Abstract: Individual participant data were obtained for five studies, which recruited a total of 635 participants, representing 80% of 798 individuals from all seven identified eligible trials. For remission outcomes, an HR of less than 1 indicates an advantage for phenytoin and for first seizure and treatment failure outcomes an HR of less than 1 indicates an advantage for phenobarbitone. 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 499 participants: 1.61, 95% CI 1.22 to 2.12, low-certainty evidence), time to treatment failure due to adverse events (pooled HR adjusted for seizure type for 499 participants: 1.99, 95% CI 1.37 to 2.87, low-certainty evidence), time to treatment failure due to lack of efficacy (pooled HR adjusted for seizure type for 499 participants: 1.87, 95% CI 1.32 to 2.66, moderate-certainty evidence), showing a statistically significant advantage for phenytoin compared to phenobarbitone. For our secondary outcomes, we did not find any statistically significant differences between phenytoin and phenobarbitone: time to first seizure post-randomisation (pooled HR adjusted for seizure type for 624 participants: 0.85, 95% CI 0.69 to 1.06, moderate-certainty evidence), time to 12-month remission (pooled HR adjusted for seizure type for 588 participants: 0.90, 95% CI 0.69 to 1.19, moderate-certainty evidence), and time to six-month remission pooled HR adjusted for seizure type for 588 participants: 0.91, 95% CI 0.71 to 1.15, moderate-certainty evidence). For individuals with focal onset seizures (73% of individuals contributing to analysis), numerical results were similar and conclusions the same as for analyses of all individuals and for individuals with generalised onset seizures (27% of individuals contributing to analysis), results were imprecise and no clear differences between the drugs were observed. Several confounding factors, most notably the differences in design of the trials with respect to blinding, were likely to have impacted on the results of the primary outcome 'time to treatment failure', and in turn, the treatment failure rates may have impacted on the secondary efficacy outcomes of time to first seizure and time to 12-month and six-month remission. Low-certainty evidence from this review suggests that phenytoin may 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-certainty evidence from this review also indicates no differences between the drugs in terms of time to seizure recurrence and seizure remission. However, the trials contributing to the analyses had methodological inadequacies and methodological design differences 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 August 2018. We assessed the evidence from seven clinical trials in which people received either phenobarbitone or phenytoin and their treatment was decided randomly. We were able to combine data for 635 people from five of the seven trials; for the remaining 163 people from two trials, data were not available to use in this review Key results This review found no evidence to suggest a difference between phenobarbitone and phenytoin in terms of the time to seizure recurrence and time to seizure remission (seizure free period of six or 12 months). Phenobarbitone treatment was more likely to be withdrawn than phenytoin treatment, however, this may have been influenced by the design of the included studies (whether the people and the clinicians treating them knew which treatment the person was receiving). 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. Also, we believe that the difference in study design with regards to whether the treatment was masked from the patients and clinicians (e.g. with a placebo tablet) had an impact on the rates of withdrawal from the study treatments, which also is likely to have impacted on the outcomes related to seizure control 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 phenytoin or phenobarbitone for the treatment of epilepsy. 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.