Objectives:Primary objectiveTo evaluate the long-term safety and tolerability of padsevonil (PSL) administered at individualized doses between 100 mg/day and 800 mg/day as adjunctive treatment for subjects with focal-onset seizures and drug-…
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Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Criteria for evaluation:
Efficacy:
Primary efficacy variables
* Change from Baseline (from the respective parent study) in observable
focal-onset seizure frequency over the Evaluation Period.
Pharmacokinetics and Pharmacodynamics:
No Pharmacokinetic or pharmacodynamic variables will be assessed in this study.
Safety:
Primary safety variables
* Incidence of treatment-emergent adverse events (TEAEs) reported by the
subject and/or caregiver or observed by the Investigator.
* Incidence of TEAEs leading to study withdrawal.
Secondary outcome
Criteria for evaluation:
Efficacy:
Other efficacy variables
* Observable focal-onset seizure frequency per 28 days by 3-month intervals
over the Evaluation Period.
* Observable focal-onset seizure frequency per 28 days by seizure type and by
3-month intervals over the Evaluation Period.
* The 50%, 75%, and 90% responder rate (RR) by 3-month intervals for
observable focal-onset seizures over the Evaluation Period. A 50%, 75%, and 90%
responder is defined as a subject with a *50%, *75%, or *90% reduction in the
observable focal-onset seizure frequency relative to the Baseline Period
defined in the parent study.
* The 50%, 75%, and 90% RR by 3-month intervals for focal-onset seizures (Type
I) over the Evaluation Period.
* Percentage of seizure-free days (for all seizure types) by 3-month intervals
over the Evaluation Period.
* Seizure-freedom status for all seizure types by 3-month intervals over the
Evaluation Period.
* Time to discontinuation.
* Change from Baseline from parent study in the Seizure Severity Global Item
(SSG) scores at each assessment.
* Changes from Baseline from parent study in Quality of Life Inventory in
Epilepsy-31-P (QOLIE-31-P) scores at each assessment.
* Changes from Baseline from parent study in Hospital Anxiety and Depression
Scale (HADS) scores at each assessment.
* Changes in drug load (ie, number of products, daily dose per given product,
ratio of dose and Defined Daily Dose, frequency, drug class) of AEDs from
Baseline to Visit 8, and to Visit 12 or end of study (EOS).
* Use of health-related outcomes and HRU, including healthcare provider
consultations not foreseen by protocol, caregiver support, concurrent medical
procedures, concomitant medications, and hospitalizations.
Pharmacokinetics and Pharmacodynamics:
No Pharmacokinetic or pharmacodynamic variables will be assessed in this study.
Safety:
Other safety variables
* Changes in laboratory tests (including hematology, blood chemistry,
urinalysis).
* Changes in 12-lead ECG parameters.
* Changes in withdrawal symptoms using Clinical Institute Withdrawal.
Assessment-Benzodiazepines (CIWA-B) from the EOS Visit, to the end of Taper
Period and to the end of the SFU Period (30 days after last PSL intake).
* Changes in vital sign parameters (pulse rate, blood pressure [BP], and
respiratory rate).
* Occurrence of a clinically-significant valvular or pericardial effusion
change or other clinically-significant abnormalities as identified by
2-dimensional Doppler echocardiogram at each assessment by central reader.
* Physical examination (including body weight) and neurological examination
findings.
* Changes in Psychiatric and Mental Status.
Background summary
Drug-resistant epilepsy
The International League Against Epilepsy (ILAE) defines drug resistance as
failure of adequate trials of 2 tolerated and appropriately chosen AEDs either
as monotherapy or in combination to achieve sustained seizure freedom. In the
US, there are 3 million adults with active epilepsy. Assuming epilepsy with
focal-onset seizures in 60% of patients and resistance to AEDs in 20% to 40% of
patients, approximately 360,000 to 720,000 patients suffer from drug-resistant
epilepsy. It is this drug-resistant epilepsy population that represents the
greatest burden of disease for individuals, physicians, and the healthcare
system. A treatment that provides a significant reduction in seizure frequency
will reduce mortality and significantly improve quality of life.
