Study to Test the Efficacy and Safety of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adults With Drug-resistant Epilepsy (ARISE)

• ClinicalTrials.gov Identifier: NCT03373383
• Recruitment Status: Completed
• First Posted: December 14, 2017
• Results First Posted: April 9, 2021
• Last Update Posted: December 21, 2022
• Sponsor: UCB Biopharma S.P.R.L.
• Information provided by (Responsible Party): UCB Pharma ( UCB Biopharma S.P.R.L. )

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Drug-resistant Epilepsy; Focal-Onset Seizures
• Interventions: Drug: Padsevonil; Other: Placebo
• Enrollment: 411

Participant Flow

Recruitment Details	The study started to enroll patients in February 2018 and concluded in January 2020.
Pre-assignment Details	The study included: a 4-week Baseline Period, a 16-week Treatment Period, a 4-week Taper Period (for participants who discontinued or choose not to enroll in the open-label extension study) and a Safety Follow-up Period. Participants continuing to the OLE study had a 3-week Conversion Period. Participant Flow refers to the Randomized Set.

Arm/Group Title	Placebo	Padsevonil 50mg BID	Padsevonil 100mg BID	Padsevonil 200mg BID	Padsevonil 400mg BID
Arm/Group Description	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19.	Participants were randomized to receive a combination of tablets of padsevonil 50 milligrams (mg) and placebo (as appropriate) to maintain the blinding, twice daily (bid) up to week 19	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 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 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.
Period Title: Treatment Period: Wk0-16
Started	83	81	83	82	82
Completed Titration and Stabilization	78	72	71	68	65
Completed Maintenance Period	70	66	68	61	58
Had Taper and Safety Follow-up	6	11	8	18	21
Completed	70	66	68	61	58
Not Completed	13	15	15	21	24
Reason Not Completed
Adverse Event	7	6	11	15	21
Lack of Efficacy	2	1	0	0	0
Protocol Violation	0	4	2	1	0
Lost to Follow-up	2	0	0	0	0
Withdrawal by Subject	2	3	2	3	3
As advised by the sponsor	0	1	0	0	0
By opinion of investigator	0	0	0	1	0
Sponsor decision	0	0	0	1	0
Period Title: Post-Treatment Period: Wk16-23
Started	70	66	68	61	58
Started Conversion Period	69	64	66	55	57
Completed Conversion Period	68	64	66	55	57
Had Taper and Safety Follow-up	3	3	3	6	1
Enrolled in EP0093	67	63	65	55	57
Completed	69	66	68	61	58
Not Completed	1	0	0	0	0
Reason Not Completed
Participant decided not to roll over	1	0	0	0	0

Baseline Characteristics

Arm/Group Title		Placebo	Padsevonil 50mg BID	Padsevonil 100mg BID	Padsevonil 200mg BID	Padsevonil 400mg BID	Total Title
Arm/Group Description		Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19.	Participants were randomized to receive a combination of tablets of padsevonil 50 milligrams (mg) and placebo (as appropriate) to maintain the blinding, twice daily (bid) up to week 19	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 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 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.	[Not Specified]
Overall Number of Baseline Participants		83	81	83	82	82	411
Baseline Analysis Population Description		Baseline characteristics refer to the Randomized Set (RS) consisting of all participants randomized into the study.
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	83 participants	81 participants	83 participants	82 participants	82 participants	411 participants
	<=18 years	0 0.0%	0 0.0%	2 2.4%	1 1.2%	1 1.2%	4 1.0%
	Between 18 and 65 years	82 98.8%	76 93.8%	80 96.4%	79 96.3%	80 97.6%	397 96.6%
	>=65 years	1 1.2%	5 6.2%	1 1.2%	2 2.4%	1 1.2%	10 2.4%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	83 participants	81 participants	83 participants	82 participants	82 participants	411 participants
		40.0 (12.9)	42.5 (11.6)	36.9 (13.1)	40.9 (12.0)	38.8 (12.1)	39.8 (12.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	83 participants	81 participants	83 participants	82 participants	82 participants	411 participants
	Female	48 57.8%	46 56.8%	47 56.6%	51 62.2%	43 52.4%	235 57.2%
	Male	35 42.2%	35 43.2%	36 43.4%	31 37.8%	39 47.6%	176 42.8%
Race/Ethnicity, Customized; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	83 participants	81 participants	83 participants	82 participants	82 participants	411 participants
	American Indian or Alaska Native	1 1.2%	1 1.2%	1 1.2%	2 2.4%	0 0.0%	5 1.2%
	Asian	7 8.4%	7 8.6%	5 6.0%	7 8.5%	7 8.5%	33 8.0%
	Black or African American	2 2.4%	1 1.2%	1 1.2%	2 2.4%	2 2.4%	8 1.9%
	Native Hawaiian or Other Pacific Islander	1 1.2%	1 1.2%	1 1.2%	1 1.2%	1 1.2%	5 1.2%
	White	69 83.1%	69 85.2%	73 88.0%	69 84.1%	71 86.6%	351 85.4%
	Other/mixed	3 3.6%	2 2.5%	2 2.4%	1 1.2%	1 1.2%	9 2.2%

