Study to Test the Safety and Efficacy of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adult Subjects With Drug-resistant Epilepsy

• Sponsor: UCB Biopharma SRL (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT03370120
• Collaborator: (none)
• Enrollment: 406
• Locations: 156
• Arm: 1
• Actual Duration (Months): 27.5
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the long-term safety and tolerability of Padsevonil administered at individualized doses as adjunctive treatment for subjects with drug-resistant epilepsy.

Condition or Disease	Intervention/Treatment	Phase
Drug-Resistant Epilepsy; Focal-Onset Seizures	Drug: Padsevonil	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 406 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter, Extension Study to Evaluate the Safety and Efficacy of Padsevonil as Adjunctive Treatment of Focal-Onset Seizures in Adult Subjects With Drug-Resistant Epilepsy
• Actual Study Start Date: Aug 27, 2018
• Actual Primary Completion Date: Dec 11, 2020
• Actual Study Completion Date: Dec 11, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Padsevonil Padsevonil will be administered in an open-label manner. The individual starting dose of each subject will be the one at the end of the parent study. Once subjects enter EP0093 further individual dose adjustments are allowed after 1 week to the extent possible with the combination of tablet strengths available.	Drug: Padsevonil; Pharmaceutical Form: film-coated tablet Route of Administration: Oral use

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Reported by the Participant and/or Caregiver or Observed by the Investigator During the Entire Study [From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)]

   An Adverse Event is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment.

2. Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal [From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)]

   An Adverse Event is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment.

3. Change From Baseline (From the Respective Parent Study [EP0091 or EP0092]) in Observable Focal-onset Seizure Frequency Over the Evaluation Period [From Baseline in respective parent study over the Evaluation Period (up to approximately 2 years) in this study]

   Seizure frequency refers to 28-day adjusted frequency. Observable focal-onset seizures refer to Type IAl, IB, and IC (according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures, 1981). Focal-onset seizures include all Type I seizures.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject is an adult (18 years of age or more )

• Subject with epilepsy who has completed 1 of the previous Padsevonil (PSL) studies which allow access to the present study

• Female subjects of child bearing potential must have a serum negative pregnancy test at the Entry Visit, which is confirmed to be negative by urine testing prior to further dispensing at each study visit thereafter. Subjects will be withdrawn from the study as soon as pregnancy is known. Female subjects will use an efficient form of contraception for the duration of the study and for a period of 3 months after their final dose of PSL.

Exclusion Criteria:

• Subject has any severe medical, neurological, or psychiatric condition, or laboratory value which may have an impact on the safety of the subject

• Subject has active suicidal ideation as indicated by a positive response ('Yes') to either Question 4 or Question 5 of the 'Since Last Visit' version of the Columbia-Suicide Severity Rating Scale (C-SSRS)

• Subject has >2x upper limit of normal (ULN) of any of the following: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), or >ULN total bilirubin (>= l.5x ULN total bilirubin if known Gilbert's syndrome) at the Entry Visit

• Subject has a clinically-significant abnormality on electrocardiogram (ECG) that, in the opinion of the investigator, increases the risks associated with participating in the study

• Subject has an abnormality on echocardiogram at last echocardiogram assessment, or foreseen in parent study as assessed by central reader that is accompanied by clinical symptoms or a Grade 2* (or higher)/moderate severity abnormality, or a history of rheumatic heart disease, or other known valvular abnormalities (*according to the ASE Guidelines, 2017; Zoghbi et al 2017)

