EP0092

UCB Biopharma SRL

Allée de la Recherche 60, Brussels, Belgium, 1070

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

No

No

No

Final

16 Nov 2020

No

Yes

28 Sep 2020

Yes

The primary objective was to evaluate the efficacy of the 3 selected dose regimens of padsevonil (PSL) administered concomitantly with up to 3 anti-epileptic drugs (AEDs) compared with placebo for treatment of observable focal-onset seizures in subjects with drug-resistant epilepsy.

During the conduct of the study all participants were closely monitored.

06 Mar 2019

Yes

Yes

Japan: 23

Australia: 5

Bosnia and Herzegovina: 10

Bulgaria: 26

Croatia: 8

Czechia: 7

Denmark: 14

Estonia: 8

Finland: 3

France: 2

Germany: 9

Greece: 5

Hungary: 2

Ireland: 4

Italy: 2

Norway: 1

Poland: 19

Portugal: 1

Romania: 5

Serbia: 4

Spain: 16

Sweden: 4

Turkey: 17

United Kingdom: 5

United States: 29

Belgium: 3

232

139

0

0

0

0

0

0

218

14

0

Treatment Period: Wk0-16

Randomised - controlled

Yes

Placebo

PBO

Film-coated tablet

Oral use

Placebo was provided as tablets of matching size and aspect to padsevonil tablets allowing a double-blind packaging. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Padsevonil

PSL

Film-coated tablet

Oral use

Padsevonil was administered as film-coated tablets of different doses, sizes, and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Padsevonil

PSL

Film-coated tablet

Oral use

Padsevonil was administered as film-coated tablets of different doses, sizes, and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Padsevonil

PSL

Film-coated tablet

Oral use

Padsevonil was administered as film-coated tablets of different doses, sizes, and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Post-Treatment Period: Wk16-23

Randomised - controlled

Yes

Placebo

PBO

Film-coated tablet

Oral use

Placebo was provided as tablets of matching size and aspect to padsevonil tablets allowing a double-blind packaging. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Padsevonil

PSL

Film-coated tablet

Oral use

Padsevonil was administered as film-coated tablets of different doses, sizes, and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Padsevonil

PSL

Film-coated tablet

Oral use

Padsevonil was administered as film-coated tablets of different doses, sizes, and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Padsevonil

PSL

Film-coated tablet

Oral use

Padsevonil was administered as film-coated tablets of different doses, sizes, and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

Placebo

Padsevonil 100 mg BID

Padsevonil 200 mg BID

Padsevonil 400 mg BID

Placebo

Padsevonil 100 mg BID

Padsevonil 200 mg BID

Padsevonil 400 mg BID

Placebo

Padsevonil 100 mg BID

Padsevonil 200 mg BID

Padsevonil 400 mg BID

Placebo (FAS)

Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19. Participants formed the Full Analysis Set (FAS).

Padsevonil 100 mg BID (FAS)

Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the FAS.

Padsevonil 200 mg BID (FAS)

Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the FAS.

Padsevonil 400 mg BID (FAS)

Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the FAS.

Placebo (SS)

Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19. Participants formed the Safety Set (SS).

Padsevonil 100 mg BID (SS)

Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

Padsevonil 200 mg BID (SS)

Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

Padsevonil 400 mg BID (SS)

Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

Placebo Treatment Period (SS)

Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19. Participants formed the Safety Set (SS).

Padsevonil 100 mg BID Treatment Period (SS)

Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

Padsevonil 200 mg BID Treatment Period (SS)

Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

Padsevonil 400 mg BID Treatment Period (SS)

Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

Placebo Conversion Period (SS)

A 3-Week Conversion Period was required for study participants who chose to enroll in the open-label extension (OLE) study at the end of the 12-Week Maintenance Period. Participants initially randomized to placebo progressively received padsevonil in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the Safety Set (SS).

Padsevonil 100 mg BID Conversion Period (SS)

A 3-Week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-Week Maintenance Period. The dose for participants initially randomized to padsevonil 100 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the SS.

Padsevonil 200 mg BID Conversion Period (SS)

A 3-Week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-Week Maintenance Period. The dose for participants initially randomized to padsevonil 200 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the SS.

Padsevonil 400 mg BID Conversion Period (SS)

A 3-Week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-Week Maintenance Period. The dose for participants initially randomized to padsevonil 400 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the SS.

Placebo Taper and SFU Period (SS)

A 4-Week Taper Period was required for participants who chose not to enroll in the OLE study or discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to the placebo group received 5-6 placebo tablets to maintain the blinding and have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the Safety Set (SS).

Padsevonil 100mg BID Taper and SFU Period (SS)

A 4-Week Taper Period was required for participants who chose not to enroll in the OLE study or discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to padsevonil 100 mg bid have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

Padsevonil 200mg BID Taper and SFU Period (SS)

A 4-Week Taper Period was required for participants who chose not to enroll in the OLE study or discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to padsevonil 200 mg bid have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

Padsevonil 400mg BID Taper and SFU Period (SS)

A 4-Week Taper Period was required for participants who chose not to enroll in the OLE study or discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to padsevonil 200 mg bid have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

The 75 % responder rate, where a responder was a participant experiencing a ≥75 % reduction in observable focal-onset seizure frequency from Baseline, over the 12-Week Maintenance Period. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period. Here, number of participants were included who were evaluable for the assessment.

