A study to evaluate efficacy and safety of perampanel when administered together with other current antiepileptic medications in children with epilepsy

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Eisai Limited

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Trial duration

11 Nov 2019 → ongoing

Decision date (initial)

2024-05-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Eisai Inc.

External identifiers

EU CT number

2023-507794-17-00

EudraCT number

2018-004456-38

WHO UTN

U1111-1304-4278

ClinicalTrials.gov

NCT04015141

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacodynamic, Therapy, Safety

To evaluate the efficacy of perampanel as measured by the 50% responder rate during the
Maintenance Period of the Core Study for seizure frequency (percent of subjects with at least 50%
reduction in their seizure frequency per 28 days compared to baseline) in each cohort and each
epileptic syndrome.

Secondary objectives 10

1. To evaluate the efficacy of perampanel as measured by the proportion of subjects who are seizure-free during the Maintenance Period of Core Study and during the Treatment Period of Core Study and Extension A
2. To evaluate the efficacy of perampanel as measured by absolute reduction and percentage of reduction in seizure frequency per 28 days during the Treatment Period of Core Study and during the Treatment Period of Core Study and Extension A
3. To evaluate the effects of perampanel on the Clinical Global Impression (CGI), as measured by the CGI of Change (CGIC) at the end of the Treatment Period of Core Study and at the end of Extension A
4. To evaluate the effects of perampanel on the Subject Global Impression (SGI), as measured by the SGI of Change (SGIC) at the end of the Treatment Period of Core Study and at the end of Extension A
5. To evaluate the effects of perampanel on growth and development, including cognition, behavior, visuomotor skills, and sexual maturation, in the pediatric population at the end of the Treatment Period of Core Study and at the end of Extension A (revised per Amendment 02)
6. To evaluate the efficacy of perampanel as measured by the proportion of responders (≥25% and ≥75%) during the Maintenance Period of Core Study and during the Treatment Period of Core Study and Extension A
7. To evaluate the efficacy of perampanel as measured by the 50% responder rate during the Treatment Period of Core Study and Extension A
8. To characterize the pharmacokinetics (PK) of perampanel and to explore relationships between exposure and safety endpoints, including most common treatment-emergent adverse events (TEAEs), cognition, and behavior
9. To explore graphically the relationship between perampanel exposure and partial-onset seizures (POS) response. (revised per Amendment 02)
10. To evaluate the safety and tolerability of perampanel

Conditions and MedDRA coding

Childhood Epilepsy

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-000467-PIP01-08

Plan to share IPD

Yes

IPD plan description

Eisai’s data sharing commitment and further information on how to request data can be found on our website https://eisaiclinicaltrials.com/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Male or female subject, from age 1 month to less than 18 years for Cohort 1, or age 1 month to less than 2 years for Cohort 2 at the time of informed consent/assent. Subjects below the age of 1 year must have been at least 36 weeks of gestational age at birth. (revised per Amendments 01 and 02)
2. Have a diagnosis of epilepsy with a pediatric epileptic syndrome (Cohort 1) or epilepsy with POS with or without secondary generalization (Cohort 2) according to the International League against Epilepsy (ILAE) Classification of Epileptic Seizures (1981). The eligibility criteria for the 2 cohorts are not mutually exclusive as a subject may experience POS as part of an epilepsy syndrome; these subjects are eligible for Cohort 1 if: (1) they are 2 to less than 18 years of age; or (2) they are 1 month to less than 2 years of age AND Cohort 2 is filled. Diagnosis must have been established by clinical history and an EEG that is consistent with the diagnosis; normal interictal EEGs will be allowed provided that the subject meets the other diagnosis criterion (ie, clinical history).
3. Subjects must have had equal or greater than 4 seizures over the 4-week interval prior to Visit 2. For Cohort 1, all seizures except simple POS without motor signs are counted toward this inclusion. For Cohort 2, only simple POS with motor signs, complex POS, and complex POS with secondary generalization are counted toward this inclusion for POS.
4. Absence of any progressive cause of epilepsy that has been confirmed clinically or based on brain imaging (eg, magnetic resonance imaging [MRI] scan, computed tomography [CT], or ultrasound [only for subjects <1 year old]). (revised per Amendment 02).
5. Are currently being treated with stable doses of 1 to a maximum of 4 approved AEDs. A prescription medical marijuana (including products containing cannabidiol) is counted as 1 of the maximum of 4 allowed AEDs; however, it cannot be the only concomitant AED if this product is not an approved AED in the country where the study site is located. Doses must be stable for at least 4 weeks (at least 2 weeks for subjects <6 months old) before Visit 1; only 1 enzyme-inducing AED (EIAED) (defined as carbamazepine, phenytoin, oxcarbazepine, or eslicarbazepine) out of the maximum of 4 AEDs is allowed. (revised per Amendment 01).

