Safety and efficacy of transcutaneous auricular vagus nerve stimulation in patients with narcolepsy type 1 (TARGET-2): study protocol for a randomised, double-blind, sham-controlled trial

Abstract

Introduction

Narcolepsy type 1 (NT1) is a chronic neurological disorder characterised by excessive daytime sleepiness, cataplexy and disturbed nocturnal sleep. Current pharmacological treatments often have limited efficacy, significant side effects or potential for abuse. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that has shown promise in regulating sleep–wake cycles and neural network activity. Preliminary evidence from our prior study on Transcutaneous Auricular Vagus Nerve Stimulation in patients with NT1 (TARGET-NT1 study) suggests potential benefits of taVNS for NT1. The TARGET-2 trial aims to evaluate the efficacy and safety of bilateral taVNS compared with unilateral taVNS and sham stimulation in patients with NT1.

Methods and analysis

TARGET-2 is a randomised double-blind trial. A total of 153 participants with NT1 will be recruited from four centres in China. Participants will be randomly allocated (1:1:1) to receive either (1) bilateral taVNS (active stimulation on both ears), (2) unilateral taVNS (active stimulation on the left ear only) or (3) sham taVNS (minimal intensity stimulation on both ears). Participants and outcome assessors are blinded. The intervention will be administered twice daily for 30 min per session over 12 weeks. The primary outcome is the change in the Epworth Sleepiness Scale (ESS) score from baseline to the 12-week endpoint. Secondary outcomes are changes in the narcolepsy severity scale score, Pittsburgh Sleep Quality Index, fatigue severity scale score, 14-item Hamilton Anxiety Rating Scale score and 17-item Hamilton Depression Rating Scale score, as well as responder rates (proportion with ≥25% ESS reduction) from baseline to week 12. Safety will be assessed by monitoring adverse events.

Ethics and dissemination

Ethical approval has been granted by the Medical Ethical Committee of Xijing Hospital (Approval Number: XJLL-KY-20252403). Written informed consent will be obtained from all participants before initiating any study-specific procedures. The results will be submitted for publication in a peer-reviewed journal. The anticipated completion date for reporting of the study results is 31 March 2027.

Trial registration

Chinese Clinical Trial Registry, ChiCTR2500110531 (registered on 15 October 2025).

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The three-arm design enables assessment of both the absolute efficacy of transcutaneous auricular vagus nerve stimulation (taVNS) versus sham tVNS and the relative efficacy of bilateral tVNS versus unilateral tVNS.

• Blinding is ensured by using the same devices and electrode placements across all groups, with the sham group receiving a fixed low-intensity stimulation of 0.1 mA to reduce noticeable sensations.

• The study uses clinical scales for outcome assessment instead of the maintenance of wakefulness test due to varying medical infrastructure across hospitals

Introduction

Narcolepsy type 1 (NT1) is a chronic and debilitating neurological sleep disorder arising from the selective loss of hypocretin (orexin)-producing neurons in the hypothalamus.^{1 2} Its core clinical symptoms include excessive daytime sleepiness (EDS), cataplexy (sudden loss of muscle tone triggered by emotions), sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep.³ Severe EDS significantly impairs quality of life, academic and occupational performance and increases the risk of accidents.4,8

The mainstay of NT1 management is a pharmacological approach, targeting symptom control. Stimulants, such as modafinil and methylphenidate, are used for EDS, and antidepressant agents or sodium oxybate are prescribed for cataplexy.^{9 10} Newer agents such as pitolisant (an H3 receptor antagonist/inverse agonist) and solriamfetol (a dopamine and norepinephrine reuptake inhibitor) have become first-line or major therapeutic options for NT1.¹¹ However, these treatments are often suboptimal. A substantial proportion of patients (up to 40%) continue to experience refractory sleepiness despite medication.¹² Furthermore, these drugs are associated with significant side effects, such as tolerance development, cardiovascular concerns, psychiatric symptoms and risk of abuse and dependence. The limitations and drawbacks of current pharmacotherapies underscore the critical need for developing novel, effective and safe non-pharmacological interventions for NT1.

