A Brain Imaging Study With Positron Emission Tomography and the Radiotracer [11C]UCB-J to Estimate How Fast Brivaracetam and Levetiracetam Enter the Brain in Healthy Volunteers

Sponsor

UCB Pharma (Industry)

Overall Status

Completed

CT.gov ID

NCT02602860

Collaborator

PRA Health Sciences (Industry), Yale University (Other)

Enrollment

Location

Arms

Actual Duration (Months)

0.6

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This study will estimate how fast two antiepileptic drugs (Levetiracetam and Brivaracetam) enter the human brain. Brain imaging will be used to measure how quickly the radioactive probe [11C]UCB-J exits the brain when Levetiracetam or Brivaracetam are given. This will be used to estimate how fast the antiepileptic drugs enter the brain.

Condition or Disease	Intervention/Treatment	Phase
Healthy Volunteers	Radiation: [11C]UCB-J Drug: Brivaracetam Drug: Levetiracetam Drug: Brivaracetam	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

13 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Other

Official Title:

A Single-center, Open-label Positron Emission Tomography Study to Evaluate the Time-course of Displacement of [11C]UCB-J by Brivaracetam and Levetiracetam in Healthy Volunteers

Actual Study Start Date :

Nov 1, 2015

Actual Primary Completion Date :

Sep 1, 2017

Actual Study Completion Date :

Sep 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Levetiracetam Cohort 1: Half of the subjects will receive LEV as a 5 minute iv infusion during the second Positron Emission Tomography (PET) scan, 60 minutes after the start of [11C]UCB-J administration. Cohort 2: Half of the subjects will receive LEV as a 5 minute iv infusion during the first PET scan, 60 minutes after the start of [11C]UCB-J administration. The dose of LEV (500 mg to 2500 mg) or BRV (50 mg to 200 mg) will be decided based on the data obtained in Cohort 1. Subjects will return for a second PET imaging session (Visit 4), 7 to 28 days after completion of their first session (Visit 3) to enter the BRV arm.	Radiation: [11C]UCB-J Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 20 mCi Route of Administration: iv Other Names: [11C]APP311 Drug: Levetiracetam Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 100 mg/ml Route of Administration: iv Other Names: Keppra L059
Experimental: Brivaracetam Cohort 1:Half of the subjects will receive BRV as a 5 minute iv infusion during the second Positron Emission Tomography (PET) scan, 60 minutes after the start of [11C]UCB-J administration. Cohort 2:Half of the subjects will receive BRV as a 5 minute iv infusion during the first PET scan, 60 minutes after the start of [11C]UCB-J administration. The dose of BRV (50-200 mg) will be decided based on the data obtained in Cohort 1. Subjects will return for a second PET imaging session,7 to 28 days after completion of their first session to enter the LEV arm. Cohort 3:void Cohort 4:Subjects will take oral BRV (25-100 mg bid) for 4 days and a single dose of BRV on Day 5. Pre-/post-block scans will be obtained at the first dose, one post-block scan after the last dose. Additional post-block scans may be obtained 8-10 and 28h or later after last dose; if last scan not needed, subject will return 7 to 28 days later for a post-block scan. Dose range for LEV in Cohort 4 will be 250 to <1500mg.	Radiation: [11C]UCB-J Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 20 mCi Route of Administration: iv Other Names: [11C]APP311 Drug: Brivaracetam Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 10 mg/ml Route of Administration: iv Other Names: UCB34714 Drug: Brivaracetam Pharmaceutical form: Tablets for oral intake Concentration: 25 mg Route of Administration: oral Other Names: UCB34714

Arm

Intervention/Treatment

Experimental: Levetiracetam

Cohort 1: Half of the subjects will receive LEV as a 5 minute iv infusion during the second Positron Emission Tomography (PET) scan, 60 minutes after the start of [11C]UCB-J administration. Cohort 2: Half of the subjects will receive LEV as a 5 minute iv infusion during the first PET scan, 60 minutes after the start of [11C]UCB-J administration. The dose of LEV (500 mg to 2500 mg) or BRV (50 mg to 200 mg) will be decided based on the data obtained in Cohort 1. Subjects will return for a second PET imaging session (Visit 4), 7 to 28 days after completion of their first session (Visit 3) to enter the BRV arm.

