Clinical Research Directory

A Clinical Study to Evaluate the Safety and Efficacy of ETX101 in Infants and Children With SCN1A-Positive Dravet Syndrome

ENDEAVOR is a Phase 1/2, 2-part, multicenter study to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome aged ≥6 to \<36 months (Part 1A), aged ≥48 months to \<18 years (Part 1B), and aged ≥6 to \<48 months (Part 2). Part 1A follows an open-label, dose-escalation design, Part 1B follows an open-label design, and Part 2 is a randomized, double-blind, sham delayed-treatment control study.

A Study to Evaluate Safety, Tolerability, and Pharmacokinetics of Fenfluramine (Hydrochloride) in Infants 1 Year to Less Than 2 Years of Age With Dravet Syndrome

The primary purpose of this study is evaluate the safety and tolerability of fenfluramine hydrochloride (HCl) 0.2 to 0.8 mg/kg/day in infants 1 year to less than 2 years of age with Dravet syndrome.

The FINTEPLA as an Anti-SUDEP Therapy in Dravet Syndrome Project

This study investigates cerebrovascular reactivity (CVR) and functional brain connectivity in Dravet Syndrome (DS) patients with convulsive seizures. Using functional MRI (fMRI), we will define differences in brain responses to CO₂ changes before administration of the drug Fintepla (Baseline), with a library of healthy controls and with those obtained after administration of Fintepla (Day \~60). Changes in CVR and their relation to ventilatory responses will also be assessed during fMRI.

Assessment of Potential for Chronic Liver Injury in Participants Treated With Epidiolex (Cannabidiol) Oral Solution

This study will monitor for potential chronic liver injury and liver fibrosis, in participants treated with cannabidiol oral solution.

A Phase 3, Placebo-Controlled Study to Investigate LP352 in Children and Adults With Dravet Syndrome (DS)

This (DEEp SEA Study) is a double-blind, randomized, placebo-controlled, multicenter study to investigate the efficacy, safety, and tolerability of LP352 in the treatment of seizures in children and adults with DS. The study consists of 3 main phases: Screening, Titration period, and Maintenance period, followed by a Taper period and Follow-Up. Participants will be randomized to LP352 or placebo. The total duration of the study will be approximately 24 months.

A Double-blind Study Evaluating the Efficacy, Safety, and Tolerability of Zorevunersen in Patients With Dravet Syndrome

The purpose of the study is to evaluate the efficacy, safety, and tolerability of zorevunersen in Patients with Dravet syndrome.

A PET-MRI Study of Serotoninergic Brainstem Pathway in Patients With Dravet Syndrome

Dravet Syndrome (DS) is a severe neurodevelopmental disease, which is predominantly caused by mutations of SCN1A, the gene coding for Nav1.1 voltage-gated sodium channels. DS is characterized by infancy onset, severe cognitive deficit and drug-resistant seizures, including several generalized convulsive seizures per day and frequent status epilepticus, often triggered by fever or hyperthermia. Among the causes of premature deaths in patients with epilepsy, sudden and unexpected death in epilepsy (SUDEP) represents a major cause. SUDEP is a non-traumatic and non-drowning death in patients with epilepsy, unrelated to a documented status epilepticus. The risk of SUDEP is particularly high in patients suffering from DS, reaching about 9/1000-person-year, as compared to about 1/1000-person-year in people with epilepsy including all disease types. The main clinical risk factor of SUDEP is the frequency of convulsive seizures. Beyond improving seizure control, which we showed to mitigate the SUDEP risk, more specific preventive treatment strategies are still lacking. Experimental and clinical data suggest that most SUDEP cases result from postictal brainstem dysfunction, including central respiratory arrest There is a body of evidence suggesting involvement of serotonin (5HT) dysfunction both in the pathogenesis of epilepsy in DS and in seizure-related respiratory dysfunction. Serotonin indeed plays a key role in the regulation of respiration. Population firing of serotoninergic neurons in the medullary raphe is significantly decreased during the ictal and post-ictal periods, in association with decreased breathing and heart rate during and after seizures. Most importantly, post-mortem data in patients, including DS, showed alteration of neuronal populations in the medulla in SUDEP cases with evidence for greater reduction in neuromodulatory neuropeptidergic and monoaminergic, including serotoninergic, systems. SUDEP in DS might therefore be the result of a seizure-induced fatal apnea in a patient who has developed epilepsy-related vulnerability to central respiratory dysfunction favored by 5HT dysfunction. However, several issues remain to be addressed to identify detailed mechanisms and effective therapies. Among them, a key issue is the exact relation between the alterations of the 5HT pathway observed in DS and epilepsy-related respiratory dysfunction In the present study, the hypothesis is that adult patients with DS might demonstrate specific alterations of the 5HT pathway within the brainstem as assessed by PET imaging. The DRAPETOTINE study will thus focus on imaging 5HT brainstem pathway with PET and MRI in patients with DS to assess if abnormalities can be observed and through comparison with data collected in patients drug-resistant focal epilepsy whether these abnormalities are DS specficic or reflect the consequence on brainstem 5HT pathway of refractory seizures. This study will involve 20 adult patients, including 10 adults with established diagnosis of Dravet Syndrome and 10 patients with drug-resistant focal epilepsy. Ten healthy adults will also be included. Participants will be recruited over a period of 18 months and the duration of participation for each participant will be 2 weeks to 8 weeks

Multicentre Real-life Follow-up Study of Rare Epileptic Syndromes in Children and Adolescents

Rare epilepsies as a whole account for 20-30% of epilepsies, but knowledge about prognostic factors is currently limited. This means that it is difficult to provide adequate information to families at diagnosis and during follow-up. Prognostic factors are also important for management as they can have an impact on the patient's outcome (time to intervention, choice of one molecule over another, etc.). Finally, few treatments are currently available for these epilepsies. One of the limitations to the development of treatments is the lack of real life data as it is difficult to create reliable primary endpoints such as the rate of patients becoming seizure free naturally compared to a therapeutic intervention. The aim of this real-life study is to evaluate the response to treatment as well as to see the evolution of cognitive and psychiatric comorbidities. As explained above, there are very few randomised trials except for 3 rare epilepsies (infantile spasm syndrome, Dravet syndrome, Lennox-Gastaut syndrome). This has led to the virtual absence of management recommendations, including for the three syndromes mentioned above, where attempts at treatment algorithms have been proposed, although these have not been able to be considered as evidence-based recommendations. As a result, there is some diversity in the management of rare epilepsies from one centre to another. However, this diversity in management can be an asset in a real-life study. This will make it possible to compare different management methods, both in terms of seizure control and medium-term outcome.

Epidyolex® in Lennox Gastaut, Dravet Syndrome and Tuberous Sclerosis Complex: an Observational Study in ITALY

This is a prospective, observational study on approximately 70-100 Real World participants affected by LGS, DS, or TSC treated with Epidyolex® as prescribed in the summary of product characteristics. The eligible participants are expected to participate in the study for a duration of 52 weeks of treatment.

An Open-Label Extension Study of STK-001 for Patients With Dravet Syndrome

Stoke Therapeutics is evaluating the long-term safety \& tolerability of repeated doses of zorevunersen (STK-001) in patients with Dravet syndrome who previously participated in studies of zorevunersen. Change in seizure frequency and overall clinical status, and quality of life will be measured as secondary endpoints in this open-label study.

Longitudinal Study of Phenotypic and Developmental Severity in Patients With Dravet Syndrome With SCN1A Gene Mutation

Dravet syndrome with SCN1A gene mutation is a developmental and epileptic encephalopathy characterized by treatment-resistant epilepsy and global developmental delay. Despite the considerable attention recently Dravet syndrome (DS) in drug development, studies characterising the progression of the neurodevelopmental phenotype over time remain limited. In particular, many previous studies of natural history studies have been of short duration or have focused only on a subgroup of the paediatric population. This prospective natural history study is being conducted to define more precisely the neurodevelopmental trajectory of SCN1A-positive Dravet syndrome in patients aged aged 6 months to 21 years with SCN1A mutations. The study will examine these characteristics over a 4-year period using standardised assessments. The study will also explore potential metabolomic biomarkers and their relationship with clinical outcomes.

Neurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome

Dravet Syndrome (DS) is a severe epileptic encephalopathy, which main cause is mutations of SCN1A, the gene coding for the Nav1.1 voltage-gated sodium channel. DS is characterized by childhood onset, severe cognitive deficit and drug-resistant seizures, including several generalized convulsive seizures per day, frequent status epilepticus and high seizure-related mortality rate. Sudden and unexpected death in epilepsy (SUDEP) represents the major cause of premature deaths. The risk of SUDEP is thus about 9/1000-person-year in comparison with about 5/1000-person-year in the whole population of patients with drug-resistant epilepsies. Experimental and clinical data suggest that SUDEP primarily result from a postictal central respiratory dysfunction. SUDEP in DS, might be the result of a seizure-induced fatal apnea in a patient who had developed epilepsy-related vulnerability to central autonomic and/or respiratory dysfunction. However, a key clinical issue which remains to be addressed is the temporal dynamics of the onset and evolution of the autonomic vulnerability in these patients. The main clinical risk factor of SUDEP is the frequency of convulsive seizures and the SUDEP risk can vary along the evolution of epilepsy. Although non-fatal seizure-induced ataxic breathing can be observed in patients with DS, whether or not repetition of seizures results in long-term alterations of breathing remains unclear. In the AUTONOMIC project, it will be investigate in a homogenous population of patients with DS the exact interplay between epilepsy-related cardiac and respiratory alterations on the one hand and the relation between the underlying neurodevelopmental disease, the repetition of seizure per se and these epilepsy-related autonomic alterations on the other hand. Autonomic functions will be investigated in the inter-ictal period (i.e. in the absence of immediate seizures, Work Package 1 (WP1)) and in the peri-ictal period, i.e. in the immediate time before, during (if possible) and after seizures (WP2). A multicenter cohort will be constituted, allowing to collect the inter-ictal and ictal cardio-respiratory data required in the 2 WP. The study will be sponsored by the Lyon's University Hospital. Patients will be recruited over a period of 24 months in one of the three participating clinical center. All patients will first enter in a prospective baseline period of 3 to 6 months duration in order to collect seizure frequency. After this period, all patients will then undergo a 24-48 hours video-EEG recordings as part of the routine clinical care. The monitoring will also include a full-night polysomnography. This patients will be eligible for inclusion in an extension follow-up study will monitor vital status every year in order to investigate long-term mortality, including SUDEP. The AUTONOMIC project will provide important results which will pave the way to develop and eventually validate therapeutic intervention to prevent SUDEP. By deciphering the exact interplay between epilepsy-related cardiac and respiratory alterations on the one hand and the relation between the underlying neurodevelopmental disease, the repetition of seizure per se and these epilepsy-related autonomic alterations on the other hand, the project will primarily deliver clinically relevant biomarkers.

A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome

EXPEDITION is a Phase 1/2 study in the UK to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet Syndrome aged 6 to \< 48 months. The study follows and open-label, dose-escalation design.

A Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome (Australia Only)

WAYFINDER is a Phase 1/2 study in Australia to evaluate the safety and efficacy of ETX101 in participants with SCN1A-positive Dravet syndrome aged 6 to \<84 months. The study follows an open-label, dose-escalation design.

A Study of EPX-100 (Clemizole Hydrochloride) in Participants With Dravet Syndrome

This is a multicenter, Phase 3, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of clemizole hydrochloride (EPX-100) as adjunctive therapy in children and adult participants with Dravet syndrome (DS).

