|Principal Investigator: Amir Arain|
|Keywords: Focal seizures , Epilepsy , Seizure , Neurology , Antiepileptic drug , AED , intractable seizures , localized onset , new drug||Department: Neurology|
|IRB Number: 00122229||Co Investigator: Angela Peters|
|Specialty: Neurology, Neurology, Neurology|
|Sub Specialties: Epilepsy, Seizures|
|Recruitment Status: Not yet recruiting|
The primary objective is to evaluate the efficiently of the 3 selected dose regimens of PSL administered concomitantly with up to 3 AEDs compared with placebo for treatment of observable focal-onset seizures in subjects with drug-resistant epilepsy. The secondary objective is to assess the safety and tolerability of PSL in relation to placebo.
1. An Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written
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 40kg (for males and females).
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 ILAE
Classification of Epileptic Seizures, 1981):
- Epileptic seizures have been documented using video-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.
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.
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 IMP 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 IMP. Hormonal contraception may be susceptible
to an interaction with the IMP, 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 IMP.
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).
Subject has either:
- >2.0x upper limit of normal (ULN) of any of the following
- alanine aminotransferase (ALT)
- aspartate aminotransferase (AST)
- alkaline phosphatase (ALP)
- >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).
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
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 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 >450ms
- Bundle branch blocks and other conduction abnormalities that are clinically significant according to the Investigator and/or with a PR interval ≥220ms, 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,
Zoghbi et al, 2017).
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.
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 (Scheffer et al, 2017).
16. Subject has a history of status epilepticus within the 6-month period prior to Screening
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.
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.
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 cytochrome P450 (CYP)3A4 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
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.
33. Female subject who plans to become pregnant or is breastfeeding.