Pharmacotherapy for Dravet Syndrome: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials
Simona Lattanzi 1, Eugen Trinka 2 3 4, Emilio Russo 5, Cinzia Del Giovane 6 7, Sara Matricardi 8, Stefano Meletti 9 10, Pasquale Striano 11, Payam Tabaee Damavandi 12, Mauro Silvestrini 13, Francesco Brigo 14
- 1Department of Experimental and Clinical Medicine, Neurological Clinic, Marche Polytechnic University, Via Conca 71, 60020, Ancona, Italy. alfierelattanzisimona@gmail.com.
- 2Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria.
- 3Center for Cognitive Neuroscience, Salzburg, Austria.
- 4Public Health, Health Services Research and HTA, University for Health Sciences, Medical Informatics and Technology, Hall in Tirol, Austria.
- 5Science of Health Department, University Magna Grecia of Catanzaro, Catanzaro, Italy.
- 6Department of Medical and Surgical Sciences for Children and Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy.
- 7Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland.
- 8Department of Pediatrics, University of Chieti, Chieti, Italy.
- 9Neurology Unit, OCB Hospital, AOU Modena, Modena, Italy.
- 10Department of Biomedical, Metabolic and Neural Science, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
- 11Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, “G. Gaslini” Institute, University of Genoa, Genoa, Italy.
- 12Department of Neurology, Fondazione IRCCS San Gerardo, School of Medicine and Surgery and Milan Center for Neuroscience, University of Milano-Bicocca, Monza, Italy.
- 13Department of Experimental and Clinical Medicine, Neurological Clinic, Marche Polytechnic University, Via Conca 71, 60020, Ancona, Italy.
- 14Division of Neurology, “Franz Tappeiner” Hospital, Merano, BZ, Italy.
Affiliationer
Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs).
Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA).
Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry ( http://www.
Clinicaltrials: gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework.
Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07-0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57-76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04-5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06-0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59-1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS.
Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.
