| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10073682 |
| E.1.2 | Term | Dravet syndrome |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy to SOC as compared with placebo during the full treatment period (titration + maintenance).
- To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy to SOC compared with placebo during the maintenance period only. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the following in subjects taking soticlestat as compared with placebo during the full treatment period, unless otherwise noted:
- Proportion of treatment responders defined as those with ≥50% reduction in convulsive seizures from baseline during the maintenance period and the full treatment period.
- Effect on total seizure frequency of all seizure types during the maintenance period and the full treatment period.
- Change from baseline in proportion of convulsive seizure-free days.
- Longest convulsive seizure-free interval.
- Number of days when rescue antiseizure medications (ASMs) are used.
- Effect on the Clinical Global Impression of Improvement (CGI-I) (clinician) and Caregiver Global Impression of Improvement (Care GI-I).
- Effect on CGI-I Seizure Intensity and Duration.
- Effect on the CGI-I Nonseizure Symptoms completed by clinician with input from the caregivers.
- Effect on Quality of Life Inventory-Disability (QI-Disability). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. In the opinion of the investigator, the subject and/or parent or legal guardian is capable of understanding and complying with protocol requirements including the use of digital tools, complete appropriate assessments, maintain an accurate and complete daily seizure diary and take study drug for the duration of the study.
2. The subject or the subject’s parent or legal guardian are willing and able to read, understand, and sign and date a written or an electronic informed consent form (ICF), assent form (if applicable), and any required privacy authorization prior to the initiation of any study procedures.
3. The subject is male or female and aged 2 to 21 years, inclusive, at the time of informed consent.
4. Documented clinical diagnosis of DS supported by:
- Onset of seizures usually in the first year of life.
- History of fever-induced prolonged seizure as determined by the investigator:
- May include prolonged (approximately 15 minutes or longer) hemi-clonic seizures.
- Multiple seizure types, which may include:
– Generalized tonic-clonic.
– Focal to bilateral tonic-clonic.
– Clonic.
– Myoclonic seizures.
- History of developmental delay/intellectual disability presenting after onset of seizures and usually presenting after 12 months of age.
- Documented genetic mutation consistent with DS is not required, but results of genetic testing will be collected if available. If genetic testing was not performed previously or if the SCN1A result is negative (without any other positive gene reported that is consistent clinically with DS), testing for SCN1A will be offered at the time of screening.
5. Has ≥4 convulsive seizures in each 1-month period in the 3 months before screening based on the historical information and has ≥4 convulsive seizures per 28 days during the 4- to 6- week prospective baseline period.
6. Weighs ≥10 kg at the screening visit (Visit 1).
7. Failure to control seizures despite appropriate trials of at least 2 ASMs based on historical information and is currently on an antiseizure therapy (eg ASMs, vagus nerve stimulation (VNS), ketogenic/modified Atkins diet) or other treatment options considered as SOC.
8. Currently taking 0 to 4 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. ASM dosing regimen must remain constant throughout the study.
9. If using a VNS, the subject must have had VNS placed at least 3 months before the screening visit with stable settings for >1 month; VNS parameters must remain constant throughout the study (VNS will not be counted as an ASM).
10. If on ketogenic diet (or any other diet used for treatment of epilepsy, such as modified Atkins diet), the subject must have started the diet at least 3 months before the screening visit (Visit 1), and the subject’s diet should be stable for 1 month before the screening visit (Visit 1); the subject should continue this diet throughout the duration of the study (ketogenic diet, or any
other diet for the treatment of epilepsy will not be counted as an ASM).
11. The use of felbamate is allowed provided that the subject does not meet the liver function test (LFT) exclusion criteria, the dose has been stable for at least 6 months before screening, and the subject has had stable liver function (as determined by serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels) and hematology laboratory tests during the
course of treatment.
12. Approved to participate by the sponsor and/or designee (ie, TESC) after review of medical history and seizure classification.
13. Female subjects of childbearing potential (defined as first menarche) must have a negative pregnancy test and agree to use an effective method of birth control during the study and for 30 days following the last dose of study drug.
Effective contraceptive methods are as follows:
- Double-barrier method (contraceptive sponge, diaphragm, or cervical cap with spermicidal jellies or creams PLUS male condom).
- Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action, PLUS condom with or without spermicide.
- Sexual abstinence:
i. Sexual abstinence may be considered as a method only if defined as refraining from heterosexual intercourse and determined to be the usual lifestyle before entering the study with reliability of abstinence for the duration of the study participation and for
30 days after last dose of study drug.
- Sterilization:
ii. Bilateral tubal occlusion.
iii. Vasectomized partner (provided that the partner is the sole sexual partner of the subject and the absence of sperm in the ejaculate has been confirmed). |
|
| E.4 | Principal exclusion criteria |
1. Investigator site personnel directly affiliated with this study and/or their immediate family. Note: Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
2. Takeda employees or immediate family members.
3. Currently enrolled in a clinical study involving an investigational product or nonapproved use of a drug or device (other than the investigational product used in this study), 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.
4. 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).
5. Received soticlestat in a previous clinical study.
6. Known hypersensitivity to any component of the soticlestat formulation.
7. 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). Status epilepticus is defined as continuous seizure activity lasting longer than 5 minutes or repeated seizures without return to baseline in between seizures.
8. 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.
9. Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V), within the 2 years immediately before the screening visit (Visit 1).
10. Considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the subject has attempted suicide within 12 months before the screening visit (Visit 1). Subjects who have positive answers on item numbers 4 or 5 on the C-SSRS before randomization (Visit 2) are excluded. This scale will only be administered to subjects aged ≥6 years.
11. History of HIV infection (subject has tested positive for HIV-1 or HIV-2 antibodies), history of hepatitis B infection, or current active hepatitis C infection. Note: Subjects who have been vaccinated against hepatitis B (hepatitis B surface antibody-positive] and who test negative for other markers of prior hepatitis B infection (eg, negative for hepatitis B core antibody) are eligible. Also note that subjects who test positive for hepatitis C antibody are eligible if they have a negative hepatitis C viral load by quantitative polymerase chain reaction.
12. 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 the medical monitor.
13. 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 serum ALT and/or AST level >2.5 times the upper limit of normal (ULN), the medical monitor should be consulted.
14. Unable to withhold the use of strong inducers and inhibitors of cytochrome P450 (CYP) 3A4 during the entire clinical trial, except for ASMs (eg, carbamazepine, phenobarbital, phenytoin).
15. Unwilling to withhold the fruit and juice of grapefruit, Seville oranges, and starfruit from their diet during the entire clinical trial.
16. Use of herbal preparations (when used as an ASM) or artisanal cannabidiol (CBD) during the entire clinical trial.
17. Currently pregnant or breastfeeding or is planning to become pregnant within 30 days of the last dose of study drug. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Percent change from baseline in convulsive seizure frequency per 28 days in subjects receiving soticlestat as compared with placebo during the full treatment period.
- Percent change from baseline in convulsive seizure frequency per 28 days in subjects receiving soticlestat as compared with placebo during the maintenance period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary end points will be assessed throughout the study. |
|
| E.5.2 | Secondary end point(s) |
- Proportion of responders defined as those with ≥50% reduction from baseline in convulsive 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 convulsive 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 in convulsive seizures in a cumulative response curve.
- Change from baseline in proportion of convulsive seizure-free days.
- Longest convulsive 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary end points will be assessed throughout the study. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| China |
| Japan |
| Russian Federation |
| Serbia |
| Ukraine |
| United States |
| Belgium |
| France |
| Hungary |
| Italy |
| Latvia |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| Greece |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
Print
