Vision Restoration through transorbital electrical stimulation in Optic Neuropathy in patients with significant optic atrophy due to primary open-angle glaucoma—a randomised, controlled, double-blind, multicentre clinical trial: the VIRON study protocol

Abstract

Introduction

Glaucoma is one of the most common causes of blindness and affects more than 70 million people worldwide. The disease is characterised by the loss of retinal ganglion cells associated with a progressive optic neuropathy, resulting in an impairment of visual functions, for example, visual field loss. Nowadays, the only modifiable risk factor is the increase in intraocular pressure, and its treatment is to lower this pressure by medication, laser treatment or surgery to avoid disease progression. New methods for preventing and reversing vision loss are thus urgently needed. Several small and two multicentre studies have presented evidence that repetitive transorbital alternating current stimulation (rtACS) can lead to long-lasting visual field improvement. This could open a new and inexpensive therapeutic option for optic atrophy. However, the level of evidence for this method is still fairly rather poor, and further trials are needed. Therefore, this clinical trial aims to prove the effectiveness of rtACS compared with sham stimulation in patients with primary open-angle glaucoma (POAG).

Methods and analysis

VIRON (Vision Restoration in Optic Neuropathy) is a national, multicentre, prospective, randomised, placebo-controlled, double-blind trial with three arms. The primary objective is to assess the effectiveness of rtACS in patients with POAG compared with sham stimulation. The primary outcome is the change in mean defect (MD) in the visual field immediately after 10 sessions of rtACS (days 9, 16 and 23) compared with the values of initial perimetry (days −21 to –14 and 0) after applying electrical stimulation with a classical montage, compared with sham and electrical stimulation using individualised montage. Secondary outcome measures comprise a long-term effect with changes in MD at 24 weeks after stimulation, and data from the National Eye Institute Visual Function-25 and quality of life (Short Form 36) questionnaires. The target population are patients with glaucomatous optic atrophy and significant glaucomatous visual field defects (MD of 5–22 dB) due to POAG.

After randomisation, patients received either classical rtACS (group 1), individual rtACS (group 2) or sham stimulation (group 3) in daily 25 min stimulation sessions in two series of five consecutive days separated by a weekend interval. In group 1, active stimulation will be via the routinely applied montage using two electrodes affixed on the right and left side of the head, next to the eyes, with straightforward fixation. In group 2, the current flow will be individually modelled (MRI-based) to target areas of partial visual field defects by optimising electrode positions in conjunction with an optimised visual fixation direction. Group 3 with sham stimulation will serve as control.

The calculated sample size required to achieve a statistical power of 80% for a relevant effect size and allow for dropouts was 300 (100 per group). The trial has already begun with the first patient in July 2023. The planned recruitment period is 24 months with an estimated end of the study in November 2025 (last patient out). An adjusted extension of the study period is planned.

Ethics and dissemination

VIRON was approved by the Central Ethics Committee of the University Medical Center Göttingen (19 October 2022) and those of the individual participating centres (Bonn: 446/23-EP, Hamburg: 2023-200889-BO-bet, Cologne: 23-1487 and Mainz: 2023-17399-§23b). The study protocol complies with the Declaration of Helsinki, the national medicine device regulation (MDR) laws and the international standards of good clinical practice (GCP).

The study protocol (V.5, 24 November 2023) was designed following the Standard Protocol Items: Recommendations for Interventional Trials guidelines and is registered on https://drks.de/search/de/trial/DRKS00029129.

As study initiatior the University Medical Center Göttingen (UMG) is responsible for data ownership and data management of the VIRON study. The study data will be published within 6 months of the study being completed. After the publication of the primary results, all data are anonymised and published in an open-access journal to ensure access to the data for third parties.

Trial registration number

https://drks.de/search/de/trial/DRKS00029129.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Patients will have a two out of three chance to receive transorbital electrical stimulation, a treatment with a low probability of adverse effects or side effects that intends to reduce the existing visual field defects and thus improve the patient’s vision.

• The dosages of transorbital electric stimulation in this study were chosen according to previous trials.

