AMENDMENT 1 India. Reporting overdose: Section 13.1.6 of the protocol, Reporting of Overdose, has been modified to indicate that the procedures to be followed are based on Sponsor safety reporting standards. The new language conforms to the reporting requirements specified in previous clinical study protocols for evenamide. This modification of the protocol was a procedural change and had no impact on the safety of patients enrolled in the study

AMENDMENT 2 Increase in the number of participating sites (up to 25); sites in Sri Lanka and Italy being added to the study. Changes based on feedback from investigators for the use of concomitant psychotropic medication: e.g. maximum dose of quetiapine increased up to 150 mg hs as soporific, no restrictions on the maximum dose of lorazepam, or equivalent short half-life BDZ, for patients not receiving a benzodiazepine upon entry into the trial, administration of 0.5 mg lorazepam (or equivalent dose of another benzodiazepine) is allowed as rescue medication during the study on a prn basis, with a maximum daily dose of 2 mg. The protocol has been modified to allow daily doses greater than 2 mg (or equivalent) to be administered, if clinically necessary.

AMENDMENT 3 Update of information related to the study, and correct some errors and inconsistencies in the protocol, change/addition of the local CROs (Malaysia and Italy) and change of Planned Trial Period in light of the global COVID 19 pandemic.

AMENDMENT 4 Protocol modifications in response to the following requests made by the Agenzia Italiana del Farmaco (AIFA) to allow opening of investigational centers in Italy: criteria have been added regarding discontinuation of a subject from treatment, in addition to the reasons for discontinuing the subject from the study. Procedures have been described for collecting data from subjects who discontinue treatment but remain in the study and return for scheduled visits.

AMENDMENT 5 Based on an Investigators request, indicating that the requirement for the diagnosis of schizophrenia within the past 10 years was too restrictive then excluding many patients who would otherwise be eligible for the trial. The Amendment modified the inclusion criteria related to the duration of the diagnosis of schizophrenia and the classification of the patient as “treatment-resistant.” Patients were eligible for the study if the diagnosis of schizophrenia was made within the past 15 years. Additionally, patients must have been identified as being treatment-resistant within the past 10 years. Additional modifications have been made to correct minor errors and omissions and clarification of the timing of the following assessments Vital signs, ECGs, Ratings of PANSS, CGI-S and CGI-C, Sample collection for laboratory tests, have been made.

AMENDMENT 6 The dosing and the randomization to the three treatment groups, were modified based on the interim safety assessment of the data from the first 50 patients randomized in Study 014, as well as the available results from Study 008 (NW-3509/008/II/2019). This safety data were reviewed by the Independent Safety Monitoring Board, which determined that it was safe to proceed with the 30 mg bid dose. This decision, lead to the discontinuation of the evenamide 7.5 mg bid dose group from the study, and the modification of the randomization to a 1:3 ratio for the 15 mg bid and 30 mg bid dose groups, respectively.

AMENDMENT 7 Addition of an interim analysis of the data for all efficacy measures from the first 100 patients who complete their participation in the study. This analysis was performed as the Independent Safety Monitoring Board has requested evidence of benefit following their review of the safety data from these 100 patients, to determine whether a benefit-risk assessment justifies the long-term treatment of patients with evenamide. None of these changes impacted the patient population to be enrolled, or the planned safety and efficacy assessments to be performed in the trial.

AMENDMENT 8 The study sample size was increased from a minimum of 150 to approximately 180 patients. This change was made to ensure that at least 50 patients are randomized to each of the three treatment groups (evenamide 7.5 mg, 15 mg and 30 mg, bid). Malaysia was removed as a participating country in the study. Appropriate changes have been made throughout the protocol.