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
• Last Update Posted: December 16, 2020
• Sponsor: UCB Biopharma S.P.R.L.
• Information provided by (Responsible Party): UCB Pharma ( UCB Biopharma S.P.R.L. )

Tracking Information

• First Submitted Date: December 7, 2017
• First Posted Date: December 14, 2017
• Last Update Posted Date: December 16, 2020
• Actual Study Start Date: February 12, 2018
• Actual Primary Completion Date: January 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 9, 2019)

• Change in log-transformed observable focal onset seizure frequency from Baseline over the 12 week Maintenance Period [ Time Frame: From Baseline over the 12 week Maintenance Period ]
  During the study, subjects will keep diaries to record daily seizure activity. Seizure frequency refers to 28-day adjusted frequency. Seizure frequency will be based on investigator assessment of subjects' reports of daily seizure type and frequency. Observable focal-onset seizures refer to Type IA1, IB, and IC (ILAE Classification of Epileptic Seizures, 1981).
• Incidence of Treatment-Emergent Adverse Events (TEAEs) reported by the subject and/or caregiver or observed by the investigator during the entire study [ Time Frame: 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.
• Incidence of Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal [ Time Frame: 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.
• Incidence of Treatment-Emergent Serious Adverse Events (SAEs) during the entire study [ Time Frame: 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 as infection that requires treatment parenteral antibiotics
  • Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above.

Original Primary Outcome Measures (submitted: December 13, 2017)

Change in log-transformed observable focal onset seizure frequency from Baseline over the 12 week Maintenance Period [ Time Frame: From Baseline over the 12 week Maintenance Period ]

During the study, subjects will keep diaries to record daily seizure activity. Seizure frequency refers to 28-day adjusted frequency. Seizure frequency will be based on investigator assessment of subjects' reports of daily seizure type and frequency. Observable focal-onset seizures refer to Type IA1, IB, and IC (ILAE Classification of Epileptic Seizures, 1981).

Current Secondary Outcome Measures (submitted: January 9, 2019)

• 75 % responder rate over the 12 week Maintenance Period [ Time Frame: End of Maintenance Period (Week 16) following 3 weeks of titration and 1 week stabilization ]
  The 75% responder rate, where a responder is a subject 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 [ Time Frame: End of Maintenance Period (Week 16) following 3 weeks of titration and 1 week stabilization ]
  The 50% responder rate, where a responder is a subject experiencing a ≥50% reduction in observable focal-onset seizure frequency from Baseline, over the 12-Week Maintenance.
• Percent change 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 ]
  During the study, subjects will keep 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) will be assessed.

Original Secondary Outcome Measures (submitted: December 13, 2017)

• 75 % responder rate over the 12 week Maintenance Period [ Time Frame: End of Maintenance Period (Week 16) following 3 weeks of titration and 1 week stabilization ]
  The 75 % responder rate is defined as 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 [ Time Frame: End of Maintenance Period (Week 16) following 3 weeks of titration and 1 week stabilization ]
  The 50 % responder rate is defined as 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 [ Time Frame: End of Maintenance Period (Week 16) following 3 weeks of titration and 1 week stabilization ]
  During the study, subjects will keep 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) will be assessed.
• Incidence of Treatment-Emergent Adverse Events (TEAEs) reported by the subject and/or caregiver or observed by the investigator during the entire study [ Time Frame: 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.
• Incidence of Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal [ Time Frame: 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.
• Incidence of Treatment-Emergent Serious Adverse Events (SAEs) during the entire study [ Time Frame: 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 as infection that requires treatment parenteral antibiotics
  • Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Test the Efficacy and Safety of Padsevonil as Adjunctive Treatment of Focal-onset Seizures in Adults With Drug-resistant Epilepsy
• 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
• 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 Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Drug-resistant Epilepsy
• Focal-Onset Seizures

Intervention

• Drug: Padsevonil
  Padsevonil in different dosages.
• Other: Placebo
  Placebo will be provided matching Padsevonil.

Study Arms

• Experimental: Padsevonil dosing regimen 1
  Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
  Interventions:

  • Drug: Padsevonil
  • Other: Placebo
• Experimental: Padsevonil dosing regimen 2
  Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
  Interventions:

  • Drug: Padsevonil
  • Other: Placebo
• Experimental: Padsevonil dosing regimen 3
  Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
  Interventions:

  • Drug: Padsevonil
  • Other: Placebo
• Experimental: Padsevonil dosing regimen 4
  Subjects will be randomized to receive a combination of tablets of Padsevonil and Placebo (as appropriate) to maintain the blinding.
  Interventions:

  • Drug: Padsevonil
  • Other: Placebo
• Placebo Comparator: Placebo
  Subjects randomized to the placebo group will receive a combination of several Placebo tablets to maintain the blinding.
  Intervention: Other: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 25, 2019): 515
• Original Estimated Enrollment (submitted: December 13, 2017): 250
• Actual Study Completion Date: January 30, 2020
• Actual Primary Completion Date: January 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Belgium, Bulgaria, Canada, Czechia, France, Germany, Hungary, Italy, Japan, Lithuania, Mexico, Poland, Portugal, Slovakia, Spain, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT03373383
• Other Study ID Numbers: EP0091; 2017-003200-48 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: UCB Pharma ( UCB Biopharma S.P.R.L. )
• Study Sponsor: UCB Biopharma S.P.R.L.
• Collaborators: Not Provided

Investigators

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

• PRS Account: UCB Pharma
• Verification Date: December 2020