| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Moderate to Severe Pruritus (itching) caused by primary biliary cholangitis (PBC) | |
| E.1.1.1 | Medical condition in easily understood language | | Moderate to Severe Pruritus (itching) caused by primary biliary cholangitis (PBC) | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10064190 | | E.1.2 | Term | Cholestatic pruritus | | E.1.2 | System Organ Class | 10040785 - Skin and subcutaneous tissue disorders | |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10080429 | | E.1.2 | Term | Primary biliary cholangitis | | E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders | |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial | | To evaluate the safety and tolerability of long-term linerixibat treatment in participants with cholestatic pruritus in PBC | |
| E.2.2 | Secondary objectives of the trial | -To characterize the effects of long-term linerixibat treatment on disease
burden and health related QOL in participants with
cholestatic pruritus in PBC
-To characterize the effects of long-term linerixibat treatment in
participants with cholestatic pruritus in PBC
For (Group 2: GLISTEN participants) Only
-To evaluate the maintenance of efficacy of linerixibat on itch over 52
weeks.
-To evaluate the effect of linerixibat on health-related QoL | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Participants are eligible to be included in the study only if all the
following criteria apply:
Age
1. Male or female participants must be 18 to 80 years of age inclusive, at
the time of signing the informed consent in the participant's parent study
BAT117213, GLIMMER or GLISTEN
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 with a diagnosis of PBC and a history of associated
pruritus as evidenced by randomization into a prior eligible linerixibat
clinical study(BAT117213, GLIMMER or GLISTEN)
3. Participants must have completed the main treatment period(s) in a
prior eligible linerixibat clinical study (BAT117213, GLIMMER or GLISTEN)
Contraception 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, etc.).
-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 10.4 Pregnancy Testing.
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 Section 8.3.5 Pregnancy Testing and Section
10.4 Appendix 4: Contraceptive Guidance and Collection of Pregnancy
Information.
• 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 Appendix 1
of protocol, which includes compliance with the requirements and
restrictions listed in the informed consent form (ICF) and in this
protocol. | |
| E.4 | Principal exclusion criteria | Participants are excluded from the study if any of the following criteria
apply:
Medical Conditions
1. Screening total bilirubin >2x ULN.
Note: Total bilirubin >2x ULN but <3x ULN is acceptable if bilirubin is
fractionated and direct bilirubin is <35%
2. Screening ALT or aspartate aminotransferase (AST) >6x ULN
3. Screening estimated glomerular filtration rate (eGFR) <30
mL/min/1.73m² based on the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) equation
4. Group 2 Participants who meet increased liver chemistry monitoring
criteria or any stopping criteria during LLSAT Screening period (GLISTEN
Week 28 to Week 32 visit) or temporarily discontinue study treatment
due to a drug-related adverse event
during the LLSAT Screening period, which is ongoing before Baseline Visit.
• Note: participants that meet increased liver chemistry monitoring
criteria or stopping criteria at any timepoint during GLISTEN and restart
of study intervention has not been approved by GSK are excluded
5. Presence of hepatic decompensation (e.g., variceal
bleeding, encephalopathy or ascites)
6. 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
7. Current clinically significant diarrhea in the Investigator's medical
opinion
8. Current symptomatic cholelithiasis or cholecystitis. Participants with
history of cholecystectomy ≥3 months before screening may be eligible
for enrollment
9. Current diagnosis or previous diagnosis of colorectal cancer
10. Any current malignancies (including hematologic and solid
malignancies).
11. History of bariatric surgery with ileal bypass at any time, or any
bariatric surgery performed in the past 3 years.
12. 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
13. 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 early
study withdrawal. [Rationale: The potential for a Drug-Drug Interaction
(DDI) between obeticholic acid and linerixibat is under investigation. A
DDI study assessing the concomitant use of OCA and 40 mg linerixibat
twice daily is planned and depending on those results this OCA exclusion
may be removed]
14. Administration of any other IBAT inhibitor in the 1 month prior to
screening until after End of Study or Early study withdrawal [Rationale:
Effects of another IBAT inhibitor may confound interpretation of the
linerixibat safety and tolerability profile]
Prior/Concurrent Clinical Study Experience
15. Current enrollment or participation in any other clinical study
(except for GLISTEN)
involving an investigational study treatment within 8 weeks prior to the
screening visit
Note: For participants coming from the GLISTEN study there is no
specified waiting period before enrollment into this safety study.
Diagnostic assessments
16. QTc >480 msec at screening (12-lead ECG)
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
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 7.1.3] of Protocol
Other Exclusions
17. Participants with moderate (or greater) alcohol consumption defined
as more than one standard drink per day for women and two drinks per
day for men; whereby one standard drink is equivalent to: 12 oz beer
(5% alcohol), 5 ounces of wine (12% alcohol), or 1.5 ounces of 80 proof
spirits (40% alcohol). | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Frequency and severity of adverse events | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | From start of treatment (Day1) to end of study or until the follow up phone call after early study withdrawal (Day 7 to 14 post-final dose
ofIP). 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 (Additional visits as needed) and final follow phone call on Day 7 to Day 14 post final dose of IP. | |
| E.5.2 | Secondary end point(s) | 1.Change in domain scores of the PBC-40 over time
2.Change in the BDI-II over time
3.Change in health-related QoL by the EQ-5D-3L summary index
score(utility) over time (Group 1 participants only)
4.Change in the EQ VAS (within the EQ-5D-3L) over time (Group 1
participants only)
5.Change in clinically meaningful laboratory values including liver
parameters and lipids over time
For (Group 2: GLISTEN participants) Only
1.Responder (>2, >3 and >4 points reduction in MIS) at Week 24 of
continuous treatment
2.Responder (>2, >3 and >4 points reduction in MIS) at Week 52 of
continuous treatment
3.Maintenance of efficacy at Week 52 of continuous treatment in those
that were responders at Week 24 of continuous treatment
4.Change from Baseline in Monthly Sleep Score as measured by 0-10
NRS over 52 weeks of continuous treatment
5.Change from Baseline in Monthly Fatigue Score as measured by 0-10
NRS over 52 weeks of continuous treatment | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | For secondary endpoints numbers 1-4 the timepoints of evaluation are:
From start of treatment (Day 1) until the final study visit (approximately Month 48 or longer as needed). 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.
For secondary endpoint number 5 the timepoints of evaluation are:
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.
| |
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description | |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 | The trial involves single site in the Member State concerned | No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | | Argentina | | Brazil | | Canada | | China | | Israel | | Japan | | Mexico | | United States | | Switzerland | | Russian Federation | | Bulgaria | | Czechia | | Greece | | United Kingdom | |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