• Female subject who plans to be pregnant or is breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ep0093 839	Chandler	Arizona	United States	85226
2	Ep0093 815	La Jolla	California	United States	92037
3	Ep0093 801	San Francisco	California	United States	94115
4	Ep0093 803	Honolulu	Hawaii	United States	96817
5	Ep0093 638	Fort Wayne	Indiana	United States	46804
6	Ep0093 707	Lexington	Kentucky	United States	40536
7	Ep0093 822	Baltimore	Maryland	United States	21287
8	Ep0093 818	Bethesda	Maryland	United States	20817
9	Ep0093 889	Boston	Massachusetts	United States	02215
10	Ep0093 645	Golden Valley	Minnesota	United States	55422
11	Ep0093 817	Saint Paul	Minnesota	United States	55102
12	Ep0093 806	Hackensack	New Jersey	United States	07601
13	Ep0093 895	Bronx	New York	United States	10467-24 01
14	Ep0093 893	Syracuse	New York	United States	13210
15	Ep0093 890	Chapel Hill	North Carolina	United States	27514
16	Ep0093 884	Charlotte	North Carolina	United States	28204
17	Ep0093 642	Columbia	Ohio	United States	43210
18	Ep0093 802	Philadelphia	Pennsylvania	United States	19107
19	Ep0093 838	Cordova	Tennessee	United States	38018
20	Ep0093 835	Nashville	Tennessee	United States	37232
21	Ep0093 805	Austin	Texas	United States	78701
22	Ep0093 844	Austin	Texas	United States	78758
23	Ep0093 824	Round Rock	Texas	United States	78681
24	Ep0093 870	San Antonio	Texas	United States	78229
25	Ep0093 639	Renton	Washington	United States	98055
26	Ep0093 855	Box Hill		Australia
27	Ep0093 857	Clayton		Australia
28	Ep0093 850	Fitzroy		Australia
29	Ep0093 853	Heidelberg		Australia
30	Ep0093 859	Herston		Australia
31	Ep0093 852	Melbourne		Australia
32	Ep0093 856	Randwick		Australia
33	Ep0093 854	Westmead		Australia
34	Ep0093 102	Brugge		Belgium
35	Ep0093 101	Brussels		Belgium
36	Ep0093 105	Gent		Belgium
37	Ep0093 100	Leuven		Belgium
38	Ep0093 107	Ottignies		Belgium
39	Ep0093 075	Sarajevo		Bosnia and Herzegovina
40	Ep0093 082	Tuzla		Bosnia and Herzegovina
41	Ep0093 150	Blagoevgrad		Bulgaria
42	Ep0093 151	Pleven		Bulgaria
43	Ep0093 153	Pleven		Bulgaria
44	Ep0093 156	Pleven		Bulgaria
45	Ep0093 152	Sofia		Bulgaria
46	Ep0093 154	Sofia		Bulgaria
47	Ep0093 155	Sofia		Bulgaria
48	Ep0093 200	Greenfield Park		Canada
49	Ep0093 205	London		Canada
50	Ep0093 201	Montréal		Canada
51	Ep0093 125	Zagreb		Croatia
52	Ep0093 254	Brno		Czechia
53	Ep0093 255	Ostrava		Czechia
54	Ep0093 251	Praha 6		Czechia
55	Ep0093 250	Praha		Czechia
56	Ep0093 253	Praha		Czechia
57	Ep0093 016	Aarhus		Denmark
58	Ep0093 015	Odense		Denmark
59	Ep0093 277	Tallinn		Estonia
60	Ep0093 276	Tallin		Estonia
61	Ep0093 275	Tartu		Estonia
62	Ep0093 027	Tampere		Finland
63	Ep0093 307	Clermont-Ferrand		France
64	Ep0093 309	Dijon		France
65	Ep0093 300	Lille		France
66	Ep0093 302	Montpellier		France
67	Ep0093 303	Rennes		France
