Protocol amendment 1 was implemented before first patient was enrolled. The major changes were: Removal of body temperature measurement from the vital sign examinations as BI 409306 rarely interfered with temperature regulation and there is no fatal or lifethreatening change in body temperature caused by BI 409306, according to the preclinical and clinical data to date. Addition of a window to allow more flexibility for the ECG testing. To provide updated fasting instructions for blood sampling in this study in order to align with the fasting requirement of BI 409306 administration. To clarify the unblinding procedure for Stage 1 analysis. The unblinded results of Stage 1 were to be reviewed only by the trial and project team, including TAH, TMM, TCM, SEG member for CNS, PSTAT, TSTAT, and TPROG.

Protocol amendment 2 was implemented before first patient was enrolled. The major changes were: Setting additional restrictions for the current antipsychotic and concomitant psychotropic medications in order to minimize the effect on the cognitive function caused by the patient’s current treatment. Adding C-SSRS assessment to Visit 3, Visit 5 and Follow-up Visit to align with the FDA’s suggestion and FDA guidance: “Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of Occurrence in Clinical Trials (August, 2012)”. Adding new exclusion criterion to exclude patients who needed to take strong or moderate CYP3A4 inhibitors because CYP3A4 inhibitors potentially might increase exposure to BI 409306 in CYP2C19 Poor Metabolizers (PM) based on the up-to-date clinical trial data. Adding new requirement to exclusion criterion number 16 to exclude patients who received any cognitive-enhancing therapy or procedure recently because the patient’s cognitive impairment severity might be changed by receiving this kind of therapy or procedure. Adding additional requirements and instructions to the prohibited concomitant treatment section to avoid the drug-drug interaction and the possible effect on the patient’s cognitive function caused by those medications and to avoid the drug-drug interaction. Revising the (S)AE reporting instruction of vision-related AEs according to FDA’s comment. Revising Japan specific safety reporting instruction in Section 5.2.2.2. Removing the Visit 2 final PK blood sampling time point to shorten the length of PK blood sampling time schedule in order to reduce the burden of complying with study procedures. Revising the wordings of CANTAB domain selection criteria to clarify the criteria which were to be used as a guide for CANTAB domain selection. Updating the instruction and procedures of DILI case follow-up in order to align with the updated DILI Checklist.

Protocol amendment 3 was implemented after study initiation. The major changes were: To update recruitment plan for Japan based on the local regulatory requirement and to add the interim analysis plan. To add criterion 1b-4 to clarify the washout period for anticholinergics, antiepileptics and lithium. To update the fasting requirement of the study drug administration. Patients were instructed to take the study drug orally with water in the morning at approximately the same time every day with or without food. To correct, update and clarify statistical methods which will be used for data analysis. To update the unblinding procedures for pharmacokinetic data analysis, thus to allow the bioanalytical group to perform some appropriate pharmacokinetic analytical determination (e.g. exclusion from the analyses of pharmacokinetic samples taken from placebo patients). To update the instruction of suicidality assessment and AEs/SAEs reporting rule, thus to align with the FDA guidance on prospective assessment of suicidal ideation and behavior.