Transcutaneous Auricular Vagal Nerve Stimulation for the Treatment of the Fatigue Syndrome in Patients with Primary CNS Lymphoma – A Protocol for a Randomized and Controlled Single Center Clinical Trial

Abstract

Introduction

Cancer-Related Fatigue (CRF) is characterized as a distressing, persistent, and subjective sensation of physical, emotional, and/or cognitive exhaustion that is associated with cancer or its treatment. CRF is commonly observed in patients with cancer and a severely impairing symptom also in patients with the rare primary central nervous lymphoma (PCNSL). While its exact etiology remains unclear, elevated levels of tumor-induced inflammatory cytokines are believed to contribute to its development. Transcutaneous auricular vagal nerve stimulation (taVNS) is a non-invasive method to activate the vagal nerve through electrical stimulation of a vagally innervated area at the tragus. It has shown to modulate the immunsystem, to activate central arousal pathways and to reduce fatigue in autoimmune conditions. In this study, the effect of taVNS on the fatigue syndrome in patients with PCNSL will be investigated.

Methods

For this single-blinded, sham controlled, randomized controlled trial (RCT), 45 adult patients with PCNSL and fatigue in Multidimensional Fatigue Inventory (MFI20)-questionnaire after active treatment will be recruited and randomized to above-threshold-stimulation (A) sub-threshold-stimulation (B) or sham group (C). In Arm A, taVNS is perfomed on the left tragus (25 Hz, pulse width 250 µs,28 s on/32 s off,4 h/day). In Arm B, the patients will be asked to regulate the stimulator below perception threshold. In Arm C, the patients are initially shown how stimulation feels and then asked to decrease the intensity below perception threshold. They then take a non-functional sham-electrode home. Validated questionnaires data (MFI20, Beck Depression Inventory (BDI2), Short-form 26 (SF36), NeuroCogFx and Neurologic Assessment in Neuro-Oncology (NANO) and Hospital Anxiety Depression Scale (HADS)) will be collected at the beginning of the study and after 4 and 8 weeks.

Planned Outcomes

This is the first clinical trial to assess if taVNS improves fatigue symptoms in patients with the primary CNS lymphoma. If taVNS improves fatigue in these patients, it will be a significant gain in quality of life.

Trial Registration

The study was approved by the ethics committee (2024-368-f-S) and registered at the DRKS database (DRKS00036323).

Key Summary Points

Fatigue is a common burden in patients with primary CNS lymphoma.

Transcutaneous auricular vagus nerve stimulation (taVNS) might have the potential to increase arousal and reduce fatigue.

This study investigates taVNS against fatigue in patients with primary CNS lymphoma.

Introduction

Background

Primary central nervous system lymphomas (PCNSL) are highly aggressive tumors with a poor prognosis if left untreated [1]. For younger patients with PCNSL, highly effective curative treatment options are now available, leading to favorable prognoses [2–7]. Despite long-term survival with good neuropsychological outcomes [8], a significant proportion of patients does not return to work [9].

The 2015 National Comprehensive Cancer Network (NCCN) guidelines define fatigue as a “distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or its treatment, which is disproportionate to recent activity levels and interferes with daily functioning” [10]. Although often seen in other conditions, fatigue is frequently seen among patients with cancer and the most prevalent short- and long-term side effects of cancer treatment. At the time of cancer diagnosis, up to 40% of patients report experiencing fatigue symptoms (cancer related fatigue, CRF) [11]. As treatment progresses, over 90% of patients develop CRF, which can manifest on physical, emotional, and cognitive levels. Common symptoms include persistent tiredness, reduced strength and motivation, concentration difficulties, and diminished quality of life (QoL). CRF can emerge before, during, or after cancer therapy and may persist for varying durations. Even after completing oncological treatment, up to 40% of patients with cancer continue to suffer from CRF, significantly affecting their QoL [12].

