S230815 for children with KCNT1-related developmental and epileptic encephalopathy

A Phase Ib/II First-in-human, Multicentre, Open-label, Multiple Ascending Dose Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effect of Intrathecal S230815 in Pediatric Participants With KCNT1-related Developmental and Epileptic Encephalopathy

This study will test whether the investigational medicine S230815 is safe, well tolerated, and affects seizures and related symptoms in children aged 2–12 who have KCNT1-related developmental and epileptic encephalopathy.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 2 Years to 12 Years
• Sex: All
• Sponsor: Servier (Industry-sponsored)
• Locations: 16 sites (Orange, California and 15 other locations)
• Trial ID: NCT07227857 on ClinicalTrials.gov

What this trial studies

CL1-230815-001 (KANDLE) is a first-in-human, open-label Phase Ib/II multiple-ascending-dose trial of S230815 in pediatric participants aged 2–12 with genetically confirmed KCNT1-related developmental and epileptic encephalopathy. Part 1 will enroll escalating-dose cohorts to characterize safety, tolerability, pharmacokinetics, and pharmacodynamics, with central confirmation of KCNT1 pathogenic or likely pathogenic variants at screening. Participants who complete Part 1 may seamlessly roll over into Part 2, a long-term extension in which they continue the same assigned dose for up to 72 weeks. Concomitant antiseizure medications and interventions must be stable and participants will be regularly monitored for adverse events and seizure-related outcomes.

Who should consider this trial

Good fit: Children aged 2–12 with developmental epileptic encephalopathy caused by a pathogenic or likely pathogenic KCNT1 variant confirmed by central testing and on stable antiseizure therapies are the intended participants.

Not a fit: Patients with KCNT1-associated clinical phenotypes other than early-onset epileptic encephalopathy, those with other known pathogenic epilepsy gene variants, or those outside the 2–12 age range are unlikely to be eligible or to benefit.

Why it matters

Potential benefit: If successful, S230815 could reduce seizures and improve neurologic function in children with KCNT1 mutations.

How similar studies have performed: This is a first-in-human program for S230815; KCNT1-directed treatments have had only small, mixed reports historically, so the approach is largely novel and unproven.

Eligibility criteria

Inclusion Criteria:

* Male or female pediatric participants aged 2-12 years old at screening, with a genetically confirmed diagnosis of Developmental Epileptic Encephalopathy (DEE) due to a pathogenic or likely pathogenic variant in KCNT1 confirmed by central genetic testing.
* Stable dose of other regular medications and/or stable antiseizure interventions (such as ketogenic diet and vagal nerve stimulation).

Exclusion Criteria:

* Other clinical phenotypes associated with pathogenic or likely pathogenic variants in KCNT1 other than Epilepsy of Infancy with Migrating Focal Seizures or Early-Onset Epileptic Encephalopathy
* Documented pathogenic or likely pathogenic variants in any other gene known to cause epilepsy identified through prior genetic testing. Variants of uncertain significance in other genes known to cause epilepsy may be considered on discussion with the sponsor.
* Clinically significant medical history or clinical findings on physical examination, other than DEE, that in the judgment of the investigator, make the participant unsuitable for participation in the study and/or completion of the trial procedures, including, but not limited to:

  * Clinically significant prior or ongoing medical conditions within 30 days of the screening visit, as per investigator judgement.
  * Clinically significant abnormality on Electrocardiogram (ECG) at the screening visit, as per investigator judgement.
  * Clinically significant abnormality on laboratory testing at screening, including, but not limited to:
  * Renal insufficiency, which is defined as creatinine clearance \< 40 mL/min assessed as estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (MDRD) formula
  * Hepatic derangement defined as transaminase values more than 3 times the Upper Limit of Normal (ULN) range, or total bilirubin values more than 1.5 times the ULN.
* Positive hepatitis B surface antigen test, positive hepatitis C antibody test, positive for human immunodeficiency virus (HIV), as reported by a laboratory test within 6 months prior to the screening visit, or on screening bloods.
* Bone, spine, bleeding disorders, or other disorder that exposes the participant to risk of injury or unsuccessful Lumbar puncture (e.g., haemophilia, Von Willebrand's disease, liver disease).
* Contraindications to undergoing Magnetic Resonance Imaging (MRI), Lumbar puncture procedure and Intrathecal administration.
* History of Central Nervous System (CNS) tumors or malignancies, including CNS metastatic disease.
* Continuous respiratory support, defined as oxygen supplementation or non-invasive ventilation (e.g.: continuous positive airway pressure, bi-level intermittent positive airway pressure), required during waking hours. This does not include suctioning; cough assist devices or other devices that may be used regularly to clear airways.
* Invasive ventilation including the presence of a tracheostomy.
* Use of quinidine within 30 days prior to the screening visit.
* Current use or anticipated use of antiplatelet or anticoagulant therapy during the study.
* Current or past enrolment in an interventional clinical study in which an investigational therapy is/was administered within 30 days (or 5 half-lives of study agent, whichever is longer) prior to the screening visit.
* Implantable CNS device that may interfere with the ability to administer the study drug via Lumbar puncture.
* Known hypersensitivity to any oligonucleotide, as demonstrated by a systemic allergic reaction (e.g., changes in pulse, blood pressure, breathing function, etc.), or any other drug that in the opinion of the investigator may preclude study participation.

Where this trial is running

Orange, California and 15 other locations

• Children's Hospital of Orange County — Orange, California, United States (Not_yet_recruiting)
• Boston Children's Hospital — Boston, Massachusetts, United States (Not_yet_recruiting)
• University of Rochester Medical Center — Rochester, New York, United States (Not_yet_recruiting)
• Nationwide Children's Hospital — Columbus, Ohio, United States (Not_yet_recruiting)
• The Children's Hospital of Philadelphia — Philadelphia, Pennsylvania, United States (Not_yet_recruiting)
• Children's Health Dallas — Dallas, Texas, United States (Not_yet_recruiting)
• Institut Des Neurosciences De La Timone — Marseille, France (Recruiting)
• Hopital Necker Enfants Malades — Paris, France (Recruiting)
• Robert Debre University Hospital — Paris, France (Recruiting)
• Azienda Ospedaliera Universitaria Meyer IRCCS — Florence, Italy (Not_yet_recruiting)
• Ospedale Pediatrico Bambino Gesu — Roma, Italy (Not_yet_recruiting)
• Shinshu University Hospital — Nagano, Japan (Recruiting)
• Osaka City General Hospital — Osaka, Japan (Recruiting)
• Shizuoka Institute of Epilepsy and Neurological Disorders — Shizuoka, Japan (Recruiting)
• Hospital Sant Joan De Deu Barcelona — Esplugues de Llobregat, Spain (Recruiting)
• Hospital Ruber Internacional — Madrid, Spain (Recruiting)

Study contacts

• Study coordinator: Institut de Recherches Internationales Servier

Conditions Epileptic Encephalopathy