Evenamide, a Glutamate Release Modulator, as Add-On to Standard of Care in Subjects With Documented Treatment-Resistant Schizophrenia

Official title

A Phase III, 12-week, Prospective, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multi-center Study to Determine the Efficacy, Safety, and Tolerability of a Dose of 15 mg Bid of Evenamide as add-on in Patients With Documented Treatment-resistant Schizophrenia, Which is Not Adequately Controlled by a Stable Therapeutic Dose of the Patient's Current Antipsychotic Medication(s)

Overview

This is a prospective, 12-week, randomized, double-blind, placebo-controlled study, designed to evaluate the efficacy, safety, and tolerability of a dose of evenamide of 15 mg bid, compared to placebo, as add-on treatment in patients with documented treatment-resistant schizophrenia (TRS) who have prospectively demonstrated inadequate response to their current stable therapeutic dose of an antipsychotic(s). Approximately 400 patients will be randomized equally (1:1) to each of the two treatment groups in this study.

Interventions

• Drug Evenamide 15 mg bid
  Evenamide capsules 15 mg bid for a total of 12 weeks of add-on treatment
• Drug Placebo
  Matching placebo capsules bid for a total of 12 weeks of add-on treatment

Primary outcome measures

• Change from baseline to endpoint (Week 12) on the total score of the Positive and Negative Syndrome Scale (PANSS). [Time frame: From Baseline to Week 12]
• Incidence of treatment-emergent adverse events (TEAEs), AEs leading to discontinuation (ADOs), and serious AEs (SAEs). [Time frame: From Baseline to 30-day Safety Follow up (12 Weeks of treament + 30-day safety follow up)]

Secondary outcome measures (5)

• Change from baseline to endpoint (Week 12) on the Clinical Global Impression - Severity of illness (CGI-S) score. [Time frame: From Baseline to Week 12]
• Proportion of patients rated as 'improved' on the CGI-C at endpoint (Week 12). [Time frame: Week 12]
• Change from baseline to endpoint (Week 12) on the Positive Symptoms sub-scale score of the PANSS. [Time frame: From Baseline to Week 12]
• Change from baseline to endpoint (Week 12) on the Personal and Social Performance (PSP) scale. [Time frame: From Baseline to Week 12]
• Change from baseline to endpoint (Week 12) on the Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form scale (Q-LES-Q-SF). [Time frame: From Baseline to Week 12]

Eligibility criteria

Inclusion criteria

• Age - 18 years, or older.
• If female, the subject has a negative pregnancy test at the screening visit and at baseline, is not lactating, and agrees to use adequate contraception, unless not of childbearing potential.
• Meets current DSM-5-TR criteria for schizophrenia.
• Has shown treatment-resistance to antipsychotics as per TRRIP working group definition (Howes et al., 2017).
• Currently receiving "standard of care" therapy of a minimal recommended therapeutic dose of one or more antipsychotic(s).
• Has a Clinical Global Impression - Severity of disease (CGI-S) rating of "mildly ill" to "among the most extremly ill" at baseline.
• Has a BPRS total score ≥ 45 at screening and baseline.
• Has a PANSS total score ≥ 70 at baseline.
• Has a Global Assessment of Functioning (GAF) scale total score ≤ 50.
• Adherence to prescribed antipsychotic treatment.
• Patient has provided written informed consent prior to participating in the study.

Exclusion criteria

• Current DSM-5-TR diagnosis of schizophreniform disorder, schizoaffective disorder, or other primary psychiatric diagnosis, such as bipolar disorder or major depressive disorder
• History (within three months of study entry) or current diagnosis of "Substance Use Disorder" as defined by the DSM-5-TR criteria.
• Severity of current episode of psychosis requires that the patient be hospitalized to stabilize the severity of his/her psychotic symptoms. However, these patients may qualify for the study provided their antipsychotic dose has been stable for 6 weeks prior to screening.
• History or current diagnosis of other psychiatric or behavioral disorders.
• Known suicidal risk, or a suicide attempt within the past 2 years.
• History of neuroleptic malignant syndrome or priapism.
• Disease/medical condition of any type that may impact the patient's safety or interfere with any of the study evaluations.
• History or current diagnosis of epilepsy or seizure disorder, or occurrence of a seizure within the past year, or repeated drug-induced seizures.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

India · 7 centers

• Help Hospital — Vijayawada
• Gauhati Medical College and Hospital — Guwahati
• Masina Hospital Trust — Mumbai
• New Manak Healthcare Hospital — Navi Mumbai
• Ahana Hospitals LLP — Madurai
• Udyan Health Care — Lucknow
• Seth Sukhlal Karnani Memorial Hospital — Kolkata

United States · 5 centers

• UCLA DGSOM, UCLA Health, UCLA Semel Institute — Los Angeles
• University of Miami, Miller School of Medicine; Jackson Behavioral Health Hospital — Miami
• Grady Behavioral Health Center, -Department of Psychiatry and Behavioral Sciences, Emory U — Atlanta
• Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medic — Baltimore
• Manhattan Psychiatric Center, The Nathan Kline Institute for Psychiatric Research — New York

Malaysia · 3 centers

• Hospital Tuanku Fauziah — Kangar
• Sentosa Hospital — Kuching
• Sultan Abdul Halim Hospital — Sungai Petani

Publications

• Anand R, Turolla A, Chinellato G, Sansi F, Roy A, Hartman R. Efficacy and safety of evenamide, a glutamate modulator, added to a second-generation antipsychotic in inadequately/poorly responding patients with chronic schizophrenia: Results from a randomized, double-blind, placebo-controlled, phase 3, international clinical trial. Neuropharmacology. 2025 Mar 15;266:110275. doi: 10.1016/j.neuropharm PMID 39708914
• Anand R, Turolla A, Chinellato G, Roy A, Hartman RD. Therapeutic Effect of Evenamide, a Glutamate Inhibitor, in Patients With Treatment-Resistant Schizophrenia (TRS): Final, 1-Year Results From a Phase 2, Open-Label, Rater-Blinded, Randomized, International Clinical Trial. Int J Neuropsychopharmacol. 2024 Dec 28;28(1):pyae061. doi: 10.1093/ijnp/pyae061. PMID 39661380
• Anand R, Turolla A, Chinellato G, Roy A, Hartman RD. Phase 2 Results Indicate Evenamide, A Selective Modulator of Glutamate Release, Is Associated With Clinically Important Long-Term Efficacy When Added to an Antipsychotic in Patients With Treatment-Resistant Schizophrenia. Int J Neuropsychopharmacol. 2023 Aug 29;26(8):523-528. doi: 10.1093/ijnp/pyad035. PMID 37349110

Identifiers

NCT: NCT07184619 · NW-3509/022/III/2024

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