Clinical trial NCT01364597: Open-label Long-term Study of Adjunctive Brivaracetam in Pediatric Subjects With Epilepsy
Official title: Open-label, Single-arm, Multicenter, Long-term Study to Evaluate Safety and Efficacy of Brivaracetam Used as Adjunctive Treatment in Pediatric Subjects With Epilepsy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Epilepsy
Keywords: Brivaracetam
Epilepsy
Child
Infant
Adolescents
Partial onset seizures
Lead sponsor: UCB Pharma
Sponsor class: INDUSTRY
First posted: 2011-06-02
Enrollment: 257
Sex: ALL
Minimum age (years): 28
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will evaluate the safety and tolerability of brivaracetam in pediatric subjects with epilepsy.

Detailed description: This is a Phase 3, open-label, single-arm, multicenter, long-term study to evaluate the safety and efficacy of brivaracetam (BRV) in children with epilepsy.

This study was initially designed for pediatric subjects who had completed a previous BRV study.

With protocol amendment 4, enrollment for "directly enrolled" subjects was modified from 'up to' an additional 100 subjects to "at least" 100 subjects, keeping the planned total enrollment of approximately 600 subjects to allow flexibility in the number of patients reaching 1 year of exposure.

With protocol amendment 5, entry criteria for subjects coming for other pediatric core studies in development were included. Additional clarity was provided for subjects enrolled in N01266 that temporary roll over to one of those studies and resume participation in N01266.

With protocol amendment 6, central EEG reading and entry visit EEG were removed. Some clarifications on study assessments (questionnaires, EEGs) was provided and inclusion criteria were aligned from an earlier local amendment.

With protocol amendment 7, the pregnancy section was updated to clarify that Pregnancy Report and Outcome Form has to be completed in all pregnancies.

With protocol amendment 8, re-categorization of study variables in compliance with reporting registries was performed. Modifications due to COVID19 pandemic were implemented and clarification provided that participants may transition to another BRV study.

The primary objective is to evaluate the long-term safety and tolerability of BRV. The secondary objective is to assess the efficacy of BRV during long-term exposure.

Eligibility criteria: Inclusion Criteria:

All Subjects:

* Informed Consent form (ICF) is signed and dated by the parent(s) or legal representative(s)
* Subject/legal representative is considered reliable and capable of adhering to the protocol
* For female subjects:
* Subject is not of childbearing potential

OR if women of childbearing potential, and sexually active only if:

* Adequate Contraceptive method
* Negative pregnancy test
* Understands the consequences and potential risks of inadequately protected sexual activity, understands and properly uses contraceptive methods, and is willing to inform the Investigator of any contraception changes

Long Term Follow-up Subjects:

- Male or female subjects having participated in a core study with a confirmed diagnosis of epilepsy and for whom a reasonable benefit from long-term administration of BRV is expected

Directly Enrolled Subjects:

* Subject is a male or female ≥4 years to \<17 years of age
* Subject has a clinical diagnosis of partial-onset seizures (POS) according to the International League Against Epilepsy (ILAE) classification
* Subject has an EEG compatible with the clinical diagnosis of POS
* Subject has been observed to have uncontrolled POS after an adequate course of treatment (in the opinion of the Investigator) with at least 1 antiepileptic drug (AED; concurrently or sequentially)
* Subject had at least 1 seizure (POS) during the 3 weeks before the Screening Visit (ScrV)
* Subject is taking at least 1 AED. All AEDs need to be at a stable dose for at least 7 days before the ScrV. Vagal nerve stimulator stable for at least 2 weeks before the ScrV is allowed and will be counted as a concomitant AED. Benzodiazepines taken more than once a week (for any indication) will be considered as a concomitant AED

Exclusion Criteria:

All Subjects:

