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Introduction Treatment-resistant schizophrenia (TRS) develops in ˜30% of patients, resulting in higher hospitalization rates, morbidity, mortality, and suicidality, and increased costs (Pompili et al CNS NDDT 2017; 16 870-884). Despite inconsistent findings of its efficacy, antipsychotic polypharmacy (APP) is frequently prescribed in an attempt to treat refractory symptoms (Correll ClinNorthAm 2012; 35 661-681). While marketed APs all act through the modulation of 5HT/DA transmission, clozapine, the only drug approved for TRS, seems to act on multiple receptor systems (Brunello et al NPP 1995; 13 177-213). The need to modulate non-monoaminergic targets is supported by findings of excessive glutamatergic activity, rather than increased dopamine synthesis, in patients with TRS (Demjaha et al BioPsy 2014; 75 11-3). Evenamide, devoid of biological activity at >150 CNS targets, is able to normalize excessive glutamate release without affecting basal levels. Evenamide has demonstrated benefits in several animal models of psychosis (monotherapy and add-on to AP). Benefit of evenamide as add-on was demonstrated in a phase 2, open-label trial (Anand et al IJNPP 2023; 174 216-229) and in a phase 2/3 randomized, double-blind study in patients not responding adequately to SGAs. Objectives Evaluate the efficacy, safety, and tolerability of evenamide 30 mg bid as add-on treatment in patients with documented TRS receiving AP treatment but not adequately benefitting from a stable therapeutic dose. Methods This is a prospective, potentially pivotal, phase 3, randomized, double-blind, placebo-controlled, 1-year international study, with a primary efficacy endpoint at 12 weeks and long-term efficacy endpoints at 26 and 52 weeks. Eligible patients must have a diagnosis of TRS according to the TRRIP consensus guidelines (Howes et al AmJPsy 2017; 174 216-229). During the 6-week screening period and throughout the study, adherence to background AP(s) and evenamide will be confirmed through measurements of plasma levels. Selection criteria include CGI-S of mildly to severely ill (3-6); BPRS total score ≥45, with a score ≥18 on core symptoms of psychosis, and PANSS total score ≥70. An Independent Eligibility Committee will determine patients’ eligibility. Patients improving ≥20% on the BPRS or ≥1 category on the CGI-S during the screening period will be excluded. Efficacy (PANSS, CGI-S/C, Q-LES-Q-SF, PSP scales) and safety (vital signs, ECG, lab tests, physical/neurological/eye exams, ESRS-A, CDSS, C-SSRS) will be evaluated at regular intervals. Results Results from this study will determine whether addition of evenamide 30 mg bid to APs is associated with clinically important benefit in TRS patients. Conclusions Positive results would support the role of glutamate modulators for the optimal treatment of TRS. Disclosure of Interest R. Anand Consultant of: AbbVie, Acadia, BiolineRx, Domain, Enkam,Erydel, Forest, Janssen, Hoffman La Roche, Lundbeck, Noema, Ono, Pfizer, UCB, Shire, Sigma-Tau, Takeda, Teva, A. Turolla Employee of: Newron Pharmaceuticals SpA, G. Chinellato Employee of: Newron Pharmaceuticals SpA, R. Giuliani Employee of: Newron Pharmaceuticals SpA, F. Sansi Employee of: Newron Pharmaceuticals SpA, R. Hartman Employee of: Newron Pharmaceuticals SpA