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Disorder of ConsciousnessREVELATIONNCT07077135

Vagal Nerve Stimulation to Treat Disorders of Consciousness

A study testing stimulated group in people with Disorder of Consciousness, run by Fondazione IRCCS San Gerardo dei Tintori at 11 sites in Italy.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Disorder of Consciousness
What is being tested?
stimulated group
Type of treatment
Medical device
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
106 participants
Where
11 sitesItaly
Study dates
1 Sep 2025to 1 Sep 2028
Phase
Interventional
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.

Who cannot join

  • 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.

Trial locations and contacts

11 sites in 1 country. Contact the study team or a site near you to ask about taking part.

Giuseppe Citerio, MD, Full Professor contact

+390392334316

giuseppe.citerio@unimib.it

11 sites in 1 country

Italy11 sites

  • ASST Papa Giovanni XXIII

    Bergamo

    Paolo Gritti, MD, pgritti@asst-pg23.it

    Paolo Gritti, MD

  • ASST degli Spedali Civili di Brescia

    Brescia, BS

    Francesco Rasulo, MD, Professor, francesco.rasulo@unibs.it

    Francesco Rasulo, MD, Professor

  • ASST Lariana Ospedale S. Anna

    Como

    Simone M Zerbi, MD, simonemaria.zerbi@asst-lariana.it

    Simone M. Zerbi, MD

  • Ospedale Policlinico San Martino IRCCS

    Genova

    Chiara Robba, MD, Professor, kiarobba@gmail.com

    Chiara Robba, MD, Professor

  • ASST Grande Ospedale Metropolitano Niguarda

    Milan

    Arturo Chieregato, MD, arturo.chieregato@ospedaleniguarda.it

    Arturo Chieregato, MD

  • Fondazione IRCCS San Gerardo dei Tintori

    Monza, MB, 20900

    Alberto Addis, MD, +390392334335, alberto.addis@irccs-sangerardo.it

    Alberto Addis, MD

  • Azienda Ospedaliera Università di Padova

    Padova

    Marina Munari, MD, marina.munari@aopd.veneto.it

    Marina Munari, MD

  • Azienda Ospedaliera Universitaria di Parma

    Parma

    Edoardo Picetti, MD, edo74icuwild@hotmail.com

    Edoardo Picetti, MD

  • Fondazione Policlinico Universitario Agostino Gemelli IRCCS

    Roma

    Anselmo Caricato, MD, Professor, anselmo.caricato@unicatt.it

    Anselmo Caricato, MD

  • Humanitas Research Hospital

    Rozzano

    Federico Villa, MD, federico.villa@humanitas.it

    Federico Villa, MD

  • ASST Sette Laghi Ospedale di Circolo e Fondazione Macchi

    Varese

    Luca Cabrini, MD, l.cabrini@asst-settelaghi.it

    Luca Cabrini, MD

Other trials in Italy

About this study

Official title: Transcutaneous Vagal Nerve Stimulation to Treat Disorders of Consciousness

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.

Read the detailed description

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).

Being tested
stimulated group, Sham (No Treatment)
Keywords
vagal nerve stimulation, transcutaneous, auricolar, disorder of consciousness, coma
Medical subject headings
Consciousness Disorders, Coma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • stimulated groupDevice

    Also called experimental arm

    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).

  • Sham (No Treatment)Device

    Also called control group

    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).

Study groups in NCT07077135
Study groupRoleWhat they receive
Stimulated groupExperimentaltaVNS 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).
Receives: Device: stimulated group
Control groupSham comparatorThe 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.
Receives: Device: Sham (No Treatment)

What is being measured

The primary outcome is the main question the study is designed to answer.

  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.

    Measured: 90 days post-randomization

Secondary outcomes (3)

  1. taVNS efficacy in speeding the time of recovery from the disorder of consciousness

    To evaluate whether taVNS is effective in achieving a faster time to recovery of consciousness in DoC patients compared to controls.

    Measured: 90 days post-randomization

  2. CRS-R score difference

    To evaluate if the coma recovery scale revised score (CRS-R) differs in the two groups at 3 and 6 months post-randomization. The CRS-R scale is a standardized neurobehavioral assessment measure designed for use in patients with disorders of consciousness, and is intended to be used to establish diagnosis, monitor behavioral recovery, predict outcome, and assess treatment effectiveness. It consists of 6 subscales designed to assess auditory function, receptive and expressive language, visuoperception, communication ability, motor functions, and arousal level. Minimum score: 0 - Maximum score: 23.

    While the CRS-R total score should not be relied upon to establish a diagnosis, a total score of 10 or greater indicates a diagnosis of MCS or eMCS. The CRS-R can also be used to differentiate patients into "MCS+" and "MCS-" subgroups, based on the presence or absence of receptive or expressive language function.

    Measured: 90 days and 180 days post randomization

  3. Efficacy duration

    To evaluate if improvements persist in the treated group

    Measured: 180 days post-randomization

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jul 2025
  2. Study start1 Sep 2025 (estimated)
  3. Primary completion1 Mar 2028 (estimated)
  4. Study completion1 Sep 2028 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
106 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07077135
Sponsor's protocol ID
REVELATION
Acronym
REVELATION
Status last verified
Mar 2025
First submitted
16 May 2025
Last updated
22 Jul 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: Patients recruited in this study cannot provide informed consent at the time of recruitment. The responsible research staff will act as Consultee and consent-eligible patients after discussion with the next-of-kin. If the patient has a Power of Attorney or a Legal tutor, he/she will act as a Consultee and will be asked to consent/decline participation in the study on legal behalf of the patient. If patients have an Advance Decision Plan, including participation in research studies, the Plan will be respected, and recruitment pursued/abandoned accordingly. At follow-up, patients who have regained capacity will be asked to provide Informed Consent and will be given the possibility to: * Provide Informed Consent for the acute data and follow-up. * Deny research participation and request destruction of acute data collected. Furthermore, participants, their legal representatives, or substitute decision-makers may withdraw consent and discontinue participation at any time during the study.

Publications

  • 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

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

    PubMed 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.

    PubMed 19954851

  • 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.

    PubMed 19150228

  • 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.

    PubMed 35773500

  • 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.

    PubMed 30098791

Questions about this trial

What is this clinical trial studying?

A study testing stimulated group in people with Disorder of Consciousness, run by Fondazione IRCCS San Gerardo dei Tintori at 11 sites in Italy.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 22 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Giuseppe Citerio, MD, Full Professor (+390392334316, giuseppe.citerio@unimib.it), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Rate of response to stimulation (time frame: 90 days post-randomization). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07077135, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Jul 2025.

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