inerixibat Long-term Safety and Tolerability Study

Phase 1

Conditions: Moderate to Severe Pruritus (itching) caused by primary biliary cholangitis (PBC)
MedDRA version: 21.1Level: PTClassification code 10064190Term: Cholestatic pruritusSystem Organ Class: 10040785 - Skin and subcutaneous tissue disorders
MedDRA version: 21.0Level: PTClassification code 10080429Term: Primary biliary cholangitisSystem Organ Class: 10019805 - Hepatobiliary disorders
Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Registration Number: EUCTR2019-003158-10-FR

Lead Sponsor: GlaxoSmithKline Research & Development Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 75

Inclusion Criteria

Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Participant must be 18 to 80 years of age inclusive, at the time of signing the informed consent in the participant’s parent trial BAT117213 or 201000
Type of Participant and Disease Characteristics
2. Participants with a diagnosis of PBC and a history of associated pruritus as evidenced by randomization into a prior eligible linerixibat clinical trial(BAT117213 or 201000)
3. Participants must have completed the main treatment period in a prior eligible linerixibat clinical trial (BAT117213 or 201000)
Sex
4. Male or female
Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Contraception by male participants or male partners of female participants is not required in this protocol
a. Female Participants:
-A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
o Is not a woman of childbearing potential (WOCBP)
OR
o Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in [Appendix 4] of Protocol, during the intervention period and for at least 4 weeks, after the last dose of study intervention. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention
o A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours before the first dose of study intervention
o If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
-Additional requirements for pregnancy testing during and after study intervention are listed in [Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information] of Protocol
-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
-Informed Consent
5. Capable of giving signed informed consent as described in [Appendix 1] of protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 65
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 10

Exclusion Criteria

Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Screening total bilirubin >2x ULN. Total bilirubin >2x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%
2. Screening ALT or aspartate aminotransferase (AST) >6x ULN
3. Screening estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m² based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
4. History or presence of hepatic decompensation (e.g., variceal bleeds, encephalopathy or ascites)
5. Presence of actively replicating viral hepatitis B or C (HBV, HCV) infection and/or confirmed hepatocellular carcinoma or biliary cancer
Note: 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
6. Recent or current clinically significant diarrhea in the Investigator’s medical opinion
7. Current symptomatic cholelithiasis or inflammatory gallbladder disease is exclusionary. Participants with history of cholecystectomy =3 months before screening may be eligible for enrollment
8. Current diagnosis or previous diagnosis of colorectal cancer
9. 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
Prior/Concomitant Therapy
10. Use of Obeticholic acid: within 8 weeks prior to the date of the screening visit and may not restart until after the end of the study or study withdrawal. [Rationale: The potential for a Drug-Drug Interaction (DDI) between obeticholic acid and linerixibat has not been determined. A DDI study assessing the concomitant use of OCA and linerixibat is planned and depending on those results this OCA exclusion may be removed]
11. Administration of any other IBAT inhibitor in the 1 month prior to screening
[Rationale: Effects of another IBAT inhibitor may confound interpretation of the linerixibat safety and tolerability profile]
Prior/Concurrent Clinical Study Experience
12. Current enrollment or participation in any other clinical study (except for 201000)
involving an investigational study treatment within 8 weeks prior to the screening visit
Note: For participants coming from the 201000 study there is no specified waiting period before enrollment into this safety study.
Diagnostic assessments
13. QTc >480 msec
NOTES: The QTc is the QT interval corrected for heart rate according to Bazett’s formula (QTcB), Frederica’s formula (QTcF), and/or another method. It is either machine-read or manually over-read
The specific formula used to determine eligibility and discontinuation for an individual participant should be determined prior to initiation of the study and maintained for individual participants throughout study participation. The specific QT correction formula used must be specified in the eCRF
A QTc >480 msec (12-lead ECG) at screening is exclusionary
Note: The QT interval will be assessed at screening and at each long visit (yearly) by 12-Lead ECG. QTc stopping criteria are established for this study and are detailed in [Section 7.1.2] of Protocol
Other Exclusions
14. 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 g of al

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the safety and tolerability of long-term linerixibat treatment in participants with cholestatic pruritus in PBC;Secondary Objective: -To characterize the effects of long-term linerixibat treatment on disease burden and health related QOL in participants with<br>cholestatic pruritus in PBC<br><br>-To characterize the effects of long-term linerixibat treatment in PBC population<br><br>;Primary end point(s): Frequency and severity of adverse events;Timepoint(s) of evaluation of this end point: From start of treatment (Day1) to follow up phone call (Day 7 to 14 post-final dose of IP). Assessments are made on Day 1, Week 1, Month 1, Month 2, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, Month 30, Month 36, Month 42, Month 48 and final follow phone call on Day 7 to Day 14 post final dose of IP.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): 1.Change in domain scores of the PBC-40 over time<br>2.Change in health-related QoL by the EQ-5D-3L summary index number (utility) over time <br>3.Change in the EQ VAS (within the EQ-5D-3L) over time<br>4.Change in the BDI-II over time<br><br>5.Trends in clinically meaningful laboratory values including liver parameters and lipids over time;Timepoint(s) of evaluation of this end point: For secondary endpoints numbers 1-4 the timepoints of evaluation are:<br>From start of treatment (Day 1) until the final study visit (approximately Month 48). Assessments are made on Day 1, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24,Month 30, Month 36, Month 42 and Month 48.<br><br><br>For secondary endpoint number 5 the timepoints of evaluation are:<br>From start of treatment (Day 1) until the final study visit (approximately Month 48). Assessments are made on Day 1, Month 3, Month 6, Month 9, Month 12, Month 24, Month 36 and Month 48.<br>

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