| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Epileptic Encephalitis: Dravet and Lennox Gastuat syndrome (LGS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Epileptic Encephalitis: Dravet and Lennox Gastuat syndrome (LGS) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To investigate the effect on the frequency of all seizures (convulsive and drop) in patients treated with TAK-935 as an adjunctive therapy compared to placebo in the Maintenance Period |
|
| E.2.2 | Secondary objectives of the trial |
Effect on freq. of convulsive and drop seizures in pts treated with TAK-
935 as adjunctive therapy compared to placebo throughout the
Treatmeant Period.
Effect on freq. of convulsive seizure in pts with Dravet Syndrome(DS) treated with TAK-935 as compared to placebo throughout Maintenance Period
Effect on freq. of drop seizure in patients with LGS treated with TAK-935 compared to placebo in Maintenance Period
Investigate the seizure freq. of LGS and Dravet pts, patients considered treatment responders throughout the Maintenance Period; treatment responders: Worsening of 25% or more, 1%-25%, no change in drop seizures from baseline(Worsening of 1% to Reduction of 1%);Reduction of: 25% or more, 50% or more, 75% or more, or 100% in drop seizures from baseline.
Change in CGI-S/C responses of Investigator and Care GI-C assessment in pts treated with TAK-935 compared to placebo
characterize relationship between plasma 24S-hydroxycholesterol levels and seizure frequency
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient and patient's legal representative (i.e., parent or legal guardian) are willing and able to read, understand, and sign the informed consent form and assent, if applicable
2. Male and female patients aged ≥2 and ≤17 years at the time of informed consent and the first dose of study drug
3. Clinical diagnosis of LGS and a history of, on average, ≥4 drop seizures per month during the 3 months immediately prior to Screening based on the historic information, and the patient has ≥4 drop seizures during a minimum of 4 weeks of seizure data collection during the prospective Baseline Period - OR - Clinical diagnosis of Dravet syndrome and a history of, on average, ≥3 convulsive seizures per month during the past 3 months based on the historic information, and the patient has ≥3 convulsive seizures during a minimum of 4 weeks of seizure data collection during the prospective Baseline Period
4. Weight of ≥10 kg at the Screening visit (Visit 1)
5. Currently taking 1 to 4 AEDs at a stable dose for 4 weeks prior to the Screening visit (Visit 1); benzodiazepines used chronically (on daily frequency) to treat seizures are considered AEDs
6. If using a vagal nerve stimulator (VNS), must have VNS placed at least 3 months prior to the Screening visit with stable settings for >1 month; VNS parameters must remain constant throughout the study (VNS will not be counted as an AED)
7. If on a ketogenic diet, must have started the ketogenic diet at least 3 months prior to the Screening visit (Visit 1), diet should be stable for 4 weeks before the Screening visit (Visit 1); and should continue through the duration of the study (ketogenic diet will not be counted as an AED)
8. Failed to become and remain seizure free with trials of at least 2 AEDs
9. The patient and patient's legal representative (i.e., parent or legal guardian) are willing to keep the AED, VNS, and ketogenic diet regimen(s) stable throughout the study
10. The patient is able to carry out all appropriate assessment and take study drug in the opinion of the Investigator and parent/caregiver
11. The patient has a documented clinical diagnosis of Dravet syndrome or LGS:
Diagnosis of Dravet syndrome supported by:
• Onset of seizures around 6 months of age
• Initial seizures
- Fever-induced or fever-triggered seizures
- Hemiclonic or generalized tonic seizures
- Prolonged seizures (approximately 15 minutes or longer, some >30 min)
• Between 1 and 5 years, other seizure types emerge:
- Myoclonic seizures
- Focal awareness altered
- Absence
- Non-convulsive status (absence or myoclonic)
- Convulsive status epilepticus
• Development normal within 1st year of life, then intellectual disability emerges
- May regress with recurrent status epilepticus
Diagnosis of Lennox-Gastaut syndrome supported by:
• History of abnormal EEG consistent with LGS
- EEG with slow and/or disorganized background AND one of the following:
o EEG with bursts of generalized 2.5 Hz (or less) spike and wave activity, OR
o Generalized paroxysmal fast activity (GPFA)
• Greater than 1 type of generalized seizure for at least 6 months
- At least 1 seizure type with drop seizures
• Less than 11 years of age at the onset of LGS
- Evidence of development delay or regression OR history of special education classed OR measured IQ <70
12. Sexually active female patients of childbearing potential (defined as first menarche) must agree to use a highly effective method of birth control during the study and for 1 month following the last dose of study drug. |
|
| E.4 | Principal exclusion criteria |
1. The patient has been admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months immediately prior to the screening visit
2. Non-epileptic events that cannot be reliably distinguished from epileptic seizures (eg, gastroesophageal reflux, muscle cramps, etc.)
