A Study to Investigate the Drug-Drug Interactions of Brivaracetam and Ethanol in Healthy Male Subjects

Study Overview
=================
Brief Summary
-----------------
To evaluate if Brivaracetam (BRV) influences the psychomotor and cognitive impairing effects of Ethanol

Official Title
-----------------
A Double-blind, Randomized, Placebo-controlled, Three-way Crossover Study to Investigate the Drug-Drug Interactions of Brivaracetam and Ethanol in Healthy Male Subjects.

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: Brivaracetam
* Other: Ethanol
* Other: Brivaracetam Placebo
* Other: Ethanol Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy male volunteers with the age between 18 and 55 years old Exclusion Criteria: Subject has participated or is participating in any other clinical studies of investigational drug or another investigational medical product within the last 3 months or has participated in 4 or more Investigational Medicinal Product (IMP) studies within 1 year prior to screening Subject is not healthy (eg, taking any drug treatments except use of Paracetamol, excessive amount of alcohol, cigarettes, caffeine consumption, having a positive drug / alcohol abuse, having abnormal safety parameters) Subject has not been vaccinated for hepatitis Subjects has consumed any grapefruits, grapefruits juice, grapefruit-containing products or star fruit within 14 days prior to dosing or not able to refrain from these products during the study Subject has Ethanol intolerance Subject has a known hypersensitivity to any components of the Investigational Medicinal Product (IMP) Subject has made a blood donation or a comparable blood loss (500 ml) within the last 3 months prior to screening subject is an employee of the investigator or study center or subject is a first line family member of an employee working in the respective study center or of the investigator

