Global Amendment 1: substance name “BI 425809” replaced by “iclepertin”; Key secondary efficacy endpoint VRFCAT updated to include T-score; clarified that the key secondary efficacy endpoint for the VRFCAT is the total adjusted time T-score; clarified that study partner is required for SCoRS and PANSS interviews at least at Visit 2 and end of trial (EoT); changed the requirement for ophthalmologic assessments to be performed for all ocular AEs, rather than only moderate to severe vision-related AEs; clarified that Paxlovid™ should not be used concomitantly with the trial medication and that patients who required treatment with Paxlovid should be temporarily discontinued from trial medication; revised the further endpoint for health care resource utilization (HCRU) to include the number of any health care visits due to the underlying disease during the on-treatment period; inclusion criterion #5 updated to require patients taking 2 antipsychotic medications to be taking at least one with a dose within the approved label dose range and the other not to exceed the maximum daily dose per local label; inclusion criterion #6 updated to remove reference to hypnotic load up to 0.25 mg brotizolam equivalence and clarified that other psychoactive medications could not exceed the maximum daily dose per local label; exclusion criterion #2 updated to exclude potential patients with epilepsy; exclusion criterion #8 updated to exclude the use of esketamine as well as ketamine; exclusion criterion #10 updated to exclude potential patients previously treated with iclepertin, however, patients who may have screen failed in another trial with iclepertin could be considered for the CONNEX trial; exclusion criterion #11 updated to indicate that potential patients who were taking antiepileptic medications for the treatment of epilepsy were to be excluded, however, taking antiepileptic medications as monotherapy to treat other conditions was allowed (continues)

Global amendment 1 (continued): exclusion criterion #18 updated to exclude potential patients who had anaemia; exclusion criterion #26 (excluding potential patients with an allergy to iclepertin and/or any of the excipients) updated to refer to the Investigator’s Brochure for the list of ingredients in iclepertin and placebo; added guidance related to patients who were lost to follow-up and included a reference to the retention guide; removed the requirement to follow patients after permanent discontinuation of trial treatment until EoT plus 28 days; revised the list of reasons for withdrawing individual patients from trial treatment to include needing to take restricted medications; removed quetiapine as an example of restricted sedative medication; clarified restriction on short term use of opioids for pain, cough, or diarrhoea; added vaccination for COVID-19 to the permitted therapies; allowed re-testing for urine drug screen at Visit 1a if results were positive at Visit 1; added requirement that all patients consent to use the adherence monitoring application at screening but allowed randomised patients on treatment who refused to continue using the application to remain in the trial; clarified that duplication check would be used only for countries that had not opted out by local amendment; clarified that patients could start trial procedures after providing written informed consent even if the study partner informed consent was not yet signed; clarified the procedures for rolling over into the extension trial; clarified that the randomised set would exclude patients randomised in error and discontinued from the trial before the start of trial medication; updated the statistical model, revised wording to indicate that the caregiver would be asked to complete the additional questionnaires; clarified that in case of exceptional circumstances such as the COVID-19 pandemic, secondary endpoint assessments could not be performed remotely as it would reduce quality.

Global amendment 2: Substance name “BI 425809” replaced by “iclepertin” in places where this change was not made in Amendment 1; Reference literature for Placebo Control Reminder Script was added, as it was mistakenly omitted in Amendment 1.

Global amendment 3: Updated address of Coordinating Investigator; added footnote to the Flow Chart to state that Columbia Suicide Severity Rating Scale (C-SSRS) could be repeated based on investigator discretion; based on DMC recommendation, reinforced documenting details of any positive suicidal ideation and providing comments on clinical significance and any additional follow-up action items; also added that the C-SSRS could be repeated at an unscheduled visit based on investigator discretion; added substance use to the Flow Chart; clarified calculation of treatment compliance based on tablets removed from blisters; added text to clarify the time schedule of PK blood sampling and added reminder that actual times were to be collected in the electronic case report form (CRF).

Global amendment 4: Change of coordinating investigator.