Altough frequently seen in clinical routine, the role and prevalence of fatigue among patients with PCNSL during and after therapy remains insufficiently understood. Results of the HOVON105-study showed that fatigue was one of the symptoms which did not improve under therapy and remained clinically relevant even 60 months after therapy [13].

The exact pathophysiology of CRF remains poorly understood, and no standardized treatment approach has been established. To distinguish CRF from an underlying depressive disorder, the two-question screening test developed by Whooles has gained widespread acceptance [14]. Evidence suggests that chronic inflammation and an associated increase in inflammatory cytokines may contribute to CRF development [15]. In addition to their pro-inflammatory effects, both radiation therapy and chemotherapy may directly impact the central nervous system. A meta-analysis has identified a positive correlation between the severity of CRF and elevated levels of inflammatory cytokines [16], highlighting the role of chronic inflammation in its pathogenesis. Moreover, a sympathetic imbalance in the autonomic nervous system [17, 18] and dysbalance in central arousal pathways [19] may be involved in CRF. An ongoing Chinese study investigates the effect of transcutaneous auricular VNS (taVNS) on radiotherapy-related pain and fatigue [20].

Invasive vagus nerve stimulation (iVNS) has been Food and Drug Administration (FDA) approved for the treatment of epilepsy and depression around the year 2000 [21]. Vagal activation through VNS leads to immunomodulation, which appears to have beneficial effects in the treatment of autoimmune diseases such as inflammatory bowel disease [22], rheumatoid arthritis [23], and pancreatitis [24].

Building on the anatomical finding that the cymba conchae of the ear is exclusively innervated by the vagus nerve [25–27], electrical stimulation of this region has been explored as a non-invasive alternative to iVNS. Research indicates that taVNS induces brain activation patterns comparable to those observed with iVNS [28, 29]. Moreover, taVNS has demonstrated beneficial effects on epilepsy [30], depression [31], and cytokine regulation in rheumatoid arthritis [32].

TaVNS has been found to reduce inflammatory cytokines [33–35], regulate cardiac vagal tone [36], influence arousal via central pathways [37], and exert positive effects on depressive disorders [38, 39], all of which may be relevant to the development of fatigue. Additionally, the impact of taVNS on fatigue syndromes associated with systemic lupus erythematosus [40] or Sjögren’s syndrome [41] has been investigated. TaVNS against CRF in gastrointestinal tumors is being evaluated in the FATIVA-trial our group is conducting [42]. However, it remains unclear whether taVNS alleviates fatigue primarily by reducing inflammatory cytokines or through direct central nervous system mechanisms [37], and fatigue in healthy volunteers does not seem to be improved by taVNS [43].

Objectives

Building on these observations that CRF may be triggered by inflammatory processes potentially modulated by taVNS, this feasibility study aims to assess whether daily taVNS has an impact on the fatigue syndrome in patients with PCNSL over the course of a four-week trial. Patients who were assigned to one of the control groups will get the possibility to evaluate real taVNS during a second 4-week-period in a crossover design.

To evaluate these effects, we will utilize well-established and sensitive questionnaires for neurological status, follow-up, anxiety, depression, quality of life (QoL) and fatigue. These questionnaires are the “Neurologic Assessment in Neuro-Oncology” (NANO) Score [44], a computer-based follow-up scoring system for neurological patients (NeuroCogFx) [45, 46], the “Hospital Anxiety and Depression Scale” (HADS, © Hogrefe, Goettingen) [47], the Beck Depression Inventory (BDI, © Hogrefe, Goettingen) [48] and the Short-Form 36 (SF36, © Hogrefe, Goettingen) [49] for QoL-assessment. Finally, the Multidimensional Fatigue Inventory (MFI-20, contact information and permission to use: Mapi Research Trust, Lyon, France, https://eprovide.mapi-trust.org) [50] allows to quantify different aspects of fatigue and compare these results with values assessed in the general population [51], and the “Nurses` Global Assessment of Suicide Risk” (NGASR) allows for suicidal assessment. Full permissions will be sought for the use of questionnaires, scales, and scores in this study.

Trial Design

This study aims to determine the potential impact of taVNS on the fatigue, QoL, depression and follow-up-scores of patients with PCNSL.The primary endpoints are the prevalence of fatigue symptoms in patients with PCNSL and the change in the MFI-20 total score from pre- to post-treatment (H₀: There is no difference between the three groups in the difference scores of the MFI-20; H₁: There is a difference between the three groups regarding the difference scores of the symptom score). From those patients with significant fatigue 45 will be recruited and randomized in our study.

Primary endpoints:

• Prevalence of fatigue symptoms in patients assessed using the MFI-20 questionnaire (evaluation during screening at the outpatient visit).

• Improvement in fatigue symptoms in patients with PCNSL assessed using the MFI-20 questionnaire following non-invasive vagus nerve stimulation (evaluation on Day 0 before the start of stimulation and on Day 28).

Secondary endpoints:

• Collection of marital status and educational background.

• Documentation of previous treatments, remission status, comorbidities, and concomitant medications.

• Assessment of neuropsychological deficits using the NeuroCogFx before and after treatment (evaluation on Day 0 before the start of stimulation and on Day 28).

• Evaluation of neurological status using the NANO score before and after treatment (evaluation on Day 0 before the start of stimulation and on Day 28).

• Assessment of depressive and suicidal symptoms using HADS, NGASR, and BDI-II before and after treatment (evaluation on Day 0 before the start of stimulation and on Day 28).

• Evaluation of quality of life using the SF-36 before and after treatment (evaluation on Day 0 before the start of stimulation and on Day 28).

Methods

The study will be performed at the University Medical Center Bochum (Department of Neurology and Department of Neurosurgery). See attached Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-table (Table 1) for interventions and questionnaires during enrolment, visit 0, visit 1 and – if applicable – visit 2. This trial received ethical approval from the Ethics Commission Westfalen Lippe (Reference number: 2024-368-f-S) on 19/09/2024. The approved version of the study protocol is version 2. The study was designed in accordance with Good Clinical Practice (GCP), the principles outlined in the Declaration of Helsinki, and established professional conduct standards. Before enrollment, participants will receive detailed information about the study and provide written informed consent. The findings of this randomized pilot study will be disseminated through peer-reviewed publications and conference presentations. This protocol was developed following the Standard Protocol Items for Clinical Trials (SPIRIT) guidelines.

Table 1.

Course of the study according to SPIRIT

(BDI Beck Depression Inventory, HADS Hospital Anxiety and Depression Scale, NANO Neurologic Assessment in Neuro-Oncology, NGASR Nurses` Global Assessment of Suicide Risk-Skala, MFI Multidimensional Fatigue Inventory)

Sample Selection

Patients with PCNSL are routinely seen in the neuro-oncology outpatient clinic every 3–12 months, depending on the time since treatment completion. At their next scheduled appointment, patients will be informed about the study participation opportunity and asked whether they are willing to initially complete the MFI20 questionnaire. Following informed consent, patients will complete the questionnaire in the presence of a study team member. Attention is paid to achieving a balanced gender distribution.

Patients will be allocated into three groups of 15 individuals each: one receiving standard stimulator settings (Arm A), one receiving subthreshold stimulation settings without perceptible stimulation (Arm B), and one receiving sham stimulation (Arm C). After 28 days, fatigue symptoms, depressive symptoms, and physical condition will be reassessed using the same questionnaires utilized at baseline, and outcomes will be compared across groups. Patients from the Arm B and C will be revealed their status on day 28 and will have the option to crossover into the active stimulation group on day 29 right after they filled out the questionnaires. After 28 days they will again fill out the questionnaires.

Inclusion criteria:

• Patients with confirmed primary CNS lymphoma (PCNSL)

• Age > 18 years

• No depression or stable depression therapy for at least 4 weeks

• Evidence of clinically relevant fatigue symptoms assessed by MFI20 defined by a total score higher then the age adjusted mean value [51].