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

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ethanol + Brivaracetam<br>Treatment A: Ethanol + Brivaracetam | Drug: Brivaracetam<br>* Strength: 200 mg (4 x 50 mg) Form: oral tablet Frequency: single dose Description: All subjects will receive a single oral dose of Brivaracetam (BRV) 200 mg, given as 50 mg tablets times 4 followed by an adequate volume of water (approximately 200 ml) in 2 of the 3 crossover periods. This dose will be administered 30 minutes after the initiation of the Ethanol / Ethanol Placebo infusion on Day 1.<br>Other: Ethanol<br>* Form: intravenous infusion Frequency: continuous infusion Description: The ethanol infusion rate is initially based on weight, height, age, and sex. Subsequently, the infusion rate will be adjusted based on Breath Ethanol Measurements to maintain Breath Ethanol Levels (and by extension, blood ethanol levels) of 0.6 g / L.<br>|
| Experimental: Ethanol Placebo + Brivaracetam<br>Treatment B: Ethanol Placebo + Brivaracetam | Drug: Brivaracetam<br>* Strength: 200 mg (4 x 50 mg) Form: oral tablet Frequency: single dose Description: All subjects will receive a single oral dose of Brivaracetam (BRV) 200 mg, given as 50 mg tablets times 4 followed by an adequate volume of water (approximately 200 ml) in 2 of the 3 crossover periods. This dose will be administered 30 minutes after the initiation of the Ethanol / Ethanol Placebo infusion on Day 1.<br>Other: Ethanol Placebo<br>* In 1 crossover period subjects will receive Ethanol Placebo (5% glucose). On Day 1, the continuous infusion of Ethanol Placebo will begin with a 30 minute Loading Phase prior to administration of Brivaracetam (BRV) / BRV Placebo and will continue until 5 hours after administration of BRV/BRV Placebo. During the first 10 minutes, the infusion will be accompanied by an infusion of 5% Glucose via the same line in order to mask the sensation at the beginning of the Ethanol infusion.<br>|
| Experimental: Ethanol + Brivaracetam Placebo<br>Treatment C: Ethanol + Brivaracetam Placebo | Other: Ethanol<br>* Form: intravenous infusion Frequency: continuous infusion Description: The ethanol infusion rate is initially based on weight, height, age, and sex. Subsequently, the infusion rate will be adjusted based on Breath Ethanol Measurements to maintain Breath Ethanol Levels (and by extension, blood ethanol levels) of 0.6 g / L.<br>Other: Brivaracetam Placebo<br>* In 1 of the 3 crossover periods, all subjects will receive 4 Placebo tablets to match the 50 mg Brivaracetam (BRV) tablets. The Placebo tablet will contain the same excipients as the BRV tablets but without BRV.<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Saccadic Eye Movements from 60 minutes Pre-Dose up to 10 hours Post-Dose | Average values of Latency (reaction time), Saccadic Peak Velocity, and Inaccuracy (difference between stimulus angle and corresponding saccade in percentages) will be calculated for all artifact-free saccades. | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 
| Smooth pursuit eye movements from 60 minutes Pre-Dose up to 10 hours Post-Dose | The time during which the eyes are in smooth pursuit of the target will be calculated for each frequency and expressed as a percentage of stimulus duration. The average percentage of smooth pursuit for all stimulus frequencies will be used as a parameter. | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 
| Adaptive tracking from 60 minutes Pre-Dose up to 10 hours Post-Dose | Performance will be scored after a fixed period of 3.5 minutes and reflected visuo motor control and vigilance. The average performance scores will be used in the analysis. | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 
| Body sway from 60 minutes Pre-Dose up to 10 hours Post-Dose | The body sway meter allows measurement of body movements in a single plane, providing a measure of postural stability. (antero-posterior sway in mm / 2 minutes) | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 
| Visual Analog Scales for Mood From 60 minutes Pre-Dose up to 10 hours Post-Dose | Visual Analog Scales according to Bond and Lader | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 
| Visual Analog Scale for alcohol intoxication From 60 minutes Pre-Dose up to 10 hours Post-Dose | The scale consists of a 10 cm line anchored on the left end by sober and on the right end by drunk. Subjects mark a point on the line that best represents their subjective state corresponding to the condition tested. The result is a distance calculated from the mark on the line. | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 
| Visual Verbal Learning Test from 1.5 hours Post-Dose up to 6 hours Post-Dose | Immediate recall, immediate recognition, delayed recall, and delayed recognition to evaluate memory | From 1.5 hours Post-Dose up to 6 hours Post-Dose | 
| Visual Analog Scales for Alertness From 60 minutes Pre-Dose up to 10 hours Post-Dose | Visual Analog Scales according to Bond and Lader | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 
| Visual Analog Scales for Calmness From 60 minutes Pre-Dose up to 10 hours Post-Dose | Visual Analog Scales according to Bond and Lader | From 60 minutes Pre-Dose up to 10 hours Post-Dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The area under the plasma concentration-time curve from zero to infinity (AUC) | Blood samples will be taken - 5 minutes Pre-Dose, 15, 30, and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours Post-Dose. | From Pre-Dose (- 5 minutes) to 36 hours Post-Dose | 
| The area under the plasma concentration-time curve from zero to the time of the last measured concentration above the limit of quantification [AUC(0-t)] | Blood samples will be taken - 5 minutes Pre-Dose, 15, 30, and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours Post-Dose. | From Pre-Dose (- 5 minutes) to 36 hours Post-Dose | 
| The maximum plasma concentration (Cmax) | Blood samples will be taken - 5 minutes Pre-Dose, 15, 30, and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours Post-Dose. | From Pre-Dose (- 5 minutes) to 36 hours Post-Dose | 
| The time to reach the maximum plasma concentration (tmax) | Blood samples will be taken - 5 minutes Pre-Dose, 15, 30, and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours Post-Dose. | From Pre-Dose (- 5 minutes) to 36 hours Post-Dose | 
| The terminal disposition rate constant (λz) with the respective terminal half-life (t1/2) | Blood samples will be taken - 5 minutes Pre-Dose, 15, 30, and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, 10, 12, 24 and 36 hours Post-Dose. | From Pre-Dose (- 5 minutes) to 36 hours Post-Dose | 
| Serum Ethanol concentrations | Blood samples for Ethanol concentrations will be taken - 30 minutes, - 15 and - 5 minutes Pre-Dose, then 15, 30 and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, and 10 hours Post-Dose. | From - 30 minutes Pre-Dose to 10 hours Post-Dose | 
| Breath Ethanol concentrations | Blood samples for Ethanol concentrations will be taken - 30 minutes, - 15 and - 5 minutes Pre-Dose, then 15, 30 and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, and 10 hours Post-Dose. | From - 30 minutes Pre-Dose to 10 hours Post-Dose | 
| Total Ethanol Dose analyzed by a model independent parameter estimate | Blood samples for Ethanol concentrations will be taken - 30 minutes, - 15 and - 5 minutes Pre-Dose, then 15, 30 and 60 minutes Post-Dose and then 2, 3, 4, 5, 6, 8, and 10 hours Post-Dose. | From - 30 minutes Pre-Dose to 10 hours Post-Dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Brivaracetam, Ethanol, Pharmacodynamics, Pharmacokinetic, Interaction