Clinical trial NCT06681168: Vagal Nerve Stimulation to Treat Disorders of Consciousness
Official title: Transcutaneous Vagal Nerve Stimulation to Treat Disorders of Consciousness
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Disorder of Consciousness
Keywords: vagal nerve stimulation
transcutaneous
auricolar
disorder of consciousness
coma
Lead sponsor: University of Milano Bicocca
Sponsor class: OTHER
First posted: 2024-11-08
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Eligibility criteria: Inclusion Criteria:

* 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.

Exclusion Criteria:

* 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.

Primary outcomes:
measure: Rate of response to stimulation
timeFrame: 90 days post-randomization
Secondary outcomes:
measure: taVNS effectiveness
timeFrame: 90 days post-randomization
measure: CRS-R score difference
timeFrame: 90 days and 180 days post randomization
measure: Efficacy duration
timeFrame: 180 days post-randomization
Other outcomes:
measure: Responders phenotype
timeFrame: 180 days
Locations:
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII
state: BG
city: Brescia
country: Italy
facility: ASST degli Spedali Civili
state: BS
city: Como
country: Italy
facility: ASST Lariana Ospedale S. Anna
state: CO
city: Genova
country: Italy
facility: Ospedale Policlinico San Martino IRCCS
state: GE
city: Monza
country: Italy
facility: Fondazione IRCCS San Gerardo dei Tintori
state: MB
city: Milano
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda
state: MI
city: Rozzano
country: Italy
facility: Humanitas Research Hospital
state: MI
city: Padova
country: Italy
facility: Azienda Ospedale Università di Padova
state: PD
city: Parma
country: Italy
facility: Azienda Ospedaliero Universitaria di Parma
state: PR
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
state: RM
city: Varese
country: Italy
facility: ASST Sette Laghi Ospedale di Circolo e Fondazione Macchi
state: Virginia
Study officials:
affiliation: University of Milano Bicocca
name: Giuseppe Citerio, MD, Full Professor
role: PRINCIPAL_INVESTIGATOR
affiliation: Fondazione IRCCS San Gerardo dei Tintori
name: Alberto Addis, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.