Clinical trial NCT01253304: A Single Dose Study of LY2189265 in Subjects With Varying Degrees of Hepatic (Liver) Impairment
Official title: A Single Dose Pharmacokinetic Study of LY2189265 in Subjects With Varying Degrees of Hepatic Impairment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes Mellitus, Type 2
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2010-12-03
Enrollment: 26
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary purpose of this study is to help answer the following research questions, and not to provide treatment for any condition:

* To evaluate how much of the study drug (LY2189265) is in the blood of participants with varying degrees of liver impairment compared to those with normal liver function.
* To assess the safety of LY2189265 and any side effects that might be associated with it.


Eligibility criteria: Inclusion Criteria:

All Participants (including participants with type 2 diabetes mellitus \[T2DM\]):

* Male participants - Agree to use a reliable method of birth control (for example, barrier methods) during the study and for at least 3 months following dosing of study drug
* Female participants:

  * Women must be of non-child-bearing potential due to surgical sterilization (hysterectomy, bilateral oophorectomy, or tubal ligation) or menopause
  * Women with an intact uterus are deemed postmenopausal if they are over 45 years old and have had cessation of menses for at least 1 year or have had 6 to 12 months of spontaneous amenorrhea with follicle stimulating hormone (FSH) \>40 international units per milliliter (IU/mL) and have not taken hormone replacement therapy or oral contraceptives within 1 year of study start and are otherwise healthy
  * Women who have had cessation of menses for at least 2 years are permitted to take hormone replacement therapy
* Have a body mass index (BMI) between 19.0 and 40.0 kilograms per meters squared (kg/m\^2), inclusive, at screening.
* Have venous access sufficient to allow blood sampling
* 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 governing the site

Control Participants:

* Overtly healthy participants with normal hepatic function
* Participants with T2DM with normal hepatic function
* Have normal sitting blood pressure and pulse rate as determined by the investigator or with changes compatible with their age and disease status in case of patients with T2DM
* Have clinical laboratory test results within normal reference range for the investigator site or results with minor deviations not considered to be clinically significant by the investigator or with changes compatible with their age and disease status in case of T2DM

Hepatic Impaired Participants:

* Have stable hepatic impairment (such as, post-alcoholic, chronic hepatitis, biliary cirrhosis, or cryptogenic) classified as Child-Pugh Class A, B, or C (mild, moderate, and severe impairment) who are considered by the investigator as acceptable for participation in the study. The hepatic-impaired participant population may include patients with T2DM.
* Have sitting blood pressure and pulse rate compatible with their disease state \[including T2DM, if applicable\] as determined by the investigator.

Participants with T2DM (All Study Groups)

* Have T2DM controlled with diet and exercise alone or T2DM is stable on a single, oral agent antihyperglycemic medication (metformin, sulfonylureas, repaglinide, nateglinide, acarbose \[or other disaccharidase inhibitors\], or thiazolidinediones) for at least 3 weeks (3 months for thiazolidinediones) prior to admission
* Have a glycosylated hemoglobin (HbA1C) value at screening (or within 4 weeks prior to screening) of 6.5% to 9.0%
* Have clinical laboratory test results within normal range or deemed clinically insignificant by the investigator. Abnormalities of serum glucose, serum lipids, urinary glucose, and urinary protein consistent with T2DM are acceptable
* Have acceptable blood pressure and pulse rate (sitting), as determined by the investigator

Exclusion Criteria:

All participants (including participants with T2DM)