* Subject is a pregnant or nursing female
* Subject has severe medical, neurological, or psychiatric disorders or laboratory values, which may have an impact on the safety of the subject.
* Subject has planned participation in any clinical study of another investigational drug or device.
* Subject has \>1.5x upper limit of normal (ULN) of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or \>1.0xULN total bilirubin (≥1.5xULN total bilirubin if known Gilbert's syndrome). If subject has elevations only in total bilirubin that are \>ULN and \<1.5xULN, fractionate bilirubin to identify possible undiagnosed Gilbert's syndrome (ie, direct bilirubin \<35%). N01349 subjects with a total bilirubin \> ULN may be considered for the study if benign unconjugated hyperbilirubinemia is suspected in the context of prolonged neonatal jaundice, after discussion with the medical monitor. For randomized subjects with a baseline result \>ULN for ALT, AST, ALP, or total bilirubin, a baseline diagnosis and/or the cause of any clinically meaningful elevation must be understood and recorded in the eCRF. If subject has \>ULN ALT, AST, or ALP that does not meet the exclusion limit at the baseline referenced in Table 5-1 for LTFU subjects and at the Screening Visit for directly enrolled subjects, repeat the tests, if possible, prior to dosing to ensure there is no further ongoing clinically relevant increase. In case of a clinically relevant increase, inclusion of the subject must be discussed with the Medical Monitor. Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may be repeated once for confirmation. This includes re-screening.
* Subject has chronic liver disease.

Long Term Follow-up Subjects:

* Subject had hypersensitivity to BRV or excipients or comparative drugs as stated in this protocol during the course of the core study.
* Subject had poor compliance with the visit schedule or medication intake in the core study.
* Subject ≥6 years of age has a lifetime history of suicide attempt (including actual attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ("Yes") to Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) at the EV. If a subject has active suicidal ideation without a specific plan as indicated by a positive response ("Yes") to Question 4 of Columbia-Suicide Severity Rating Scale (C SSRS) at the EV, the subject should be referred immediately to a Mental Healthcare Professional and may be excluded from the study based upon the Investigator's judgment of benefit/risk of continuing the subject in the study/on study medication.

Directly Enrolled Subjects:

* Subject has previously received BRV.
* Subject had concomitant use of LEV at the ScrV. In addition, the use of LEV is prohibited for at least 4 weeks prior to the ScrV.
* Subject has epilepsy secondary to a progressive cerebral disease or tumor, or any other progressively neurodegenerative disease. Stable arteriovenous malformations, meningiomas or other benign tumors may be acceptable according to Investigator's opinion.
* Subject has a history of primary generalized epilepsy.
* Subject has a history of status epilepticus in the month immediately prior to the ScrV or during the Up Titration Period.
* Subject has a history or presence of pseudoseizures.
* Subject is suffering only from febrile seizures.
* Subject is on felbamate with less than 18 months continuous exposure. Subject who has taken felbamate for a combined duration of treatment and wash out of \<18 months before the ScrV.
* Subjects treated with vigabatrin who have visual field defects.
* Subject has an allergy to pyrrolidone derivatives or investigational product excipients or a history of multiple drug allergies.
* Subject has any clinically significant acute or chronic illness as determined during the physical examination or from other information available to the Investigator (eg, bone marrow depression, chronic hepatic disease, severe renal impairment, psychiatric disorder).
* Subject has an underlying disease or is receiving a treatment that may interfere with the absorption, distribution, metabolism, and elimination of the study drug.
* Subject has any medical condition that might interfere with his/her study participation (eg, serious infection or scheduled elective surgery).
* Subject has a terminal illness.
* Subject has any clinically significant deviations from reference range values for laboratory parameters as determined by the Investigator.
* Subject has a clinically relevant ECG abnormality according to the Investigator.
* Subject had major surgery within 6 months prior to the ScrV.
* Subject received any investigational drug or device within the 30 days prior to the ScrV.