68	Ep0093 301	Strasbourg		France
69	Ep0093 365	Berlin		Germany
70	Ep0093 362	Bernau		Germany
71	Ep0093 363	Bielefeld		Germany
72	Ep0093 358	Bonn		Germany
73	Ep0093 350	Frankfurt		Germany
74	Ep0093 360	Freiburg		Germany
75	Ep0093 368	Jena		Germany
76	Ep0093 366	Kehl		Germany
77	Ep0093 357	Leipzig		Germany
78	Ep0093 353	Marburg		Germany
79	Ep0093 354	München		Germany
80	Ep0093 351	Münster		Germany
81	Ep0093 356	Osnabrück		Germany
82	Ep0093 352	Tübingen		Germany
83	Ep0093 426	Thessaloníki		Greece
84	Ep0093 427	Thessaloníki		Greece
85	Ep0093 400	Budapest		Hungary
86	Ep0093 403	Budapest		Hungary
87	Ep0093 402	Debrecen		Hungary
88	Ep0093 035	Cork		Ireland
89	Ep0093 462	Bologna		Italy
90	Ep0093 450	Cagliari		Italy
91	Ep0093 451	Foggia		Italy
92	Ep0093 461	Foggia		Italy
93	Ep0093 452	Milano		Italy
94	Ep0093 459	Pavia		Italy
95	Ep0093 458	Pozzilli		Italy
96	Ep0093 455	Roma		Italy
97	Ep0093 457	Roma		Italy
98	Ep0093 460	Roma		Italy
99	Ep0093 526	Asahikawa		Japan
100	Ep0093 501	Asaka		Japan
101	Ep0093 521	Bunkyō-Ku		Japan
102	Ep0093 511	Fukuoka		Japan
103	Ep0093 504	Hamamatsu		Japan
104	Ep0093 505	Hiroshima		Japan
105	Ep0093 513	Hōfu		Japan
106	Ep0093 507	Itami		Japan
107	Ep0093 514	Kyoto		Japan
108	Ep0093 512	Nagakute		Japan
109	Ep0093 510	Niigata		Japan
110	Ep0093 515	Saitama		Japan
111	Ep0093 509	Shizuoka		Japan
112	Ep0093 529	Yonago		Japan
113	Ep0093 703	Kaunas		Lithuania
114	Ep0093 702	Vilnius		Lithuania
115	Ep0093 553	Culiacán		Mexico
116	Ep0093 552	Mexico		Mexico
117	Ep0093 601	Gdańsk		Poland
118	Ep0093 607	Grodzisk Mazowiecki		Poland
119	Ep0093 605	Katowice		Poland
120	Ep0093 616	Katowice		Poland
121	Ep0093 603	Kraków		Poland
122	Ep0093 614	Kraków		Poland
123	Ep0093 604	Lublin		Poland
124	Ep0093 610	Lublin		Poland
125	Ep0093 606	Nowa Sól		Poland
126	Ep0093 600	Poznań		Poland
127	Ep0093 609	Poznań		Poland
128	Ep0093 602	Świdnik		Poland
129	Ep0093 926	Bucuresti		Romania
130	Ep0093 327	Belgrade		Serbia
131	Ep0093 004	Bardejov		Slovakia
132	Ep0093 662	Alicante		Spain
133	Ep0093 668	Barakaldo		Spain
134	Ep0093 651	Barcelona		Spain
135	Ep0093 652	Barcelona		Spain
136	Ep0093 664	Barcelona		Spain
137	Ep0093 666	Córdoba		Spain
138	Ep0093 658	Hospitalet de Llobregat		Spain
139	Ep0093 656	Madrid		Spain
140	Ep0093 660	Madrid		Spain
141	Ep0093 667	Madrid		Spain
142	Ep0093 674	Madrid		Spain
143	Ep0093 659	Málaga		Spain
144	Ep0093 665	Terrassa		Spain
145	Ep0093 657	Valencia		Spain
146	Ep0093 653	Valladolid		Spain
147	Ep0093 900	Istanbul		Turkey
148	Ep0093 901	Istanbul		Turkey
149	Ep0093 904	Istanbul		Turkey
150	Ep0093 906	Istanbul		Turkey
151	Ep0093 909	Istanbul		Turkey
152	Ep0093 752	Birmingham		United Kingdom
153	Ep0093 766	Brighton		United Kingdom
154	Ep0093 751	Swansea		United Kingdom
155	Ep0093 753	Swansea		United Kingdom
156	Ep0093 764	Swansea		United Kingdom

