Dose Response Study of GSK2330672 for the Treatment of Pruritus in Participants With Primary Biliary Cholangitis

NCT ID: NCT02966834

Last Updated: 2021-05-04

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 147 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-01-11
• Study Completion Date: 2020-04-15

Brief Summary

This study is being conducted to evaluate the efficacy, safety and tolerability of GSK2330672 administration for the treatment of pruritus (itch) in participants with primary biliary cholangitis (PBC). Participants will receive either placebo or one of the 4 dose regimens of GSK2330672 (20 milligram [mg], 90 mg or 180 mg taken once daily or 90 mg twice daily). Participants on GSK2330672 will also receive placebo tablets to maintain blinding. The study has a prospectively defined adaptive design that will utilize interim data to further inform and potentially optimize the doses under investigation. Hence, additional dose regimen may be added during study. The total duration of a participant in the study will be up to 45 days of screening and 24 weeks of study including follow-up.

Conditions

Cholestasis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo

Participants will receive matching placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

GSK2330672 matching placebo will be supplied as white film-coated tablets.

GSK2330672 20 mg once daily

Participants will receive GSK2330672 and matching placebo to maintain blind

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

GSK2330672 matching placebo will be supplied as white film-coated tablets.

GSK2330672

Intervention Type: DRUG

GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

GSK2330672 90 mg once daily

Participants will receive GSK2330672 and matching placebo to maintain blind

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

GSK2330672 matching placebo will be supplied as white film-coated tablets.

GSK2330672

Intervention Type: DRUG

GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

GSK2330672 180 mg once daily

Participants will receive GSK2330672 and matching placebo to maintain blind

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

GSK2330672 matching placebo will be supplied as white film-coated tablets.

GSK2330672

Intervention Type: DRUG

GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

GSK2330672 40 mg twice daily

Participants will receive GSK2330672 and matching placebo to maintain blind

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

GSK2330672 matching placebo will be supplied as white film-coated tablets.

GSK2330672

Intervention Type: DRUG

GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

GSK2330672 90 mg twice daily

Participants will receive GSK2330672 and matching placebo to maintain blind

Group Type: EXPERIMENTAL

Placebo

Intervention Type: DRUG

GSK2330672 matching placebo will be supplied as white film-coated tablets.

GSK2330672

Intervention Type: DRUG

GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

Interventions

Placebo

GSK2330672 matching placebo will be supplied as white film-coated tablets.

Intervention Type: DRUG

GSK2330672

GSK2330672 will be supplied in 2 dose strengths of 10 mg and 45 mg white film-coated tablets.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
• Participants who have proven PBC, as demonstrated by having at least 2 of the following: History of sustained increased ALP levels >ULN first recognized at least 6 months prior to the Screening Visit (Sustained ALP elevations at the time of Screening is not required, recognizing that the ALP may have decreased after institution of ursodeoxycholic acid (UDCA) therapy as described in inclusion number 4). Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific antinuclear antibodies (antinuclear dot and/or nuclear rim positive). Liver biopsy (at any time in the past) consistent with PBC.
• Participants must rate their itch severity as being >=4 on a 0 to 10 point scale for the majority of time (at least half the days, as recalled by the participant) during the 8 weeks prior to the Screening Visit. Periods of low itch or no itch are acceptable as long as the worst daily itch score is >=4 on the majority of days.
• Participants who are currently taking UDCA should be on stable doses of UDCA for >8 weeks at time of screening. Participants not taking UDCA due to intolerance may be enrolled 8 weeks after their last dose of UDCA. No changes or discontinuation is permitted until completion of the Main Study Period.
• Male and/or female: Female participants- 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 the contraceptive guidance during the treatment period and until at least 4 weeks after the last dose of study treatment.
• Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria

• Screening total bilirubin >2x ULN. Total bilirubin >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35 percent (%).
• Screening ALT or AST >6x ULN.
• Screening eGFR <45 milliliter (mL)/minute/1.73 square meter (m^2) based on the CKD-EPI.
• History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy or ascites).
• Presence of actively replicating viral hepatitis due to hepatitis B or C virus (HBV, HCV) infection, and/or confirmed hepatocellular carcinoma or biliary cancer. Other hepatic conditions ( e.g., primary sclerosing cholangitis [PSC], alcoholic liver disease, autoimmune hepatitis, non-alcoholic steatohepatitis [NASH] ) are permitted if PBC is the dominant liver injury in the investigator's opinion.
• Current diarrhea.
• Current symptomatic cholelithiasis or inflammatory gall bladder disease. Participants with history of cholecystectomy >=3 months before screening may be eligible for enrolment.
• Any current medical condition (e.g. psychiatric disorder, senility or dementia), which may affect the participant's ability to comply with the protocol specified procedures.
• Initiation or increase in dose of colchicine, methotrexate, azathioprine, or systemic corticosteroids in the 2 months prior to screening. If a change in dose in any of these medications is anticipated during the course of the study, the participant should be excluded.
• Initiation or increase in dose of bezafibrate or fenofibrate at any time during the 3 months prior to screening. Participants may join the study on stable doses of these medications, but no change or discontinuation is permitted until completion of the Main Study Period.
• Initiation or increase in dose of any of the following in the 8 weeks prior to screening: rifampicin, naltrexone, naloxone, nalfurafine, or sertraline. Participants may join the study on stable or decreased doses of these medications, but no change in dose is permitted until completion of the Main Study Period.
• Bile acid binding resin use: a participant must discontinue use of cholestyramine, colesevelam, colestipol or colestimide prior to the start of the Initial Study Period (no later than Day-2). Note: these drugs may be administered after completion of the Main Study Period, if clinically indicated.
• Obeticholic acid use: a participant must discontinue use of obeticholic acid at least 8 weeks prior to the start of the Initial Study Period and may not restart until after the end of the study.
• Administration of any other Inhibitor of the Human Ileal Bile Acid Transporter (IBAT) in the 3 months prior to screening.
• Current enrolment or participation within the 8 weeks before start of the Initial Study Period, in any other clinical study involving an investigational study treatment.
• QT interval corrected for heart rate QTc >480 millisecond (msec).
• History of sensitivity to the study treatment or components thereof or a history of drug or other allergy that, in the opinion of the investigator or GlaxoSmithKline (GSK) Medical Monitor, contraindicates their participation in the study.
• History of regular alcohol consumption within 6 months of the study defined as an average weekly intake of >21 units for males or >14 units for females. One unit is equivalent to 8 gram of alcohol: a half-pint (approximately 240 mL) of beer, 1 glass (125 mL) of wine or 1 measure (25 mL) of spirits.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

GlaxoSmithKline

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

GSK Clinical Trials

Role: STUDY_DIRECTOR

GlaxoSmithKline

Locations

GSK Investigational Site

Phoenix, Arizona, United States

GSK Investigational Site

Sacramento, California, United States

GSK Investigational Site

Miami, Florida, United States

GSK Investigational Site

Novi, Michigan, United States

GSK Investigational Site

Manhasset, New Jersey, United States

GSK Investigational Site

New York, New York, United States

GSK Investigational Site

Allentown, Pennsylvania, United States

GSK Investigational Site

Dallas, Texas, United States

GSK Investigational Site

Seattle, Washington, United States

GSK Investigational Site

Camperdown, New South Wales, Australia

GSK Investigational Site

Herston, Queensland, Australia

GSK Investigational Site

Prahran, Victoria, Australia

GSK Investigational Site

Nedlands, Western Australia, Australia

GSK Investigational Site

Calgary, Alberta, Canada

GSK Investigational Site

Edmonton, Alberta, Canada

GSK Investigational Site

Winnipeg, Manitoba, Canada

GSK Investigational Site

London, Ontario, Canada

GSK Investigational Site

Toronto, Ontario, Canada

GSK Investigational Site

Montreal, Quebec, Canada

GSK Investigational Site

Clermont-Ferrand, , France

GSK Investigational Site

Grenoble, , France

GSK Investigational Site

Lille, , France

GSK Investigational Site

Paris, , France

GSK Investigational Site

Pessac, , France

GSK Investigational Site

Erlangen, Bavaria, Germany

GSK Investigational Site

Homburg, Saarland, Germany

GSK Investigational Site

Hamburg, , Germany

GSK Investigational Site

Bologna, Emilia-Romagna, Italy

GSK Investigational Site

Milan, Lombardy, Italy

GSK Investigational Site

Monza (MB), Lombardy, Italy

GSK Investigational Site

Florence, Tuscany, Italy

GSK Investigational Site

Padua, Veneto, Italy

GSK Investigational Site

Chiba, , Japan

GSK Investigational Site

Fukui, , Japan

GSK Investigational Site

Gunma, , Japan

GSK Investigational Site

Hiroshima, , Japan

GSK Investigational Site

Hokkaido, , Japan

GSK Investigational Site

Kagawa, , Japan

GSK Investigational Site

Kanagawa, , Japan

GSK Investigational Site

Nagasaki, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Osaka, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Tokyo, , Japan

GSK Investigational Site

Częstochowa, , Poland

GSK Investigational Site

Katowice, , Poland

GSK Investigational Site

Mysłowice, , Poland

GSK Investigational Site

Warsaw, , Poland

GSK Investigational Site

Wroclaw, , Poland

GSK Investigational Site

Barcelona, , Spain

GSK Investigational Site

Madrid, , Spain

GSK Investigational Site

Madrid, , Spain

GSK Investigational Site

Seville, , Spain

GSK Investigational Site

Valencia, , Spain

GSK Investigational Site

Basingstoke, , United Kingdom

GSK Investigational Site

Edgbaston, , United Kingdom

GSK Investigational Site

Glasgow, , United Kingdom

GSK Investigational Site

Liverpool, , United Kingdom

GSK Investigational Site

London, , United Kingdom

GSK Investigational Site

Manchester, , United Kingdom

GSK Investigational Site

Middlesbrough, , United Kingdom

GSK Investigational Site

Newcastle upon Tyne, , United Kingdom

GSK Investigational Site

Nottingham, , United Kingdom

GSK Investigational Site

Plymouth, , United Kingdom

GSK Investigational Site

Sheffield, , United Kingdom

Countries

United States; Australia; Canada; France; Germany; Italy; Japan; Poland; Spain; United Kingdom

References

Carreno F, Karatza E, Mehta R, Collins J, Austin D, Swift B. Population Dose-Response-Time Analysis of Itch Reduction and Patient-Reported Tolerability Supports Phase III Dose Selection for Linerixibat. Clin Pharmacol Ther. 2024 Feb;115(2):288-298. doi: 10.1002/cpt.3103. Epub 2023 Dec 3.

Reference Type: DERIVED

PMID: 37953500 (View on PubMed)

Tanaka A, Atsukawa M, Tsuji K, Notsumata K, Suyama A, Ito H, Das S, von Maltzahn R, McLaughlin MM. Japanese subgroup analysis of GLIMMER: A global Phase IIb study of linerixibat for the treatment of cholestatic pruritus in patients with primary biliary cholangitis. Hepatol Res. 2023 Jul;53(7):629-640. doi: 10.1111/hepr.13895. Epub 2023 Mar 13.

Reference Type: DERIVED

PMID: 36852705 (View on PubMed)

Levy C, Kendrick S, Bowlus CL, Tanaka A, Jones D, Kremer AE, Mayo MJ, Haque N, von Maltzahn R, Allinder M, Swift B, McLaughlin MM, Hirschfield GM; GLIMMER Study Group. GLIMMER: A Randomized Phase 2b Dose-Ranging Trial of Linerixibat in Primary Biliary Cholangitis Patients With Pruritus. Clin Gastroenterol Hepatol. 2023 Jul;21(7):1902-1912.e13. doi: 10.1016/j.cgh.2022.10.032. Epub 2022 Nov 4.

Reference Type: DERIVED

PMID: 36343847 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2016-002416-41

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

201000

Identifier Type: -

Identifier Source: org_study_id