Outcome Measures

1. Primary Outcome

Title	Change in Log-transformed Observable Focal Onset Seizure Frequency From Baseline Over the 12 Week Maintenance Period
Description	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, 28-day adjusted 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.
Time Frame	From Baseline over the 12 Week Maintenance Period

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo (FAS)	Padsevonil 50mg BID (FAS)	Padsevonil 100mg BID (FAS)	Padsevonil 200mg BID (FAS)	Padsevonil 400mg BID (FAS)
Arm/Group Description:	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Full Analysis Set (FAS).	Participants were randomized to receive a combination of tablets of padsevonil 50 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.	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.	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.
Overall Number of Participants Analyzed	81	80	82	81	81
Least Squares Mean (95% Confidence Interval); Unit of Measure: loge seizures per 28 days
	-0.27585; (-0.44311 to -0.10858)	-0.46424; (-0.63276 to -0.29573)	-0.48804; (-0.65436 to -0.32172)	-0.48960; (-0.65734 to -0.32187)	-0.40831; (-0.57485 to -0.24177)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 50mg BID (FAS)
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.102
	Comments	Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent reduction
	Estimated Value	17.2
	Confidence Interval	(2-Sided) 95%; -3.8 to 33.9
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 100mg BID (FAS)
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.064
	Comments	Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent reduction
	Estimated Value	19.1
	Confidence Interval	(2-Sided) 95%; -1.2 to 35.4
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 200mg BID (FAS)
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.063
	Comments	Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent reduction
	Estimated Value	19.2
	Confidence Interval	(2-Sided) 95%; -1.2 to 35.5
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 400mg BID (FAS)
	Comments	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.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.248
	Comments	Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Percent reduction
	Estimated Value	12.4
	Confidence Interval	(2-Sided) 95%; -9.7 to 30.1
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Reported by the Subject and/or Caregiver or Observed by the Investigator During the Entire Study
Description	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.
Time Frame	From Baseline until Safety Follow-Up (up to Week 23)

Outcome Measure Data

Analysis Population Description

The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.

Arm/Group Title	Placebo (SS)	Padsevonil 50mg BID (SS)	Padsevonil 100mg BID (SS)	Padsevonil 200mg BID (SS)	Padsevonil 400mg BID (SS)
Arm/Group Description:	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Safety Set (SS).	Participants were randomized to receive a combination of tablets of padsevonil 50 mg and Placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.	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.	Participants were randomized to receive tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the SS.
Overall Number of Participants Analyzed	83	81	83	82	81
Measure Type: Number; Unit of Measure: percentage of participants
	78.3	84.0	80.7	75.6	92.6

3. Primary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal
Description	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.
Time Frame	From Baseline until Safety Follow-Up (up to Week 23)

Outcome Measure Data

Analysis Population Description

The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.

Arm/Group Title	Placebo (SS)	Padsevonil 50mg BID (SS)	Padsevonil 100mg BID (SS)	Padsevonil 200mg BID (SS)	Padsevonil 400mg BID (SS)
Arm/Group Description:	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Safety Set (SS).	Participants were randomized to receive a combination of tablets of padsevonil 50 mg and Placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.	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.	Participants were randomized to receive tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the SS.
Overall Number of Participants Analyzed	83	81	83	82	81
Measure Type: Number; Unit of Measure: percentage of participants
	8.4	7.4	12.0	18.3	25.9

4. Primary Outcome

Title	Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) During the Entire Study
Description	A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: Results in death; Is life-threatening; Requires in patient hospitalization or prolongation of existing hospitalization; Is a congenital anomaly or birth defect; Is an 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.
Time Frame	From Baseline until Safety Follow-Up (up to Week 23)

Outcome Measure Data

Analysis Population Description

The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.

Arm/Group Title	Placebo (SS)	Padsevonil 50mg BID (SS)	Padsevonil 100mg BID (SS)	Padsevonil 200mg BID (SS)	Padsevonil 400mg BID (SS)
Arm/Group Description:	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Safety Set (SS).	Participants were randomized to receive a combination of tablets of padsevonil 50 mg and Placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.	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.	Participants were randomized to receive tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the SS.
Overall Number of Participants Analyzed	83	81	83	82	81
Measure Type: Number; Unit of Measure: percentage of participants
	4.8	7.4	4.8	6.1	6.2