Exclusion criteria 25

1. Females who are breastfeeding or pregnant at Screening/Baseline (as documented by a positive beta-human chorionic gonadotropin [β-hCG] or human chorionic gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of β-hCG [or hCG]). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the 1st dose of study drug.
2. Females of childbearing potential who: • Within 28 days before study entry, did not use a combination of a barrier method with a highly effective method of contraception, which includes any of the following: (revised per Amendment 01) o Total abstinence (if it is their preferred and usual lifestyle). o An intrauterine device or intrauterine hormone-releasing system (IUS). o A contraceptive implant. o An oral contraceptive (with additional barrier method). Subject must be on a stable dose of the same oral contraceptive product for at least 28 days before dosing and throughout the study and for 28 days after study drug discontinuation. o Have a vasectomized partner with confirmed azoospermia. Do not agree to use a combination of a barrier method with a highly effective method of contraception (as described above) throughout the entire study period and for 28 days after study drug discontinuation. (revised per Amendment 01). For sites outside of the EU, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the subject, then the subject must agree to use a medically acceptable method of contraception, ie, double-barrier methods of contraception such as latex or synthetic condom plus diaphragm or cervical/vault cap with spermicide. NOTE: All postpuberty females should be considered to be of childbearing potential unless they have been sterilized surgically (ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing).
3. Current or history of pseudo-seizures (psychogenic nonepileptic seizures) within approximately 5 years before Visit 1.
4. Have a history of status epilepticus that required hospitalization during the 6 months before to Visit 1.
5. Have an unstable psychiatric diagnosis that may confound subjects’ ability to participate in the study or that may prevent completion of the protocol specified tests (eg, significant suicide risk, including suicidal behavior and ideation within 6 months before Visit 1, current psychotic disorder, acute mania).
6. Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 (ie, answering “Yes” to questions 4 or 5 on the Suicidal Ideation section of the Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above or based on the opinion of the Investigator for subject less than 6 years.
7. Are scheduled or confirmed or both to have epilepsy surgery within 6 months after Visit 1; however, those who have previously documented “failed” epilepsy surgery will be allowed.
8. Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator could affect the subject’s safety or interfere with the study assessments.
9. Evidence of moderate or severe renal insufficiency as defined by estimated glomerular filtration rates (eGFRs) based on Bedside Schwartz equation [eGFR=0.413×Height (cm)/Serum Creatinine (mg/dL)] of 31 to less than 60 mL/min/1.73m2 and less than 30 mL/min/1.73m2, respectively. (revised per Amendment 01)
10. Evidence of significant active hepatic disease. Stable elevation of liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) due to concomitant medications, will be allowed if they are less than 3 times the upper limit of normal (ULN).
11. Evidence of significant active hematological disease; white blood cell (WBC) count equal or less than 2500/μL (2.50 1E+09/L), or an absolute neutrophil count equal or less than 1000/μL (1.00 1E+09/L).
12. Clinically significant ECG abnormality, including Fridericia prolonged corrected QT interval (QTcF) defined as greater than 450 msec.
13. Have a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors.
14. Multiple drug allergies or a severe drug reaction to AEDs, including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions.
15. Concomitant use of felbamate as an AED for less than 2 years or where the dose has not been stable for at least 8 weeks before Visit 1. They must not have a history of WBC count below equal or less than 2500/μL (2.50 1E+09/L), platelets below 100,000, 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 8 weeks before Visit 1 to be eligible for study participation.
16. Concomitant or recent (within last 5 months before Visit 1) use of vigabatrin or any evidence of vigabatrin-associated clinically significant vision abnormality.
17. Benzodiazepines for any indications other than epilepsy (eg, anxiety/sleep disorders) prohibited from 1 month before Visit 1 and during the study. Benzodiazepines for seizure control and as rescue medication are allowed. (revised per Amendments 01 and 02)
18. A vagal nerve stimulator (VNS), responsive neurostimulator (RNS), or deep brain stimulator (DBS) implanted less than 5 months before Visit 1 or changes in parameter less than 4 weeks before Visit 1 (or thereafter during the study).
19. On a ketogenic diet for which the diet is not stable regimen for at least 4 weeks before Visit 1.
20. History of or a concomitant medical condition that in the opinion of the investigator would preclude the subject’s participation in a clinical study or compromise the subject’s ability to safely complete the study.
21. Use of perampanel within 30 days before Visit 1, or perampanel was discontinued due to adverse reactions (perampanel-related) or lack of efficacy in case of previous exposure.
22. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
23. Have participated in a study involving administration of an investigational drug or device within 4 weeks before Visit 1, or within approximately 5 half-lives of the previous investigational compound, whichever is longer.
24. Hypersensitivity to the active substance or to any of the excipients of the study drug. (revised per Amendment 01)
25. Weight less than 4.0 kg at Visit 1. (revised per Amendment 02).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of 50% responders for all seizures during the Maintenance Period of Core Study.

