A Study to Evaluate Pharmacokinetic (PK) and Safety of GSK1265744 in Subjects With Hepatic Impairment and Control Healthy Volunteers



Status:Completed
Conditions:HIV / AIDS, HIV / AIDS, HIV / AIDS, Gastrointestinal
Therapuetic Areas:Gastroenterology, Immunology / Infectious Diseases
Healthy:No
Age Range:18 - 70
Updated:3/30/2019
Start Date:June 22, 2015
End Date:September 16, 2016

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A Phase I Study to Evaluate the Pharmacokinetics and Safety of GSK1265744 in Subjects With Hepatic Impairment and Healthy Matched Control Subjects

This will be a Phase 1, open-label, parallel group, two-part, single-dose adaptive study in
adults with moderate and mild (if needed) hepatic impairment and matched, healthy control
subjects with normal hepatic function. In Part 1, healthy control subjects (n=8) matched to
subjects with moderate (n=8) hepatic impairment will be enrolled. If the geometric mean total
plasma area under the concentration-time curve from time zero (pre-dose) extrapolated to
infinite time (AUC[0-infinity]) of GSK1265744 is increased by >2-fold in moderately impaired
subjects relative to matched controls, Part 2 will be conducted to evaluate GSK1265744 PK in
subjects with mild hepatic impairment (n=8) and matched, control subjects (n=8). All subjects
will receive a single 30 milligram (mg) oral dose of GSK1265744. The primary objective of the
study is to compare plasma PK parameters of GSK1265744 in subjects with hepatic impairment to
healthy controls matched in gender, age, and body mass index (BMI).


Inclusion Criteria:

- Hepatic Impaired Subjects (Cohort 1 and 3)

- Between 18 and 70 years of age

Part 1 subjects with Moderate Hepatic Impairment Only (Cohort 1):

- Subject is considered to have moderate hepatic impairment (of any etiology) and has
been clinically stable for at least 1 month prior to screening. Having moderate
hepatic impairment with a Child-Pugh score of 7-9 and previous confirmation of liver
cirrhosis.

Part 2 subjects with Mild Hepatic Impairment Only (Cohort 3):

- Subject is considered to have mild hepatic impairment (of any etiology) and has been
clinically stable for at least 1 month prior to screening. Having mild hepatic
impairment, with a Child-Pugh score of 5-6 and previous confirmation of chronic liver
disease.

- Supplemental inclusion criteria for all hepatically impaired subjects: Chronic (>6
months), stable (no acute episodes of illness within the previous 1 month prior to
screening due to deterioration in hepatic function) hepatic impairment due to any
etiology. Subjects must also remain stable throughout the Screening period. - Body
weight >=50 kilogram (kg) and BMI within the range 19 - 41 kilogram per meter square
(kg/m^2) (inclusive).

- Male or female: Capable of giving signed informed consent which includes compliance
with the requirements and restrictions listed in the consent form and the protocol.

Inclusion Criteria for Healthy Subjects (Cohorts 2 and 4):

- Healthy control subjects will be matched for age +/-10 years to subjects in the
respective hepatic impairment cohort but must also remain in the age range between 18
and 70 years inclusive, at the time of signing the informed consent.

- Healthy as determined by the investigator or medically qualified designee. Healthy
control subjects will be matched for BMI +/-25 percent to subjects in the respective
hepatic impairment cohort but must also remain in the range of: Body weight >=50 kg
and BMI within the range 19 - 41 kg/m^2 (inclusive)

- Male or female: Capable of giving signed informed consent which includes compliance
with the requirements and restrictions listed in the consent form and in the protocol.

Exclusion Criteria:

- Exclusion Criteria for Hepatic Impaired Subjects (Cohort 1 and 3):

- Presence of Grade 3 or 4 elevations in aspartate aminotransferase (AST), alanine
aminotransferase (ALT), or bilirubin; corrected QT interval (QTc) > 480 milliseconds
(msec);

- The subject's systolic BP is outside the range of 90-160 millimeter of mercury (mmHg),
or diastolic BP is outside the range of 45-95mmHg or heart rate is outside the range
of 50-100 beats per minute (bpm) for female subjects or 45-100 bpm for male subjects

- Evidence of previous myocardial infarction in the past 12 months or any clinically
significant active cardiovascular disease that, in the opinion of the investigator,
could interfere with the safety of the subject.

- Any clinically significant conduction abnormality

- Any significant arrhythmia.

- Non-sustained or sustained ventricular tachycardia.

