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

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

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.

Study Overview

• Status: Completed
• Conditions: Central Nervous System Diseases; Schizophrenia; Schizoaffective Disorder
• Intervention / Treatment: Drug: Placebo; Drug: Antipsychotic therapy; Drug: EVP-6124 (1.0 mg/day); Drug: EVP-6124 (0.3 mg/day)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Wichita, Kansas, United States, 67211
      • Clinical Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo was administered as one capsule per day for 21 days.	Drug: Placebo; Matching placebo was administered as one capsule per day for 21 days.; Drug: Antipsychotic therapy; 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.
Experimental: EVP-6124 (1.0 mg/day); EVP-6124 was administered as one 1.0 mg capsule per day for 21 days.	Drug: Antipsychotic therapy; 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.; Drug: EVP-6124 (1.0 mg/day); EVP-6124 was administered as one 1.0 mg capsule per day for 21 days.
Experimental: EVP-6124 (0.3 mg/day); EVP-6124 was administered as one 0.3 mg capsule per day for 21 days.	Drug: Antipsychotic therapy; 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.; Drug: EVP-6124 (0.3 mg/day); EVP-6124 was administered as one 0.3 mg capsule per day for 21 days.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: FORUM Pharmaceuticals Inc
• Investigators: Principal Investigator: Sheldon H. Preskorn, M.D., Clinical Research Institute

Publications and helpful links

General Publications

• Preskorn SH, Gawryl M, Dgetluck N, Palfreyman M, Bauer LO, Hilt DC. Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: a proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract. 2014 Jan;20(1):12-24. doi: 10.1097/01.pra.0000442935.15833.c5.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: March 14, 2012
• First Submitted That Met QC Criteria: March 15, 2012
• First Posted (Estimate): March 16, 2012

Study Record Updates

• Last Update Posted (Estimate): June 21, 2012
• Last Update Submitted That Met QC Criteria: May 21, 2012
• Last Verified: May 1, 2012

More Information

Terms related to this study

• Keywords: Schizophrenia; Schizoaffective; CNS
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Nervous System Diseases; Central Nervous System Diseases; Physiological Effects of Drugs; Central Nervous System Depressants; Tranquilizing Agents; Psychotropic Drugs; Antipsychotic Agents
• Other Study ID Numbers: EVP-6124-005