A Study of LY2140023 in Hepatically-Impaired Participants

Denovo Biopharma

Status and phase

Completed

Phase 1

Conditions

Hepatic Insufficiency

Treatments

Drug: LY2140023

Study type

Interventional

Funder types

Industry

Identifiers

NCT01475136

H8Y-MC-HBCH (Other Identifier)

2011-003033-34 (EudraCT Number)

12677

Details and patient eligibility

About

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

Full description

The study included 4 groups, based on the Child-Pugh classification of hepatic impairment as follows:

Group 1: Participants with normal hepatic function (Control); Group 2: Participants with mild hepatic impairment (Child-Pugh class A); Group 3: Participants with moderate hepatic impairment (Child-Pugh class B); and Group 4: Participants with severe hepatic impairment (Child-Pugh class C).

Enrollment

37 patients

Sex

All

Ages

18 to 65 years old

Volunteers

Accepts Healthy Volunteers

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)