Study to Determine the Safety, Tolerability, and Efficacy of Evenamide in Patients With Chronic Schizophrenia

This 4-week study will evaluate the safety, tolerability and preliminary evidence of efficacy of evenamide (7.5,and 15 mg and placebo, bid) treatment in outpatients with chronic schizophrenia.

This is a prospective, 4-week, randomized, double-blind, placebo-controlled, study designed to evaluate the safety, tolerability, EEG effects, and preliminary efficacy of two fixed oral doses of evenamide of 7.5 mg and 15 mg bid (15 and 30 mg/day) in outpatients with chronic schizophrenia who are receiving treatment at constant doses of one of the following atypical antipsychotics: aripiprazole, clozapine, quetiapine, olanzapine, paliperidone or risperidone. Approximately 120 patients will be randomized in a 1:1:1 ratio to receive either evenamide 7.5 or 15 mg, or placebo, given bid.

Eligibility Criteria:
Inclusion Criteria:

Demographics

* Age - 18 years, or older
* Sex - male, or non-childbearing potential female unless practicing adequate contraception

Psychiatric

* Has a current diagnosis of schizophrenia in accordance with DSM-5.
* Has been treated with antipsychotics for at least 2 years.
* Has a total score on the PANSS \< 80.
* Has a Clinical Global Impression - Severity of disease (CGI-S) rating of mildly, moderately or moderately severely ill (score of 3, 4 or 5).
* Needs antipsychotic treatment and is currently receiving a stable dose (minimally for 4 weeks prior to screening) of aripiprazole, clozapine, quetiapine, olanzapine, paliperidone, or risperidone (at least 2 mg risperidone dose-equivalent)
* Current symptoms have been stably present for at least one month

Procedural

* Patient resides at home or in a residential care facility
* If taking clozapine, patient agrees to blood monitoring

Exclusion Criteria:

Psychiatric

* Severity of current episode of psychosis requires that the patient be hospitalized. Patients who are chronically hospitalized or in psychiatric day-care, whose hospitalization is for logistic reasons and not due to the severity of their illness, will be eligible for the study.
* Severity of psychosis is rated severe or higher (CGI-S of 6 or greater).
* Known suicidal risk. A "yes" response on the C-SSRS Suicidal Ideation Item 4 or Item 5, or a "yes" response on any of the five C-SSRS Suicidal Behavior items, at screening, or a suicide attempt within the past 6 months, excludes the patient from the study.
* Patients with a diagnosis of Treatment resistance
* History of neuroleptic malignant syndrome, priapism.
* Current moderate or severe tardive dyskinesia.

Medical Status

* Abnormal epileptiform phenomena (3 per second spike and slow wave discharges) observed on screening EEG. History or current diagnosis of epilepsy or seizure disorder (other than febrile seizures in childhood)
* Insulin-dependent diabetes mellitus
* History or current diagnosis of any neurodegenerative illnesses
* Loss of 500 ml or more of blood during the 3-month period before study enrollment, e.g. as a donor

Cardiovascular

* A current diagnosis of severe or unstable cardiovascular disease
* Any clinically significant ECG abnormality
* Abnormal vital signs

Laboratory abnormalities

* Clinically significant abnormalities in routine laboratory examinations
* History and/or presence of hepatitis B and/or C
* Positive results from the HIV serology.
* Positive results of the drug and alcohol tests
* Clinically significant or unstable hypothyroidism or hyperthyroidism

Concomitant therapy

* Treatment with SSRIs that are moderate/potent inhibitors of CYP2D6 (e.g. fluoxetine)
* Treatment with drugs capable of inducing/inhibiting hepatic enzyme metabolism
* Current treatment with sodium channel blockers
* Exposure to any investigational drug within 5 weeks or 5 half-lives (whichever is longer) prior to screening
* A known exaggerated pharmacological sensitivity or hypersensitivity to drugs similar to evenamide (e.g. lamotrigine, carbamazepine, oxcarbazepine, topiramate, etc.), or any components of the evenamide or matching placebo capsules
* Treatment with a drug or treatment known to cause major organ system toxicity, e.g. tamoxifen, within 4 weeks, or received radiation therapy or a drug with cytotoxic potential, e.g. chemotherapy, during the past year
* Electroconvulsive therapy (ECT) or treatment with a transcranial magnetic stimulation (TMS) device within 6 months prior to screening