Protocol Ver1.00 (24Apr2019) amended: MADRS, BNSS, UPSA-B total score removed from objectives & left for discussion under subsequent sections; Added tobacco use endpoint to align with the rest of the protocol; Inclusion/exclusion criteria were updated as follows: 1)subject’s schizophrenia diagnosis must be supported by medical records or documented correspondence with a treating psychiatrist 2)clarified requirement for no more than 3 prior lifetime hospitalizations for the treatment of an acute psychotic episode or exacerbation of schizophrenia 3)assessment of subject’s health at screening was specified to include ECG results 4)Clarified that subject eligibility must be confirmed through formal adjudication process 5) substance use disorder was amended to exclude history of significant substance abuse that could have had a permanent impact on the brain or other body systems 6) window for taking an antipsychotic equivalent to ≥ 12 mg/day of haloperidol was updated from “at screening” to “the current episode” 7)Subjects with unstable hypertension excluded. Subjects with a known cardiovascular condition, including hypertension, must be discussed with Medical Monitor (MM) before randomization. Subjects with an ECG that had a significant or potentially significant centrally read ECG alert had to be discussed with the MM. Specific blood pressure thresholds must be met for entry into the study 8) Outlined who determines clinical significance of abnormal lab values at screening; specified that the MM must approve lab retests during screening for use in determining eligibility; allowed extensions to the screening period for technical issues 9) Excluded subjects with a positive or indeterminate test for hep C, regardless of ALT or AST levels 10)Language regarding drug test results at screening was simplified. Subjects who test positive for cannabinoids at screening are excluded 11)Restrictions on prior receipt of an investigational drug product or device were expanded.

Protocol Ver2.00 (16Sep2020) amended: A comparative interim analysis for unblinded sample size re-estimation was added. The purpose of the interim analysis was to assess the need for a sample size increase. Inclusion/exclusion criteria were updated as follows: 1)Based on FDA feedback, criterion regarding exclusion of subjects with a history of substantial substance use disorder that may result in significant confounding on diagnosis, presentation, and/or treatment responsiveness was revised to make the criterion more specific 2)Based on FDA feedback restrictions on prior clinical trial participation were refined to those that would meaningfully interfere with the conduct of the study 3)clarifications were made regarding medical record requirements for documenting previous course and treatment of the subject’s schizophrenia illness.

Protocol Ver3.00 (26Jan2021) amended: Inclusion/exclusion criteria were updated as follows: 1)clarifications made regarding medical record requirements for documenting previous course and treatment of the subject’s schizophrenia illness and number of prior inpatient hospitalizations 2) range of acceptable BMI at screening was expanded to 18 to 40 kg/m2, inclusive 3) discontinuation requirement for clozapine dosed at ≤ 200 mg/day for insomnia, agitation, or anxiety was adjusted to over a 1- to 2 week period prior to randomization, as judged to be safe by the PI 4) The time requirement for prior receipt of an investigational drug product or device was reduced from 1 year to 90 days prior to signing informed consent, and the maximum lifetime participation was increased to 3 studies in psychiatric indications 5)Clarified the language regarding duration of hospitalization subsequent to last dose of study drug that would qualify as an SAE 6)Based on FDA feedback, the process for collection and recording of AEs was clarified to indicate that additional information would be collected for non-serious psychiatric AEs that led to discontinuation from the study, as well as all serious psychiatric AEs during the study.