- Expanded study from elderly to adult population - Changed timeframe of assessment for primary endpoint (HAMD-17) to change from BL to Week 5 - Revised secondary endpoints to include SDS, CGI-I, CSFQ-14, KSS, HAMD-17, and BIS-11; revised secondary endpoint analyses - Removed PK, PK/PD, exploratory objectives, endpoints, and analyses - Removed MMSE score as assessment, changed assessment timeframe for ESRS-A to Week 5 from Baseline - Decreased number of planned study sites to 40 sites - Revised timeframes for screening and double-blind periods; deleted stratification by region - Changed safety follow-up period to at least 30 days; removed DSMB - Updated duration of patient participation to 14 weeks - Removed allowance of patients with comorbid neurodegenerative disorders from inclusion criteria - Revised list of acceptable SSRI/SNRI antidepressants in inclusion criteria - Clarified procedure and inclusion criteria for repeat screening test for SSRI/SNRI - Removed exclusion criterion on Huntington’s disease or motor neuron disease; revised assessment for exclusion of active suicidality - Clarified that bradycardia explained by exercise would not lead to exclusion; explained procedure for positive test for illicit drugs or cannabis and retesting criteria - Revised sample size to 266 evaluable patients - Revised statistical methods for efficacy, descriptive statistical analyses - Removed rescue medication procedures - Revised randomization methodology; removed stratified randomization by region - Eliminated collection of dementia history and neurological history - Revised timeframes for concomitant SSRI/SNRI antidepressant blood sampling - Clarified interview guides for MADRS, HAMD-17, CGI-S - Provided description for CSFQ-14 assessment, BIS-11 questionnaire - Clarified safety laboratory evaluations - Revised procedure for following a pregnancy to outcome - Updated information on prohibited, unrestricted medications

- Removed the option of abstinence as an acceptable method of contraception - Implemented a less restrictive definition of suicidality in the exclusion criteria

- Added new safety and tolerability endpoint (sexual dysfunction) - Extended screening period to 3-28 days - Clarified procedure for confirming subject eligibility - Clarified dosing requirements for the background antidepressant prior to SAFER interview for inclusion criteria - Clarified barrier methods of contraception for inclusion criteria - Clarified several exclusion criteria (medical conditions; cardiovascular history; viral serology; heart rate) - Added sexual dysfunction summary and shift tables to the safety analyses - Added a definition of “inadequate response” to current SSRI/SNRI antidepressant therapy - Added review of background antidepressant adherence - Added text on benefits and risks of the study - Clarified follow-up procedures for discontinued patients - Clarified prior, concomitant, and prohibited therapy and restrictions on controlled substances - Clarified major protocol deviations

- Included description of changes necessitated by the COVID-19 pandemic - Added description of Study ACP-103-059 - Described impact of the COVID-19 pandemic on Studies ACP-103-054 and ACP-103-059, the study conduct during the time when screening and randomization was suspended, and the decision to combine the 2 studies for the purpose of analysis - Added COVID-19 relatedness of AEs and concomitant medications - Described the impact of the COVID-19 pandemic on efficacy and safety assessments; unscheduled visits - Added description of protocol deviation review and described handling of protocol deviations with respect to relationship to COVID-19 - Updated the statistical methods section to align with statistical Analysis plan - Changed the statistical comparison method used for both the response and remission rates