X-TOLE3

15 evidence topics · 4 sources

Objective

Trial objective: second Phase 3 trial of adjunctive azetukalner in focal onset seizures

“The X-TOLE3 Phase 3 clinical trial is a randomized, double-blind, placebo-controlled study that will evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive therapy in focal-onset seizures.” (opens the source at this quote in a new tab)

Regulatory purpose stated by the sponsor

“The Phase 3 X-TOLE3 study of azetukalner in FOS continues to enroll and is intended to support regulatory submissions outside of the United States. X-TOLE3 enrollment outside of Japan is expected to complete in 2026.” (opens the source at this quote in a new tab)

Location and study date

Summary: sponsor, identifiers, sites, and study dates

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).

Study design

Randomization, baseline period, and double-blind period

“Approximately 360 subjects will be randomized in a blinded manner to one of two active treatment groups or placebo in a 1:1:1 fashion (XEN1101 25 mg : 15 mg : Placebo). Eligible subjects will have up to 9.5 weeks of baseline to assess frequency of seizures, followed by 12 weeks of blinded treatment. In order to be included in the study, subjects must be treated with a stable dose of 1 to 3 allowable antiseizure medications (ASMs) for at least one month prior to screening, during baseline, and throughout the double-blind treatment period (DBP) of the study. During the DBP, subjects will be instructed to orally take XEN1101 or placebo once daily with an evening meal.” (opens the source at this quote in a new tab)
“Subjects who complete the 12-week DBP will have the opportunity to qualify and enroll in a separate open-label extension (OLE) study for continued treatment with XEN1101. Subjects who do not enroll in the OLE will enter a 8-week post treatment follow-up period.” (opens the source at this quote in a new tab)

Design shared with X-TOLE2 as described by the sponsor

“The completed X-TOLE2 study and the ongoing X-TOLE3 study were both designed as multicenter, randomized, double-blind, placebo-controlled studies to evaluate the clinical efficacy, safety, and tolerability of 15 mg or 25 mg of azetukalner administered orally with food as adjunctive treatment in approximately 360 patients per study with FOS.” (opens the source at this quote in a new tab)

Eligibility criteria

Inclusion criteria

“Diagnosis (≥2 years) of focal epilepsy according to the International League Against Epilepsy (ILAE) Classification of Epilepsy (2017). Subject must have had adequate trials of at least 2 ASMs, which were given (and tolerated) at adequate therapeutic doses, without achieving sustained seizure freedom.” (opens the source at this quote in a new tab)
“Treatment with a stable dose of 1 to 3 allowable current ASMs for at least one month prior to screening, during baseline, and throughout the duration of the DBP” (opens the source at this quote in a new tab)
“Able to keep accurate seizure diaries” (opens the source at this quote in a new tab)

Exclusion criteria

“Previously documented electroencephalogram which shows any pattern not consistent with focal etiology of seizures.” (opens the source at this quote in a new tab)
“History of focal aware non-motor seizures only, non-epileptic psychogenic seizure, primary generalized seizure, developmental and epileptic encephalopathy, including Lennox-Gastaut syndrome.” (opens the source at this quote in a new tab)
“History of status epilepticus or repetitive seizures within the 12-month period preceding Visit 1 where the individual seizures cannot be counted.” (opens the source at this quote in a new tab)

Treatment

Summary: study arms and interventions

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.

Study outcomes

Rationale for using median percent change in monthly focal onset seizure frequency as the primary endpoint

Primary outcome measure

“Median percent change (MPC) in focal seizure frequency from baseline to DBP for XEN1101 versus placebo.” (opens the source at this quote in a new tab)

Secondary outcome measures

“Proportion of subjects experiencing ≥50% reduction in focal seizure frequency from baseline through the DBP for XEN1101 versus placebo.” (opens the source at this quote in a new tab)
“MPC in weekly (7 days) focal seizure frequency from baseline to Week 1 for XEN1101 versus placebo.” (opens the source at this quote in a new tab)
“Proportion of subjects experiencing "at least much improved" (including "much" and "very much improved") in Patient Global Impression of Change (PGI-C).” (opens the source at this quote in a new tab)
“To assess adverse events as criteria for safety and tolerability of XEN1101.” (opens the source at this quote in a new tab)

Primary efficacy endpoint shared with X-TOLE2

“The primary efficacy endpoint is median percent change (MPC) in monthly seizure frequency from baseline through the 12-week double-blind period (DBP) of azetukalner compared to placebo.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Planned randomization ratio and enrollment

“Approximately 360 subjects will be randomized in a blinded manner to one of two active treatment groups or placebo in a 1:1:1 fashion (XEN1101 25 mg : 15 mg : Placebo).” (opens the source at this quote in a new tab)

Planned enrollment in Japan

“Xenon has aligned with PMDA to enroll approximately 60 of the planned 360 X-TOLE3 participants in Japan.” (opens the source at this quote in a new tab)

Participants analyzed

No evidence found.

Description of analysis sets

No evidence found.

Results

Participant disposition

No evidence found.

Baseline characteristics

No evidence found.

Efficacy results

No evidence found.

Health-related quality of life and patient-reported outcomes

Patient Global Impression of Change as a prespecified secondary endpoint

“Proportion of subjects experiencing "at least much improved" (including "much" and "very much improved") in Patient Global Impression of Change (PGI-C).” (opens the source at this quote in a new tab)

Safety results

No evidence found.

Study limitations

Summary: status of the X-TOLE3 evidence

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.