Global Linerixibat Itch Study of Efficacy and Safety in Primary Biliary Cholangitis (PBC) (GLISTEN)

Itch Scores were assessed using a NRS twice daily, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The worst daily itch score was defined as the worst of the two scores recorded daily. The weekly itch score was defined as the average of the worst daily itch scores in one week. The monthly itch score was defined as the worst weekly itch score for the month (4 weeks). Higher monthly itch scores indicate worse itching. Baseline is the worst weekly itch score in the 28 days prior to randomization (Day 1). Change from Baseline is defined as the post dose value minus baseline value. Least-squares (LS) means and the corresponding 95% confidence intervals are reported by taking average of LS means of change from baseline in monthly itch scores obtained over 24 weeks using equal weighting for all time points. Analyzed using Mixed Model Repeated Measures (MMRM) method.

Time frame: Baseline and up to Week 24

Population: The analysis was performed on the Intent to Treat (ITT) set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized.

Blood samples were collected at indicated time points for evaluation of ALP. Change from Baseline in ALP at Week 24 was evaluated. Baseline was established using an average of two sets of laboratory values obtained at least 4 weeks apart within 56 days prior to randomization (Day 1). Change from Baseline was calculated as Week 24 value minus Baseline value.

Time frame: Baseline and Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data at baseline and at least one post-baseline time point were included.

Blood samples were collected at indicated time points for evaluation of Bilirubin. Change from Baseline in total bilirubin at Week 24 was evaluated. Baseline was established using an average of two sets of laboratory values obtained at least 4 weeks apart within 56 days prior to randomization (Day 1). Change from Baseline was calculated as Week 24 value minus Baseline value.

Time frame: Baseline and Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data at baseline and at least one post-baseline time point were included.

Sleep Scores were assessed using an NRS scale, ranging from 0 to 10, where 0 represents no sleep interference and 10 is complete sleep interference. The weekly sleep scale is the average of the daily sleep scores for each week. The monthly sleep score was defined as the worst weekly sleep score for the month (4 weeks). Higher monthly sleep scores indicate higher impact on sleep. Baseline is the worst Weekly Sleep Score in the 28 days prior to randomization (Day 1). Change from Baseline is defined as the post dose value minus baseline value. LS means and the corresponding 95% confidence intervals are reported by taking average of LS means of change from baseline in monthly sleep scores obtained over 24 weeks using equal weighting for all time points analyzed using Mixed Model Repeated Measures (MMRM) method. Mean Change from Baseline in Monthly Sleep Score over 24 weeks was the second endpoint tested in the hierarchical analysis.

Time frame: Baseline up to Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data at baseline and at least one post-baseline time point were included.

The Patient's Global Impression of Severity (PGI-S) is a patient-reported outcome measure used to assess the severity of symptoms from the participant's perspective. The PGI-S asks participant to rate the severity of their itch in the past 7 days on a single item, using a scale ranging from 0 (absent) to 5 (very severe). Higher score indicates higher severity. Baseline is the last assessment prior to the first dose of randomized treatment for Part A (Day 1). Change from Baseline is defined as the post dose value minus baseline value. LS means and the corresponding 95% confidence intervals are reported by taking average of LS means of change from baseline in PGI-S obtained over 24 weeks using equal weighting for all time points, analyzed using Mixed Model Repeated Measures (MMRM) method.

Time frame: Baseline and up to Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data at baseline and at least one post-baseline time point were included.

PBC-40 is a disease-specific health-related quality of life (HRQoL) questionnaire validated for use in participants with PBC. It consists of 40 questions, which are grouped into 6 domains with 3 to 11 questions per domain. Each question is scored from 1 (least impact) to 5 (greatest impact). For all questions, an answer of Does/Did not apply was scored 0. All questions within a domain are summed to obtain individual domain score. Domains were: Symptoms (7 questions) with score range 6 to 35, Itch (3 questions) with score range 0 to 15, Fatigue (11 questions) with score range 11 to 55 , Cognitive (6 questions) with score range 6 to 30 , Emotional (3 questions) with score range 3 to 15 and Social (10 questions) with score range 8 to 50 . Higher scores for individual domains represent poorer quality of life. Baseline is the last assessment prior to the first dose of randomized treatment (Day 1). Change from Baseline was calculated as Week 24 value minus Baseline value.

Time frame: Baseline up to Week 24

Population: ITT population set included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Number of Participants Analyzed (N) was the maximum number of participants analyzed for any domain, while Number analyzed (n) was the number of participants included in the model for each domain.

Itch Score was assessed using a twice daily NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The worst daily itch score was defined as the worst of the two scores recorded daily. The weekly itch score was defined as the average of the worst daily itch scores in one week. Higher weekly itch scores indicate worse itching. Baseline is the average of the Worst Daily Itch scores in the 7 days prior to randomization (Day 1). Change from Baseline is defined as the Week 2 value minus baseline value. Key secondary endpoints were tested in a step-down/hierarchical approach. Mean Change from Baseline in Weekly Itch Score at Week 2 was the first endpoint tested in the hierarchical analysis. LS mean and the corresponding 95% confidence intervals are reported using Mixed Model Repeated Measures (MMRM) method.

Time frame: Baseline and at Week 2

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data at baseline and at least one post-baseline time point were included

Patient's Global Impression of Change (PGI-C) was assessed using a 7-level response scale, ranging from 1 (very much improved) to 7 (very much worse). Higher score indicates higher level of change. LS means and the corresponding 95% confidence intervals are reported by taking average of LS means of PGI-C obtained over 24 weeks using equal weighting for all timepoints, analyzed using Mixed Model Repeated Measures (MMRM) method.

Time frame: Week 4 up to Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Only participants with data for at least one time point were included.

Monthly Itch Score was assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The Monthly Itch Score was determined from the worst weekly itch score for the month (4 weeks). Baseline is the worst weekly itch score in the 28 days prior to randomization. Responders were defined as participants achieving \>=3-point reduction (improvement) from baseline in the Monthly Itch Score. Percentage of Responders achieving \>= 3-point Reduction from Baseline in the Monthly Itch Score at Week 24 was the fourth endpoint to be tested in the hierarchical analysis.

Time frame: At Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Percentage values were rounded to the nearest whole number.

Monthly Itch Score was assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The Monthly Itch Score was determined from the worst weekly itch score for the month (4 weeks). Baseline is the worst weekly itch score in the 28 days prior to randomization. Responders were defined as participants achieving \>=4-point reduction (improvement) from baseline in the Monthly Itch Score. Percentage of Responders achieving \>= 4-point Reduction from Baseline in the Monthly Itch Score at Week 24 was the fifth endpoint to be tested in the hierarchical analysis.

Time frame: At Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Percentage values were rounded to the nearest whole number.

Monthly Itch Score was assessed using an NRS, ranging from 0 to 10, where 0 represents no itching and 10 the worst imaginable itching. The Monthly Itch Score was determined from the worst weekly itch score for the month (4 weeks). Baseline is the worst weekly itch score in the 28 days prior to randomization (Day 1). Responders were defined as participants achieving \>=2-point reduction (improvement) from baseline in the Monthly Itch Score. Percentage of Responders achieving \>= 2-point Reduction from Baseline in the Monthly Itch Score at Week 24 was the third endpoint tested in the hierarchical analysis.

Time frame: At Week 24

Population: The analysis was performed on the ITT set that included all randomized participants. Participants in the ITT Population were classified according to the treatment as randomized. Percentage values were rounded to the nearest whole number.