• In contrast to previous studies, the multicentre design, the large cohort, a very precisely defined patient population (glaucomatous optic atrophy only) and using standardised perimetry are the main strengths of the study.

Introduction

Glaucoma is one of the most common causes of blindness and affects more than 70 million people worldwide, with approximately 10% of the patients developing bilateral blindness.¹ The disease is characterised by the loss of retinal ganglion cells associated with a progressive optic neuropathy resulting in an impairment of visual function, for example, visual field (VF) loss.² Recent studies³ have described an anterograde degeneration of the ascending visual pathway, including post-chiasmatic axons of the third-order neurons, tractus opticus, as well as the visual cortex.

At present, the only modifiable risk factor is the increased intraocular pressure, and treatment is to lower this pressure by medication, laser treatment or surgery to retard disease progression. However, the underlying mechanisms are probably not fully addressed by the current treatment strategies, and vision loss, once present, cannot be restored with current established therapies. It is, therefore, critical to stop or delay the disease at an early stage. In addition, new treatment options are required to improve vision since the loss of ganglion cells and optic nerve damage, once manifest, is not reversible by medical or surgical methods.

Strong evidence from animal studies supports the hypothesis that electrical optic nerve stimulation could restore vision in patients with optic neuropathies.⁴ Repetitive transorbital alternating current stimulation (rtACS) was successfully applied in retinopathia pigmentosa⁵ and in patients with retinal arterial occlusion.⁶ In several small trials and one multicentre study, rtACS was performed daily to reactivate residual vision in optic neuropathy using frequencies ranging from 0.5 to 37 Hz via electrodes placed near the eye. The treatment increased light detection performance and reduced the patient-reported, vision-related impairment of daily living that correlated moderately with VF gains.7,13 In a multicentre trial comprising 82 patients, rtACS or sham stimulation was applied in two series of five consecutive days separated by a weekend interval. The participants included patients with optic nerve damage.¹⁴ The rtACS group had a significantly greater mean improvement of VF compared with the sham stimulation group for up to 2 months post treatment.

Since previous studies of the method were in inhomogeneous patient groups, used non-standardised perimetry methods, did not monitor eye movements and had inadequately defined endpoints, there are justified doubts as to its effectiveness, and it is not recognised by the ophthalmological community.¹⁵ But in view of the fact that the method is, nonetheless, already in commercial use, the need for a well-designed study is broadly accepted.

Summary and aims

This aim of the study is to clarify the contradictory data in the field of transorbital electrical stimulation in neurodegeneration. Well-established VF testing will be used to investigate a well-defined homogeneous patient population with glaucomatous optic atrophy as a model of neurodegeneration. Its novel aspects are the implementation of individual current flow modelling based on the visual impairment, and the application of a stimulation protocol with predefined electrode montage and fixation of a target during the stimulation.

Methods and analysis

This study was designed following the Standard Protocol Items: Recommendations for Interventional Trials guidelines.¹⁶ It is registered on www.drks.de (DRKS00029129). The protocol complies with the Declaration of Helsinki, national laws and ICH-GCP. Results and underlying data from this trial are to be disseminated through peer-reviewed publications and conference presentations. Any change or addition to the protocol can only be made in a written protocol amendment that must be approved by the independent ethics committee. Information regarding important protocol modifications will be provided in due time to further relevant parties (eg, investigators, trial participants, trial registries). Potential participants will be informed in writing and orally by the investigator about the nature, significance, scope of the examinations and treatment, as well as the benefits and risks of the study. Only patients meeting all inclusion criteria with no exclusion criterion will be included after having voluntarily given their written consent to participate in the study. A patient can withdraw his or her consent at any time without giving reasons and without disadvantages for their further medical care. If a patient should withdraw from the study, the data that have already been collected will be deleted if the patient does not agree to it being evaluated. The patient data are subject to medical confidentiality and the provisions of the General Data Protection Regulation (GDPR).

Study design and setting

We conduct a prospective, multicentre, randomised, sham-controlled, double-blind interventional study. Patients will be randomised to either active group 1 to receive rtACS using the ‘classical’ electrode montage^{14 17} or to active group 2 to be fitted with an individual montage based on calculated current flow in the affected VF and MRI-based individual modelling, or to group 3 with sham stimulation. Two-thirds of the patients will thus receive active stimulation. In an ambulatory setting, the patients will receive a daily application of their allotted stimulation in two series of five consecutive days separated by a 2-day weekend interval.

The trial is sponsored by the University Medical Centre, Göttingen, Germany (Von-Bar-Straße 2/4, 37075 Göttingen). Participating trial sites are the University Medical Centres in Bonn, Cologne, Hamburg and Mainz. To ensure independence, the primary outcome (VF) will be evaluated by an independent and blinded reading centre (Glaucoma Reading Center Göttingen).

Research question

The aim of the study is to determine the effectiveness of both classical and individually modelled rtACS compared with sham stimulation in patients with primary open-angle glaucoma (POAG). For this purpose, change in mean defect (MD) immediately after rtACS (days 9, 16 and 23) to the initial values (days −21 to –14 and 0) will be compared between groups.

Study population

300 patients aged 40–85 years with a diagnosis of POAG and significant VF impairment (MD>5–22 dB) are to be included.

Inclusion and exclusion criteria

Inclusion criteria*

• Male or female outpatients with POAG (according to the European Glaucoma Society criteria) and significant VF impairment (MD>5 dB).

• Age>40 years.

• Typical glaucomatous optic disc damage and VF loss in one eye, and either VF loss or typical glaucomatous optic disc damage, or both, in the fellow eye.

• ‘Experienced’ patients who are familiar with VF testing (at least five examinations prior to this study),

• Intraocular pressure<22 mm Hg (topically treated or untreated).

• Signed informed consent, willingness to participate.

* The criteria refer to the study eye.

Exclusion criteria*

• Any type of glaucoma other than POAG,

• Age>85 years

• VF defect>22 dB

• Corrected visual acuity<0.2 decimal,

• Variation of MD>2 dB between screening and visit 2 (day −21) to rule out learning effects misinterpreted for therapeutical improvement,

• Significant media opacity (ie, cataract or corneal scars) which would interfere with the detection of any study effects during follow-up,

• Other ophthalmological reasons for impaired vision (eg, age-related macular degeneration).

• Any kind of surgery in the previous 3 months.

• Laser or any other kind of glaucoma surgery in the previous 3 months

• Intraocular surgery in the previous 6 months

• Any change in the glaucoma medication in the previous 3 months and/or use of more than two topical (or any oral) IOP-lowering medications at the baseline visit in the glaucoma medication in the previous 3 months and/or use of more than two topical (or any oral) medication lowering the intraoculare pressure at the baselie visit.

• Refractive error: spherical equivalent worse than +6 or −6 (cylinder value worse than 3 dpt),

• Patients with comprehensive VF impairment caused by ptosis or dermatochalasis,

• Women of childbearing potential without contraception, pregnancy and nursing mothers.

• History of brain surgery or neurological disorders (stroke, seizures or epilepsy),

• Uncontrolled hypertension (>160 mm Hg).

• Claustrophobia and/or non-willingness for MRI examination,

• Electronic implants (eg, pacemaker, cerebral implants) or metallic artefacts

• Psychological diseases (substance dependence, schizophrenia) or mental conditions that do not enable to understand the nature of the study and give legally valid informed consent,

• Poor cooperation,

• Non-compliance,

• Participation in other clinical trials within the 12 weeks prior to start of the study,

• Autoimmune diseases.

• Acute (intra-) ocular inflammation in the study or fellow eye,

• Therapy with opiates, calcium antagonists or benzodiazepines.

*The criteria refer to the study eye.

