Amendment 1. No. of patients: 15 • Original protocol under which patients were first enrolled

Amendment 2. No. of patients: 16. •Clarified that enrolment of patients with PFIC1 will be targeted to 15% Exclusion criterion 9 was revised to clarify that patients listed for liver transplant will not be excluded if primary reason for listing was symptomatic pruritus and not disease progression •Guidelines for contraceptive requirements were updated that required patients to use reliable contraceptive methods throughout duration of study and 90 days thereafter •Additional examples of prohibited medications, including erythromycin and 4-phenylbutyrate were added •Requirement for genetic testing at screening was removed for patients with prior genotyping results confirming PFIC1 or 2 •Procedure for breaking the randomisation code was clarified •Calculation to determine patient eligibility relating to the ObsRO data collection was revised •Primary efficacy endpoint for US (and secondary endpoint for Europe and RoW) was revised to include more data collected in the analysis. The statistical analyses were modified to align with that change •All secondary and exploratory endpoints referring to PRO/ObsRO instrument using a reference time point of Week 24 were revised to include a specified duration over treatment period, for example over first of last 3 or 5 months of treatment period •Assessment of change in gamma-glutamyl transferase was added to exploratory endpoint •Clarification was made to include all laboratory tests related to safety including vitamins, and alpha-fetoprotein •Additional assessments for physical examination, vitamins, urine pregnancy test, and blood sampling for PK analysis were added to schedule of assessments •Approach to calculate baseline weekly itching and scratching scores was revised •Following changes were made to liver monitoring criteria: requirement of cholestatic marker elevations without alternative explanation was removed; ALP was removed from list of repeat liver profile assessments; INR criteria increase was revised

Amendment 3. No. of patients: 6 • Exclusion criterion 17 was revised to remove barrier protection as an acceptable contraceptive method • Exclusion criterion 9 was revised to specify that patients will be excluded if their liver transplant is planned within 6 months of randomisation • Statistical methodology to analyse the primary efficacy endpoint for United States (and secondary endpoint of Europe and rest of world) of change in pruritus between active and placebo arms was revised • Secondary endpoints of change from baseline to Week 24 in serum bile acid, ALT, and growth were updated to include additional assessments at Week 12. As a result, change from baseline in ALT and serum bile acid at Week 12 were removed from the list of exploratory endpoints • The secondary endpoint of proportion of patients achieving meaningful reduction in caregiver-reported observed scratching was revised to include assessment of patient-reported outcomes and to indicate how “meaningful reduction” was defined. An additional assessment timepoint of Week 12 was also added • The secondary endpoint of change from baseline in sleep parameters was updated so multiple timepoints were evaluated in the study period rather than a single timepoint at end of therapy. • The following additional secondary endpoints were added for all regions: - Proportion of individual assessments and of individual AM and PM assessments meeting the definition of a positive pruritus assessment at the patient level from Weeks 0-4, Weeks 0-8, Weeks 0-12, Weeks 0-18, Weeks 0-24, respectively, or the proportion of positive pruritus assessments at each 4-week interval. • The exploratory efficacy endpoint of change in patient-reported and observer-reported night-time itching and scratching severity scores was revised so both morning and evening scores were analysed rather than a single daily score.

Amendment 4. No. of patients: 8 • Exclusion criterion 8 was updated so patients post biliary diversion surgery were eligible for the study • Clarification was made to the secondary endpoint to assess liver transplantation events • Revised baseline covariate in the ANCOVA model of US primary efficacy analysis to include both AM baseline and PM baseline pruritus scores, instead of the averaged value.

Amendment 5. No. of patients: 9 • The timing for rescreening was removed; patients could be rescreened at any time after failing eligibility criteria after consultation with the Medical Monitor • Exclusion criterion 14 was revised to exclude patients with total bilirubin >10×ULN

Amendment 6. No. of patients: 8 • The provision to allow patients experiencing intolerable symptoms of underlying disease to roll over to active treatment after completion of 12 weeks of the treatment period was removed