Primary Objectives:• To assess the efficacy of soticlestat in reducing major motor drop (MMD) seizure frequency as add-on therapy to SOC as compared with placebo during the full treatment period (titration + maintenance).For European Medicines…
ID
Source
Brief title
Condition
- Seizures (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
• Percent change from baseline in MMD seizure frequency per 28 days in subjects
receiving soticlestat as compared with placebo during the full treatment
period.
For EMA registration:
• Percent change from baseline in MMD seizure frequency per 28 days in subjects
receiving soticlestat as compared with placebo during the maintenance period.
Secondary outcome
Secondary Endpoints: To assess the following in subjects receiving soticlestat
as compared with placebo during the full treatment period, unless otherwise
noted: • Proportion of responders defined as those with >=50% reduction from
baseline in MMD seizures during the maintenance period and the full treatment
period. • Percent change from baseline in frequency of all seizures per 28 days
during the maintenance period and the full treatment period. • Percent change
from baseline in MMD seizure frequency per 28 days during the maintenance
period. • Responder analysis of the proportion of subjects with <=0%, >0% to
<=25%, >25% to <=50%, >50% to <=75%, and >75% to <=100% reduction from
baseline in MMD seizures in a cumulative response curve. • Change from baseline
in proportion of MMD seizure-free days. • Longest MMD seizure-free interval. •
Number of days when rescue ASM is used. • CGI-I (clinician). • Care GI-I
(caregiver). • CGI-I Seizure Intensity and Duration. • CGI-I Nonseizure
Symptoms. • Change in QI-Disability score.
Background summary
Lennox-Gastaut syndrome (LGS) is rare and is one of the most severe forms of
childhood epilepsy. The syndrome usually has its onset between the ages of 1
and 8 years, but occasionally it occurs in children who are older than 8 years,
or even into adulthood. LGS includes the presence of multiple seizure types:
the hallmark tonic-atonic drop seizures. Other seizure types include atypical
absence seizures, but tonic-clonic, myoclonic, and partial seizures are also
frequently present.
Soticlestat is a first-in-class small molecule inhibitor of cholesterol-24
hydroxylase (CH24H) in the brain. It is hypothesized that soticlestat treatment
will decrease the levels of 24S-hydroxycholesterol (24HC) and improve MMD
seizure control in LGS subjects. Nonclinical studies have demonstrated that
soticlestat modulates the glutamatergic signaling and significantly reduces
spontaneous seizure in murine models of LGS. Clinical Study TAK-935-2002
(ELEKTRA) showed efficacy of soticlestat in subjects with DS or LGS.
Study objective
Primary Objectives:
• To assess the efficacy of soticlestat in reducing major motor drop (MMD)
seizure frequency as add-on therapy to SOC as compared with placebo during the
full treatment period (titration + maintenance).
For European Medicines Agency (EMA) registration:
• To assess the efficacy of soticlestat in reducing MMD seizure frequency as
add-on therapy to SOC compared with placebo during the maintenance period only.
Study design
This is a phase 3, global, multicenter,1:1 randomized, double-blind,
placebo-controlled, parallel-group study to evaluate the efficacy, safety, and
tolerability of soticlestat as an adjunctive therapy in pediatric and adult
subjects with Lennox-Gastaut Syndrome (LGS). The treatment period is 16 weeks.
The total duration of the study is approximately 25 weeks for subjects who
complete the study and choose not to roll over to the open-label extension
(OLE) study. For those who roll over to the OLE study, the study duration is 3
weeks shorter.
The study will consist of the following periods:
• 4- to 6-week screening/baseline period.
• 16-week treatment period.
- 4-week titration period.
- 12-week maintenance period.
• 1-week taper period for those discontinuing study drug, followed by a 2-week
safety follow-up visit or a phone call.
This is a 2-arm study. All subjects will be randomized at a 1:1 ratio to
receive standard of care (SOC) plus one of the following adjunctive therapies:
soticlestat or placebo.
Intervention
Soticlestat or placebo will be available as yellow-red colored, film-coated
tablets and mini-tablets. The study drug (tablets/minitablets) can be swallowed
whole or can be crushed and mixed well in applesauce or a thick liquid.
The study drug should be taken by the subject 2 times a day (morning and
evening). Study drug can be taken orally with or
without food or via a gastrostomy tube (G tube) or via a percutaneous
endoscopic gastrostomy tube (PEG tube).
Study burden and risks
The following side effects are commun:
- Feeling tired and sluggish
- Common cold
- Difficulty sleeping
- Headache
- Nausea or feeling like he/she needs to vomit
- Difficulty paying attention or confusion
- Anxiety or feeling nervous
- Euphoric mood (exaggerated feeling of happiness) or feeling abnormally happy
- Feeling constantly tense, on guard, or abnormally aware of one*s environment
- Difficulty speaking
- Hallucinations include seeing, feeling, smelling, tasting, or hearing things
that are not real and which can be disturbing
Potential discomforts from the measurements:
- Blood draw: Obtaining blood may sometimes cause pain/discomfort at the site
where the blood is drawn, bruising, bleeding,
occasional light-headedness, and, rarely, infection or fainting.
- ECG: The ECG sticky patches or suction cups placed on his/her skin may cause
slight discomfort during their placement and
removal. The subject may also feel a little embarrassed as some upper clothing
may need to be removed.
