Randomized Controlled Trial of Vagal Nerve Stimulation for Younger Pediatric Patients with Intractable Epilepsy

Background: Vagal nerve stimulation (VNS) may control seizures of pediatric intractable epilepsy (PIE) as a clinically adjunctive therapy. However, high-evidence level data for younger children are needed. Methods: In this multicenter, double-blind, randomized controlled trial (VNS-PIE), we recruited children aged 3-6 years with PIE from eleven hospitals specialized in epilepsy in China. Enrolled children underwent computer-generated randomization at 1:1 ratio. Within first 12-week double-blind period, children in stimulation group received active electrical stimulation while others in control group received sham treatment. Children, their parents and investigators assessing outcomes were masked to random allocation; unmasked investigators were responsible for stimulation parameter programming. After unblinding, all children received active electrical stimulation for the subsequent 12 weeks. The primary outcome was the reduction percentage of seizure frequency between two groups at the end of the double-blind period. Findings: Between Sep 29, 2017, and May 29, 2018, 93 children were enrolled and randomly assigned to 47(51%) in stimulation group and 46(49%) in control group (Dropout: one (2%) in stimulation group). At the end of the double-blind period, the median reduction in seizure from baseline was 40·0%(IQR:[0, 71·7%]) in stimulation group, compared to 21·2%(IQR:[-15·9, 68·0%]) in control group (Adjusted median difference(AMD), 12·6%; 95% CI, 10·3% to 34·7%; p=0·23; n=93, FAS); Between-group difference of seizure decrease significantly favored electrical stimulation with respect to subgroup analysis without surgery honeymoon effect (AMD: 21·6 %; 95% CI, -4·2% to 43·3%; p=0·043; n=78, PPS). There was no significant difference in the efficacy of mental development on Gesell scale. Incision infection was common in 9 severe adverse events and cough was most frequent in 41 adverse events. Interpretation: The results from this trial of VNS supported its clinical use for younger children with PIE. Trial Registration: This trial was registered with ClinicalTrials.gov, number NCT03062514. Funding: Pins Medical Ltd; NKRDPC; NSFC; SICRP. Declaration of Interests: ZY, JD, XYQ, TYC, XF, YY and ZYW reports grants from The National Key Research and Development Program of China, grants from National Natural Science Foundation of China, grants from Shenzhen International Cooperative Research Project during the conduct of the study. TYJ, QZL, JXL, FY, YHC, LPZ, BML, YXG, XMS, SPH, FG, JML, SFL, JP, SWS, JW, CC, WXS, MQT, LY, YH, YPH, YW, HX, LXC and YWJ reports institution remunerated for recruitment of patients from Pins Medical during the conduct of the study. HWH reports grants from The National Key Research and Development Program of China, grants from National Natural Science Foundation of China, grants from Shenzhen International Cooperative Research Project during the conduct of the study; grants for advisory broad outside the submitted work. LML reports grants from The National Key Research and Development Program of China, grants from National Natural Science Foundation of China, grants from Shenzhen International Cooperative Research Project during the conduct of the study; grants for neuromodulation research outside the submitted work. Ethics Approval Statement: The trial was approved by each ethical committee of participating hospitals (Trial protocol number: G112L31101; version date: 7/31/2017) and was performed in accordance with the principles of the Declaration of Helsinki.