BMB-101 in Absence Epilepsy and DEE

The study is a pilot, open-label, study to test whether BMB-101 is safe and effective in reducing the frequency of seizures in subjects with Absence Epilepsy including Epilepsy with Eyelid Myoclonia (also called Jeavons Syndrome) as well as Developmental Epileptic Encephalopathies such as Dravet and Lennox Gastaut. The study will last up to 6 months. There will be a 1 month screening period, then up to 3 months on open-label BMB-101 including titration and tapering/washout periods, and then a 1 month follow-up period. There will be 6 clinic visits.

Early Check: Expanded Screening in Newborns

Early Check provides voluntary screening of newborns for a selected panel of conditions. The study has three main objectives: 1) develop and implement an approach to identify affected infants, 2) address the impact on infants and families who screen positive, and 3) evaluate the Early Check program. The Early Check screening will lead to earlier identification of newborns with rare health conditions in addition to providing important data on the implementation of this model program. Early diagnosis may result in health and development benefits for the newborns. Infants who have newborn screening in North Carolina will be eligible to participate, equating to over 120,000 eligible infants a year. Over 95% of participants are expected to screen negative. Newborns who screen positive and their parents are invited to additional research activities and services. Parents can enroll eligible newborns on the Early Check electronic Research Portal. Screening tests are conducted on residual blood from existing newborn screening dried blood spots. Confirmatory testing is provided free-of-charge for infants who screen positive, and carrier testing is provided to mothers of infants with fragile X. Affected newborns have a physical and developmental evaluation. Their parents have genetic counseling and are invited to participate in surveys and interviews. Ongoing evaluation of the program includes additional parent interviews.

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.

Tissue Repository Providing Annotated Biospecimens for Approved Investigator-directed Biomedical Research Initiatives

To collect, preserve, and/or distribute annotated biospecimens and associated medical data to institutionally approved, investigator-directed biomedical research to discover and develop new treatments, diagnostics, and preventative methods for specific and complex conditions.

EXploring novEl Molecular Determinants of DRAvet Syndrome Phenotype Heterogeneity

Dravet syndrome is characterized as a developmental encephalopathy resulting from mutations of SCN1A, the gene encoding the alpha subunit of the voltage-gated sodium channel Nav1.1. The syndrome typically presents with drug-resistant epilepsy and varying degrees of cognitive disorders. Current treatment efficacy may be hindered by insufficient knowledge of undiscovered molecular determinants of the disease and its heterogeneous nature. Utilizing induced pluripotent stem cells (iPSCs) derived from skin biopsies, accessibility to patients' brain neurons has enabled successful modeling of various genetic neurological diseases. Neurons and brain organoids will be obtained from Dravet syndrome patients exhibiting diverse phenotypic severities, encompassing behavioral and developmental delays, to discern the molecular determinants of phenotypic diversity. Specifically, emphasis will be placed on investigating cellular and molecular mechanisms linking altered neuronal excitability with synaptic dysfunction.The study will focus on exploring the expression of newly identified modifiers potentially associated with neuronal excitability and synaptic function in iPSC-derived human neurons. This aims to establish correlations between the severity of epileptic and cognitive phenotypes and the altered expression of these proteins, whose functions are not fully understood.In the mid to long term, efforts will be directed towards overcoming the limitations of conventional therapeutic approaches for Dravet syndrome. This will involve attempting to reverse the observed morphological and functional alterations in Dravet syndrome neurons using viral vectors to promote overexpression/downregulation of identified modifiers correlated with disease severity. The anticipated outcomes of this project are expected to unveil novel molecular mechanisms underlying the pathophysiology of this severe neurogenetic disease, characterized by varying degrees of cognitive impairment. Moreover, these findings may pave the way for the discovery of innovative therapeutic strategies.

GABA Biomarkers in Dravet Syndrome

This study will non-invasively obtain levels of GABA in the brain of children with SCN1A+DS and neurodeveloping children through evoked and induced cortical responses, correlate them with the BOLD responses, and with the levels of GABA in their blood.