SCN1A Horizons A Natural History Study of SCN1A-related Epilepsies in the United Kingdom

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.

Study Overview

• Status: Recruiting
• Conditions: Epilepsy; Dravet Syndrome; SCN1A

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

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Kirsty Hendry, PhD; Phone Number: 0141 451 5888; Email: SCN1AHorizons@glasgow.ac.uk
• Study Contact Backup: Name: Andreas Brunklaus, MD PhD; Phone Number: 0141 451 5888; Email: andreas.brunklaus@glasgow.ac.uk

Study Locations

• United Kingdom
  • Glasgow, United Kingdom, G51 4TF
    • Recruiting
    • Royal Hospital For Children
    • Contact: Kirsty Hendry, PhD; Phone Number: 0141 4515888; Email: kirsty.hendry@glasgow.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• 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.

Description

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.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Countable convulsive seizures per month	A 4-week seizure diary will be completed by caregivers or participants (where they have capacity to do so) every 6 months.	Up to 3 year follow up
Bayley Scales of Infant and Toddler Development 4th UK Edition (Bayley-4)	Patients in the comprehensive arm who are <30 months of age will be administered the Bayley-4. Participants older than 30 months old may be administered the Bayely-4 if they are unable to access age-appropriate assessment. Standard scores range from 45-155 on each domain (cognitive, language & motor). Growth Scale Values range from 428-559. Higher scores are indicative of higher developmental functioning.	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.
Wechsler Preschool and Primary Scale of Development 4th UK Edition (WPPSI-IV)	Patients in the comprehensive arm who are ≥2 years 5 months and ≤6 years of age will be administered the WPPSI-IV at Baseline. If the patient is unable to access the WPPSI-IV, they will be administered the Bayley-4 in addition to the WPPSI-IV at Baseline. Composite score for each domain ranges from 45-155. Composite full scale score ranges from 40-160. Higher scores are indicative of higher developmental functioning.	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.
Wechsler Intelligence Scale for Children 5th UK Edition (WISC-V)	Patients in the comprehensive arm aged 6 years to 16 years will be administered the WISC-V at baseline. If the patient is unable to access the WISC-V they will be administered the WPPSI-IV in addition to the WISC-V at Baseline. Participants will drop down to the Bayley-4 if they are unable to access the WPPSI-IV. Administration will occur 6-monthly for patients <7 years old and 12-monthly for patients 7 years and older. Composite score for each domain ranges from 45-155. Composite full scale score ranges from 40-160. Higher scores are indicative of higher developmental functioning.	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.
Wechsler Adult Intelligence Scale 4th UK Edition (WAIS-IV)	Patients in the comprehensive arm aged 16 years and older will be administered the WAIS-IV, 12-monthly. Composite score for each domain ranges from 50-150. Composite full scale score ranges from 40-160. Higher scores are indicative of higher developmental functioning.	Administration will occur 12-monthly. There is a planned 2-3 year follow up.
Vineland Adaptive Behaviour Scales - Third Edition	All patients in the comprehensive and basic arm will be administered the Vineland Adaptive Behaviour Scales - Third Edition, which will be completed by the caregiver. Raw scores range from 0-116. Standard scores range from 20-140. Growth Scale Values range from 10-197. Higher scores are indicative of higher developmental functioning.	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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence and frequency of status epilepticus	Information obtained during 6-monthly standard of care clinical visit with Consultant Paediatric Neurologist for all patients.	Up to 3 year follow up
Grantham Score	A measure of physiochemical difference between amino acids. The score can range from 5-215, with a higher score indicative of more radical change in amino acid properties.	Baseline
Combined Annotation Dependent Depletion (CADD) score	Score of the deleteriousness of single nucleotide variants and insertion/deletion variants in the human genome. The score can range from 1-99, with higher values indicating more deleterious cases.	Baseline
Rare Exam Variant Ensemble Learner (REVEL) score	Predicts the pathogenicity of missense variants. The score can range from 0-1, with higher scores indicating a higher likelihood of the variant being disease-causing.	Baseline

Collaborators and Investigators

• Sponsor: NHS Greater Glasgow and Clyde
• Investigators: Principal Investigator: Andreas Brunklaus, MD PhD, NHS Greater Glasgow & Clyde

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: June 4, 2024
• First Submitted That Met QC Criteria: July 15, 2024
• First Posted (Actual): July 16, 2024

Study Record Updates

• Last Update Posted (Actual): July 16, 2024
• Last Update Submitted That Met QC Criteria: July 15, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Epilepsy; Natural History; SCN1A; Developmental Outcome
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy, Generalized; Epileptic Syndromes; Epilepsy; Epilepsies, Myoclonic
• Other Study ID Numbers: GN20NE522P; 295069 (Other Identifier: IRAS); 316675 (Other Identifier: IRAS)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No