Treatment

The stimulation will be performed via two electrodes positioned on the periorbital skin using a fixed frequency of 10 Hz and an intensity of 600 µA alternating current (peak-to-peak, sinusoidal waveform) with eyes open (figure 1). The sham group receive a stimulation with an intensity of 200 µA, a frequency of 40 Hz and a shorter duration (60 s). The stimulation will be applied to the patients in an outpatient setting on 10 consecutive days with a 2-day weekend break after the first five sessions (see online supplemental table). A stimulation session will last approximately 30–35 min (25 min of stimulation plus electrode placement).

Figure 1. (A) Transorbital electrode positioning (classical electrical stimulation and sham stimulation). (B) Example of electrode positioning for individualised electrode positioning.

• Group 1: Classical rtACS using two electrodes fixed at the temples, always in the same positions.¹⁴ Stimulation is performed with a frequency of 10 Hz and an intensity of 600 µA.

• Group 2: Patients receive individually adapted stimulation with two electrodes placed to target the current flow to the sites of visual impairment. The individualised electrical stimulation is based on current flow modelling based on MRI measurements on day −14.

• Group 3: Sham stimulation will be performed with an intensity of 200 µA (peak-to-peak) current for a shorter period of 60 s. The majority of patients in group 3 will receive transorbital sham stimulation via the electrode montage used in group 1. The desired direction of vision for the patients is straight ahead. In order to maintain blinding, approximately 10% of patients undergo sham stimulation with individually adapted electrode positioning and the desired direction of vision during stimulation as in group 2.

Outcome and safety measures

	Outcome measures
Primary	Effectiveness of classical or individual rtACS compared with sham stimulation: change in MD immediately after rtACS (days 9, 16 and 23) compared with the values of initial perimetry (days −21 to –14 and 0).
Secondary	Effectiveness of individualised electrostimulation compared with classical rtACS stimulation: change in MD immediately after rtACS (days 9, 16 and 23) from the values at initial perimetry (days −21 to –14 and 0) compared with the results with classical rtACS and sham stimulation.
	Time-dependent effect of classical, individual and sham stimulation: change in MD at 24 weeks (day 168±3 days) after rtACS or sham stimulation compared with perimetry on days −21 to –14 and 0.
	Short Form 36 questionnaire: analysis of group differences and changes in quality of life after rtACS or sham stimulation (day 9 and 24 weeks after stimulation) compared with baseline visit (day −14).
	NEI-VFQ-25 questionnaire: analysis of group differences and changes in subjective visual acuity after rtACS or sham stimulation (day 9 and 24 weeks after stimulation) compared with baseline visit (day −14).
Safety	Effects of electrical or sham stimulation on blood pressure and heart rate (measurements immediately before and after stimulation).
	Changes in visual acuity after electrical or sham stimulation (days 9 and 168) compared with screening measurement (day −28).
	Changes in intraocular pressure after electrical or sham stimulation (day 16 and day 168) compared with screening measurement (day −28).
	Ophthalmological examination on day −28, day 9 and day 168.
	Retinal ganglion cell optical coherence tomography, retinal nerve fibre layer-optical coherence tomography and fundus photography: changes after electrical or sham stimulation (days 9 and 168) compared with screening measurement (day −28).
	Registration of side effects, adverse events and serious adverse events and evaluation of their relation to electrical or sham stimulation.

Patient and public involvement

The organisation ‘Bundesverband Glaukom-Selbsthilfe e.V.’ (Selbsthilfegruppe Göttingen, Dr Kombrink) was involved and included in the preparation of the study design, the informed consent (see online supplemental file 2), the final version of the protocol, including the number of visits. The group gave us feedback on the study concept, and their suggestions were incorporated in the development of the essential study documents. From July 2023, when we started our recruitment period, patients were additionally informed either in person by our staff or by posters, advertisement in local newspapers or patient flyers that we have shared with regional ophthalmologists. Patient representatives are invited to comment on the protocol and educational materials used during the intervention. The patient organisation will also be involved in disseminating the results.

Study assessments (see online supplemental file 1)

Patient demographics

Patient demographics include age, sex, height and weight.

Medical history

At screening, a detailed medical history is obtained that includes all medical diagnoses and any previous surgical and pharmacological interventions. All concomitant medications administered at any time during the study are to be documented in the electronic case report form (eCRF).

Concomitant medication

The patient’s current medication will be recorded initially and during the study.

Visual acuity

Subjective refraction will be performed to obtain the best-corrected visual acuity of each eye according to Early Treatment Diabetic Retinopathy Study guidelines.¹⁸

Tonometry

Intraocular pressure will be measured using Standard Goldman tonometry and documented in mm Hg.

Ophthalmological examination

Slit-lamp examination to rule out significant media opacity, which would interfere with the study results and an inspection of the eyelids to rule out any pathology that would interfere with VF testing. The funduscopic examination contains the classical description of the glaucomatous changes of the optic disc (including cup-to-disc ratio) and the macula.

Blood pressure and heart rate measurement

Blood pressure measured with a standard blood pressure cuff and heart rate are obtained in a sitting position and documented before and after each stimulation. If the systolic blood pressure is >160 mm Hg before stimulation, the stimulation will be put on hold and control measurements will be performed. Stimulation will only commence after systolic blood pressure has fallen below 160 mm Hg.

VF measurement

At each visit (see online supplemental file 1), VF testing starts with the G program (30° VF) from Octopus 900 (Eye Suite software V.9, Haag Streit International, Köniz, Switzerland), which is typically used to detect optic nerve damage, beginning with the study eye. After a 30 min rest break (without any other examinations in order to allow the study patient time to relax), the 10° VF is examined to analyse the central VF, which might be more relevant for vision, in greater detail. Optimal near correction is required for every examination.

A rate of false-positive and false-negative answers of <20% was set as a quality parameter. If the rate of false-positive and/or false-negative answers exceeds >20%, the result is invalid (this only applies to the G-program) and must be repeated on the same examination day. An initial quality control of the abovementioned quality parameters and a plausibility check of the perimetry data will be carried out immediately by the study doctor at each study centre.

VF Reading Centre

A second, independent quality and plausibility check (validation) of the perimetry data will be performed by the Reading Centre. The Reading Centre staff is blinded to all study data (except study ID and VF data) and in general do not have any contact with the study patients. They read out the MD, which is stored pseudonymously in a separate database (SecuTrial).

Retinal nerve fibre layer and ganglion cell optical coherence tomography

The retinal nerve fibre layer thickness and ganglion cell optical coherence tomography examinations are performed using a Spectralis-OCT (Heidelberg Engineering, Heidelberg, Germany).

Fundus photography

This is performed with the fundus camera used in clinical routine. The photograph of the optic disc serves to retrospectively objectify any adverse events (AEs) that might occur.

MRI

An MRI scan of the head and cervical spine (without contrast medium) is to be performed in all patients randomised into group 2. In order to maintain blinding, an MRI scan will be performed in approximately 10 patients from group 3. All examinations will be performed with a 3.0-Tesla MR scanner (Göttingen site: Magnetom Prisma fit, Siemens Healthineers, Erlangen, Germany; Bonn site: 3.0-Tesla MR scanner, Philips; Mainz site: Magnetom Skyra, Siemens Healthineers). Imaging of the head and cervical spine (vertex to cervical vertebra 5, nose to inion, both ears included) will be performed with a resolution of at least 1 mm × 1 mm × 1 mm. The sequences listed below will be used for subsequent analyses:

MRI sequences

• T1-weighted scan (T1w): 3D Turbo Field Echo, relaxation time (TR)=6 ms, echo time (TE)=2.7 ms, flip angle (FA)=8°, voxel size=0.85 mm³.

• T2-weighted scan (T2w): 3D Turbo Spin Echo, TR=2500 m, TE=272 ms, FA=90°, voxel size=0.85 mm³.

• mDixon scan: TR=4.1 ms, TE1=1.34 ms, TE2=2.4 ms, FA=9°, voxel size=1.1 mm³

• Venogram: TR=18 ms, TE=6.9 ms, FA=8°, voxel size=0.8 × 1.1 × 1.6 mm^3_.