Padsevonil mechanism of action
Padsevonil is a novel chemical entity that has selective affinity for SV2
proteins and postsynaptic cBZR sites on the GABA-A receptor. It has shown
compelling efficacy in several preclinical models of epilepsy, including the
amygdala kindling model. This model is considered the most translatable
approach to assess compounds with potential efficacy against drug-resistant
focal epilepsy. Based on this compelling preclinical profile, UCB designed and
conducted a proof-of-concept study (EP0069) in patients with highly
drug-resistant focal epilepsy.
Nonclinical studies
A comprehensive nonclinical development program has been conducted with PSL,
including oral toxicology studies up to 26 weeks in rats and 39 weeks in dogs,
a standard battery of genotoxicity studies, safety pharmacology and secondary
pharmacology studies, and fertility and embryofetal development studies in rats
and rabbits. Details of these nonclinical studies can be found in the
Investigator*s Brochure (IB). Padsevonil was well tolerated up to 150mg/kg
twice daily (bid) (ie, 300mg/kg/day) over 26 weeks in rats and up to 50mg/kg
bid (ie, 100mg/kg/day) over 39 weeks in dogs. The minimal cardiac findings
reported in a limited number of animals in the 39-week toxicity study in dogs
were judged to be of very low risk (long-term exposure) to nonexistent risk
(short-term exposure) to humans by a panel of internal and external experts.
Furthermore, echocardiographic screening of human study participants at
Baseline (to exclude study participants with valvulopathies) and ongoing
echocardiographic monitoring during treatment and post treatment has been
implemented in the Phase 2 studies. There have been no major findings to date.
Clinical studies
Clinical development (Phase 1 and Phase 2) of PSL is underway, the objective of
which is to address an unmet medical need by developing a treatment that will
provide incremental efficacy when added to existing AED treatment for patients
with drug-resistant epilepsy. The proposed indication of PSL is as an
adjunctive therapy in the treatment of focal-onset seizures in adult patients
with epilepsy.
Phase 1
Studies of single oral doses of PSL up to 490mg and repeated oral dose of up to
400mg bid for up to 12 days have been completed. In addition, studies to
determine SV2A receptor occupancy and pharmacokinetics (PK) in Japanese study
participants are ongoing. Tolerability up to 400mg bid was considered
acceptable to progress to Phase 2. At the time of initiation of Phase 2, the
important identified risks based on the human pharmacology studies included
drug-drug interactions with potent cytochrome P450(CYP)3A4 enzyme inducers and
the risk of developing psychiatric symptoms. Further details of the Phase 1
studies are available in the IB.
Phase 2
A Phase 2 study, EP0069, conducted in the in the EU to evaluate the potential
efficacy, safety/tolerability, and PK profile of PSL administered to subjects
with highly drug-resistant focal epilepsy was recently completed. The analysis
is ongoing, but the study showed that PSL 400mg bid as an adjunctive treatment
to each study participant*s current, stable AED regimen was associated with
clinically meaningful improvements in seizure control. There were no new or
unexpected safety signals. Interim data (cutoff date of 07 Mar 2017) from the
ongoing open-label extension (OLE) study (EP0073) to EP0069 indicate that the
safety and tolerability profile continues to remain acceptable and support the
maintenance of PSL efficacy. Refer to the
IB for full details regarding the safety and efficacy. UCB proposes the
initiation of a Phase 2 dose-finding study of PSL (EP0091) and the current OLE
study (EP0093), in adult patients having focal-onset seizures associated with
drug-resistant
epilepsy.
Rationale for this study
This open-label, long-term study will provide subjects, who participated in
previous PSL studies, the opportunity to have continued access to PSL. EP0093
will assess the long-term safety, tolerability, and efficacy of PSL as an
adjunctive treatment for focal-onset seizures in adult subjects with
drug-resistant epilepsy.
