Drug-Resistant Epilepsy, Focal-Onset Seizures
Conditions
Keywords
Epilepsy, Padsevonil
Brief summary
The purpose of the study is to evaluate the efficacy, safety and tolerability of the 3 selected dose regimens of padsevonil (PSL) administered concomitantly with up to 3 anti-epileptic drugs (AEDs) compared with placebo for treatment of observable focal-onset seizures in subjects with drug-resistant epilepsy.
Interventions
DRUGPadsevonil
Padsevonil in different dosages.
DRUGPlacebo
Placebo will be provided matching padsevonil.
Sponsors
UCB Biopharma SRL
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 (up to Week 16) | 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 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) | 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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the 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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment. |
| Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 50% Responder Rate From Baseline Over the 12-week Maintenance Period | From Baseline over the 12 Week Maintenance Period (up to Week 16) | 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 | From Baseline over the 12 Week Maintenance Period (up to Week 16) | 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) were assessed. |
| 75% Responder Rate From Baseline Over the 12-week Maintenance Period | From Baseline over the 12 Week Maintenance Period (up to Week 16) | The 75 % responder rate, where a responder was a participant experiencing a ≥75 % reduction in observable focal-onset seizure frequency from Baseline, over the 12-Week Maintenance Period. |
Countries
Australia, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Japan, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The study started to enroll participants in March 2019 and concluded in September 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. The Participant Flow refers to the Randomized Set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, twice daily (bid) up to Week 19. | 56 |
| Padsevonil 100 mg BID 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. | 60 |
| Padsevonil 200 mg BID 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. | 57 |
| Padsevonil 400 mg BID 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 | 59 |
| Total Title | 232 |
| Total | 464 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Post-Treatment Period: Wk16-23 | Adverse Event | 3 | 0 | 0 | 0 |
| Post-Treatment Period: Wk16-23 | Consent Withdrawn | 0 | 0 | 0 | 1 |
| Post-Treatment Period: Wk16-23 | Early Study Closure | 0 | 0 | 1 | 0 |
| Post-Treatment Period: Wk16-23 | Sponsor Closed Study- Subject Was Discontinued | 0 | 1 | 0 | 0 |
| Post-Treatment Period: Wk16-23 | Sponsor Decision + Subject Refusal | 0 | 0 | 1 | 0 |
| Post-Treatment Period: Wk16-23 | Sponsor Decision To Terminate The Study | 1 | 0 | 0 | 0 |
| Post-Treatment Period: Wk16-23 | Sponsor's Decision | 0 | 1 | 0 | 0 |
| Post-Treatment Period: Wk16-23 | Trial Closed By Sponsor Decision | 0 | 0 | 1 | 0 |
| Treatment Period: Wk0-16 | Adverse Event | 2 | 6 | 6 | 12 |
| Treatment Period: Wk0-16 | Consent Withdrawn | 1 | 3 | 1 | 1 |
| Treatment Period: Wk0-16 | Due To Sponsor Instruction | 0 | 0 | 0 | 1 |
| Treatment Period: Wk0-16 | Lack of Efficacy | 0 | 1 | 0 | 3 |
| Treatment Period: Wk0-16 | Per Sponsor Study Closed | 0 | 1 | 0 | 0 |
| Treatment Period: Wk0-16 | Premature Closure Of The Study | 0 | 0 | 1 | 0 |
| Treatment Period: Wk0-16 | Premature Program Termination | 0 | 1 | 0 | 0 |
| Treatment Period: Wk0-16 | Premature Study Termination By Sponsor | 0 | 0 | 1 | 0 |
| Treatment Period: Wk0-16 | Program Termination | 3 | 0 | 1 | 1 |
| Treatment Period: Wk0-16 | Promotor Decision | 0 | 1 | 0 | 0 |
| Treatment Period: Wk0-16 | Protocol Violation | 0 | 0 | 1 | 0 |
| Treatment Period: Wk0-16 | Sponsor Closed Study- Subject Was Discontinued | 1 | 0 | 0 | 0 |
| Treatment Period: Wk0-16 | Sponsors Decision | 3 | 2 | 1 | 3 |
| Treatment Period: Wk0-16 | Study Early Closure | 0 | 0 | 1 | 0 |
| Treatment Period: Wk0-16 | Study Has Been Cancelled By The Sponsor | 0 | 0 | 0 | 1 |
| Treatment Period: Wk0-16 | Trial Closed By Sponsor | 0 | 1 | 0 | 0 |
