Kwan 2014.
| Methods |
Study design: phase 3, randomised, double‐blind, PBO‐controlled, parallel‐group, flexible‐dose, multi‐centre Countries: Austria, Belgium, Czech Republic, Germany, Hong Kong, India, Italy, Norway, Republic of South Africa, Russian Federation, Singapore, South Korea, Sweden, Taiwan, and Ukraine Duration: 1. Prospective baseline period (4 weeks) 2. Treatment period (16 weeks) including 8‐week dose‐finding and 8‐week maintenance 3. Down‐titration period (2 weeks) and drug‐free period (2 weeks) or entry into a long‐term follow‐up study |
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| Participants |
Randomised population: BRV = 359 PBO = 121 ITT populationa: BRV = 359 PBO = 121 Safety populationc: BRV = 359 PBO = 121 Age (mean and SD)d: ≥ 16 to 70 years BRV = 35.6 (11.5) PBO = 36.5 (11.5) Gender, male, n (%)d: BRV = 181 (50.4) PBO = 69 (57.0) Ethnicity white, n (%)d: BRV = 209 (58.2) PBO = 69 (57.0) Types of seizure: drug‐resistant focal onset or generalised epilepsy |
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| Interventions | All treatment groups received tablets administered in 2 equally divided doses per day: BRV 20, 50, 100, 150 mg/d (BID) PBO (BID) For participants randomised to BRV, BRV was initiated at 20 mg/d. Participants were then up‐titrated in a stepwise manner to 50, 100, or 150 mg/d at 2‐week intervals based on the investigator’s assessment of efficacy and tolerability |
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| Outcomes |
Safety and tolerability outcomes: 1. Adverse events (AEs) 2. Discontinuations due to AEs 3. Vital signs 4. Physical and neurological examination findings 5. Laboratory tests 6. Electrocardiography (ECG) recordings Primary efficacy outcome: 1. Per cent reduction in baseline‐adjusted FOS frequency/week during the treatment period over PBO Secondary outcomes: 1. Median per cent reduction from baseline in FOS frequency/week 2. ≥ 50% responder rate in FOS frequency/week 3. Seizure freedom rate 4. Time to first, fifth, and 10th focal seizure |
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| Notes | Trial registry number N01254, NCT00504881 Sponsored by the manufacturer of BRV (UCB Pharma) |
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| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Low risk | Quote: "patients were randomized 3:1 in random permuted blocks to BRV or PBO at the end of the baseline period. Randomization was stratified by epilepsy type (focal or generalized) (International League Against Epilepsy, 1989), concomitant levetiracetam (LEV) use (yes or no), and geographic region" |
| Allocation concealment (selection bias) | Unclear risk | Comment: details regarding allocation concealment were not provided |
| Blinding of participants and personnel (performance bias) All outcomes | Low risk | Quote: "matching PBO tablets" Comment: appropriate measures were taken to maintain blinding |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk |
Quote: "the date and number of seizures were recorded using a daily record card" Comment: outcomes were self‐reported by the participants who remained appropriately blinded throughout the study; moreover, the study was double‐blind, meaning that investigators, including those responsible for data analysis, would also have been effectively blinded |
| Incomplete outcome data (attrition bias) All outcomes | Low risk | Comment: attrition was reported and intent‐to‐treat analysis conducted, which correctly included all randomised participants |
| Selective reporting (reporting bias) | Low risk | Comment: protocol was not provided; however, all outcomes defined in methods were reported in results |
| Other bias | Unclear risk |
Quote: "patients were randomized 3:1 in random permuted blocks to BRV or PBO" Comment: 3:1 randomisation ratio produces uneven treatment group sizes, which reduces the statistical power and can augment the placebo effect (Hey 2014) |