Clinical trial NCT06504511: SCN1A Horizons A Natural History Study of SCN1A-related Epilepsies in the United Kingdom
Official title: SCN1A Horizons A Natural History Study of SCN1A-related Epilepsies in the United Kingdom
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: SCN1A
Dravet Syndrome
Epilepsy
Keywords: Epilepsy
SCN1A
Natural History
Developmental Outcome
Lead sponsor: NHS Greater Glasgow and Clyde
Sponsor class: OTHER
First posted: 2024-07-16
Enrollment: 400
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Approximately 400 participants with a minimum of 2 years of follow-up are planned to be enrolled. Recruitment will be stratified according to the following age distribution:

* 300 patients in the Comprehensive study arm (clinical and face-to-face neurodevelopmental assessments)

  * Approximately 60 participants aged 6 to 35 months
  * Approximately 80 participants aged 3 to 6 years inclusive
  * Approximately 100 participants aged 7 to 16 years inclusive
  * Approximately 60 participants aged 17 years and older
* 100 patients in the Basic study arm (clinical and non-face-to-face neurodevelopmental assessments), in case the age specific quota in the Comprehensive study arm has been filled.

Brief summary: The aims of this prospective natural history study are to define the seizure, neuro-developmental, and behavioural characteristics of SCN1A-related epilepsies/Dravet syndrome in children and adults longitudinally over a period of three years. In addition, this study will compare missense and truncating genotypes in terms of i) rates of change of countable convulsive seizures per month and ii) neurodevelopmental outcome and trajectories.

Detailed description: Our aim is to define the seizure, neurodevelopmental, and behavioural characteristics of SCN1A-related epilepsies/Dravet syndrome in children and adults longitudinally over a period of three years. In addition, this study will compare missense and truncating genotypes in terms of i) rates of change of countable convulsive seizures per month and ii) rate of change in neurodevelopmental outcomes over time. The investigators will therefore prospectively study the natural history of SCN1A-related epilepsies and Dravet syndrome in the UK. In order to explore established and novel treatments, including new medications, it is important to not only document seizure frequency but also behaviour, learning and motor function. Treatment interventions are key to prevent the neurodevelopmental comorbidities of Dravet syndrome; as such sensitive measures of disease progression and a clear prospective description of the natural history of the disease across the lifespan is required to know whether therapies are transformative.

Although the decline in neurodevelopmental profile and motor function in patients with SCN1A-related epilepsies/Dravet syndrome have been described, no large scale long-term, prospective studies of cognition and motor function have been conducted in SCN1A-related epilepsies/Dravet syndrome with established measures.

The SCN1A/Dravet syndrome natural history study will provide a platform to systematically collect longitudinal validated outcome measures for SCN1A variant-carrying patients across the UK. The study will prospectively assess changes in cognition, behaviour, and quality of life, as well as other co-morbidities.

A number of important questions relating to the natural history of SCN1A-related epilepsies/Dravet syndrome over the lifespan remain unanswered:

* It is not understood the precise neurodevelopmental profile and decline of individuals with SCN1A-related epilepsies over time and which factors might modify this?
* There are no reliable biomarkers that can inform disease severity or treatment planning
* What impact does the underlying genotype have on the neurodevelopmental outcome?
* Do clinical features such as the occurrence of repeated episodes of status epilepticus and/or contraindicated medication use worsen the neurodevelopmental outcome?
* What is the seizure burden across different ages and does treatment response change over the lifespan?
* There is a lack of understanding of the comorbidity profile that individuals with SCN1A-related epilepsies experience over the lifespan
* More information is required on the socio-economic impact SCN1A-related epilepsies have on affected individuals, families and society

Eligibility criteria: Patients meeting the following inclusion criteria will be considered eligible for this study:

1. Patient and/or legally authorised representative must be willing and able to give informed consent/assent for participation in the study.
2. Patient and parent/caregiver are willing and able (in the Investigator's opinion) to comply with all study requirements (including ability and willingness to comply with virtual visits).
3. Participant has a confirmed pathogenic (class 5) or likely pathogenic (class 4. SCN1A variant, as demonstrated by genetic testing.

Exclusion criteria:

Patient has any other significant disease or disorder which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study, or may affect the patient's ability to participate in the study.

Primary outcomes:
measure: Countable convulsive seizures per month
timeFrame: Up to 3 year follow up
measure: Bayley Scales of Infant and Toddler Development 4th UK Edition (Bayley-4)
timeFrame: Administration will occur 6-monthly for patients <7 years old and 12-monthly for patients 7 years and older. There is a planned 2-3 year follow up.
measure: Wechsler Preschool and Primary Scale of Development 4th UK Edition (WPPSI-IV)
timeFrame: Administration will occur 6-monthly for patients <7 years old and 12-monthly for patients 7 years and older. There is a planned 2-3 year follow up.
measure: Wechsler Intelligence Scale for Children 5th UK Edition (WISC-V)
timeFrame: Administration will occur 6-monthly for patients <7 years old and 12-monthly for patients 7 years and older. There is a planned 2-3 year follow up.
measure: Wechsler Adult Intelligence Scale 4th UK Edition (WAIS-IV)
timeFrame: Administration will occur 12-monthly. There is a planned 2-3 year follow up.
measure: Vineland Adaptive Behaviour Scales - Third Edition
timeFrame: Participants age <7 will have a Vineland assessment completed every 6 months, participants age 7 years and older will have a Vineland assessment completed every 12 months.
Secondary outcomes:
measure: Occurrence and frequency of status epilepticus
timeFrame: Up to 3 year follow up
measure: Grantham Score
timeFrame: Baseline
measure: Combined Annotation Dependent Depletion (CADD) score
timeFrame: Baseline
measure: Rare Exam Variant Ensemble Learner (REVEL) score
timeFrame: Baseline
Other outcomes:
Locations:
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Children
Study officials:
affiliation: NHS Greater Glasgow & Clyde
name: Andreas Brunklaus, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: