Auricular Vagus Nerve Stimulation in Painful and Inflammatory Erosive Hand Osteoarthritis (ESTIVAL)

September 10, 2025 updated by: Assistance Publique - Hôpitaux de Paris

Trial of Auricular Vagus Nerve Stimulation in Painful and Inflammatory Erosive Hand Osteoarthritis

Erosive hand osteoarthritis (EHOA) is a difficult-to-treat subtype of HOA characterized by local and systemic low-grade inflammation as well as by high level of pain and of disability.

Auricular transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic strategy that may reduce inflammation and pain level.

ESTIVAL is a 12 weeks randomized sham-controlled trial investigating the symptomatic efficacy and safety of tVNS in patients with symptomatic and inflammatory EHOA.

tVNS will be performed using a transcutaneous electrical nerve stimulation (TENS) device connected to an auricular electrode stimulating the cutaneous area of the left ear innervated by the auricular ascendant branch of the vagus nerve.

The active and sham device's will display similar appearance but the sham one will not give electric signal.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Symptomatic hand osteoarthritis (HOA) affects 8-16% of the general population above 50 years and involves interphalangeal (IP) joints. HOA symptoms include pain, stiffness and are responsible for disability and substantial burden. Erosive HOA (EHOA) (10% prevalence among symptomatic HOA from the general population and 40-50% prevalence in tertiary centers) is the most severe HOA phenotype characterized by inflammatory flares, more IP joint destruction, pain, soft swelling joints (ie, synovitis), and more disability (similar to rheumatoid arthritis (RA)) than its non-erosive counterpart.

Current symptomatic pharmacological treatments of HOA or EHOA have a poor efficacy on pain (ie, paracetamol) or safety issues (ie, non-steroidal anti-inflammatory drugs (NSAIDs)) in this aging population with frequent comorbidities. Systemic and joint inflammation contribute to EHOA but 4 studies using TNF inhibitors, 2 using hydroxychloroquine, 1 using methotrexate and 1 using a new anti-IL1α/β failed to show any efficacy on pain in HOA or in EHOA. Therefore, innovative therapeutic approaches are awaited.

Stimulation of the vagus nerve (VNS), belonging to parasympathetic system, dampens pro-inflammatory cytokines production by splenic macrophages, through to the binding of acetylcholine neurotransmitter to α7nicotinic receptor on macrophages: this is the cholinergic anti-inflammatory pathway (CAP). VN stimulation (VNS) by cervical implantable device activating CAP has given promising results in refractory RA patients. Beyond its anti-inflammatory effects, VNS is analgesic in chronic pain disorders (headache, fibromyalgia). However, the use of such implantable device is limited by the need of cervical surgery and subsequent potential side effects.

Besides implantable devices, VNS may be also performed using transcutaneous VNS (tVNS) of the ascendant auricular branch of the VN that selectively innervates the cutaneous zone of cymba conchae at the left ear. Auricular tVNS avoids invasive neurosurgery and its potential side effects and is less expensive than implantable VNS, making it an attractive candidate for neurostimulation. Auricular tVNS has given positive results in chronic migraine and is currently tested in RA, Crohn's disease, widespread pain, irritable bowel syndrome and musculoskeletal pain related to systemic lupus.

We hypothesize that auricular tVNS using a transcutaneous electrical nerve stimulation (TENS) device could be a novel, simple and well-tolerated analgesic and anti-inflammatory treatment of symptomatic (i.e., painful) and inflammatory EHOA.

ESTIVAL is a 12 weeks randomized sham-controlled trial investigating the symptomatic efficacy and the safety of tVNS in patients with symptomatic and inflammatory EHOA.

tVNS will be performed using an active or sham transcutaneous electrical nerve stimulation (TENS) device connected to an auricular electrode stimulating the cutaneous area of the left ear innervated by the auricular ascendant branch of the vagus nerve.

Exploratory and ancillary studies will include i) changes of serum biomarkers of inflammation and of cartilage degradation that will be assess at inclusion and at week 12 ii) hand MRI at W0 and W12 of the most symptomatic joint at inclusion for HOAMRIS socring at W0 and W12 for the center of Saint Antoine.

A phone call at D7± 3 days by the clinical research technician or the clinical nurse or the doctor who has performed the education during the D0 visit to check the proper use of the device.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
148

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75012
        • Service de Rhumatologie - Hôpital Saint Antoine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Age ≥ 18 years
  • Symptomatic HOA according to the American College of Rheumatology criteria
  • Erosive HOA according to hand radiographs performed in routine practice showing ≥1 erosive digital joint based on Verbruggen-Veys scoring definition
  • Hand pain level ≥ 40/100 mm on VAS at inclusion at least half of days of the 30 last days
  • At least ≥1 symptomatic IP joint with clinical soft swelling or erythema at inclusion
  • reported inadequate response or adverse effects or contraindication with existing medication (including acetaminophen, oral NSAIDs)
  • Informed written consent
  • Patient affiliated to a social security scheme NB: Clinical inflammation, ultrasound abnormalities and radiographic erosions have not have to be present in the same joint.

Exclusion Criteria:

  • Isolated thumb-base OA (i.e., rhizarthrosis)
  • Predominance of the pain in the thumb base rather than digital pain
  • Other inflammatory joint disease (e.g. gout, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, Lyme disease)
  • Psoriasis
  • Current skin disease of the left ear (e.g., eczema, urticarial lesion, skin infection, external otitis)
  • Ear canal not adapted to apply the auricular electrode
  • Known history of cardiac rhythm disturbances, atrio-ventricular block > first degree, or total bundle branch block
  • Symptomatic orthostatic hypotension or repeated vasovagal syncope history
  • History of vagotomy
  • Severe Asthma
  • Treated sleep apnea
  • Existence of a pain syndrome of the upper limbs, which would interfere with the monitoring of pain
  • Fibromyalgia
  • Use of other electrically active medical devices (e.g. pacemaker, TENS for chronic pain)
  • Use of oral, intramuscular or intra-articular or intravenous steroids, other anti-synovial agents (e.g. slow-acting anti-rheumatic drugs such as methotrexate, sulfasalazine), intra-articular hyaluronic acid to the hand joints within the last 3 months
  • Any new hand OA treatment in the previous 2 months, including physiotherapy and provision of new hand splint.
  • Planned hand surgery in the next 3 months.
  • Use of any investigational (unlicensed) drug within 3 months prior to screening.
  • Evidence of serious uncontrolled concomitant medical condition, including cardiovascular, nervous system, pulmonary, renal, hepatic, endocrine, gastro-intestinal disease or epilepsy, which in the opinion of the investigator makes them unsuitable for the study
  • Pregnant or breastfeeding woman
  • Patient under legal protection measure (tutorship or curatorship) and patient deprived of freedom
  • Use of VNS before the study
  • Use of NSAIDs or paracetamol less than 48h before the D0 visit