Radiation: [11C]UCB-J

Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 20 mCi Route of Administration: iv

Other Names:

[11C]APP311

Drug: Levetiracetam

Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 100 mg/ml Route of Administration: iv

Other Names:

Keppra

L059

Experimental: Brivaracetam

Cohort 1:Half of the subjects will receive BRV as a 5 minute iv infusion during the second Positron Emission Tomography (PET) scan, 60 minutes after the start of [11C]UCB-J administration. Cohort 2:Half of the subjects will receive BRV as a 5 minute iv infusion during the first PET scan, 60 minutes after the start of [11C]UCB-J administration. The dose of BRV (50-200 mg) will be decided based on the data obtained in Cohort 1. Subjects will return for a second PET imaging session,7 to 28 days after completion of their first session to enter the LEV arm. Cohort 3:void Cohort 4:Subjects will take oral BRV (25-100 mg bid) for 4 days and a single dose of BRV on Day 5. Pre-/post-block scans will be obtained at the first dose, one post-block scan after the last dose. Additional post-block scans may be obtained 8-10 and 28h or later after last dose; if last scan not needed, subject will return 7 to 28 days later for a post-block scan. Dose range for LEV in Cohort 4 will be 250 to <1500mg.

Radiation: [11C]UCB-J

Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 20 mCi Route of Administration: iv

Other Names:

[11C]APP311

Drug: Brivaracetam

Pharmaceutical form: Sterile solution for intravenous infusion Concentration: 10 mg/ml Route of Administration: iv

Other Names:

UCB34714

Drug: Brivaracetam

Pharmaceutical form: Tablets for oral intake Concentration: 25 mg Route of Administration: oral

Other Names:

UCB34714

Outcome Measures

Primary Outcome Measures

Level of synaptic vesicle glycoprotein 2A (SV2A) receptor occupancy during the displacement scans [Displacement scans (120 minutes)]
The receptor occupancy will be determined using occupancy plots from the apparent volume of distribution, Vapp values.
Equilibrium tissue to plasma activity ratio (VT) of [11C]UCB-J [Baseline (120 minutes) and Displacement scans (120 minutes)]
The equilibrium tissue to plasma activity ratio (VT) will be used to quantify [11C]UCB-J binding in each brain region of interest before and after administration of Brivaracetam and Levetiracetam.
Tracer displacement halftimes [Baseline (120 minutes) and Displacement scans (120 minutes)]
Tracer displacement halftimes will be estimated from Displacement scans and Baseline scans on the average standardized uptake value (SUV) for all regions over time during 60-minute timeframe.
Tracer-exit corrected halftimes of Brivaracetam or Levetiracetam entry [Baseline (120 minutes) and Displacement scans (120 minutes)]
Tracer-exit corrected halftimes of Brivaracetam or Levetiracetam entry will be estimated by subtracting the tracer clearance halftime from the displacement halftime.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Subject is male or female and between 18 to 55 years of age (inclusive)
Subject is in good physical and mental health, in the opinion of the Investigator, determined on the basis of medical history, physical and neurological examinations, vital signs, 12-lead Electrocardiography (ECG), and clinical laboratory tests
Female subjects of childbearing potential must have a negative pregnancy test; female subjects of childbearing potential have to confirm that, for 1 month prior to the first administration of the study medication and during the entire study until the Safety Follow-Up (SFU) Visit she will either use a highly effective contraceptive method (eg, oral contraception, intrauterine device, diaphragm with spermicide) or abstain from sexual activity that can cause pregnancy

Exclusion Criteria:

History or presence of clinically significant respiratory, gastrointestinal, renal, hepatic, pancreatic, hematological, cardiovascular, musculoskeletal, genitourinary, immunological, or dermatological disorders, or any type of cancer
Subject has a history of a neurological diagnosis, including but not limited to stroke, traumatic brain injury, epilepsy, space occupying lesions, multiple sclerosis, Parkinson's disease, vascular dementia, transient ischemic attack, or any other neurological disorder that may influence the outcome or analysis of the scan results
History of donation of more than 450 mL of blood within 60 days prior to dosing in the Yale PET center or planned donation before 30 days has elapsed since intake of study drug
The subject has Magnetic Resonance Imaging -incompatible (MRI - incompatible) implants and other contraindications for MRI, such as a pacemaker, artificial joints, non-removable body piercings, etc.
Subjects who have received a diagnostic or therapeutic radiopharmaceutical less than 7 days prior to participation in this study
Participation in other recent research studies < 1 month or < 1 year for studies involving ionizing radiation that would cause the subject to exceed the yearly dose limits for healthy volunteers