| Treatment Period: Wk0-16 | Trial Was Closed By Sponsor | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Padsevonil 100 mg BID | Padsevonil 200 mg BID | Padsevonil 400 mg BID | Total Title |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 4 Participants | 0 Participants | 5 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 5 Participants | 3 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 52 Participants | 57 Participants | 48 Participants | 56 Participants | 213 Participants |
| Age, Continuous | 41.9 years STANDARD_DEVIATION 13.6 | 40.7 years STANDARD_DEVIATION 13 | 39.5 years STANDARD_DEVIATION 14.3 | 39.7 years STANDARD_DEVIATION 13.6 | 40.4 years STANDARD_DEVIATION 13.6 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants | 5 Participants | 7 Participants | 7 Participants | 24 Participants |
| Race/Ethnicity, Customized Black | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other/mixed | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 49 Participants | 50 Participants | 49 Participants | 51 Participants | 199 Participants |
| Sex: Female, Male Female | 34 Participants | 34 Participants | 29 Participants | 34 Participants | 131 Participants |
| Sex: Female, Male Male | 22 Participants | 26 Participants | 28 Participants | 25 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 55 | 0 / 60 | 0 / 57 | 0 / 59 | 0 / 33 | 0 / 31 | 0 / 29 | 0 / 28 | 0 / 27 | 0 / 30 | 0 / 31 | 0 / 32 |
| other Total, other adverse events | 25 / 55 | 37 / 60 | 40 / 57 | 41 / 59 | 7 / 33 | 0 / 31 | 1 / 29 | 1 / 28 | 2 / 27 | 6 / 30 | 4 / 31 | 2 / 32 |
| serious Total, serious adverse events | 3 / 55 | 0 / 60 | 1 / 57 | 5 / 59 | 1 / 33 | 0 / 31 | 0 / 29 | 0 / 28 | 1 / 27 | 2 / 30 | 0 / 31 | 1 / 32 |
Outcome results
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 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 (up to Week 16)
Population: 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. Here, number of participants were included who were evaluable for the assessment.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo (FAS) | Change in Log-transformed Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | -0.41 log e seizures per 28 days |
| Padsevonil 100 mg BID (FAS) | Change in Log-transformed Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | -0.35 log e seizures per 28 days |
| Padsevonil 200 mg BID (FAS) | Change in Log-transformed Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | -0.47 log e seizures per 28 days |
| Padsevonil 400 mg BID (FAS) | Change in Log-transformed Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | -0.47 log e seizures per 28 days |
Comparison: 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.p-value: =0.68795% CI: [-38.1, 19.2]ANCOVA
Comparison: 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.p-value: =0.68795% CI: [-22.7, 28.7]ANCOVA
Comparison: 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.p-value: =0.68795% CI: [-22.9, 28.6]ANCOVA
Primary
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)
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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment.
Time frame: From Baseline until Safety Follow-Up (up to Week 23)
Population: The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 69.1 percentage of participants |
| Padsevonil 100 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 83.3 percentage of participants |
| Padsevonil 200 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 78.9 percentage of participants |
| Padsevonil 400 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) | 84.7 percentage of participants |
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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment.
Time frame: From Baseline until Safety Follow-Up (up to Week 23)
Population: The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal | 7.3 percentage of participants |
| Padsevonil 100 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal | 10.0 percentage of participants |
| Padsevonil 200 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal | 10.5 percentage of participants |
| Padsevonil 400 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) Leading to Study Withdrawal | 20.3 percentage of participants |
Primary
Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs)
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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the treatment.
