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

• ClinicalTrials.gov Identifier: NCT04461119
• Recruitment Status: Completed
• First Posted: July 8, 2020
• Last Update Posted: May 20, 2021
• Sponsor: Newron Pharmaceuticals SPA
• Information provided by (Responsible Party): Newron Pharmaceuticals SPA

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Schizophrenia	Drug: Evenamide; Drug: Placebo	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 138 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: June 16, 2020
• Actual Primary Completion Date: February 20, 2021
• Actual Study Completion Date: March 13, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Evenamide 7.5 mg bid; Evenamide capsules 7.5 mg BID for a total of 28 dosing days	Drug: Evenamide; oral capsules for 4 weeks of treatment; Other Name: NW-3509
Experimental: Evenamide 15 mg bid; Evenamide capsules 15.0 mg BID for a total of 28 dosing days	Drug: Evenamide; oral capsules for 4 weeks of treatment; Other Name: NW-3509
Placebo Comparator: Placebo; Matching placebo capsules BID for a total of 28 dosing days	Drug: Placebo; oral capsules for 4 weeks of treatment

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability - incidence of Treatment-Emergent Adverse Events [TEAEs], Serious Adverse Events [AEs], and Adverse Events leading to discontinuation [ADOs] [ Time Frame: 4 Week study ]
   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].
2. Change from baseline in Positive and Negative Syndrome Scale [PANSS] total score [ Time Frame: 4 Week study ]
   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).

Secondary Outcome Measures :

1. Key secondary - Change from baseline in clinical global impression severity of Illness [CGI-S] score [ Time Frame: 4 Week study ]
   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).
2. Rating at endpoint on the CGI - Change from baseline (CGI-C) [ Time Frame: 4 Week study ]
   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".
3. Evaluate plasma drug concentrations over time for evenamide and its major metabolite, (3-butoxy-phenyl)-acetic acid [ Time Frame: 4 Week study ]

   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. 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 [ Time Frame: 4 Week study ]
   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.
5. Efficacy - changes in daily functioning [ Time Frame: 4 Week study ]
   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.
6. Efficacy - rating score of patient satisfaction with the study medication [ Time Frame: 4 Week study ]

   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

Behavioral Research Specialists, LLC

Glendale, California, United States, 91206

United States, Maryland

CBH Health, LLC

Gaithersburg, Maryland, United States, 20877

United States, Texas

Community Clinical Research CCR

Austin, Texas, United States, 78754

India

Help Hospitals Clinical Research Department

Vijayawada, Andhra Pradesh, India, 520002

St. John's Medical College Hospital

Koramangala, Karnataka, India

Mangala Hospital and Mangala Kidney Foundation, Department of Psychiatry

Mangalore, Karnataka, India

IQRAA Psychiatry Care and Rehabilitation Centre

Kozhikode, Kerala, India

Deenanath Mangeshkar Hospital Research Center

Pune, Maharashtra, India

Sujata Birla Hospital

Pune, Maharashtra, India

Post Graduate Institute of Medical Education and Research

Chandigarh, Punjab, India, 160012

Dayanand Medical College & Hospital

Ludhiana, Punjab, India

Sri Ramachandra Medical College, Department of Psychiatry

Chennai, Tamil Nadu, India, 600116

Ahana Hospital LLP

Madurai, TamilNadu, India

Asha Hospital

Hyderabad, Telangana, India, 500034

Sponsors and Collaborators

Newron Pharmaceuticals SPA

Investigators

• Study Director: Ravi Anand, MD; Newron Pharmaceuticals

More Information

• Responsible Party: Newron Pharmaceuticals SPA
• ClinicalTrials.gov Identifier: NCT04461119
• Other Study ID Numbers: NW-3509/008/II/2019
• First Posted: July 8, 2020
• Last Update Posted: May 20, 2021
• Last Verified: May 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Schizophrenia; Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders