Evaluation of the Safety, Tolerability, and Efficacy of Azetukalner as Adjunctive Therapy in Adults with Focal-Onset Epilepsy: A Randomized, Double-Blind, Placebo-Controlled Study
- Trial ID
- 2023-508681-15-00
- Protocol
- XPF-008-201
- Sponsor
- Xenon Pharmaceuticals Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **efficacy** of XEN1101 compared to placebo on focal seizure frequency in adults with focal epilepsy who are taking 1 to 3 anti-seizure medications (ASMs) during the double-blind phase (DBP). Additionally, the study aims to evaluate the safety and **tolerability** of XEN1101 in this patient population. These objectives are clinically relevant as they address the potential of XEN1101 to reduce seizure frequency and improve patient safety profiles, which are critical factors in the management of focal epilepsy.
Secondary objectives include:
- Evaluating the 50% XEN1101 response rates in comparison to placebo in the DBP.
- Assessing trends in focal seizure frequency over time in the DBP.
- Determining the effect of XEN1101 versus placebo on seizure severity and impact in adults with focal epilepsy taking 1 to 3 ASMs in the DBP.
Participants
The clinical trial involves a total of **144 participants** diagnosed with **adult focal (partial onset) epilepsy**. The study population comprises both male and female subjects, aged between 18 to 75 years, with a body mass index of 40 kg/m² or less. Participants were selected based on their diagnosis of focal epilepsy for at least two years, as per the ILAE Classification of Epilepsy (2017), and must have undergone prior neuroimaging within the last decade. All participants are required to be on a stable dose of 1 to 3 allowable antiseizure medications (ASMs) for at least one month prior to screening and throughout the double-blind period (DBP) of the study. The trial includes individuals who are able to maintain accurate seizure diaries and are committed to participating for the full duration of the study. The study population is characterized by a willingness to comply with specific contraception requirements, and both male and female participants must agree not to donate reproductive cells for a specified period after the last dose of the study drug. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the efficacy and safety of the investigational drug, XEN1101, compared to placebo in reducing focal seizure frequency.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the safety, tolerability, and efficacy of XEN1101 as an adjunctive therapy in adults with **focal epilepsy**. The trial includes an open-label extension phase. The study aims to assess the efficacy of XEN1101 compared to placebo on focal seizure frequency in adults taking 1 to 3 anti-seizure medications (ASMs) and to evaluate the safety and tolerability of the drug. The trial is expected to run from May 28, 2019, to October 31, 2028, with a maximum treatment period of 372 days for participants.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of focal epilepsy, and stable ASM treatment. Following the screening, participants will be randomized to receive either XEN1101 or a placebo in a double-blind manner. The study will include regular follow-up visits to monitor seizure frequency, adverse events, and compliance with the study protocol. The primary endpoint is the median percent change in monthly focal seizure frequency from baseline to the double-blind phase (DBP) for XEN1101 versus placebo. Secondary endpoints include the percentage of responders experiencing a ≥50% reduction in seizure frequency and changes in clinical global impression scores.
The expected length of participant involvement is up to 372 days, with conditions for early termination including non-compliance with study requirements, significant protocol deviations, or adverse events that, in the investigator's opinion, preclude continued participation. The study is conducted under strict adherence to ethical guidelines, ensuring informed consent and participant safety throughout the trial duration.
Treatment
The clinical trial involves the administration of **XPF-010**, an experimental medication formulated as a capsule. The active substance in XPF-010 is **azetukalner**, a chemical compound classified under the ATC code N03AX, indicating its use as an "Other Antiepileptic" agent. The medication is administered orally, with a maximum daily dose of 20 mg, and the treatment period can extend up to 372 days. The trial aims to evaluate the efficacy, safety, and tolerability of XPF-010 in adults with focal-onset epilepsy. The medication is provided by Xenon Pharmaceuticals Inc.
