An interventional study of stimulated group and Sham (No Treatment) in Disorder of Consciousness, sponsored by Fondazione IRCCS San Gerardo dei Tintori. Not yet recruiting at 11 sites in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-07-22.
Sponsored by Fondazione IRCCS San Gerardo dei Tintori · Not applicable, Interventional, and Treatment
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.
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:
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).
290 studies on the registry are indexed under Consciousness Disorders; 109 are open to participants now.
This study's planned enrollment of 106 is above the median of 47 across 191 interventional studies indexed under Consciousness Disorders.
Browse Consciousness Disorders studies →Fondazione IRCCS San Gerardo dei Tintori is the lead sponsor of 9 studies on the registry; 7 are open to participants now.
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Exclusion Criteria:
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
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)
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
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
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.
Time frame: 90 days post-randomization
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.
Time frame: 90 days post-randomization
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.
Time frame: 90 days and 180 days post randomization
Efficacy duration
To evaluate if improvements persist in the treated group
Time frame: 180 days post-randomization
Responders phenotype
To evaluate the phenotype of clinical responders by identifying factors after stratification of patients by clinical diagnosis (different etiology, such as traumatic brain injury, subarachnoid hemorrhage, versus intracranial hemorrhage, or ischemic/hemorrhagic stroke).
Time frame: 180 days
Plan to share: 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.
Supporting information: Study protocol, Informed consent form
Start is estimated for Sep 2025; primary completion for Mar 2028, 30 months later.
Of 89 non-industry interventional studies with no phase under Consciousness Disorders, half reached primary completion within 20 months of starting (the median), counting those still running; a quarter within 9 and three quarters within 52. This study's planned 30 months is above that.
Counting every sponsor, half of 94 studies reached it within 19 months; a quarter within 8 and three quarters within 52.
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This study is not yet recruiting, as verified in Mar 2025. You cannot join it, but the record below documents what was studied.
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Fondazione IRCCS San Gerardo dei Tintori