|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Moderate to severe Cholestatic pruritus with primary biliary cholangitis (PBC).
|Medical condition in easily understood language
|Moderate to Severe itch (Pruritus) in patients with primary biliary cholangitis (PBC)
|Diseases [C] - Digestive System Diseases [C06]
|E.1.2 Medical condition or disease under investigation
|System Organ Class
|10040785 - Skin and subcutaneous tissue disorders
|E.1.2 Medical condition or disease under investigation
|Primary biliary cholangitis
|System Organ Class
|10019805 - Hepatobiliary disorders
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|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 objectives of the trial
|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 )
To evaluate the safety of oral linerixibat compared with placebo (Part A and Part B)
|Trial contains a sub-study
|Principal 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 <3 for any other week.
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)
-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.
• 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.
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.
|Principal exclusion criteria
|Participants are excluded from the study if any of the following criteria apply:
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 < 3x ULN is acceptable if bilirubin is fractionated and direct bilirubin is < 35%
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%. 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.
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. (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.)
22. 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, pregabalin, gabapentin, sertraline or other SSRIs. (Participants may join the study on stable doses of these medications, but no change in dose nor addition of new treatment for cholestatic pruritus is permitted during the study.) Note: Dosing of linerixibat and bile acid binding resins should be staggered by at least 4 hours.
23. Initiation, discontinuation or change in dose of opioids, regardless of indication, in the 8 weeks prior to Screening. (Participants may join the study on stable doses of these medications)
24. Initiation, discontinuation or change in dose of colchicine, methotrexate, azathioprine, or systemic corticosteroids in the 8 weeks prior to Screening Note: If a change in dose in any of these medications is anticipated during the course of the study, the participant should be excluded.
Refer Protocol Page No. 45 to 48 for other Exclusion Criteria.
|E.5 End points
|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 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
• 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
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|The end of the study is defined as the date of the last visit of the last participant in the study in the trial globally. A participant is considered to have completed the study if he/she has completed all phases of the study including the last visit. For participants that will enroll into a follow on study this last visit is Week 32. If the participant will not enrolled in a follow-on study, this would include completion of the follow-up phone call as shown in the SoA (Section 1.3) of protocol
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months