Transcutaneous auricular vagus nerve stimulation (taVNS) has garnered significant interest for its potential therapeutic applications in various neuropsychiatric disorders, such as epilepsy, depression and insomnia.13,15 Its favourable safety profile, non-invasiveness and potential for home-based use make it an attractive therapeutic candidate. However, the lack of a standardised taVNS protocol limits its application. While some trials stimulate the left ear to minimise cardiac risks, others suggest that bilateral stimulation may offer superior efficacy, creating a divergence.^{13 16 17}

Our research group conducted the preliminary Transcutaneous Auricular Vagus Nerve Stimulation in patients with NT1 (TARGET-NT1 study, a randomised sham-controlled trial investigating taVNS in NT1.¹⁸ The results demonstrated that active taVNS significantly improved objective wakefulness, as measured by the maintenance of the wakefulness test (MWT), compared with sham stimulation. Furthermore, functional MRI data suggest that the therapeutic effects might be mediated through modulation of brainstem activity and functional connectivity within sleep–wake regulatory networks.

Building on these promising findings, we designed the TARGET-2 trial to directly compare the effects of bilateral taVNS (btVNS) against unilateral taVNS (utVNS) and sham control (stVNS) in a larger, multicentre cohort. We hypothesise that (1) active taVNS can effectively alleviate EDS in NT1, (2) btVNS will demonstrate greater efficacy than utVNS and (3) taVNS will be safe and well-tolerated.

Study objectives

Primary objective

To evaluate the safety and efficacy of taVNS to alleviate EDS in patients with NT1 from baseline to week 12.

Secondary objectives

(1) To assess the effects of taVNS on other clinical features of NT1, including narcolepsy severity, sleep quality, fatigue, anxiety and depressive symptoms from baseline to week 12 and (2) to evaluate the proportion of responders (defined as ≥25% reduction in the Epworth Sleepiness Scale (ESS) score) in each group from baseline to week 12.

Methods and analysis

Study design

TARGET-2 is a multicentre, randomised, double-blind trial. The design of certain elements in the current study is adapted from a previous exploratory trial¹⁸ . Participants will be randomly assigned in a 1:1:1 ratio to one of three groups: btVNS group (active stimulation applied to both ears), utVNS group (two-sided electrodes, but active stimulation applied only to the left ear) and stVNS group (sub-therapeutic intensity stimulation applied to both ears). The total duration of participation for each participant will be approximately 16 weeks, including a 4- week screening/baseline period and a 12-week intervention period with assessments at baseline, 4, 8 and 12 weeks. The study design adheres to the standard protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. The protocol received formal approval from the medical ethical committee of Xijing Hospital (XJLL-KY-20252403) prior to participant enrolment. An independent data and safety monitoring board (DSMB) will be established to oversee the trial.

Setting

The trial will be conducted across four clinical centres in Northwest China: (1) Xijing Hospital (leading centre), (2) Xi’an Daxing Hospital, (3) Yan’an Hospital of Traditional Chinese Medicine and (4) Baoji Hospital of Traditional Chinese Medicine.

Participant selection

Inclusion criteria

(1) Age ≥18 years; (2) fulfil the International Classification of Sleep Disorders, Third Edition, Text Revision diagnostic criteria for NT1; (3) persistent EDS (ESS score ≥12) despite stable standard pharmacological treatment for at least 3 months prior to screening or intolerance to standard therapies; (4) stable concomitant medication regimen for NT1 (if applicable) for at least 4 weeks before randomisation and willingness to maintain a stable regimen throughout the trial; (5) ability and willingness to comply with the protocol-required 3-month follow-up period; and (6) ability to comprehend the study procedures and questionnaires and provide written informed consent.

