Natural History Study of Infants and Children With Developmental and Epileptic Encephalopathies

Study Overview
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Brief Summary
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This is a multicenter, prospective, 2-year observational study in infants and children with developmental and epileptic encephalopathies (DEEs). The DEE currently being investigated is SCN1A-positive Dravet Syndrome.

Detailed Description
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This prospective, longitudinal, natural history master protocol has been designed to define the seizure, neurodevelopmental, and behavioral characteristics of SCN1A-positive Dravet Syndrome in infants and children between 6 and 60 months. It will also explore the impact of the disease on the participant's parent/caregiver quality of life (QoL) and healthcare resource utilization (HCRU).

Official Title
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ENVISION: Natural History Study of Infants and Children With Developmental and Epileptic Encephalopathies

Conditions
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Dravet Syndrome

Intervention / Treatment
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* Other: No Intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 6 months and 60 months. Confirmed SCN1A mutation. Normal development prior to onset of first seizure as defined by the Centers for Disease -Control and Prevention (CDC 2019). Onset of seizures between age 3 and 15 months, inclusive. Exclusion Criteria: Copy number variant of SCN1A, including SCN1A microdeletion, if affecting other genes. SCN1A mutation present on both alleles. Known pathogenic or clinically suspected mutation in a seizure-associated gene besides SCN1A. Confirmed mutation in a gene besides SCN1A that is known to increase the severity of the seizure phenotype. Known gain-of-function genetic mutation, as defined by functional studies, including p.Thr226Met. History of notable developmental deficit that was evident prior to seizure onset. Known central nervous system structural abnormality as found on magnetic resonance imaging or computed tomography scan of brain. Currently taking or has taken for 6 or more consecutive weeks anti-seizure medications (ASMs) at a therapeutic dose that are contraindicated in SCN1A-positive Dravet Syndrome, including sodium channel blockers. Known concomitant genetic mutation or clinical comorbidity that potentially confounds typical Dravet phenotype.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 60 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| SCN1A-positive Dravet Syndrome<br>Participants aged between 6 and 60 months of age who have SCN1A-positive Dravet Syndrome. Clinical, neurocognitive, laboratory, the burden of disease, and health care resource utilization will be assessed. | Other: No Intervention<br>* No Intervention<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure burden | Measured using monthly seizure frequency derived from seizure diaries. | Change from Baseline at 24 months | 
| Seizure freedom | Measured using the proportion of seizure-free days observed. | Change from Baseline at 24 months | 
| Use of anti-seizure medication(s) | Measured using the incidence of anti-seizure medication usage observed during the 60 days leading up to each nominal visit. | Baseline through Month 24 | 
| Use of Special Diet | Measured using the incidence of ketogenic/high-fat diet usage observed during the 60 days leading up to each nominal visit. | Change from Baseline at 24 months | 
| Cognitive functioning | Measured using composite scores from 3 domains in the Bayley Scales of Infant and Toddler Development (3rd Edition) instrument. Domains include: (1) Cognitive; (2) Language; (3) Motor. Composite scores are normalized to a mean and SD of 100 and 15, respectively (range is not applicable as the scores are unbounded). Higher scores correspond to better outcomes compared to a normal population. | Change from Baseline at 24 months | 
| Behavioral and social functioning | Measured using raw scores from 2 domains in the Brief Infant Toddler Social Emotional Assessment. Domains include: (1) Problem; and (2) Competence. Domain raw scores range from 31 to 93 and 11 to 33 for the Problem and Competence domains, respectively. Higher Problem scores correspond to worse outcomes. Higher Competence scores correspond to better outcomes | Change from Baseline at 24 months | 
| Motor functioning | Measured using categorical outcomes of 7 motor items adapted from the Bayley Scales of Infant and Toddler Development instrument and NorthStar Ambulatory Assessment. Motor milestones include: (1) Sit unassisted for 30 seconds; (2) Walk with assistance; (3) Stand alone; (4) Walk alone; (5) Walk upstairs; (6) Run with Coordination; and (7)Jump forward. | Baseline through Month 24 | 
| Incidence of Adverse Events | Measured using the incidence of adverse events and serious adverse events (broken down by preferred term) observed during the study. | Baseline through Month 24 | 
| Overall survival | Measured using the incidence of death observed by a given time point during the study. | Baseline through Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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severe myoclonic epilepsy, epilepsy, severe myoclonic epilepsy of infancy, SMEI, SCN1A related seizure disorder, epileptic encephalopathy, developmental and epileptic encephalopathies, DEE