ENVISION: Natural History Study on Children with Dravet Syndrome

  • Research type

    Research Study

  • Full title

    ENVISION: Natural History Study of Infants and Children with SCN1A-positive Dravet Syndrome

  • IRAS ID

    289946

  • Contact name

    Andreas Brunklaus

  • Contact email

    Andreas.Brunklaus@ggc.scot.nhs.uk

  • Sponsor organisation

    Encoded Therapeutics, Inc.

  • ISRCTN Number

    ISRCTN00000000

  • Clinicaltrials.gov Identifier

    NCT04537832

  • Duration of Study in the UK

    3 years, 6 months, 17 days

  • Research summary

    Research Summary

    The ENVISION study is being conducted to describe the seizure, neurodevelopmental, and behavioural characteristics of Dravet Syndrome in children 6 to 60 months of age who have an SCN1A genetic mutation.

    Studies like the ENVISION study are important for medical advances. Current treatments for diseases are only available because of research study volunteers. This study is being done to understand as much as we can about the trajectory of children living SCN1A+ Dravet syndrome. The data collected from this study will contribute to a planned clinical trial examining a gene therapy drug that aims to improve the seizure burden and neurodevelopmental aspects of SCN1A+ Dravet Syndrome patients.

    Approximately 50 children and their caregivers will participate in this study at approximately 15 locations in Australia, the United Kingdom and the United States.
    Participants will be children (both male and female) aged between 6 months and 60 months, previously diagnosed with SCN1A-positive Dravet Syndrome.

    Participation includes a Screening Period (up to 3 months) and an Observation Period (24 months). The duration of the Screening Period depends on when the results of the screening assessments, inclusive of the eligibility review by the Independent Adjudication Committee (IAC) and the Sponsor.

    The participants are expected to undergo the following assessments:
    Site and Clinician Assessments will include informed consent, participant eligibility, demographics and medical history, assessment of International League Against Epilepsy (ILAE), characteristics, safety assessments (physical examination, vital signs, clinical laboratory tests non-treatment adverse events [NT-AEs], concomitant medications, procedures), in-depth interviews of parents/caregivers and participants (optional), survival, ketogenic diet use, Bayley Scales of Infant and Toddler Development® 3rd Edition (BSID-III), Wechsler Preschool & Primary Scale of Intelligence™ 4th Edition (WPPSI-IV), motor developmental milestones, and the Neuromuscular Gross Motor Outcome (GRO).
    Parent/Caregiver Reported:
    Assessments pertaining to subject
    Observer reported assessments will include a seizure diary, at-home video documentation of seizures and motor milestones (optional), Gillette Functional Assessment Questionnaire (Gillette FAQ), Pediatric Quality of Life Inventory (PedsQL), Parent Report Form of Vineland Adaptive Behavior Scales 3rd Edition (Vineland-3), Children’s Sleep Habits Questionnaire (CSHQ), Brief Infant Toddler Social Emotional Assessment (BITSEA), Behavior Rating Inventory of Executive Function – Preschool
    Version (BRIEF-P), Child Behavior Checklist (CBCL), Strengths Difficulties Questionnaire (SDQ), and Pediatric Evaluation of Disability Inventory (PEDI).
    Assessments pertaining to parent/caregiver
    Pittsburg Sleep Quality Index (PSQI), EuroQol-5 Dimension-5 Level (EQ-5D-5L), Work Productivity and Activity Impairment Dravet Syndrome Caregiver Questionnaire (WPAI: DS-CG), and 12-Item Short Form Survey Version 2 (SF-12).
    Assessments pertaining to participant and parent/caregiver
    Health Care Resource Utilization questionnaire

    Summary of Results

    Encoded has conducted a prospective natural history study of children living with SCN1A+ Dravet Syndrome. The objectives of this natural history study, called ENVISION, were to further define the seizure, neurodevelopmental, and behavioral characteristics of SCN1A-positive Dravet Syndrome in children aged 6 to 60 months, inclusive at the time of enrollment. The data collected from this study will serve to as an external control to clinical trials examining ETX101in patients with SCN1A-positive Dravet Syndrome.
    Between December 2020 and March 2023, 70 children with DS were screened and 58 enrolled at 16 sites in North America, United Kingdom, Spain and Australia. Participants were followed and assessed for up to 2 years with the median follow-up being 17.5 months (range 0.0–24.0 months), 54/58 (93.1%) followed for at least 6 months and 51/58 (87.9%) for 12 months. The median age was 2.3 years (range: 0.5–4.9 years) and 46.6% of participants were younger than 2 years at Baseline. Eligible participants had a clinical diagnosis of DS and a pathogenic or likely pathogenic SCN1A variant (SCN1A+ DS). Truncating variants were identified in 70.7% of participants and pathogenic missense variants in 25.9% of participants.
    Results
    Participants were evaluated every 3 months during the study. Seizure burden was assessed using an electronic diary completed during the 28 days leading up to each post-Baseline visit. The diary captured daily seizure counts and rescue medications used for calculation of the following endpoints: monthly countable seizure frequency (MCSF), total seizure-free days, number of prolonged seizures (lasting 5 to 30 minutes) and status epilepticus (seizure lasting >30 minutes) (24), and days of rescue medication use. MCSF was defined as the (scaled) sum of countable seizures over 28 days, which included focal motor seizures with observable clinical signs (including hemiclonic seizures), tonic, generalized tonic-clonic/clonic, and atonic seizures.
    The median age at first seizure was 5.0 months (range: 2–10). The cohort had a median of 3 seizure types (range: 1–7), the most common being tonic‐clonic (84.3% at Baseline) and hemiclonic (83.0% at Baseline). Participants were taking a median of 3 ASMs (range: 0–7), which increased with age (3.0 in the youngest vs. 4.0 in the oldest age group). Clobazam (60.3%), valproic acid (53.4%), cannabidiol (43.1%), levetiracetam (37.9%), and fenfluramine (36.2%) were the most frequently used ASMs.
    Seizure burden increased with age from a median (range) MCSF of 1.0 in the youngest (1.0 to 70.0) and middle (1.0 to 242.0) age groups to 4.5 (0.0 to 2647.0) in the oldest age group. Participants with extremely high seizure burden (>14 seizures and/or use of rescue medication on >4 days within a 28-day period) constituted 16-28% of the cohort and typically had very frequent atonic seizures. Potential predictors of seizure frequency were examined using a mixed model for the log-transformation of MCSF. Age at the time of assessment was the only significant covariate (effect size 0.52, P=0.024); age at first seizure, sex, pathogenic variant type and the number of Baseline ASMs were not predictive of seizure burden.
    Between nominal visits, cognitive raw scores of the BSID-III showed a significant increase only in those <2 years of age at enrollment. Despite the gains in the <2 years cohort, a continued decline in normalized scores by 2 points/year suggests widening cognitive deficits relative to neurotypical peers. Similarly, language develop shows a similar distinctive pattern between those <2 and >= 2 years. Composite communication scores from BSID-III and Vineland-III showed that prior to 2 years of age, participants were comparable to neurotypical peers. However, those >2 years of age exhibited substantial delay in communication functioning. Motor function mirrored the same pattern. Mobility scores from the PEDI showed a critical threshold at age 2 years, when mobility gains slowed noticeably.
    All assessments applied in the ENVISION study consistently illustrated severe global developmental delay in children by the time they are 4 years of age. Adaptive functioning, as measured by the ABC score of the Vineland-III showed that after age 3 years 7 months, all participants showed developmental quotient <60%. The BRIEF-P showed executive function deficits were evident by age 2 years and worsened over time, with some children falling 5 SDs above the normative mean. The BSID-III gross motor, cognitive, and language assessments show developmental quotients below 60% after 3:6. Linear mixed-effects modeling showed that global developmental delay is independent of seizure burden.
    Health-related quality of life showed clear impacts for both the child and caretakers in ENVISION- with effects of both mental and physical health as shown using quantitative tools such as the PedsQL and SF-12. In-depth, qualitative interviews, illustrated that caregivers’ HRQoL is particularly challenging and negatively impacted during the early years and, as the child grows, the physical burden of caregiving increases.

  • REC name

    London - Camden & Kings Cross Research Ethics Committee

  • REC reference

    21/LO/0064

  • Date of REC Opinion

    16 Feb 2021

  • REC opinion

    Further Information Favourable Opinion