Another experimental treatment in the study is **XPF-008**, also formulated as a capsule and containing the active substance **azetukalner**. Similar to XPF-010, XPF-008 is administered orally with a maximum daily dose of 20 mg and a treatment duration of up to 372 days. XPF-008 is classified under the ATC codes N03AX and N06A, indicating its use as both an "Other Antiepileptic" and an "Antidepressant." This medication is also supplied by Xenon Pharmaceuticals Inc.
The study includes a **placebo** group, utilizing a product named XEN1101 placebo. The placebo is designed to match the experimental medications in appearance and administration route, ensuring the study remains double-blind. The placebo is administered orally, and its use is critical for comparing the effects of the experimental treatments against a non-active control.
Efficacy
The efficacy of XEN1101 as an adjunctive therapy in adults with focal-onset epilepsy will be assessed through a randomized, double-blind, placebo-controlled, multicenter study. The primary efficacy endpoint is the median percent change in monthly (28 days) focal seizure frequency from baseline to the double-blind period (DBP) for XEN1101 compared to placebo. Secondary endpoints include the percentage of subjects experiencing a ≥50% reduction in monthly focal seizure frequency from baseline compared to the DBP, percent change from baseline in weekly focal seizure frequency for each week in the DBP, and scores from the Clinical Global Impression of Change (CGI-C) and Patient Global Impression of Change (PGI-C) during the DBP.
Efficacy parameters will be measured and collected at specified intervals throughout the trial. The assessment of seizure frequency will be based on patient-reported outcomes, specifically seizure diaries maintained by participants. The CGI-C and PGI-C scores will be used to evaluate overall changes in the condition as perceived by clinicians and patients, respectively. These assessments will be conducted at various timepoints during the DBP to ensure comprehensive evaluation of the treatment's efficacy.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Be properly informed of the nature and risks of the study and give informed consent in writing, prior to entering the study.
- Male or female, 18 to 75 years of age (inclusive) with a body mass index ≤40 kg/m2.
- Diagnosis (≥2 years) of focal epilepsy according to the ILAE Classification of Epilepsy (2017).
- Prior neuroimaging within the last 10 years and documentation is available.
- 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 DBP.
- Must be willing to comply with the contraception requirements as defined in Section 5.4.
- Males must agree not to donate sperm from the time of the first administration of study drug until 6 months after the last dose of study drug. Females must agree not to donate ova from the time of the first administration of study drug until 6 months after the last dose of study drug.
- Able to keep accurate seizure diaries.
- Able to participate for the full term of the study.
- Criteria for OLE 1. Be properly informed of the nature and risks of the study and give informed consent in writing.
- Criteria for OLE 2. Must have met all eligibility requirements and completed the DBP (to Visit 8* with a minimum of 80% compliance with eDiary entries and study drug), did not terminate early, subject had no important protocol deviations, (eg, that may impact subject safety, or data integrity) that in the opinion of the sponsor should preclude participation in the OLE, and had no AEs that, in the opinion of the investigator, would preclude the subject’s entry into the OLE.
- Criteria for OLE 3. Subject is expected to experience benefit from their participation, in the opinion of the investigator.
- Criteria for OLE 4. Must be willing to comply with the contraception requirements as defined in the protocol.
- Criteria for OLE 5. Males must agree not to donate sperm until 6 months after the last dose of study drug. Females must agree not to donate ova until 6 months after the last dose of study drug.
Exclusion Criteria
- Previously documented EEG which shows any pattern not consistent with focal etiology of seizures. (A new EEG is not required, if not available.)
- History of focal aware non-motor seizures only.
- History of pseudoseizures or psychogenic seizures.
- History of a primary generalized seizure.
- Presence or previous history of Lennox-Gastaut syndrome.
- Seizures secondary to illicit drug or alcohol use, ongoing infection, neoplasia, demyelinating disease, degenerative neurological disease, or central nervous system disease deemed progressive, metabolic illness, or progressive degenerative disease, progressive structural lesion or encephalopathy.
- History of repetitive seizures within the 12-month period preceding study entry where the individual seizures cannot be counted.
- Status epilepticus within the last 12 months prior to enrollment.
- History of neurosurgery for seizures <1 year prior to enrollment, or radiosurgery <2 years prior to enrollment.
