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The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS)

The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS)
The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS)
Background: attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action.

Methods: a confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment.

Discussion: this multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD.

Trial registration: ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .
ADHD, Trigeminal Nerve Stimulation, fMRI, eTNS, Attention, External transcutaneous Trigeminal Nerve Stimulation, Transcutaneous supraorbital nerve stimulation
1471-244X
Rubia, Katya
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Johansson, Lena
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Carter, Ben
f27540ee-2b8f-43b4-ac06-8bdcafb1ef5f
Stringer, Dominic
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Paramala, Santosh
8e28cc84-2fb0-48c5-88dc-ca86a4b295bc
Mehta, Mitul A.
656d4095-c3a0-4161-8cb7-0dafcaf1404e
Conti, Aldo Alberto
4900702e-d877-485e-80e3-25ae0de19a90
Bozhilova, Natali
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Eraydin, Irem Ece
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Cortese, Samuele
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Rubia, Katya
5f6c0771-6e32-4924-b3f1-e48ace6de377
Johansson, Lena
8a13f487-4ce4-463e-ac62-5070f2e9063c
Carter, Ben
f27540ee-2b8f-43b4-ac06-8bdcafb1ef5f
Stringer, Dominic
80bdc5aa-1fad-4874-be2d-6c4459e40531
Paramala, Santosh
8e28cc84-2fb0-48c5-88dc-ca86a4b295bc
Mehta, Mitul A.
656d4095-c3a0-4161-8cb7-0dafcaf1404e
Conti, Aldo Alberto
4900702e-d877-485e-80e3-25ae0de19a90
Bozhilova, Natali
26780039-aa04-4479-9b01-1dfd9e8394b2
Eraydin, Irem Ece
ae07a51a-3dc7-4cb0-8d9d-9ac7650bea3e
Cortese, Samuele
53d4bf2c-4e0e-4c77-9385-218350560fdb

Rubia, Katya, Johansson, Lena, Carter, Ben, Stringer, Dominic, Paramala, Santosh, Mehta, Mitul A., Conti, Aldo Alberto, Bozhilova, Natali, Eraydin, Irem Ece and Cortese, Samuele (2024) The efficacy of real versus sham external Trigeminal Nerve Stimulation (eTNS) in youth with Attention-Deficit/Hyperactivity Disorder (ADHD) over 4 weeks: a protocol for a multi-centre, double-blind, randomized, parallel-group, phase IIb study (ATTENS). BMC Psychiatry, 24 (1), [326]. (doi:10.1186/s12888-024-05650-1.).

Record type: Article

Abstract

Background: attention Deficit/Hyperactivity Disorder (ADHD), if severe, is usually treated with stimulant or non-stimulant medication. However, users prefer non-drug treatments due to side effects. Alternative non-medication treatments have so far only shown modest effects. External trigeminal nerve stimulation (eTNS) is a minimal risk, non-invasive neuromodulation device, targeting the trigeminal system. It was approved for ADHD in 2019 by the USA Food and Drug administration (FDA) based on a small proof of concept randomised controlled trial (RCT) in 62 children with ADHD showing improvement of ADHD symptoms after 4 weeks of nightly real versus sham eTNS with minimal side effects. We present here the protocol of a larger confirmatory phase IIb study testing efficacy, longer-term persistency of effects and underlying mechanisms of action.

Methods: a confirmatory, sham-controlled, double-blind, parallel-arm, multi-centre phase IIb RCT of 4 weeks of eTNS in 150 youth with ADHD, recruited in London, Portsmouth, and Southampton, UK. Youth with ADHD will be randomized to either real or sham eTNS, applied nightly for 4 weeks. Primary outcome is the change in the investigator-administered parent rated ADHD rating scale. Secondary outcomes are other clinical and cognitive measures, objective hyperactivity and pupillometry measures, side effects, and maintenance of effects over 6 months. The mechanisms of action will be tested in a subgroup of 56 participants using magnetic resonance imaging (MRI) before and after the 4-week treatment.

Discussion: this multi-centre phase IIb RCT will confirm whether eTNS is effective in a larger age range of children and adolescents with ADHD, whether it improves cognition and other clinical measures, whether efficacy persists at 6 months and it will test underlying brain mechanisms. The results will establish whether eTNS is effective and safe as a novel non-pharmacological treatment for ADHD.

Trial registration: ISRCTN82129325 on 02/08/2021, https://doi.org/10.1186/ISRCTN82129325 .

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Accepted/In Press date: 1 March 2024
Published date: 30 April 2024
Keywords: ADHD, Trigeminal Nerve Stimulation, fMRI, eTNS, Attention, External transcutaneous Trigeminal Nerve Stimulation, Transcutaneous supraorbital nerve stimulation

Identifiers

Local EPrints ID: 493657
URI: http://eprints.soton.ac.uk/id/eprint/493657
ISSN: 1471-244X
PURE UUID: 1243f461-d0ce-488f-a9e3-668231939c43
ORCID for Irem Ece Eraydin: ORCID iD orcid.org/0000-0002-3468-1719
ORCID for Samuele Cortese: ORCID iD orcid.org/0000-0001-5877-8075

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Date deposited: 10 Sep 2024 16:36
Last modified: 11 Sep 2024 02:37

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Contributors

Author: Katya Rubia
Author: Lena Johansson
Author: Ben Carter
Author: Dominic Stringer
Author: Santosh Paramala
Author: Mitul A. Mehta
Author: Aldo Alberto Conti
Author: Natali Bozhilova
Author: Irem Ece Eraydin ORCID iD
Author: Samuele Cortese ORCID iD

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