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Trial registered on ANZCTR


Registration number
ACTRN12624000620527
Ethics application status
Approved
Date submitted
12/04/2024
Date registered
14/05/2024
Date last updated
14/05/2024
Date data sharing statement initially provided
14/05/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
A feasibility study of non-invasive auricular vagus nerve stimulation in people with rheumatoid arthritis.
Scientific title
A feasibility study of non-invasive auricular vagus nerve stimulation in people with rheumatoid arthritis.
Secondary ID [1] 311951 0
None
Universal Trial Number (UTN)
U1111-1283-9429
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
rheumatoid arthritis (RA) 333547 0
Condition category
Condition code
Inflammatory and Immune System 330230 330230 0 0
Rheumatoid arthritis
Anaesthesiology 330231 330231 0 0
Pain management

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A single-arm, repeated measures feasibility study will be undertaken. Participants will receive 14 sessions of daily respiratory-gated transcutaneous auricular Vagus Nerve Stimulation (taVNS) for 20 minutes. Two of these sessions on day 1 and day 8 will be supervised and take place at North Shore Hospital, as part of an assessment session, while 12 of these sessions will be completed unsupervised, in the participant’s home.

The supervised sessions will be administered by the study co-investigator. As part of the induction during the first supervised session (day 1), participants will be trained on 1. How to insert the earpiece with the stimulation electrodes in the left ear with the electrode pins resting at the cymba concha; 2. How to position the heart rate sensor on the left index finger; 3. How to wear the respiration sensor strap just under their rib cage.

A user application, developed to accompany the prototype system, will be loaded on a mobile tablet that will be supplied to the participant. The application will instruct the participant to be seated in a chair and fit the equipment appropriately. It will check that the equipment is being worn correctly and is transmitting the data to the application. Each participant will set the taVNS stimulation intensity in the application to ensure it is strong but not uncomfortable. During each taVNS session, the stimulation will be administered at 30 Hz for 1 second during exhalation only for a total of 20 minutes after which the session will be completed.

The co-investigator will monitor the usage of the device and application as the participants progress through the intervention. If they miss a single session, they will be sent a follow-up text message and email as a reminder to complete the next session. If they miss 2 consecutive sessions, they will receive a call the next day to remind them to continue with the training and address any issues they may be experiencing with the equipment.
Intervention code [1] 328409 0
Treatment: Devices
Comparator / control treatment
None
Control group
Uncontrolled

Outcomes
Primary outcome [1] 337979 0
To determine if a future single-centre clinical trial of home-based taVNS is feasible in people with RA by estimating how many eligible patients can be recruited.
Timepoint [1] 337979 0
From the beginning of the recruitment phase to the recruitment of the final participant.
Primary outcome [2] 337980 0
To determine if a future single-centre clinical trial of home-based taVNS is feasible in people with RA by estimating the intervention adherence based on the percentage of the taVNS sessions started and completed.
Timepoint [2] 337980 0
From the start of the intervention for the first participant to the completion of the trial.
Primary outcome [3] 337981 0
To determine if a future single-centre clinical trial of home-based taVNS is feasible in people with RA by the evaluation of the usability and acceptability questionnaire scores.
Timepoint [3] 337981 0
From the start of the intervention for the first participant to the completion of the trial.
Secondary outcome [1] 433978 0
Change in resting pain
Timepoint [1] 433978 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [2] 433979 0
Psychological distress as a composite measure of depression, anxiety and stress.
Timepoint [2] 433979 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [3] 433980 0
Change in grip pain intensity after 5 x 5kg repetitions.
Timepoint [3] 433980 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [4] 433981 0
Change in pressure pain threshold at the wrist.
Timepoint [4] 433981 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [5] 433982 0
Change in pressure pain threshold at the tibialis anterior.
Timepoint [5] 433982 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [6] 433983 0
Patient global assessment of disease activity
Timepoint [6] 433983 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [7] 433984 0
Change in inflammatory blood biomarkers.
Timepoint [7] 433984 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [8] 433985 0
Change in inflammatory blood biomarkers.
Timepoint [8] 433985 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [9] 433986 0
Change in inflammatory blood biomarkers
Timepoint [9] 433986 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [10] 433987 0
Change in inflammatory blood biomarkers.
Timepoint [10] 433987 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [11] 433988 0
Change in inflammatory blood biomarkers.
Timepoint [11] 433988 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [12] 433989 0
Change in resting vagal tone
Timepoint [12] 433989 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [13] 434419 0
Additional primary outcome - To determine if a future single-centre clinical trial of home-based taVNS is feasible in people with RA by estimating the proportion of patients with RA that meet the eligibility criteria.
Timepoint [13] 434419 0
From the beginning of the recruitment phase to the recruitment of the final participant.
Secondary outcome [14] 434420 0
Change in disability score
Timepoint [14] 434420 0
From day 1 hospital visit to the second hospital visit on day 8 and from day 1 hospital visit to the third hospital visit on day 15.
Secondary outcome [15] 434422 0
The total number of adverse events
Timepoint [15] 434422 0
From the start of the intervention for the first participant to the completion of the trial.
Secondary outcome [16] 434423 0
Participant withdrawals
Timepoint [16] 434423 0
From the start of the intervention for the first participant to the completion of the trial.
Secondary outcome [17] 434783 0
The percentage of participants experiencing TEAEs
Timepoint [17] 434783 0
From the start of the intervention for the first participant to the completion of the trial.

