Global Linerixibat Itch Study of Efficacy and Safety in Primary Biliary Cholangitis (PBC) (GLISTEN)

Study Overview
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Brief Summary
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This is a 2-part study in PBC participants with cholestatic pruritus and will evaluate the efficacy, safety and impact on health-related quality of life of linerixibat compared with placebo.

Official Title
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A Two-part, Randomized, Placebo Controlled, Double Blind, Multicenter, Phase 3 Study to Evaluate the Efficacy and Safety of Linerixibat for the Treatment of Cholestatic Pruritus in Participants With Primary Biliary Cholangitis (PBC)

Conditions
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Pruritus

Intervention / Treatment
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* Drug: Linerixibat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female participants must be between 18 to 80 years of age inclusive, at the time of signing the informed consent. Participants who have documented PBC. Participants who have moderate to severe itch. Exclusion Criteria: Symptoms suggestive of active coronavirus disease 2019 (COVID-19) infection whilst symptoms persist or known COVID-19 positive contacts within the past 14 days should be excluded for at least 14 days from the exposure. Total bilirubin >2.0 times Upper Limit of Normal (ULN) using the average of two Baseline measures. Screening Alanine Aminotransferase (ALT) > 6 times ULN in a single Baseline measure or ALT > 5 times ULN using the average of two Baseline measures. Screening estimated glomerular filtration rate (eGFR) <30 milliliter per minute per 1.73 square meter (mL/min/1.73m^2). History or presence of hepatic decompensation (e.g., variceal bleeding, hepatic encephalopathy or ascites). Presence of actively replicating viral hepatitis B or C (HBV, HCV) infection, primary sclerosing cholangitis (PSC), alcoholic liver disease and/or confirmed hepatocellular carcinoma or biliary cancer. Current clinically significant diarrhea or active inflammatory ileal disease according to Investigator´s clinical judgment. Current symptomatic cholelithiasis or cholecystitis. Current diagnosis of primary skin disorders with itch symptoms (e.g., atopic dermatitis, psoriasis). Primary sleep disorders such as but are not limited to sleep apnea, narcolepsy, hypersomnia. Current/previous diagnosis of colorectal cancer. Initiation, discontinuation or change in dose of ursodeoxycholic acid (UDCA), bezafibrate or fenofibrate in the 8 weeks prior to Screening. Use of obeticholic acid: within 8 weeks prior to Screening. (Participants may not initiate or restart during the study). Initiation, discontinuation, or change in dose of any of the following in the 8 weeks prior to Screening: bile acid binding resins, rifampicin, naltrexone, naloxone, nalfurafine, pregabalin, gabapentin, sertraline or other selective serotonin reuptake inhibitor (SSRIs), antihistamines used for the treatment of itching. Administration of any other human ileal bile acid transporter (IBAT) inhibitor in the 12 weeks prior to screening. Any planned procedures intended to treat cholestatic pruritus such as nasobiliary drainage or ultraviolet light therapy from Screening and throughout the study. History of sensitivity or intolerance to the study treatment.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized to receive linerixibat and/or placebo during the study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants receiving linerixibat<br> | Drug: Linerixibat<br>* Participants will receive linerixibat.<br>|
| Experimental: Participants receiving linerixibat followed by placebo<br> | Drug: Linerixibat<br>* Participants will receive linerixibat.<br>Drug: Placebo<br>* Participants will receive placebo.<br>|
| Placebo Comparator: Participants receiving placebo<br> | Drug: Placebo<br>* Participants will receive placebo.<br>|
| Experimental: Participants receiving placebo followed by linerixibat<br> | Drug: Linerixibat<br>* Participants will receive linerixibat.<br>Drug: Placebo<br>* Participants will receive placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Monthly Itch Scores over 24 weeks using Numerical Rating Scale (NRS) | Monthly Itch Score will be assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. | Baseline and up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Mean Worst Daily Itch score at Week 2 | Mean Worst Daily Itch score will be assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. | Baseline and Week 2 | 
| Change from Baseline in Monthly Sleep Score as measured by NRS over 24 weeks | Monthly Sleep Score will be assessed using an NRS scale, ranging from 0 to 10, where 0 represents no sleep interference and 10 is complete sleep interference. | Baseline and up to 24 weeks | 
| Change from Baseline in Primary Biliary Cholangitis-40 (PBC-40) domain scores at Week 24 | PBC-40 questionnaire 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. | Baseline and Week 24 | 
| Number of participants achieving a >=2-point reduction from Baseline in the Monthly Itch Score at Week 24 | Number of participants achieving a >=2-point reduction from Baseline in the Monthly Itch Score will be assessed. | Baseline and Week 24 | 
| Number of participants achieving a >=3-point reduction from Baseline in the Monthly Itch Score at Week 24 | Number of participants achieving a >=3-point reduction from Baseline in the Monthly Itch Score will be assessed. | Baseline and Week 24 | 
| Number of participants as achieving a >=4-point reduction from Baseline in the Monthly Itch Score at Week 24 | Number of participants as achieving a >=4-point reduction from Baseline in the Monthly Itch Score will be assessed. | Baseline and Week 24 | 
| Change from Baseline in Patient's Global Impression of Severity (PGI-S) over 24 weeks | Participant-reported overall impression of itch severity will be assessed by PGI-S questionnaire using a 5-level response scale, ranging from absent to very severe. | Baseline and up to 24 weeks | 
| Patient's Global Impression of Change (PGI-C) scores over 24 weeks | Participant-reported change in itch severity will be assessed by PGI-C questionnaire using a 7-level response scale, ranging from very much improved to very much worse. | Up to 24 weeks | 
| Change from Baseline in alkaline phosphatase (ALP) at Week 24 | Change from Baseline in ALP at Week 24 will be evaluated. | Baseline and Week 24 | 
| Change from Baseline in bilirubin at Week 24 | Change from Baseline in bilirubin at Week 24 will be evaluated. | Baseline and Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cholestasis, GLISTEN, GSK2330672, Itch, Primary biliary cholangitis, Pruritus