The KCNT1-Related Epilepsy Study

Abstract

Background and Objectives

KCNT1-related epilepsy is an ultra-rare pediatric-onset developmental and epileptic encephalopathy with a broad clinical phenotype ranging from, most commonly, severe infantile-onset epilepsy and global developmental delay to, less commonly, milder phenotypes including sleep-related seizures, autism spectrum disorder, and learning disability. We initiated the first-ever prospective natural history study to comprehensively clinically phenotype individuals affected by this disorder.

Methods

The primary aim of this study was to characterize seizures in individuals with KCNT1-related epilepsy. Secondary and exploratory aims included characterization of the full spectrum of disease symptoms, understanding caregiver burden, and collection of blood and urine samples for biomarker exploration. All study activities were conducted remotely (e.g., home-based assessments, telehealth visits).

Results

Thirty-five participants (n = 20 male, 15 female) were enrolled in this study. The average age at the baseline visit was 76.0 months (s.d. = 75.5). This article presents the study design and methods and several challenges that arose in its implementation and discusses various solutions implemented in this medically complex population.

Discussion

Future work will apply the lessons from this study in the planning and design of clinical trials for KCNT1-related epilepsy and possibly other developmental and epileptic encephalopathies.

Introduction

Potassium-sodium-activated channel subfamily T member 1 (KCNT1)–related epilepsy is an ultra-rare genetic disorder resulting from de novo or inherited pathogenic variants in the KCNT1 gene. KCNT1 encodes the “Slack” or Slo2.2 sodium-activated potassium channel, affecting neuronal excitability through its role in neuronal repolarization and hyperpolarization following action potentials. Incidence or prevalence are not well known. A recent study in Denmark reported a birth incidence of ≤1.12 per 100,000 live births, and annual incidence rate of 0.04 per 100,000 persons.¹ A prior, 2-year study of patients in the United Kingdom found slightly higher birth incidence of 0.26 and 0.55 cases per 100,000 live births in the first and second years of the study, respectively, leading the authors to estimate UK prevalence of 0.11 per 100,000 persons across the study period.² However, estimated incidence and prevalence may increase as gene panel, exome, and genome testing become more commonplace in pediatric epilepsy, and research and awareness of this disorder grows. For example, patient advocacy efforts powered by social media and word-of-mouth have identified around 500 confirmed cases globally, half of which were identified in the United States.³

The most common and severe clinical phenotypes of KCNT1-related epilepsy are epilepsy of infancy with migrating focal seizures (EIMFS) and early infantile developmental and epileptic encephalopathies (EIDEE). Both involve multiple, treatment-resistant daily seizures beginning in the first 6 months of life, acquired microcephaly, and profound intellectual and developmental delay.^4-6 Individuals with EIMFS or EIDEE are also at a high risk of sudden unexpected death in epilepsy.^5,7 A less severe phenotype is sleep-related hypermotor epilepsy (SHE), previously called autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Seizure onset for individuals with SHE commonly begins in the first decade of life and can be accompanied by intellectual and developmental delay, autism spectrum disorder ranging in severity from level 1 (requiring support) to level 3 (requiring very substantial support), executive dysfunction, psychiatric symptoms, and/or sleep disorders.^6,8

Irrespective of phenotype, no available disease-modifying therapies exist; care is focused on symptom management, particularly seizure control. However, there is little systematic knowledge regarding clinical phenotype, symptom progression, and clinical outcomes for affected individuals. Therefore, current management strategies are individually based, and further guidance is desirable regarding the collective patient experience. In addition, with multiple drug development efforts in progress, including potential disease-modifying therapies, there is a need to establish valid, responsive clinical outcome measures that are meaningful for patients and families. It would also be helpful to identify biomarkers sensitive to disease state and provide precise and responsive signals for efficacy and safety monitoring. The authors therefore established “A Natural History Study of Participants With KCNT1-Related Epilepsy (K1Te). The study goals were to characterize the natural history of KCNT1-related epilepsy and inform biomarker discovery to aid future clinical studies. The study's primary end point was seizure frequency and type. Secondary and exploratory study objectives included measurement of developmental and growth milestones, understanding the full spectrum of KCNT1-related symptoms and their management, collection of samples for biomarker and genetic analyses, and assessment of adaptive function, quality of life, and caregiver burden.

Study Design

Methods—Overview

The K1Te Study was a nonrandomized, nondrug, 12-month prospective, longitudinal, fully-decentralized, single-center study conducted by the University of Rochester Medical Center (URMC), Rochester, New York. All study visits were completed at home by contracted health care vendors, virtual appointments with study personnel, and questionnaires. The investigators, study sponsor, and contract research organization (CRO) met weekly to discuss study progress.

Recruitment Strategy and Advocacy Group Partnership

The KCNT1 Epilepsy Foundation, a national nonprofit organization with global outreach, provided input on study design and heavily supported recruitment. IRB-approved recruitment materials were disseminated by the Foundation and to participants enrolled in the KCNT1/Migrating Partial Seizures of Infancy contact registry at URMC. The ultimate decision to implement a fully remote study design was borne out of the COVID-19 pandemic but was also critically informed by needs and preferences expressed by the KCNT1 patient community who advocated for a decentralized study plan.

Inclusion/Exclusion Criteria

Target enrollment was 40 participants, based on the number of affected individuals within the contact registry and known by the KCNT1 Epilepsy Foundation. Eligible participants were birth through 50 years of age with clinical signs and a confirmed genetic diagnosis of KCNT1-related epilepsy. Individuals were excluded if they had a known benign variant. Other exclusion criteria were HIV infection history, CNS tumors, malignancies/metastatic disease, current or past enrollment in an investigational gene therapy study; current enrollment in an interventional study of an investigational or approved drug; positive urine pregnancy test; and any condition that in the judgment of the PI would interfere with assessment of KCNT1-related epilepsy features and was not clearly related to that primary diagnosis. Any and all concomitant therapies including prescription and nonprescription medications, supplements, vaccines, etc., were allowed; their use was neither prescribed nor modified by the investigator.

Visit Structure

Participants completed a screening visit and 5 study visits. The screening visit preceded the baseline/visit 1 to review inclusion/exclusion criteria and obtain informed consent (parental permission). Visits 1–5 were performed at 3-month intervals over 1 year. Study activities included collection of medical history, demographics, history of seizures and antiseizure treatment, completion of a seizure diary, a home-based wearable seizure tracking device, and identification of up to 4 participant-specific “most concerning symptoms” tracked throughout the study using a visual analog scale. For premature withdrawals (self- or investigator-directed), the study team attempted to conduct a final visit per the scheduled activities for visit 5.

Before each study visit, the coordinator contacted families to schedule study activities. The coordinator and PI met with the participant and caregiver(s), in all cases one or both of the child's parents, at the beginning of each study visit via telehealth. During this meeting, medication reconciliation and a physical examination, including neurologic examination, were conducted, and the Clinical Global Impression (CGI) scale (description below) was completed. Parents received education on diary compliance and were asked to alert the study team to any adverse or reportable events including new symptoms, hospitalizations, or changes in medications or seizure type. Separately, the Vineland Adaptive Behavior Scales-Third Edition (Vineland-3) Comprehensive Interview was completed with a study psychologist via telehealth.⁹

Parents maintained a daily seizure diary throughout study participation, and a one-week sleep diary for each study visit. Parents also completed assessments of quality of life, sleep, mood, and behavior. Adults with a milder phenotype and capacity to self-report on their function completed patient-reported outcome measures of mood, behavior, and the presence of psychotic symptoms. Outcome measures are explained in greater detail below.

Standard Protocol Approvals, Registrations, and Patient Consents

All research activities were conducted under an IRB-approved protocol (WCG IRB Tracking Number 20212955). The study was also registered at clinicaltrials.gov (NCT04924153). Parents provided written permission (informed consent) for participation of their affected family member in this research study. Owing to the severe cognitive impairment associated with KCNT1-related epilepsy, the IRB waived assent for affected children and consent for affected adults.

Data Availability

Individual participant data collected during this study may be shared after anonymization and on approval of the research proposal. Biogen commits to sharing patient-level data, study-level data, CSRs, and protocols with qualified scientific researchers who provide a methodologically sound proposal. Biogen reviews all data requests internally based on the review criteria and in accordance with our Clinical Trial Transparency and Data Sharing Policy. Deidentified data and documents will be shared under agreements that further protect against participant reidentification. To request access to data, please visit vivli.org/.

Seizure Outcome Measures

Electronic Seizure Diary

The primary study end points were seizure frequency and type, recorded by parents in a daily electronic seizure diary which captured the number, date, portion of day (in 6-hour blocks) of seizures, seizure type, and rescue medication use.

Overnight EEG

A qualified vendor conducted overnight, home-based video EEG, remotely monitored by an EEG technologist. Electrodes were applied using the standard International 10–20 system. The EEG unit was battery-operated. Data were saved to a storage card and then uploaded to a secure server. Parents pushed an event-button to mark the EEG if a clinical seizure was noted or suspected and recorded the time and observations in an event log. Parents received extra supplies (e.g., tape) to resecure exposed or loose electrodes and a guide on positioning monitoring equipment (laptop, camera) and ensuring EEG recording equipment was secure and safe on their child. A 24/7 tech support phone number was provided, and the technologist contacted parents if problems were noted remotely, e.g., loss of laptop signal or a problem with an electrode. The EEG technologist returned to the home the following day to disconnect the EEG. Recordings were approximately 12 hours long, to capture awake, drowsy, and sleep states.

All EEGs were centrally read by a pediatric epileptologist who coded EEGs for seizure type, frequency, duration, background features including organization and interictal epileptiform discharges, and sleep architecture.

Wearable Device

A wrist-worn wearable device was available for up to 15 participants to capture exploratory end points. The device did not perform automated seizure detection, but captured physiologic and movement data (including possible seizures).

Adaptive Function

The Vineland Adaptive Behavior Scales, Third edition, Comprehensive Interview (Vineland-3)⁹ is a proxy (parent) assessment of the ability to perform various age-expected skills. The Vineland-3 assesses functional domains of communication, daily living skills, socialization, and motor skills. Because participants' chronological age typically exceeded the developmental level, we estimated a composite developmental age score (mean age-equivalent [AE] score across all nonmotor domains). The mean AE guided selection of other assessments (Table 1 and 2).

Table 1.

Measure Selection Based on Developmental Age (DA)^a or Chronologic Age (CA)

Domain	Measurement tool/Method	Measure selection
Mood, behavior	Child Behavior Checklist (CBCL)10–12	• Preschool CBCL: DA = 1.5–5 y old • CBCL school age: DA = 6–18 y old • Adult self-report: DA >18 y old • Adult behavior checklist: DA>18 y old
	Screen for Child Anxiety Related Disorders (SCARED)13	• DA ≥8 y old
	Questionnaire for Psychotic Experiences (QPE)16	• DA ≥18 y old
Quality of life	Pediatric Quality of Life (PedsQL)17,18	• PedsQL infant: DA <25 mos • PedsQL toddler: DA = 2–4 y old • PedsQL Young children: DA = 5–7 y old • PedsQL child: DA = 8–12 y old • PedsQL Teen: DA = 13–18 y old • PedsQL Adult (self-report): DA ≥18 y old
Sleep	Brief Infant Sleep Questionnaire (BISQ)21	• CA ≤36 mo old
	Children's Sleep Habits Questionnaire (CSHQ)22	• CA = 37 mos.–17 y 11 mos • CA ≥18 y with DA<12 y old.
	Pittsburgh Sleep Quality Index (PSQI)23	• CA ≥18 years old with DA ≥12 y old
Cognition and development	Bayley Scales of Infant & Toddler Development, Fourth edition (Bayley-4)24	• DA ≤36 mos
	Wechsler Scales of Intelligence25-27	• Wechsler Preschool and Primary Scales of Intelligence, fourth ed: DA = 37 mos. to <6 y old • Wechsler Intelligence Scales for Children, fifth ed.: DA = 6 y to 15 y, 11 mos. • Wechsler Adult Intelligence Scale, fourth ed. DA≥16 y old

^aDA calculated as the mean of Vineland-3 Age Equivalent scores for all nonmotor subdomains.

Table 2.