Exclusion criteria:

• Severe psychiatric conditions such as schizophrenia

• Score > 8 points on the NGASR [52] suicide questionnaire

• Pre-existing vagus nerve stimulation or history of vagotomy

• Severe cardiac conditions such as significant cardiac arrhythmias or history of myocardial infarction

• Active implants such as pacemakers, defibrillators, neurostimulators, cochlear implants, medication infusion pumps, or ventricular shunts (an implanted Ommaya reservoir is acceptable)

• Known Parkinson’s disease, multiple sclerosis, or epilepsy

• Pregnancy

• Skin conditions such as infection, psoriasis, or eczema in the treatment area

• Anatomical anomalies preventing the successful placement of the ear electrode

• Presence of any severe medical condition that could prevent successful participation in the study

• PCNSL recurrence or severe neurological adverse events such as a new leukencephalopathy during the study period

• Severe cognitive impairment and thereby inability to understand the study protocol

Abort Criteria.

• Occurrence of an exclusion criteria

• Occurrence of severe cardiac arrhythmias

• Withdrawal of consent

Data Collection

The patient is instructed to download the manufacturer’s app, available for both Android and iOS, which connects to the stimulator via Bluetooth® and records daily stimulation duration and average intensity. No cloud connection or registration is required. The app also notifies the patient when the recommended total stimulation time of 4 h per day has been reached. While the stimulator automatically turns off after 4 h of continuous use, it does not impose a cumulative 4-h limit. After the 4-week study period, the recorded data is exported from the patient’s smartphone and analyzed regarding the mean daily stimulation duration and intensity. However, as we experienced reliability issues in the automatic logging function of the app in previous studies (FATIVA and COVIVA), patients are asked to also manually log their daily stimulation time.

Determination of Prevalence and Questionnaires

Within the scope of a questionnaire-based study conducted in a neuro-oncology outpatient clinic, the prevalence of fatigue syndrome will be evaluated using an established questionnaire—the MFI20—and analyzed in relation to additional patient- and therapy-related data. Normative data [53] and reference values from other cancer types [54] are available for the MFI20 questionnaire. Patients with a total score above the age-adjusted mean total score [51] are included in the study. To detect concurrent neuropsychological deficits, standardized neuropsychological testing analogous to NeuroCogFx will be performed. Neurological deficits will be assessed using the NANO scale. Depressive symptoms will be measured by employing the HADS-scale, NGASR suicide questionnaire, and BDI-II. Concurrently, the SF-36 will be administered as a generic instrument to assess health-related quality of life. To contextualize the findings, comorbidities, current remission status, as well as timing and type of previous therapies will also be recorded. These questionnaires will be performed at the beginning of the study (before the stimulation period), after 4 weeks of stimulation and – in case the patient was either in Arm B oder C – after another 4 weeks of real stimulation.

During initial instruction, the patients are shown how to use the stimulator and where to place the electrode in the left concha. Every patient is demonstrated how the stimulation feels.

Arm A – Above-Threshold-Stimulation

This group receives a standard stimulation with the intensity adjusted to be above the perception threshold and below the pain threshold. 4 h per day, for a minimum of 1 h at a time in the left ear. We recommend 2 h in the morning and 2 h in the afternoon.

Arm B – Sub-Threshold-Stimulation

This group receives a standard stimulation with the intensity adjusted to be below the perception threshold. Patients are asked to start stimulation and adjust the intensity so they can feel the stimulation, and then lower the intensity so they just do not feel it. 4 h per day, for a minimum of 1 h at a time in the left ear.

Arm C – Sham-Stimulation

This group receives a sham stimulation. During initial instruction the patients are shown how stimulation feels like. Then the intensity is reduced so they do not feel any tingling. In contrast to Arm B the patients are now asked to keep the intensity-setting as it is. Without notification, they then take home a non-functional fake electrode. 4 h per day, for a minimum of 1 h at a time in the left ear.

All results of the questionnaires, along with electronic case report forms (eCRFs), will be stored on our institutional RedCap system, ensuring audit-proof storage.

Study Plan

Patients with fatigue who provide informed consent to participate in the study will be assigned to one of three treatment or control groups and equipped with a auricular vagus nerve stimulator for 28 days. We will use the CE-certified device tVNS-L (tVNS Systems GmbH, Erlangen, Germany). It has a fixed set of parameters (25 Hz frequency and 250 µs pulse-width) and allows the user to adjust the intensity as desired. The paradigm is 28 s on and 32 s off.

Visit 0

At this stage, the patient will provide informed consent. Subsequently, they will receive the stimulator along with instructions on its proper use. They will also be asked to download the manufacturer’s app (“tvns research” on Google Play® and Apple App Store®) onto their smartphone. The stimulator is then paired with the app, which records daily stimulation intensity and duration while also reminding the patient to perform the stimulation. The app data is accessible only to the patient and will be reviewed and documented by the physician together with the patient at the end of the study.

Personal information, including age, sex, height, and weight, will be collected, along with details on whether the patient is currently undergoing radio- or chemotherapy and other personal data and their medical history. The study questionnaires will be completed, and the patient will then be discharged. After one week, the study nurse will contact the patient to address any questions or concerns regarding the stimulation. The final visit will take place four weeks later. Patients are instructed to contact the principal investigator immediately in the event of any side effects.

Visit 1

After four weeks, the patients receive an email with the link to the online questionnaires and are asked to send the stimulation data from the smartphone via email. The patients are then informed of the group assignment. In case the patients were in Arm A, the study is terminated. If the patients were in Arm B, they will be asked to continue for additional 4 weeks with a stimulation above the threshold. Arm-C-patients will receive a functional electrode vial mail and are then asked to perform stimulation above the threshold for 4 weeks.

Visit 2

After another 4 weeks, the patient receives an email with the link to the online questionnaires. They are allowed to either return the stimulator in person or send it via mail.

Justification of Sample Size

Statistical analysis will be conducted to compare the three groups in terms of continuous data (primary outcome parameter and ordinal rating scales) using an exact rank-based variance analysis according to Kruskal and Wallis (R package “coin”) with a significance level of p = 0.05 (two-tailed). Due to the relatively small sample size (see below), a robust nonparametric approach is chosen. To further interpret potential effects, both treatment groups will be compared to the placebo group as well as to each other.

Secondary outcome parameters include SF-36, HADS, and BDI-II, which will be analyzed analogously to the primary outcome parameter. Since only one primary endpoint (change in MFI-20) is evaluated confirmatorily, no adjustment for type I error is required. Descriptive statistics will include mean values, medians, quantiles, and the respective sample sizes of available data. For between-group contrasts, the effect measure will be the mean difference with 95% confidence intervals. Additionally, a nonparametric estimation of the group effect (shift) using the Hodges-Lehmann estimator will be calculated. Any missing data points will be excluded pairwise.

Based on the expectation of superiority for the two target groups (low- and high-threshold stimulation) with an effect size of approximately 0.72 (corresponding to a minimum difference of five or ten MFI units compared to placebo (shift) and a standard deviation of 5.7) and assuming a type I error (alpha) of 0.05, a total of 3 × 12 = 36 cases are required to achieve 80% statistical power. These numbers represent the minimum required sample size and should be increased by a safety margin of approximately 10%–20% to account for potential dropouts. If an adjustment is necessary, a final sample size of 3 × 15 = 45 cases will be included. The sample size calculation was performed using the R package “MultNonParam” [55].

Data Analysis

Determination of the Prevalence of Fatigue Symptoms in Patients with PCNSL

As part of the statistical analysis, the following tests will be conducted to determine the prevalence of fatigue symptoms in patients with PCNSL:

1. Mean score difference in MFI-20 between the patient cohort and normative values [53], relative to the standard deviation. Since no multiple comparisons are performed in this analysis, no adjustment is required.

2. Descriptive statistics to assess the influence of age, sex, and other patient-specific, disease-related, and therapy-associated factors as described above. Since no multiple comparisons are performed, no adjustment is necessary.

Evaluation of Non-Invasive Vagus Nerve Stimulation Regarding Its Effect on Fatigue Symptoms in Patients with PCNSL

The statistical analysis will be conducted in the ITT population (intention-to-treat), including all patients who were randomized and for whom a change score (pre-post treatment) in the MFI-20 is available. Additionally, a safety cohort (all treated patients) and a per-protocol cohort (i.e., all patients who completed the study according to protocol) will be analyzed. The assignment of patients to the respective analysis populations will be defined in a statistical analysis plan (SAP) prior to the start of the evaluation.

Analysis Populations—Intention-to-Treat (ITT) Population

The ITT population includes all randomized patients from the safety population for whom at least one pre- and one post-baseline measurement has been recorded. It serves as the primary analysis population for evaluating efficacy. Patients are analyzed according to their randomization assignment.

Analysis Populations—Safety Population

The safety population includes all patients who have received treatment as part of the study. It serves as the primary analysis population for assessing safety. Patients are analyzed according to their actual treatment received.

Analysis Populations—Per-Protocol (PP) Population

The PP population consists of all patients from the ITT population who have no major protocol violations. Detailed criteria for inclusion in this population will be outlined in the statistical analysis plan (SAP). Protocol violations will be assessed before the start of the analysis. The PP population serves as the secondary population for efficacy evaluation.

Analysis Populations—Evaluation of Demographic and Baseline Data

Demographic and baseline data will be presented descriptively for all three analysis populations, separated by treatment groups. The assessment and classification of prior and concomitant medications will be conducted according to the Anatomical Therapeutic Chemical (ATC) classification system (Level 2).

Efficacy Analysis and Study Design

Statistical computations will be performed using the most recent version of the R software package (currently version 4.3.3). It will be ensured that only validated procedures are applied. The study follows a parallel-group design with three independent groups and a primary outcome parameter, defined as the change in MFI-20 (post- minus pre-treatment score).

Secondary outcome parameters include changes in the SF-36, HADS, and BDI-II scores.

Discussion

Endpoints

Our ongoing studies investigating the effects of taVNS on CRF [42] and Long COVID (submitted) demonstrate high acceptance of taVNS with daily 4-h application and a markable effect in reducing fatigue in a similar study population. We therefore chose the reduction of MFI20 score as a primary endpoint of this study. Additionally, we will investigate the prevalence of fatigue in patients with PCNSL using the MFI20 questionnaire.

Sham-Intervention

Creating a control group with sham stimulation presents a significant challenge in stimulation studies. By implementing sub-threshold stimulation and sham stimulation groups, it is possible to blind patients to their assignment within the sham group, as they remain unaware whether they are receiving sub-threshold or no stimulation at all. This design effectively addresses the fundamental issue of assigning patients in a stimulation study to a placebo group, as the absence of stimulation would otherwise be immediately noticed by participants.

A commonly used sham-approach involves stimulating other body parts [56] or the auricle [57] instead of the vagally innervated tragus. However, medically knowledgeable participants can often recognize this as a sham condition, particularly since the electrode geometry frequently prevents such intentional misapplication. Additionally, incorrect electrode placement poses the risk of unintended stimulation of facial muscles [58, 59], potentially inducing confounding effects that may interfere with the study outcomes.

