Effects of ganaxolone on non-seizure outcomes in CDKL5 Deficiency Disorder: Double-blind placebo-controlled randomized trial.

S Amin, H Cross, O Devinsky, J Downs, P Jacoby, N Specchio, N Bahi-Buisson, R Rajaraman, B Suter, A Aimetti, G Busse, H E Olson, S Demarest, T A Benke, E Pestana-Knight

Journal: European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society 2024;51():140-146

PMID: 38959712

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Abstract

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy. Ganaxolone, a neuroactive steroid, reduces the frequency of major motor seizures in children with CDD. This analysis explored the effect of ganaxolone on non-seizure outcomes. Children (2-19 years) with genetically confirmed CDD and ≥ 16 major motor seizures per month were enrolled in a double-blind randomized placebo-controlled trial. Ganaxolone or placebo was administered three times daily for 17 weeks. Behaviour was measured with the Anxiety, Depression and Mood Scale (ADAMS), daytime sleepiness with the Child Health Sleep Questionnaire, and quality of life with the Quality of Life Inventory-Disability (QI-Disability) scale. Scores were compared using ANOVA, adjusted for age, sex, number of anti-seizure mediations, baseline 28-day major motor seizure frequency, baseline developmental skills, and behaviour, sleep or quality of life scores. 101 children with CDD (39 clinical sites, 8 countries) were randomized. Median (IQR) age was 6 (3-10) years, 79.2 % were female, and 50 received ganaxolone. After 17 weeks of treatment, Manic/Hyperactive scores (mean difference 1.27, 95%CI -2.38,-0.16) and Compulsive Behaviour scores (mean difference 0.58, 95%CI -1.14,-0.01) were lower (improved) in the ganaxolone group compared with the placebo group. Daytime sleepiness scores were similar between groups. The total change in QOL score for children in the ganaxolone group was 2.6 points (95%CI -1.74,7.02) higher (improved) than in the placebo group but without statistical significance. Along with better seizure control, children who received ganaxolone had improved behavioural scores in select domains compared to placebo.

Address: Telethon Kids Institute, The University of Western Australia, Australia; Curtin School of Allied Health, Curtin University, Perth, Australia. Electronic address: [email protected].; Telethon Kids Institute, The University of Western Australia, Australia.; Rare and Complex Epilepsy Unit, Department of Neuroscience, Bambino Gesù Children's Hospital IRCCS, Full Member of European Reference Network EpiCARE, Rome, Italy.; UCL Great Ormond Street Institute of Child Health, London, United Kingdom.; Department of Paediatric Neurology, Bristol Royal Hospital for Children, Bristol, United Kingdom.; Pediatric Neurology, Necker Enfants Malades, Université de Paris, Paris, France.; Division of Pediatric Neurology, David Geffen School of Medicine and UCLA Mattel Children's Hospital, Los Angeles, CA, USA.; Pediatrics & Neurology, Baylor College of Medicine & Texas Children's Hospital, Houston, USA.; Department of Neurology, New York University, New York, NY, USA.; Marinus Pharmaceuticals, Inc, USA.; Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.; University of Colorado, Department of Pediatrics and Neurology, Children's Hospital Colorado, Aurora, CO, USA.; Depts of Pediatrics, Pharmacology, Neurology and Otolaryngology, University of Colorado School of Medicine/Children's Hospital Colorado, Aurora, CO, USA.; Charles Shor Epilepsy Center, Cleveland Clinic Neurological Institute, Cleveland, OH, USA.

DOI: 10.1016/j.ejpn.2024.06.005

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MeSH Terms: Adolescent, Child, Child, Preschool, Female, Humans, Male, Young Adult, Double-Blind Method, Epileptic Syndromes, Pregnanolone, Quality of Life, Seizures, Spasms, Infantile, Treatment Outcome