Study objective
Objectives:
Primary objective
To evaluate the long-term safety and tolerability of padsevonil (PSL)
administered at individualized doses between 100 mg/day and 800 mg/day as
adjunctive treatment for subjects with focal-onset seizures and drug-resistant
epilepsy.
Secondary objective
The secondary objective is to evaluate the long-term efficacy of PSL as an
adjunctive treatment for focal-onset seizures in adults with drug-resistant
epilepsy.
Exploratory objective
The exploratory objective is to assess the impact of PSL as an adjunctive
treatment for subjects with focal-onset seizures and drug-resistant epilepsy on
health-related outcomes and healthcare resources utilization (HRU).
Study design
Methodology:
This is an open-label extension study that will assess the safety,
tolerability, and change in focal-onset seizure frequency associated with
long-term oral PSL as an adjunctive therapy in adult subjects with
drug-resistant epilepsy. This study will enroll consenting subjects, or
subjects whose legal representatives have given consent, and who have completed
a PSL parent study (eg, EP0091 or subsequent PSL studies).
The study consists of 3 periods: evaluation, taper and safety follow-up (SFU)
periods. The list of activities to be carried out at each of these periods is
detailed in the schedule of assessments table provided at the end of this
section.
The total study duration per subject will be up to approximately 2 years.
Subjects benefitting from the drug and willing to continue will either take
commercial drug, if available, or will be transferred to a Managed Access
Program or other PSL study depending on local regulations. The end of the study
is defined as the date of the last SFU Visit (30 days after the last PSL
intake) of the last subject in the study. Serious adverse events will continue
to be reported until the 6-month follow-up echocardiogram is obtained.
Intervention
Treatment, doses, mode of administration, and duration:
Padsevonil will be supplied as 25 mg, 100 mg, and 200 mg film-coated tablets of
different sizes and appearance.
Padsevonil will be administered in an open-label manner. Subjects will be
instructed to take 2 doses approximately 12 hours apart. PSL should be dosed
within 30 minutes after food when practically feasible.
The individual starting dose of each subject will be the one at the end of the
parent study. Further individual dose adjustments are allowed after 1 week,
between 100 mg/day up to a maximum of 800 mg/day to the extent possible with
the combination of tablet strengths available (ie, 25 mg, 100 mg and 200 mg).
Study burden and risks
What participation involves
If you participate, your participation will last up to 2 years.
Screening
The Entry Visit (Visit 1) will be done the same day as the last visit of the
parent study. During this visit, your eligibility criteria will be checked in
order to determine whether you can participate. Then, the following will take
place:
- You will be asked to provide updates about your habits and lifestyle, medical
history and fill out the study questionnaires.
- The assessments you performed for the parent study will not be repeated
during this visit but the results will be used for this study: physical and
neurological examination, vital signs, ECG, body weight assessment, seizure
evaluation, ongoing medication and procedures, recording of side effects,
blood/urine sample collection, health-related outcomes and healthcare
utilization (your use of healthcare services) assessment and psychiatric and
mental status assessment.
- After it has been confirmed that you can join the study, your investigator
will give you a participant card and a diary card. You will be asked to
complete the diary card to record seizures and other events occurring every
day.
- After it has been confirmed that you can join the study, you will receive
padsevonil for use until the next visit.
More information on all procedures performed during the screening can be found
in Appendix C and D.
Your investigator may find out after this visit that you are not eligible to
participate in the study. If this is the case, the investigator will discuss
this with you and offer you an alternative treatment.
Treatment
Once you enter this study, your individual starting dose of padsevonil will be
the one at the end of the parent study (400 mg/day). Thereafter, your dose may
be adjusted after 1 week depending on how you receive padsevonil. The minimum
daily dose will be 100 mg/day and the maximum dose 800 mg/day. As this is an
open-label study, everyone (which is you, your investigator, the study team and
the sponsor) will know the treatment and doses you are taking. Tablets should
be taken twice daily approximately 12 hours apart each day within 30 minutes
after food. The padsevonil tablets should not be crushed or cut in half and
must be taken as a whole. Your investigator may adjust the frequency of intakes
to improve tolerability and/or efficacy. Sufficient tablets will be provided
till your next visit, including some reserve tablets for emergencies. Your
investigator will inform you on how to take padsevonil. In addition to
padsevonil, you will continue with your current anti seizure drug treatment
(also known as antiepileptic drugs or AEDs). Your investigator will prescribe
these (including rescue) drugs for you. Some drugs are not allowed during the
study. Your investigator will check these. Dose adjustments of padsevonil
and/or other current seizure medications are allowed at any time during the
study, if your seizures are not sufficiently controlled or in case of
tolerability issues.
Visits and tests
Evaluation Period
Time point: up to Month 24
During this period, you have to visit the research institution 11 times. You
may have to attend regular appointments every 2 weeks during the first month,
every month during month 2 and month 3, and every 3 months after month 3 to the
end of the year 2 (end of the study).
The following will take place in addition to the procedures mentioned during
screening:
- Your investigator will confirm that you still fulfill the condition to
participate in the study.
- Questions will be asked about changes to your psychiatric and mental status
and the seizures or unusual events you experienced since last visit.
- Your ongoing treatments will be reviewed.
- Any side effects that you might have experienced, caregiver support and
healthcare utilization will be noted.
- You will undergo various assessments including vital signs, body weight,
physical and neurological examinations, ECGs (approximately every 6 months),
echocardiograms and blood/urine samples.
- If you are a female, urine pregnancy tests will be performed.
- You will bring the padsevonil packs back at each visit even if empty.
- You will bring your filled-out diary to your next appointment and make sure
not to lose or displace the diary as your diary will be reviewed at each visit.
End Of Study Visit/Early Discontinuation Visit
Time point: at the end of the evaluation period or after you discontinue from
study
During this visit, already mentioned procedures will take place, except for
padsevonil dispensing if you discontinue from the study or continue in the
study without padsevonil and expect for the echocardiogram.
Tapering Period (purpose: gradual decrease of dosage to zero)
Time point: up to Week 4 after you discontinue from the study or continue in
the study without padsevonil
This period involves 1 visit. During this visit, all the procedures mentioned
will be performed. The only exception is that you will not receive padsevonil
anymore.
Safety Follow up Period (purpose: to check how you are after taking padsevonil)
Time point: 30 days after the last dose or 6 months after you discontinue from
study
This period involves 1 visit. During this visit, already mentioned procedures
will take place. This will allow your investigator to determine how you are
after you stop using padsevonil.
Unscheduled Visit or Telephone Call
At any time, you may have an unscheduled study visit or telephone call if your
investigator and/or you feel it is necessary. An unscheduled visit may be
conducted due to safety or effectiveness reasons and appropriate assessments
will be conducted.
----------------------------
Possible side effects
Just like any drug, padsevonil may cause side effects. So far 201 healthy
people have received various doses of padsevonil. In addition, 75 patients with
epilepsy have received padsevonil. While some of these side effects are already
known, there may be other risks associated with the use of padsevonil that are
currently unforeseeable.
You should not take padsevonil if you have any allergies to the ingredients in
the tablet or have had serious side effects to drugs which are closely related
to padsevonil, for example levetiracetam or benzodiazepines. Please ask the
investigator about the ingredients.
Below is a list of very common side effects, experienced in more than 1 of 10
individuals who took padsevonil:
- Sleepiness, dizziness and headache.
- Irritability and behavior.
- Tiredness.
Please refer to Appendix E for more details about the side effects, padsevonil
interactions and other risks and discomforts of the procedures.