5. Secondary Outcome

Title	75 % Responder Rate Over the 12 Week Maintenance Period
Description	The 75% responder rate, where a responder is a participant experiencing a ≥75% reduction in observable focal-onset seizure frequency from Baseline, over the 12-Week Maintenance Period.
Time Frame	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo (FAS)	Padsevonil 50mg BID (FAS)	Padsevonil 100mg BID (FAS)	Padsevonil 200mg BID (FAS)	Padsevonil 400mg BID (FAS)
Arm/Group Description:	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Full Analysis Set (FAS).	Participants were randomized to receive a combination of tablets of padsevonil 50 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.	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.	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.
Overall Number of Participants Analyzed	81	80	82	81	81
Measure Type: Number; Unit of Measure: percentage of participants
	6.2	13.8	12.2	11.1	16.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 50mg BID (FAS)
	Comments	PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.081
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.72
	Confidence Interval	(2-Sided) 95%; 0.88 to 8.39
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 100mg BID (FAS)
	Comments	PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.137
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.37
	Confidence Interval	(2-Sided) 95%; 0.76 to 7.41
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 200mg BID (FAS)
	Comments	PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.192
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.16
	Confidence Interval	(2-Sided) 95%; 0.68 to 6.89
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 400mg BID (FAS)
	Comments	PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.041
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.14
	Confidence Interval	(2-Sided) 95%; 1.05 to 9.42
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	50 % Responder Rate Over the 12 Week Maintenance Period
Description	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.
Time Frame	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo (FAS)	Padsevonil 50mg BID (FAS)	Padsevonil 100mg BID (FAS)	Padsevonil 200mg BID (FAS)	Padsevonil 400mg BID (FAS)
Arm/Group Description:	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Full Analysis Set (FAS).	Participants were randomized to receive a combination of tablets of padsevonil 50 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.	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.	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.
Overall Number of Participants Analyzed	81	80	82	81	81
Measure Type: Number; Unit of Measure: percentage of participants
	21.0	33.8	31.7	25.9	32.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 50mg BID (FAS)
	Comments	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 (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.045
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.09
	Confidence Interval	(2-Sided) 95%; 1.02 to 4.30
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 100mg BID (FAS)
	Comments	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 (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.079
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95%; 0.93 to 3.93
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 200mg BID (FAS)
	Comments	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 (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.338
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 95%; 0.68 to 3.02
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 400mg BID (FAS)
	Comments	PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.087
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Regression, Logistic
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.88
	Confidence Interval	(2-Sided) 95%; 0.91 to 3.87
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Percent Change in Observable Focal-onset Seizure Frequency From Baseline Over the 12 Week Maintenance Period
Description	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) was assessed.
Time Frame	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Placebo (FAS)	Padsevonil 50mg BID (FAS)	Padsevonil 100mg BID (FAS)	Padsevonil 200mg BID (FAS)	Padsevonil 400mg BID (FAS)
Arm/Group Description:	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Full Analysis Set (FAS).	Participants were randomized to receive a combination of tablets of padsevonil 50 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.	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.	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.
Overall Number of Participants Analyzed	81	80	82	81	81
Mean (Standard Deviation); Unit of Measure: percent change
	12.49 (58.26)	24.70 (46.62)	25.25 (51.73)	20.79 (66.54)	15.79 (67.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 50mg BID (FAS)
	Comments	Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.316
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	7.40
	Confidence Interval	(2-Sided) 95%; -6.59 to 21.89
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 100mg BID (FAS)
	Comments	Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.133
