-the-counter medication (including herbal remedies/health
             supplements) within 7 days prior to dosing, or prescription medication (other than
             hormone replacement therapy as described above) within 14 days prior to dosing

               -  Mild Hepatic Impaired Participants (Child-Pugh A):

          -  show evidence of any significant active disease other than that responsible for or
             associated with hepatic impairment

          -  have a platelet count of less than 50 x 10^9 cells/L, unless after consultation with
             the Lilly Clinical Pharmacologist (CP), they are considered as acceptable for
             participation in the study

               -  Moderate and Severe Hepatic Impaired Participants (Child-Pugh B and C):

          -  Show evidence of any significant active disease other than that responsible for or
             associated with moderate or severe hepatic impairment

          -  Have shown signs of spontaneous bacterial peritonitis within 6 months prior to dosing

          -  Have severe hyponatremia

          -  Show evidence of significant active neuropsychiatric disease

          -  Have hepatic encephalopathy (Grades 2 to 4)

          -  Have hemoglobin concentrations <9.0 grams per deciliter (g/dL)

          -  Show signs of hepatocellular carcinoma

          -  Have a surgical portosystemic shunt

          -  Have a platelet count of less than 40 x 10^9 cells/L (moderate impairment) or less
             than 30 x 10^9 cells/L (severe impairment), unless after consultation with the Lilly
             CP they are considered as acceptable for participation in the study

          -  Have shown signs of variceal bleeding during the last 2 weeks prior to screening
             (severe hepatic impaired participants only)