A multicenter study to evaluate the safety, tolerability and efficacy of XEN1101 as additional therapy to standard treatment in focal epilepsy, with an Open-label Extension.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Xenon Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

28 May 2019 → ongoing

Decision date (initial)

2024-09-02

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Xenon Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-508681-15-00

EudraCT number

2018-003221-29

ClinicalTrials.gov

NCT03796962

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Others, Efficacy

- To assess the efficacy of XEN1101 compared to placebo on focal seizure frequency in adults with focal epilepsy taking 1 to 3 ASMs in the DBP.
- To assess the safety and tolerability of XEN1101 in adults with focal epilepsy taking 1 to 3 ASMs in the DBP.

Secondary objectives 3

1. To evaluate the 50% XEN1101 response rates in comparison to placebo in the DBP.
2. To evaluate trends in focal seizure frequency over time in the DBP.
3. To assess the effect of XEN1101 vs. placebo on seizure severity and impact in adults with focal epilepsy taking 1 to 3 ASMs in the DBP.

Conditions and MedDRA coding

Adult focal (partial onset) epilepsy

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Be properly informed of the nature and risks of the study and give informed consent in writing, prior to entering the study.
2. 2. Male or female, 18 to 75 years of age (inclusive) with a body mass index ≤40 kg/m2.
3. 3. Diagnosis (≥2 years) of focal epilepsy according to the ILAE Classification of Epilepsy (2017).
4. 4. Prior neuroimaging within the last 10 years and documentation is available.
5. 5. 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.
6. 6. Must be willing to comply with the contraception requirements as defined in Section 5.4.
7. 7. 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.
8. 8. Able to keep accurate seizure diaries.
9. 9. Able to participate for the full term of the study.
10. Criteria for OLE 1. Be properly informed of the nature and risks of the study and give informed consent in writing.
11. 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.
12. Criteria for OLE 3. Subject is expected to experience benefit from their participation, in the opinion of the investigator.
13. Criteria for OLE 4. Must be willing to comply with the contraception requirements as defined in the protocol.
14. 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 28

1. 1. Previously documented EEG which shows any pattern not consistent with focal etiology of seizures. (A new EEG is not required, if not available.)
2. 2. History of focal aware non-motor seizures only.
3. 3. History of pseudoseizures or psychogenic seizures.
4. 4. History of a primary generalized seizure.
5. 5. Presence or previous history of Lennox-Gastaut syndrome.
6. 6. 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.
7. 7. History of repetitive seizures within the 12-month period preceding study entry where the individual seizures cannot be counted.
8. 8. Status epilepticus within the last 12 months prior to enrollment.
9. 9. History of neurosurgery for seizures <1 year prior to enrollment, or radiosurgery <2 years prior to enrollment.
10. 10. 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.
11. 11. 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.
12. 12. 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.
13. 13. History of cancer within the past 2 years, with the exception of appropriately treated basal cell or squamous cell carcinoma.
14. 14. ALT or AST levels >3 times the ULN at screening or baseline.
15. 15. 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.
16. 16. 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.
17. 17. 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
18. 18. Exposure to any other investigational drug or device within 5 half-lives or 30 days prior to screening, whichever is longer.
19. 19. 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).
20. 20. 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.
21. 21. 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.
22. 22. Current use of a ketogenic diet.
23. 23. 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.
24. 24. 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.
25. Exclusion criteria for OLE 1. Subjects who met any of the withdrawal criteria in the DBP.
26. 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.
27. 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.
28. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 1. Median percent change in monthly (28 days) focal seizure frequency from baseline to DBP for XEN1101 versus placebo.
2. 2. Severity and frequency of associated AEs/SAEs, clinically significant changes in clinical laboratory findings and/or 12-lead ECG, increase in suicide risk as assessed by the C-SSRS Scale including increase in suicidal thoughts or an attempt, clinically significant changes in vital signs including blood pressure, pulse, or weight, and clinically significant changes in urological symptoms including retention as measured by the AUA-SI in the DBP.

Secondary endpoints 3

1. 3. Responders are defined as subjects experiencing ≥50% reduction in monthly (28 days) focal seizure frequency from baseline compared to DBP.
2. 4. Percent change from baseline in weekly focal seizure frequency for each week in the DBP.
3. 5. CGI-C and PGI-C scores during the DBP.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Xenon Pharmaceuticals Inc.

Sponsor organisation

Xenon Pharmaceuticals Inc.

Address

3650 Gilmore Way

City

Burnaby

Postcode

V5G 4W8

Country

Canada

Scientific contact point

Organisation

Xenon Pharmaceuticals Inc.

Contact name

Xenon Regulatory Affairs

Public contact point

Organisation

Xenon Pharmaceuticals Inc.

Contact name

Xenon Medical Affairs

Third parties 8

Locations

3 EU/EEA countries · 23 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 31 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications