Randomized Study of XEN1101 Versus Placebo in Focal-Onset Seizures (X-TOLE3)

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

27 Sep 2023 → ongoing

Decision date (initial)

2023-05-17

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Xenon Pharmaceuticals Inc.

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Safety

To assess the effect of XEN1101 versus placebo on reducing focal seizure frequency.

Secondary objectives 2

1. To assess the early treatment effect of XEN1101 versus placebo on focal seizure frequency
2. To assess the effect of XEN1101 versus placebo on seizure impact

Conditions and MedDRA coding

Focal Onset Seizures

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Subject is properly informed of the nature and risks of the study and gives informed consent in writing prior to entering the study.
2. Subject is able to participate for the full term of the study.
3. Subject has a diagnosis (≥2 years) of focal epilepsy according to the International League Against Epilepsy 2017 classification criteria. 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.
4. 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.
5. Subject is able to keep accurate seizure diaries
6. Subject is ≥18 years of age with a BMI ≤40 kg/m2 at Visit 1.
7. Subject has prior neuroimaging (CT or MRI) within the last 10 years and documentation is available.
8. Subject is willing to comply with the contraception requirements as defined in Protocol
9. Male subjects must agree not to donate sperm from the time of the first administration of study drug until 3 months after the last dose of study drug. Female subjects 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.
10. Subject with an implanted vagal nerve stimulator, deep brain stimulation, or responsive neurostimulator system will be allowed to participate in the study if the stimulator, stimulation, or neurostimulator system is present for >1 year prior to entry into the DBP, and the battery does not need to be replaced during the DBP. The stimulation parameters must have been kept constant for >3 months prior to Visit 1 and for the duration of the study.

Exclusion criteria 26

1. Subject has previously documented electroencephalogram which shows any pattern not consistent with focal etiology of seizures.
2. Subject has history of focal aware non-motor seizures only
3. Subject has a history of non-epileptic psychogenic seizures
4. Subject has history of a primary generalized seizure.
5. Subject has presence or history of a developmental and epileptic encephalopathy, including Lennox-Gastaut syndrome.
6. Subject is on a ketogenic diet at, or within 1 month prior to, Visit 1.
7. 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.
8. Subject has history of drug or alcohol abuse within 1 year prior to Visit 1 that is 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.
9. Subject has history of repetitive seizures within the 12-month period preceding Visit 1 where the individual seizures cannot be counted.
10. Subject has status epilepticus within the last 12 months prior to Visit 1.
11. Subject has history of neurosurgery for seizures <1 year prior to Visit 1, or radiosurgery <2 years prior to enrollment.
12. 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
13. Subject had an active suicidal plan/intent in the past 6 months, history of suicide attempt in the last 2 years, or more than 1 lifetime suicide attempt.
14. Subject has history or presence of any significant medical or surgical condition or uncontrolled medical illness including, but not limited to, hematologic, cardiovascular, pulmonary, severe renal impairment (<30 mL/min CLCR), gastrointestinal, endocrine, hepatic (including those with mild, moderate, or severe hepatic impairment, defined as Child Pugh score >5), or urogenital systems, or other conditions that would place the subject at increased risk or prevent adherence to the protocol, as determined by the investigator.
15. Subject has ALT or AST levels >3-times the ULN at Visit 1.
16. 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.
17. Subject has history of skin or retinal pigment epithelium abnormalities or maculopathy caused by ezogabine/retigabine
18. Subject has history of cancer within the past 2 years, with the exception of appropriately treated basal cell or squamous cell carcinoma.
19. Female subject who is pregnant, breastfeeding, or planning to become pregnant from the first administration of study drug until 6 months after the last dose of study drug
20. Subject has any previous exposure to XEN1101.
21. Subject has exposure to any other investigational drug or device within 5 half lives or 30 days prior to Visit 1, whichever is longer.
22. 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).
23. Concomitant medication restrictions: If felbamate is used as a concomitant ASM, subject must have been on felbamate for at least 2 years, with a stable dose for 2 months (or no less than 49 days) prior to Visit 1. Subject must not have a history of WBC count below 2500/µL (2.50 × 109/L), platelets below 100,000/mm3 (100 × 109/L), liver function tests >3-times the ULN, or other indication of hepatic or bone marrow dysfunction while receiving felbamate. If subject received felbamate in the past, it must have been discontinued 2 months (or no less than 49 days) prior to screening; systemic use of a strong CYP3A4 inhibtor for >7 days in accordance with Section 6.3.1.
24. Subject has had multiple drug allergies or a severe drug reaction to an ASM(s), including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
25. Any personal circumstance that, in the opinion of the investigator, prevents adherence to the protocol
26. Employees of Xenon Pharmaceuticals Inc., the CRO, 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of subjects experiencing ≥50% reduction in monthly (28 days) focal seizure frequency from baseline through the DBP for XEN1101 versus placebo

Secondary endpoints 3

1. MPC in monthly (28 days) focal seizure frequency from baseline through the DBP for XEN1101 versus placebo
2. Proportion of subjects experiencing ≥50% reduction in weekly (7 days) focal seizure frequency from baseline to Week 1.
3. Proportion of subjects experiencing “at least much improved” (including “much” and “very much improved”) in PGIC at Week 12.

Investigational products

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

Test 4

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

Daniela Nenciu

Public contact point

Organisation

Xenon Pharmaceuticals Inc.

Contact name

Xenon Medical Affairs

Third parties 14

Locations

14 EU/EEA countries · 45 investigational sites

By country

Investigational sites

Country notifications

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

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Serious breaches 1 · Art. 52 CTR

Results and documents

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

Documents 379 files

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

Application history

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