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

Drug-resistant Epilepsy Clinical Trial

— ARISE  

Official title:

A Randomized, Double-Blind, Placebo-Controlled, Dose Finding Study to Evaluate the Efficacy and Safety of Padsevonil as Adjunctive Treatment of Focal-Onset Seizures in Adult Subjects With Drug-Resistant Epilepsy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03373383
• Other study ID #: EP0091
• Secondary ID: 2017-003200-48
• Status: Completed
• Phase: Phase 2
• Start date: February 12, 2018
• Est. completion date: January 30, 2020

Study information

• Verified date: December 2023
• Source: UCB Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study is to characterize the dose-response relationship with respect to efficacy of Padsevonil administered concomitantly with up to 3 anti-epileptic drugs (AEDs) for treatment of observable focal-onset seizures in subjects with drug-resistant epilepsy.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 411
• Est. completion date: January 30, 2020
• Est. primary completion date: January 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Diagnosis of focal epilepsy per 1989 International League Against Epilepsy (ILAE) criteria at least 3 years before study entry

• Subject has failed to achieve seizure control with 4 tolerated and appropriately chosen prior antiepileptic drugs (AED), including past and ongoing treatment, that were individually optimized for adequate dose and duration. Prior discontinued AED treatment would need to be assessed by the Investigator considering the patient medical records and patient and/or caregiver interview. 'Prior AED' is defined as all past and ongoing AED treatments with a start date before the Screening Visit (Visit 1)

• Average of >= 4 spontaneous and observable focal seizures (type IA1 (i.e. focal aware), IB (i.e. focal impaired awareness), IC (i.e. focal to bilateral tonic-clonic)) per month

• Current treatment with an individually optimized and stable dose of at least 1 and up to 3 AEDs for the 8 weeks prior to the Screening Visit with or without additional Vagus Nerve Stimulation (VNS) or other neurostimulation treatments

Exclusion Criteria:

• Subject has a history of or signs of generalized or combined generalized and focal epilepsy

• Cluster seizures which are uncountable in the previous 8 weeks before study entry and during 4 weeks prospective baseline

• Current treatment with carbamazepine, phenytoin, primidone, phenobarbital

• Current treatment/ use of (non-AED) prescription, nonprescription, dietary (eg, grapefruit or passion fruit), or herbal products that are potent inducers or inhibitors of the CYP3A4 or 2C19 pathway for 2 weeks (or 5 half-lives, whichever is longer) prior to the Baseline Visit

• Subjects taking sensitive substrates of CYP2C19 for 2 weeks (or 5 half-lives, whichever is longer) prior to the Baseline Visit

• Subject has been taking vigabatrin less than 2 years at study entry

• Subject has been taking felbamate for less than 12 months

• Subject taking retigabine for less than 4 years

• Current treatment with benzodiazepines (i.e. GABA-A-ergic drugs like zolpidem, zaleplon, or zopiclone, excluding GABA-A-ergic AEDs) <3 times per week for emergencies

• Subject has a current medical condition that occurred within the last 12 months which, in the opinion of the investigator, could compromise his/her safety or ability to participate in this study

Related Conditions & MeSH terms

• Drug Resistant Epilepsy
• Drug-resistant Epilepsy
• Epilepsy
• Focal-Onset Seizures
• Seizures

Intervention

Drug:
• Padsevonil
Padsevonil in different dosages.

Other:
• Placebo
Placebo will be provided matching Padsevonil.

