Van Paesschen 2013.

Methods	Study design: phase 2b, randomised, double‐blind, PBO‐controlled, parallel‐group, multi‐centre Countries: Belgium, Czech Republic, Finland, France, Germany, The Netherlands, Poland, Spain, and the United Kingdom Duration: 1. Prospective baseline period (4 weeks) 2. Treatment period (10 weeks: 3 weeks up‐titration and 7 weeks maintenance) 3. Conversion period (2 weeks): entry into a long‐term open‐label follow‐up study or down‐titration (2 weeks)
Participants	Randomised population: BRV 150 mg/d = 52 BRV 50 mg/d = 53 PBO = 52 ITT populationa: BRV 150 mg/d = 52 BRV 50 mg/d = 53 PBO = 52 Safety populationc: BRV 150 mg/d = 52 BRV 50 mg/d = 53 PBO = 52 Age (mean and SD)d: ≥ 16 to 65 years BRV 150 mg/d = 34.4 (10.1) BRV 50 mg/d = 38.2 (12.1) PBO = 40.0 (11.7) Gender, male, n (%)d: BRV 150 mg/d = 21 (40.4) BRV 50 mg/d = 24 (45.3) PBO = 25 (48.1) Ethnicity white, n (%)d: BRV 150 mg/d = 52 (100.0) BRV 50 mg/d = 53 (100.0) PBO = 51 (98.1) Type of seizure: drug‐resistant focal onset seizures
Interventions	All treatment groups received their respective treatment via oral capsules in 2 equally divided doses per day: BRV 150 mg/d (BID) BRV 50 mg/d (BID) PBO (BID) Participants randomised to BRV 150 mg/d began the up‐titration period on a dose of 50 mg/d. After 1 week, the dosage was increased to 100 mg/d and was then increased again to 150 mg/d after 2 weeks. Patients were permitted 1 fallback during the maintenance period to 100 mg/d Participants randomised to BRV 50 mg/d started at a dose of 25 mg/d and were up‐titrated to 50 mg/d after 1 week. They were again permitted 1 fallback to 25 mg/d during the maintenance period. Participants randomised to placebo continued to receive placebo during the up‐titration and maintenance periods
Outcomes	Primary outcome: 1. Per cent reduction in baseline‐adjusted FOS frequency/week over PBO during the maintenance period Secondary outcomes: 1. Reduction in FOS frequency/week over PBO during the treatment period 2. Per cent reduction from baseline in FOS frequency/week (maintenance and treatment periods) 3. ≥ 50% responder rate in FOS seizure frequency from baseline during maintenance and treatment periods 4. Seizure freedom rate Safety and tolerability outcomes: 1. Treatment‐emergent adverse events (TEAEs) 2. Physical and neurological examinations 3. Vital signs 4. Clinical laboratory tests 5. Electrocardiography (ECG) recordings
Notes	Trial registry number: N01114, NCT00175929 Sponsored by the manufacturer of BRV (UCB Pharma)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "central randomization method (random permuted blocks) stratified for concomitant use of LEV... and carbamazepine (CBZ)"
Allocation concealment (selection bias)	Low risk	Quote (from protocol): "each investigator will receive numbered subjects’ kits. When a subject is determined to be eligible for randomization (at visit 2), the Investigator or designee will call the Central Randomization Center (CRC) and will be assigned a subject’s kit number, according to the operating manual given by CRC"
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote: "matching placebo"
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Quote: "efficacy assessments were made using data recorded by the patients on daily record cards and assessed by the investigator at each study visit" Comment: participants were adequately blinded by matching placebo; the study was double‐blind, meaning that investigators, including those responsible for data analysis, would also have been blinded
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: attrition was reported and intent‐to‐treat analysis conducted; no randomised participants were excluded from the ITT population
Selective reporting (reporting bias)	Unclear risk	Comment: protocol was provided; not all outcomes defined in the protocol are reported in the journal article Quote: "secondary efficacy outcomes included..."
Other bias	Low risk	Comment: none detected

AE: adverse event; AED: antiepileptic drug; BID: twice a day; BRV: brivaracetam; CBZ: carbamazepine; ECG: electrocardiogram; FOS: focal onset seizure; ITT: intention‐to‐treat; IVRS: interactive voice response system; LEV: levetiracetam; mITT: modified intention‐to‐treat; PBO: placebo; TEAEs: treatment‐emergent adverse effects.

^aITT population was defined as all randomised patients who received at least one dose (≥ 1) of study drug, with the exception of Klein 2015, who defined ITT as all randomised patients who received at least one dose (≥ 1) of study drug and had at least one (≥ 1) post‐baseline seizure diary entry.

^bBiton 2014 used a modified intent‐to‐population, excluding four participants (three for extreme non‐compliance and one as a clinical outlier).

^cSafety population was defined as all randomised patients who received at least one dose (≥ 1) of study drug in Klein 2015. For all other studies, the safety population was identical to the intent‐to‐treat population.

^dCalculated using the safety population.