Title: 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)
Funder: Medical Research Council

Abstract: Background:_x000D_ Attention Deficit Hyperactivity Disorder (ADHD) affects 7% of children worldwide; it consists of problems with poor attention, impulsivity, and hyperactivity. Most have problems in adulthood where ADHD can lead to poor social and employment outcomes. Children with ADHD also struggle with cognitive (thinking) skills (e.g., attention) and self-control. Treatment is with stimulant medication. However, this has side effects, does not work for everyone, and has limited longer-term effects. Non-drug treatments with fewer side effects would be preferred but most have shown little effects. _x000D_ The first non-drug ADHD treatment device was approved in 2019 by the USA Food and Drug administration (FDA), called external trigeminal nerve stimulation (eTNS). eTNS is a battery charged device that sends small electrical pulses or currents under the skin on the forehead and can be applied during sleep. eTNS activates the trigeminal nerve on the forehead which leads to the activation of the brain stem and frontal brain regions that are important for arousal and attention._x000D_ A pilot study in 62 children with ADHD showed improvement of ADHD symptoms after 4 weeks of eTNS compared to placebo (fake, with no electrical currents) eTNS after it was used every night with children by their parents for 4 weeks, with minimal side effects. An earlier smaller study with 22 ADHD children showed that eTNS improved ADHD behaviours and cognitive abilities (e.g., inattention)._x000D_ This study: _x000D_ In our study, we therefore want to further confirm in a large group of 150 children and adolescents with ADHD tested in London and Southampton Universities whether eTNS improves ADHD symptoms, whether it improves academic abilities (e.g., attention), whether the effects are still observed 6 months later and how it works on the brain. For this purpose, we will randomise 75 patients to eTNS, and another 75 patients to placebo eTNS treatment (with no electrical currents), to test whether eTNS is better than placebo eTNS in improving parent and teacher-rated ADHD symptoms and cognitive performance in tests of self-control and attention. We also want to understand how it works in the brain. Therefore, we will use functional magnetic resonance imaging (fMRI) to test effects of eTNS on the brain function of ADHD children in a subgroup of 56 patients. Furthermore, we will test whether eTNS has side effects and whether effects continue 6 months after treatment. _x000D_ The study is important as it will establish whether eTNS is an effective non-drug treatment for ADHD with minimal side effects that can be administered at home and would therefore be preferred by patients, parents, and clinicians. Such a treatment would improve the healthcare and reduce the strain of the disease for patients. _x000D_ Patient Public Involvement: _x000D_ Representatives of public advisory groups, the Lambeth ADHD Support group (parents/clinicians), the Young Person Mental Health Advisory Group (YPMHAG), FAST-R (service user groups), ADDISS (national ADHD support service), and ADHD Richmond & Kingston UK were involved in study design and are represented on trial management and steering committees. _x000D_ Dissemination: _x000D_ Findings will be circulated to the scientific community and the public via written publications (e.g., scientific journal articles), (inter)national conferences, the media, a website, ADHD Guideline groups, presentations at science festivals, social media, charities, parent & patient support groups, and clinic

Lay abstract: 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. _x000D_ 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. _x000D_ 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. _x000D_ 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

Research activity codes: 5.3 MEDICAL DEVICES;6.3 MEDICAL DEVICES
Health categories: MENTAL HEALTH