Vagal Nerve Stimulation to Treat Disorders of Consciousness

Официальное название

Transcutaneous Vagal Nerve Stimulation to Treat Disorders of Consciousness

Обзор

This interventional study aims to assess the clinical efficacy of transcutaneous auricular vagal nerve stimulation (taVNS) against sham stimulation on the recovery of consciousness in patients with disorders of consciousness. The main question it aims to answer is: will taVNS improve patients' behavioral scores or will it produce an improvement in the diagnosed level of consciousness? Researchers will compare the results with non-stimulated unconscious patients to see if the re-gain of consciousness is faster in the treated group. Participants will undergo taVNS stimulation using the Parasym device or sham stimulation will be applied from the time of enrolment. Active stimulations will be carried out for 60 minutes twice daily during the acute phase and daily during the rehabilitation phase.

Подробное описание

This is a prospective, multicentric, double-blind, parallel, 2 arms, randomized controlled trial that compares active taVNS stimulation against sham stimulation.

The primary objective of this study is to assess the clinical efficacy of transcutaneous auricular vagal nerve stimulation (taVNS) against sham stimulation on the recovery of consciousness in patients with disorders of consciousness (DoC), including comatose patients, unresponsive wakefulness syndrome (UWS) or minimally conscious state (MCS). The hypothesis is that taVNS will improve patients' behavioral scores compared to sham stimulation, as measured by an improvement of at least 3 points in the Coma Recovery Scale-Revised score (CRS-R) or an improvement in the diagnosed level of consciousness, measured at 3 months post-randomization, coinciding with the end of stimulation.

As a secondary objective, we will investigate whether:

1. taVNS is effective in achieving a faster time to recovery of consciousness in DoC patients compared to controls; 2. the CRS-R score differs in the two groups at 3 and 6 months post-randomization; 3. the persistence of improvements in the treated group also at 6 months post-randomization.

taVNS stimulation using the Parasym device or sham stimulation will be applied from the time of enrolment (between 7 to 15 days since admission in ICU) un-til day 90 post-enrolment.

Active stimulations will be carried out daily for 60 minutes twice daily during the acute phase and daily during the rehabilitation phase The stimulation waveform includes trains of pulses with widths of 200 µs and repetition rate of 20 Hz (Nurosym proprietary waveform); current delivery will be set at a prede-fined therapeutic level below 0.25 W/cm² (Watts per centimeter squared), that being the defined risk threshold for a thermal burn. The device adjusts stimulation intensity at 0.8 mA steps; the starting intensity will be set at 16 mA (level 20).

Assuming a delta of response of 30% at 3 months between the experimental and the sham group and considering a 1:1 randomization ratio and a 20% drop-out rate, a sample of 53 patients per group (106 in total) is required to reach a power of 80% (alpha=5% and two-sided test on proportion).

Вмешательства

• Устройство stimulated group
  Participants will be randomly assigned to receive either taVNS applied to the tragus of the ear or a sham stimulation from the time of randomization for 90 days. Active simulations will be carried out daily using the Parasym device for 60 minutes twice daily during the acute phase (two sessions, one in the morning and one in the afternoon), and once daily (single session) during the rehabilitation phase. The stimulation waveform includes trains of pulses with widths of 200 µs and repetition rate
• Устройство Sham (No Treatment)
  The sham stimulation involves placing the electrode on the same site without delivering any electrical current. The device will be applied to the tragus without electrical current delivered from the time of randomization for 90 days (i.e., the time of randomization coincides with the first stimulation session).

Первичные конечные точки

• Rate of response to stimulation [Срок оценки: 90 days post-randomization]

Вторичные конечные точки (3)

• taVNS efficacy in speeding the time of recovery from the disorder of consciousness [Срок оценки: 90 days post-randomization]
• CRS-R score difference [Срок оценки: 90 days and 180 days post randomization]
• Efficacy duration [Срок оценки: 180 days post-randomization]

Критерии участия

Критерии включения

• Age ≥ 18 years old;
• any acquired cerebral damage of any known etiology;
• diagnosis of coma, UWS, or MCS with the corresponding basal CRS-R (Coma Recovery Scale-Revised) score performed during the screening period from 7 to 15 days since admission in ICU;
• intact ear skin;
• availability of the device.