3. Patients with history of confirmed cataract (untreated with surgery)
4. 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, which 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.
5. Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), within the 2 years immediately prior to the Screening Visit (Visit 1)
6. Suicide attempt within the last year, at significant risk of suicide (either in the opinion of the Investigator or defined as ‘yes’ to suicidal ideation question 4 or 5 on the Columbia-Suicide Severity Rating Scale [C-SSRS] at Screening) or appearing suicidal per Investigator judgment.
7. History of human immunodeficiency virus (HIV) infection (patient who has tested positive for human immunodeficiency virus antibodies (HIV)-
1/2Ab), or history of active hepatitis B, or active hepatitis C infection. (Note that patients who have been vaccinated against hepatitis B [hepatitis B surface antibody {Ab}-positive] who are negative for other markers of prior hepatitis B infection [eg, negative for hepatitis B Core Ab] are eligible)
8. Abnormal and clinically significant ECG abnormality at Screening
a. QT interval with Fridericia’s correction method (QTcF) >450 ms (males) or >470 ms (females), confirmed with one repeat testing, at the Screening visit
9. Abnormal clinical laboratory test results at the Screening visit that suggest a clinically significant underlying disease that would compromise the well-being of the patient (if the patient has alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST] >2.5 × the upper limit of normal [ULN], the Medical Monitor should be consulted)
10. Participated in a clinical study involving another study drug in the previous month (or 5 half-lives of the study drug, whichever is longer) or currently receiving another study drug
11. Received TAK-935 in a previous clinical study or as a therapeutic agent
12. Immediate family members, or in a dependent relationship with a study site employee who is involved in the conduct of this study (eg, child, sibling)
13. Known hypersensitivity to any component of the TAK-935 formulation
14. Currently pregnant or breastfeeding or is planning to become pregnant within 90 days of the last dose of study drug |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Efficacy Endpoint
• Percent change from Baseline in seizure frequency per 28 days (based only on convulsive seizures for the patients in the Dravet syndrome stratum and drop seizures for the patients in the LGS stratum) in patients receiving TAK-935 as compared to placebo during the Maintenance Period. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary end point will be assessed throughout the study. |
|
| E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints
• Percent change from Baseline in seizure frequency per 28 days (based only on convulsive seizures for the patients in the Dravet syndrome stratum and drop seizures for the patients in the LGS stratum) in patients receiving TAK-935 as compared to placebo during the Treatment Period.
• Percent change from Baseline in convulsive seizure frequency per 28 days in patients randomized to the Dravet syndrome stratum and receiving TAK-935 as compared to placebo during the Maintenance Period
• Percent change from Baseline in drop seizure frequency per 28 days in patients randomized to the LGS stratum and receiving TAK-935 as compared to placebo during the Maintenance Period
• Proportion of patients in the LGS stratum considered treatment responders throughout the Maintenance Period; treatment responders defined as those with:
- Worsening of 25% or more in drop seizures from baseline
- Worsening of 1% to 25% in drop seizures from baseline
- No change in drop seizures from baseline (Worsening of 1% to
Reduction of 1%)
- Reduction of 25% or more in drop seizures from baseline
- Reduction of 50% or more in drop seizures from baseline
- Reduction of 75% or more in drop seizures from baseline
- Reduction of 100% in drop seizures from baseline
• Proportion of patients in the Dravet syndrome stratum considered treatment responders throughout the Maintenance Period; treatment responders are defined as those with:
- Worsening of 25% or more in convulsive seizures from baseline
- Worsening of 1% to 25% in convulsive seizures from baseline
- No change in convulsive seizures from baseline (Worsening of 1% to
Reduction of 1%)
- Reduction of 25% or more in convulsive seizures from baseline
- Reduction of 50% or more in convulsive seizures from baseline
- Reduction of 75% or more in convulsive seizures from baseline
- Reduction of 100% in convulsive seizures from baseline
• Change in CGI-S/C responses of Investigator reported impression of efficacy and tolerability of study drug
• Change in Care GI-C responses of parent/family reported impression of efficacy and tolerability of study drug
• To characterize plasma 24HC levels and change in seizure frequency in patients treated with TAK-935 as an adjunctive therapy
|
|
| 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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Israel |
| Poland |
| Portugal |
| Spain |
| 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
|
| It has been defined as the last subject last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 8 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 22 |
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