Eligibility
Key inclusion criteria
Males and females 18 years of age or older who have been diagnosed with adult-onset rheumatoid arthritis (RA) according to the American College of Rheumatology (ACR)/ the European Alliance of Associations for Rheumatology (EULAR) 2010 RA classification criteria; have the presence of at least 3/28 swollen and/or at least 3/28 tender joints with 1 tender joint being in the hand or wrists
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded from the study if they have any of the following:
• Ear infection (otitis media or otitis externa)
• Poor hand dexterity and no access to a helper at home who could assist in fitting the in-ear taVNS device and the respiration sensor strap
• Changes in oral or biologic disease-modifying antirheumatic drugs (DMARDs) in the last 4 weeks
• Have had intraarticular or intramuscular corticosteroids within 2 weeks prior to study entry
• Unstable dosing regimen of non-steroidal anti-inflammatory drugs (NSAIDs) or analgesics in the last 2 weeks
• History of arrhythmia, myocardial infarction in the last 12 months, currently on beta-blocker medication or history of stroke affecting the brainstem
• Previous vagotomy
• Currently implanted electrical and/or neurostimulator device
• Active malignancy or history of active malignancy in the last 2 years, with the exception of non-melanoma skin carcinoma or carcinoma in situ
• Severe comorbidities which in the judgement of the study physicians would deem the participant not suitable as it may impact the safety of study conduct
• Known cognitive impairments
• Psychiatric illness with active psychosis
• Pregnant

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Participant eligibility and recruitment: The percentage of participants screened who meet the eligibility criteria and the percentage of eligible participants who consented will be calculated and reported.
Intervention adherence: The percentage of sessions completed out of 14 will be calculated for each participant and the mean, median and range will reported for all 12 participants.
Estimates of mean intervention effect and dose-response: Cohen’s d effect sizes will be calculated and reported to estimate the mean treatment effect from baseline (Day 1) to 7 sessions (Day 8) and baseline (Day 1) to 14 sessions (Day 15) for each of the secondary outcome measures.
Relationships between changes in HRV and pain measures: We will explore the relationships between changes in heart rate variability (RMSSD) and each of resting pain, grip pain, and pressure pain thresholds from pre to immediately post 20 mins taVNS on treatment Day 1, 8 and 15 using Pearson correlation coefficients or Spearman’s rank coefficient.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
27/05/2024
Actual
Date of last participant enrolment
Anticipated
17/03/2025
Actual
Date of last data collection
Anticipated
31/03/2025
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment outside Australia
Country [1] 26245 0
New Zealand
State/province [1] 26245 0
Auckland