Modelling for individual stimulation

Modelling the current flow is a prerequisite for optimising the electrical stimulation targeting the position of optic nerve fibre damage (figure 2). For this purpose, the electrode positions are determined for the stimulation with the eyes in straight-ahead fixation. Based on the MRI data sets, the open-source modelling software SimNIBS and the implemented Charm pipeline are used to create tissue models of the head.¹⁹ The models generated included the following tissue compartments (with assigned standard conductivity values in S/m): skin (0.456), blood (0.6), spongy bone (0.025), compact bone (0.008), cerebrospinal fluid (1.654), grey matter (0.275) and white matter including the optic nerve head (0.126). Further, they are semiautomatically refined to include tissues of the eye: eye muscles (0.16), cornea (0.5), sclera (0.56), retina (0.7), vitreous humour (1.55), aqueous humour (1.8) and lens (0.32).20,23 The created finite element mesh (FEM) subdivides the head into tetrahedral volume elements.

Figure 2. Pipeline to find individual electrode positions of a patient. The CHARM algorithm¹⁹ is used to segment the patient’s MRI. A semiautomatic segmentation of the eye using the Segment Editor of 3D Slicer³⁵ is added before creating the finite element mesh (FEM) head model and electrode models and using the optimisation methods in SimNIBS³⁶ to maximise the current density in the target regions. Target regions are the visual field defects of the patient projected onto the retina of the model.

The distribution of the current flow across the entire model is computed by solving the quasi-static approximation of Maxwell’s equation using the finite element method.²⁴ Combined with the perimetry data from the initial examinations, the custom software calculates the individually optimised transorbital electrode positioning. Recorded VFs are projected onto the retina of the FEM to define the goal function for the optimisation. The probability values calculated from the VF recordings in the EyeSuite Software (Haag Streit) are used to define the target points for the electrical stimulation. The p values represented the probability of a normal person showing this sensitivity loss at the test location. A location with at least one p value ≤0.5% in the two VF recordings previous to rtACS therapy is defined as the target for the optimisation.

We adapted an optimisation technology that was established for low-intensity transcranial electrical stimulation (tES) using multiple targets for our transorbital application.²⁵ In contrast to most tES applications, our goal is to maximise the current density within the target regions, without considering the direction and focality of the field. In proof of principle with a single person and 29 different combinations of targets, we achieved an average current density in the target regions of 0.18±0.02 A/m² with the individual montages, compared with 0.09±0.01 A/m² in the standard electrode montage.

Short Form 36 questionnaire

The standard Short Form 36 questionnaire will be used to record health-related quality of life. It consists of 36 items and covers eight areas of subjective health.²⁶ The evaluation is carried out according to the manufacturer’s instructions.

National Eye Institute Visual Function-25 questionnaire

Subjective visual acuity is recorded using the standard National Eye Institute Visual Function-25 questionnaire consisting of 25 questions.²⁷ The evaluation is carried out according to the manufacturer’s instructions.

Statistical analysis

The primary efficacy analysis is performed as soon as the follow-up visit of the last recruited patient has been completed, the study has been terminated, and the database has been locked.

Statistical analysis of the primary endpoint

The time-averaged threshold VF measurements (primary endpoint) of the first three visits after the final treatment day will be compared using a generalised linear mixed model analysis with time and treatment group as factors and baseline time-averaged VF measurements as covariates. A random effect is modelled for paired eye data.

Statistical analyses of the comparisons between the two stimulation methods and the sham control group will be performed using Dunnett’s test.²⁸ A p<0.05 is considered statistically significant.

Greater mean improvements after stimulation are expected in the stimulation groups with more pronounced improvements in the individualised montage group. Group effects are reported as estimated marginal means with 95% CIs. The primary estimator is based on the intention-to-treat principle (treatment policy). Multiple imputation procedures will be used to cope with missing data, and sensitivity analyses with different imputation methods will be conducted, if necessary.