Locations

Country	Name	City	State
Australia	Ep0091 855	Box Hill
Australia	Ep0091 857	Clayton
Australia	Ep0091 850	Fitzroy
Australia	Ep0091 859	Herston
Australia	Ep0091 852	Melbourne
Australia	Ep0091 853	Melbourne
Australia	Ep0091 856	Randwick
Australia	Ep0091 854	Westmead
Belgium	Ep0091 102	Brugge
Belgium	Ep0091 101	Brussels
Belgium	Ep0091 105	Gent
Belgium	Ep0091 100	Leuven
Bulgaria	Ep0091 150	Blagoevgrad
Bulgaria	Ep0091 151	Pleven
Bulgaria	Ep0091 153	Pleven
Bulgaria	Ep0091 152	Sofia
Bulgaria	Ep0091 154	Sofia
Bulgaria	Ep0091 155	Sofia
Canada	Ep0091 200	Greenfield Park
Canada	Ep0091 205	London
Canada	Ep0091 201	Montréal
Czechia	Ep0091 254	Brno
Czechia	Ep0091 255	Ostrava-Poruba
Czechia	Ep0091 251	Praha
Czechia	Ep0091 252	Praha 4
Czechia	Ep0091 250	Praha 5
Czechia	Ep0091 253	Praha 8
France	Ep0091 307	Clermont-Ferrand Cedex 1
France	Ep0091 309	Dijon
France	Ep0091 300	Lille
France	Ep0091 302	Montpellier
France	Ep0091 305	Paris
France	Ep0091 303	Rennes
France	Ep0091 306	Toulouse Cedex 9
Germany	Ep0091 361	Bad Neustadt An Der Saale
Germany	Ep0091 365	Berlin
Germany	Ep0091 362	Bernau
Germany	Ep0091 363	Bielefeld
Germany	Ep0091 358	Bonn
Germany	Ep0091 350	Frankfurt am main
Germany	Ep0091 360	Freiburg
Germany	Ep0091 364	Hamburg
Germany	Ep0091 368	Jena
Germany	Ep0091 366	Kork
Germany	Ep0091 357	Leipzig
Germany	Ep0091 353	Marburg
Germany	Ep0091 354	München
Germany	Ep0091 351	Münster
Germany	Ep0091 356	Osnabrück
Germany	Ep0091 367	Ravensburg
Germany	Ep0091 301	Strausberg
Germany	Ep0091 352	Tübingen
Hungary	Ep0091 400	Budapest
Hungary	Ep0091 403	Budapest
Hungary	Ep0091 402	Debrecen
Italy	Ep0091 462	Bologna
Italy	Ep0091 450	Cagliari
Italy	Ep0091 461	Foggia
Italy	Ep0091 452	Milano
Italy	Ep0091 459	Pavia
Italy	Ep0091 453	Perugia
Italy	Ep0091 458	Pozzilli
Italy	Ep0091 454	Reggio Calabria
Italy	Ep0091 455	Roma
Italy	Ep0091 457	Roma
Italy	Ep0091 460	Roma
Japan	Ep0091 501	Asaka
Japan	Ep0091 511	Fukuoka
Japan	Ep0091 505	Hiroshima
Japan	Ep0091 513	Hofu
Japan	Ep0091 507	Itami
Japan	Ep0091 503	Kodaira
Japan	Ep0091 514	Kyoto
Japan	Ep0091 512	Nagakute
Japan	Ep0091 510	Niigata
Japan	Ep0091 515	Saitama
Japan	Ep0091 509	Shizuoka
Lithuania	Ep0091 703	Kaunas
Lithuania	Ep0091 701	Vilnius
Lithuania	Ep0091 702	Vilnius
Mexico	Ep0091 553	Culiacán
Mexico	Ep0091 552	Mexico Distrito Federal
Poland	Ep0091 601	Gdansk
Poland	Ep0091 607	Grodzisk Mazowiecki
Poland	Ep0091 605	Katowice
Poland	Ep0091 608	Katowice
Poland	Ep0091 603	Kraków
Poland	Ep0091 604	Lublin
Poland	Ep0091 606	Nowa Sól
Poland	Ep0091 600	Poznan
Poland	Ep0091 609	Poznan
Poland	Ep0091 602	Swidnik
Portugal	Ep0091 952	Santa Maria Da Feira
Slovakia	Ep0091 004	Bardejov
Slovakia	Ep0091 001	Hlohovec
Spain	Ep0091 662	Alicante
Spain	Ep0091 651	Barcelona
Spain	Ep0091 652	Barcelona
Spain	Ep0091 658	Barcelona
Spain	Ep0091 664	Barcelona
Spain	Ep0091 668	Bilbao
Spain	Ep0091 666	Córdoba
Spain	Ep0091 650	Madrid
Spain	Ep0091 656	Madrid
Spain	Ep0091 660	Madrid
Spain	Ep0091 661	Madrid
Spain	Ep0091 659	Málaga
Spain	Ep0091 663	Sevilla
Spain	Ep0091 665	Terrassa
Spain	Ep0091 657	Valencia
Spain	Ep0091 667	Valencia
Spain	Ep0091 653	Valladolid
Turkey	Ep0091 904	Eskisehir
Turkey	Ep0091 900	Istanbul
Turkey	Ep0091 901	Istanbul
United Kingdom	Ep0091 752	Birmingham
United Kingdom	Ep0091 751	Cardiff
United Kingdom	Ep0091 756	Inverness
United Kingdom	Ep0091 757	London
United Kingdom	Ep0091 750	Manchester
United Kingdom	Ep0091 753	Swansea
United States	Ep0091 873	Atlanta	Georgia
United States	Ep0091 805	Austin	Texas
United States	Ep0091 844	Austin	Texas
United States	Ep0091 822	Baltimore	Maryland
United States	Ep0091 818	Bethesda	Maryland
United States	Ep0091 839	Chandler	Arizona
United States	Ep0091 838	Cordova	Tennessee
United States	Ep0091 830	Dallas	Texas
United States	Ep0091 836	Dallas	Texas
United States	Ep0091 806	Hackensack	New Jersey
United States	Ep0091 803	Honolulu	Hawaii
United States	Ep0091 815	La Jolla	California
United States	Ep0091 810	Little Rock	Arkansas
United States	Ep0091 835	Nashville	Tennessee
United States	Ep0091 827	New York	New York
United States	Ep0091 809	Ocala	Florida
United States	Ep0091 823	Orlando	Florida
United States	Ep0091 832	Peoria	Illinois
United States	Ep0091 800	Philadelphia	Pennsylvania
United States	Ep0091 802	Philadelphia	Pennsylvania
United States	Ep0091 825	Port Charlotte	Florida
United States	Ep0091 824	Round Rock	Texas
United States	Ep0091 817	Saint Paul	Minnesota
United States	Ep0091 870	San Antonio	Texas
United States	Ep0091 801	San Francisco	California
United States	Ep0091 820	Tallahassee	Florida
United States	Ep0091 845	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
UCB Biopharma S.P.R.L.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Bulgaria,  Canada,  Czechia,  France,  Germany,  Hungary,  Italy,  Japan,  Lithuania,  Mexico,  Poland,  Portugal,  Slovakia,  Spain,  Turkey,  United Kingdom, 

References & Publications (2)

Kramer H, Bicer C, Otoul C, Rospo C, Macpherson M, Watling M, Bani M, Sciberras D, Chanteux H. Clinical Bridging Studies and Modeling Approach for Implementation of a Patient Centric Sampling Technique in Padsevonil Clinical Development. AAPS J. 2023 Nov — View Citation

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-bli — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Log-transformed Observable Focal Onset Seizure Frequency From Baseline Over the 12 Week Maintenance Period	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.	From Baseline over the 12 Week Maintenance Period
Primary	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	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.	From Baseline until Safety Follow-Up (up to Week 23)
Primary	Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal	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.	From Baseline until Safety Follow-Up (up to Week 23)
Primary	Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) During the Entire Study	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.	From Baseline until Safety Follow-Up (up to Week 23)
Secondary	75 % Responder Rate Over the 12 Week Maintenance Period	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.	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization
Secondary	50 % Responder Rate Over the 12 Week Maintenance Period	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.	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization
Secondary	Percent Change in Observable Focal-onset Seizure Frequency From Baseline Over the 12 Week Maintenance Period	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.	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization