Phase I Study of Linerixibat in Adults With Moderate Hepatic Impairment and Healthy Controls

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

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.

Study Overview

• Status: Completed
• Conditions: Pruritus
• Intervention / Treatment: Drug: Linerixibat

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orlando, Florida, United States, 32809
      • GSK Investigational Site
  • Texas
    • San Antonio, Texas, United States, 78215
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 (Moderate hepatic impairment participants); Eligible participants to receive single dose of linerixibat.	Drug: Linerixibat; Linerixibat dose and administration as per study intervention.
Experimental: Cohort 2 (Matched healthy control participants); Eligible participants to receive single dose of linerixibat	Drug: Linerixibat; Linerixibat dose and administration as per study intervention.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	Up to Day 3
Maximum observed concentration (Cmax) following a single dose of linerixibat	Up to Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events (AEs) and serious adverse events (SAEs)	AEs and SAEs will be collected	Up to Day 14
Number of participants with clinically significant change from baseline in electrocardiogram (ECG)		Baseline (Day -1) and up to Day 3
Number of participants with clinically significant change from baseline in vital signs		Baseline (Day -1) and up to Day 3
Number of participants with clinically significant change from baseline in clinical laboratory tests	Blood samples will be collected for the assessment of clinical laboratory tests	Baseline (Day -1) and up to Day 3
Plasma area under the concentration-time curve from time zero (pre-dose) to 24 hours [AUC (0- 24)] following a single dose of linerixibat		Up to Day 3
Apparent terminal phase half-life (t1/2) of linerixibat		Up to Day 3
Apparent clearance (CL/F) of linerixibat		Up to Day 3
Time to Cmax (tmax) of linerixibat		Up to Day 3
Apparent terminal phase volume of distribution (Vz/F) of linerixibat		Up to Day 3

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2022
• Primary Completion (Actual): December 6, 2022
• Study Completion (Actual): December 6, 2022

Study Registration Dates

• First Submitted: May 23, 2022
• First Submitted That Met QC Criteria: May 23, 2022
• First Posted (Actual): May 26, 2022

Study Record Updates

• Last Update Posted (Actual): January 18, 2023
• Last Update Submitted That Met QC Criteria: January 13, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Liver Cirrhosis; Pharmacokinetics; Pruritus; Hepatic impairment; Linerixibat; GSK2330672; Primary biliary cholangitis
• Additional Relevant MeSH Terms: Skin Diseases; Skin Manifestations; Pruritus
• Other Study ID Numbers: 214899

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
• IPD Sharing Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.
• IPD Sharing Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No