Sponsors and Collaborators

• UCB Biopharma SRL

Investigators

• Study Director: UCB Cares, 001 844 599 2273 (UCB)

Study Documents (Full-Text)

• Study Protocol - Feb 4, 2020
• Statistical Analysis Plan - Sep 25, 2020

More Information

Publications

None provided.

• Responsible Party: UCB Biopharma SRL
• ClinicalTrials.gov Identifier: NCT03370120
• Other Study ID Numbers: EP0093; 2017-003241-26
• First Posted: Dec 12, 2017
• Last Update Posted: Dec 29, 2021
• Last Verified: Nov 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by UCB Biopharma SRL: Drug-Resistant Epilepsy; Padsevonil
• Additional relevant MeSH terms: Epilepsy; Seizures; Drug Resistant Epilepsy

Study Results

Participant Flow

Recruitment Details	The study started to enroll study participants in August 2018 and concluded in December 2020.
Pre-assignment Detail	Participant Flow refers to the Safety Set. Participants who had completed a padsevonil (PSL) parent study (EP0091 [NCT03373383] or EP0092 [NCT03739840]) were enrolled in this study.

Arm/Group Title	Padsevonil
Arm/Group Description	Participants received padsevonil tablets at a dose of 100 milligrams/day (mg/day) to 800 mg/day up to approximately 2 years.
Period Title: Overall Study
STARTED	406
COMPLETED	0
NOT COMPLETED	406

Baseline Characteristics

Arm/Group Title	Padsevonil
Arm/Group Description	Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years.
Overall Participants	406
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	395 97.3%
>=65 years	11 2.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.8 (12.5)
Sex: Female, Male (Count of Participants)
Female	231 56.9%
Male	175 43.1%
Race/Ethnicity, Customized (Count of Participants)
American Indian / Alaskan native	5 1.2%
Asian	38 9.4%
Black	6 1.5%
Native Hawaiian or other Pacific Islander	5 1.2%
White	343 84.5%
Other/mixed	9 2.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Reported by the Participant and/or Caregiver or Observed by the Investigator During the Entire Study
Description	An Adverse Event is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment.
Time Frame	From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)

Outcome Measure Data

Analysis Population Description

The Safety Set (SS) consisted of all enrolled participants who were administered at least 1 dose of PSL, based on the first dose date from the first administration of study medication CRF.

Arm/Group Title	Padsevonil (SS)
Arm/Group Description	Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years. Participants formed the Safety Set (SS).
Measure Participants	406
Number [percentage of participants]	72.2 17.8%

2. 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 participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment.
Time Frame	From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)

Outcome Measure Data

Analysis Population Description

The SS consisted of all enrolled participants who were administered at least 1 dose of PSL, based on the first dose date from the first administration of study medication CRF.

Arm/Group Title	Padsevonil (SS)
Arm/Group Description	Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years. Participants formed the SS.
Measure Participants	406
Number [percentage of participants]	5.2 1.3%

3. Primary Outcome

Title	Change From Baseline (From the Respective Parent Study [EP0091 or EP0092]) in Observable Focal-onset Seizure Frequency Over the Evaluation Period
Description	Seizure frequency refers to 28-day adjusted frequency. Observable focal-onset seizures refer to Type IAl, IB, and IC (according to the International League Against Epilepsy (ILAE) Classification of Epileptic Seizures, 1981). Focal-onset seizures include all Type I seizures.
Time Frame	From Baseline in respective parent study over the Evaluation Period (up to approximately 2 years) in this study

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all enrolled participants who were administered at least 1 dose of PSL or a partial dose of PSL and completed at least 1 seizure diary during the Evaluation Period.

