Principal Investigator: Blake Newman
Keywords: Epilepsy , Seizures , Brivaracetam , Briviact , AED , Antiepileptic drug , Partial onset seizures Department: Neurology
IRB Number: 00104824
Specialty: Neurology
Sub Specialties: Epilepsy
Recruitment Status: Enrolling by invitation

Contact Information

Lilly Fagatele

Brief Summary

EP0088 is a postmarketing, multicenter, prospective, noninterventional study (NIS) conducted at up

to approximately 45 sites in the US, with an estimated 18-month Enrollment Period and a 12-month

Observation Period per patient from the initiation of BRV. Brivaracetam will be prescribed

according to normal clinical practice. Brivaracetam is indicated as adjunctive therapy in the

treatment of POS with or without secondary generalization in patients 16 years of age and older with

epilepsy. The plan is to enroll up to 350 patients in the study.

Primary objective

The primary objective of the study is to determine BRV retention in daily clinical practice at

12 months.

Secondary objective

The secondary objectives of the study are to determine the association between BRV retention and

the following:

•Time to discontinuation of LEV, OXC, CBZ, and/or LTG (<6 months, >6 months after initiation).

•Reason for discontinuation for past use of LEV, OXC, CBZ, and/or LTG.

Other objectives

For patients enrolled and receiving LEV, to determine if there is seizure exacerbation or adverse

events during the conversion from LEV to BRV

Primary variable

The primary variable will be BRV retention 12 months after the initiation of BRV.

Secondary variable

The secondary variable will be BRV retention at 3 and 6 months from initiation of BRV.

Other variables

The number of unplanned hospitalizations, proportion of patients hospitalized, number of days

hospitalized, and number of emergency department (ED) visits due to epilepsy for up to 12 months

