E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Five different types of developmental and epileptic encephalopathies (DEEs): SYNGAP1 and STXBP1 encephalopathies, inv-dup(15) encephalopathy, multifocal or bilateral Malformations of Cortical Development and Continuous Spikes And Waves During Sleep Syndrome. |
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E.1.1.1 | Medical condition in easily understood language |
A group of 5 severe epilepsies that are characterized both by seizures, which are often drug-resistant, as well as encephalopathy (significant developmental delay or even loss of developmental skills) |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053551 |
E.1.2 | Term | Intractable epilepsy |
E.1.2 | System Organ Class | 100000004852 |
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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 |
The main goal is to identify if there is a reduction in seizure frequency in patients comparing before and after treatment with fenfluramine in five specific types of developmental and epileptic encephalopathies (DEEs). |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives of this study are the analysis of changes in seizure intensity and duration, and "non-epileptic outcomes" such as variations in cognitive activity, level of alertness, impulsivity/self-control, gait stability and other alterations that might be detected during the interview and physical examination. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
General inclusion criteria:
- Age between 2 and 35 years (both included). - Diagnosis of epilepsy associated with some degree of intellectual disability, starting before 11 years of age. - All patients will have a phenotype consistent with their genetic, electroclinical or neuroimaging diagnosis.
Specific inclusion criteria per group:
o Group 1:
Non-controlled epilepsy after failing at least 3 antiseizure medications, with a minimum of 4 countable seizures with motor semiology per month during the baseline period of 3 months.
- Group 1A: Patients with genetic testing showing a pathogenic or likely pathogenic variant in main synaptopathy genes (SYNGAP1 and STXBP1).
- Group 1B: Patients with genetic testing showing a pathogenic or likely pathogenic inverted duplication of chromosome 15 [inv-dup (15)].
- Group 1C: Patients with neuroimaging showing multifocal or bilateral malformations of cortical development.
o Group 2:
Electroclinical diagnosis of Continuous Spikes and Waves during Sleep (CSWS) syndrome, with baseline video-EEG monitoring showing epileptiform activity occupying at least 50% of slow sleep tracing, after failing at least 3 antiseizure medications.
Additional inclusion criteria:
In addition, all subjects must meet all of the following inclusion criteria to be enrolled into the study:
- Subject is male or non-pregnant, non-lactating female. Female subjects of childbearing potential must not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative urine or serum pregnancy test at screening and during the study.
- Receiving at least 1 concomitant antiseizure medications (ASMs) and up to 4 concomitant ASMs, inclusive. KD and VNS are permitted but do not count towards the total number of ASMs. Rescue medications for seizures are not counted towards the total number of ASMs.
- All medications or interventions for epilepsy (including ketogenic diet and vagal nerve stimulation) must be stable for at least 4 weeks prior to screening and are expected to remain stable throughout the study.
- Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian.
- Subject has provided assent in accordance with Institutional Review Board (IRB)/Ethics Committee requirements, if capable.
- Subject’s parent/caregiver is willing and able to be compliant with diary completion, visit schedule and study drug accountability. |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria will not be enrolled into the study:
- Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication. - Subject has only non-motor seizures (such as absences), for group 1. - Subject has pulmonary arterial hypertension. - Subject has current or past history of cardiovascular or cerebrovascular disease. - Subject has current or recent history of Anorexia Nervosa, bulimia, or depression within the prior year that required medical treatment or psychological treatment for a duration greater than 1 month. - Subject has a current or past history of glaucoma. - Subject has moderate or severe renal or hepatic impairment. - Subject is receiving concomitant therapy with any of the following: centrally-acting anorectic agents; monoamine-oxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; other centrally-acting noradrenergic agonists. - Subject is currently receiving an investigational product. - Subject has participated in another clinical trial within the past 30 days (calculated from that study’s last scheduled visit). - Subject is at imminent risk of self-harm or harm to others. - Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions. - Subject is institutionalized in a general nursing home (i.e., in a facility that does not provide skilled epilepsy care). - Subject does not have a reliable caregiver who can provide seizure diary information throughout the study. - Subject has a severe clinically significant condition. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Regarding the goal of evaluating a reduction in seizure frequency and to assess favorable response or lack of favorable response in the selected groups of patients treated with fenfluramine the following will be evaluated:
- Percent change in frequency of seizures with motor semiology (both groups) and quantified epileptiform activity during slow sleep (group 2), after 12 weeks of treatment.
- Responder rate (percentage of patients experimenting a 50% decrease in seizure frequency -group 1- or quantified epileptiform activity during slow sleep -group 2) after 12 weeks of treatment. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 12 weeks of treatment. |
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E.5.2 | Secondary end point(s) |
Regarding the secondary goal of assessing changes in seizure intensity and duration, and in non-epileptic outcomes, to assess favorable response or lack of favorable response in the selected groups of patients treated with fenfluramine, the following will be evaluated:
- Percent change in seizure intensity scales, executive and behavioral measures, sleep evaluation, functional scales and quality of life measures (for both groups), after 12 weeks of treatment. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 12 weeks of treatment. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Changes in cognition, motor and behaviour functions. |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | Yes |
E.8.1.7.1 | Other trial design description |
exploratory, proof of concept |
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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.8.2.4 | Number of treatment arms in the trial | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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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Responders will have the option to continue into a 9-month extension. Minimum response to allow patients to continue with treatment will be 25% decrease in seizure frequency (group 1) and 25% decrease in quantified epileptiform activity (group 2). In the case that this minimum is not reached but there is a clinical impression of significant improvement from both caregivers and investigators, it will be analysed, taking into account if there is a relevant improvement in functional scales. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 12 |
E.8.9.1 | In the Member State concerned days | 0 |