Exclusion criteria

(1) Other significant neurological disorders (eg, stroke, significant traumatic brain injury, epilepsy and neurodegenerative diseases); (2) other significant untreated sleep disorders that could confound results (eg, moderate-to-severe obstructive sleep apnoea (apnoea–hypopnoea index≥15) and severe restless legs syndrome); (3) severe arrhythmias or bradycardia; (4) significant unstable or uncontrolled medical conditions (eg, hepatic or renal failure and active cancer); (5) major psychiatric disorders (eg, major depressive disorder, schizophrenia, bipolar disorder and active psychosis); (6) cognitive impairment or any condition impairing the ability to understand study instructions or complete questionnaires; (7) implanted electrical medical devices (eg, pacemaker, vagus nerve stimulator and deep brain stimulator); (8) history of substance or alcohol abuse or dependence within the past year; (9) pregnancy or lactation; (10) local skin lesions, dermatitis or infection at the auricular stimulation sites; known hypersensitivity to electrode materials (silver/silver chloride); (11) contraindications to MRI (eg, metallic implants and claustrophobia); and (12) participation in another interventional clinical trial within 30 days prior to screening.

Recruitment and consent

Potential participants will be identified from the outpatient clinics of the participating neurology and sleep medicine departments. Recruitment will also be facilitated through hospital websites, social media platforms (eg, WeChat official accounts) and posted advertisements. Individuals expressing interest will undergo an initial screening for basic eligibility.

Eligible candidates will be invited to the study site for a detailed explanation of the study. A designated investigator will provide comprehensive verbal and written information using the approved informed consent form, detailing the study’s purpose, procedures, potential benefits and risks, alternative treatments, confidentiality measures and the right to withdraw at any time without penalty. Ample time will be given for questions. Written informed consent will be obtained from all participants before initiating any study-specific procedures.

Randomisation and blinding

Eligible participants will be randomised using a computer-generated, stratified block randomisation schedule. Stratification will be by study centre to ensure balance across sites. Block sizes will be varied and concealed to maintain allocation unpredictability. The randomisation list will be prepared by an independent statistician using SAS V.9.4 and will be uploaded and secured within a centralised interactive web response system (IWRS).

Following baseline assessments, authorised site personnel will log into the password-protected IWRS to randomise an eligible participant. The system will then instantly assign, conceal and log the treatment group. The statistician will have no access to the IWRS allocation module, ensuring allocation concealment.

This is a double-blind trial. Outcome assessors will be blinded to group assignment throughout the trial. To maintain blinding, (1) sham stimulation and active stimulation use the same device; (2) the stimulation parameters for the stVNS group will be set at a low intensity (0.1 mA) that may produce minimal or no perceptible sensation, mimicking the initial setup phase of active stimulation; (3) participants will be instructed not to discuss their stimulation experience (eg, sensation intensity and location) with the outcome assessors; (4) the personnel responsible for setting up the devices and adjusting stimulation intensities (eg, unblinded study coordinator) will not be involved in outcome assessments.

The success of blinding will be assessed at the end of the study using the bang blinding index (BBI) for participants. A BBI value between −0.2 and 0.2 will indicate successful blinding.

Emergency unblinding will be permitted only in situations where knowledge of the actual treatment is absolutely essential for the clinical management of a serious adverse event (SAE). The principal investigator (PI) must approve any unblinding request. The date, time, reason and requesting party for any unblinding event will be thoroughly documented.

Intervention

Device

taVNS will be delivered using the TVNS-100 device (Xinzhile, Jiangxi, China), which has received approval from the national medical products administration of China.¹⁴ All groups will be instructed to use the device twice daily (once each in the morning and evening) for 30 min per session. At least one session should be administered within 2 hours before bedtime. Electrodes will be placed on the cymba conchae and cavum conchae of both ears.¹⁹ Stimulation parameters will be frequency of 25 Hz and pulse width of 500 μs. The intensity for both the btVNS and utVNS will be set at a level above the sensory perception threshold but below the pain threshold (typically between 0.5 and 5.0 mA). Participants will be trained to adjust the intensity to maintain this perceptible but acceptable level throughout the intervention period. In contrast, for the stVNS, the intensity will be fixed at 0.1 mA, which is expected to be barely perceptible or imperceptible for most participants after the initial setup. (1) For btVNS, stimulation will be delivered in an alternating pattern: 30 s of stimulation on the left ear and 30 s of stimulation on the right ear repeated throughout the 30 min session. (2) For utVNS, stimulation will be delivered in a cyclic pattern: 30 s of stimulation on the left ear and 30 s OFF, repeated throughout the 30 min session. (3) For stVNS, the stimulation protocol will be consistent with btVNS to ensure that the participants received stimulation that is similar in form to active stimulation.

