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A Multicenter, Open-Label Study to Evaluate the Safety and Tolerability of Intravenous Brivaracetam as Replaement for Oral Brivaracetam in Japanese Subjects >=16 Years of Age with Partial Seizures With or Without Secondary Generalization

A Multicenter, Open-Label Study to Evaluate the Safety and Tolerability of Intravenous Brivaracetam as Replaement for Oral Brivaracetam in Japanese Subjects >=16 Years of Age with Partial Seizures With or Without Secondary Generalization

10

The mean age of study participants was 39.4 years, and there were 6 males (60.0%) and 4 females (40.0%). All study participants were Japanese. The mean epilepsy duration of the 10 study participants was 23.7 years. Among the study participants, 8 participants (80.0%) had simple partial seizures and 9 participants (90.0%) had complex partial seizures and partial seizures secondarily generalized. All study participants had at least 1 concomitant disease. Overall, the most common SOC in which concomitant diseases were reported was Nervous system disorders (7 study participants [70.0%]).

A total of 10 study participants were screened at 7 sites; 9 participants completed the study and 1 study participant discontinued from the study due to AE. All study participants received at least 1 dose of iv BRV and composed the SS (Safety Set); of the study participants in the SS, all study participants had evaluable partial seizure frequency data during the Treatment Period and were included in the FAS (Full Analysis Set). Study participants in the SS who had valid concentration data for at least 1 PK sampling time point after iv BRV administration were included in the PK-PPS (Pharmacokinetic Per-Protocol Set).

Of the 10 study participants in the study, 6 participants (60.0%) reported 11 TEAEs, all of which were of mild or moderate intensity. Treatment-emergent AEs included headache, somnolence, dizziness, vomiting, myalgia, vessel puncture site erythema, dysmenorrhoea, phlebitis, and vasculitis. Except for dysmenorrhoea, all TEAEs were considered by the Investigator to be related to BRV with onset during the Treatment Period. Headache and somnolence were each reported by 2 study participants; all other TEAEs were reported by 1 participant each. A total of 5 study participants received BRV 200mg/day in this study; one study participant receiving BRV 200mg/day reported serious TEAEs (vomiting, dizziness, and headache) on the same day as the study drug initiation, which required hospitalization and resulted in the study participant's withdrawal from the study. The participant made a complete recovery following hospitalization. The other 4 participants completed the study, and BRV was considered to be well-tolerated. Therefore, the occurrence of these SAEs reported by 1 participant did not result in reducing the dose of BRV treatment within the investigated dose range (50mg/day to 200mg/day) of this study. No study participant reported severe AEs or AESIs; no participant died during the study. No pregnancy or PDILI events were reported by any participant. Overall, there was no evidence for any clinically important effect of BRV treatment on laboratory parameters, vital signs, ECG evaluations, or neurological examinations. There were no TEAEs related to laboratory parameters, vital signs, or ECG findings reported during the study.

A total of 10 study participants were enrolled in the study; 9 participants completed the study (all 10 were included in the SS, the FAS, and the PK-PPS). One study participant (receiving 200mg/day iv BRV) discontinued from the study due to AEs after Day 1. The occurrence of these AEs reported by 1 participant did not result in reducing the dose of BRV treatment within the investigated dose range (50mg/day to 200mg/day) of this study. At doses ranging from 50mg/day to 200mg/day, iv BRV (as a replacement for oral BRV) was safe and generally well tolerated in study participants receiving concomitant AEDs with uncontrolled POS when administered as adjunctive therapy. The safety profile in EP0118 was determined to be consistent with the safety profile in the ongoing open-label extension study EP0085 and with the overall established safety profile of BRV.

There was no apparent change in partial seizure frequency count after switching from oral to iv BRV. Overall, the pattern of seizure frequency and seizure type for the individual study participants did not appear to be different compared with the 8 weeks prior to their entry into EP0118. No TEAEs or SAEs of seizures were reported during the study. The geometric mean of the predose Ctrough values on Day 1 were similar or slightly higher compared with the geometric mean of the redose Ctrough values on Day 2 after switching from oral to iv administration of BRV (50mg/day to 200mg/day). The geometric mean of the Ctrough and C5min values on Day 2 and Day 5 after repeated iv administration of BRV 50mg/day to 200mg/day did not show a trend during the Treatment Period. Results of this study show that iv BRV can be used as a short-term replacement for oral BRV in study participants with POS with or without secondary generalization.