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	9.99
	Confidence Interval	(2-Sided) 95%; -3.15 to 23.26
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 200mg BID (FAS)
	Comments	Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.203
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	8.19
	Confidence Interval	(2-Sided) 95%; -3.95 to 21.37
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo (FAS), Padsevonil 400mg BID (FAS)
	Comments	Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	=0.784
	Comments	Nominal p-values were not adjusted for multiplicity.
	Method	Wilcoxon (Mann-Whitney)
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	2.39
	Confidence Interval	(2-Sided) 95%; -13.65 to 17.79
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Treatment-emergent AEs were collected from Baseline to Safety Follow-Up (up to Week 23)
Adverse Event Reporting Description	Adverse events refer to the SS which consisted of all participants who were administered at least 1 dose or a partial dose of IMP. TEAEs counts are for each study period: Treatment Period, Conversion Period for participants who entered the OLE study and Taper Period followed by SFU for participants not entering OLE study.
Arm/Group Title	Placebo Treatment Period (SS)		Padsevonil 50mg BID Treatment Period (SS)		Padsevonil 100mg BID Treatment Period (SS)		Padsevonil 200mg BID Treatment Period (SS)		Padsevonil 400mg BID Treatment Period (SS)		Placebo Conversion Period (SS)		Padsevonil 50mg BID Conversion Period (SS)		Padsevonil 100mg BID Conversion Period (SS)		Padsevonil 200mg BID Conversion Period (SS)		Padsevonil 400mg BID Conversion Period (SS)		Placebo Taper and SFU Period (SS)		Padsevonil 50mg BID Taper and SFU Period (SS)		Padsevonil 100mg BID Taper and SFU Period (SS)		Padsevonil 200mg BID Taper and SFU Period (SS)		Padsevonil 400mg BID Taper and SFU Period (SS)
Arm/Group Description	Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding up to week 19. Participants formed the Safety Set (SS).		Participants were randomized to receive a combination of tablets of padsevonil 50 mg and placebo (as appropriate) to maintain the blinding, bid up to week 19. Participants formed the 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.		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.		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.		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 400mg/day for the OLE. Participants formed the Safety Set (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 50mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400mg/day for the OLE. Participants formed the 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 100mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400mg/day for the OLE. Participants formed the 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 200mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400mg/day for the OLE. Participants formed the 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 400mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400mg/day for the OLE. Participants formed the SS.		A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to 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. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the Safety Set (SS).		A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to padsevonil 50 mg bid have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.		A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to 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. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.		A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to 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. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.		A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to padsevonil 400 mg bid have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.
All-Cause Mortality
	Placebo Treatment Period (SS)		Padsevonil 50mg BID Treatment Period (SS)		Padsevonil 100mg BID Treatment Period (SS)		Padsevonil 200mg BID Treatment Period (SS)		Padsevonil 400mg BID Treatment Period (SS)		Placebo Conversion Period (SS)		Padsevonil 50mg BID Conversion Period (SS)		Padsevonil 100mg BID Conversion Period (SS)		Padsevonil 200mg BID Conversion Period (SS)		Padsevonil 400mg BID Conversion Period (SS)		Placebo Taper and SFU Period (SS)		Padsevonil 50mg BID Taper and SFU Period (SS)		Padsevonil 100mg BID Taper and SFU Period (SS)		Padsevonil 200mg BID Taper and SFU Period (SS)		Padsevonil 400mg BID Taper and SFU Period (SS)
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/83 (0.00%)		0/81 (0.00%)		0/83 (0.00%)		0/82 (0.00%)		0/81 (0.00%)		0/69 (0.00%)		0/64 (0.00%)		0/66 (0.00%)		0/55 (0.00%)		0/57 (0.00%)		0/9 (0.00%)		0/14 (0.00%)		0/11 (0.00%)		0/24 (0.00%)		0/22 (0.00%)
Serious Adverse Events
