A randomized study of XEN1101 versus placebo in Primary Generalised Tonic Clonic Seizures (X-ACKT)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Xenon Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

27 Oct 2023 → ongoing

Decision date (initial)

2023-06-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Xenon Pharmaceuticals Inc.

External identifiers

EU CT number

2022-502286-16-00

ClinicalTrials.gov

NCT05667142

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others, Efficacy, Safety

To assess the effect of XEN1101 versus placebo on reducing Primary Generalized Tonic-Clonic Seizures (PGTCS) frequency in subjects with PGTCS.

Secondary objectives 2

1. To assess the effect of XEN1101 versus placebo on the frequency of PGTCS freedom in subjects with PGTCS.
2. To assess the effect of XEN1101 versus placebo on seizure impact in subjects with PGTCS.

Conditions and MedDRA coding

Primary Generalized Tonic-Clonic 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 14

1. Subject is properly informed of the nature and risks of the study and gives informed consent or assent in writing prior to entering the study. Legal representatives/Parents will provide consent for minors to participate in the study
2. Subject has probable or possible PGTCS (with or without other subtypes of generalized seizures) for ≥1 year, in the setting of generalized epilepsy according to the International League Against Epilepsy 2017 classification criteria, and subject is approved by TESC.
3. 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.
4. Subject is able to keep accurate seizure diaries.
5. Subject is ≥12 years of age, [CCI], and has a BMI ≤40 kg/m2 at Visit 1.
6. 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.
7. Subject had onset of PGTCS before age 40 years
8. Subject has prior neuroimaging (CT or MRI) within the last 10 years (performed after the onset of seizures) and documentation is available.
9. Subject must have had at least 3 PGTCS during the 8 weeks prior to Visit 1, verified by historical seizure diary or by reliable subject and/or caregiver report, in the opinion of the investigator.
10. Subject is willing to comply with the contraception requirements
11. 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
12. Subject has a documented routine EEG within 5 years prior to Visit 1 or during the prerandomization period
13. Subject with an implanted vagal nerve, deep brain stimulator, or responsive neurostimulator system will be allowed to participate in the study if the stimulator was implanted at least 5 months prior to Visit 1, and the battery does not need to be replaced nor the stimulator parameters changed from 30 days prior to Visit 1 and for the duration of the study
14. Subject is able to participate for the full term of the study.

Exclusion criteria 24

1. Subject has had status epilepticus within the 12 months prior to Visit 1.
2. Subject has presence or history of a developmental and epileptic encephalopathy, including Lennox-Gastaut syndrome.
3. 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.
4. 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.
5. Subject has history of neurosurgery for seizures <1 year prior to Visit 1, or radiosurgery <2 years prior to Visit 1.
6. Any personal circumstance that, in the opinion of the investigator, prevents adherence to the protocol
7. Subject is on a ketogenic diet at, or within 1 month prior to, Visit 1
8. 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: History or presence of long QT syndrome; QTcF >450 msec at Visit 1; family history of sudden death of unknown cause.
9. 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.
10. Subject has schizophrenia or other psychotic disorders (eg, schizophreniform disorder, schizoaffective disorder, psychosis not otherwise specified), bipolar disorder, obsessive-compulsive disorder, or another serious mental health disorder. Subject has uncontrolled unipolar major depression where changes in pharmacotherapy are needed or anticipated during the study
11. 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.
12. Subject has any previous exposure to XEN1101
13. 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.
14. Subject has ALT or AST levels >3-times the ULN at Visit 1
15. Subject has history of skin or retinal pigment epithelium abnormalities or maculopathy caused by ezogabine/retigabine.
16. Subject has history of cancer within the past 2 years, with the exception of appropriately treated basal cell or squamous cell carcinoma
17. 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
18. Subject has exposure to any other investigational drug or device within 5 half-lives or 30 days prior to Visit 1, whichever is longer.
19. Subject has history of repetitive seizures within the 12-month period preceding Visit 1 where the individual seizures could not be counted.
20. 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).
21. Concomitant medications 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. Subjects must not have a history of WBC count below 2500/μL (2.50 × 10^9/L), platelets below 100,000/mm3 (100 × 10^9/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; [CCI]
22. 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.
23. Subject has a history of nonepileptic psychogenic seizures.
24. Subject has a concomitant diagnosis of Focal-onset Seizures.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

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

Secondary endpoints 3

1. MPC in monthly (28 days) PGTCS frequency from baseline through the DBP for XEN1101 versus placebo
2. Proportion of subjects experiencing PGTCS freedom from baseline through the DBP for XEN1101 versus placebo.
3. Proportion of subjects experiencing “At least much improved” (including “Much” and “Very much improved”) in PGI-C 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

Karla Mark-Lantz

Public contact point

Organisation

Xenon Pharmaceuticals Inc.

Contact name

Xenon Medical Affairs

Third parties 13

Locations

12 EU/EEA countries · 48 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 397 files

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

Application history

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