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

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

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).

Study Overview

• Status: Completed
• Conditions: Epilepsy
• Intervention / Treatment: Drug: Brivaracetam bolus; Other: Placebo; Drug: Brivaracetam tablets; Drug: Brivaracetam infusion

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 105
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Czechia
  • Brno, Czechia
    • 917
  • Hradec Kralove, Czechia
    • 915
  • Kromeriz, Czechia
    • 916
  • Ostrava Poruba, Czechia
    • 913
• Germany
  • Bielefeld, Germany
    • 332
  • Bonn, Germany
    • 903
• Poland
  • Katowice, Poland
    • 795
  • Poznan, Poland
    • 479
  • Warszawa, Poland
    • 794
• United States
  • Arizona
    • Phoenix, Arizona, United States
      • 001
  • Arkansas
    • Little Rock, Arkansas, United States
      • 775
  • Kentucky
    • Lexington, Kentucky, United States
      • 780
  • Maryland
    • Bethesda, Maryland, United States
      • 008
  • Ohio
    • Columbus, Ohio, United States
      • 778
  • Tennessee
    • Nashville, Tennessee, United States
      • 776
  • Texas
    • Dallas, Texas, United States
      • 777
  • Virginia
    • Charlottesville, Virginia, United States
      • 036

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo tablets / Brivaracetam bolus; 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; 10 mL (= 100 mg) of Brivaracetam administered intravenously over 2 minutes twice daily (BID) during Evaluation Period; Other: Placebo; 100 mg twice daily (BID) for 7 days during Run-In Period
Experimental: Brivaracetam (BRV) tablets / BRV bolus; 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 bolus; 10 mL (= 100 mg) of Brivaracetam administered intravenously over 2 minutes twice daily (BID) during Evaluation Period; Drug: Brivaracetam tablets; 100 mg, intake twice daily (BID) for 7 days during Run-In Period
Experimental: Placebo tablets / Brivaracetam infusion; 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	Other: Placebo; 100 mg twice daily (BID) for 7 days during Run-In Period; Drug: Brivaracetam infusion; 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
Experimental: Brivaracetam (BRV) tablets / BRV infusion; 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; 100 mg, intake twice daily (BID) for 7 days during Run-In Period; Drug: Brivaracetam infusion; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: UCB Pharma

Publications and helpful links

General Publications

• Toledo M, Brandt C, Quarato PP, Schulz AL, Cleveland JM, Wagener G, Klein P. Long-term safety, efficacy, and quality of life during adjunctive brivaracetam treatment in patients with uncontrolled epilepsy: An open-label follow-up trial. Epilepsy Behav. 2021 May;118:107897. doi: 10.1016/j.yebeh.2021.107897. Epub 2021 Mar 27.

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: July 27, 2011
• First Submitted That Met QC Criteria: July 28, 2011
• First Posted (Estimate): July 29, 2011

Study Record Updates

• Last Update Posted (Actual): July 11, 2018
• Last Update Submitted That Met QC Criteria: June 13, 2018
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Epilepsy; Brivaracetam; intravenous; N01258; IV
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Anticonvulsants; Brivaracetam
• Other Study ID Numbers: N01258; 2008-004714-27 (EudraCT Number)