Abstract: We included 13 trials in this review and IPD were available for 836 individuals out of 1455 eligible individuals from six trials, 57% of the potential data. For remission outcomes, a HR of less than 1 indicates an advantage for phenobarbitone and for first seizure and treatment failure outcomes a HR of less than 1 indicates an advantage for carbamazepine. Results for the primary outcome of the review were: time to treatment failure for any reason related to treatment (pooled HR adjusted for seizure type for 676 participants: 0.66, 95% CI 0.50 to 0.86, moderate-quality evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 619 participants: 0.69, 95% CI 0.49 to 0.97, low-quality evidence), time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 487 participants: 0.54, 95% CI 0.38 to 0.78, moderate-quality evidence), showing a statistically significant advantage for carbamazepine compared to phenobarbitone. For our secondary outcomes, we did not find any statistically significant differences between carbamazepine and phenobarbitone: time to first seizure post-randomisation (pooled HR adjusted for seizure type for 822 participants: 1.13, 95% CI 0.93 to 1.38, moderate-quality evidence), time to 12-month remission (pooled HR adjusted for seizure type for 683 participants: 1.09, 95% CI 0.84 to 1.40, low-quality evidence), and time to six-month remission pooled HR adjusted for seizure type for 683 participants: 1.01, 95% CI 0.81 to 1.24, low-quality evidence). Results of these secondary outcomes suggest that there may be an association between treatment effect in terms of efficacy and seizure type; that is, that participants with focal onset seizures experience seizure recurrence later and hence remission of seizures earlier on phenobarbitone than carbamazepine, and vice versa for individuals with generalised seizures. It is likely that the analyses of these outcomes were confounded by several methodological issues and misclassification of seizure type, which could have introduced the heterogeneity and bias into the results of this review. Limited information was available regarding adverse events in the trials and we could not compare the rates of adverse events between carbamazepine and phenobarbitone. Some adverse events reported on both drugs were abdominal pain, nausea, and vomiting, drowsiness, motor and cognitive disturbances, dysmorphic side effects (such as rash), and behavioural side effects in three paediatric trials. Moderate-quality evidence from this review suggests that carbamazepine is likely to be a more effective drug than phenobarbitone in terms of treatment retention (treatment failures due to lack of efficacy or adverse events or both). Moderate- to low-quality evidence from this review also suggests an association between treatment efficacy and seizure type in terms of seizure recurrence and seizure remission, with an advantage for phenobarbitone for focal onset seizures and an advantage for carbamazepine for generalised onset seizures. However, some of the trials contributing to the analyses had methodological inadequacies and inconsistencies that may have impacted upon the results of this review. Therefore, we do not suggest that results of this review alone should form the basis of a treatment choice for a patient with newly onset seizures. We recommend that future trials should be designed to the highest quality possible with consideration of masking, choice of population, classification of seizure type, duration of follow-up, choice of outcomes and analysis, and presentation of results.

Plain-language summary: The last search for trials was in May 2018. We assessed the evidence from 13 clinical trials in which people received either carbamazepine or phenobarbitone and their treatment was decided randomly. We were able to combine data for 836 people from six of the 13 trials; for the remaining 619 people from seven trials, data were not available to use in this review. Key results Results of the review suggest that people are likely to stop taking phenobarbitone treatment earlier than carbamazepine treatment, because of seizure recurrence, side-effects of the drug, or both. Results also suggest that recurrence of seizures after starting treatment with phenobarbitone may happen later than treatment with carbamazepine (and therefore a seizure free period of 6 months or 12 months may occur earlier with phenobarbitone than with carbamazepine) for people with focal onset seizures, and vice-versa for people with generalised onset seizures. Some side effects reported by people taking carbamazepine and people taking phenobarbitone were abdominal pain, nausea, vomiting, tiredness, motor problems (such as poor co-ordination), cognitive problems (poor memory), rashes and other skin problems. Behavioural side effects such as aggression were reported on both drugs in three trials in children. Quality of the evidence Some of the trials contributing data to the review had methodological problems, which may have introduced bias and inconsistent results into this review, and some individuals over the age of 30 with newly diagnosed generalised onset seizures may have had their seizure type wrongly diagnosed. These problems may have affected the results of this review and we judged the quality of the evidence provided by this review to be moderate to low quality. We do not suggest using the results of this review alone for making a choice between carbamazepine or phenobarbitone for the treatment of epilepsy. We recommend that all future trials comparing these drugs or any other antiepileptic drugs should be designed using high-quality methods to ensure results are also of high quality.