Last updated: 11/17/2022 03:50:05
Dose response study of GSK2330672 for the treatment of pruritus in participants with primary biliary cholangitis
EudraCT ID
EU CT Number
Not applicable
Trial status
Completed
Completed
Trial overview
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)
Trial description: 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.
Primary purpose:
Treatment
Trial design:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Allocation:
Randomized
Primary outcomes:
Mean change from Baseline at Week 16 in the Mean Worst Daily Itch Score
Timeframe: Baseline and Week 16
Secondary outcomes:
Mean change from Baseline at Week 16 in Primary Biliary Cholangitis-40 (PBC-40) scale
Timeframe: Baseline and Week 16
Mean change from Baseline at Week 16 in serum alkaline phosphatase (ALP) concentrations, in participants with high risk of PBC progression
Timeframe: Baseline and Week 16
Number of participants with serum ALP concentrations <1.67xULN and total bilirubin concentrations =<ULN at Week 16, among those with a high risk of PBC progression
Timeframe: Week 16
Mean change from Baseline at Week 16 in serum alanine aminotransferase (ALT)among those with a high risk of PBC progression
Timeframe: Baseline and Week 16
Mean change from Baseline at Week 16 in serum aspartate aminotransferase (AST) among those with a high risk of PBC progression
Timeframe: Baseline and Week 16
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 Week 16
Mean change from Baseline at Week 16 in total bilirubin concentration, among those with a high risk of PBC progression
Timeframe: Baseline and Week 16
Mean change from Baseline at Week 16 in albumin concentration, among those with a high risk of PBC progression
Timeframe: Baseline and Week 16
Mean change from Baseline at Week 16 in prothrombin time/international normalized ratio (PT/INR), among those with a high risk of PBC progression
Timeframe: Baseline and Week 16
Number of participants with any adverse event (AE) or serious adverse event (SAE)
Timeframe: Up to Week 20
Number of participants with abnormal clinical chemistry parameters, as a measure of safety
Timeframe: Up to Week 20
Number of participants with abnormal hematology laboratory parameters, as a measure of safety
Timeframe: Up to Week 20
Electrocardiogram (ECG) assessment as a measure of safety
Timeframe: Up to Week 20
Blood pressure assessment as a measure of safety
Timeframe: Up to Week 20
Measurement of heart rate as a measure of safety
Timeframe: Up to Week 20
Gastrointestinal Symptom Rating Scale (GSRS) assessment
Timeframe: Up to Week 20
Number of participants with Mean Worst Daily Itch Score of <4 at Week 16
Timeframe: Week 16
Number of participants with at least a 30% reduction from Baseline in the Mean Worst Daily Itch Score at Week 16
Timeframe: Baseline and Week 16
Number of participants with at least a 2-point reduction from Baseline in the Mean Worst Daily Itch Score at Week 16
Timeframe: Baseline and Week 16
Mean number of days with Worst Daily Itch Score of <4
Timeframe: Baseline to Week 16
Mean number of days with Worst Daily Itch Score at least 30% lower than the Baseline Mean Worst Daily Itch Score
Timeframe: Baseline to Week 16
Mean number of days with Worst Daily Itch Score at least 2-points lower than the Baseline Mean Daily Score
Timeframe: Baseline to Week 16
Change from Baseline in the Mean Daily Sleep Score at Week 16
Timeframe: Baseline and Week 16
Change from Baseline in the Mean Daily Fatigue Score at Week 16
Timeframe: Baseline and Week 16
Change from Baseline in the 5-Dimensional (5-D) Itch Scale at Week 16
Timeframe: Baseline and Week 16
Mean change from Baseline at Week 16 in serum total bile acid concentration
Timeframe: Baseline and Week 16
Mean change from Baseline at Week 16 in serum 7-alpha hydroxy-4-cholesten-3-one (C4)
Timeframe: Baseline and Week 16
Plasma concentration of GSK2330672 after sparse sampling
Timeframe: Week 8 and Week 12 (Between 1 and 3 hours post-dose, and between 5 and 8 hours post-dose)
Interventions:
Drug: Placebo
Drug: GSK2330672
Enrollment:
147
Observational study model:
Not applicable
Primary completion date:
2020-15-04
Time perspective:
Not applicable
Clinical publications:
Cynthia Levy, Stuart Kendrick, Christopher L. Bowlus, Atsushi Tanaka, David Jones, Andreas E. Kremer, Marlyn J. Mayo, Nazneen Haque, Robyn von Maltzahn, Matthew Allinder, Brandon Swift, Megan M. McLaughlin, Gideon M. Hirschfield on behalf of the GLIMMER study group. GLIMMER: A randomized Phase 2b dose-ranging trial of linerixibat in primary biliary cholangitis patients with pruritus. Clin Gastroenterol Hepatol. 2022;
DOI: 10.1016/j.cgh.2022.10.032
PMID: 36343847
Medical condition
Cholestasis
Product
GSK2330672
Collaborators
Not applicable
Study date(s)
January 2017 to April 2020
Type
Interventional
Phase
2
Participation criteria
Sex
Female & Male
Age
18 - 80 Years
Accepts healthy volunteers
No
- Inclusion Criteria
- Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent.
Inclusion and exclusion criteria
Inclusion 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.
Trial location(s)
Location
GSK Investigational Site
Allentown, Pennsylvania, United States, 18104
Status
Study Complete
Location
GSK Investigational Site
Camperdown, New South Wales, Australia, 2050
Status
Study Complete
Location
GSK Investigational Site
Dallas, Texas, United States, 75390-8887
Status
Study Complete
Location
GSK Investigational Site
Manhasset, New Jersey, United States, 11030
Status
Study Complete
Location
GSK Investigational Site
Middlesbrough, United Kingdom, TS4 3BW
Status
Study Complete
Location
GSK Investigational Site
Nedlands, Western Australia, Australia, 6009
Status
Study Complete
Location
GSK Investigational Site
New York, New York, United States, 10032
Status
Study Complete
Location
GSK Investigational Site
Newcastle-upon-Tyne, United Kingdom, NE1 4LP
Status
Study Complete
Location
GSK Investigational Site
Phoenix, Arizona, United States, 85054
Status
Study Complete
Location
GSK Investigational Site
Sacramento, California, United States, 95817
Status
Study Complete
Location
GSK Investigational Site
Seattle, Washington, United States, 981104
Status
Study Complete
Study documents
Protocol
Available language(s): English
Statistical analysis plan
Available language(s): English
If you wish to request for full study report, please contact - [email protected]
Results overview
Results posted on ClinicalTrials.gov
Recruitment status
Completed
Actual primary completion date
2020-15-04
Actual study completion date
2020-15-04
Plain language summaries
Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.
Additional information about the trial
Additional information
Not applicable
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