| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | Dravet Syndrome (DS)
Lennox-Gastaut Syndrome (LGS) | |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10048816 | | E.1.2 | Term | Lennox-Gastaut syndrome | | E.1.2 | System Organ Class | 10029205 - Nervous system disorders | |
| 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 long-term safety and tolerability of soticlestat when administered as adjunctive therapy to SOC (eg, ASMs, vagus nerve stimulation, ketogenic diet, modified Atkins diet) in subjects with DS or LGS. | |
| E.2.2 | Secondary objectives of the trial | - To assess the effect of soticlestat on seizure frequency (convulsive seizures for the DS cohort, MMD seizures for the LGS cohort, and total seizure count for each cohort).
- To assess the effect of soticlestat on the Clinical Global Impression of Improvement (CGI-I) (clinician) and Caregiver Global Impression of Improvement (Care GI-I).
- To assess the effect of soticlestat on CGI-I Seizure Intensity and Duration.
- To assess the effect of soticlestat on the CGI-I Nonseizure Symptoms completed by clinician with input from the caregiver.
- To assess the effect on Quality of Life Inventory-Disability (QI-Disability). | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Subject must have:
Been previously enrolled in soticlestat clinical study TAK-935-3001 or TAK-935-3002.
1. Received at least 10 weeks of treatment (combined titration and Maintenance Period) with the study drug in the antecedent study and not have a serious or severe AE that, in the investigator’s or sponsor’s opinion, was related to the study drug and would make it unsafe for the patient to continue receiving the study drug.
2. In the opinion of the investigator, the subject has the potential to benefit from the administration of soticlestat.
3. 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.
4. 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.
5. 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. 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.
2. Abnormal and clinically significant ECG abnormality at Visit 1 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.
3. Subject is currently pregnant or breastfeeding or is planning to become pregnant during the study or within 30 days of the last dose of study drug.
4. Subject is considered by the investigator to be at imminent risk of suicide or injury to self, others, or property. Subjects who have positive answers on item numbers 4 or 5 on the CSSRS before dosing are excluded. This scale will only be administered to subjects aged ≥6 years. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | - Incidence of TEAEs.
- Change from baseline in the Columbia-Suicide Severity Rating Scale (C-SSRS) categorization based on Columbia Classification Algorithm of Suicide Assessment categories 1, 2, 3, 4, and 5 for patients ≥6 years of age.
- Incidence of clinically significant clinical safety laboratory test values, vital signs, weight, height, and electrocardiogram (ECG) evaluations, recorded as AEs.
- Clinically significant change from baseline in ophthalmological evaluations at 52 weeks, recorded as AEs.
- Change from baseline (Visit 1) in body weight and height, insulin-like growth factor 1 (IGF-1), and Tanner stage for children 10 to 17 years of age. | |
| 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) | - Percent change from baseline in total seizure frequency per 28 days for each (DS and LGS) cohort.
- Percent change from baseline in convulsive seizure frequency (DS) per 28 days.
- Percent change from baseline in MMD seizure frequency (LGS) per 28 days.
- Effect on the CGI-I and 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 QI-Disability. | |
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | | Belgium | | Canada | | China | | France | | Greece | | Hungary | | Italy | | Japan | | Latvia | | Netherlands | | Poland | | Russian Federation | | Serbia | | Spain | | Ukraine | | United States | |
| 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 | The end of the study for an individual subject is defined as the last protocol-specified contact with that subject.
The overall end of the study is defined as the last protocol-specified contact with the last subject ongoing in the study. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