Concomitant medication

Participants will be allowed to continue their pre-existing stable regimen of NT1 medications. However, they must agree not to change the type or dosage of these medications throughout the study period unless medically necessary, in which case it will be recorded. Initiation of new NT1 medications or non-pharmacological therapies for NT1 symptoms during the trial is prohibited.

Compliance monitoring

Device usage data (session duration, frequency and stimulation intensity) will be automatically recorded by the TVNS-100 devices. Participants will also maintain a paper or electronic daily diary to log their stimulation sessions and any issues encountered.

Outcome assessments

To ensure the consistency and quality of data collection throughout the follow-up period, all participant assessments are conducted by trained investigators using a standardised protocol. Each structured assessment required approximately 40 min to complete. For participants unable to attend in-person visits, assessments are administered via a combination of telephone interviews and secure online video-conferencing platforms to maximise retention and accommodate individual circumstances.

A set of rigorous measures is implemented to optimise the accuracy and reliability of the assessments and minimise potential biases. First, assessment sessions will be scheduled at a time of day when the participant reported feeling most alert and comfortable, thereby reducing the potential for performance variability due to fatigue or environmental anxiety. Second, all evaluations will be conducted in a quiet, well-lit room free from auditory and visual distractions. Participants are explicitly requested to minimise external interruptions by turning off televisions, radios and other non-essential electronic devices for the duration of the interview.

Furthermore, to enhance the veracity of the collected information, a collateral verification procedure is employed. While the participant provided primary responses to all questions, an accompanying family member or caregiver is invited to corroborate or clarify the responses, particularly for questions pertaining to daily functioning, symptom history and medication adherence. Finally, the investigator continuously monitored the participant’s level of engagement and comfort. If signs of significant distress, agitation or fatigue are observed during the assessment, the session will be paused or discontinued and rescheduled to ensure the participant’s well-being and data integrity. These combined strategies are designed to uphold the highest standards of data quality while prioritising ethical conduct and participant comfort.

Table 1 lists the comprehensive schedule of all assessments.

Table 1. Schedule of enrolment, interventions and assessments.

Activity	Screening/baseline (T0)	Intervention period	Endpoint (T3)
Informed consent	X
Eligibility screening	X
Demographics/medical history	X
Physical examination	X
PSG/MSLT/CSF-Hcrt review	X
MRI scan	X
Randomisation		X (Day 0)
Intervention		X	X
Concomitant medications		X	X
ESS, NSS, PSQI, FSS, HAMA-14 and HAMD-17		X	X
AEs		X	X
Vital signs		X	X
Compliance check (diary/device log)		X	X
Interim analysis		X
Final analysis			X

AEs, adverse events; CSF-Hcrt, cerebrospinal fluid-hypocretin; ESS, Epworth Sleepiness Scale; FSS, Fatigue Severity Scale; HAMA-14, 14-item Hamilton Anxiety Rating Scale; HAMD-17, 17-item Hamilton Depression Rating Scale; MSLT, Multiple Sleep Latency Test; NSS, Narcolepsy Severity Scale; PSG, polysomnography; PSQI, Pittsburgh Sleep Quality Index.

