Clinical trial NCT05393076: Phase I Study of Linerixibat in Adults With Moderate Hepatic Impairment and Healthy Controls
Official title: A Phase 1, Open-label, Single-dose Study to Evaluate the Pharmacokinetics and Safety of Linerixibat in Adults With Moderate Hepatic Impairment and Healthy Matched Control Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pruritus
Keywords: Linerixibat
Pruritus
GSK2330672
Pharmacokinetics
Primary biliary cholangitis
Hepatic impairment
Liver Cirrhosis
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2022-05-26
Enrollment: 8
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This phase 1 study is an open-label, non-randomized, single-dose linerixibat study with 2 cohorts (moderate hepatic impairment and matched healthy control participants).
Primary purpose: TREATMENT

Brief summary: This is a phase 1, open-label, single-dose study in adults with moderate hepatic impairment (defined as Child-Pugh B cirrhosis) and matched healthy control participants with normal hepatic function. All participants in both cohorts (moderate hepatic impairment and matched healthy controls) will receive a single dose of the study drug, linerixibat. The purpose of this study is to assess the effect of hepatic impairment on the pharmacokinetics (PK) and safety of linerixibat.


Eligibility criteria: Inclusion Criteria:

All Participants:

* Age: 18 to 75 years of age (inclusive).
* Weight greater than (\>) 45 kilograms (kg) and body mass index (BMI) 18.5 - 40 kg per square meter (kg/m\^2) (inclusive).
* Male and female- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies; not a woman of childbearing potential (WOCBP) or a WOCBP who agrees to follow contraceptive guidance during the treatment period and until at least 4 weeks after the last dose of study treatment.
* Participant capable of giving signed informed consent.

Participants with Moderate Hepatic Impairment (Cohort 1):

* Moderate hepatic impairment (of any etiology) and clinically stable for at least 1 month prior to screening.
* Child-Pugh score of 7-9.
* Previous confirmation of liver cirrhosis confirmed by either- Liver biopsy, Imaging technique, or Noninvasive liver assessment consistent with cirrhosis.
* Hepatic impairment needs to be chronic (\>6 months), stable.

Matched Healthy Control Participants (Cohort 2):

* Participants will be matched by age plus or minus (±)10 years to a corresponding participant in the hepatic impairment group. Age should remain between 18 and 75 years of age (inclusive).
* Participants will be matched by total body weight ±15 percentage (%) to a corresponding participant in the hepatic impairment group.
* Participants will be matched by gender and race to a corresponding participant in the hepatic impairment group.
* Healthy participant as determined by the investigator or medically qualified designee based on a medical evaluation including medical history, physical examination, laboratory tests and ECG.

Exclusion Criteria:

All Participants:

* Participants are excluded from the study if any of the following medical conditions apply:
* History of cholecystectomy, current symptomatic cholelithiasis or inflammatory gallbladder disease.
* Significant history of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, hematological, or neurological disorders capable of significantly altering the absorption, metabolism, or elimination of drugs; constituting a risk when taking the study intervention; or interfering with the interpretation of data.
* Any clinically relevant abnormality identified at the screening medical assessment (physical examination/medical history review), clinical laboratory tests, or 12-lead ECG.
* Current clinically significant diarrhea.
* History of gastrointestinal surgery with ileal resection or ileal bypass at any time.
* Any malignancy within the past 5 years except for basal cell or squamous cell carcinoma of the skin disease for 3 years.
* Participants with unstable cardiac function or participants with uncontrolled hypertension.
* Any current medical or psychiatric condition, clinical or laboratory abnormality, or examination finding which may affect study compliance or investigational procedures or possible consequences of the study.
* Administration of any other Ileal bile acid transport (IBAT) inhibitor (including linerixibat) in the 3 months prior to screening.
* For healthy participants, past or intended use of over the counter or prescription medication, including vitamins and dietary or herbal supplements) within 7 days prior to the first dose of study medication.
* Current enrolment in a clinical trial or recent participation in a clinical trial and has received an investigational product within the following time-period prior to study drug administration in the current study: 30 days.
* Positive pregnancy test at screening or at Day -1 in women of childbearing potential.
* Positive human immunodeficiency virus (HIV) antibody test.
* Healthy control participant has corrected interval using the Fridericia's QT correction formula (QTcF) \>450 millisecond (msec); or participant with hepatic impairment has a baseline QTcF \>480 msec on ECG.
* Regular use of known drugs of abuse or history of drug abuse or dependence within 6 months of the study.
* Moderate (or greater) alcohol consumption defined as one standard drink per day for women and two drinks per day for men.
* History of regular use of tobacco or nicotine-containing products.
* Positive drug/alcohol screen at Screening or at Day -1.
* Where participation in the study would result in donation of blood or blood products more than 500 milliliter (mL) within a 56-day period.
* Unwillingness or inability to follow the procedures outlined in the protocol.
* Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that contraindicates participation in the study.

