Study design

ESTIVAL (Essai randomisé comparant STImulation auriculaire transcutanée du nerf Vague versus sham stimulation dans l’Arthrose digitaLe érosive symptomatique et inflammatoire) is a superiority double-blinded multicentre and sham-controlled randomised trial comparing two parallel arms. A total of 18 centres, all involved in caring for patients with EHOA, are participating in this trial. The sponsor is the Assistance Publique–Hôpitaux de Paris (Délégation à la Recherche Clinique et à l’Innovation). The trial is funded by a grant from Programme Hospitalier de Recherche Clinique 2019 (French Ministry of Health). The study is conducted in accordance with the Declaration of Helsinki and has been approved by an ethics committee (Ile de France, number 2020-A02213_36). The protocol follows the Consolidated Standards of Reporting Trials (CONSORT) guidelines.29 30 ESTIVAL is registered at ClinicalTrials.gov.

All patients included undergo the auricular tVNS with the Vagustim or sham treatment with the same device, which has the same appearance but does not deliver any electric current. Patients are randomised to receive the active or sham tVNS for 12 weeks with no crossover design. Each patient is scheduled for a visit at baseline and at 4, 8 and 12 weeks (figure 1). At each visit, patients complete questionnaires and undergo a clinical examination for efficacy and safety assessments (table 1). An 8.5 mL blood sample is collected at baseline and at the 12-week visit. Patients followed up in Saint-Antoine Hospital Center undergo non-contrast MRI of the most symptomatic hand at the baseline visit and week 12.

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Figure 1

Schematic flow of the design of the randomised study comparing symptomatic effects of auricular tVNS versus sham tVNS in patients with symptomatic and inflammatory EHOA. Patients with symptomatic EHOA and inflammatory clinical and ultrasonography-evidenced synovitis are randomised (1:1) to active tVNS (n=65) or sham tVNS (n=65) for 20 min each day for 12 weeks. The two treatment arms are assessed at 4, 8 and 12 weeks. The primary outcome is assessed at 12 weeks. ß-hCG, ß-human Chorionic Gonadotropin; EHOA, erosive hand osteoarthritis; tVNS, transcutaneous vagus nerve stimulation.

Study participants

Patients are recruited during outpatient visits in each centre. During a screening visit, patients who fulfil inclusion criteria are informed about the trial and the protocol. They are informed about the two arms of the protocol and that they might be in the sham group. The investigator confirms the selection criteria (radiographic EHOA and presence of at least one joint with soft swelling or erythema, ie, synovitis) and then proposes the trial to the patient. If the patient agrees to participate, an inclusion visit is planned, and the patient is told to stop taking non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen 48 hours before the inclusion visit.

The inclusion visit is conducted by a medical doctor and includes checking inclusion and non-inclusion criteria, the patient giving informed written consent, a physical examination, completing questionnaires, hand US (to look for interphalangeal (IP) synovitis), electrocardiography, an urinary beta-human chorionic gonadotropin test for women of childbearing age, an 8.5 mL blood sample taken and bilateral anteroposterior hand radiography (table 2). A subset of patients, all included in Saint-Antoine Hospital Center, undergo MRI of the most symptomatic hand at IP joints.

Inclusion, exclusion and randomisation criteria

The study includes patients aged ≥18 years with symptomatic HOA according to the American College of Rheumatology criteria and EHOA (defined by ≥1 erosive digital joint based on Verbruggen-Veys hand radiographic scoring).2 31 32 Patients must have pain intensity of the hand of ≥40/100 mm on a visual analogue scale (VAS) at inclusion at least half of the last 30 days, at least ≥1 symptomatic proximal or distal IP (proximal or distal IP) joint with clinical soft swelling or erythema at inclusion, and reported adverse effects with or inadequate response or contraindication to existing medication (including acetaminophen, topical and oral NSAIDs). Additionally, patients must give informed written consent (online supplemental file 1) and must be affiliated with a social security scheme. Exclusion criteria are in table 1.

To be randomised, included patients must also have the following:

• At least ≥1 proximal or distal IP joint with presence of moderate or major grey scale synovitis (score 2 or 3) and/or power Doppler signal (score ≥1) on hand joint US.

• No contraindication to tVNS use, diagnosed on electrocardiography at inclusion (cardiac rhythm disturbances, atrioventricular block of >first degree or total bundle branch block >120 ms).

• Negative urine pregnancy test at inclusion, if appropriate.

Interventions

The trial intervention is auricular active or sham tVNS for 20 min/day, every day for 12 weeks. Staff at each centre receive a training session by the main investigator or the clinical researcher associate (CRA) about the device and settings, how to use the device and how to explain its use to the patient to maintain blinding.

The tVNS device pack was graciously provided by Schwa-Medico (Rouffach, France) and contains the following (figure 2):

• The Vagustim device (EC certificate, registration number DD 60136841 0001; report number 28417062 004 dated 4 March 2019, CE0197-2020/04/28), which is a transcutaneous electrical nerve stimulation (TENS) device from Schwa-Medico especially designed to connect to an ear electrode. The waveform is biphasic, asymmetrically balanced, with amplitude from 0 to 99 mA. Frequency preset modes are at 25, 10 and 1 Hz and will be set at 25 Hz, 100 µs.

