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

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
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

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Drug: Evenamide
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Evenamide 7.5 mg bid<br>Evenamide capsules 7.5 mg BID for a total of 28 dosing days | Drug: Evenamide<br>* oral capsules for 4 weeks of treatment<br>* Other names: NW-3509;|
| Experimental: Evenamide 15 mg bid<br>Evenamide capsules 15.0 mg BID for a total of 28 dosing days | Drug: Evenamide<br>* oral capsules for 4 weeks of treatment<br>* Other names: NW-3509;|
| Placebo Comparator: Placebo<br>Matching placebo capsules BID for a total of 28 dosing days | Drug: Placebo<br>* oral capsules for 4 weeks of treatment<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability - incidence of Treatment-Emergent Adverse Events [TEAEs], Serious Adverse Events [AEs], and Adverse Events leading to discontinuation [ADOs] | Comparison will be made between the evenamide and placebo groups in the proportion of patients experiencing Serious Adverse Events [SAEs], Adverse Events leading to discontinuation [ADOs] and, Treatment-Emergent Adverse Events [TEAEs]. | 4 Week study | 
| Change from baseline in Positive and Negative Syndrome Scale [PANSS] total score | Efficacy measure of mean change from baseline to endpoint of Positive and Negative Syndrome Scale [PANSS] total score: this is a 30-item scale that was designed to assess various symptoms of schizophrenia each rated on a 7-point scale that ranges from 1 (absent) to 7 (extreme psychopathology). | 4 Week study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Key secondary - Change from baseline in clinical global impression severity of Illness [CGI-S] score | Efficacy measure by mean change from baseline top endpoint of the Clinical Global Impression Severity of Illness [CGI-S]: the investigator rates the severity of a subject's condition on a 7-point scale ranging from 1 (no symptoms) to 7 (very severe). | 4 Week study | 
| Rating at endpoint on the CGI - Change from baseline (CGI-C) | Efficacy measured by Clinical Global Impression of Change [CGI-C]: 7-point scale requiring the clinician to rate how much the patient's illness has improved at endpoint relative to the baseline state (score of 1, 2, 3); CGI-C ranges from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. | 4 Week study | 
| Evaluate plasma drug concentrations over time for evenamide and its major metabolite, (3-butoxy-phenyl)-acetic acid | Determine the multiple-dose plasma concentrations of evenamide and its major metabolite, (3-butoxy-phenyl)-acetic acid, at the doses tested. Doses of evenamide to be evaluated in this study, compared to placebo, will be 7.5 mg bid, and 15 mg bid, with key information being collected at or near the time of the predicted maximal plasma concentration (Tmax) for evenamide. | 4 Week study | 
| Comparison of plasma drug concentrations over time for evenamide and its major metabolite, (3-butoxy-phenyl)-acetic acid between the dosing arms 7.5 mg BID and 15.0 mg BID | Determine if the PK parameters are dose proportional. Doses of evenamide to be evaluated in this study, compared to placebo, will be 7.5 mg bid, and 15 mg bid, with key information being collected at or near the time of the predicted maximal plasma concentration (Tmax) for evenamide. | 4 Week study | 
| Efficacy - changes in daily functioning | Determine the effect of evenamide, compared to placebo, on daily functioning, based on changes on the Strauss-Carpenter Level of Functioning (LOF) scale; The LOF is a semi-structured, clinician-administered scale of nine items. The individual items fall into four domains, with higher scores on a 5-point scale (0 - 4) reflecting better functioning. The subscales are Social Contacts (frequency and quality of social contacts), Work (quantity and quality of useful work), Symptomatology (absence of symptoms and recent hospitalization), and Function (ability to meet basic needs, fullness of life, and overall level of function). A total score is calculated as the sum of the raw scores across the nine items. | 4 Week study | 
| Efficacy - rating score of patient satisfaction with the study medication | Determine the patient's satisfaction with the study medication, compared to their previous treatment, based on improvements on the Medication Satisfaction Questionnaire (MSQ) which is a single-item, 7-point Likert-type scale for patients with schizophrenia to rate their satisfaction with their antipsychotic medication. The patient's response to the question Overall, how satisfied are you with your current antipsychotic medication(s)? is rated by the clinician as follows: 1 = extremely dissatisfied, 2 = very dissatisfied, 3 = somewhat dissatisfied, 4 = neither satisfied nor dissatisfied, 5 = somewhat satisfied, 6 = very satisfied, and 7 = extremely satisfied | 4 Week study |