Statistical analysis of the secondary and safety endpoints

Secondary parameters will be evaluated in the same manner as the primary endpoint. Relevant parameters of patient safety are reported in tabular form to allow for descriptive comparisons between groups. AEs and serious AEs (SAEs) are reported group-specifically as frequencies with relative proportions. Other nominal and ordinal parameters are summarised in tables and crosstabs. Continuous values are described by mean, SD and range over time.

Sample size

The required sample size was determined based on the minimal clinically relevant effect according to ref.²⁹ The confirmatory individual hypotheses are that classic electrical stimulation as well as individualised stimulation will each induce a greater improvement than sham stimulation. The global hypothesis is that one of the two intervention groups (classic or individual stimulation) will have a different effect compared with sham treatment. For sample size calculation, we assume a minimal clinically relevant effect of 2 dB.²⁹ A sample size of 85 patients per group was calculated to be sufficient to reject the global hypothesis with 80% power, with a standardised difference between the intervention groups and the control group of 0.4 (two-sided adjusted significance level of 5%). In order to prevent a loss of statistical significance given an assumed dropout rate of up to 15%, a group size of 100 patients per group was chosen. Since sample size planning was based on only a few preliminary studies, a blinded sample size recalculation will be performed when data on the primary endpoint of 90 patients (approximately 30 per group) are available.³⁰

Recruitment

Recruitment into this study will be through several avenues:

1. Information leaflets (containing clinical trial information) have been distributed to local ophthalmologists to inform them of the study and relate information to potential participants.

2. The organisation ‘Bundesverband Glaukom-Selbsthilfe e.V.’ (Göttingen) is involved in patient recruitment.

3. A dedicated page on the website of the ophthalmic clinic in Göttingen was created to inform potential participants and collaborators.

4. Announcement in local newspapers.

Data management

Data management will be conducted with SecuTrial, a web-based GCP-compliant electronic data capture system. The currently applicable regulations of the EU Data Protection Regulation (GDPR) are followed. The collected data will be transferred to the SecuTrial database and stored without identifying information, using a pseudonym. It can only be assigned to individual patients using an identification list that is available to the study doctors. Access to the system is controlled and monitored by individually assigned user identification codes and passwords, only available to authorised personnel who have completed the required training. The investigator, or a deputy designated by the investigator, will document the trial data in a trial-specific eCRF in a timely manner. The storage period for study-related data is 10 years.

Randomisation and blinding

Randomisation

The patients will be randomised into the three groups in a 1:1:1 ratio using the study database. Block randomisation is carried out with random block lengths. Stratification is performed according to sex and MD at the screening visit (>5 dB to <12 dB; >12 dB to <16 dB; >16 to <22 dB) based on the work of Liebmann et al ³¹ following visit 2 (day −21).

Blinding

The patients and study staff are blinded to the randomised treatment arms. The stimulators will be programmed before the start of the sessions by staff not involved in the study. The trained personnel carrying out the stimulation treatment will set the stimulation device to an appropriate mode (B, C—the letter appearing on the stimulator screen) and attach the electrodes using the instructions received through the electronic platform.

In order to maintain blinding of the patients and the examiners, 10 patients from group 3 (sham stimulation) will have an MRI scan in addition to the group 2 patients, who all have MRI scans as part of the protocol. These group 3 patients will also have individualised electrode positioning. During sham stimulation, very low-intensity electrical currents are applied at 40 Hz. Sham and active stimulators are optically identical.

With regard to a possible placebo effect, a parallel group design will be used so that patients are not able to directly compare the different types of stimulation. A placebo effect is always possible, regardless of the type of treatment. The patients’ expectations at study begin and their subjective changes over the course of treatment will be documented using the questionnaires.

Unblinding

The investigators are obliged to adhere to the specifications of a randomised, double-blind study. It is ensured that the patient code will only be broken when required by protocol. In principle, unblinding in double-blind clinical studies only occurs after data recruitment for subsequent data analysis has been completed. However, the coding system includes a mechanism that permits rapid identification of the treatment procedure in a medical emergency.

One of the following points is defined as a reason for early unblinding:

• Emergency situations that could endanger the safety of the participating patients

• Cases in which further treatment of the patient depends on the knowledge of the treatment provided by the medical device.

• In case of administration of an incorrect stimulation dose that could endanger the patient

• In case of SAEs

Safety

According to the results of previous clinical studies using the stimulation treatment described here, mild AEs (mild headaches, fatigue and sleep disturbances) were noted in approximately 10% of patients. Based on the literature, no SAEs are expected. Established safety guidelines for the use of external stimulation procedures are followed during the study.32,34

To assess and ensure patient safety, the occurrence of AEs is regularly monitored according to the guidelines of Good Clinical Practice and German law regulating clinical trials. An independent Data Safety Monitoring Board has been established to monitor patient safety and trial progress. AE and SAEs are to be specified as treatment-related or not (adverse reaction).

Data monitoring

An independent Data Management Committee was established to monitor the course of the study and, if necessary, give recommendations to the coordinating investigator and/or sponsor of the trial regarding discontinuation, modification or continuation of the study. Risk-based monitoring is conducted in accordance with ICH-GCP E6 and applicable standard operating procedures to verify that the patients’ rights and welfare are protected, and that the reported study data are accurate, plausible, complete and verifiable against source documents. To ensure safety and integrity of the clinical trial data, it must also be verified that all trial procedures are conducted in accordance with the currently approved protocol/amendment, with ICH-GCP and applicable regulatory requirements. Regular monitoring ensures that all study sites upload the study data correctly and on time.

Medical device

A DC-Stimulator PLUS from neuroConn GmbH (Ilmenau, Germany) is used for electrical stimulation (table 1). This device is categorised as a class IIa medical device in accordance with the European guidelines 93/42/EWG (MDR 2017/745). The test devices were all calibrated and checked by the manufacturer neuroConn before the trial began. The electrostimulation device is a certified medical product, carrying the CE mark. A safety assessment was carried out. No additional invasive or stressful procedures are used as part of the study. The study does not serve the purpose of product development, and the data generated will not be used for the purpose of conformity assessment. In accordance with Article 82 of the Medical Device Regulation and Section 47 (3) of the Medical Devices Law Implementation Act, the study is performed as an ‘other study’ without additional invasive or stressful procedures.

Table 1. Technical data of the stimulation device.

Manufacturer	neuroConn GmbH
Model no.	0021, SN 23-28
Product family	DC-Stimulator, stimulator for cranial electrotherapy
Frequency	10 Hz
Current strength	600 µA peak-to-peak
Duration of stimulation	25 min
Conformity	EG certificate according to 93/42/EWG
Risk class	IIa

Study timeline and progress

The trial started in July 2023 (first patient in) with the opening of the first study centre in Göttingen. In July and August 2024, all participating sites were successfully initiated by the initiating site Göttingen. In September 2024, the University Medical Centres Cologne and Mainz started recruitment after receiving the green light. It is foreseeable that the sites Bonn and Hamburg will also be allowed to begin shortly. At the moment, the intended recruitment period is 24 months, with the estimated end of the study in November 2025 (last patient out). An adjusted extension of the study period is planned.

Ethics and dissemination

VIRON has been approved by the Central Ethics Committee of the University Medical Centre Göttingen (19 October 2022) and those of the individual participating centres: the Ethics Committee of the University Hospital Bonn (446/23-EP), the Ethics Committee of the Medical Association Hamburg (2023-200889-BO-bet), the Ethics Committee of the University Medical Centre Cologne (23-1487) and the Ethics Committee of the medical association Rheinland-Pfalz (2023-17399-§23b).

The study initiator (UMG) is responsible for data ownership and data management of the VIRON study. The study data will be published within 6 months of the study being completed. After publication of the primary results, all data are anonymised and published in an open-access journal to ensure access to the data for third parties. After deactivation of the database, a copy of the database is archived at the UMG. Participation in the clinical study includes coauthorship beginning with the initiation of the study. Sole publications by one of the study centres is prohibited. Publications are made jointly with coauthorship by all participating study centres.