* Are currently enrolled in, discontinued within the last 30 days from a clinical trial involving use of an investigational drug or device other than the study drug, 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 LY2189265 or related compounds
* Have previously completed or withdrawn from this study or any other study investigating LY2189265
* Have a current, functioning organ transplant
* Show evidence of significant active, uncontrolled, endocrine or autoimmune abnormalities (such as, thyroid disease or pernicious anemia) as judged by the screening physician
* Have shown febrile illness within 3 days prior to screening
* 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
* Regularly use known drugs of abuse and/or show positive findings on urinary drug screening that are not otherwise explained by permitted concomitant medications
* Show evidence of human immunodeficiency virus (HIV) and/or positive human HIV antibodies
* Are women with a positive pregnancy test or women who are lactating
* Have donated blood of more than 500 milliliters (mL) within the last month prior to screening
* Have an average weekly alcohol intake that exceeds 21 units per week (men) and 14 units per week (women) (1 unit = 12 ounces \[oz\] or 360 mL of beer, 5 oz or 150 mL of wine, or 1.5 oz or 45 mL of distilled spirits)
* Are unwilling to stop alcohol consumption for the duration of the study (from screening until the follow-up visit)
* Are participants who smoke more than 10 cigarettes per day, are unwilling to refrain from smoking on the day of LY2189265 administration, or are unable to abide by clinical research unit (CRU) restrictions on other inpatient days
* Have a history or presence of pancreatitis (history of chronic pancreatitis or idiopathic acute pancreatitis) or gastrointestinal disorder, (for example relevant esophageal reflux or gall bladder disease, or any gastrointestinal disease which impacts gastric emptying \[such as, gastric bypass surgery, pyloric stenosis, with the exception of appendectomy\] or could be aggravated by glucagon like peptide \[GLP\] analogs). Participants with mild hypertension and dyslipidemia, and participants who had cholecystolithiasis (removal of gall stones) and/or cholecystectomy (removal of gall bladder) in the past, with no further sequelae, may be included in the study at the discretion of the screening physician.
* Are participants deemed to be unsuitable by the investigator for any reason.

Control participants:

* Have a history or presence of cardiovascular (such as, myocardial infarction, cerebrovascular accident, venous thromboembolism), respiratory, renal, endocrine (with exception of participants with T2DM), hematological, neurological disorders, cancer, hepatic (including Gilbert's disease), or dermatological disorders or diseases capable of significantly altering the absorption, metabolism, or elimination of drugs; of constituting a risk when taking the study medication; or of interfering with the interpretation of data
* Show evidence of significant active neuropsychiatric disease
* Have creatinine clearance less than 80 milliliters per minute (mL/min) (as calculated by the Cockcroft-Gault equation)
* Show evidence of hepatitis B and/or positive hepatitis B surface antigen
* 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
  * Prescription medication within 14 days prior to dosing participants with mild, moderate, and severe hepatic impairment
* Show evidence of any significant active disease other than that responsible for or associated with hepatic impairment. Participants with hypertension and hyperlipidemia may be permitted at the investigator's discretion.
* Show, in the opinion of the investigator, evidence of significant neuropsychiatric disease other than Grade 1 hepatic encephalopathy
* Show evidence of spontaneous bacterial peritonitis within 6 months of dosing.
* Show evidence of severe hyponatremia (Sodium \[Na\] \<120 millimoles per liter \[mmol/L\])
* Show presence of hepatocellular carcinoma
* Have a portal shunt
* Show evidence of severe ascites
* Have hemoglobin \<9.0 grams per deciliter (g/dL)
* Have platelet count \<40 x 10\^9 cells per liter (cells/L)
* Have total serum bilirubin \>15 milligrams per deciliter (mg/dL)
* Use medication known to interfere with hepatic metabolism (that is, barbiturates, phenothiazines) or known to alter other major organs or systems

Mild, Hepatic Impaired Participants (Child-Pugh A)

* Show evidence of active renal disease with creatinine clearance \<70 mL/min calculated by the Cockcroft-Gault equation.
* Moderate and Severe Hepatic Impaired Subjects (Child-Pugh B and C)
* Show evidence of hepatorenal syndrome as shown by creatinine clearance \<50 mL/min calculated by the Cockcroft-Gault equation.

Primary outcomes:
measure: Pharmacokinetics: Maximum Observed Concentration (Cmax)
timeFrame: Predose to 336 hours postdose
measure: Pharmacokinetics: Time of Maximum Concentration (Tmax)
timeFrame: Predose to 336 hours postdose
measure: Pharmacokinetics: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUC[0-tlast])
timeFrame: Predose to 336 hours postdose
measure: Pharmacokinetics: AUC From Time Zero to Infinity (AUC[0-infinity])
timeFrame: Predose to 336 hours postdose
measure: Pharmacokinetics: Apparent Terminal Elimination Half-life (t1/2)
timeFrame: Predose to 336 hours postdose
measure: Pharmacokinetics: Apparent Total Plasma Clearance (CL/F)
timeFrame: Predose to 336 hours postdose
measure: Pharmacokinetics: Apparent Volume of Distribution (Vz/F)
timeFrame: Predose to 336 hours postdose
Secondary outcomes:
Other outcomes:
Locations:
city: Munich
country: Germany
facility: 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.
city: Budapest
country: Hungary
facility: 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.
Study officials:
affiliation: Eli Lilly and Company
name: 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)
role: STUDY_DIRECTOR
References: