| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 |
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| 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. |
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| 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). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. In the opinion of the investigator, the subject or the subject´s parent or legal guardian or caregiver 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. If the subject is living in a residential facility, a minimally possible number of staff member (s) at the facility who are the subject´s primary(s) caretaker(s) may be identified as caregivers who (per investigator´s judgment) are capable of complying with protocol requirements as indicated above.
2. The subject or the subject's parent or legal guardian is willing and able to read, understand, and sign and date an informed consent form (ICF), assent form (if applicable), and any required privacy authorization
before 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 variable combinations of typical clinical features, such as those noted in the protocol.
5. Has had ≥12 convulsive seizures in over 12 weeks before screening based on the historical information and has had ≥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 1 ASM based on historical information and is currently on an antiseizure therapy (eg ASMs, vagus nerve stimulation, ketogenic/modified Atkins diet) or other treatment options considered as SOC.
8. 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.
9. 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. Fenfluramine and cannabidiol are allowed where available and should be counted as ASM. ASM dosing regimen must remain constant throughout the study.
10. If using a VNS, the subject must have had VNS placed at least 3 months before the screening visit (visit 1) with stable settings for 4 weeks; VNS parameters must remain constant throughout the study (VNS will not be counted as an ASM).
11. 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 4 weeks 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).
12. 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 (visit 1), 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.
13. Approved to participate by the sponsor 's designee (ie, TESC) based on the review of medical history and seizure classification, as well as review of electroencephalogram (EEG) and imaging results (if available and permitted by local regulations). The sponsor may be consulted if needed.
14. 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.
Effective contraceptive methods include the following:
- 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.
Highly effective methods include the following:
- Nonhormonal methods: Intrauterine device (IUD), Bilateral tubal occlusion, Vasectomized partner, Sexual abstinence.
Hormonal methods:
- Combined (estrogen and progestogen) hormonal contraception
- Progestogen-only hormonal contraception
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| 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 treatment device (ie, not approved in that country, other than soticlestat), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study.
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). for the purpose of this exclusion criterion, 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 (DSMV), 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 dosing (Visit 2) are excluded. This scale will only be administered to subjects aged ≥6 years.
11. The following medical history:
a) History of HIV infection (subject who has tested positive for HIV-1/2),
b) History of hepatitis B infection, or current active 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.
c) History of hepatitis C infection or current active infection. Note: 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 dosing (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 of cytochrome P450 (CYP) 3A during the entire clinical trial, except for ASMs (eg, carbamazepine, phenobarbital, phenytoin) and topical preparations.
15. Use of herbal preparations (when used as an ASM) during the entire clinical trial.
16. Currently pregnant or breastfeeding or is planning to become pregnant within 30 days of the last dose of study drug. |
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| 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. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary end points will be assessed throughout the study. |
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| 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.
- 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.
- Care GI-I (caregiver).
- CGI-I (clinician).
- CGI-I Nonseizure Symptoms.
- Change in QI-Disability score.
- CGI-I Seizure Intensity and Duration.
- 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.
- Change from baseline in proportion of convulsive seizure-free days.
- Longest convulsive seizure-free interval.
- Number of days when rescue ASM is used. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary end points will be assessed throughout the study. |
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| 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 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| China |
| Japan |
| United States |
| Latvia |
| Russian Federation |
| Serbia |
| Ukraine |
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| 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
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The end of study for an individual subject who does not enroll in the OLE study on the same day as Visit 11/early termination is either:
- The day of the scheduled safety follow-up phone call or visit.
OR
- Midnight of the day after Visit 11/early termination but before the scheduled safety follow-up phone call, if decide on that day to enroll in the OLE study.
Subject who enrolls in the OLE study on the same day as Visit 11/early termination is midnight of that same day. |
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| E.8.9 Initial estimate of the duration of the trial |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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