Критерии исключения

• Patients with severe hemodynamic, respiratory, infectious, or neurological instability requiring active treatment requiring mechanical ventilation or vasoactive drugs or pending acute neurosurgical interventions;
• Need for deep sedation, including general anesthetics (e.g., propofol) or a combination of central-acting sedatives;
• Documented pregnancy;
• Active implant (e.g., pacemaker, cochlear implant);
• History of previous serious neurological disability before the brain injury;
• Seizures or status epilepticus as cause sustaining the disorder of consciousness;
• Patients already enrolled in another ongoing interventional trial.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Италия · 11 центров

• ASST degli Spedali Civili di Brescia — Brescia
• Fondazione IRCCS San Gerardo dei Tintori — Monza
• ASST Papa Giovanni XXIII — Bergamo
• ASST Lariana Ospedale S. Anna — Como
• Ospedale Policlinico San Martino IRCCS — Genova
• ASST Grande Ospedale Metropolitano Niguarda — Milan
• Azienda Ospedaliera Università di Padova — Padova
• Azienda Ospedaliera Universitaria di Parma — Parma
• … и ещё 3 центра

Публикации

• Sanz LRD, Laureys S, Gosseries O. Towards modern post-coma care based on neuroscientific evidence. Int J Clin Health Psychol. 2023 Jul-Sep;23(3):100370. doi: 10.1016/j.ijchp.2023.100370. Epub 2023 Feb 3. PMID 36817874
• Vitello MM, Briand MM, Ledoux D, Annen J, El Tahry R, Laureys S, Martin D, Gosseries O, Thibaut A. Transcutaneous vagal nerve stimulation to treat disorders of consciousness: Protocol for a double-blind randomized controlled trial. Int J Clin Health Psychol. 2023 Apr-Jun;23(2):100360. doi: 10.1016/j.ijchp.2022.100360. Epub 2022 Nov 29. PMID 36467262
• Urbin MA, Lafe CW, Simpson TW, Wittenberg GF, Chandrasekaran B, Weber DJ. Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans. Brain Stimul. 2021 Jul-Aug;14(4):990-1001. doi: 10.1016/j.brs.2021.06.002. Epub 2021 Jun 18. PMID 34154980
• Briand MM, Gosseries O, Staumont B, Laureys S, Thibaut A. Transcutaneous Auricular Vagal Nerve Stimulation and Disorders of Consciousness: A Hypothesis for Mechanisms of Action. Front Neurol. 2020 Aug 25;11:933. doi: 10.3389/fneur.2020.00933. eCollection 2020. PMID 32982941
• Sharon O, Fahoum F, Nir Y. Transcutaneous Vagus Nerve Stimulation in Humans Induces Pupil Dilation and Attenuates Alpha Oscillations. J Neurosci. 2021 Jan 13;41(2):320-330. doi: 10.1523/JNEUROSCI.1361-20.2020. Epub 2020 Nov 19. PMID 33214317
• Gerges ANH, Williams EER, Hillier S, Uy J, Hamilton T, Chamberlain S, Hordacre B. Clinical application of transcutaneous auricular vagus nerve stimulation: a scoping review. Disabil Rehabil. 2024 Dec;46(24):5730-5760. doi: 10.1080/09638288.2024.2313123. Epub 2024 Feb 16. PMID 38362860
• Wu X, Xie L, Lei J, Yao J, Li J, Ruan L, Hong J, Zheng G, Cheng Y, Long L, Wang J, Huang C, Xie Q, Zhang X, He J, Yu X, Lv S, Sun Z, Liu D, Li X, Zhu J, Yang X, Wang D, Bao Y, Maas AIR, Menon D, Xue Y, Jiang J, Feng J, Gao G; ACES Participants. Acute traumatic coma awakening by right median nerve electrical stimulation: a randomised controlled trial. Intensive Care Med. 2023 Jun;49(6):633-644. doi PMID 37178149
• Schiff ND. Recovery of consciousness after brain injury: a mesocircuit hypothesis. Trends Neurosci. 2010 Jan;33(1):1-9. doi: 10.1016/j.tins.2009.11.002. Epub 2009 Dec 1. PMID 19954851

Идентификаторы

NCT: NCT07077135 · REVELATION

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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