A multi-centre, double-blind, parallel-group, randomized controlled study to compare the efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) on symptoms in youth with Attention Deficit/Hyperactivity Disorder (ADHD)

Background: ADHD affects 7% of children and is characterised by age-inappropriate, impairing symptoms of impulsiveness, inattention and hyperactivity. Symptoms persist into adulthood in most cases where it has worse academic and social outcomes. ADHD children also have impairments in executive functions, mostly in sustained attention, working memory, and inhibitory control and in the function of mediating fronto-striatal and fronto-parietal networks. Stimulant medication is the prevalent treatment, but not preferred due to side effects, is not suitable for all patients, and compliance is poor in adolescence. Alternative non-drug treatments with less side effects are desirable but have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is the first non-drug ADHD treatment approved in 2019 by the US Food and Drug Administration based on pilot data and without knowledge on mechanisms of action. eTNS is a minimal risk, non-invasive neuromodulation that sends low electrical pulses under the skin on the forehead and is applied during sleep. eTNS activates the trigeminal system, the locus-coeruleus arousal system and its connections to frontal brain regions that are typically underfunctioning in ADHD. A proof of concept pilot randomised controlled trial (RCT) in 62 ADHD children showed improvement of ADHD symptoms after 4 weeks of real compared to sham eTNS administered nightly for 8 hours by parents, with minimal side effects. An open trial of eTNS of 6 weeks in ADHD children showed improvements of executive functions concomitant with clinical improvement. Aims: To conduct a sham-controlled, parallel-arm, blinded, multicenter RCT in 150 ADHD children and adolescents to test whether 4 weeks of eTNS improves investigator-scored ADHD symptoms, other associated clinical problems, executive function performance, whether effects persist 6 month later, whether it is safe, and to understand the underlying mechanisms of action on ADHD brain function and how it relates to symptom improvement. Methods and study design: The study is powered to detect an effect size of 0.5 based on the US pilot study. We will randomise 150 children and adolescents, 8-18 years, with a clinical ADHD diagnosis to real or sham eTNS over 4 weeks across 3 sites, London, Southampton and Portsmouth, to test the hypothesis that eTNS improves researcher-scored parent-rated ADHD symptoms (primary outcome), measured at baseline, weekly and 6 months follow-up. Secondary outcomes measured at baseline, 4 weeks and 6 months follow-up are cognitive performance on executive function tasks of attention, working memory and inhibitory control and other associated clinical symptoms. Safety will also be assessed. For the mechanistic sub-study, functional magnetic resonance imaging (fMRI) will be used to test the effects of eTNS on brain function in a subgroup of 56 non-medicated ADHD children, measured before and after 4 treatment weeks. Analyses will test treatment effects on outcome measures using general linear model adjusted for baseline ADHD scores, site, age, gender, and medication, in an intention to treat analysis and explore mediators, moderators and predictors of treatment response. Anticipated impact: the study will confirm whether eTNS is an effective non-drug treatment for ADHD with minimal side effects that can be administered in-house and is likely preferred by patients. Such treatment would improve the healthcare and disease burden for patients