Trial Outcomes & Findings for This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC Types 1 or 2 (NCT NCT03566238)

This Phase 3, double-blind, placebo-controlled study was conducted in children with progressive familial intrahepatic cholestasis (PFIC) at 33 study centers in 12 countries between 16 May 2018 and 28 July 2020.

The study included up to an 8-week screening period, a 24-week treatment period, and a 4-week follow-up period. A total of 62 participants were enrolled in the study.

This Study Will Investigate the Efficacy and Safety of A4250 in Children With PFIC Types 1 or 2

Fasting s-BA baseline was calculated as the average of the last 2 values prior to the first dose. The end value was the average of the values at Weeks 22 and 24 after the start of double-blind treatment. Participants who had at least 70% reduction in fasting s-BA from baseline to the end of treatment or reached \<=70 mcmol/L after 24 weeks of treatment were considered as responder. Participants with missing average at the end of treatment were classified as non-responder. Percentages are rounded to hundredth decimal.

A positive pruritus assessment was defined as a scratching score of \<=1 or at least 1 point drop from baseline. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100.

Blood samples for analysis of s-BA were drawn at all visits. Participants were to fast (water intake only was permissible) for at least 4 hours prior to the collection of samples. Exceptions could be made for infants \<12 months of age if they were unable to fast for the full 4 hours. Baseline was the average of the last 2 non-missing values of fasting s-BA concentration prior to the first dose of study treatment.

Blood samples were collected to determine the ALT concentration. Baseline was the last available assessment before the first dose of study treatment.

The change in the growth parameters was assessed using linear growth deficit \[height (centimeter), weight (kilogram) and body mass index (BMI) (kg/meter square)\] compared to standard growth curve (Z-score) calculated by using the software or methods from the centers for disease control (CDC) website for participants with age \>=2 years old and from the world health organization website for participants with age \<2 years old. Participants whose accurate age was not available, Z-score was not calculated. A Z-score indicated how many standard deviation's (SD) a participant's measurement (like height, weight and BMI), was from the average for their age and sex. A Z-score of 0 represents the median or 50th percentile, while positive or negative values show how far above or below average a measurement was. Baseline was the last available assessment before the first dose of study treatment.

The responder for pruritus scores was defined as a participant who achieved at least a 1-point reduction in the ObsRO pruritus score. Percentages are rounded to hundredth decimal.

The sleep disturbance were recorded twice daily via the electronic diary (eDiary). Participants and/or caregivers completed the eDiary every day in the morning and in the evening. The morning diary was completed shortly after the participant woke up and was used to record nighttime itching and scratching severity, aspects of sleep disturbance, and tiredness upon waking (AM scores). The evening/bedtime diary was completed just before the participant went to bed and recorded participant's itching and scratching severity, and tiredness during the day (PM scores). Both morning and bedtime diaries included Albireo ObsRO and PRO items. Baseline was the average of 14-day scores before the first dose of study treatment.

The ObsRO and electronic diary (eDiary) PRO scale called PRUCISION was used to assess pruritus and sleep outcomes. Participants and/or caregivers completed the eDiary every day in the morning (AM scores) and in the evening (PM scores). Specifically, for difficulty falling or staying asleep, the following 2 respective questions were asked in the Morning Daily eDiary: 1) How hard was it to fall asleep last night because of your itching. and 2) How hard was it to stay asleep last night because of your itching. The PRO was a 5-point scale, and scores ranged from 0 (no itching) to 28 (the worst itching), where higher scores indicated a greater amount of itching, sleep disturbance, and tiredness. No subscales were used. Change in sleep parameters measured with the Albireo PRO and ObsRO instruments by each 4-week interval over the 24-week treatment period was assessed. Baseline was the average of 14-day scores before the first dose of study treatment.

A positive pruritus assessment was defined as a scratching score of \<=1 or at least 1 point drop from baseline based on the Albireo ObsRO instrument. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively.

A positive pruritus assessment was defined as a scratching score of \<=1 or at least 1 point drop from baseline based on the Albireo PRO instrument, only participants \>=8 years of age completed the Albireo PRO instrument. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively.

A positive pruritus assessment was defined as a scratching score of \<=1 or at least 1 point drop from baseline based on the Albireo ObsRO instrument. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100. At each assessment, the AM or PM score was compared to the baseline AM or PM average, respectively.

The number of participants underwent biliary diversion surgery and liver transplantation was determined.

A positive pruritus assessment was defined as a scratching score of \<=1 or at least 1 point drop from baseline based on the Albireo ObsRO and PRO instruments. The percentage of positive pruritus assessment was calculated as the number of positive pruritus assessments divided by the total number of reported assessments only when more than 50% of planned assessment recorded by each participant multiplied by 100.