Safety, Tolerability, and Pharmacokinetic Study of EVP-6124 in Patients With Schizophrenia

Study Overview
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Brief Summary
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This study in patients with schizophrenia is designed to provide preliminary evidence of the safety, tolerability, and pharmacokinetics as well as the effects on cognitive function of 2 doses of EVP-6124 compared with placebo when given with the patient's usual antipsychotic medication.

Detailed Description
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Study drug will be supplied as capsules and will be orally administered once daily for a total of 21 days. Eligible subjects will be admitted to an inpatient study unit on Day -6 (six days before the first dose of study drug is administered) and will remain confined to the inpatient study unit throughout the dosing phase. Safety assessments, PK sampling, and cognitive testing will be performed.

Official Title
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A Double-Blind, Placebo-Controlled Randomized Study to Assess the Safety, Tolerability, and Pharmacokinetics of EVP-6124 in Participants With Schizophrenia on Stable Monotherapy With Selected Antipsychotics

Conditions
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Schizophrenia, Schizoaffective Disorder, Central Nervous System Diseases

Intervention / Treatment
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* Drug: EVP-6124 (0.3 mg/day)
* Drug: EVP-6124 (1.0 mg/day)
* Drug: Placebo
* Drug: Antipsychotic therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18 to 55 years (both inclusive). Females must be surgically sterile, post-menopausal, or using reliable contraception and have negative pregnancy tests at screening and at Day -1. A clinical diagnosis of schizophrenia or schizoaffective disorder and prescribed a stable dose of aripiprazole (10 to 30 mg/day), olanzapine (10 to 20 mg/day), paliperidone (3 to 12 mg/day), or risperidone (2 to 16 mg/day) for a minimum of 2 weeks before initial screening. In good general health and expected to complete the clinical trial as designed. Body Mass Index (BMI) of 18 kg/m^2 to 38 kg/m^2 (both inclusive) at screening. Adequate hearing, vision, and language skills to perform the cognitive testing and other procedures specified in the protocol. Voluntarily provided informed consent and signed an informed consent form (ICF) indicating that the purpose of the study was explained, and was willing and able to adhere to the study regimen and study procedures described in the ICF, including all confinement requirements. Negative urine drug screen at screening and inpatient observation baseline period (Day -6), except for a short-acting benzodiazepine if prescribed for insomnia. Fluent in English (speaking, writing, and reading). Exclusion Criteria: Female subject who was pregnant or breast-feeding. Any active clinically significant medical condition within 1 month (30 days) prior to screening. A history of substance (drug) dependence or substance or alcohol abuse within the 12 months before randomization as defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV). A score of >5 on any item on the PANSS (Positive and Negative Syndrome Scale) Positive subscale at baseline during the inpatient observation period (Day -1). Any laboratory test abnormalities at screening indicating hepatic or renal dysfunction, or any other laboratory test abnormalities deemed by the investigator to be clinically significant. Any hematologic malignancy or solid tumor diagnosed within 3 years prior to study entry with the exception of localized skin cancer or carcinoma in situ of the cervix. Known to have had or was a carrier of HBsAg, HCV antibody, or had a positive result to the HIV-1 and/or HIV-2 antibodies. Uncooperative with or could not complete the study procedures. Received an investigational drug within 30 days before screening. Donated blood within 30 days before randomization on Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Matching placebo was administered as one capsule per day for 21 days. | Drug: Placebo<br>* Matching placebo was administered as one capsule per day for 21 days.<br>Drug: Antipsychotic therapy<br>* Concomitant therapy with antipsychotic medication (aripiprazole [10 to 30 mg/day], olanzapine [10 to 20 mg/day], paliperidone [3 to 12 mg/day], or risperidone [2 to 16 mg/day]), taken at the same time each day as the EVP-6124 dose. Patients must have been taking concomitant therapy for at least 2 weeks at a stable dose to be eligible for the study.<br>|
| Experimental: EVP-6124 (1.0 mg/day)<br>EVP-6124 was administered as one 1.0 mg capsule per day for 21 days. | Drug: EVP-6124 (1.0 mg/day)<br>* EVP-6124 was administered as one 1.0 mg capsule per day for 21 days.<br>Drug: Antipsychotic therapy<br>* Concomitant therapy with antipsychotic medication (aripiprazole [10 to 30 mg/day], olanzapine [10 to 20 mg/day], paliperidone [3 to 12 mg/day], or risperidone [2 to 16 mg/day]), taken at the same time each day as the EVP-6124 dose. Patients must have been taking concomitant therapy for at least 2 weeks at a stable dose to be eligible for the study.<br>|
| Experimental: EVP-6124 (0.3 mg/day)<br>EVP-6124 was administered as one 0.3 mg capsule per day for 21 days. | Drug: EVP-6124 (0.3 mg/day)<br>* EVP-6124 was administered as one 0.3 mg capsule per day for 21 days.<br>Drug: Antipsychotic therapy<br>* Concomitant therapy with antipsychotic medication (aripiprazole [10 to 30 mg/day], olanzapine [10 to 20 mg/day], paliperidone [3 to 12 mg/day], or risperidone [2 to 16 mg/day]), taken at the same time each day as the EVP-6124 dose. Patients must have been taking concomitant therapy for at least 2 weeks at a stable dose to be eligible for the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serious and Non-serious Adverse Events Spontaneously Reported by Subject and/or Observed by Investigator. | Safety and tolerability was measured by number of reported adverse events (serious and non-serious) and repeated clinical evaluation of physical examinations, vital signs, 12-lead electrocardiogram (ECG), 24-hour continuous cardiac monitoring, and laboratory tests (hematology/blood chemistry/urinalysis). | Screening (Day -5 for continuous cardiac monitoring) to Day 22 | 
| EVP-6124 Maximum Plasma Concentration (Cmax), Patients on Aripiprazole | Blood samples for pharmacokinetic (PK) analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 
| EVP-6124 Time to Maximum Concentration (Tmax), Patients on Aripiprazole | Blood samples for PK analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 
| EVP-6124 Area Under the Curve (AUC[0-24 h]), Patients on Aripiprazole | Blood samples for PK analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 
| EVP-6124 Half-life (T[1/2]), Patients on Aripiprazole | Blood samples for PK analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 
| EVP-6124 Maximum Plasma Concentration (Cmax), Patients on Paliperidone/Risperidone | Blood samples for PK analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 
| EVP-6124 Time to Maximum Concentration (Tmax), Patients on Paliperidone/Risperidone | Blood samples for PK analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 
| EVP-6124 Area Under the Curve (AUC[0-24 h]), Patients on Paliperidone/Risperidone | Blood samples for PK analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 
| EVP-6124 Half-life (T[1/2]), Patients on Paliperidone/Risperidone | Blood samples for PK analyses were taken before dosing with EVP-6124 on Days 1 and 21. | Days 1 and 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| N100 Gating Ratio | N100 auditory evoked potential response (amplitude measured in microvolts) using the sensory gating paradigm. Measured by electroencephalography (EEG) as the amplitude ratio of test stimulus to conditioning stimulus. Plotted on a unitless scale of 0 to 2. Normalization is suggested by a lower value. | Days -1 to 20 | 
| P50 Amplitude Difference | P50 auditory evoked potential response (amplitude measured in microvolts) using sensory gating paradigm. Measured by EEG as amplitude difference (conditioning stimulus minus test stimulus). Plotted on a scale of -0.2 to 0.8 microvolts. Normalization is suggested by a higher value. | Days -1 to 20 | 
| MMN Summed Amplitude | Mismatch negativity (MMN) auditory evoked potential response (amplitude in microvolts) using orienting paradigm. Measured by EEG and calculated as the voltage difference over 100-200 msec following stimulus onset (rare stimulus minus frequent stimulus). Plotted on a scale of -1.2 to 0.2 microvolts. Normalization is suggested by a more negative value. | Days -1 to 20 | 
| P300 Peak Amplitude | P300 auditory evoked potential response (amplitude in microvolts) using orienting paradigm. Measured by EEG and calculated as the peak amplitude over 250-500 msec following stimulus onset (rare stimulus minus frequent stimulus). Plotted on a scale of -0.4 to 1.2 microvolts. Normalization is suggested by a more positive value. | Days -1 to 20 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CNS, Schizophrenia, Schizoaffective