Participants with Hepatic Impairment (Cohort 1):

* History of gastric or oesophageal variceal bleeding within the past 6 months and for which varices have not been adequately treated medically or endoscopically.
* Grade 3 ascites (large ascites with marked abdominal distension) refractory to medical therapy.
* Refractory hepatic encephalopathy as judged by the investigator.
* Child-Pugh score of 10 or higher or Child-Pugh score of 6 or lower.
* Hepatopulmonary or hepatorenal syndrome and history of liver transplantation.
* Evidence of active infection, including spontaneous bacterial peritonitis.
* Confirmed hepatocellular carcinoma (HCC) or biliary cancer.
* Alanine amino transferase (ALT) value \>3 x upper limit of normal (ULN).
* Platelet count less than (\<) 50,000/microliter (μl).

Matched Healthy control participants (Cohort 2):

* Current or chronic history of liver disease or known hepatic or biliary abnormalities and/or confirmed hepatocellular carcinoma or biliary cancer.
* Screening ALT or aspartate aminotransferase (AST) above the upper limit of normal (ULN).
* Elevated bilirubin above the ULN unless this is due to underlying Gilbert's syndrome.
* Presence of hepatitis B surface antigen (HBsAg) at screening or within 3 months prior to first dose of study intervention.
* Positive hepatitis C antibody ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose of study intervention.

Primary outcomes:
measure: Plasma area under the concentration-time curve from time zero (pre-dose) to the time of the last quantifiable concentration [AUC(0-t)] following a single dose of linerixibat
timeFrame: Up to Day 3
measure: Maximum observed concentration (Cmax) following a single dose of linerixibat
timeFrame: Up to Day 3
Secondary outcomes:
measure: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to Day 14
measure: Number of participants with clinically significant change from baseline in electrocardiogram (ECG)
timeFrame: Baseline (Day -1) and up to Day 3
measure: Number of participants with clinically significant change from baseline in vital signs
timeFrame: Baseline (Day -1) and up to Day 3
measure: Number of participants with clinically significant change from baseline in clinical laboratory tests
timeFrame: Baseline (Day -1) and up to Day 3
measure: Plasma area under the concentration-time curve from time zero (pre-dose) to 24 hours [AUC (0- 24)] following a single dose of linerixibat
timeFrame: Up to Day 3
measure: Apparent terminal phase half-life (t1/2) of linerixibat
timeFrame: Up to Day 3
measure: Apparent clearance (CL/F) of linerixibat
timeFrame: Up to Day 3
measure: Time to Cmax (tmax) of linerixibat
timeFrame: Up to Day 3
measure: Apparent terminal phase volume of distribution (Vz/F) of linerixibat
timeFrame: Up to Day 3
Other outcomes:
Locations:
city: Orlando
country: United States
facility: GSK Investigational Site
state: Florida
city: San Antonio
country: United States
facility: GSK Investigational Site
state: Texas
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: