Vagal Nerve Stimulation to Treat Disorders of Consciousness

NCT07077135 | Not Yet Recruiting

• 1 other identifier: REVELATION
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 11

Brief Summary

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.

Conditions

Disorder of Consciousness

Keywords

vagal nerve stimulation; transcutaneous; auricolar; disorder of consciousness; coma

Outcome Measures

Primary Outcomes (1)

• Rate of response to stimulation

  A response is defined as an increase of at least 3 points in the Coma Recovery Scale-Revised (CRS-R), or a clinical change in the diagnosed level of consciousness: from coma to unresponsive wakefulness syndrome (UWS), from UWS to minimally conscious state (MCS), or emergence from MCS. Clinical markers for the diagnostic improvements are derived from the CRS-R scale: • The transition from coma to UWS will be defined as the appearance of eyes opening. • The MCS minus state will be defined by the appearance of visual pursuit, object localization, automatic motor responses, or object manipulation. • The MCS plus will be defined by the appearance of non-functional intentional communication, intelligible verbalization, object recognition, or movement to command. • Emergence from MCS will be defined by the appearance of functional accurate communication or functional object use.

  90 days post-randomization

Secondary Outcomes (3)

• taVNS efficacy in speeding the time of recovery from the disorder of consciousness

  90 days post-randomization

• CRS-R score difference

  90 days and 180 days post randomization

• Efficacy duration

  180 days post-randomization

Other Outcomes (1)

• Responders phenotype

  180 days

Study Arms (2)

Stimulated group

EXPERIMENTAL

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) until 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 predefined 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).

Device: stimulated group

Control group

SHAM COMPARATOR

The Parasym device will be positioned on the patients as for the stimulated group (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 but it won't be switched on.

Device: Sham (No Treatment)

Interventions

stimulated group DEVICE

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 of 20 Hz (Nurosym proprietary waveform); current delivery will be set at a predefined 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).

Also known as: experimental arm

Stimulated group

Sham (No Treatment) DEVICE

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).

Also known as: control group

Control group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Fondazione IRCCS San Gerardo dei Tintori: lead

Study Sites (11)

ASST degli Spedali Civili di Brescia

Brescia, BS, Italy

Location

Fondazione IRCCS San Gerardo dei Tintori

Monza, MB, 20900, Italy

Location

ASST Papa Giovanni XXIII

Bergamo, Italy

Location

ASST Lariana Ospedale S. Anna

Como, Italy

Location

Ospedale Policlinico San Martino IRCCS

Genova, Italy

Location

ASST Grande Ospedale Metropolitano Niguarda

Milan, Italy

Location

Azienda Ospedaliera Università di Padova

Padua, Italy

Location

Azienda Ospedaliera Universitaria di Parma

Parma, Italy

Location

Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Roma, Italy

Location

Humanitas Research Hospital

Rozzano, Italy

Location

ASST Sette Laghi Ospedale di Circolo e Fondazione Macchi

Varese, Italy

Location

Related Publications (11)

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

• 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: 10.1007/s00134-023-07072-1. Epub 2023 May 13.

  PMID: 37178149 RESULT

• 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 RESULT

• Manta S, Dong J, Debonnel G, Blier P. Optimization of vagus nerve stimulation parameters using the firing activity of serotonin neurons in the rat dorsal raphe. Eur Neuropsychopharmacol. 2009 Apr;19(4):250-5. doi: 10.1016/j.euroneuro.2008.12.001. Epub 2009 Jan 15.

  PMID: 19150228 RESULT

• Sandroni C, Citerio G, Taccone FS. Automated pupillometry in intensive care. Intensive Care Med. 2022 Oct;48(10):1467-1470. doi: 10.1007/s00134-022-06772-4. Epub 2022 Jun 30. No abstract available.

  PMID: 35773500 RESULT

• Giacino JT, Katz DI, Schiff ND, Whyte J, Ashman EJ, Ashwal S, Barbano R, Hammond FM, Laureys S, Ling GSF, Nakase-Richardson R, Seel RT, Yablon S, Getchius TSD, Gronseth GS, Armstrong MJ. Practice Guideline Update Recommendations Summary: Disorders of Consciousness: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology; the American Congress of Rehabilitation Medicine; and the National Institute on Disability, Independent Living, and Rehabilitation Research. Arch Phys Med Rehabil. 2018 Sep;99(9):1699-1709. doi: 10.1016/j.apmr.2018.07.001. Epub 2018 Aug 8.

  PMID: 30098791 RESULT

MeSH Terms

Conditions

Consciousness Disorders; Coma

Interventions

Control Groups

Condition Hierarchy (Ancestors)

Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurocognitive Disorders; Mental Disorders; Unconsciousness

Intervention Hierarchy (Ancestors)

Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Giuseppe Citerio, MD, Full Professor

  University of Milano-Bicocca / Fondazione IRCCS San Gerardo dei Tintori

  PRINCIPAL INVESTIGATOR

• Alberto Addis, MD

  Fondazione IRCCS San Gerardo dei Tintori

  STUDY DIRECTOR

Central Study Contacts

Giuseppe Citerio, MD, Full Professor

CONTACT

+390392334316; giuseppe.citerio@unimib.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 16, 2025
• First Posted: July 22, 2025
• Study Start: September 1, 2025
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: July 22, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF

Locations

IT (11)