A Study to Evaluate XEN1101 as Adjunctive Therapy in Primary Generalized Tonic-Clonic Seizures

Study Overview
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Brief Summary
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This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the clinical efficacy, safety, and tolerability of XEN1101 administered as adjunctive treatment in primary generalized tonic-clonic seizures (PGTCS).

Detailed Description
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This is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the clinical efficacy, safety, and tolerability of XEN1101 administered as adjunctive treatment in adult subjects diagnosed with generalized epilepsy and experiencing probable or possible PGTCS (with or without other subtypes of generalized seizures), and taking 1 to 3 anti-seizure medications (ASMs). Approximately 160 subjects will be randomly assigned 1:1 to XEN1101 25 mg or placebo, with stratification at randomization based on region and background use of CYP 3A4-inducer ASMs. Eligible subjects will have up to 9.5 weeks durations to assess the baseline frequency of seizures, followed by a double-blind treatment period (DBP) where subjects will receive 12 weeks of blinded treatment. During the DBP, subjects will be instructed to orally take XEN1101 or placebo once daily with an evening meal. Subjects who complete the 12-week DBP will have the opportunity to enroll in a separate open-label-extension (OLE) study for continued treatment with XEN1101. Subjects who do not enroll in the OLE will enter an 8 week post-treatment follow-up period.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Phase 3 Study to Evaluate the Safety, Tolerability, and Efficacy of XEN1101 as Adjunctive Therapy in Primary Generalized Tonic-Clonic Seizures

Conditions
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Primary Generalized Tonic-Clonic Seizures

Intervention / Treatment
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* Drug: XEN1101
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is properly informed of the nature and risks of the study and gives informed consent in writing prior to entering the study. Subject is ≥18 years of age with a BMI ≤40 kg/m2 at Visit 1. 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. Subject has a diagnosis (≥2 years) of PGTCS (with or without other subtypes of generalized seizures) in the setting of generalized epilepsy according to the International League Against Epilepsy 2017 classification criteria, and subject is approved by The Epilepsy Study Consortium (TESC). Subject is on a stable dose of 1 to 3 allowable current ASMs for at least 1 month prior to screening (Visit 1), during screening/baseline, and throughout the DBP. Subject is able to keep accurate seizure diaries. Exclusion Criteria: Subject has had status epilepticus within the 12 months prior to Visit 1. Subject has history of repetitive seizures within the 12-month period preceding Visit 1 where the individual seizures cannot be counted. Subject has a history of non-epileptic psychogenic seizures. Subject has a concomitant diagnosis of FOS. Subject has presence or history of a developmental and epileptic encephalopathy, including Lennox-Gastaut syndrome. Subject has seizures secondary to drug or alcohol use, ongoing infection, neoplasia, demyelinating disease, degenerative neurological disease, metabolic illness, progressive structural lesion, encephalopathy, or progressive CNS disease. Subject has history of neurosurgery for seizures <1 year prior to Visit 1, or radiosurgery <2 years prior to Visit 1. Subject has schizophrenia and other psychotic disorders (eg, schizophreniform disorder, schizoaffective disorder, psychosis not otherwise specified), bipolar disorder, and/or obsessive-compulsive disorder, or other serious mental health disorders including uncontrolled unipolar major depression where changes in pharmacotherapy are needed or anticipated during the study. Subject has any clinically significant laboratory abnormalities or clinically significant abnormalities on prestudy physical examination, vital signs, or ECG that, in the judgment of the investigator, indicate a medical problem that would preclude study participation, including but not limited to: a. History or presence of long QT syndrome; QTcF >450 msec at baseline; family history of sudden death of unknown cause. Any personal circumstance that, in the opinion of the investigator, prevents adherence to the protocol. The criteria to be eligible for randomization are: During the last 56 days of the baseline period that preceded the randomization visit (Visit 2), subject must have had a documented seizure frequency of ≥3 PGTCS, including ≥1 PGTCS during each of the first and second 4-week periods preceding randomization. Seizure diary was completed a minimum of 80% of all days (ie, ≥45 days) during the last 56 days of the baseline period that preceded randomization as evidence of adequate compliance. Subject did not change dose of, stop, or initiate any new ASM(s) during the baseline period and plans on maintaining a stable dose of ASM(s) during the DBP.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: XEN1101 25 mg/day<br>XEN1101 25 mg/day | Drug: XEN1101<br>* XEN1101 capsules<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br>* Placebo capsules<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median percent change (MPC) in monthly (28 days) PGTCS frequency | Median percent change (MPC) in monthly (28 days) PGTCS frequency from baseline through the DBP for XEN1101 versus placebo. | Baseline through DBP (Week 12) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects | Proportion of subjects experiencing ≥50% reduction in monthly (28 days) PGTCS frequency from baseline through the DBP for XEN1101 versus placebo. | Baseline through DBP (Week 12) | 
| Proportion of subjects | Proportion of subjects experiencing PGTCS freedom from baseline through the DBP for XEN1101 versus placebo. | Baseline through Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Epilepsy