- Ophthalmological assessments: The subject will have eye examinations during
this study. The subject may feel temporary
discomfort during the eye examinations due to the bright lights and with the
drops which will be put in his/her eyes before
performing any examinations to make their pupils larger.
- Questionnaires about his/her well-being, behavior, quality of life and risk
for suicide: Some questions may cause the subject to
have distress or make him/her feel uncomfortable. The subject may inform the
site staff if he/she has these feelings.
Hayden Avenue 95
Lexington 02421
US
Hayden Avenue 95
Lexington 02421
US
Listed location countries
Age
Inclusion criteria
• Male or female and aged 2 to 35 years, inclusive, at the time of informed
consent. • Documented clinical diagnosis of LGS supported by: - Onset of
seizures usually between ages of 1 and 8 years. - Presence of multiple seizure
types: including drop seizures (eg, tonic-atonic seizures) and other seizure
types including atypical absence seizures, tonic-clonic, myoclonic, and partial
seizures. - History of abnormal electroencephalogram (EEG) (eg, slow spike and
wave [<2.5 Hz], slow or disorganized EEG background, generalized paroxysmal
fast activity). - Developmental delay or intellectual disability consistent
with LGS. • The participant has >=8 MMD seizures each month in the 3 months
prior to screening based on the historical information and has >=8 MMD seizures
per 28 days during the 4- to 6-week prospective baseline period. MMD seizures
include: - Hemi-clonic or focal clonic. - Focal to bilateral tonic-clonic. -
Generalized tonic-clonic. - Bilateral clonic. - Focal seizures with major motor
signs (eg hypermotor seizures or involving major body areas such as lower
extremities or trunk) leading to fall or likely fall. - Tonic seizures
involving major body areas such as lower extremities or trunk leading to fall
or likely fall. - Atonic seizures involving major body areas such as lower
extremities or trunk leading to fall or likely fall. - Convulsive status. •
Weighs >=10 kg at the screening visit (Visit 1). • Failure to control seizures
despite appropriate trials of at least 1 ASMs based on historical information,
and is currently on an anti-seizure therapy (eg, ASMs, vagus nerve stimulation,
ketogenic/modified Atkins diet) or other treatment options considered as SOC. •
Artisanal cannabidiols are allowed at a stable dose for at least 4 weeks before
the screening visit (Visit 1); the dosing regimen and manufacturer should
remain constant throughout the study. • Currently taking 0 to 3 ASMs at stable
doses for at least 4 weeks before the screening visit (Visit 1);
benzodiazepines used chronically (daily) to treat seizures are considered ASMs.
Fenfluramine and cannabidiol (Epidiolex) are allowed where available and
counted as an ASM. ASM dosing regimen must remain constant throughout the
study. • If on a diet, the subject's diet should be stable for 4 weeks before
the screening visit; the subject should continue this diet throughout the
duration of the study • Stable liver function • Female subjects of childbearing
potential (defined as first menarche) must have a negative pregnancy test and
agree to use an effective or highly effective method of birth control during
the study and for 30 days following the last dose of study drug.
Exclusion criteria
• Currently enrolled in a clinical study involving an investigational product
(meaning not approved in that country other then soticlestat), or concurrently
enrolled in any other type of medical research judged not to be scientifically
or medically compatible with this study. Note: compatibility will be determined
based on consultation with the medical monitor or the sponsor. • Participated
in a clinical study involving another study drug in the last 30 days (or 5
half-lives of the study drug, whichever is longer) before screening (Visit 1).
• Received soticlestat in a previous clinical study. • Known hypersensitivity
to any component of the soticlestat formulation. • Admitted to a medical
facility and intubated for treatment of status epilepticus 2 or more times in
the 3 months immediately before screening (Visit 1). For this study status
epilepticus is defined as continuous seizure activity lasting longer than 5
minutes or repeated seizures without return to baseline in between seizures. •
Unstable, clinically significant neurologic (other than the disease being
studied), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic,
renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic,
endocrine disease, malignancy including progressive tumors, or other
abnormality that may impact the ability to participate in the study or that may
potentially confound the study results. It is the responsibility of the
investigator to assess the clinical significance; however, consultation with
the medical monitor may be warranted. • Any history of alcohol, opioid, or
other drug use disorder, as per the Diagnostic and Statistical Manual of Mental
Disorders, 5th Edition, within the 2 years immediately before the
screening(Visit 1). • Abnormal and clinically significant ECG abnormality at
screening (Visit 1) or before randomization (Visit 2, including QT interval
with Fridericia correction method (QTcF) >450 ms, confirmed with a repeat
ECG using manual measurement of QTcF. Clinically significant ECG abnormalities
should be discussed with medical monitor. • Abnormal clinical laboratory test
results at screening (Visit 1) that suggest a clinically significant underlying
disease that would compromise the well-being of the subject. If the subject has
a serum alanine aminotransferase and/or aspartate aminotransferase level
>2.5 times the upper limit of normal (ULN), the medical monitor should be
consulted. • Currently pregnant or breastfeeding or is planning to become
pregnant within 30 days of the last dose of study drug.
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 | EUCTR2021-002481-40-NL |
| CCMO | NL78269.075.21 |