Linerixibat and Obeticholic Acid Drug Interaction Study i... | NCT04053023

Description Module

Brief Summary

In participants with inadequate response/intolerance to ursodeoxycholic acid (UDCA) taking obeticholic acid (OCA) who experience pruritus (due to primary biliary cholangitis [PBC], OCA, or both) the addition of linerixibat to OCA therapy may be considered following marketing approval. It is therefore important to characterize any potential effect of linerixibat on the pharmacokinetics of OCA in humans at clinically relevant dosages. Accordingly, a drug-drug interaction (DDI) study with linerixibat (potential perpetrator) and OCA (potential victim) will be conducted to inform both future clinical trials with linerixibat and the potential concomitant administration of these drugs in a clinical setting. This is a single-center, one part (with optional second part) open-label, single sequence crossover, drug interaction study to investigate the effect of linerixibat on plasma concentrations of OCA and OCA conjugates in healthy participants. Approximately 19 participants will be enrolled in part A and further 19 participants in part B (if performed) in the study and will have a phone call follow-up till 7-14 days post-last linerixibat dose.

Label	Type	Description	Intervention Names
Participants receiving obeticholic acid and linerixibat	Experimental	In Part A, participants will be administered one tablet of 10 milligrams (mg) obeticholic acid once daily continuously for 37 days (study Day 1 to study Day 37). Two tablets of 45 mg linerixibat will be administered twice daily from study Day 20 to study Day 37. 1 tablet of 45 mg linerixibat will be administered on Day 38. After evaluation of Part A, if optional part B is conducted, participants will be administered linerixibat and obeticholic acid at an alternative dosing regimen.	Drug: GSK2330672 (linerixibat) Drug: Obeticholic acid

Name	Type	Description	Arm Group Labels	Other Names
GSK2330672 (linerixibat)	Drug	GSK2330672 is available as a tablet with unit dose strength of 45 mg.	Participants receiving obeticholic acid and linerixibat

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Part A- Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-t]) for Total-OCA at Steady State: OCA Arm	Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. Pharmacokinetic (PK) Parameters Population consisted of all participants for whom pharmacokinetic parameters were derivable.	Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose
Part A- AUC(0-t) for Total-OCA at Steady State: OCA + Linerixibat Arm	Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.	Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose
Part A- Area Under the Concentration-time Curve From Time 0 to 24 Hour (AUC[0-24]) for Total-OCA at Steady State: OCA Arm	Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.	Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose
Part A- AUC(0-24) for Total-OCA at Steady State: OCA + Linerixibat Arm	Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.	Days 35 and 36: Pre-dose; Day 37: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 38) post-dose
Part A- Maximum Observed Concentration (Cmax) for Total-OCA at Steady State: OCA Arm

Secondary Outcomes

Measure	Description	Time Frame
Part A- Time to Reach Maximum Observed Plasma Concentration (Tmax) for Total-OCA: OCA Arm	Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis.	Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Between 18 and 80 years of age inclusive, at the time of signing the informed consent.
Healthy, as determined by the investigator or medically qualified designee, based on a medical evaluation including medical history, physical examination, vital signs, laboratory tests, and ECG. A participant with a clinical abnormality or laboratory parameter (i.e., outside the reference range for the population being studied), which is not specifically listed in the eligibility criteria, may be included only if the investigator agrees in consultation with the GlaxoSmithKline (GSK) medical monitor and documents in the source documentation that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures or outcomes.
Body weight > 50 kilogram (kg) and body mass index (BMI) within the range 18.5 to 32 kg per square meter (inclusive).
Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and protocol.
Male and female- A female participant is eligible to participate if she is not pregnant not 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. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.

Exclusion Criteria:

