BI 425809 was replaced by Iclepertin in the title page and whole document; Clarification that the key secondary efficacy endpoint for the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) is the adjusted total time T-score in the synopsis and sections 2.1.3 and 7; Placebo Control Reminder Script (PCRS) was added to the flowchart and abbreviations; Footnote number changes for Mini International Neuropsychiatric Interview (MINI) and AiCure to 7 and 8 respectively; Addition of footnote #20 to clarify that study partner is required for Schizophrenia Cognition Rating Scale (SCoRS) and Positive and Negative Syndrome Scale (PANSS) interviews at least at Visit 2 and end of trial (EOT) in the flowchart endnotes; Change in the requirement for ophthalmologic assessments to be performed in case of moderate to severe vision related AEs in Sections 1.4.2 and 5.2.6.3; Clarification that Paxlovid should not be used concomitantly with the study drug in Sections 1.4.2 and 3.3.4.1. Patients who require treatment with Paxlovid should temporarily discontinue the study drug; Refinement of the Healthcare resource utilization (HCRU) further endpoint; Inclusion criteria #5 updated to permit patients who are on 2 anti-psychotics that at least one has to be within the approved label dose range and the other must not exceed the maximum daily dose per local label in Section 3.3.2; Inclusion criteria #6 updated – removed reference to hypnotic load up to 0.25 mg brotizolam equivalence. Clarified that other psychoactive medications cannot exceed the maximum daily dose per local label in Section 3.3.2; Exclusion criteria #2 updated to exclude patients with epilepsy in Section 3.3.3; Exclusion criteria #8 updated to exclude the use of esketamine as well as ketamine; Exclusion criteria #10 updated to exclude only those patients who have previously been treated with iclepertin in Section 3.3.3;

Exclusion criteria #11 updated including related footnote in Section 3.3.3; Exclusion criteria #18 updated to exclude patients who currently have anemia in Section 3.3.3; Exclusion criteria #26 (Section 3.3.3) updated to clarify that list of ingredients can be found in the Investigator’s Brochure; Added guidance related to lost to follow-up patients and included a reference to retention guide in Section 3.3.4; Removal that patients need to be followed until EOT+28 days in Section 3.3.4.2; Addition of new reason for withdrawing (patients need to take restricted medications) in Section 3.3.4.2; Removal of quetiapine as an example for sedative medications in 4.2.2.1; Clarify that short term use of opioids for pain, cough or diarrhea during the treatment period was not allowed in 4.2.2.1; Addition of vaccination for COVID-19 in the permitted therapies in 4.2.2.1; Addition of reference to section 6.2.1 for Clinical Global Impressions – Severity (CGI-S), Updated number of items included in the Schizophrenia Caregiver Questionnaire (SCQ), and Addition of HCRU details that are collected in Section 5.1; Removal of number of items for AIMS in Section 5.2; Confirmation that re-test is permitted at visit 1a in case patients are drug screen positive at Visit 1 in 5.2.3; Addition of reference to section 3.3.4.2 in case patient becomes pregnant in 5.2.6.2.3;

Confirm that patients must consent to the use of AiCure app. Use of AiCure was not a specific reason for discontinuation in Section 5.6.2; Confirmed that Verified Clinical Trials will be used only for countries that have not opted-out by local amendment in Section 5.6.3; Removal of examples of scales that should be done by the same rater in Section 6.2.1; Description added for CGI-S requirements in 6.2.1; Updated paragraph regarding patient and study partner informed consents in 6.2.2; Addition of reference to appendix 10.3 in Section 6.2.3; Update of the different scenarios in case of early discontinuation and clarify re-start trial medication in Section 6.2.3.4; Clarification that randomized set will exclude patients randomized by error and discontinued from the study before the start of trial medication in Section 7.2.1; Update of the statistical model in Section 10.2; Revision of wording to indicate that the caregiver will be asked to complete the additional questionnaires in 10.2; Addition of exceptional circumstances in addition to COVID-19 in Section 10.3; Clarification that study partner contacts and assessments can be also impacted in 10.3; Inclusion of analysis by the Central Lab in addition to blood sampling and inclusion of also secondary endpoints description in case of any exceptional circumstances in Section 10.3.

Added footnote 21 to flowchart and footnotes: Columbia Suicidality Severity Rating Scale (C-SSRS) may be repeated based on investigator discretion; Corrected typo in drug name (BI 425908 was changed to Iclepertin) in Section 3.3; Clarification on calculation of compliance based on tablets removed from blisters in 4.3 Compliance; Reinforcement of documenting details for any positive suicidal ideation and to provide comments on the clinical significance and any additional follow-up action items. The C-SSRS may be repeated at an unscheduled visit based on investigator discretion (Section 5.2, Assessment of Safety); Added “preferably” within 30 minutes before dose to on treatment PK sampling timepoints, added “approximately” to other PK sampling timepoints. Added reminder that actual times are collected in the eCRF (Appendix 10.1).