	Placebo Treatment Period (SS)		Padsevonil 50mg BID Treatment Period (SS)		Padsevonil 100mg BID Treatment Period (SS)		Padsevonil 200mg BID Treatment Period (SS)		Padsevonil 400mg BID Treatment Period (SS)		Placebo Conversion Period (SS)		Padsevonil 50mg BID Conversion Period (SS)		Padsevonil 100mg BID Conversion Period (SS)		Padsevonil 200mg BID Conversion Period (SS)		Padsevonil 400mg BID Conversion Period (SS)		Placebo Taper and SFU Period (SS)		Padsevonil 50mg BID Taper and SFU Period (SS)		Padsevonil 100mg BID Taper and SFU Period (SS)		Padsevonil 200mg BID Taper and SFU Period (SS)		Padsevonil 400mg BID Taper and SFU Period (SS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/83 (3.61%)		5/81 (6.17%)		4/83 (4.82%)		3/82 (3.66%)		5/81 (6.17%)		0/69 (0.00%)		0/64 (0.00%)		0/66 (0.00%)		2/55 (3.64%)		0/57 (0.00%)		1/9 (11.11%)		1/14 (7.14%)		0/11 (0.00%)		0/24 (0.00%)		0/22 (0.00%)
Cardiac disorders
Atrial flutter * 1	0/83 (0.00%)	0	1/81 (1.23%)	1	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Infections and infestations
Diverticulitis * 1	0/83 (0.00%)	0	1/81 (1.23%)	1	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Injury, poisoning and procedural complications
Concussion * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	1/83 (1.20%)	1	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Fall * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	1/82 (1.22%)	1	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Head injury * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	1/83 (1.20%)	1	0/82 (0.00%)	0	1/81 (1.23%)	1	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	1/14 (7.14%)	1	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Toxicity to various agents * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	1/82 (1.22%)	1	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Traumatic haemothorax * 1	1/83 (1.20%)	1	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Metabolism and nutrition disorders
Hyperkalaemia * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	1/83 (1.20%)	1	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Nervous system disorders
Altered state of consciousness * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	1/81 (1.23%)	1	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Encephalopathy * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	1/81 (1.23%)	1	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Focal dyscognitive seizures * 1	0/83 (0.00%)	0	1/81 (1.23%)	1	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Partial seizures * 1	0/83 (0.00%)	0	1/81 (1.23%)	1	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Seizure cluster * 1	1/83 (1.20%)	1	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Status epilepticus * 1	1/83 (1.20%)	1	1/81 (1.23%)	1	1/83 (1.20%)	1	1/82 (1.22%)	1	1/81 (1.23%)	1	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	1/55 (1.82%)	1	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Syncope * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	1/81 (1.23%)	1	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Psychiatric disorders
Depression * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	1/55 (1.82%)	1	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Acute psychosis * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	1/9 (11.11%)	1	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Renal and urinary disorders
Renal disorder * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	1/83 (1.20%)	1	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	1/83 (1.20%)	1	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Surgical and medical procedures
Medical device battery replacement * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	1/83 (1.20%)	1	0/82 (0.00%)	0	1/81 (1.23%)	1	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
1 Term from vocabulary, MedDRA22.1; * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo Treatment Period (SS)		Padsevonil 50mg BID Treatment Period (SS)		Padsevonil 100mg BID Treatment Period (SS)		Padsevonil 200mg BID Treatment Period (SS)		Padsevonil 400mg BID Treatment Period (SS)		Placebo Conversion Period (SS)		Padsevonil 50mg BID Conversion Period (SS)		Padsevonil 100mg BID Conversion Period (SS)		Padsevonil 200mg BID Conversion Period (SS)		Padsevonil 400mg BID Conversion Period (SS)		Placebo Taper and SFU Period (SS)		Padsevonil 50mg BID Taper and SFU Period (SS)		Padsevonil 100mg BID Taper and SFU Period (SS)		Padsevonil 200mg BID Taper and SFU Period (SS)		Padsevonil 400mg BID Taper and SFU Period (SS)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/83 (54.22%)		54/81 (66.67%)		60/83 (72.29%)		53/82 (64.63%)		65/81 (80.25%)		11/69 (15.94%)		18/64 (28.13%)		10/66 (15.15%)		5/55 (9.09%)		5/57 (8.77%)		3/9 (33.33%)		3/14 (21.43%)		0/11 (0.00%)		3/24 (12.50%)		4/22 (18.18%)
Ear and labyrinth disorders
Vertigo * 1	7/83 (8.43%)	7	3/81 (3.70%)	3	2/83 (2.41%)	2	3/82 (3.66%)	3	4/81 (4.94%)	5	1/69 (1.45%)	1	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Gastrointestinal disorders
Nausea * 1	7/83 (8.43%)	7	4/81 (4.94%)	4	7/83 (8.43%)	7	2/82 (2.44%)	3	7/81 (8.64%)	13	1/69 (1.45%)	1	0/64 (0.00%)	0	1/66 (1.52%)	1	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Diarrhoea * 1	3/83 (3.61%)	3	6/81 (7.41%)	8	3/83 (3.61%)	4	5/82 (6.10%)	7	4/81 (4.94%)	5	1/69 (1.45%)	1	1/64 (1.56%)	1	1/66 (1.52%)	1	0/55 (0.00%)	0	1/57 (1.75%)	1	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	1/24 (4.17%)	1	0/22 (0.00%)	0
General disorders
Fatigue * 1	10/83 (12.05%)	10	20/81 (24.69%)	27	12/83 (14.46%)	17	14/82 (17.07%)	22	20/81 (24.69%)	21	3/69 (4.35%)	3	5/64 (7.81%)	5	2/66 (3.03%)	2	1/55 (1.82%)	1	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	1/24 (4.17%)	2	0/22 (0.00%)	0
