Linerixibat Long-term Safety, and Tolerability Study

Study Overview
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Brief Summary
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This is an open-label, non-comparator, global, multi-center, long-term safety study for evaluating safety and tolerability of linerixibat in participants with cholestatic pruritus in primary biliary cholangitis (PBC) who participated in a prior clinical trial with linerixibat (BAT117123 [NCT01899703], 201000 GLIMMER [NCT02966834] (group 1) or 212620 GLISTEN [NCT00210418]) (group 2). All participants will receive open-label linerixibat for the duration of the study. The study duration is expected to last until the study's end or until linerixibat can be lawfully made available to participants. However, the total duration of study participation will vary by participant depending upon the time of entry relative to study end in their respective country.

Official Title
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Long-term Safety and Tolerability Study of Linerixibat for the Treatment of Cholestatic Pruritus in Participants With Primary Biliary Cholangitis

Conditions
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Cholestasis

Intervention / Treatment
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* Drug: Linerixibat


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants must be 18 to 80 years of age inclusive, at the time of signing the informed consent in the participant's parent trial BAT117213, GLIMMER or GLISTEN. Participants with a diagnosis of PBC and a history of associated pruritus as evidenced by randomization into a prior eligible linerixibat clinical trial (BAT117213, GLIMMER or GLISTEN). Participants must have completed the main treatment period in a prior eligible linerixibat clinical trial (BAT117213, GLIMMER or GLISTEN). A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: a) is a woman of non-childbearing potential (WONCBP) or b) is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method. Capable of giving signed informed consent. Exclusion Criteria: Screening total bilirubin >2x upper limit of normal (ULN). Screening alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >6x ULN. Screening estimated glomerular filtration rate (eGFR) <30 milliliters per minute per 1.73 square meter (mL/min/1.73m^2) based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy or ascites). Presence of actively replicating viral hepatitis B or C (Viral Hepatitis B [HBV], viral Hepatitis C [HCV]) infection), primary sclerosing cholangitis (PSC), alcoholic liver disease and/or confirmed hepatocellular carcinoma or biliary cancer. Current clinically significant diarrhea in the Investigator's medical opinion. Current symptomatic cholelithiasis or cholecystitis. Current diagnosis or previous diagnosis of colorectal cancer. Any current malignancies (including hematologic and solid malignancies). History of bariatric surgery with ileal bypass at any time, or any bariatric surgery performed in the past 3 years. Use of Obeticholic acid: within 8 weeks prior to the date of the screening visit and may not restart until after the end of the study or early study withdrawal. Administration of any other ileal bile acid transporter (IBAT) inhibitor in the 1 month prior to screening until after the end of the study or early study withdrawal. QT interval corrected (QTc) >480 millisecond (msec) at screening (12-lead ECG) Participants with moderate (or greater) alcohol consumption defined as more than one standard drink per day for women and two drinks per day for men.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a non-comparator single group study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving linerixibat<br>Participants who previously participated in the Phase 2 studies (BAT117213 and 201000 GLIMMER [Group 1]) and Phase 3 study (212620 GLISTEN [Group 2]), will receive linerixibat. | Drug: Linerixibat<br>* All participants will receive linerixibat.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with non-serious adverse events (AEs) and Serious AEs (SAEs) | AEs and SAEs will be collected. | Up to 66 months | 
| Number of participants with Severe AEs | AEs and SAEs will be collected. | Up to 66 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in domain scores of the PBC-40 over time | The PBC-40 is a participant-derived, disease specific health-related quality of life (QoL) measure with data to support its validity in PBC. The PBC-40 measure is comprised of 40 questions, each scored on a scale of 1 to 5 (where 1 = least impact, 5 = greatest impact) grouped into six domains (symptoms, itch, fatigue, cognition, social, and emotional). | Baseline and up to 65 months | 
| Change in health-related quality of life (QoL) by the Euro Quality-5 dimension-3 level (EQ-5D-3L) scores over time (Group 1 only) | The EQ-5D-3L is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life that can be used in a wide range of health conditions and treatments. The EQ-5D consists of a descriptive system and the EQ Visual Analogue Scale (VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels: 1=no problems, 2=some problems, and 3=extreme problems. | Baseline and up to 65 months | 
| Change in self-rated health by EQ VAS scores over time (Group 1 only) | The EQ-5D-3L is a standardized instrument developed by the EuroQol Group as a measure of health-related quality of life that can be used in a wide range of health conditions and treatments. The EQ-5D consists of a descriptive system and the EQ VAS. The EQ VAS records self-rated health on a vertical visual analogue scale where the endpoints are labelled 'Best imaginable health state' and 'Worst imaginable health state'. | Baseline and up to 65 months | 
| Change in the Beck Depression Inventory (BDI-II) scores over time | The BDI-II is a 21-item questionnaire used to assess the intensity of depression in clinical and normal participants. Each item is scored from 0 (Normal) to 3 (Severe). The total score on the BDI-II ranges from 0-63, with higher scores reflecting higher levels of depression. | Baseline and up to 65 months | 
| Number of participants with clinically significant changes in hematology, biochemistry (including lipid and liver parameters), and coagulation parameters | Blood samples will be collected for the analysis of hematology, biochemistry (including lipid and liver parameters) and coagulation parameters. | Baseline and up to 65 months | 
| Percentage of responders at Week 24 and Week 52 of continuous treatment (Group 2 only) | Monthly Itch Score (MIS) will be assessed using an numerical rating scale (NRS), ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. Response thresholds of greater than or equal to (>=) 2, >=3, and >=4-point reduction in MIS will be assessed. | Week 24 and Week 52 of continuous treatment | 
| Percentage of participants with maintenance of efficacy at Week 52 of continuous treatment in those that were responders at Week 24 of continuous treatment (Group 2 only) | The MIS will be assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. Maintenance of efficacy occurs when a participant is a responder (>=2, >=3, and >=4-point reduction in MIS) at Week 24 of continuous treatment and is also a responder at Week 52 of continuous treatment. | Week 52 of continuous treatment | 
| Change from Baseline Monthly Sleep Score (MSS) (Group 2 only) | The MSS will be assessed using an NRS, ranging from 0 to 10, where 0 represents no sleep interference and 10 is complete sleep interference. This will be assessed at Week 52 of continuous treatment. | Baseline and up to Week 52 of continuous treatment | 
| Change from Baseline in Monthly Fatigue Score (MFS)(Group 2 only) | The MFS will be assessed using an NRS, ranging from 0 to 10, where 0 represents no fatigue and 10 the worst possible fatigue. This will be assessed at Week 52 of continuous treatment. | Baseline and up to Week 52 of continuous treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Linerixibat, Cholestasis, Cholestatic pruritus, Primary biliary cholangitis, LLSAT