Regulatory Aspects

Instead of sham stimulation, an alternative approach would be to use different stimulation parameters. However, this method is impractical in neuromodulatory stimulation studies for two main reasons: (1) Due to the vast parameter space, the effects of different stimulation parameters are not yet sufficiently understood to confidently define parameters that are guaranteed to be ineffective. (2) If the study is to be conducted under the simplified procedure according to §47(3) of the MPDG (German implementation of Medical Device Regulation (MDR) law), only “conformité européenne” (CE)-certified (European version of FDA-approved) medical devices may be used. This means that the device must have CE approval for a specific medical indication, which in turn fixes stimulation parameters (except for intensity), making them non-adjustable. This constraint applies to the tVNS-L® stimulator, where stimulation parameters are fixed. A research version of the same device, the tVNS-R® (R for Research), allows adjustable parameters but lacks CE certification as a medical device. The use of a non-certified system in a study significantly increases both the complexity of the approval process and the financial resources required, as such a study must undergo formal approval by the German Federal Institute for Drugs and Medical Devices (Bundesinstitut für Arzneimittel und Medizinprodukte, BfArM).

In our FATIVA and COVIVA studies, we observed that compliance significantly improves when control group participants are given the opportunity to undergo real taVNS within a crossover design. Additionally, the crossover design enhances the validity of the dataset, further strengthening the study’s conclusions.

Potential limitations of the present study include that the taVNS requires the active patient cooperation compared to an implantable VNS [35]. Another limitation is the single-blind study design. However, this issue appears to be manageable, as the physician instructing the patient is necessarily aware of the randomization group due to the nature of the instructions provided. Nevertheless, the limitation of single blinding has been mitigated by ensuring that questionnaires are completed online at home on the patient’s computer, rather than in the presence of a study physician. The responses are then securely transmitted to the online system, ensuring data integrity and minimizing potential observer bias.

Safety Considerations

Metaanalysis [60] show that taVNS is safe and harbours only minor side effects. The occurrence of side effects correlate with the length of stimulation, and 4 h/day is longer than stimulation time in other studies [61]. However, the device used in our study is CE-certified for 4 h/day-stimulation, and own experiences in the ongoing studies FATIVA [42] and COVIVA [62] showed rare and only minor side effects.

Data Logging

Accurately documenting the actual stimulation time is essential for monitoring adherence to the prescribed therapy duration [63]. To facilitate this, the manufacturer of the tVNS systems provides an app available in the Google® and Apple® stores. However, experience from our ongoing studies indicates that a stable Bluetooth® connection is not always guaranteed. For this reason, all patients are asked to manually record their therapy duration in a therapy diary.

Data Protection

All study data will be stored in a pseudonymized database. The RedCap® system does not record patient names but assigns a unique identification number instead. The correspondence between patient names and their assigned ID numbers will be securely maintained in a separate table, stored on a different clinical network within our hospital. The study adheres fully to the General Data Protection Regulation (GDPR).

Author Contribution

Mortimer Gierthmuehlen: concept, design and drafting of the manuscript. Sabine Seidel: concept, design and drafting of the manuscript. Niklas Thon: design and drafting of the manuscript. Corinna Seliger: design, statistical analysis and drafting of the manuscript.

Funding

Open Access funding enabled and organized by Projekt DEAL. The study was financed by intramural funding, registration number F1087-2024. The journal’s Rapid Service Fee was paid by the Departments of Neurosurgery and Neurology.

Data Availability

As this is a report of our trial protocol, no data is available yet.

Declarations

Conflict of Interest

Mortimer Gierthmuehlen: founder and consultant of Neuroloop GmbH, which develops an invasive vagal nerve stimulator against arterial hypertension. Sabine Seidel, Corinna Seliger and Niklas Thon have nothing to disclose.

Ethical Approval

This trial received ethical approval from the Ethics Commission Westfalen Lippe (Reference number: 2024–368-f-S) on 19/09/2024. The approved version of the study protocol is version 2. The study was designed in accordance with Good Clinical Practice (GCP), the principles outlined in the Declaration of Helsinki, and established professional conduct standards. Before enrollment, participants will receive detailed information about the study and provide written informed consent. The findings of this randomized pilot study will be disseminated through peer-reviewed publications and conference presentations. This protocol was developed following the Standard Protocol Items for Clinical Trials (SPIRIT) guidelines.