Arm/Group Title	Padsevonil (FAS)
Arm/Group Description	Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years. Participants formed the FAS.
Measure Participants	406
Mean (Standard Deviation) [seizures per 28 days]	-7.73 (27.52)

Adverse Events

Time Frame	From Entry Visit (Week 0) until the Safety Follow-up Visit (up to approximately 2 years)
Adverse Event Reporting Description	A TEAE was defined as any event that was not present prior to the initiation of the first dose of study treatment in this study or any unresolved event already present before initiation of the first dose that worsens in intensity following exposure to the treatment.
Arm/Group Title	Padsevonil (SS)
Arm/Group Description	Participants received PSL tablets at a dose of 100 mg/day to 800 mg/day up to approximately 2 years. Participants formed the SS.
All Cause Mortality
	Padsevonil (SS)
	Affected / at Risk (%)	# Events
Total	0/406 (0%)
Serious Adverse Events
	Padsevonil (SS)
	Affected / at Risk (%)	# Events
Total	48/406 (11.8%)
Endocrine disorders
Inappropriate antidiuretic hormone secretion	1/406 (0.2%)	1
Gastrointestinal disorders
Abdominal discomfort	1/406 (0.2%)	1
Large intestinal haemorrhage	1/406 (0.2%)	1
Nausea	1/406 (0.2%)	1
Vomiting	1/406 (0.2%)	1
Hepatobiliary disorders
Bile duct stone	1/406 (0.2%)	1
Cholecystitis	1/406 (0.2%)	1
Cholelithiasis	1/406 (0.2%)	1
Infections and infestations
Corona virus infection	1/406 (0.2%)	1
Cytomegalovirus infection	1/406 (0.2%)	1
Gastroenteritis viral	1/406 (0.2%)	1
Pneumonia	1/406 (0.2%)	1
Wound infection	1/406 (0.2%)	1
Injury, poisoning and procedural complications
Head injury	1/406 (0.2%)	1
Ulna fracture	1/406 (0.2%)	1
Investigations
Mycoplasma test positive	1/406 (0.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Ovarian cancer	1/406 (0.2%)	1
Phyllodes tumour	1/406 (0.2%)	1
Nervous system disorders
Cervical radiculopathy	1/406 (0.2%)	1
Epilepsy	7/406 (1.7%)	8
Focal dyscognitive seizures	2/406 (0.5%)	2
Generalised tonic-clonic seizure	5/406 (1.2%)	8
Migraine	1/406 (0.2%)	1
Partial seizures	1/406 (0.2%)	1
Partial seizures with secondary generalisation	2/406 (0.5%)	3
Postictal state	1/406 (0.2%)	1
Seizure	4/406 (1%)	4
Seizure cluster	2/406 (0.5%)	2
Status epilepticus	5/406 (1.2%)	5
Syncope	1/406 (0.2%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/406 (0.2%)	1
Pregnancy	1/406 (0.2%)	1
Psychiatric disorders
Aggression	1/406 (0.2%)	1
Suicide Attempt	1/406 (0.2%)	1
Renal and urinary disorders
Acute kidney injury	1/406 (0.2%)	1
Pelvi-ureteric obstruction	1/406 (0.2%)	1
Respiratory, thoracic and mediastinal disorders
Aspiration	1/406 (0.2%)	1
Skin and subcutaneous tissue disorders
Drug Eruption	1/406 (0.2%)	1
Drug reaction with eosinophilia and systemic symptoms	2/406 (0.5%)	2
Surgical and medical procedures
Hip arthroplasty	1/406 (0.2%)	1
Vagal nerve stimulator implantation	1/406 (0.2%)	1
Vascular disorders
Hypotension	1/406 (0.2%)	1
Other (Not Including Serious) Adverse Events
	Padsevonil (SS)
	Affected / at Risk (%)	# Events
Total	184/406 (45.3%)
General disorders
Fatigue	47/406 (11.6%)	56
Infections and infestations
Nasopharyngitis	29/406 (7.1%)	42
Nervous system disorders
Somnolence	66/406 (16.3%)	76
Headache	59/406 (14.5%)	138
Dizziness	43/406 (10.6%)	63
Memory impairment	21/406 (5.2%)	38
Psychiatric disorders
Insomnia	23/406 (5.7%)	27

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.