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

Assistance Publique - Hôpitaux de Paris

Status

Completed

Conditions

Musculoskeletal Pain

Osteoarthritis

Erosive Osteoarthritis

Treatments

Device: Active VAGUSTIM device

Device: Sham VAGUSTIM device

Study type

Interventional

Funder types

Other

Identifiers

NCT04520516

APHP 200014

Details and patient eligibility

About

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.

Full 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.

Enrollment

148 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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