A multicenter, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of padsevonil as adjunctive treatment of focal-onset seizures in adult subjects with drug-resistant epilepsy

Inclusion criteria,
General,
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
approved written informed consent form (ICF) is signed and dated by the subject
or by the parent(s) or legal representative, where applicable. The ICF or a
specific Assent form, where required, will be signed and dated according to
country-specific regulations.
2. Subject/legal representative is considered reliable and capable of adhering
to the protocol (eg, able to understand and complete diaries), visit schedule,
and medication intake according to the judgment of the Investigator.
3. Subject is an adult (18 years of age or more).
4. Subject is of normal weight of at least 40 kg (for males and females).,
Epilepsy,
5. Subject fulfills diagnostic criteria for epilepsy and has observable
focal-onset (IA1, IB, and IC) seizures for at least 3 years at the time of
enrollment (according to the International League Against Epilepsy [ILAE]
Classification of Epileptic Seizures, 1981):
- Epileptic seizures have been documented using video-electroencephalogram
(EEG) recordings or ictal EEG (±simultaneous video) in the past (description or
report is available). The Investigator must consult with the UCB Study
Physician or representative for confirmation of eligibility as per instructions
in the Study Manual.
If no video-EEG report is available and, in the opinion of the Investigator,
epileptic seizures are definite (ie, eye-witnessed seizure report, home video
documentation of habitual events, or other proof), the Investigator must
consult with the UCB Study Physician or representative for a case review.
- A brain magnetic resonance imaging (MRI) is to be performed before
randomization, if no such scan was performed in the last 10 years, and a report
is not available. If a scan was performed within the last 10 years but the
clinical condition of the subject was progressive since the last scan, a new
scan should be obtained. If MRI is contraindicated, a head computed tomography
scan within the last 3 years before randomization will suffice.
6. Subject has on average *4 spontaneous and observable focal-onset seizures
per 28 days (based on Investigator assessment of subject report) with at least
1 seizure during each 4 week interval of the 8 weeks prior to the Screening
Visit. Additionally, subject must experience *4 spontaneous and observable
focal-onset seizures per 28 days (based on Investigator assessment of subject
report) during the 4-week Baseline Period.
7. Subject has failed to achieve seizure control with *4 tolerated and
appropriately chosen prior AEDs, including past and ongoing treatments 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).,
Concomitant epilepsy treatment,
8. Subject is currently treated 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
(Visit 1) with or without additional concurrent vagus nerve stimulation (VNS)
or other neurostimulation treatments. The latter will not be counted as AEDs
for the purpose of eligibility.,
Laboratory parameters,
9. Subject has clinical laboratory test results within the reference ranges of
the laboratory or isolated test results that are outside the specified ranges
and deemed as not clinically significant by the Investigator, eg mild and
moderate renal impairment.,
Birth control,
10. Female subjects of child bearing potential must have a negative serum
pregnancy test at the Screening Visit (Visit 1), which is confirmed to be
negative by urine testing prior to the first dose of PSL/Placebo at Day 1
(Visit 2) and 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 for a period of 3 months after their last intake of PSL/Placebo.
Hormonal contraception may be susceptible to an interaction with the
PSL/Placebo, which may reduce the efficacy of the contraception method. The
potential for reduced efficacy of any hormonal contraception method requires
that a barrier method (preferably a male condom) also be used.
Birth control methods considered as an efficient form of contraception:
- Combined (estrogen- and progesterone-containing) hormonal contraception
(oral, implant, injectable) associated with inhibition of ovulation (which must
be stable for at least 1 full month prior to Screening [Visit 1] and should
remain stable during the study) in combination with a barrier method
(preferably a condom).
- Progesterone-only hormonal contraceptives (oral, implant, injectable)
associated with inhibition of ovulation (which must be stable for at least 1
full month prior to Screening [Visit 1], and should remain stable during the
study) in combination with a barrier method (preferably a condom).
- Progesterone-releasing intrauterine systems or the TCu 380A intrauterine
device in combination with a barrier method (preferably a condom).
- Progestogen-only oral hormonal contraception, where inhibition of ovulation
is not the primary mode of action, in combination with a barrier method
(preferably a male condom).
- Male or female condom with spermicide (ie, double-barrier).
- Cap, diaphragm, or sponge with spermicide (ie, double-barrier).
- Bilateral tubal ligation.
- Vasectomized partner (provided sole partner, and partner has medical proof of
surgical success).
- True heterosexual sexual abstinence is an acceptable form of contraception
when this is in line with the preferred and usual lifestyle of the person.
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation
methods), declaration of abstinence for the duration of the study, and
withdrawal are not acceptable methods of contraception.
- Women not agreeing to use birth control must be abstinent (as described in
the preceding bullet) or be of nonchildbearing potential, defined as being
postmenopausal (for at least 2 years before the Screening Visit [Visit 1]),
verified by serum follicle stimulating hormone level >40mIU/mL at the Screening
Visit (Visit 1), or permanently sterilized (eg, bilateral tubal occlusion,
hysterectomy, bilateral salpingectomy), or congenitally sterile.
- Both male and female subjects must use the above-mentioned contraception
during the study.
- To ensure a proper birth control, females who use hormonal contraception
should use an efficient barrier contraceptive in the 3 months after their last
intake of PSL/Placebo.

Exclusion criteria,
General,
1. Subject has previously been randomized in this study, or a study of the
medication under investigation in this study. Re-screening of a subject may be
permitted but requires prior Medical Monitor approval and is not permitted in
case of screen failure due to seizure count.
2. Subject has participated in another study of an investigational medication
(or a medical device) within the previous 30 days or 5 half-lives (whichever is
longer) or is currently participating in another study of an investigational
medication (or a medical device).
Laboratory parameters
3. Subject has either:
- >2.0x upper limit of normal (ULN) of any of the following:
* alanine aminotransferase (ALT).
* aspartate aminotransferase (AST).
* alkaline phosphatase (ALP).
-OR-
- >ULN total bilirubin (*1.5xULN total bilirubin if known Gilbert*s syndrome).
If subject has elevations only in total bilirubin that are >ULN and <1.5xULN,
fractionate bilirubin to identify possible undiagnosed Gilbert*s syndrome (ie,
direct bilirubin <35%).
For randomized subjects with a Baseline result >ULN for ALT, AST, ALP, or total
bilirubin, a Baseline diagnosis and/or the cause of any clinically meaningful
elevation must be understood and recorded.
If subject has >ULN ALT, AST, or ALP that does not meet the exclusion limit at
screening, repeat the tests, if possible, prior to dosing to ensure there is no
further ongoing clinically relevant increase. In case of a clinically relevant
increase, inclusion of the subject must be discussed with the Medical Monitor.
Tests that result in ALT, AST, or ALP up to 25% above the exclusion limit may
be repeated once for confirmation before Baseline (Visit 2).,
Medical conditions,
4. Subject has a history or current medical condition that, in the opinion of
the Investigator, could jeopardize or would compromise the subject*s ability to
participate in this study.
5. Subject has a current psychiatric condition that occurred within the last 12
months which, in the opinion of the Investigator, could compromise the
subject*s safety or ability to participate in this study, including but not
limited to schizophrenia, schizoaffective disorder, bipolar disorder, severe
unipolar depression, dementia, or irreversible severe or progressive
encephalopathy.
6. Subject has a lifetime history of suicide attempt (including an actual
attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in
the past 6 months as indicated by a positive response (*Yes*) to either
question 4 or question 5 of the *Screening/Baseline* version of the
Columbia-Suicide Severity Rating Scale (C-SSRS) at screening.
7. Subject has a history of chronic alcohol or drug abuse within the last 2
years.
8. Subject has a history of cerebrovascular accident, including transient
ischemic attack, in the last 6 months.
9. Subject has presence of any sign (clinical or imaging techniques) suggesting
rapidly progressing (ie, not expected to stay stable during study
participation) brain disorder or brain tumor. Stable lesions such as
arteriovenous malformations, meningiomas, or other benign tumors are acceptable
if no surgical removal is planned or likely for the duration of the study.
10. Subject has any clinical condition (eg, bone marrow depression, chronic
hepatic disease, and/or severe renal impairment) that could impair reliable
participation in the study or necessitate the use of medication not allowed by
the protocol.
11. Subject has the presence of a terminal illness.
12. Subject has the presence of a serious infection.
13. 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. In addition, any subject with any of the following
findings will be excluded:
- QT interval corrected for heart rate using Bazett*s formula (QTcB) or QT
interval corrected for heart rate using Fridericia*s formula (QTcF) interval
>450 ms.
- Bundle branch blocks and other conduction abnormalities that are clinically
significant according to the Investigator and/or with a PR interval *220 ms,
irregular rhythms other than sinus arrhythmia or occasional, rare
supraventricular or rare ventricular ectopic beats in the judgment of the
Investigator, or T-wave configurations are not of sufficient quality for
assessing QT interval duration.
