Focal Epilepsy
Conditions
Keywords
Epilepsy
Brief summary
The XEN1101 Phase 2 clinical trial is a randomized, double-blind, placebo-controlled study that will evaluate the clinical efficacy, safety and tolerability of increasing doses of XEN1101 administered as adjunctive treatment in adult patients diagnosed with focal epilepsy, followed by an optional open-label extension (OLE).
Detailed description
The XEN1101 Phase 2 clinical trial is designed as a randomized, double-blind, placebo-controlled, multicenter study with an optional open-label extension (OLE) to evaluate the clinical efficacy, safety and tolerability of XEN1101 administered as adjunctive treatment in adult patients aged 18 to 75 years diagnosed with focal epilepsy. Approximately 300 patients will be randomized in a blinded manner to one of three active treatment groups or placebo in a 2:1:1:2 fashion (XEN1101 25 mg : 20 mg : 10 mg : Placebo). After screening, patients will have 8 weeks of baseline to assess frequency of seizures, followed by 8 weeks of treatment and a 6-week post treatment follow-up period. In order to be included in the study, patients must already be treated with a stable dose of 1 to 3 allowable current anti-epileptic drugs for at least one month prior to screening, during baseline, and throughout the double-blind portion (DBP) of the study. During the treatment period, patients will be given XEN1101 or placebo once daily in the evening. An OLE will be available to eligible patients who complete the DBP. All patients will receive a 20 mg daily dose of XEN1101 during this extension period.
Interventions
DRUGXEN1101
Oral dose
Sponsors
Novotech Health Holdings Pte. Ltd.
Xenon Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Be properly informed of the nature and risks of the study and give informed consent in writing, prior to entering the study * BMI ≤40 kg/m2 * Diagnosis (≥2 years) of focal epilepsy according to the International League Against Epilepsy \[ILAE\] 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 AEDs for at least one month prior to screening, during baseline, and throughout the duration of the DBP * Must be willing to comply with the contraception requirements * Males must agree not to donate sperm from the time of the first administration of study drug until 6 months after the last dose. Females must agree not to donate ova from the time of the first administration of study drug until 6 months after the last dose. * Able to keep accurate seizure diaries Key
Exclusion criteria
* History of pseudoseizures, psychogenic seizures, primary generalized seizure, or focal aware non-motor seizures only * Presence or previous history of Lennox-Gastaut syndrome * Seizures secondary to other diseases or conditions * History of repetitive seizures within the last 12 months where the individual seizures cannot be counted * History of neurosurgery for seizures \<1 year prior to enrollment, or radiosurgery \<2 years prior to enrollment * Schizophrenia and other psychotic disorders, or 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, or history of cancer within the past 2 years, with the exception of appropriately treated basal cell or squamous cell carcinoma * Any clinically significant abnormalities on pre-study physical examination, vital signs, laboratory values or ECG indicating a medical problem that would preclude study participation including but not limited to: 1. History of presence of long QT syndrome; QTcF \> 450 msec at baseline; family history of sudden death of unknown cause 2. History of skin or retinal pigment epithelium abnormalities caused by ezogabine * Past use of vigabatrin without stable visual fields tested twice over the 12 months after the last dose of vigabatrin (concomitant use of vigabatrin is not allowed) * If felbamate is used as a concomitant AED, patients must be taking it for at least 2 years, with a stable dose for 2 months (or no less than 49 days) and acceptable hematology and LFT history and values prior to Screening. If received in the past, felbamate 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 AED(s), including dermatological (e.g., Stevens-Johnson syndrome), hematological, or organ toxicity reactions * Current use of a ketogenic diet
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Percent Change in Focal Seizure Frequency | From baseline (8 weeks prior to Day 0) through to the final dose (up to Day 56) | Median percent change in monthly (28 days) focal seizure frequency from baseline to DBP for XEN1101 versus placebo |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 50% XEN1101 Response Rate | From baseline (8 weeks prior to Day 0) through to the final dose (up to Day 56) | Responders are defined as patients experiencing ≥50% reduction in monthly (28 days) focal seizure frequency from baseline to DBP |