Time frame: From Baseline until Safety Follow-Up (up to Week 23)
Population: The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 9.1 percentage of participants |
| Padsevonil 100 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 3.3 percentage of participants |
| Padsevonil 200 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 1.8 percentage of participants |
| Padsevonil 400 mg BID (FAS) | Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) | 10.2 percentage of participants |
Secondary
50% Responder Rate From Baseline 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.
Time frame: From Baseline over the 12 Week Maintenance Period (up to Week 16)
Population: 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. Here, number of participants were included who were evaluable for the assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | 50% Responder Rate From Baseline Over the 12-week Maintenance Period | 27.8 percentage of participants |
| Padsevonil 100 mg BID (FAS) | 50% Responder Rate From Baseline Over the 12-week Maintenance Period | 35.6 percentage of participants |
| Padsevonil 200 mg BID (FAS) | 50% Responder Rate From Baseline Over the 12-week Maintenance Period | 33.9 percentage of participants |
| Padsevonil 400 mg BID (FAS) | 50% Responder Rate From Baseline Over the 12-week Maintenance Period | 42.9 percentage of participants |
Comparison: 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.p-value: =0.42595% CI: [0.61, 3.18]Regression, Logistic
Comparison: 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariatep-value: =0.62595% CI: [0.53, 2.85]Regression, Logistic
Comparison: 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariatep-value: =0.12595% CI: [0.84, 4.34]Regression, Logistic
Secondary
75% Responder Rate From Baseline Over the 12-week Maintenance Period
The 75 % responder rate, where a responder was a participant experiencing a ≥75 % reduction in observable focal-onset seizure frequency from Baseline, over the 12-Week Maintenance Period.
Time frame: From Baseline over the 12 Week Maintenance Period (up to Week 16)
Population: 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. Here, number of participants were included who were evaluable for the assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo (FAS) | 75% Responder Rate From Baseline Over the 12-week Maintenance Period | 13.0 percentage of participants |
| Padsevonil 100 mg BID (FAS) | 75% Responder Rate From Baseline Over the 12-week Maintenance Period | 15.3 percentage of participants |
| Padsevonil 200 mg BID (FAS) | 75% Responder Rate From Baseline Over the 12-week Maintenance Period | 12.5 percentage of participants |
| Padsevonil 400 mg BID (FAS) | 75% Responder Rate From Baseline Over the 12-week Maintenance Period | 14.3 percentage of participants |
Comparison: 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.p-value: =0.80395% CI: [0.39, 3.38]Regression, Logistic
Comparison: 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.p-value: =0.77295% CI: [0.27, 2.65]Regression, Logistic
Comparison: 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.p-value: =0.98995% CI: [0.33, 3.08]Regression, Logistic
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) were assessed.
Time frame: From Baseline over the 12 Week Maintenance Period (up to Week 16)
Population: 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. Here, number of participants were included who were evaluable for the assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (FAS) | Percent Change in Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | 22.34 percent change | Standard Deviation 44.56 |
| Padsevonil 100 mg BID (FAS) | Percent Change in Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | 11.72 percent change | Standard Deviation 81.52 |
| Padsevonil 200 mg BID (FAS) | Percent Change in Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | 30.29 percent change | Standard Deviation 39.58 |
| Padsevonil 400 mg BID (FAS) | Percent Change in Observable Focal-onset Seizure Frequency From Baseline Over the 12-week Maintenance Period | 22.41 percent change | Standard Deviation 62.8 |
Comparison: Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.p-value: =0.73795% CI: [-17.08, 20.36]Wilcoxon (Mann-Whitney)
Comparison: Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.p-value: =0.45895% CI: [-10, 21.91]Wilcoxon (Mann-Whitney)
Comparison: Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.p-value: =0.34195% CI: [-10.92, 28.21]Wilcoxon (Mann-Whitney)