- Subject has a history of unexplained syncope or a family history of sudden
death due to long QT syndrome.
14. Subject has an abnormality on the echocardiogram at Screening (Visit 1) as
assessed by the central reader that is accompanied by clinical symptoms (eg,
shortness of breath, palpitations, and murmur) or a *Grade 2*/moderate severity
abnormality or a history of rheumatic heart disease or other known valvular
abnormalities (*according to the ASE Guidelines).
Subjects whose echocardiograms are not interpretable at Screening Visit (Visit
1) by transthoracic echocardiogram (TTE), eg, due to technical difficulties or
position of the heart will be excluded from the study.,
Epilepsy,
15. Subject has a history of or signs of generalized (formerly referred to as
*idiopathic generalized*) or combined generalized and focal (formerly referred
to as *symptomatic generalized*) epilepsy.
16. Subject has a history of status epilepticus within the 6-month period prior
to Screening (Visit 1).
17. Subject has seizures on a regular basis that are uncountable, eg, due to
clustering (ie, an episode lasting less than 30 minutes in which several
seizures occur with such frequency that the initiation and completion of each
individual seizure cannot be distinguished) during the 8 weeks prior to the
Screening Visit and during the 4-week Baseline Period.
18. Subject has isolated auras only (ie, focal-onset seizures which involve
subjective sensory or psychic phenomena only, without impairment of
consciousness or awareness, [formerly referred to as simple partial seizures
without an observable component]).
19. Subject has a current diagnosis of pseudo- or nonepileptic seizures, or
other nonepileptic events that could be confused with epileptic seizures.
20. Subject had resective surgery for epilepsy in the last 6 months prior to
study entry or plans for such a surgery within the timeframe of the study.,
Epilepsy treatment,
21. Subject had an epilepsy dietary therapy initiated <3 months prior to
Screening (Visit 1).
22. Subject has VNS, deep brain stimulation, Responsive Neurostimulator System,
or other neurostimulation for epilepsy device:
- Implanted and activated <1 year prior to enrollment, or
- With stimulation parameters that have been stable for <3 months, or
- With battery life of unit not anticipated to extend for duration of study.
23. Subject is currently treated with carbamazepine, phenytoin, primidone, or
phenobarbital.
24. Subject previously had serious side-effects with drugs where the
side-effects were related to specific SV2A and GABA-ergic mechanisms of
action.,
Medical treatment,
25. Subject has a known hypersensitivity to any components of PSL formulation
or a history of drug or other allergy that, in the opinion of the Investigator
or UCB Study Physician or delegate, contraindicates her/his participation.
26. Subject has taken or is taking any prescription, nonprescription, dietary
(eg, grapefruit or passion fruit), or herbal products (eg, St. John's wort)
that are strong inducers or strong inhibitors of the CYP3A4 or 2C19 pathway for
2 weeks (or 5 half lives, whichever is longer) prior to the Baseline Visit
(Visit 2). Subjects taking sensitive substrates of CYP2C19 are similarly
excluded. Please also note the prohibited concomitant medications.
27. Subject has been taking vigabatrin for less than 2 years at study entry.
28. Subject has been taking vigabatrin for at least 2 years without documented
normal visual fields following at least 2 years of intake.
29. Subject with a history of vigabatrin treatment who did not have a visual
perimetry test at least 6 months following conclusion of treatment or the
results of the visual perimetry test showed either a damage or a visual field
defect associated with 1 of the following 2 conditions:
- There was a change from a visual field test done at some point while the
subject was taking vigabatrin, or
- There was a change from a visual field test done within weeks after stopping
vigabatrin administration.
30. Subject has been taking felbamate for less than 12 months and/or has no
appropriate laboratory tests showing no indication of aplastic anemia or
hepatic failure.
31. Subject has been taking retigabine for less than 4 years. In addition,
subject is currently taking retigabine or has been exposed to retigabine with
no documentation (at least every 6 months or 6 months after last exposure) of
normal/stable visual acuity, slit lamp examination, dilated fundus photography,
and macular Optical Coherence Tomography imaging.
32. Subject is taking GABA A ergic drugs regularly (agonists [ie, barbiturates]
or receptor positive allosteric modulators [ie, BZDs or non-BZDs]), excluding
as needed (PRN) intake of GABA A ergic AEDs <3 times per week for emergencies.,
Pregnancy,
33. Female subject who plans to become pregnant or is breastfeeding.