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

Phase 2

Completed

Conditions: Focal-Onset Seizures
Drug-resistant Epilepsy

Interventions: Drug: Padsevonil
Other: Placebo

Registration Number: NCT03373383

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

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 411

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Padsevonil dosing regimen 1	Placebo	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
Padsevonil dosing regimen 3	Placebo	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
Padsevonil dosing regimen 4	Placebo	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
Padsevonil dosing regimen 2	Placebo	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
Placebo	Placebo	Subjects randomized to the placebo group will receive a combination of several Placebo tablets to maintain the blinding.
Padsevonil dosing regimen 3	Padsevonil	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
Padsevonil dosing regimen 1	Padsevonil	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
Padsevonil dosing regimen 2	Padsevonil	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
Padsevonil dosing regimen 4	Padsevonil	Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.

Primary Outcome Measures

Name	Time	Method
Change in Log-transformed Observable Focal Onset Seizure Frequency From Baseline Over the 12 Week Maintenance Period	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.
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	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.
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal	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.
Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) During the Entire Study	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 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.

Secondary Outcome Measures

Name	Time	Method
75 % Responder Rate Over the 12 Week Maintenance Period	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization	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.
50 % Responder Rate Over the 12 Week Maintenance Period	End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization	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.
Percent Change 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	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.

Trial Locations

Locations (148): Ep0091 839
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Chandler, Arizona, United States
Ep0091 810
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Little Rock, Arkansas, United States
Ep0091 815
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La Jolla, California, United States
Ep0091 801
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San Francisco, California, United States
Ep0091 845
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Washington, District of Columbia, United States
Ep0091 809
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Ocala, Florida, United States
Ep0091 823
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Orlando, Florida, United States
Ep0091 825
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Port Charlotte, Florida, United States
Ep0091 820
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Tallahassee, Florida, United States
Ep0091 873
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Atlanta, Georgia, United States
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Ep0091 839
🇺🇸Chandler, Arizona, United States