Primary

From Baseline over the 12 Week Maintenance Period (up to Week 16)

PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), Region (Europe, non-Europe), Baseline SV2A use (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.

Placebo (FAS) v Padsevonil 100 mg BID (FAS)

113

Pre-specified

1.15

2-sided

PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), Region (Europe, non-Europe), Baseline SV2A use (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.

Placebo (FAS) v Padsevonil 200 mg BID (FAS)

110

Pre-specified

0.84

2-sided

PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), Region (Europe, non-Europe), Baseline SV2A use (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.

Placebo (FAS) v Padsevonil 400 mg BID (FAS)

110

Pre-specified

1.01

2-sided

An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment. The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.

Primary

From Baseline until Safety Follow-Up (up to Week 23)

An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment. The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.

Primary

From Baseline until Safety Follow-Up (up to Week 23)

A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, is as infection that requires treatment parenteral antibiotics, other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment. The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.

Primary

From Baseline until Safety Follow-Up (up to Week 23)

During the study, participants kept diaries to record daily seizure activity. Seizure frequency refers to 28-day adjusted frequency. Seizure frequency was based on investigator assessment of participants’ reports of daily seizure type and frequency. Observable focal-onset seizures refer to Type IA1, IB, and IC (ILAE Classification of Epileptic Seizures, 1981). Based on ANCOVA on change in log-transformed seizure frequency from Baseline, with treatment group as the main factor, Baseline log-transformed seizure frequency as a continuous covariate, Baseline SV2A use (Yes or No) and Region (Europe, non-Europe) as categorical factors. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period. Here, number of participants were included who were evaluable for the assessment.

Secondary

From Baseline over the 12 Week Maintenance Period (up to Week 16)

Percent reduction over placebo was calculated as 100*(1-exp(diff)), where diff was the model estimate of the log ratio between each PSL group and placebo group.

Placebo (FAS) v Padsevonil 100 mg BID (FAS)

113

Pre-specified

-5.6

2-sided

Percent reduction over placebo was calculated as 100*(1-exp(diff)), where diff was the model estimate of the log ratio between each PSL group and placebo group.

Placebo (FAS) v Padsevonil 400 mg BID (FAS)

110

Pre-specified

6.3

2-sided

Percent reduction over placebo was calculated as 100*(1-exp(diff)), where diff was the model estimate of the log ratio between each PSL group and placebo group.

Placebo (FAS) v Padsevonil 200 mg BID (FAS)

110

Pre-specified

6.5

2-sided

During the study, participants kept diaries to record daily seizure activity. The percentage of participants who experienced a 50 % or greater reduction in seizure frequency per 28 days relative to Baseline (responders) were assessed. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period. Here, number of participants were included who were evaluable for the assessment.

Secondary

From Baseline over the 12 Week Maintenance Period (up to Week 16)

Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.

Placebo (FAS) v Padsevonil 100 mg BID (FAS)

113

Pre-specified

3.25

2-sided

Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.

Placebo (FAS) v Padsevonil 400 mg BID (FAS)

110

Pre-specified

9.31

2-sided

Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.

Placebo (FAS) v Padsevonil 200 mg BID (FAS)

110

Pre-specified

6.17

2-sided

The 50% responder rate, where a responder was a participant experiencing a ≥50% reduction in observable focal-onset seizure frequency from Baseline, over the 12-week Maintenance Period. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period. Here, number of participants were included who were evaluable for the assessment.

Secondary

From Baseline over the 12 Week Maintenance Period (up to Week 16)

PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), Region (Europe, non-Europe), Baseline SV2A use (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.

Placebo (FAS) v Padsevonil 100 mg BID (FAS)

113

Pre-specified

1.4

2-sided

PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), Region (Europe, non-Europe), Baseline SV2A use (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate

Placebo (FAS) v Padsevonil 200 mg BID (FAS)

110

Pre-specified

1.23

2-sided

PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), Region (Europe, non-Europe), Baseline SV2A use (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate

Placebo (FAS) v Padsevonil 400 mg BID (FAS)

110

Pre-specified

1.9

2-sided

TEAEs were collected from Baseline until Safety Follow-Up (up to Week 23)

TEAEs counts are for the number of study participants who entered the respective study period regardless of whether or not they completed the previous period. This is the reason for the difference in number of participants in Taper and SFU period in adverse events section and participant flow.

22.1

Padsevonil 100 mg BID Treatment Period (SS)

Placebo Treatment Period (SS)

Padsevonil 200 mg BID Treatment Period (SS)

Placebo Conversion Period (SS)

Padsevonil 400 mg BID Treatment Period (SS)

Padsevonil 100 mg BID Conversion Period (SS)

Padsevonil 200 mg BID Conversion Period (SS)

Padsevonil 400 mg BID Conversion Period (SS)

Placebo Taper and SFU Period (SS)

Padsevonil 100 mg BID Taper and SFU Period (SS)

Padsevonil 200 mg BID Taper and SFU Period (SS)

Padsevonil 400 mg BID Taper and SFU Period (SS)