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
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 Itch Scores must be =4), and no Weekly Itch Score can be <3 for any other week. Contraceptive/Barrier Requirements 4. Contraceptive/Barrier Requirements (applicable for female participants only): A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies: o Is a woman of non-childbearing potential (WONCBP) OR o Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method as described in Section 10.4 during the study intervention period (at a minimum until 4 weeks after the last dose of study intervention). The investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive urine pregnancy test (or serum as required by local regulations) within 7 days before the first dose of study intervention, see Section 8.2.5 Pregnancy Testing. Note: If a serum pregnancy test is required by local regulations, sample collection must be arranged before Visit 3 to ensure the result confirming eligibility can be available before randomization. • Additional requirements for pregnancy testing during and after study intervention are located in Section 8.2.5. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy Note: Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. • Full requirements for pregnancy testing during and after study intervention are located in Section 10.4 Appendix 4. Informed Consent 5. Capable of giving signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Are the trial subjects u
Exclusion criteria
Exclusion criteria: Participants are excluded from the study if any of the following criteria apply: Medical Conditions 1. 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. 3. 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]. Sample 1 and Sample 2 must be collected at least 4 weeks apart. 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% 4. Screening estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. 5. History or presence of hepatic decompensation (e.g., variceal bleeding, hepatic encephalopathy or ascites). 6. Presence of viral hepatitis B (HBsAg positive) or C (anti-HCV positive and RNA detected) infection, primary sclerosing cholangitis (PSC), alcoholic liver disease and/or confirmed hepatocellular carcinoma or biliary cancer. 7. Infection with human immunodeficiency virus (HIV) 8. Current clinically significant diarrhea in the Investigator’s medical opinion. 9. Active inflammatory ileal disease according to Investigator´s clinical judgment. 10. 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.) 11. Current diagnosis of primary skin disorders with itch as a characteristic feature (e.g., atopic dermatitis, psoriasis). 12. Primary sleep disorders such as but are not limited to sleep apnea, narcolepsy, hypersomnia 13. Any current malignancies (including hematologic and solid malignancies). 14. History of bariatric surgery with ileal bypass at any time, or any bariatric surgery performed in the past 3 years 15. Any current uncontrolled psychiatric condition 16. 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 17. 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.) 18. Use of obeticholic acid: within 8 weeks prior to Screening. (Participants may not initiate or restart during the study, please see Section 6.8.2) 19. Initiation, discontinuation or change in dose of fibrates at any time during the 8 weeks prior to Screening. (Participants may join the study on stable doses of these medications, but no initiation, discontinuation, or change in dose is permitted until completion of the Treatment Periods.) 20. 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, pre
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 Weekly 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