after BRV initiation in patients on BRV or a subsequent AED

Detailed Description

Briviact® (brivaracetam [BRV]) has been approved by the US Food and Drug Administration (FDA) as adjunctive therapy in the treatment of partial-onset seizures (POS) with or without secondary generalization in patients 16 years of age and older with epilepsy. Three formulations have been developed for commercial use: film-coated tablets for oral administration (10, 25, 50, 75, and 100mg), an oral solution (10mg/mL), and a solution for intravenous injection (10mg/mL). Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl]butanamide) is a 2-pyrrolidone derivative and displays a high and selective interaction with a brain-specific binding site, synaptic vesicle protein 2A. This binding site appears to be the major target for its pharmacological activity. Brivaracetam is rapidly and completely absorbed throughout the gastrointestinal tract. The extent of BRV absorption is not affected by food. The pharmacokinetics are dose-proportional from 10mg to 600mg. Brivaracetam is weakly bound to plasma proteins (≤20%). The volume of distribution is 0.5L/kg, a value that is close to that of total body water. The plasma half-life of BRV is approximately 9 hours; the total plasma clearance in patients was estimated to 3.6L/hour. The main metabolic pathway of BRV is by hydrolysis of the acetamide group by amidase to the corresponding carboxylic acid, while a second pathway is the ω1-hydroxylation mediated by CYP2C19. The combination of these 2 pathways results in the hydroxyacid metabolite. These 3 metabolites are not pharmacologically active. There is no evidence of chiral inversion of BRV. Brivaracetam is eliminated primarily by oxidative metabolism and by excretion in the urine. More than 95% of the dose, including metabolites, is excreted in urine within 72 hours after dosing; less than 10% of BRV is excreted unchanged in urine. The efficacy of BRV for the adjunctive therapy of POS was established in 3 Phase 3 randomized, double-blind, placebo-controlled, fixed-dose, multicenter studies in subjects 16 years of age and older. The daily dose of BRV ranged from 5 to 200mg/day across these studies. All studies had an 8-week Baseline Period followed by a 12-week Treatment Period with no up-titration. A total of 1558 patients received study drug, of whom, 1099 received BRV. Study enrollment criteria required that patients had uncontrolled POS despite treatment with either 1 or 2 concomitant antiepileptic drugs (AEDs). Patients were required to have at least 8 POS events during the Baseline Period. Adjunctive BRV administration at doses of 50mg/day to 200mg/day without titration resulted in statistically significant and clinically relevant reductions in seizure frequency, including seizure freedom. Brivaracetam was effective and well tolerated when started at these therapeutic doses. Low incidences of adverse events (AEs) and low study discontinuation rates due to AEs were also observed with BRV. A small, open-label, Phase 3 study evaluating nonpsychotic behavioral AEs in patients receiving levetiracetam (LEV) who switched to BRV showed that, at the end of the 12-week Treatment Period, 93.1% patients (27/29) who switched to BRV had clinically meaningful reductions in behavioral AEs, which suggests that patients experiencing behavioral AEs associated with LEV may benefit from switching to BRV (Yates et al, 2015). EP0088 is a postauthorization noninterventional/observational study of BRV and is designed to collect information on real-world outcomes in patients with POS who are treated with BRV in clinical practice after the product is marketed in the US. The study will be conducted at sites in the US, with a 12-month Observation Period. Patients will be treated according to usual medical diagnostic and therapeutic procedures; commercially available BRV will be prescribed according to normal clinical practice for BRV. The decision to prescribe BRV is separate from the decision to include the patient in the study. Other than the completion of questionnaires, no additional diagnostic or monitoring procedures are applied to patients except at the discretion of the physician in the normal practice of medicine. The successful registration studies for new anti-seizure drugs are often impressive in proving that the new therapy is effective when matched against placebo; this, along with adequate safety data, meet the classic standard for approval: “safe and effective.” These data, however, provide limited information to guide the practitioner on optimal use of the drug. For example, little may be known about selection of patients most likely to benefit, optimal dosing strategy, drug interactions (with both anti-seizure drugs and other drugs), the best - and the least desirable - drug combinations, and rare adverse effects in the real-world setting. These and other unknowns typically emerge gradually with time and experience. EP0088 is an observational study designed to bridge the gaps between the registration data and the data needed for the practitioner to be able to most effectively utilize this new therapy. The study will emphasize patient-reported outcomes in a real-life setting with skilled neurologists who will be seeking answers to the questions that remain to be answered to obtain maximal utility of BRV in combination with other anti-seizure drugs in patients with difficult-to-control POS. One purpose is to determine whether “success” on the drug (as measured by retention) can be predicted based on previous AED experience. If BRV is similar to prior AEDs, then early discontinuation of BRV might be predictable based on early discontinuation from 1 or several specific prior AED studies. On the other hand, BRV discontinuation might not be predicted from experience with prior AEDs. In this protocol we will explore the relationship between prior experience with common AEDs (ie, LEV, lamotrigine [LTG], oxcarbazepine [OXC], and carbamazepine [CBZ]), and BRV retention.

Inclusion Criteria

Inclusion criteria

On or before Visit 1, the patient will be evaluated for study eligibility, using the following selection


1. The decision by the treating physician to prescribe BRV is made independent from participation

in the NIS.

2. A Patient Data Consent form is signed and dated by the patient or by the parent(s) or legal


3. Patient is considered reliable and able to understand and complete questionnaires.

4. Patient has never been treated with BRV or first-ever treatment with BRV has been initiated

within the prior 2 days.

5. Patient has a history of focal (partial) seizures. The patient must have had at least 2 observable

focal (partial) seizures (Focal aware [simple partial] with motor component, focal with altered

awareness [complex partial] or focal to bilateral tonic clonic seizure).

6. Patient is currently receiving ≥1 AED.

7. Patient has previous or current use of LEV, OXC, CBZ, and/or LTG.

8. Patient is 16 years or older.

9. Patient has been diagnosed with epilepsy for at least 1 year.

Exclusion Criteria

Exclusion criteria

1. Patient has nonepileptic seizures with or without comorbid epileptic seizures.

2. Patient is suspected of having alcohol or drug-related seizures.