Gait disturbance * 1	1/83 (1.20%)	1	2/81 (2.47%)	2	0/83 (0.00%)	0	1/82 (1.22%)	1	5/81 (6.17%)	5	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Infections and infestations
Nasopharyngitis * 1	5/83 (6.02%)	5	5/81 (6.17%)	5	9/83 (10.84%)	13	7/82 (8.54%)	11	5/81 (6.17%)	5	1/69 (1.45%)	1	1/64 (1.56%)	1	0/66 (0.00%)	0	1/55 (1.82%)	1	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Upper respiratory tract infection * 1	1/83 (1.20%)	3	5/81 (6.17%)	5	0/83 (0.00%)	0	0/82 (0.00%)	0	2/81 (2.47%)	3	0/69 (0.00%)	0	1/64 (1.56%)	1	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	1/14 (7.14%)	1	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Urinary tract infection * 1	2/83 (2.41%)	2	1/81 (1.23%)	1	1/83 (1.20%)	1	0/82 (0.00%)	0	2/81 (2.47%)	2	1/69 (1.45%)	1	0/64 (0.00%)	0	1/66 (1.52%)	1	0/55 (0.00%)	0	0/57 (0.00%)	0	1/9 (11.11%)	1	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	1/22 (4.55%)	1
Injury, poisoning and procedural complications
Fall * 1	4/83 (4.82%)	4	2/81 (2.47%)	2	1/83 (1.20%)	1	1/82 (1.22%)	2	7/81 (8.64%)	7	0/69 (0.00%)	0	0/64 (0.00%)	0	1/66 (1.52%)	2	1/55 (1.82%)	1	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Ligament sprain * 1	0/83 (0.00%)	0	2/81 (2.47%)	2	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	2/64 (3.13%)	2	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	1/9 (11.11%)	1	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Burns second degree * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	1/14 (7.14%)	1	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Investigations
Platelet count decreased * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	1/83 (1.20%)	1	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	1/9 (11.11%)	1	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Anticonvulsant drug level increased * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	1/9 (11.11%)	1	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Musculoskeletal and connective tissue disorders
Back pain * 1	0/83 (0.00%)	0	1/81 (1.23%)	1	2/83 (2.41%)	2	2/82 (2.44%)	2	5/81 (6.17%)	5	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	1/9 (11.11%)	1	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Nervous system disorders
Dizziness * 1	9/83 (10.84%)	9	18/81 (22.22%)	19	23/83 (27.71%)	31	19/82 (23.17%)	25	28/81 (34.57%)	55	3/69 (4.35%)	3	2/64 (3.13%)	2	1/66 (1.52%)	1	2/55 (3.64%)	2	2/57 (3.51%)	6	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	1/24 (4.17%)	1	1/22 (4.55%)	1
Somnolence * 1	10/83 (12.05%)	11	19/81 (23.46%)	24	24/83 (28.92%)	29	25/82 (30.49%)	26	30/81 (37.04%)	35	1/69 (1.45%)	1	4/64 (6.25%)	5	1/66 (1.52%)	1	1/55 (1.82%)	1	2/57 (3.51%)	2	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Headache * 1	10/83 (12.05%)	14	17/81 (20.99%)	29	9/83 (10.84%)	16	15/82 (18.29%)	21	9/81 (11.11%)	31	0/69 (0.00%)	0	3/64 (4.69%)	3	2/66 (3.03%)	3	0/55 (0.00%)	0	1/57 (1.75%)	5	1/9 (11.11%)	1	0/14 (0.00%)	0	0/11 (0.00%)	0	2/24 (8.33%)	2	1/22 (4.55%)	1
Memory impairment * 1	1/83 (1.20%)	1	3/81 (3.70%)	3	1/83 (1.20%)	1	8/82 (9.76%)	9	14/81 (17.28%)	14	1/69 (1.45%)	1	0/64 (0.00%)	0	1/66 (1.52%)	1	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	1/22 (4.55%)	1
Tremor * 1	0/83 (0.00%)	0	5/81 (6.17%)	5	2/83 (2.41%)	2	6/82 (7.32%)	6	5/81 (6.17%)	5	1/69 (1.45%)	1	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Balance disorder * 1	1/83 (1.20%)	2	3/81 (3.70%)	3	3/83 (3.61%)	3	5/82 (6.10%)	5	3/81 (3.70%)	3	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Nystagmus * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	1/69 (1.45%)	1	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	1/14 (7.14%)	1	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Psychiatric disorders
Irritability * 1	8/83 (9.64%)	8	4/81 (4.94%)	4	7/83 (8.43%)	7	1/82 (1.22%)	1	5/81 (6.17%)	6	0/69 (0.00%)	0	1/64 (1.56%)	1	1/66 (1.52%)	1	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	1/22 (4.55%)	1
Anxiety * 1	3/83 (3.61%)	3	1/81 (1.23%)	1	1/83 (1.20%)	2	7/82 (8.54%)	9	0/81 (0.00%)	0	1/69 (1.45%)	1	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	0/14 (0.00%)	0	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
Paranoia * 1	0/83 (0.00%)	0	0/81 (0.00%)	0	0/83 (0.00%)	0	0/82 (0.00%)	0	0/81 (0.00%)	0	0/69 (0.00%)	0	0/64 (0.00%)	0	0/66 (0.00%)	0	0/55 (0.00%)	0	0/57 (0.00%)	0	0/9 (0.00%)	0	1/14 (7.14%)	1	0/11 (0.00%)	0	0/24 (0.00%)	0	0/22 (0.00%)	0
1 Term from vocabulary, MedDRA22.1; * Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: UCB
• Organization: Cares
• Phone: +1844 599 ext 2273
• EMail: UCBCares@ucb.com

Publications of Results:

Rademacher M, Toledo M, Van Paesschen W, Liow KK, Milanov IG, Esch ML, Wang N, MacPherson M, Byrnes WJ, Minh TDC, Webster E, Werhahn KJ. Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials. Epilepsia Open. 2022 Dec;7(4):758-770. doi: 10.1002/epi4.12656. Epub 2022 Oct 22.

• Responsible Party: UCB Pharma ( UCB Biopharma S.P.R.L. )
• ClinicalTrials.gov Identifier: NCT03373383
• Other Study ID Numbers: EP0091; 2017-003200-48 ( EudraCT Number )
• First Submitted: December 7, 2017
• First Posted: December 14, 2017
• Results First Submitted: January 28, 2021
• Results First Posted: April 9, 2021
• Last Update Posted: December 21, 2022