Screening/baseline (T0, within 4 weeks pre-randomisation): informed consent, eligibility check, demographics, medical history, physical examination, polysomnography/multiple sleep latency test/cerebrospinal fluid-hypocretin review (if not recent), MRI for structural screening, concomitant medications, ESS, Narcolepsy Severity Scale (NSS), Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), 14-item Hamilton Anxiety Rating Scale (HAMA-14), 17-item Hamilton Depression Rating Scale (HAMD-17) and vital signs.

Weeks 4 (T1, 28±3 days), 8 (T2, 56±3 days) and 12 (T3, 84±3 days endpoint): concomitant medications, ESS, NSS, PSQI, FSS, HAMA-14, HAMD-17, AEs, vital signs and compliance check.

Outcome measures

Primary outcome measure

The change from baseline (T0) to the end of the 12-week intervention period (T3) in the ESS score. The ESS is a validated 8-item self-administered questionnaire measuring the severity of daytime sleepiness, with scores ranging from 0 to 24; higher scores indicate greater sleepiness.²⁰

Secondary outcome measures

1. Responder rate: the proportion of participants in each group achieving a ≥25% reduction in the ESS score from baseline to week 12.

2. Change in the NSS score: the NSS is a 15-item questionnaire specifically designed to assess the severity of narcolepsy symptoms (sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disrupted nocturnal sleep) over the past month.²¹

3. Change in the PSQI score: the PSQI is a seven-dimensional questionnaire designed to assess sleep quality and disturbances over a 1-month interval, generating a global score where higher scores indicate worse sleep quality.²²

4. Change in the FSS score: The FSS is a nine-item questionnaire measuring the severity of fatigue and its impact on daily activities.²³

5. Change in the HAMA-14 score: clinician-administered questionnaire assessing the severity of anxiety symptoms.²⁴

6. Change in the HAMD-17 score: clinician-administered questionnaire assessing the severity of depression symptoms.²⁵

Safety and tolerability

1. Incidence, type, frequency and severity of all AEs and SAEs.

2. Number of participants discontinuing treatment due to AEs.

3. Specific stimulation-related AEs (eg, skin irritation, redness, pain at electrode site, headache, dizziness, nausea and tinnitus).

4. Changes in vital signs (blood pressure and heart rate).

Data collection and management

Data will be collected using paper case report forms (CRFs) specifically designed for this study. All CRFs will be identified by participant identification (ID) number only, maintaining confidentiality. Site investigators are responsible for the accuracy, completeness and timeliness of data entry into the CRFs. Data from the CRFs will be entered into a secure, password-protected electronic database system by trained personnel. Data entry will be performed twice (double data entry) to minimise errors. Range and logic checks will be built into the electronic database to ensure data quality. The PI will have ultimate responsibility for the data. Access to the final trial dataset will be restricted to the PI, designated statisticians and DSMB. Safety data will be reviewed quarterly. All study documents (signed consent forms, CRFs and monitoring reports) will be archived securely for at least 15 years after study completion, as per regulatory requirements.

Statistical analysis

Analysis populations

• Full analysis set (FAS): will include all randomised participants, analysed according to the intention-to-treat (ITT) principle. Missing data will be handled using appropriate methods.

• Per-protocol set (PPS): will include participants in the FAS who completed the study with no major protocol violations and with a predefined level of compliance (>70% of stimulation sessions completed). This will be used for supportive analyses.

• Safety set (SS): will include all randomised participants who received at least one session of stimulation and have at least one post-baseline safety assessment.

Interim analysis

An interim analysis is scheduled to be undertaken after 60 individuals have concluded their participation in the trial. The principal focus of this analysis will be on safety monitoring, study progress and futility analysis.

Sample size

The sample size estimation is based on results from the TARGET-NT1 study and preliminary results of a pilot study investigating btVNS for NT1.¹⁸ After the 12-week intervention, the pilot results indicated mean ESS scores of 13.71 (SD=2.57) in the btVNS, 15.65 (SD=2.84) in the utVNS and 18.52 (SD=2.49) in the stVNS groups.

