Protocol Version 2.0 dated 25-Jan-2022 (FDA May Proceed Letter): - Clarification regarding prohibited medication: treatment with substrates of CYP 2B6 and CYP2C8, CYP2C8 strong inducers and CYP2C8 strong inhibitors excluded - In US and EU Renal Impairment guidances, the Food and Drug Administration and European Medicines Agency recommend expressing glomerular filtration rate (GFR) in mL/min because renal clearance of a drug is proportional to individual GFR and not to standard body surface area (BSA)-standardised GFR, therefore study parameters were modified: eGFR no-longer BSA normalised - Clarification regarding SARS-CoV-2 infection - Clarification of rational, background and study design - Clarification regarding randomisation process

Protocol Version 3.0 dated 08-Apr-2022: - Clarification regarding stratifying factors in the randomisation process - Addition of a randomisation procedure before baseline visit, allowing the treatment ordering and treatment shipment/delivery to the site - Update of patient individual study duration, due to addition of randomisation procedure - Update of exclusion criteria No. 1 & No. 2 for further clarification - Addition of the possibility to perform phone call visit if medically needed to ensure appropriate patient follow-up in case on-site visit is not possible - Update of the AESI reporting period to be in line with lanifibranor AESI reporting guidelines - To align with lanifibranor AE management guidelines across the clinical development programme, 1) the drug-Induced Liver Injury Monitoring and stopping rules were updated as were 2) the guideline for AEs requiring specific management related to anaemia, heart failure, aminotransferase elevation, bone fracture, peripheral oedema, cholelithiasis, hypoglycaemia, ovulation resumption and weight gain local guidelines/clinical practice - Update of the known potential risks of empagliflozin in line with the empagliflozin labelling - List of clinical laboratory parameters was updated (HIV-1 and HIV-2 antibodies and serum ketones measures) to document the history of HIV infection and to ensure appropriate monitoring for the risk of ketoacidosis due to the use of empagliflozin - Justification for dose updated to clarify the choice of 800 mg dosage for lanifibranor - Update of exclusion criteria N°36 with patient with history of pancreatitis excluded

Protocol Version 4.0 dated 12-Jan-2023 : - Additional details regarding exploratory endpoints related to cT1 - Update of the inclusion criteria: o No. 6, No. 19, and No. 38, for clarification o No. 7, to further define Gilberts Syndrome that is regarded as a benign trait o No. 9, to allow patients with ‘Benign ethnic neutropenia’ to be eligible based on the investigator’s clinical judgement o No. 10, to allow recruitment of patients who have mild thrombocytopenia o No. 41 o the list of prohibited medication was updated. o Correction of a typing error in Figure 1: Study design o Addition of one footnote related to screening period to the Schedule of Activities (Clarification in visit time window for screening period) o Addition of one footnote related to patient rescreening to the Schedule of Activities (allow the use of previous LMS result for patient re-screening) o Update of the allowable Medications for Standard Care or Precautions (clarification that patients who have clinically insignificant changes in the listed concomitant medications are eligible) o Addition of a reference added regarding the definition of NASH (Definition of NASH corresponding to the inclusion criterion 5 revised) o Update of the Adverse Event Reporting guidance (to precise the AESI reporting timelines applicable for the study) o Update of the guideline for Adverse Events requiring specific management related to Anemia (to clarify the guidance)

Protocol Version 5.0 dated 19-Oct-2023 : - An interim analysis was added to obtain preliminary information on observed effects sizes / variability allowing an early insight on the treatment effect on multiple mechanistic endpoints - Exclusion criterion N°48 was updated to refer to the full list of permitted and prohibited concomitant medications - Addition of the overall study termination to clarify that both investigator and Sponsor can terminate the study at any time, especially at time of interim analysis - The anti-SARS-CoV-2-IgM as serological test in case of aminotransferase elevation was deleted to align with the central lab testing availability

Protocol Version 6.0 dated 22-Feb-2024: To mimic the recommendations issued by the Data Monitoring Committee for the Phase 3 study, NATiV3 (IND140010 EudraCT 2020-004986-38), in patients with NASH and liver fibrosis, following changes were implemented: - Update of the exclusion criterion No. 1 - Addition of the exclusion criterion No. 50 related to autoimmunity and addition of corresponding laboratory parameters - Addition of liver tests and INR monitoring - Addition of the possibility to use local laboratories for the above tests - Update of the known potential risks