Moderate to severe Cholestatic pruritus with primary biliary cholangitis (PBC). MedDRA version: 24.1 Level: PT Classification code 10064190 Term: Cholestatic pruritus System Organ Class: 10040785 - Skin and subcutaneous tissue disorders MedDRA version: 21.0 Level: PT Classification code 10080429 Term: Primary biliary cholangitis System Organ Class: 10019805 - Hepatobiliary disorders
Conditions
Interventions
Product Name: GSK2330672/linerixibat 40 mg
Product Code: GSK2330672/linerixibat 40 mg
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Linerixibat
CAS Number: 1345982-69-5
Current Sponsor
Sponsors
GlaxoSmithKline Research & Development Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Participants are eligible to be included in the study only if all of the following criteria apply: Sex and Age 1. Male and female participants must be between 18 to 80 years of age inclusive, at the time of signing the informed consent. Note: if country/site age requirements for consent differ, the more stringent (e.g., higher age) restriction will be required for that country/site. Type of Participant and Disease Characteristics 2. Participants who have proven PBC, as demonstrated by historically having at least 2 of the following: • Documented history of sustained increased ALP levels greater than ULN first recognized at least 6 months prior to the Screening Visit (Note: Sustained ALP elevations at the time of Screening is not required, recognizing that the ALP may have decreased after initiation of UDCA therapy). • Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme linked immunosorbent assay [ELISA]) or PBC-specific antinuclear antibodies (antinuclear dot and/or nuclear rim positive). • Liver biopsy (documented at any time in the past) consistent with PBC. 3. Participants who, during the Screening period, record their daily itch score by entering at least 40 of the 56 required itch entries, with an entry on at least 4 days in each week, during the 4-week period immediately preceding Randomization at Day 1 and have a Monthly Itch Score of =4 (i.e., at least 1 of the 4 weekly Mean Worst Daily Itch Scores must be =4), and no Mean Worst Daily Itch Score can be =65
Exclusion criteria
Exclusion criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1. Participants with recent positive COVID-19 test results, symptoms suggestive of active COVID-19 infection (e.g. fever, loss of taste or smell, cough, shortness of breath) and/or contact within the past 14 days with someone with COVID-19 are excluded for a minimum of 14 days from the test results or time of exposure, respectively, and must be symptom free before Screening procedures may begin. If a participant tests positive for COVID-19 during the Screening period, the participant should be considered a screen failure and may be re-screened 14 days after the positive test result and after participant is symptom free. 2. Total bilirubin >2.0 x ULN using the average of two baseline measures. Note: Total bilirubin > 2x ULN but 6x ULN in a single baseline measure or ALT > 5x ULN using the average of two baseline measures. 4. Participants with abnormal liver biochemistry (ALT, aspartate aminotransferase [AST], ALP, or total bilirubin) during the Screening period (at Visit 1 or Visit 2) and the variance between these two samples for the abnormal parameter is >40%. Note: Variance will be calculated as the absolute value of [(Sample 1- Sample 2)/average of Sample 1 and Sample 2) x100] If variance of >40% is seen between Visit 1 and 2 samples, an additional sample may be taken and the variance between the additional sample (third sample) and the Screening (Visit 1) sample must be = 40% 5. Screening estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 6. History or presence of hepatic decompensation (e.g., variceal bleeding, hepatic encephalopathy or ascites). 7. 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. 8. Infection with human immunodeficiency virus (HIV) 9. Current clinically significant diarrhea in the Investigator’s medical opinion. 10. Active inflammatory ileal disease according to Investigator´s clinical judgment. 11. Current symptomatic cholelithiasis or cholecystitis. (Participants with history of cholecystectomy =12 weeks before screening may be eligible for enrolment at the discretion of the investigator.) 12. Current diagnosis of primary skin disorders with itch symptoms (e.g., atopic dermatitis, psoriasis). 13. Primary sleep disorders such as but are not limited to sleep apnea, narcolepsy, hypersomnia 14. Any current malignancies (including hematologic and solid malignancies). 15. Current/previous diagnosis of colorectal cancer. 16. History of bariatric surgery with ileal bypass at any time, or any bariatric surgery performed in the past 3 years 17. Any current uncontrolled psychiatric condition 18. Any current medical condition (e.g. senility or dementia), which may affect the participant’s ability to comply with the protocol specified procedures. Prior/Concomitant Therapy 19. Initiation, discontinuation or change in dose of UDCA in the 8 weeks prior to Screening. (Participants may join the study on stable doses of UDCA, but no initiation, discontinuation, or change in dose is permitted until completion of the Treatment Periods.) 20. Use of obeticholic acid: withi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To investigate the effect of treatment with oral linerixibat compared with placebo on itch in PBC patients with cholestatic pruritus over 24 weeks (Part A);Secondary Objective: To evaluate the early effects of oral linerixibat compared to placebo on itch in PBC patients with cholestatic pruritus (Part A) To characterize the effects of treatment with oral linerixibat compared with placebo on health related QoL(Part A) To evaluate the effects of 24 weeks of treatment with oral linerixibat compared to placebo on itch response rates in PBC patients with cholestatic pruritus (Part A) To investigate the treatment effect of oral linerixibat compared with placebo on Patient’s Global Impression of Severity (PGI-S) and Patient’s Global Impression of Change (PGI-C) throughout the treatment period (Part A) To evaluate the effects of treatment with linerixibat on markers of PBC disease activity and progression (Part A ) Safety To evaluate the safety of oral linerixibat compared with placebo (Part A and Part B);Primary end point(s): • Change from Baseline in Monthly Itch Scores over 24 weeks using a 0-10 numerical rating scale (NRS);Timepoint(s) of evaluation of this end point: Itch data will be collected daily from Screening through Week 32 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • Change from baseline in Mean Worst Daily Itch score at Week 2 • Change from Baseline in Monthly Sleep Score as measured by 0-10 NRS over 24 weeks • Change from Baseline in PBC-40 domain scores at Week 24 • Responder defined as achieving a =2-point reduction from Baseline in the Monthly Itch score at Week 24. • Responder defined as achieving a =3-point reduction from Baseline in the Monthly Itch score at Week 24. • Responder defined as achieving a =4-point reduction from Baseline in the Monthly Itch score at Week 24. • Change from baseline in Patient's Global Impression of Severity (PGI-S) over 24 weeks • PGI-C over 24 weeks Change from baseline in ALP at Week 24 • Change from baseline in bilirubin at Week 24 • Clinical assessments including, but not limited to: • Adverse Events (AEs) and Serious Adverse Events (SAEs) • Vital signs • 12-lead Electrocardiogram (ECG) Clinical laboratory evaluation (including liver chemistry panel and fasting lipids);Timepoint(s) of evaluation of this end point: Sleep data will be collected daily from Screening through Week 32. PBC-40, PGI-S, PGI-C, and lab parameters (ALP, bilirubin) will be collected at monthly clinic visits | — |
Countries
Argentina, Belgium, Brazil, Bulgaria, Canada, China, Czechia, Czech Republic, France, Germany, Greece, Israel, Italy, Japan, Mexico, Poland, Russian Federation, Spain, Switzerland, United Kingdom, United States
Contacts
Public ContactClinical Trials Helpdesk Support
GlaxoSmithKline Research & Development Ltd
Outcome results
None listed