| Percent Change in Focal Seizure Frequency Over Time | From baseline (8 weeks prior to Day 0) through to the final dose (up to Day 56) | Percent change from baseline in focal seizure frequency at Month 1 and Month 2 in the DBP |
Countries
Canada, Georgia, Germany, Italy, Moldova, Spain, Ukraine, United Kingdom, United States
Participant flow
Pre-assignment details
530 subjects were screened; 77 subjects screen failed; 124 subjects that entered the baseline period but were not randomized due seizure/eDiary-based eligibility criteria
Participants by arm
| Arm | Count |
|---|---|
| 25 mg XEN1101 Capsule filled with 25 mg XEN1101
XEN1101: Oral dose | 114 |
| 20 mg XEN1101 Capsule filled with 20 mg XEN1101
XEN1101: Oral dose | 51 |
| 10 mg XEN1101 Capsule filled with 10 mg XEN1101
XEN1101: Oral dose | 46 |
| Placebo Placebo capsule | 114 |
| Total | 325 |
Baseline characteristics
| Characteristic | 25 mg XEN1101 | Total | Placebo | 10 mg XEN1101 | 20 mg XEN1101 |
|---|---|---|---|---|---|
| Age, Customized Age | 38.7 years STANDARD_DEVIATION 13.1 | 40.8 years STANDARD_DEVIATION 13.3 | 42.9 years STANDARD_DEVIATION 13.7 | 40.0 years STANDARD_DEVIATION 12.1 | 41.7 years STANDARD_DEVIATION 13.6 |
| Monthly seizure frequency in baseline | 12.8 seizures/month (28 days) | 13.5 seizures/month (28 days) | 13.4 seizures/month (28 days) | 17.4 seizures/month (28 days) | 14.5 seizures/month (28 days) |
| Race/Ethnicity, Customized Asian | 1 Participants | 4 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 12 Participants | 7 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 5 Participants | 8 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White or Caucasian | 105 Participants | 298 Participants | 102 Participants | 42 Participants | 49 Participants |
| Sex: Female, Male Female | 54 Participants | 168 Participants | 61 Participants | 27 Participants | 26 Participants |
| Sex: Female, Male Male | 60 Participants | 157 Participants | 53 Participants | 19 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 114 | 0 / 51 | 0 / 46 | 0 / 114 |
| other Total, other adverse events | 97 / 114 | 35 / 51 | 31 / 46 | 56 / 114 |
| serious Total, serious adverse events | 3 / 114 | 2 / 51 | 2 / 46 | 3 / 114 |
Outcome results
Primary
Median Percent Change in Focal Seizure Frequency
Median percent change in monthly (28 days) focal seizure frequency from baseline to DBP for XEN1101 versus placebo
Time frame: From baseline (8 weeks prior to Day 0) through to the final dose (up to Day 56)
Population: mITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 25 mg XEN1101 | Median Percent Change in Focal Seizure Frequency | -52.8 Percent change |
| 20 mg XEN1101 | Median Percent Change in Focal Seizure Frequency | -46.4 Percent change |
| 10 mg XEN1101 | Median Percent Change in Focal Seizure Frequency | -33.2 Percent change |
| Placebo | Median Percent Change in Focal Seizure Frequency | -18.2 Percent change |
Secondary
50% XEN1101 Response Rate
Responders are defined as patients experiencing ≥50% reduction in monthly (28 days) focal seizure frequency from baseline to DBP
Time frame: From baseline (8 weeks prior to Day 0) through to the final dose (up to Day 56)
Population: mITT Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 25 mg XEN1101 | 50% XEN1101 Response Rate | 61 Participants |
| 20 mg XEN1101 | 50% XEN1101 Response Rate | 22 Participants |
| 10 mg XEN1101 | 50% XEN1101 Response Rate | 13 Participants |
| Placebo | 50% XEN1101 Response Rate | 17 Participants |
Secondary
Percent Change in Focal Seizure Frequency Over Time
Percent change from baseline in focal seizure frequency at Month 1 and Month 2 in the DBP
Time frame: From baseline (8 weeks prior to Day 0) through to the final dose (up to Day 56)
Population: mITT population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| 25 mg XEN1101 | Percent Change in Focal Seizure Frequency Over Time | Month 1 (Day 1 to 28) | -55.3 Percent change from baseline |
| 25 mg XEN1101 | Percent Change in Focal Seizure Frequency Over Time | Month 2 (Day 29 to Visit 8) | -64.7 Percent change from baseline |
| 20 mg XEN1101 | Percent Change in Focal Seizure Frequency Over Time | Month 2 (Day 29 to Visit 8) | -52.2 Percent change from baseline |
| 20 mg XEN1101 | Percent Change in Focal Seizure Frequency Over Time | Month 1 (Day 1 to 28) | -40.0 Percent change from baseline |
| 10 mg XEN1101 | Percent Change in Focal Seizure Frequency Over Time | Month 1 (Day 1 to 28) | -40.1 Percent change from baseline |
| 10 mg XEN1101 | Percent Change in Focal Seizure Frequency Over Time | Month 2 (Day 29 to Visit 8) | -30.3 Percent change from baseline |
| Placebo | Percent Change in Focal Seizure Frequency Over Time | Month 1 (Day 1 to 28) | -14.9 Percent change from baseline |
| Placebo | Percent Change in Focal Seizure Frequency Over Time | Month 2 (Day 29 to Visit 8) | -21.8 Percent change from baseline |