STUDY POPULATION

This study enrolled children aged 1 year through 18 years who had cholestasis and pruritus caused by ALGS, which was diagnosed based on study criteria (Supporting Table S1) and confirmed by JAGGED1 or NOTCH2 genotyping. Eligibility (i.e., presence of significant pruritus) was determined using twice‐daily caregiver‐based assessment of pruritus by ItchRO observation of child reported by parent/guardian/caregiver (Obs).^{( 8 )} ItchRO scores range from 0 to 4, with higher scores indicating increasing pruritus severity. The average daily score was derived from the highest score of the morning and evening observations, which reflects the worst pruritus of that day. Eligibility for this study required an average daily ItchRO(Obs) score of ≥2 for 2 consecutive weeks. Patients were excluded if they had chronic diarrhea requiring intervention, surgical interruption of the enterohepatic circulation, prior liver transplant, alanine aminotransferase (ALT) >15 times the upper limit of normal or decompensated cirrhosis (full inclusion and exclusion criteria are listed in Supporting Table S2).

Written informed consent was obtained from caregivers, and assent was obtained when appropriate from the child according to local institutional review board rules. This study was approved by local institutional review boards, complied with the Declaration of Helsinki and Good Clinical Practice Guidelines, and was registered at ClinicalTrials.gov (NCT02057692). The study was developed with and conducted in collaboration with Lumena Pharmaceuticals, now part of the Shire Group of Companies, in the context of a Cooperative Research and Development Agreement with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Lumena/Shire was not involved in the data analysis or the reporting and interpretation of the results, which were independently performed by the NIDDK‐funded Childhood Liver Disease Research Network. As set out by the Cooperative Research and Development Agreement, Lumena/Shire was permitted to read and comment on the manuscript prior to submission.