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

A Phase II, Randomized, 4-Week, Double-Blind, Placebo-Controlled, Multiple-Dose Study, Designed to Determine the Safety, Tolerability, EEG Effects and Preliminary Efficacy of Fixed Oral Doses of 7.5 and 15 MG BID of Evenamide in Patients With Chronic Schizophrenia Who Are Symptomatic on Their Current Second-Generation Antipsychotic Medication

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.

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