Funding & Sponsors
Funding source category [1] 316289 0
Commercial sector/Industry
Name [1] 316289 0
Exsurgo Ltd
Country [1] 316289 0
New Zealand
Primary sponsor type
Commercial sector/Industry
Name
Exsurgo Ltd
Address
Country
New Zealand
Secondary sponsor category [1] 318476 0
None
Name [1] 318476 0
Address [1] 318476 0
Country [1] 318476 0
Other collaborator category [1] 283010 0
University
Name [1] 283010 0
Auckland University of Technology
Address [1] 283010 0
Country [1] 283010 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 315105 0
Northern A Health and Disability Ethics Committee 
Ethics committee address [1] 315105 0
https://ethics.health.govt.nz/about/northern-a-health-and-disability-ethics-committee/
Ethics committee country [1] 315105 0
New Zealand
Date submitted for ethics approval [1] 315105 0
27/10/2023
Approval date [1] 315105 0
08/12/2023
Ethics approval number [1] 315105 0
2023 FULL 18139
Ethics committee name [2] 315111 0
Auckland University of Technology Ethics Committee
Ethics committee address [2] 315111 0
https://www.aut.ac.nz/research/researchethics
Ethics committee country [2] 315111 0
New Zealand
Date submitted for ethics approval [2] 315111 0
22/11/2023
Approval date [2] 315111 0
23/01/2024
Ethics approval number [2] 315111 0
23/370

Summary
Brief summary
Transcutaneous auricular vagus nerve stimulation (taVNS), a type of neuromodulation, is a potential non-pharmacological alternative to manage pain. Vagus nerve stimulation activates several brainstem regions involved in descending pain inhibition likely increases the release of endogenous opioids, may alter nociceptive processing at a cortical level and has anti-inflammatory effects.
In addition, the ability to deliver taVNS in synchronisation with the exhalation phase of the respiratory cycle is likely to improve its application for pain management. Activity in the vagal brainstem nuclei is cyclically modulated by respiration. Recent functional magnetic resonance imaging (fMRI) studies have shown exhalation respiratory-gated auricular vagal nerve stimulation (eRAVANS) evoked fMRI signal increase in brain regions associated with enhanced VN activity and descending pain modulation.
This study will explore if a prototype respiratory gated taVNS device is feasible to be used in a future single-centre clinical trial of home-based taVNS in people with rheumatoid arthritis.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 133698 0
A/Prof David Rice
Address 133698 0
School of Clinical Sciences, Auckland University of Technology, 90 Akoranga Drive, Northcote, Auckland, 0620
Country 133698 0
New Zealand
Phone 133698 0
+64 9 921 7032
Fax 133698 0
Email 133698 0
david.rice@aut.ac.nz
Contact person for public queries
Name 133699 0
David Rice
Address 133699 0
School of Clinical Sciences, Auckland University of Technology, 90 Akoranga Drive, Northcote, Auckland, 0620
Country 133699 0
New Zealand
Phone 133699 0
+64 9 921 7032
Fax 133699 0
Email 133699 0
david.rice@aut.ac.nz
Contact person for scientific queries
Name 133700 0
David Rice
Address 133700 0
School of Clinical Sciences, Auckland University of Technology, 90 Akoranga Drive, Northcote, Auckland, 0620
Country 133700 0
New Zealand
Phone 133700 0
+64 9 921 7032
Fax 133700 0
Email 133700 0
david.rice@aut.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Participant consent has not been given. Some of the data may be commercially sensitive.


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
22169Study protocol    387660-(Uploaded-12-04-2024-13-19-34)-Study-related document.pdf
22170Ethical approval    387660-(Uploaded-23-04-2024-07-28-20)-Study-related document.pdf
22171Ethical approval    387660-(Uploaded-23-04-2024-07-28-31)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.