Azetukalner

The registry record for NCT03796962 lists 95 investigative sites in 9 countries: the United States (54 sites), Spain (15), Germany (9), Italy (7), the United Kingdom (4), Canada (3), Georgia (1), Moldova (1), and Ukraine (1). The registry gives an actual study start date of January 30, 2019, an actual primary completion date of September 2, 2021, and an estimated completion date of October 2028 for the continuing open-label extension. The primary publication reports 97 trial sites in North America and Europe, while the open-label extension publication reports 95 sites. The sponsor is Xenon Pharmaceuticals Inc., and the protocol identifier is XPF-008-201.

The double-blind phase lasted 8 weeks, which the investigators identify as a limitation for assessing long-term safety and efficacy. Group sizes were unequal by design under the 2:1:1:2 randomization ratio, so the 10 mg group (n = 46) and 20 mg group (n = 51) were smaller than the placebo and 25 mg groups (n = 114 each), and the investigators note that the 20 mg analysis of global impression of change was underpowered. The investigators state that the effect of the COVID-19 pandemic on study outcomes is unknown and that pandemic restrictions on site access may have contributed to enrollment of a more refractory population, characterized by a median of 13.5 seizures per month and a median of 6 previously stopped antiseizure medications. Race was recorded but 298 of 325 participants (91.7%) identified as White, with less than 4% representation in any other category, so the investigators state that analysis by race would not contribute to a meaningful analysis in this single study. Seizure freedom rates derived from the 8-week treatment period were low in absolute terms, at 6.3% for 25 mg, 7.8% for 20 mg, 2.2% for 10 mg, and 1.8% for placebo among all observed participants.

The open-label extension has no control group and no blinding, and the investigators note potential selection bias because not all participants who enrolled in the double-blind phase entered the extension, although 275 of 285 completers (96.5%) did so. Long-term efficacy estimates can be biased by dropout, because participants who perceive benefit may preferentially remain on treatment; retention was 60% at 24 months, with 13.8% discontinuing for lack of efficacy and 12.0% for adverse events. The investigators report that a constant-cohort analysis restricted to participants treated for at least 24 months produced comparable improvements, indicating that the improvement is not solely attributable to attrition bias. Comparisons against extension studies of other antiseizure medications are limited by differing methods and treatment durations. The data are interim: the extension is scheduled to run 378 weeks, or 7 years, and no participant had completed it at the time of the publication.

The registry record for NCT05614063 gives Xenon Pharmaceuticals Inc. as lead sponsor, Worldwide Clinical Trials as collaborator, and XPF-010-301 as the sponsor protocol number. The actual study start date was 18 November 2022, the actual primary completion date was 12 January 2026, and the actual study completion date was 3 February 2026. The record lists 125 study locations across 18 countries: the United States (56 sites), Spain (10), Australia (9), Argentina (8), Germany (8), the United Kingdom (7), Italy (4), Poland (4), Canada (3), Portugal (3), Chile (2), Georgia (2), Latvia (2), Mexico (2), New Zealand (2), Bulgaria (1), Czechia (1), and Ireland (1).

The registry record sets a minimum age of 18 years, accepts participants of all sexes, and does not accept healthy volunteers.

Participants were randomized in a 1:1:1 ratio to azetukalner 25 mg per day, azetukalner 15 mg per day, or placebo. The investigational product is recorded in the registry as XEN1101 capsules, with azetukalner given as the other name, and the comparator as placebo capsules.

Median percent change in monthly seizure frequency from baseline through the 12-week double-blind period is the primary efficacy endpoint used across the Phase 3 epilepsy trials of azetukalner. The same measure was the primary endpoint of the Phase 2b X-TOLE trial, which allows the placebo-adjusted effect sizes of the two focal seizure trials supporting the New Drug Application to be compared directly.

As of September 2026, X-TOLE2 results are available only from company press releases and congress presentations. No peer-reviewed publication and no ClinicalTrials.gov results record have been posted, so treatment-group-level baseline characteristics, confidence intervals, the statistical testing hierarchy, and full adverse event tables are not publicly available. The double-blind period was 12 weeks, so durability of effect beyond that interval is inferred from a separate open-label extension rather than from randomized comparison. Enrollment was restricted to adults aged 18 years and older with focal epilepsy of at least 2 years duration who had failed at least 2 prior antiseizure medications and were taking 1 to 3 concomitant antiseizure medications, which limits generalizability to monotherapy use, to adolescents and children, and to newly diagnosed epilepsy. The reported analyses of the 100% responder rate over the last 8, 6, and 4 weeks of the double-blind period were post hoc and used nominal p-values. Patient Global Impression of Change was a prespecified secondary endpoint, but no results have been disclosed. Exact p-values differ between company statements, with the March 2026 topline release reporting p=0.000000000006 and p=0.00007 and the April 2026 congress release reporting p<0.0001 for both doses.

The registry record for NCT05716100 gives Xenon Pharmaceuticals Inc. as lead sponsor and XPF-010-302 as the sponsor protocol number, with an overall status of recruiting. The actual study start date was 9 May 2023, with estimated primary completion in October 2026 and estimated study completion in December 2026. The record lists 95 study locations across 20 countries: the United States (19 sites), Argentina (12), Portugal (8), Australia (6), France (6), Croatia (5), Poland (5), Chile (4), Israel (4), Mexico (4), Spain (4), Austria (3), Czechia (3), Germany (3), Belgium (2), Bulgaria (2), Italy (2), Finland (1), Hungary (1), and the Netherlands (1).

Participants are randomized in a 1:1:1 ratio to azetukalner 25 mg per day, azetukalner 15 mg per day, or placebo. The registry records the investigational product as XEN1101 capsules, with azetukalner given as the other name, and the comparator as placebo capsules.

X-TOLE3 is ongoing and recruiting, with estimated primary completion in October 2026 and estimated study completion in December 2026. No efficacy, safety, disposition, or baseline data have been reported. The trial is intended to support regulatory submissions outside the United States rather than the United States New Drug Application, which was submitted on the basis of X-TOLE and X-TOLE2. Enrollment outside Japan is expected to complete in 2026, which implies that Japanese enrollment continues beyond that date and that the full dataset will read out later than the primary completion estimate.

The registry record for NCT05718817 gives XPF-010-304 as the sponsor protocol number and X-TOLE4 as the acronym, with an overall status of enrolling by invitation. The actual study start date was 25 April 2023, with estimated primary completion in April 2033 and estimated study completion in June 2033. Estimated enrollment is 880 participants, with a minimum age of 12 years.

The registry record gives an estimated enrollment of 880 participants drawn from the completers of X-TOLE2, X-TOLE3, and X-ACKT. Of the 332 participants who completed the X-TOLE2 double-blind period, 322 entered the open-label extension study.

X-TOLE4 is an open-label extension with no control group and no blinding, enrolling by invitation from the completers of X-TOLE2, X-TOLE3, and X-ACKT. Estimated primary completion is April 2033, and no efficacy, safety, disposition, or baseline data have been reported. Because participants from three antecedent trials with two different seizure types are pooled, outcomes reported from this study will not be specific to focal onset seizures unless reported separately by antecedent trial.