Primary outcomes:
measure: Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) During the Study
timeFrame: From Baseline to end of study (up to 10 years)
measure: Percentage of Participants With Treatment-emergent Serious Adverse Events (SAEs) During the Study
timeFrame: From Baseline to end of study (up to 10 years)
Secondary outcomes:
measure: Absolute Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on Daily Record Card [DRC])
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
measure: Percent Change in 28-days Adjusted Partial-onset-seizure (POS) Frequency for Participants Aged ≥2 Years From Baseline to the End of the Evaluation Period in Participants With POS Only (Based on DRC Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
measure: 50% Responder Rate for Participants ≥2 Years of Age for Total Seizures (All Types) (Based on DRC Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
measure: Absolute Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
measure: Percent Change in Average Daily Frequency (ADF) of Partial-onset-seizures (POS) in Participants <2 Years of Age With POS Only (Based on EEG Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
measure: 50% Responder Rate for Participants <2 Years of Age for Total Seizures (All Types) (Based on EEG Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
measure: Absolute Change in Average Daily Frequency of POS in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
measure: Percent Change in Average Daily Frequency of POS in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
measure: 50% Responder Rate for Total Seizures (All Types) in Participants <2 Years of Age With Typical Absence Seizures (Based on EEG Data)
timeFrame: From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: N01266 243
state: California
city: Gulf Breeze
country: United States
facility: N01266 108
state: Florida
city: Wellington
country: United States
facility: N01266 103
state: Florida
city: Chicago
country: United States
facility: N01266 118
state: Illinois
city: Boston
country: United States
facility: N01266 106
state: Massachusetts
city: Saint Paul
country: United States
facility: N01266 101
state: Minnesota
city: Chesterfield
country: United States
facility: N01266 113
state: Missouri
city: Buffalo
country: United States
facility: N01266 105
state: New York
city: New York
country: United States
facility: N01266 252
state: New York
city: Rochester
country: United States
facility: N01266 104
state: New York
city: Durham
country: United States
facility: N01266 237
state: North Carolina
city: Cincinnati
country: United States
facility: N01266 107
state: Ohio
city: Columbus
country: United States
facility: N01266 111
state: Ohio
city: Pittsburgh
country: United States
facility: N01266 114
state: Pennsylvania
city: Houston
country: United States
facility: N01266 117
state: Texas
city: Brussels
country: Belgium
facility: N01266 202
city: Brussels
country: Belgium
facility: N01266 203
city: Leuven
country: Belgium
facility: N01266 201
city: Leuven
country: Belgium
facility: N01266 204
city: Hradec Králové
country: Czechia
facility: N01266 502
city: Ostrava Prouba
country: Czechia
facility: N01266 504
city: Praha 4
country: Czechia
facility: N01266 240
city: Lille cedex
country: France
facility: N01266 207
city: Paris
country: France
facility: N01266 206
city: Bayern
country: Germany
facility: N01266 218
city: Freiburg
country: Germany
facility: N01266 209
city: Budapest
country: Hungary
facility: N01266 210
city: Budapest
country: Hungary
facility: N01266 224
city: Budapest
country: Hungary
facility: N01266 247
city: Debrecen
country: Hungary
facility: N01266 222
city: Miskolc
country: Hungary
facility: N01266 232
city: Cork
country: Ireland
facility: N01266 211
city: Messina
country: Italy
facility: N01266 212
city: Parma
country: Italy
facility: N01266 213
city: Pavia
country: Italy
facility: N01266 238
city: Pavia
country: Italy
facility: N01266 239
city: Roma
country: Italy
facility: N01266 230
city: Roma
country: Italy
facility: N01266 256
city: Aguascalientes
country: Mexico
facility: N01266 223
city: Chihuahua
country: Mexico
facility: N01266 611
city: Culiacán
country: Mexico
facility: N01266 609
city: Guadalajara
country: Mexico
facility: N01266 603
city: Monterrey
country: Mexico
facility: N01266 610
city: Białystok
country: Poland
facility: N01266 404
city: Gdańsk
country: Poland
facility: N01266 403
city: Kielce
country: Poland
facility: N01266 406
city: Kraków
country: Poland
facility: N01266 402
city: Poznań
country: Poland
facility: N01266 401
city: Szczecin
country: Poland
facility: N01266 407
city: Wrocław
country: Poland
facility: N01266 405
city: Barcelona
country: Spain
facility: N01266 309
city: Madrid
country: Spain
facility: N01266 306
city: Palma De Mallorca
country: Spain
facility: N01266 301
city: Sevilla
country: Spain
facility: N01266 248
city: Valencia
country: Spain
facility: N01266 308
city: London
country: United Kingdom
facility: N01266 215
Study officials:
affiliation: +1 877 822 9493 (UCB)
name: UCB Cares
role: STUDY_DIRECTOR
References:
citation: Lagae L, Klotz KA, Fogarasi A, Floricel F, Reichel C, Elshoff JP, Fleyshman S, Kang H. Long-term safety and efficacy of adjunctive brivaracetam in pediatric patients with epilepsy: An open-label, follow-up trial. Epilepsia. 2023 Nov;64(11):2934-2946. doi: 10.1111/epi.17754. Epub 2023 Sep 5.
citation: Markham A. Brivaracetam: First Global Approval. Drugs. 2016 Mar;76(4):517-22. doi: 10.1007/s40265-016-0555-6.