• One auricular electrode (Monath Electronic).

• Conductive gel medical device (C+V Pharma Depot GmbH, Versmold, Germany).

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Figure 2

Description of the Vagustim device, the cymba concha, auricular electrode applied on the left cymba concha and the conductive gel provided to patients at the beginning of the study.

To properly stimulate the VN, a conductive gel is applied on the auricular electrode to ameliorate electrical transmission. The electrode is then applied on the left cymba concha for each daily use. The tVNS is performed on the left ear because efferent fibres to the heart that innervate the sinoatrial node are located on the right side and so could be connected to the VN afferent fibres of the right ear.23 The participants randomised in the sham group receive the same device pack with a Vagustim device that looks exactly the same. The active and sham devices look exactly the same. All the procedures and daily settings are exactly the same for both devices; all patients will wear the auricular electrode with conductive gel, turn on the device, will see the same screen and will set the intensity to a maximum of 8 mA or less if they feel discomfort. For the sham device, the intensity will appear as a real intensity, but no current will be delivered.

After randomisation, the patients are thoroughly instructed in how to use the device, and the first active session is performed at the hospital. This training session is performed by a nurse, another medical doctor or the clinical research technician at the baseline visit and, if necessary, at visits on weeks 4 and 8. Furthermore, the person who performs the training calls the patient to check on the proper use of the device at 10±7 days after the baseline visit.

Three parameters are set:

• Frequency at 25 Hz.

• 100 µs.

• Intensity is progressively increased from 0 to 8 mA during the daily setting. If the patient starts to feel discomfort, the intensity level below this uncomfortable intensity is selected to obtain a non-painful and non-unpleasant intensity.

Then patients self-administer their treatment using the device for 20 min/day for 12 weeks. The following pain treatments are allowed: acetaminophen (except during the 48 hours before each visit), hand orthosis if used for more than 2 months before inclusion, and physiotherapy or occupational therapy if prescribed at least 2 months before inclusion and stable during the trial. Topical or oral NSAIDs, opioids, hand surgery and hand joint infiltration (corticosteroids and hyaluronic acid) are prohibited.

Patients come for a medical visit every 4 weeks for 12 weeks (weeks 4, 8 and 12). At each visit, participants undergo hand and general clinical examinations, complete questionnaires, report the daily use of acetaminophen in a self-reporting notebook, report tolerance of the device and report adverse events (table 2). Adherence is evaluated by using a device tracker that provides information on its use with the daily time application and mean daily intensity since the previous visit. If necessary, patients undergo a new training session at weeks 4 and 8. The last visit at week 12 includes the same items of the follow-up visits plus a blood sample taken and a non-contrast MRI of the hand for the subgroup who had MRI at inclusion. Three specific additional assessments are added: asking about (1) satisfaction with the device; (2) ease of use of the device, rated on a 4-point scale; and (3) whether patients believed they had used the active or sham device. The investigators are asked whether they believe the patient has received the active or sham device.

Patients can withdraw from the study at any time for any reason. Patients will be withdrawn from the treatment if they comply with exclusion criteria but will continue to be monitored for the study.

Randomisation

The investigator randomises patients to the active or sham tVNS groups by using the electronic case report form (e-CRF) CleanWeb (Telemedecine Technologies S.A.S.). The computer-generated, blocked, balanced randomisation is prepared in a 1:1 ratio by an independent biostatistician from the clinical research unit (URC-Est). The block width is not communicated to investigators. Randomisation is stratified by the centre. The investigator in charge of the randomisation is blinded to the randomisation group and selects the device according to the code number provided by CleanWeb and placed on the related device.

Blinding

Active or sham devices look exactly the same. To homogenise between centres, the explanations given to the patients during the training session on the use of the device, a document with the verbatim to use for explanations was prepared by the coordinator and provided to the individuals in charge of training sessions in each centre. Manufacturing and preparation of the medical devices are handled by Schwa-Medico and are anonymised by the General Agency for Health Equipment and Products. Participants, investigators and all researchers involved in the data collection (investigators and nurses) or in biological and imaging analysis are blinded to the treatment allocation group until after the study completion and the analyses are fully performed at the end of the study. The investigator (outcome assessor) performs the clinical evaluation, and the clinical nurse or another medical doctor (different from the investigator) or the clinical study technician of each centre trains the patient in the device use. The investigating physician may request unblinding for any reason he considers essential to the health of the patient by contacting the project advisor. No unblinding is planned with the patient except in case of severe side effect.

During the follow-up visits, clinical efficacy is evaluated before recording potential minor stimulated site-treatment side effects. Because the clinical nurse or the person who performed the training session may guess the randomisation group according to the presence of these minor symptoms, no communication must occur between the investigator and the person who performed the training session and the patient during the study. We collect the initials of the person who performed the training session and the clinical assessor to ensure that they are different.

