Brivaracetam: a Prospective and Multicentre Post-marketing Observational Study
Brivaracetam: a Prospective and Multicentre Post-marketing Observational Study
Brivaracetam (BRV) is a new antiepileptic drug approved in March 2016 by Health Canada for
 the adjunctive treatment of focal epilepsy in adults. While randomized controlled trials
 represent the gold standard in measuring intervention efficacy, the generalizability of these
 findings to usual clinical practice remains uncertain.

 The primary objective of this study is to evaluate the effectiveness of BRV as an adjunctive
 treatment in epilepsy. The secondary objective of this study is to evaluate the tolerability
 of BRV as an adjunctive treatment in epilepsy.

 This is a prospective and multicentre post-marketing observational study. All consecutive
 adult patients (i.e. aged at least 18 years) in whom BRV is introduced in participating
 medical centres, ambulatory or hospitalized, will be approached to participate in the study.
 The investigators will exclude individuals with generalized epilepsy as those aged less than
 18 years, in order to respect current Health Canada indications. The investigators will
 exclude individuals cognitively or physically unable to complete the study questionnaires.

 The investigators will collect data from participants during three clinical visits with their
 regular treating physician. These will be the baseline visit, the 3-month visit (three months
 following the initiation of BRV), and the 6-month visit. At each visit, the investigators
 will collect data on seizure type(s) and frequency. Study participants will also complete
 four questionnaires to measure irritability, anxiety, depression, and quality of life.

 There will be two primary study outcomes. These are: a) mean percent change in monthly
 seizure frequency; and b) proportion with at least a 50% decrease in seizure frequency. There
 will be several secondary study endpoints: a) mean change in irritability [measured using the
 Brief Irritability Test (BITe)]; b) mean change in generalised anxiety [measured using the
 Generalized Anxiety Disorder - 7 (GAD-7) scale]; c) mean change in depression [measured using
 the Neurological Disorders Depression Inventory (NDDI-E) scale]; d) mean change in quality of
 life [measured using the 7-item Quality of Life Inventory in Epilepsy-10 (QOLIE-10) scale];
 e) the proportion of individuals that are seizure free, and f) change in distribution of
 seizure types (e.g. focal with motor seizures, generalized absence). The investigators will
 query for all adverse effects the participant may experience.
Study introduction/rationale:

 Brivaracetam (BRV) is a new antiepileptic drug (AED) approved in March 2016 by Health Canada
 for the adjunctive treatment of focal epilepsy in adults. Three phase III clinical trials
 (randomized, blinded, and placebo-controlled) have confirmed its efficacy with an acceptable
 adverse effects profile. While randomized controlled trials represent the gold standard in
 measuring intervention efficacy, the generalizability of these findings to usual clinical
 practice remains uncertain. These questions are in part because of certain aspects of the
 pivotal studies' design. These include: a) participation was limited to individuals with
 frequent focal seizures (at least eight seizures during an eight-week baseline period), with
 or without secondary generalization who were already treated with 1 or 2 AEDs; b) individuals
 aged less than 16 years and greater than 70 years (80 years in one study) were excluded, as
 well as individuals with cerebral neoplasms, psychogenic non-epileptic seizures, or status
 epilepticus within the preceding 12 months; d) BRV was introduced at fixed doses without a
 titration period; and e) the treatment period was limited to 12 The weeks. Inherent to any
 clinical trial, there remain questions as to what effect local clinical practice and patterns
 of reimbursement may have on intervention effectiveness (a measure of real-life efficacy that
 considers issues such as non-compliance). Clinical trials are also at high risk of the
 Hawthorne effect, where participants modify their behaviour (e.g. increased compliance) due
 to the knowledge that they are observed.

 Canada is one of the first countries where BRV was commercialized. This allows for an
 important opportunity for investigators to carry out a prospective observational study to
 establish BRV's effectiveness and tolerability in routine clinical practice.

 Primary study objective:

 The primary objective of this study is to evaluate the effectiveness of BRV as an adjunctive
 treatment in epilepsy.