Any active dermatologic disorder leading to or with the potential to cause pruritus or a recent history of unexplained clinically significant itching locally or generally within the prior 3 months
Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones) and/or confirmed hepatocellular carcinoma or biliary cancer
Participants with a history of cholecystectomy
Current symptomatic cholelithiasis or inflammatory gall bladder disease
Significant history of or current 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) clinical laboratory tests, or 12-lead ECG
Current episode, recent history (within 1 month of screening visit), or chronic history of clinically significant diarrhea
Lymphoma, leukaemia, or any malignancy within the past 5 years except for basal cell or squamous epithelial carcinomas of the skin that have been resected with no evidence of metastatic disease for 3 years
Any current medical condition (e.g. psychiatric disorder, senility, dementia, or other condition), clinical or laboratory abnormality, or examination finding that the investigator considers would put the participant at unacceptable risk, which may affect study compliance or prevent understanding of the aims or investigational procedures or possible consequences of the study
Regular use of known drugs of abuse or history of drug abuse or dependence within 6 months of the study
Regular alcohol consumption within 6 months prior to the study defined as an average weekly intake of >14 units for females and >21 units for males. One unit is equivalent to 8 gram of alcohol: a glass (approximately [~] 240 milliliter [mL]) of beer, 1 small glass (~100 mL) of wine or 1 (~25 mL) measure of spirits
History of or regular use of tobacco- or nicotine-containing products (confirmed by smokerlyzer test) in the 3 months prior to screening.
Administration of any IBAT inhibitor (including linerixibat) or OCA in the 3 months prior to screening
Past or intended use of over-the-counter or prescription medication (including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme inhibitor) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless approved by the investigator in conjunction with GSK medical monitor.
Current enrollment in a clinical trial, recent participation in a clinical trial and has received an investigational product within 30 days (or 5 half-lives of previous trial intervention, whichever is longer) before the first dose in the current study
Exposure to more than 4 new chemical entities within 12 months before the first dose in the current study.
Screening ALT or AST >1.5 times the upper limit of normal (ULN)
Bilirubin >1.5 times ULN (isolated bilirubin >1.5 times ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%)
Presence of Hepatitis B surface antigen (HBsAg) at screening or positive Hepatitis C antibody test result at screening or within 3 months of the screening visit
Positive serum pregnancy test at screening or positive urine pregnancy test at admission in WOCBP only
Positive human immunodeficiency virus (HIV) antibody test
QTc >450 millisecond (msec) on ECG performed at screening.
Positive pre-study drug/alcohol screen or positive drug/alcohol screen at any time during the study.
Female participants unable or unwilling to comply with specific contraception restrictions.
Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56-day period.
Unwillingness or inability to follow the procedures outlined in the protocol for the expected duration of study participation.
Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the investigator or medical monitor, contraindicates participation in the study.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Cambridge		CB2 0GG	United Kingdom

ID	Title	Description
FG000	Part A: OCA 10 mg Followed by OCA 10 mg + Linerixibat 90 mg	In Period 1, participants received OCA 10 milligram (mg), tablets, orally, once daily (afternoon dose) for 19 days (study Day 1 to Day 19). In Period 2 participants were administered OCA 10 mg, tablets, orally, once daily (afternoon dose) for 18 days (study Day 20 to Day 37) along with linerixibat 90 mg, tablets, orally, twice daily for 18.5 days (study Day 20 to the morning of Day 38). There was no washout period between Period 1 and Period 2.
FG001	Part B: OCA 5mg or 10mg Followed by OCA 10mg+Linerixibat 180mg	In Part B, participants were planned to receive OCA 5 mg or 10 mg, tablets, orally, once daily (evening dose) for 19 days (study Day 1 to Day 19) in Period 1; followed by OCA 10 mg, tablets, orally, once daily (evening dose) for 18 days (study Day 20 to Day 37) along with linerixibat 180 mg, tablets, orally, once daily for 18.5 days (study Day 20 to the morning of Day 38) in Period 2. There was no planned washout period between Period 1 and Period 2.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Part A: OCA 10 mg Followed by OCA 10 mg + Linerixibat 90 mg	In Period 1, participants received OCA 10 milligram (mg), tablets, orally, once daily (afternoon dose) for 19 days (study Day 1 to Day 19). In Period 2 participants were administered OCA 10 mg, tablets, orally, once daily (afternoon dose) for 18 days (study Day 20 to Day 37) along with linerixibat 90 mg, tablets, orally, twice daily for 18.5 days (study Day 20 to the morning of Day 38). There was no washout period between Period 1 and Period 2.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous	All Participants Population consisted of all participants who took at least 1 dose of study intervention.

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Part A- Area Under the Concentration-time Curve From Time 0 to Time of the Last Quantifiable Concentration (AUC[0-t]) for Total-OCA at Steady State: OCA Arm

Blood samples were collected at indicated time points for pharmacokinetic analysis of total-OCA. Pharmacokinetic parameters were calculated using standard non-compartmental analysis. Pharmacokinetic (PK) Parameters Population consisted of all participants for whom pharmacokinetic parameters were derivable.

PK Parameters Population.

Posted

Geometric Mean

Geometric Coefficient of Variation

Hours*nanogram per milliliter

Day 17: Pre-dose; Day 18: Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14 and 24 hours (Day 19) post-dose

ID	Title	Description
OG000	Part A: OCA 10 mg	In Part A, participants received OCA 10 mg, tablets, orally, once daily (afternoon dose) for 19 days (study Day 1 to Day 19) in Period 1.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Part A: OCA 10 mg	In Part A, participants received OCA 10 mg, tablets, orally, once daily (afternoon dose) for 19 days (study Day 1 to Day 19) in Period 1.

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Jun 5, 2019	Jun 18, 2020	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Feb 7, 2020	Jun 18, 2020	SAP_001.pdf

ID	Term
D002779	Cholestasis
D008105	Liver Cirrhosis, Biliary

ID	Term
D001649	Bile Duct Diseases
D001660	Biliary Tract Diseases
D004066	Digestive System Diseases
D002780	Cholestasis, Intrahepatic

ID	Term
C583160	3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid
C464660	obeticholic acid