Clinical trial NCT04520516: Auricular Vagus Nerve Stimulation in Painful and Inflammatory Erosive Hand Osteoarthritis
Official title: Trial of Auricular Vagus Nerve Stimulation in Painful and Inflammatory Erosive Hand Osteoarthritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Osteoarthritis
Musculoskeletal Pain
Erosive Osteoarthritis
Keywords: Musculoskeletal pain
Osteoarthritis
Neuromodulation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Schwa medico (device lending)
First posted: 2020-08-20
Enrollment: 148
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from Day 0 to Week 12 of self-reported hand pain
timeFrame: 12 weeks
Secondary outcomes:
measure: AUStralian CANadian Osteoarthritis Hand Index (AUSCAN)(pain, function, stiffness).
timeFrame: Between week 0 and week 12
measure: Modified Functional Index for Hand OsteoArthritis (FIHOA)
timeFrame: Between week 0 and week 12 vvv
measure: Cochin Hand Function Scale.
timeFrame: Between week 0 and week 12
measure: Percentage of patients below the Patient Acceptable Symptom State (PASS) of pain (VAS<40/100)
timeFrame: Between week 0 and week 12
measure: EuroQoL EQ-5D.
timeFrame: Between week 0 and week 12
measure: Hospital Anxiety and Depression Scale (HAD).
timeFrame: Between week 0 and week 12 vvvvvvv
measure: Fatigue intensity on a 0-100 mm VAS
timeFrame: Between week 0 and week 12
measure: Number of painful hand joints (0-30) under pressure.
timeFrame: Between week 0 and week 12
measure: Number of swollen hand joints (0-30).
timeFrame: Between week 0 and week 12
measure: Patient Global Assessment (PGA) of health status on a 0-100 mm VAS.
timeFrame: Between week 0 and week 12
measure: DN-4 Questionnaire evaluating neuropathic pain.
timeFrame: Between week 0 and week 12
measure: Change over time of VAS pain.
timeFrame: Week 0, Week 4, Week 8, and Week 12
measure: Change over time of FIHOA.
timeFrame: Week 0, Week 4, Week 8, and Week 12
measure: Change over time of AUSCAN (pain, stiffness, and function).
timeFrame: Week 0, Week 4, Week 8, and Week 12
measure: Percentage of patients with symptom levels below which they consider their condition acceptable (PASS), defined by a VAS <40/100
timeFrame: Week 12
measure: Proportion of OMERACT-OARSI responders.
timeFrame: Week 12
measure: Percentage of responders according to the Patient Global Impression of Change (PGIC) score
timeFrame: Week 12
measure: Total paracetamol consumption (g) divided by treatment duration using a patient-filled diary.
timeFrame: Between week 0 and week 12
measure: Change in percentage in serum inflammatory or pain-related markers
timeFrame: Between week 0 and week 12
measure: Change in serum cartilage degradation markers (Coll2-1 (a marker of type II collagen denaturation), Coll2-1-NO2).
timeFrame: Between week 0 and week 12
measure: Proportion of side effects
timeFrame: 4 weeks, 8 weeks and 12 weeks
measure: 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.
timeFrame: Between week 0 and week 12
Other outcomes:
measure: W0-W12 change in the WOMAC for other osteoarthritis sites (hips, knees) if present at inclusion.
timeFrame: Between week 0 and week 12
measure: Effectiveness of the blinding procedure and the ease of use of the device
timeFrame: Week 12
measure: Change in HOAMRIS subscores of synovitis and subchondral bone marrow edema using MRI examination
timeFrame: Between week 0 and week 12
measure: Clinical efficacy (primary endpoint and the OMERACT-OARSI response) according clinical, biological or radiographic characteristics at inclusion
timeFrame: Between week 0 and week 12
measure: Correlation between baseline biological biomarkers and clinical response in the active group
timeFrame: Week 12
Locations:
city: Paris
country: France
facility: Service de Rhumatologie - Hôpital Saint Antoine
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Jérémie SELLAM, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Courties A, Deprouw C, Rousseau A, Berard L, Touati A, Kalsch J, Villevieille M, Maheu E, Miquel A, Simon T, Berenbaum F, Sellam J; ESTIVAL study group. Transcutaneous vagus nerve stimulation in erosive hand osteoarthritis: protocol for the randomised, double-blind, sham-controlled ESTIVAL trial. BMJ Open. 2022 Mar 22;12(3):e056169. doi: 10.1136/bmjopen-2021-056169.