What is the Purpose of this Study?
Cholestatic pruritus burdens up to three quarters of patients with PBC during the course
of their disease. This itch due to this rare and chronic liver disease, represents a serious
condition that continues to lack effective treatments.
Linerixibat, an ileal bile acid transporter inhibitor administered as an oral tablet, is
minimally absorbed from gastrointestinal tract. Linerixibat is anticipated to reduce
pruritus and associated symptoms in patients with PBC by increasing the excretion of bile
acids and reducing bile acid concentrations in systemic circulation. Twice daily
linerixibat has demonstrated significant improvement in cholestatic pruritus in PBC
patients in previous Phase 2a and Phase 2b studies.
Moreover, the Phase 2b dose ranging study (201000 - NCT02966834 -referred to as the
GLIMMER study) demonstrated linerixibat 40 mg twice daily (BID) as the minimally
effective dose providing improvement in cholestatic pruritus over 12 weeks of treatment
with a low rate of discontinuation due to gastrointestinal (GI) intolerability.
This Phase 3 study will further investigate the efficacy and safety of 24 weeks of 40 mg
BID oral linerixibat for the treatment of pruritus in PBC patients with moderate to severe
cholestatic pruritus (Part A), as well as assess the return of itch over 8-weeks after
withdrawal of 40 mg BID oral linerixibat compared to placebo (Part B). Participants
enrolled in the study may be treatment naïve, have been previously treated, or may take
stable background itch therapy at the discretion of the physician in the best interest of the
patient. Definitions of cholestatic pruritus treatments can be found in the main protocol
Participants will record itch scores twice daily using an electronic Diary (eDiary). A 0-10
Numerical Rating Scale (NRS), which has been validated in the PBC population, will be
used to assess itch with a response option of 0 representing no itching and 10 the worst
imaginable itching. Every morning the participant will record the worst itch experienced
the night before and every evening, the participant will record the worst itch experienced
The itch scores for any day, week, and month will then be determined as follows:
Worst Daily Itch Score: the worst of the two scores recorded daily will be
considered the score for that day
Mean Worst Daily Itch Score: the average of the Worst Daily Itch scores in one
Monthly Itch Score: the worst Mean Worst Daily Itch Score for that month (i.e.,
worst week score of the 4 weeks)
Cholestatic pruritus has a negative impact on health-related quality of life (QoL) for PBC
patients. The Primary Biliary Cholangitis-40 Questionnaire (PBC-40) is a disease-
specific health-related QoL instrument consisting of 6 domains: social, emotional,
symptoms, fatigue, itch (including an item on sleep disturbance from itching) and
cognitive. Results from the GLIMMER study demonstrated significant improvement
from baseline in the social and emotional domains of PBC-40 for participants receiving
40mg BID linerixibat. Therefore, this study will further evaluate the effect of linerixibat
on PBC-40 domains. Since sleep is only a single item in PBC-40 and sleep disturbance is
a major complaint of PBC patients, participant's sleep will also be evaluated using the
daily eDiary. Participants will record a sleep interference score each morning using a 0-
10 NRS, where 0 represents no sleep interference and 10 represents complete sleep
interference. For each week, the average of the Daily Sleep Scores will be used to
calculate the Mean Daily Sleep score. The Monthly Sleep score is the worst Mean Daily
Sleep score for that month (i.e., worst week score of the 4 weeks).
1. Male and female participants must be between 18 to 80 years of age at the time of signing the consent. 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 • Documented positive anti-mitochondrial antibody (AMA) titer (>1:40 titer on immunofluorescence or M2 positive by enzyme linked immunosorbent assay [ELISA] or by an alternative validated assay) 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, 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: Is a woman of non-childbearing potential (WONCBP) OR o Is a woman of childbearing potential (WOCBP) and using an acceptable contraceptive method during the study intervention period (at a minimum until 4 weeks after the last dose of study intervention).
1. Participants with recent positive COVID-19 test results, symptoms suggestive of active COVID-19 infection and/or contact within the past 14 days with someone with COVID-19 2. Total bilirubin >2.0 x ULN using the average of two baseline measures. 3. Screening ALT > 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% 5. Screening eGFR <30ml/min/1.73m2. 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 Investigators 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. urrent/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: within 8 weeks prior to Screening. (Participants may not initiate or restart during the study, please see Section 6.8.2) 21. Initiation, discontinuation or change in dose of bezafibrate or fenofibrate at any time during the 8 weeks prior to Screening.
Where can I participate?
More about this Clinical Trial
What is the full name of this clinical trial?
A two-part, randomized, placebo controlled, double blind, multicenter, Phase 3 study to evaluate the efficacy and safety of linerixibat for the treatment of cholestatic pruritus in participants with primary biliary cholangitis .