The study requires two pre-specified superiority tests: (1) a test for statistical superiority of btVNS versus utVNS (with a non-inferiority/superiority margin, Δ=0), and (2) a test for clinical superiority of btVNS versus stVNS to detect the pre-defined minimal clinically important difference (MCID) in the ESS score (Δ=2).

The sample size is calculated using the formula for a two-sample t-test:

$$n=\frac{2{(Z_{1-\alpha }+Z_{1-\beta })}^2}{d^2}$$

A Bonferroni correction is applied to account for the two primary comparisons, resulting in a one-sided significance level (α) of 0.025 per test. The statistical power (1-β) is set at 90%. The standardised effect size (Cohen’s d) is calculated as follows:

$$n=\frac{\mid {\mu }_1-{\mu }_2\mid -\Delta }{{\sigma }_{pooled}}$$

$${\sigma }_{pooled}=\sqrt{\frac{{\sigma }_1^2+{\sigma }_2^2}{2}}$$

btVNS versus utVNS (statistical superiority)

The estimated mean difference is −1.94 (13.71–15.65). The pooled SD is sqrt[(2.57²+2.84²)/2] ≈ 2.71. The standardised effect size is | −1.94 | / 2.71 ≈ 0.716. This calculation yields a requirement of 19 participants per group.

btVNS versus stVNS (clinical superiority):

Superiority is defined as the mean difference being less than −2. The estimated mean difference is −4.81 (13.71–18.52). The pooled SD is sqrt [(2.57² + 2.49²)/2] ≈ 2.53. The standardised effect size is (| −4.81 | − 2) / 2.53 ≈ 1.111. This calculation yields a requirement of 19 participants per group.

The larger of the two sample size estimates (42 per group) is adopted to ensure adequate power for both primary comparisons. Thus, the total sample size required for the three groups is 126 participants. Accounting for an anticipated dropout rate of 20%, the final planned enrolment is 153 participants.

Primary outcome analysis

The change in the ESS score from baseline to week 12 will be analysed using a linear mixed-effects model (LMM). The model will include fixed effects for treatment group, time, group-by-time interaction and baseline ESS score as a covariate. Random effects will include participant ID (to account for repeated measures) and study centre (to account for stratification). The estimated mean change from baseline for each group and the differences between groups (btVNS vs stVNS; btVNS vs utVNS) at week 12 will be presented with 95% CIs. The primary analysis will be performed on the FAS and PPS. For the two primary comparisons, we will use a pre-specified significance level of α=0.025 (two-sided) for hypothesis testing. Additionally, the primary efficacy analysis will also implement a mixed model adjusted for baseline under the missing-at-random assumption without imputation. The last observation carried forward method will be utilised in a sensitivity analysis to evaluate the robustness of the results.

Secondary outcome analysis

Continuous secondary endpoints (changes in NSS, PSQI, FSS, HAMA and HAMD scores) will be analysed similarly using LMMs. The responder rate (proportion with ≥25% ESS score reduction) will be compared between groups using χ2 tests or Fisher’s exact tests. Safety data (AEs and vital signs) will be summarised descriptively by group, using frequencies, percentages and appropriate measures of central tendency and dispersion.

Monitoring and safety

The DSMB, comprising experts in neurology, sleep medicine, statistics and clinical trials, will conduct an interim analysis after the completion of the study procedures by the first 60 participants and make recommendations regarding the continuation, modification or termination of the trial.

Ethics and dissemination

Ethical approval has been granted by the Medical Ethical Committee of Xijing Hospital (Approval Number: XJLL-KY-20252403). Written informed consent (online supplemental material file) will be obtained from all participants before initiating any study-specific procedures. The trial is registered with the Chinese Clinical Trial Registry (ChiCTR2500110531; registered October 15, 2025). The results will be submitted for publication in a peer-reviewed journal.

The study protocol is Version 3.0, dated 18 September 2025. Participant recruitment was initiated on 30 October 2025, across the four participating centres. Patient enrolment and follow-up were ongoing at the time of manuscript submission. The anticipated completion date for the entire trial, including follow-up and data analysis, is 31 December 2026. The anticipated completion date for reporting of the study results is 31 March 2027.