All the side effects are usually more frequent at the beginning of treatment or
when the dose has been increased and get better over time. If you experience
any of these symptoms and they are very bothersome, you can decide to leave or
exit the study. If you stop taking padsevonil (note * the dose will be reduced
gradually to minimize withdrawal effects), these side effects will usually go
away quickly. Unless for emergency, padsevonil should however not be stopped
abruptly and without consulting your investigator.
Allée de la Recherche 60
Brussels 1070
BE
Allée de la Recherche 60
Brussels 1070
BE
Listed location countries
Age
Inclusion criteria
General
1. An Institutional Review Board/Independent Ethics Committee approved written
informed consent form (ICF) is signed and dated by the subject or by the
parent(s) or legal representative (where legally permitted). The ICF or a
specific Assent form, where required, will be signed and dated by minors,
according to country-specific regulations.
2. Subject/legal representative/caregiver (where legally permitted) is
considered reliable and capable of adhering to the protocol (eg, able to
understand and complete diaries), visit schedule, or medication intake
according to the judgment of the Investigator.
3. Subject is an adult (*18 years of age)., Epilepsy
4. Subject with epilepsy who has completed 1 of the previous PSL studies which
allow access to the present study.
Birth control
5. Female subjects of child bearing potential must have a serum negative
pregnancy test at the Entry Visit, which is confirmed to be negative by urine
testing prior to further dispensing of PSL 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 and for a period of 3 months after their final dose of PSL. Hormonal
contraception may be susceptible to an interaction with PSL, 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
condom) also be used.
Birth control methods considered as efficient forms of contraception:
- Combined (estrogen- and progesterone-containing) hormonal contraception
(oral, implant, injectable) in combination with a barrier method (preferably a
condom).
- Progesterone-only hormonal contraceptives (oral, implant, injectable) 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).
- Male or female condom with spermicide (ie, double-barrier).
- Cap, diaphragm or sponge with spermicide (ie, double-barrier).
- Bilateral tubal ligation.
- Vasectomized partner.
- True heterosexual sexual abstinence. 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 of nonchildbearing potential,
defined as being postmenopausal, 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 final
intake of PSL.
Exclusion criteria
A subject will be excluded from the study if she/he has:, General
1. Any severe medical, neurological, or psychiatric condition, or laboratory
value which may have an impact on the safety of the subject.
2. Active suicidal ideation as indicated by a positive response (*Yes*) to
either Question 4 or Question 5 of the *Since Last Visit* version of the
Columbia-Suicide Severity Rating Scale (C-SSRS). The subject should be referred
immediately to a mental healthcare professional and must be withdrawn from the
study.
Laboratory parameters
3. More than 2x 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) at the Entry Visit. If the subject has elevations only in total
bilirubin that are >ULN and <1.5xULN, fractionated bilirubin must be used to
identify possible undiagnosed Gilbert*s syndrome (ie, direct bilirubin <35%).
For enrolled subjects with a Baseline result >ULN for ALT, AST, ALP, or total
bilirubin, a Baseline diagnosis and/or the cause of any clinically-significant
elevation must be understood and recorded.
If subject has >ULN for ALT, AST, or ALP that does not meet the exclusion limit
at the Entry Visit (ie, the value is >ULN but *2xULN at the Entry Visit of
EP0093), the tests must be repeated, if possible, prior to dosing to ensure
there is no further ongoing clinically significant increase. In case of a
clinically-significant increase, inclusion of the subject must be discussed
with the Medical Monitor., Medical conditions
4. 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) >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.
5. An abnormality on echocardiogram at last echocardiogram assessment, or
foreseen in parent study as assessed by central reader that is accompanied by
clinical symptoms (eg, shortness of breath, palpitations, and murmur) or a
Grade 2 (or higher)/moderate severity abnormality, or a history of rheumatic
heart disease, or other known valvular abnormalities., Pregnancy
6. Female subject who plans to be pregnant or is breastfeeding.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2017-003241-26-NL |
| ClinicalTrials.gov | NCT03739840 |
| CCMO | NL69408.028.19 |