Iris E Overwater1, André B Rietman1, Karen Bindels-de Heus1, Caspar W N Looman1, Dimitris Rizopoulos1, Tafadzwa M Sibindi1, Perumpillichira J Cherian1, Floor E Jansen1, Henriëtte A Moll1, Ype Elgersma2, Marie-Claire Y de Wit2. 1. From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands. 2. From the Departments of Neurology (I.E.O., A.B.R., M.-C.Y.d.W.), Pediatrics (K.B.-d.H., H.A.M.), Public Health (C.W.N.L.), Biostatistics (D.R.), Neurophysiology (T.M.S., P.J.C.), and Neuroscience (Y.E.), ENCORE Expertise Centre for Neurodevelopmental Disorders (I.E.O., A.B.R., K.B.-d.H., H.A.M., Y.E., M.-C.Y.d.W.), Erasmus University Medical Centre, Rotterdam; and the Department of Pediatric Neurology (F.E.J.), Brain Center Rudolf Magnus, University Medical Centre Utrecht, the Netherlands. m.c.y.dewit@erasmusmc.nl y.elgersma@erasmusmc.nl.
Abstract
OBJECTIVE: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC). METHODS: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment. RESULTS: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely. CONCLUSIONS: We describe a randomized controlled trial for a non-antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.
RCT Entities:
OBJECTIVE: To investigate whether mammalian target of rapamycin complex 1 (mTORC1) inhibitors could reduce seizure frequency in children with tuberous sclerosis complex (TSC). METHODS: Due to slow inclusion rate, target inclusion of 30 children was not reached. Twenty-three children with TSC and intractable epilepsy (age 1.8-10.9 years) were randomly assigned (1:1) to open-label, add-on sirolimus treatment immediately or after 6 months. Sirolimus was titrated to trough levels of 5-10 ng/mL. Primary endpoint was seizure frequency change during the sixth month of sirolimus treatment. RESULTS: Intention-to-treat analysis showed sirolimus treatment resulted in 41% seizure frequency decrease (95% confidence interval [CI] -69% to +14%; p = 0.11) compared to the standard-care period. Per protocol analysis of 14 children who reached sirolimus target trough levels in the sixth sirolimus month showed a seizure frequency decrease of 61% (95% CI -86% to +6%; p = 0.06). Cognitive development did not change. All children had adverse events. Five children discontinued sirolimus prematurely. CONCLUSIONS: We describe a randomized controlled trial for a non-antiepileptic drug that directly targets a presumed causal mechanism of epileptogenesis in a genetic disorder. Although seizure frequency decreased, especially in children reaching target trough levels, we could not show a significant benefit. Larger trials or meta-analyses are needed to investigate if patients with TSC with seizures benefit from mTORC1 inhibition. This trial was registered at trialregister.nl (NTR3178) and supported by the Dutch Epilepsy Foundation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that sirolimus does not significantly reduce seizure frequency in children with TSC and intractable epilepsy. The study lacked the precision to exclude a benefit from sirolimus.
Authors: Martina Proietti Onori; Linda M C Koene; Carmen B Schäfer; Mark Nellist; Marcel de Brito van Velze; Zhenyu Gao; Ype Elgersma; Geeske M van Woerden Journal: PLoS Biol Date: 2021-05-26 Impact factor: 8.029
Authors: Alison J Sebold; Alyssa M Day; Joshua Ewen; Jack Adamek; Anna Byars; Bernard Cohen; Eric H Kossoff; Tomoyuki Mizuno; Matthew Ryan; Jacqueline Sievers; Lindsay Smegal; Stacy J Suskauer; Cameron Thomas; Alexander Vinks; T Andrew Zabel; Adrienne M Hammill; Anne M Comi Journal: Pediatr Neurol Date: 2020-11-02 Impact factor: 3.372