Clinical trial NCT02966834: Dose Response Study of GSK2330672 for the Treatment of Pruritus in Participants With Primary Biliary Cholangitis
Official title: A Randomized, Double-blind, Multi-dose, Placebo-controlled Study to Evaluate the Efficacy, Safety and Tolerability of GSK2330672 Administration for the Treatment of Pruritus in Patients With Primary Biliary Cholangitis (GLIMMER: GSK2330672 triaL of IBAT Inhibition With Multidose Measurement for Evaluation of Response)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cholestasis
Keywords: linerixibat
PBC
itch
GSK2330672
GLIMMER
primary biliary cholangitis
pruritus
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2016-11-17
Enrollment: 147
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Mean Change From Baseline at Week 16 in the Mean Worst Daily Itch Score
timeFrame: Baseline and Week 16
Secondary outcomes:
measure: Mean Change From Baseline at Week 16 in Primary Biliary Cholangitis-40 (PBC-40) Scale
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Serum Alkaline Phosphatase (ALP) Concentrations, in Participants With High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Number of Participants With Serum ALP Concentrations Less Than (<)1.67 Times ULN and Total Bilirubin Concentrations Less Than or Equal to (<=) ULN at Week 16
timeFrame: At Week 16
measure: Mean Change From Baseline at Week 16 in Serum Alanine Aminotransferase (ALT) Among Those With a High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Serum Aspartate Aminotransferase (AST) Among Those With a High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Serum Gamma Glutamyl Transferase (GGT), Among Those With a High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Total Bilirubin Concentration, Among Those With a High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Albumin Concentration, Among Those With a High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Prothrombin International Normalized Ratio (INR), Among Those With a High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Prothrombin Time, Among Those With a High Risk of PBC Progression
timeFrame: Baseline and at Week 16
measure: Number of Participants With Non-serious Adverse Events (Non-SAEs) and Serious Adverse Events (SAEs) -Main Study Period
timeFrame: Up to 12 weeks
measure: Number of Participants With Non-SAEs and SAEs -Final Study Period
timeFrame: Up to 4 weeks
measure: Number of Participants With Non-SAEs and SAEs - Follow-up Period
timeFrame: Up to 4 weeks
measure: Number of Participants With Clinical Chemistry Data of Potential Clinical Importance
timeFrame: At Weeks 8, 12, 16 and 20
measure: Number of Participants With Hematology Data of Potential Clinical Importance
timeFrame: At Weeks 8, 12, 16 and 20
measure: Number of Participants With Abnormal 12-Lead Electrocardiogram (ECG) Parameters
timeFrame: At Weeks 8, 12, 16 and 20
measure: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
timeFrame: Baseline and Week 20
measure: Change From Baseline in Pulse Rate
timeFrame: Baseline and Week 20
measure: Change From Baseline in Gastrointestinal Symptom Rating Scale (GSRS) Assessment
timeFrame: Baseline and Week 20
measure: Number of Participants With Mean Worst Daily Itch Score of <4 at Week 16
timeFrame: At Week 16
measure: Number of Participants With Improvement of >= 30 Percent (%) in the Mean Worst Daily Itch Score at Week 16 From Baseline
timeFrame: Baseline and At Week 16
measure: Number of Participants With Improvement of >=2 in the Mean Worst Daily Itch Score at Week 16 From Baseline
timeFrame: Baseline and At Week 16
measure: Percentage of Responder Days With Worst Daily Itch Score of <4
timeFrame: Up to Week 16
measure: Percentage of Responder Days With Improvement of >= 30% in the Mean Worst Daily Itch Score at Week 16 From Baseline
timeFrame: Baseline and at Week 16
measure: Percentage of Responder Days With Improvement of >=2 in the Mean Worst Daily Itch Score at Week 16 From Baseline
timeFrame: Baseline and at Week 16
measure: Change From Baseline in the Mean Daily Sleep Score at Week 16
timeFrame: Baseline and at Week 16
measure: Change From Baseline in the Mean Daily Fatigue Score at Week 16
timeFrame: Baseline and at Week 16
measure: Change From Baseline in the Five-Dimensional (5-D) Itch Scale at Week 16