Parent- or Patient-Reported Outcome Measures: Score Type, Range, and Direction

Outcome measures	Score type	Range	↑ or ↓a
Vineland Adaptive Behavior Scales, Third Ed.	Standard score	20–140	↑
	v-scale score	1–24	↑
Child Behavior Checklist	T scores	50–99	↓
Screen for Child Anxiety Related Disorders	Total raw score	0–82	↓
Questionnaire for Psychotic Experiences	Item raw scores	0–5	↓
Pediatric Quality of Life Inventory; Family Impact Module	Total scoreb	0–100	↑
Brief Infant Sleep Questionnaire-Revised	Total raw score	0–100	↑
Children's Sleep Habits Questionnaire	Total raw score	33–99	↓
Pittsburgh Sleep Quality Index	Global raw score	0–21	↓

^a↑: higher score = better function; ↓: lower score = better function.

^bPedsQL and FIM total score is produced by reverse scoring and linear transformation of individual item scores; see work by Varni and colleagues^17-19 for details.

Mood, Behavior, and Quality of Life

Most individuals with KCNT1-related epilepsy experience severe functional limitations. However, the range of phenotypic expression includes milder forms affecting individuals without severe encephalopathy, but with challenging behaviors, autism spectrum disorder, psychiatric symptoms, and/or functional impairments. For these participants, we characterized such symptoms with various assessments, described below, using the Vineland-3 estimated developmental age to guide selection. We also evaluated quality of life and adaptive skills for all participants, including determining whether existing tools were utile for this population.

Child Behavior Checklist

The Child Behavior Checklist (CBCL) is an observer (parent)-reported measure to assess mood and behavior symptoms in school-age children¹⁰; other versions assess preschool children (Preschool-age CBCL, age 1.5–5 years)¹¹ and adults (Adult Self Report form, ASR; Adult Behavior Checklist; ABCL [proxy report].¹²

Screen for Child Anxiety-Related Disorders

The Screen for Child Anxiety-Related Disorders (SCARED) is an observer (parent)-reported measure to assess recent anxiety symptoms and DSM-5 symptom diagnostic criteria for anxiety disorders in children age 8–18 years.¹³

Questionnaire for Psychotic Experiences

In some adults with milder KCNT1-related epilepsy, particularly the SHE phenotype, psychiatric symptoms including hallucinations have been reported.^14,15 The Questionnaire for Psychotic Experiences (QPE) is a self-report questionnaire to assess for the presence, severity, clinical features, and impact of delusional thoughts and hallucinations across various sensory modalities (e.g., auditory, visual, olfactory, etc.) and over 2 different time frames—recent (past week) and lifetime.¹⁶ The QPE was used with adult participants able to self-report their symptoms.

Pediatric Quality of Life Inventory

The Pediatric Quality of Life Inventory (PedsQL) Infant and Core parent-proxy scales were used to assess health-related quality of life.^17,18 Parents also completed the PedsQL Family Impact Module (FIM) to rate the impact of their child's health condition on parental quality of life and general family well-being.¹⁹

Sleep Quality

Disrupted sleep is a core component of SHE in which focal seizures emerge during non-rapid eye movement (nREM) sleep stages^7,20 and is also presumed to occur in other KCNT1 phenotypes because of the high daily burden of seizure activity. A sleep questionnaire, selected based on participant chronologic and developmental age, was used to assess various components of sleep function, including onset, duration, maintenance, quality, and parasomnias.

Brief Infant Sleep Questionnaire—Revised

The Brief Infant Sleep Questionnaire—Revised (BISQ-R) is an observer (parent)–reported questionnaire to assess infant and toddler sleep patterns, including bedtime routine, sleep behaviors, daytime sleeping, and parental responses (e.g., helping the child resume sleep after nighttime waking).²¹

Children's Sleep Habits Questionnaire

The Children's Sleep Habits Questionnaire (CSHQ) is an observer (parent)–reported measure. Domains assessed include bedtime routines, asleep and awake times, sleep onset delay, sleep duration and persistence, sleep-disordered breathing, parasomnias, and sleep-related anxiety. Parents rated the presence, frequency, and impact of any sleep problems reported.²²

Pittsburgh Sleep Quality Index

The Pittsburgh Sleep Quality Index (PSQI) is a self-report measure that assesses subdomains of sleep onset (latency), sleep quality, duration, persistence, and efficiency, sleep disturbances, daytime sleepiness, and use of sleep aid medications.²³

Physical Measures

Head circumference (centimeters) was measured for visits 1, 3, and 5 by the EEG technologist. At visit 1, measurements were taken by a home study nurse for height, weight, BMI, temperature, heart rate, blood pressure, and respiratory rate. A 12-lead ECG was also performed.

CGI Scale

The Clinical Global Impression Scale-Severity (CGI-S) score was a single, 7-point rating score of illness severity (1 = normal, 7 = severely ill) and was assigned by the investigator at visits 1–5. The rating considered the participant's current function and health status compared with the overall population of individuals with KCNT1-related epilepsy. At visits 2–5, the CGI-Change (CGI-C) score was also assigned to describe change relative to a participant's baseline assessment (1 = much better, 7 = much worse).

Laboratory Collections for Genetic and Biomarker Assessments

At visit 1, plasma, serum, and/or whole blood were collected using a home-based phlebotomy service for blood chemistry and hematology, KCNT1 gene testing and biomarker research, including KCNT1 protein, proteins potentially associated with KCNT1, potential KCNT1 substrates, and biomarkers of neurologic disease including but not limited to neurofilament light chain (NfL) and neurofilament heavy chain (NfH). If a sample could not be obtained at visit 1, a second attempt was scheduled for visit 5. The protocol also permitted optional donation of CSF (CSF) left over from clinically obtained samples (not part of the study activities directly). The initial plan was to conduct CSF biomarker research including evaluation of KCNT1 protein, proteins potentially associated with KCNT1, potential KCNT1 substrates, and NfL/NfH; however, no CSF samples were donated by any participants.

Cognitive and Developmental Assessments

To address a gap in the extant literature, we sought to systematically characterize cognitive, language, and motor milestones using normative-referenced, gold-standard assessments. Our additional objective was to assess the feasibility of using the selected measures with this patient population. The Vineland-3 also provided information on attainment of developmental milestones, and the Vineland-3 mean AE score guided selection of other developmentally appropriate assessments.

Bayley Scales of Infant and Toddler Development, Fourth Edition

The Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) evaluates developmental milestones from infancy through 42 months of age, requires the child to engage with physical test materials (e.g., stacking blocks), and includes motor tasks (e.g., grasping, crawling). Though included in the initial study protocol, the Bayley-4 ultimately was not used because of the choice to implement a fully decentralized (home-based) study.²⁴

Wechsler Scales of Intelligence

The Wechsler Scales of Intelligence measure intellectual ability (IQ). The specific test administered was guided by the participant's developmental age (Table 1). As with the Bayley-4, the preschool Wechsler measure could not be administered remotely. Verbally mediated subtests from the child and adult versions of the Wechsler scales could be administered via telehealth for participants developmentally capable of completing the assessment.^25-27

Safety Considerations

Participants were monitored for study-related risks including complications from blood draws, EEG-related risks, completion of neurobehavioral assessments and questionnaires, and risks to privacy and confidentiality. Only qualified vendors were used for home-based study procedures. Because seizure frequency and type were primary outcomes, they were not considered adverse events, except for status epilepticus, a clinically significant increase in seizure frequency or intensity, or emergence of a new seizure type. During the EEG, a remote technologist monitored the video feed and EEG recordings; if a seizure lasted more than 3 minutes, they could call the parent or local emergency number if needed. Also, parents were advised to remain with the child for the duration of the EEG, i.e., sleeping in the same room.

Sample Characteristics

In total, 35 participants (n = 20 male, 15 female) enrolled. The average age at the baseline visit was 76.0 months (s.d. = 75.5), with most participants (n = 28, 80%) at least 24 months of age. Developmental age was notably lower; the mean developmental age, estimated by the Vineland-3, was 8.5 months (s.d. = 24.4). Most participants were classified as having an EIMFS (n = 29, 82.9%), with n = 3 (8.6%) each having EIDEE or SHE phenotypes. Table 3 presents detailed sample demographic characteristics.

Table 3.

Demographic Features of K1Te Participants

	Total (n = 35)
Chronologic age at screening (mo)
Mean (SD)	76.0 (75.5)
Median	53.0
Q1, Q3	26.0, 112.0
Min, Max	1.0, 336.0
<24 mo	7
≥24 mo	28
Vineland-3 developmental age-equivalent at screening (mo)
Mean (SD)	8.5 (24.4)
Median	0.00
Q1, Q3	0.0, 12.0
Min, Max	0.0, 120.0
Sex, n (%)
Male	20 (57.1)
Female	15 (42.9)
Ethnicity, n (%)
Hispanic or Latino	2 (5.7)
Not Hispanic or Latino	33 (94.3)
Race, n (%)
Asian	1 (2.9)
Black or African American	1 (2.9)
White	30 (85.7)
Other/mixed	3 (8.6)
Phenotype, n (%)
EIMFS	29 (82.9)
EIDEE	3 (8.6)
SHE	3 (8.6)
Duration of symptoms at screening, n (%)
≤2 y	8 (22.9)
EIMFS	8
EIDEE	0
SHE	0
>2 y	27 (77.1)
EIMFS	21
EIDEE	3
SHE	3
Age at KCNT1-related epilepsy diagnosis (mo)
Mean (SD)	34.9 (56.7)
Median	0.0
Q1, Q3	0.0, 60.0
Min, Max	0.0, 240.0

With one exception, all participants completed all scheduled study visits. One participant did not complete the final visit (month 12). Altogether, blood samples were obtained from n = 32 participants (91%) at visit 1 or 5. No blood was obtainable at either visit from 3 participants because of poor venous access. Four additional samples were obtained but received at ambient temperature (not frozen) thus could not be processed for analysis. Altogether, n = 28/35 (80%) of participants provided a blood sample that could be used for biomarker analysis. In addition, sufficient blood was collected to support genetic analysis in 21 of 31 participants who provided a sample (68%), above and beyond the amount needed for biomarker analysis. For remaining participants, there was no obtainable sample (n = 11) or an insufficient (n = 2) or contaminated (n = 1) sample that precluded genetic analysis. However, this was not deemed a critical analysis because information about genetic diagnosis including the pathogenic variant was obtained during eligibility screening.

Remote neuropsychological evaluation was planned for 2 visits among participants whose developmental level was high enough to complete a virtual assessment with verbal subtests from the WISC-V. Two participants met this criterion and each completed one of the 2 planned assessments. All scheduled Vineland-3 assessments were completed for all participants, for a 100% completion rate.

Discussion

Study Strengths, Limitations, Challenges, and Learnings

The major objective of the K1Te study was to perform detailed clinical phenotyping KCNT1-related epilepsy natural history, with a particular focus on characterizing seizures. A strength of the study was the prospective, longitudinal design that engaged participants and families for a full year. Another strength was the patient-informed design, which we believe optimized participant engagement and retention, with 99% of all possible study visits completed over the 1-year study period. Nevertheless, we acknowledge this study model may introduce potential limitations such as missing data, variability in data quality, and difficulties implementing study procedures, which we discuss further below.

Fully Decentralized Operations

A fully remote study plan limited the extent of neuropsychological and developmental assessment that could be performed. Neither the Bayley scales (to assess infant/toddler developmental milestones) nor the preschool version of the Wechsler scales, each part of the original nonremote protocol, could be administered remotely as both require in-person hands-on evaluation. Verbal subtests from the Wechsler school-age test (WISC-V) were administered via telehealth, using a method established previously by the study neuropsychologist for remote cognitive evaluation in other pediatric rare disease populations.²⁸ All participants were assessed as planned with the Vineland-3, providing extensive information about adaptive function and early motor and language developmental milestones.

Although home-based visits reduced participants' travel burden, they introduced potential for exposure to communicable illnesses via in-home research staff. A safety protocol was established including rescheduling home visits if visiting staff or family members were unwell, and notifying family members of potential exposures, i.e., if visiting staff later tested positive for COVID-19. Before completion of home-based EEGs, a health screening questionnaire obtained information on whether any household member had signs or symptoms of, or exposure to someone with upper respiratory illnesses, or a known history of allergy to adhesives or latex.

We did not conduct an economic analysis of the cost of implementing the protocol fully remotely, compared with a hybrid or entirely site-based model. The sponsor bore the cost of contracts for in-home activities (e.g., overnight EEG, phlebotomy). Conversely, the sponsor did not incur costs (e.g., airfare, hotel) for participant and parent travel to the study site. Home-based visits were scheduled at the convenience of families, enabling children to maintain their regular routine and reducing parents' lost time/reduced productivity at work. Overall, decentralized clinical studies are viewed as cost-effective and desirable by study participants²⁹ and may be especially useful for studies of individuals with rare diseases to optimize enrollment for those who because of wide geographic dispersal and/or medical fragility may have difficulty traveling to a centralized study site.^29,30

The Role of Technology in the Home-Based Research Visit

Ensuring privacy and confidentiality of participants and their data, supporting access to and ease with remote technologies, and maintaining study rigor were paramount for this decentralized study. To ensure high-quality, contextually relevant prospective and longitudinal data, substantial efforts were made to accomplish all study activities within the home at the level of rigor expected of a clinical trial, by leveraging certain technologies and using Good Clinical Practice (GCP) standards when available. An Internet-capable tablet was used to perform electronic consent as aided by a virtual telehealth visit or phone call, collect seizure end points via an electronic diary, and administer patient- or parent-reported outcomes. Validated questionnaires were used to mitigate variability introduced by home-based parent reporting. Telemedicine visits were completed on parents' personal Internet-enabled devices using a HIPAA-compliant Zoom video conferencing platform (Zoom Video Communications, Inc). The study team also maintained ongoing communication with participants and families throughout the study period to provide reminders about upcoming study visits, review changes in clinical status, and address any questions or concerns.

Parents had varying levels of literacy and comfort with the technologies required for study participation, particularly the tablet used to complete questionnaires and the electronic seizure diary. The coordinator met with parents via a secure online video meeting soon after enrollment to provide remote training and assisted with troubleshooting throughout the study. The vendor who programmed and supplied the tablets also provided direct, ad hoc technical assistance to the coordinator.

EEG

Video EEG monitoring is the gold standard to evaluate epileptic activity. Ambulatory EEGs without video are suboptimal in this population who typically have very abnormal EEG backgrounds and movements that are not necessarily ictal. Video EEG monitoring within an epilepsy monitoring unit is ideal, but challenging because of travel burden and/or other childcare responsibilities, and places the child at risk for nosocomial infections. Home-based, overnight video EEG supported longer EEG recordings, minimized burden and risk, and worked well in most households. Parents received guidelines to ensure the EEG video capture was adequate, e.g., ensuring participants remained in view of the camera and were not overly obscured by blankets throughout the monitoring period. Most participants were nonambulatory and had few independent movements, facilitating stable placement of EEG leads. Parents were also given additional materials and instructions for reattaching leads if disconnected. Secure upload, storage, and review processes were established between the site and vendors.

Laboratory Draws

Home-based collection of blood samples, which lack resources available in hospital settings, can be challenging for participants with difficult-to-access vasculature and/or with developmental disability can be challenging. The protocol allowed one reattempt on a separate date, but if that also failed, then no sample was collected for that participant. Noted above, we were able to obtain a blood sample in over 90% of the sample, but acknowledge the acquired volume was less than expected for some participants, and several samples were not analyzable because of protocol deviations.

Visit Windows

The study protocol included various home-based activities reliant on different health care vendors (EEG, ECG, phlebotomy, etc.) deployed to participant homes across the United States. Scheduling flexibility within designated multiday visit windows was appreciated by participating families and vendors alike. Consistent with this population, some participants required hospitalization for illness or procedure, necessitating rescheduling of study activities. A 14-day study visit window and a 21-day window for the baseline visit (with the most activities to coordinate) provided flexibility to complete all study activities while minimizing protocol deviations.

Cognitive and Developmental Assessments

With a fully-remote study, certain originally planned in-person assessments (e.g., Bayley-4; Wechsler preschool IQ assessment) could not be completed. Future studies of KCNT1-related epilepsy should evaluate feasibility and utility of these assessments, either with participants attending site-based study visits, or possibly through “research house calls,” i.e., study personnel conducting assessments at participants' homes. The latter approach requires an adequately controlled home environment (i.e., quiet, nondistracting, private) that emulates conditions for research-grade cognitive and developmental evaluations and should consider operational challenges of specialists covering large geographic territories.

Wearable Devices

Behavioral barriers may limit a participant's ability to tolerate wearable devices such as a wrist-worn monitor. It can be helpful for the study team to provide guidance to parents for a gradual and positive introduction to these items (e.g., encouraging participants to first touch/handle the item, then wear for increasing amounts of time) and to associate use of wearable devices with preferred activities.

Study Adherence

Remote end points require participants to complete study activities on schedule in an unsupervised environment. Reminders may prompt the participant or parent to keep a device charged and connected to the Internet, receive and respond to communications from study personnel, and/or attend telehealth visits. The study team maintained ongoing communication with parents to provide encouragement, manage adherence for remote assessments, and troubleshoot issues for those struggling to maintain adherence. Some nonadherence was anticipated because of participant medical issues that could detract from parents' time and attention to study activities. The remote study design helped mitigate this burden by providing greater flexibility for study activity scheduling and removing the travel burden. Future studies should also anticipate and support patients and their parents who may experience these often unavoidable and disease-related barriers to adherence.

We used the STROBE reporting guideline and checklist (supplement A) to draft and edit this manuscript.³¹

Conclusion

The K1Te study allowed for prospective and longitudinal measurement of the natural history of KCNT1-related epilepsy using a fully-decentralized design. This study design captured participant and parental burden of disease while minimizing demands of study participation, in a population for whom in-person study visits are challenging and may influence outcome measures. Results and data analysis will be separately reported when available. Future research efforts can consider these design choices and challenges and learnings to develop better therapies and care decisions for individuals affected by KCNT1-related epilepsy and other rare developmental and epileptic encephalopathies.

Glossary

ADNFLE

autosomal dominant nocturnal frontal epilepsy

CBCL

Child Behavior Checklist

CGI

Clinical Global Impression

CSHQ

Children's Sleep Habits Questionnaire

EIMFS

epilepsy of infancy with migrating focal seizures

EIDEE

early infantile developmental and epileptic encephalopathies

K1Te

A Natural History Study of Participants with Potassium-Sodium-Activated Channel Subfamily T Member 1 (KCNT1)-Related Epilepsy

KCNT1

potassium-sodium-activated channel subfamily T member 1

NfH

neurofilament heavy chain

NfL

neurofilament light chain

QPE

Questionnaire for Psychotic Experiences

SHE

sleep-related hypermotor epilepsy

Author Contributions

H.R. Adams: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data. V. Nguyen: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. L. Seltzer: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data. C. Dickinson: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. C. Aponte: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data. S. Hubbard: drafting/revision of the manuscript for content, including medical writing for content; study concept or design. M. Rizzo: drafting/revision of the manuscript for content, including medical writing for content; study concept or design; analysis or interpretation of data. D.R. Bearden: drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data.

Study Funding

This research was supported by a grant to the University of Rochester from Biogen.

Disclosure

H.R. Adams received salary support to conduct this research through a grant from Biogen to the University of Rochester, and previously served as a paid consultant to Biogen; V. Nguyen received support from Biogen in connection with this work as an employee; L. Seltzer received salary support to conduct this research through a grant from Biogen to the University of Rochester; C. Dickinson received salary support to conduct this research through a grant from Biogen to the University of Rochester; C. Aponte received salary support to conduct this research through a grant from Biogen to the University of Rochester; S. Hubbard received support from Biogen in connection with this work as an employee; M. Rizzo received support from Biogen in connection with this work as an employee and owns Biogen stock; D.R. Bearden received salary support to conduct this research through a grant from Biogen to the University of Rochester. D.R. Bearden has served as a paid consultant for Biogen, Servier, Actio Bio, and UCB. D.R. Bearden serves in an unpaid role as the Chairperson of the Scientific Advisory Board for the KCNT1 Epilepsy Foundation. Go to Neurology.org/NG for full disclosures.