 Secondary study objective(s):

 The secondary objective of this study is to evaluate the tolerability of BRV as an adjunctive
 treatment in epilepsy.

 Participant recruitment:

 This is a prospective and multicentre post-marketing observational study. As an observational
 study, the study investigators will not determine which individuals receive BRV nor how it is
 prescribed. The study investigators will not have any role in providing BRV to enrolled study
 participants.

 Data will be collected from participants during three clinical visits with their regular
 treating physician (MD). These will be the baseline visit, the 3-month visit (three months
 following the initiation of BRV), and the 6-month visit. The baseline visit will be the
 regularly scheduled clinical visit where the MD will decide to begin BRV in their patient.
 The patient will be asked by their MD if they are interested in participating in the proposed
 study. If the offer is accepted, the individual will be consented by the research assistant
 (RA). The baseline data questionnaire will be completed by the MD, with the input of the
 participant. The participant will then complete the four questionnaires to measure baseline
 irritability, anxiety, depression, and quality of life. The study participant will be given a
 seizure diary and asked to prospectively record their seizures. At the 3-month visit the MD
 will record the seizure frequency (preferably based on the seizure diary but retrospectively
 assessed if necessary) and any adverse effects reported by the participant. The participant
 will complete the 3-month irritability, anxiety, depression, and quality of life measures.
 The data collected at the 3-month visit will be re-collected at the 6-month visit.

 The study is planned for 10 recruitment sites across Canada. Dr Mark Keezer (Université de
 Montréal) is the study principal investigator. The Centre Hospitalier de l'Université de
 Montréal (CHUM) is the primary study site. Véronique Cloutier (CHUM) is the primary study
 coordinator.

 Study safety endpoints:

 This is an observational study. The investigators will include, however, a statement in the
 participant consent form stating "Brivaracetam is approved by Health Canada for the adjuvant
 treatment of focal epileptic seizures in adults. It is currently not approved for the
 treatment of generalized epilepsies nor epilepsy in children. There are no data on the safety
 of brivaracetam during pregnancy and during breast feeding." If during this study there is
 any information learned by the investigators that may be relevant to the health of the
 participant, the investigators will immediately communicate this to the study participant and
 their MD.

 Study specific assessments/instruments/scales:

 The baseline data questionnaire will collect the following participant data: age, gender, age
 of epilepsy onset, type and aetiology of epilepsy, seizure type(s) and average seizure
 frequency over the preceding one month, name of the AED(s) currently used and previously
 tried, and past medical history (including psychiatric). If levetiracetam was previously
 tried but since withdrawn, the reason for its discontinuation will be noted.

 When possible, the baseline mean number of seizures per month will be calculated from the
 seizure diary (if the participant completes at least 30 days of data). This will occur
 following their recruitment into the study but before the initiation of BRV, where the
 investigators expect there will be a delay. If at least 30 days of baseline seizure frequency
 are not recorded prospectively, the analyses will be conducted using the retrospectively
 collected frequency recorded in the baseline data questionnaire.

 The Brief Irritability Test (BITe), Generalized Anxiety Disorder - 7 (GAD-7) scale,
 Neurological Disorders Depression Inventory (NDDI-E) scale, and Quality of Life Inventory in
 Epilepsy-10 (QOLIE-10) scale, will be used to measure irritability, anxiety, depression, and
 quality of life, respectively. English- and French-language versions of these questionnaires
 have been validated, apart from the BITe which has only been validated in English. The
 investigators will follow standard cross-cultural methods to create a French-language version
 of the BITe. The original English version will be translated to French by a professional
 translator. A second translator, blinded to the original English-language instrument, will
 back-translate the new French-language instrument to English. One study investigator, fluent
 in both English and French, will then compare the documents to ensure that the different
 versions are concordant.

 Adverse effects will be recorded by the MD, spontaneously reported by the participant, or in
 response to a standardized question. Each participant will be asked the standardized question
 "Since the start of the brivaracetam, is there anything changed about your health?" For each
 reported adverse effect, the MD will judge whether it is mild (i.e. does not interfere with
 their daily lives), moderate (i.e. sometimes interferes with their daily lives), or severe
 (i.e. most of the time interferes with their daily lives). The MD will judge whether the
 adverse effect is unlikely, possibly, or probably related to BRV. This method of assessing
 for adverse effects is modeled on those used in phase IV trials of levetiracetam.

 Study sample size calculation:

 Eleven participants are sufficient to identify a mean percent seizure reduction of 20%
 [standard deviation (SD): 15], between the baseline versus the 3- and 6-month follow-ups,
 using ANCOVA for repeated measures. In addition, 76 participants are sufficient to identify a
 mean percent seizure difference of 5% between the 3- and 6-month follow-ups [i.e. 25% (SD:
 15) versus 20% (SD: 15)], using paired student's T-test. These sample size calculations
 assume a power of 90%, no correlation between the baseline and follow-up parameters but an
 80% correlation between 3- and 6-month follow-ups, and using a significance level of 0.05.

 Following the ten events per variable rule, 115 participants are sufficient to construct
 valid logistic regression models for the proportion of individuals with at least a 50%
 decrease in seizure frequency, assuming the inclusion of four independent variables
 [follow-up timing (i.e. baseline, 3-month, or 6-month), age, sex, number of baseline AEDs]
 and an expected prevalence of 40% of participants with at least a 50% decrease in seizure
 frequency. Of note, the ten events per variable rule is considered by some to be overly
 conservative.

 The expected effectiveness of BRV is based upon the pooled phase III trial data.

 Stratified analyses are planned and so to guarantee sufficient sample size our target is 200
 participants.

 Study statistical methods:

 The effectiveness analyses will be limited to participants with at least three months of
 on-treatment follow-up data. The BRV tolerability analyses will be carried out in all
 participants that received at least one dose of BRV.

 Mean percent change in monthly (30 days) seizure frequency [95% confidence interval (95% CI)]
 will be compared between the baseline, 3- , and 6-month visits using ANCOVA for repeated
 measures. The same will be used to compare BITe, GAD-7, NDDI-E, and QOLIE-10 scores. For the
 analysis of these continuous outcomes, normality will be confirmed with visual inspection of
 histograms. If normality is not satisfied, the data will be transformed to meet normality, or
 the investigators will calculate median estimates and use non-parametric tests. The
 investigators will measure the association between the start of BRV and the average
 probability of participants experiencing at least a 50% decrease in seizure frequency (95%
 CI) at the baseline, 3-, and 6-month visits using conditional logistic regression. The same
 will be used to assess the association between BRV and the probability of participants being
 seizure-free (95% CI). The investigators will control for the following potentially
 confounding variables: sex, age, and the number of baseline AEDs.

 The investigators will stratify analyses by BRV starting dose (≥ 100 mg/day versus < 100
 mg/day), epilepsy type, the prior or concomitant use of levetiracetam (versus not), and the
 use of a retrospectively (versus prospectively) collected baseline seizure frequency data.
 Sensitivity analyses will include: the exclusion of any participant where changes to another
 AED occurred during the study period; the exclusion of any participant whose baseline mean
 seizure frequency was less that 4 seizures per month.

 The investigators will descriptively assess tolerability, as measured by the reported adverse
 effects. The mean duration of BRV use, the distribution of seizures types (baseline, versus 3
 months and 6 months), and the reason (if any) for BRV discontinuation will also be presented
 descriptively.

 Statistical analyses will be carried out using STATA/SE, version 12.0 (StataCorp LP, College
 Station, Texas, USA). Statistical significance will be defined as a p-value < 0.05.
Inclusion Criteria:

 -  All consecutive adult patients (i.e. aged at least 18 years) with focal epilepsy in
 whom BRV was introduced (no more than 48 hours prior to their time of recruitment) at
 participating medical centres, ambulatory or hospitalized, will be approached to
 participate in the study.

 Exclusion Criteria:

 -  We will exclude individuals with generalized epilepsy as well as those aged less than
 18 years, in order to respect current Health Canada indications. We will exclude
 individuals cognitively or physically unable to complete the study questionnaires.