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: tVNS active device
VAGUSTIM device from Schwa-Medico Length of use : 12 weeks
Device: Active VAGUSTIM device
Settings: 25 Hz stimulation, 100 microsec pulse width, intensity escalation up to 8 mA or below if tingling sensation, 20 min/day of stimulation in one daily session
Sham Comparator: Sham tVNS device
Sham VAGUSTIM device from Schwa-Medico Length of use : 12 weeks
Device: Sham VAGUSTIM device
The sham device : no electrical signal for VNS will be delivered.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Change from Day 0 to Week 12 of self-reported hand pain
Time Frame: 12 weeks
Change from Day 0 to Week 12 of self-reported hand pain in the previous 48 hours measured on a 100 mm visual analogue scale (VAS) : "How much pain in your hands did you experience during the past 48 h?"
12 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
AUStralian CANadian Osteoarthritis Hand Index (AUSCAN)(pain, function, stiffness).
Time Frame: Between week 0 and week 12
AUStralian CANadian Osteoarthritis Hand Index (AUSCAN) 3.1 pain, function and stiffness subscores (for each subscore: 0-100 mm scale)
Between week 0 and week 12
Modified Functional Index for Hand OsteoArthritis (FIHOA)
Time Frame: Between week 0 and week 12 vvv
scale minimum 0 , and maximum 30.
Between week 0 and week 12 vvv
Cochin Hand Function Scale.
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Percentage of patients below the Patient Acceptable Symptom State (PASS) of pain (VAS<40/100)
Time Frame: Between week 0 and week 12
Between week 0 and week 12
EuroQoL EQ-5D.
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Hospital Anxiety and Depression Scale (HAD).
Time Frame: Between week 0 and week 12 vvvvvvv
Between week 0 and week 12 vvvvvvv
Fatigue intensity on a 0-100 mm VAS
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Number of painful hand joints (0-30) under pressure.
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Number of swollen hand joints (0-30).
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Patient Global Assessment (PGA) of health status on a 0-100 mm VAS.
Time Frame: Between week 0 and week 12
Between week 0 and week 12
DN-4 Questionnaire evaluating neuropathic pain.
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Change over time of VAS pain.
Time Frame: Week 0, Week 4, Week 8, and Week 12
Week 0, Week 4, Week 8, and Week 12
Change over time of FIHOA.
Time Frame: Week 0, Week 4, Week 8, and Week 12
Week 0, Week 4, Week 8, and Week 12
Change over time of AUSCAN (pain, stiffness, and function).
Time Frame: Week 0, Week 4, Week 8, and Week 12
Week 0, Week 4, Week 8, and Week 12
Percentage of patients with symptom levels below which they consider their condition acceptable (PASS), defined by a VAS <40/100
Time Frame: Week 12
Week 12
Proportion of OMERACT-OARSI responders.
Time Frame: Week 12
Week 12
Percentage of responders according to the Patient Global Impression of Change (PGIC) score
Time Frame: Week 12
Week 12
Total paracetamol consumption (g) divided by treatment duration using a patient-filled diary.
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Change in percentage in serum inflammatory or pain-related markers
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Change in serum cartilage degradation markers (Coll2-1 (a marker of type II collagen denaturation), Coll2-1-NO2).
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Proportion of side effects
Time Frame: 4 weeks, 8 weeks and 12 weeks
report of side effects during the study period
4 weeks, 8 weeks and 12 weeks
Average daily use duration and cumulative use duration of the Vagustim device since the last visit, collected from the device's tracking system before each visit.
Time Frame: Between week 0 and week 12
Between week 0 and week 12

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
W0-W12 change in the WOMAC for other osteoarthritis sites (hips, knees) if present at inclusion.
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Effectiveness of the blinding procedure and the ease of use of the device
Time Frame: Week 12
  • Patient satisfaction with the treatment, assessed on a 5-point scale (from very satisfied to not at all satisfied).
  • Ease of use assessed on a 4-point scale (from very easy to very difficult).
  • Indication by patients whether they believe they received the active or sham device. d. Indication by the investigator whether they believe the patient received the active or sham device.
Week 12
Change in HOAMRIS subscores of synovitis and subchondral bone marrow edema using MRI examination
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Clinical efficacy (primary endpoint and the OMERACT-OARSI response) according clinical, biological or radiographic characteristics at inclusion
Time Frame: Between week 0 and week 12
Between week 0 and week 12
Correlation between baseline biological biomarkers and clinical response in the active group
Time Frame: Week 12
Week 12

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Assistance Publique - Hôpitaux de Paris

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Schwa medico (device lending)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Jérémie SELLAM, Professor, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 8, 2021

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 30, 2022

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 30, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
August 17, 2020

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 17, 2020

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
August 20, 2020

Study Record Updates

Last Update Posted (Estimated)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 16, 2025

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 10, 2025

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • APHP200014

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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