The results of this open-label study evaluating the safety and tolerability of iv BRV as adjunctive therapy administered as short-term replacement for oral BRV in adult Japanese study participants with POS with or without secondary generalization suggest that at doses ranging from 50 to 200mg/day, iv BRV was safe and generally well tolerated. Results of this study show that iv BRV can be used as a short-term replacement for oral BRV in study participants with POS with or without secondary generalization.

No

UCB Japan Co., Ltd.

8-17-1 Nishi-shinjuku, Shinjuku-ku, Tokyo

CTR_SCC_UCBJapan@UCB.com

UCB Japan Co., Ltd.

8-17-1 Nishi-shinjuku, Shinjuku-ku, Tokyo

-

CTR_SCC_UCBJapan@UCB.com

completed

Jan. 04, 2019

Interventional

open-label, multicenter study

treatment purpose

3

- Subject has, in the opinion of the Investigator, adequate seizure control for participation in the study, and is willing and able to comply with all study requirements including hospitalization, multiple blood draws, and intravenous (iv) injection
- Female subjects without childbearing potential (postmenopausal for at least 2 years, bilateral oophorectomy or tubal ligation, complete hysterectomy) are eligible. Female subjects with childbearing potential are eligible if they use a medically accepted contraceptive method
- Japanese subject is currently enrolled in EP0085 [NCT03250377] receiving oral brivaracetam (BRV) for the treatment of partial seizures and has been enrolled for at least 8 weeks prior to entry into EP0118
- Subject has been on a stable twice daily dosage regimen of BRV 50 mg/day to 200 mg/day for the 4 weeks prior to entry into EP0118
- Subject has been receiving concomitant antiepileptic drug (AED(s)) at doses that have remained stable for the 4 weeks (12 weeks for phenobarbital, phenytoin, and primidone) prior to entry into EP0118
- Subject has been receiving drugs with possible central nervous system (CNS) effects at doses that have remained stable for the 4 weeks prior to entry into EP0118, if applicable
- Subject has been receiving drugs that significantly influence the metabolism of BRV at doses that have remained stable for the 4 weeks prior to entry into EP0118, if applicable
- Subject has had stable vagal nerve stimulation (VNS) settings for the 4 weeks prior to entry into EP0118, if applicable

- Subject is receiving an investigational medicinal product (IMP) or unapproved medication other than oral BRV, or using an experimental medical device
- Subject has previously been treated with intravenous (iv) brivaracetam (BRV)
- Subject has a known hypersensitivity to any components of the investigational medicinal product (IMP) or comparative drugs as stated in this protocol
- Subject has a confirmed clinically relevant abnormality by electrocardiogram (ECG)
- Subject has a severe medical, neurological, or psychiatric disorder, or abnormal laboratory values which may have an impact on the safety of the subject
- Subject has demonstrated poor compliance with the visit schedule or medication intake in previous BRV studies
- Subject has planned participation in any other clinical study of another IMP or device during this study
- Subject is a pregnant or lactating female
- Subject has any medical condition which, in the Investigator's opinion, warrants exclusion
- Subject has a lifetime history of suicide attempt (including an active attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a positive response ("Yes") to either Question 4 or Question 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) "Since Last Visit" at Screening
- Subject has >2x upper limit of normal (ULN) of any of the following prior to Day 1 (from liver function assessment in EP0085): alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or >ULN total bilirubin (>=1.5x ULN total bilirubin if known Gilbert's syndrome)tion (VNS) settings for the 4 weeks prior to entry into EP0118, if applicable

Both

Epilepsy and epilepsy syndrome

investigational material(s)
Generic name etc : brivaracetam
INN of investigational material : brivaracetam
Therapeutic category code : 113 Antiepileptics
Dosage and Administration for Investigational material : Intravenous (iv) injection

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
- Adverse Events (AEs) as reported spontaneously by the subject or observed by the Investigator
- Subject withdrawal due to Adverse Events (AEs)
- Occurrence of Serious Adverse Events (SAEs)

efficacy
pharmacokinetics
- Partial seizure frequency during the Treatment Period
- Brivaracetam (BRV) plasma concentration

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Aug. 24, 2018