Amendment 1, dated 01 December 2020, had the following key changes: Removed the statement that ursodeoxycholic acid (UDCA) was not considered a study drug for the AE reporting purposes. The change was made based on a recommendation from the United States Food and Drug Administration (US FDA) to avoid potential misunderstandings regarding reporting of safety events. Clarified which women must use contraception per Clinical Studies Facilitation Arm Recommendations related to contraception and pregnancy testing in clinical studies (Version 1.1, 21 September 2020). Added the following additional individual participant stopping criteria: Grade 3 events and above not already described by the safety monitoring criteria and related to study drug: any participant who experienced a Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 event that was considered possibly or probably related to study drug, was to be discontinued from study drug. Grade 4 events not already described by the safety monitoring criteria and not related to study drug: Any participant was to be considered for discontinuation from study drug. The Investigator, in consultation with the Sponsor's Medical Monitor, could consider the specific medical nature of the event, the causality assessment, and the possible outcome of the event. Added additional overall study stopping criteria in Section 12; these were to be assessed by the Data safety monitoring board (DSMB): Three participants develop the same Grade 3 CTCAE attributed to study drug Two participants develop any Grade 4 CTCAE attributed to study drug One participant develops a Grade 5 CTCAE Clarified the threshold of abnormal eosinophilia (absolute count > 1× upper limit of normal (ULN)) in Drug-induced liver injury (DILI) criteria for participants with normal baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and DILI criteria for participants with abnormal baseline ALT and AST.

Amendment 2, dated 30 June 2021, had the following key changes: Removed the requirement of having at least 24 participants to participate in pharmacokinetic (PK) sample collection for the evaluation of seladelpar and its metabolites plasma concentration based on recommendations from the FDA. The intention was to allow all participants to be invited to participate in PK sample collection to support the planned exposure-response analysis. The PK sample collection schedule was revised from Months 1 and 3 to Months 3 and 12, and the number of PK blood samples to be collected was revised from 2 to 3. Added the following 2 exclusion criteria and updated the list of prohibited medications. Immunosuppressant therapies (eg, cyclosporine, tacrolimus, anti-Tumor Necrosis Factor (TNF), or other immunosuppressive biologics). Other medications affecting liver or GI functions, such as absorption of medication or the Roux-en-Y gastric bypass procedure could be prohibited and should be discussed with the Medical Monitor on a case-by-case basis. Added text to allow use of liver biopsy tissues collected within 6 months prior to Screening to ease the burden from participants. Outcomes related to adverse events (AEs) and definitions for action taken with study medication were revised to align with the Clinical Data Interchange Standards Consortium definitions.

Amendment 3, dated 09 February 2022, had the following key changes: The estimated glomerular filtration rate (eGFR) Inclusion Criterion 5e was revised to > 45 mL/min/1.73m^2 from >60 mL/min/1.73m^2 after review by the Food and Drug Administration (FDA) of results from the seladelpar renal impairment study. Added a note in Inclusion Criterion 5 that prothrombin time, INR, and platelets could be performed locally at the Screening Visit, if deemed necessary by the Investigator after consultation with the Medical Monitor in cases in which centrally read samples were deemed invalid. Changed the washout period for use of prior obeticholic acid (OCA) and fibrate from 3 months to 6 weeks in Exclusion Criterion 9 to more accurately reflect the washout period that spanned 5 half-lives per each drug’s half-life. Added Exclusion Criterion 17: Active coronavirus disease-2019 (COVID-19) infection during screening. The Safety Follow-up Window for subjects who were not enrolled in the long-term study (ASSURE) was reduced from 1 month (±7 days) to 14 (+3) days after last study drug dose based on the long-term safety of seladelpar in subjects with PBC and the half-life of seladelpar. The Screening and Run-in Period windows were revised to align with sites’ average time to schedule screening assessments and to provide clarity. Clarified the text regarding which procedures participants should follow after discontinuation of study treatment on study and added a new section of annual follow-up for primary biliary cholangitis (PBC) outcomes assessment. Added that ascites and encephalopathy information should be collected during the physical examination at specified timepoints to allow for Child-Pugh (CP) score calculation. Updated the guideline for management of pancreatitis (Pancreatic Safety Criteria for Study Drug Interruption or Stopping Rules) based on recommendations from the United States (US) FDA.