Discussion

The TARGET-2 trial is designed to address an unmet need in the management of NT1 by rigorously evaluating a novel non-pharmacological intervention. This protocol outlines a methodology for a multicentre, randomised, double-blind, sham-controlled trial.

The choice of a three-arm design (btVNS, utVNS and stVNS) is a strength. It allows for the assessment of both the absolute efficacy of taVNS versus stVNS and the relative efficacy of btVNS versus utVNS, a question with practical implications for clinical application.

The rationale for exploring taVNS in NT1 is strongly supported by both the pathophysiology of NT1 and prior neuromodulation evidence. NT1 is characterised by the loss of hypocretin-producing neurons, leading to dysregulation of sleep–wake stability and REM sleep control—processes deeply influenced by brainstem structures such as the locus coeruleus and the dorsal raphe nucleus. The vagus nerve, with its extensive projections to these key regions via the nucleus tractus solitarius, represents a compelling non-invasive target for therapeutic intervention. Our previous TARGET-NT1 trial provided preliminary support, demonstrating that active taVNS not only improved objective wakefulness but also modulated functional connectivity within brainstem-centred networks relevant to sleep-wake regulation.

utVNS, typically applied to the left ear to minimise potential cardiac side effects, has been widely used in previous trials.^{26 27} Evidence from other neurological and psychiatric conditions suggests that btVNS might yield superior outcomes. For instance, studies in insomnia and mild cognitive impairment have begun exploring bilateral paradigms. It is hypothesised that simultaneous engagement of vagal afferents from both ears may lead to more robust and symmetrical modulation of central nervous system pathways, including enhanced noradrenergic signalling from the locus coeruleus and broader network effects. A systematic review and meta-analysis by Kim et al including 177 studies and 6322 participants indicated that although bilateral stimulation is less commonly applied than unilateral stimulation, it is not found to be associated with additional safety risks. The TARGET-2 trial directly tests this hypothesis in the context of NT1.

Blinding is a major strength of the TARGET-2 trial, achieved through several measures: identical devices and electrode placements for all groups, low-intensity sham stimulation below sensory perception, consistent stimulation patterns with the active group, separate roles for outcome assessors and setup personnel and participant instructions to avoid discussing sensations. Blinding effectiveness will be assessed using the BBI. Collectively, these measures minimise performance and detection biases, enhancing the internal validity of the trial’s findings.

The primary outcome is a patient-reported measure that is clinically meaningful and directly addresses the core symptom (EDS) of NT1. The comprehensive set of secondary outcomes captures the multifaceted nature of the disorder, including sleep quality, fatigue and mood symptoms, providing a broader assessment of the impact of taVNS.

Potential challenges include ensuring participant compliance with the twice-daily stimulation regimen over 12 weeks and managing the logistical complexities of a multicentre trial. The automated data logging feature of the stimulation devices and regular compliance checks will help mitigate the former. Centralised training, standardised protocols and regular monitoring visits will address the latter.

Several methodological limitations need to be noted. First, the anticipated dropout rate is 20%, which could bias the intention-to-treat analysis if dropouts differ between groups. Second, the sham stimulation may be detectable, which could affect blinding; this will be evaluated using the BBI. Third, the 12-week intervention period may not reveal long-term effects or safety. Fourth, we used clinical scales for outcome assessment instead of the maintenance of MWT due to varying medical infrastructure across hospitals. Lastly, the study’s restriction to four centres in Northwest China may limit generalisability.

In conclusion, the TARGET-2 trial is poised to generate high-quality evidence regarding the efficacy, safety and potential differential effects of bilateral versus unilateral taVNS for NT1. If the hypotheses are supported, taVNS could offer a non-pharmacological, well-tolerated and potentially home-based treatment option for NT1.

Data availability statement

The individual participant data underlying the trial results will be made available upon reasonable request to the corresponding author. Proposals should be directed to corresponding author email; to gain access, requestors will need to sign a data access agreement.