Outcomes

Statistical power

The study is powered to detect a difference between groups in change of at least 13 mm at 12 weeks on a 100 mm pain VAS scale. Considering an improvement in the sham group of 11.3±24 mm, a two-sided alpha risk of 0.05, a non-parametric test and a 10% drop-out rate with a power of 80%, and an additional margin of 20%, 156 patients are needed to randomise 130 of them45 (East 6 (2020), statistical software for the design, simulation and monitoring clinical trials; Cytel, Cambridge, Massachusetts, USA). The choice of this 13 mm cut-off is based on the expected important placebo effect in the sham group (effect size of the TENS placebo in knee OA is 0.44, 95% CI 0.14 to 0.74), the stable placebo effect on pain level at 3 and 6 months in HOA and known minimal clinically important changes in pain level in OA.45 46 The additional margin of 20% in recruitment is justified because some patients will not have US-evidenced synovitis. From the study of Vlychou et al, among 22 patients with EHOA, 19 had a thickened synovium; 18 had power Doppler signals; and thus 4 of 22 (18%) had no US features of joint inflammation.10

Data collection and management

Data are collected in an e-CRF, devised by the study coordinator in collaboration with URC-Est. Data are completed by the investigators with the help of a clinical research technician. Data entry checks and a posteriori checks are planned. All information required by the protocol are recorded in physical or electronic report files, and an explanation must be provided for any missing data. All questionnaires used are validated. A CRA will be responsible for the good completion of the study, for collecting, documenting, recording and reporting all handwritten data, in accordance with the standard operating procedures applied within the clinical research and innovation department. A steering committee with a coordinator, coinvestigators and a methodologist decides what to do in unexpected situations. The committee monitors the progress of the research and meets every 12 months.

Source documents (original document or item that can prove the existence or accuracy of a data or a fact recorded during the study) are kept for 15 years by the investigator or by the hospital in the case of a hospital medical file.

During and after the research involving human participants, all data collected concerning the participants are rendered anonymous. Under no circumstances are the names and addresses of the participants shown. Only the participant’s initials are recorded, accompanied by an encoded number specific to the study indicating the order of enrolment.

An audit can be carried out at any time by individuals appointed by the sponsor and independent of those responsible for the research.

Data analysis

Analysis will be performed at the end of the study after a blind data review and database lock. A flowchart will be drawn according to the CONSORT statement. Continuous variables will be summarised with mean±SD or median (IQR), depending on the distribution of the variable. Categorical variables will be described with frequency (percentage). Primary analysis will be performed on the intent-to-treat (ITT) population defined as all patients randomised.

Patient recruitment strategies

Recruitment of patients started in April 2021 and is expected for 2 years. In total, 18 French recruitment centres are involved: 17 rheumatology departments and 1 rehabilitation department in 18 hospitals (4 in Paris and 14 throughout France); 15 are academic hospitals (including 4 departments of Paris Assistance Publique des Hôpitaux de Paris (AP-HP) hospitals); 2 are regional or departmental hospitals (Western region); and 1 is a private non-profit hospital (South of France, Marseille) for recruiting a wide range of patients with EHOA throughout France. However, because patients with EHOA are also often followed up in outpatient clinics, patients are also recruited from hospital consultations and by rheumatologists from private practice who work in collaboration with the investigator centres.

We used several communication channels to communicate about the study (French Society of Rheumatology and French Association for the Fight against Rheumatism (the largest patient’s association devoted to musculoskeletal diseases in France)), the Arthritis Foundation, and publications in social network and the general media. We aimed also to contact the AP-HP network for communicating about ESTIVAL to the AP-HP patient community, which includes 39 hospitals. Flyers and posters are sent to the rheumatologists who participate to the OA study group of the French Society of Rheumatology. Finally, patients with EHOA can also contact us directly by letter or email. An ESTIVAL mailbox has been created for this purpose and is managed by the main investigator and/or the scientific director to refer patients to the nearest centre.

Adverse events

Tolerance to the intervention was good in the pilot study and in studies in other indications with the only adverse event observed being an unpleasant sensation in the ear, mostly transitory, in a few patients.47 However, information about adverse events and serious adverse events is collected throughout the study in the patient file and the eCRF. The investigator can temporarily or permanently withdraw a participant from the study or the patient may withdraw on their own for any safety reason or if it is in the participant’s best interests.

Patient and public involvement

There is no patient or public involvement.

Ethics and dissemination

Ethics approval was obtained from the institutional review board at the main site (Comité de Protection des Personnes (CPP), 2020-A02213-36). All participants are required to provide written informed consent. Any substantial modification to the protocol by the coordinating investigator is sent to the sponsor for approval. After approval is given, the sponsor obtains approval from the CPP (research ethics committee) before the amendment can be implemented. The information note and the consent form can be revised if necessary, particularly in case of a substantial amendment to the study or if adverse reactions occur. Results of this study, whether positive or negative, will be presented at national and international congresses and published in a peer-reviewed journal.