Safety and Tolerability of Intravenous Brivaracetam (Infusion or Bolus) as Adjunctive Antiepileptic Therapy

Study Overview
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Brief Summary
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This is a multicenter, open-label, 4-arm, randomized, parallel-group study to evaluate safety and tolerability of Brivaracetam Intravenous (BRV iv) as adjunctive treatment for adults with epilepsy according to an initiation or a conversion scheme, during repeated dosing (100 mg/administration twice daily for 4.5 days).

Detailed Description
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Eligible subjects will be randomized in a 1:1:1:1 ratio to the 4 treatment arms

Official Title
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A Multi-center, Open-label, Four-arm, Randomized Trial Evaluating the Safety and Tolerability of Brivaracetam Intravenous Infusion and Bolus, Administered in BID Regimen as an Adjunctive Antiepileptic Treatment in Subjects From 16 to 70 Years Suffering From Epilepsy

Conditions
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Epilepsy

Intervention / Treatment
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* Drug: Brivaracetam tablets
* Drug: Brivaracetam bolus
* Drug: Brivaracetam infusion
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: An Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written Informed Consent form signed and dated by the subject or by parent(s) or legal representative Subjects from 16 to 70 years Subjects with a body weight of >/= 40 kg Female subjects without childbearing potential or female subjects with childbearing potential if they use a medically accepted contraceptive method Subject/legal representative considered as reliable and capable of adhering to the protocol Subjects with well-characterized focal or generalized epilepsy or epileptic syndrome Subjects with a history of partial-onset seizures whether or not secondarily generalized or primary generalized seizures Subjects being uncontrolled while treated with 1 to 2 permitted concomitant antiepileptic drugs (AEDs) Permitted concomitant antiepileptic drugs (AEDs) and vagus nerve stimulation (VNS) being stable and at optimal dosage for the subject from at least 1 month before Visit 1 and expected to be kept stable during the Run-In and Evaluation Periods Exclusion Criteria: Mentally impaired subjects unable to understand the study purpose History or presence of status epilepticus during 1 year preceding Visit 1 or Baseline Subjects on felbamate with less than 18 months continuous exposure before Visit 1 Subjects currently on vigabatrin Subject taking any drug with possible relevant central nervous system effects except is stable from at least 1 month before Visit 1 and expected to be kept stable during the trial Subjects taking any drug that may significantly influence the metabolism of Brivaracetam (BRV) except if the dose has been kept stable at least 1 month before Visit 1, and is expected to be kept stable during the trial History of cerebrovascular accident in the last 6 months Subjects suffering from severe cardiovascular disease or peripheral vascular disease Presence of any sign suggesting rapidly progressing brain disorder or brain tumor Any clinical conditions which impair reliable participation in the study or necessitate the use of medication not allowed by protocol Presence of a terminal illness Presence of a serious infection Subjects with a history of sever adverse hematologic reaction to any drug Subjects suffering from severe disturbance of hemostasis Impaired hepatic function: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT) values of more than 3 times the upper limit of the reference range Subjects having clinically significant deviations from reference range values for laboratory parameters: creatinine clearance calculated < 50 ml / min, platelets < 100,000 / µL, or neutrophil cells < 1,800 / µL Clinically significant electrocardiogram (ECG) abnormalities according to the Investigator History of suicide attempt In the Investigator's medical judgment, any current suicidal ideation or other serious psychiatric disorders requiring of having required hospitalization or medication Known allergic reaction or intolerance to pyrrolidone derivatives and / or investigational product excipients Known multiple drug allergies or severe drug allergy Pregnant or lactating women Known alcohol or drug addiction or abuse within the last 2 years Subject institutionalized under judicial decision Problems of venous accessibility Subject taking part in another clinical / pharmacological study in the month preceding enrollment (Visit 1) Investigators, coinvestigators, their spouses or children, or any study collaborators Subjects previously treated with Brivaracetam (BRV) Subject previously screened within this study

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 70 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo tablets / Brivaracetam bolus<br>Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week | Drug: Brivaracetam bolus<br>* 10 mL (= 100 mg) of Brivaracetam administered intravenously over 2 minutes twice daily (BID) during Evaluation Period<br>Other: Placebo<br>* 100 mg twice daily (BID) for 7 days during Run-In Period<br>|
| Experimental: Brivaracetam (BRV) tablets / BRV bolus<br>Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week | Drug: Brivaracetam tablets<br>* 100 mg, intake twice daily (BID) for 7 days during Run-In Period<br>Drug: Brivaracetam bolus<br>* 10 mL (= 100 mg) of Brivaracetam administered intravenously over 2 minutes twice daily (BID) during Evaluation Period<br>|
| Experimental: Placebo tablets / Brivaracetam infusion<br>Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week | Drug: Brivaracetam infusion<br>* 10 mL (= 100 mg) of Brivaracetam diluted in 90 mL 0.9 % isotonic saline sterile solution for intravenous administration infused over 15 minutes twice daily (BID) during Evaluation Period<br>Other: Placebo<br>* 100 mg twice daily (BID) for 7 days during Run-In Period<br>|
| Experimental: Brivaracetam (BRV) tablets / BRV infusion<br>Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week | Drug: Brivaracetam tablets<br>* 100 mg, intake twice daily (BID) for 7 days during Run-In Period<br>Drug: Brivaracetam infusion<br>* 10 mL (= 100 mg) of Brivaracetam diluted in 90 mL 0.9 % isotonic saline sterile solution for intravenous administration infused over 15 minutes twice daily (BID) during Evaluation Period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With at Least One Treatment-emergent Adverse Event During the Study (Maximum 40 Days) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | 40 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Withdrew Due to a Treatment-emergent Adverse Event During the Study (Maximum 40 Days) | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | 40 days | 
| Number of Subjects With at Least One Injection-related Treatment-emergent Adverse Event (TEAE) During the Evaluation Period. | An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product, which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. | 4.5-day Evaluation Period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IV, N01258, Brivaracetam, Epilepsy, intravenous