- Schizophrenia and other psychotic disorders (eg, schizophreniform disorder, schizoaffective disorder, psychosis NOS), bipolar disorder, and/or obsessive-compulsive disorder, or other serious mental health disorders. Uncontrolled unipolar major depression where changes in pharmacotherapy are needed or anticipated during the study.
- Active suicidal plan/intent in the past 6 months, or a history of suicide attempt in the last 2 years, or more than 1 lifetime suicide attempt.
- History or presence of any significant medical or surgical condition or uncontrolled medical illness at screening including, but not limited to, hematologic, cardiovascular, pulmonary, renal, gastrointestinal, endocrine, hepatic or urogenital systems, or other conditions that would place the subject at increased risk as determined by the investigator.
- History of cancer within the past 2 years, with the exception of appropriately treated basal cell or squamous cell carcinoma.
- ALT or AST levels >3 times the ULN at screening or baseline.
- Any clinically significant laboratory abnormalities or clinically significant abnormalities on pre-study physical examination, vital signs, or ECG that in the judgment of the investigator indicates a medical problem that would preclude study participation including but not limited to: a. History of presence of long QT syndrome; QTcF >450 ms at baseline; family history of sudden death of unknown cause. b. History of skin or retinal pigment epithelium abnormalities caused by ezogabine.
- Females who are pregnant, breastfeeding, or planning to become pregnant during the first administration of study drug until 6 months after the last dose of study drug.
- History of illicit drug or alcohol abuse within 1 year prior to screening judged by the investigator to be excessive or compulsive, or currently using drugs of abuse or any prescribed or over-the-counter medication in a manner that the investigator considers indicative of abuse, dependence, or habitual use
- Exposure to any other investigational drug or device within 5 half-lives or 30 days prior to screening, whichever is longer.
- Use of vigabatrin in the last 5 years without stable visual fields tested twice over the 12 months after the last dose of vigabatrin. (Subjects stopping vigabatrin more than 5 years prior to screening, must have no vigabatrin-related visual field abnormalities confirmed by examination within the past 6 months - concomitant use of vigabatrin is not allowed).
- If felbamate is used as a concomitant ASM, subjects must be on felbamate for at least 2 years, with a stable dose for 2 months (or no less than 49 days) prior to screening. They must not have a history of WBC count below 2500/µL (2.50 x 109/L), platelets below 100,000/mm3(100 X 109/L), liver function tests above 3 times the ULN, or other indication of hepatic or bone marrow dysfunction while receiving felbamate. If subjects received felbamate in the past, it must have been discontinued 2 months (or no less than 49 days) prior to screening.
- Have had multiple drug allergies or a severe drug reaction to an ASM(s), including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
- Current use of a ketogenic diet.
- Any medical condition or personal circumstance that in the opinion of the investigator exposes the subject to unacceptable risk by participating in the study or prevents adherence to the protocol.
- Employees of Xenon Pharmaceuticals Inc., the contract research organization, or study site personnel directly affiliated with this study and their immediate family members. Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
- Exclusion criteria for OLE 1. Subjects who met any of the withdrawal criteria in the DBP.
- Exclusion criteria for OLE 2. Any medical condition, personal circumstance, or ongoing AE that in the opinion of the investigator exposes the subject to unacceptable risk by participating in the OLE or prevents adherence to the protocol.
- Exclusion criteria for OLE 3. Females who are pregnant, breastfeeding, or planning to become pregnant until 6 months after the last dose of study drug.
- Exclusion criteria for OLE 4. Subjects planning to enter a clinical trial with a different investigational drug or plan to use any experimental device for treatment of epilepsy or any other medical condition.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 28 May 2019 | 27 |
 Italy | Not Recruiting | 28 May 2019 | 25 |
 Spain | Not Recruiting | 28 May 2019 | 130 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
XPF-010 | Test | CAPSULE | ORAL | 20 | 372 | PRD11253013 |
XPF-008 | Test | CAPSULE | ORAL | 20 | 372 | PRD7634825 |
XEN1101 placebo | Placebo | N/A | — | — | — | N/A |