Secondary endpoints 13

1. Proportion of 50% responders for all seizures during Treatment Period of Core Study and Extension A (revised per Amendment 02).
2. Proportion of 25% and 75% responders for all seizures during Maintenance Period of Core Study and during Treatment Period of Core Study and Extension A
3. Proportion of subjects who are seizure-free during the Maintenance Period of Core Study and during the Treatment Period of Core Study and Extension A
4. Absolute and percent change from baseline in seizure frequency for all seizures during the Treatment Period of Core Study and during the Treatment Period of Core Study and Extension A
5. CGIC (Investigator Based) at the end of the Treatment Period of Core Study and at the end of Extension A
6. SGIC (Subject Based) at the end of the Treatment Period of Core Study and at the end of Extension A
7. Change from baseline in CDR parameters at the end of the Treatment Period of Core Study and at the end of Extension A (revised per Amendment 02)
8. Change from baseline in CBCL parameters at the end of the Treatment Period of Core Study and at the end of Extension A (revised per Amendment 02)
9. Change from baseline in LGPT parameters at the end of the Treatment Period of Core Study and at the end of Extension A (revised per Amendment 02)
10. Changes from baseline in growth and development parameters (height, weight, thyroid, IGF-1, and sexual maturation assessed by Tanner Staging) during Treatment Period of Core Study and Extension A (revised per Amendment 02)
11. Proportion of subjects with any treatment-emergent reports of suicidal ideation and behavior on the C-SSRS and intensity of these behaviors assessed using C-SSRS scores during Treatment Period of Core Study, Extension A, and Extension B (revised per Amendment 02)
12. Change from baseline in number of seizures recorded on EEG at the end of the Treatment Period of Core Study and at the end of Extension A
13. Safety and tolerability, which include incidence of TEAEs and serious AEs (SAEs), laboratory parameters, vital signs, and ECG parameters during Treatment Period of Core Study, Extension A, and Extension B (revised per Amendment 02)

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Eisai Limited

Sponsor organisation

Eisai Limited

Address

European Knowledge Center, Mosquito Way Mosquito Way

City

Hatfield

Postcode

AL10 9SN

Country

United Kingdom

Scientific contact point

Organisation

Eisai Limited

Contact name

Medical Information

Public contact point

Organisation

Eisai Limited

Contact name

Medical Information

Third parties 8

Locations

4 EU/EEA countries · 13 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 1 file

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