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Serum Total Bile Acid Concentration
timeFrame: Baseline and at Week 16
measure: Mean Change From Baseline at Week 16 in Serum 7-alpha Hydroxy-4-cholesten-3-one (C4)
timeFrame: Baseline and at Week 16
measure: Plasma Concentration of GSK2330672 After Sparse Sampling
timeFrame: At Week 4 (between 1 and 3 hours post-dose) and At Weeks 8, 12 and 16 (between 1 and 3 hours post-dose, and between 5 and 8 hours post-dose)
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Miami
country: United States
facility: GSK Investigational Site
state: Florida
city: Novi
country: United States
facility: GSK Investigational Site
state: Michigan
city: Manhasset
country: United States
facility: GSK Investigational Site
state: New Jersey
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Allentown
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Camperdown
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Herston
country: Australia
facility: GSK Investigational Site
state: Queensland
city: Prahran
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Nedlands
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Calgary
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Winnipeg
country: Canada
facility: GSK Investigational Site
state: Manitoba
city: London
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montréal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Clermont-Ferrand
country: France
facility: GSK Investigational Site
city: Grenoble Cedex 9
country: France
facility: GSK Investigational Site
city: Lille cedex
country: France
facility: GSK Investigational Site
city: Paris cedex 12
country: France
facility: GSK Investigational Site
city: Pessac cedex
country: France
facility: GSK Investigational Site
city: Erlangen
country: Germany
facility: GSK Investigational Site
state: Bayern
city: Homburg
country: Germany
facility: GSK Investigational Site
state: Saarland
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Bologna
country: Italy
facility: GSK Investigational Site
state: Emilia-Romagna
city: Milano
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Monza (MB)
country: Italy
facility: GSK Investigational Site
state: Lombardia
city: Firenze
country: Italy
facility: GSK Investigational Site
state: Toscana
city: Padova
country: Italy
facility: GSK Investigational Site
state: Veneto
city: Chiba
country: Japan
facility: GSK Investigational Site
city: Fukui
country: Japan
facility: GSK Investigational Site
city: Gunma
country: Japan
facility: GSK Investigational Site
city: Hiroshima
country: Japan
facility: GSK Investigational Site
city: Hokkaido
country: Japan
facility: GSK Investigational Site
city: Kagawa
country: Japan
facility: GSK Investigational Site
city: Kanagawa
country: Japan
facility: GSK Investigational Site
city: Nagasaki
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Osaka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
city: Czestochowa
country: Poland
facility: GSK Investigational Site
city: Katowice
country: Poland
facility: GSK Investigational Site
city: Myslowice
country: Poland
facility: GSK Investigational Site
city: Warszawa
country: Poland
facility: GSK Investigational Site
city: Wroclaw
country: Poland
facility: GSK Investigational Site
city: Barcelona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Sevilla
country: Spain
facility: GSK Investigational Site
city: Valencia
country: Spain
facility: GSK Investigational Site
city: Basingstoke
country: United Kingdom
facility: GSK Investigational Site
city: Edgbaston
country: United Kingdom
facility: GSK Investigational Site
city: Glasgow
country: United Kingdom
facility: GSK Investigational Site
city: Liverpool.
country: United Kingdom
facility: GSK Investigational Site
city: London
country: United Kingdom
facility: GSK Investigational Site
city: Manchester
country: United Kingdom
facility: GSK Investigational Site
city: Middlesbrough
country: United Kingdom
facility: GSK Investigational Site
city: Newcastle-upon-Tyne
country: United Kingdom
facility: GSK Investigational Site
city: Nottingham
country: United Kingdom
facility: GSK Investigational Site
city: Plymouth
country: United Kingdom
facility: GSK Investigational Site
city: Sheffield
country: United Kingdom
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.