- Evidence of recent infection with Hepatitis B and/or Hepatitis C within preceding 6
months. Subjects with chronic Hepatitis B or C (duration>6 months)

- Subjects with a pre-existing condition (except hepatic impairment) interfering with
normal gastrointestinal anatomy or motility that could interfere with the absorption,
metabolism, and/or excretion of the study drugs. Subjects with a history of
cholecystectomy and inflammatory bowel disease should be excluded.

Subjects with a history of peptic ulceration or pancreatitis within the preceding 6 months
of screening should be excluded.

- Subjects with previous gastrointestinal (GI) surgery (except appendectomy more than
three months prior to study) should be excluded.

- Subjects with creatinine clearance (CLCR) <=60 milliliter per minute (mL/min)
(calculated by the Modification of Diet in Renal Disease [MDRD] equation).

- Subjects with advanced ascites (Grade 3 or 4).

- Subjects with refractory encephalopathy as judged by the investigator or significant
Central Nervous System (CNS) disease.

- History of gastric or esophageal variceal bleeding within the past 6 months;

- Subjects with Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement;

- Presence of hepatopulmonary or hepatorenal syndrome;

- Presence of primarily cholestatic liver diseases;

- History of liver transplantation;

- Subjects with signs of active infection;

- Subjects with unstable cardiac function or subjects with hypertension whose blood
pressure is not controlled;

- Diabetic subjects whose diabetes is not controlled;

- Subjects with any other medical condition (other than hepatic impairment) which, in
the judgment of the investigator and medical monitor, could jeopardize the integrity
of the data derived from that subject or the safety of the subject;

- Subjects requiring any concurrent prohibited medication listed in study protocol;

- Subjects receiving lactulose who are medically unable to halt lactulose administration
from 8 hours before dosing with study drug to 4 hours after dosing with study drug;

- Subjects with a change in dose regimen of medically required medication within the 2
weeks prior to dosing;

- History of regular alcohol consumption within 6 months of the study;

- Inability or unwillingness to comply with lifestyle and/or dietary restrictions
outlined in protocol;

- History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or Medical
Monitor, contraindicates their participation. ;

- Unwillingness or inability to follow the procedures outlined in the protocol;

- A positive pre-study drug/alcohol screen;

- A positive test for human immunodeficiency virus (HIV) antibody;

- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period;

- Subject's with a platelet count <50,000 x 10^9 per liter (/L) of blood who have had a
major bleeding episode within the past 6 months;

- Subjects with electrolyte imbalance;

- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).

- Exclusion Criteria for Healthy Subjects (Cohorts 2 and 4):

- ALT and bilirubin >1.5x upper limit of normal (ULN) (isolated bilirubin >1.5xULN is
acceptable if bilirubin is fractionated and direct bilirubin <35 percent). A single
repeat is allowed for eligibility determination;

- Current or chronic history of liver disease;

- QTc > 450 msec;

- Exclusion criteria for screening ECG as per study protocol;

- Systolic BP outside the range of 90-145 mmHg, or diastolic BP outside the range of
45-95 mmHg or heart rate outside the range of 50-100 bpm for female subjects or 45-100
bpm for male subjects;

- Evidence of previous myocardial infarction;

- Any clinically significant conduction abnormality;

- Any significant arrhythmia.

- Non-sustained or sustained ventricular tachycardia;

- Subjects with a pre-existing condition interfering with normal gastrointestinal
anatomy or motility that could interfere with the absorption, metabolism, and/or
excretion of the study drugs. Subjects with a history of cholecystectomy and
inflammatory bowel disease. Subjects with a history of peptic ulceration or
pancreatitis within 6 months of screening. Subjects with previous GI surgery (except
appendectomy more than three months prior to study).

- The use of any concurrent prohibited medications as outlined in study protocol.

- History of regular alcohol consumption within 6 months of the study,

- Inability or unwillingness to comply with lifestyle and/or dietary restrictions
outlined in study protocol.

- History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or Medical
Monitor, contraindicates their participation.

- Unwillingness or inability to follow the procedures outlined in study protocol.

- Presence of hepatitis B surface antigen (HBsAg) (or positive hepatitis B core antibody
with negative hepatitis B surface antibody) or positive hepatitis C antibody test
result.

- A positive pre-study drug/alcohol screen.

- A positive test for HIV antibody.

- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within 56 days.

- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).
We found this trial at
3
sites
Orlando, Florida 32806
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Lakewood, Colorado 80228
Phone: 877-379-3718
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Minneapolis, Minnesota 55404
Phone: 877-379-3718
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Minneapolis, MN
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