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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
1/09/2024
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.
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Scientific title
A feasibility study of non-invasive auricular vagus nerve stimulation in people with rheumatoid arthritis.
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Secondary ID [1]
311951
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None
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Universal Trial Number (UTN)
U1111-1283-9429
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
rheumatoid arthritis (RA)
333547
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Condition category
Condition code
Inflammatory and Immune System
330230
330230
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0
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Rheumatoid arthritis
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Anaesthesiology
330231
330231
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0
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Pain management
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Intervention/exposure
Study type
Interventional
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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.
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Intervention code [1]
328409
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Treatment: Devices
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Comparator / control treatment
None
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Control group
Uncontrolled
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Outcomes
Primary outcome [1]
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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.
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Assessment method [1]
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Percentage of eligible participants recruited greater than or equal to 60%. This will be calculated by auditing the recruitment records.
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Timepoint [1]
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From the beginning of the recruitment phase to the recruitment of the final participant.
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Primary outcome [2]
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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.
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Assessment method [2]
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Percentage of the taVNS sessions started and completed greater than or equal to 75%. This will be calculated from the session analytics data uploaded to the cloud by the application.
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Timepoint [2]
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From the start of the intervention for the first participant to the completion of the trial.
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Primary outcome [3]
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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.
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Assessment method [3]
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An overall acceptability of 60% or higher to be considered adequate using a custom questionnaire based on the Theoretical Framework of Acceptability (TFA).
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Timepoint [3]
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From the start of the intervention for the first participant to the completion of the trial.
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Secondary outcome [1]
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Change in resting pain
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Assessment method [1]
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Brief Pain Inventory Interference Score
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Timepoint [1]
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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.
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Secondary outcome [2]
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Psychological distress as a composite measure of depression, anxiety and stress.
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Assessment method [2]
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DASS-21 score
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Timepoint [2]
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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.
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Secondary outcome [3]
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Change in grip pain intensity after 5 x 5kg repetitions.
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Assessment method [3]
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Visual analog scale
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Timepoint [3]
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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.
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Secondary outcome [4]
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Change in pressure pain threshold at the wrist.
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Assessment method [4]
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Visual analog scale
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Timepoint [4]
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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.
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Secondary outcome [5]
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Change in pressure pain threshold at the tibialis anterior.
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Assessment method [5]
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Visual analog scale
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Timepoint [5]
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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.
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Secondary outcome [6]
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Patient global assessment of disease activity
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Assessment method [6]
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Visual analog scale
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Timepoint [6]
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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.
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Secondary outcome [7]
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Change in inflammatory blood biomarkers.
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Assessment method [7]
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C-reactive protein (CRP)
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Timepoint [7]
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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.
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Secondary outcome [8]
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Change in inflammatory blood biomarkers.
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Assessment method [8]
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Tumor Necrosis Factor-a (TNF-a)
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Timepoint [8]
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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.
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Secondary outcome [9]
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Change in inflammatory blood biomarkers
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Assessment method [9]
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Interleukin (IL)-1ß.
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Timepoint [9]
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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.
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Secondary outcome [10]
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Change in inflammatory blood biomarkers.
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Assessment method [10]
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Interleukin (IL)-10
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Timepoint [10]
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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.
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Secondary outcome [11]
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Change in inflammatory blood biomarkers.
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Assessment method [11]
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Interleukin (IL)-17A
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Timepoint [11]
433988
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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.
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Secondary outcome [12]
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Change in resting vagal tone
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Assessment method [12]
433989
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root mean square of successive differences between normal heartbeats (RMSSD) measured using the finger-tip based heart rate sensor
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Timepoint [12]
433989
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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.
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Secondary outcome [13]
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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.
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Assessment method [13]
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Percentage of patients with RA that meet the eligibility criteria greater than or equal to 30%. This will be calculated by auditing the recruitment records.
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Timepoint [13]
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From the beginning of the recruitment phase to the recruitment of the final participant.
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Secondary outcome [14]
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Change in disability score
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Assessment method [14]
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Health assessment questionnaire's disability index (HAQ-DI) used in rheumatology
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Timepoint [14]
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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.
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Secondary outcome [15]
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The total number of adverse events
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Assessment method [15]
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The total number of treatment-emergent adverse events (TEASs) such as ear pain, headaches, skin irritation on the outer ear, dizziness and nausea, assessed by patient interview. Any TEAEs identified will be categorised in accordance with the Common Terminology Criteria for Adverse Events (CTCAE5.0).
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Timepoint [15]
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From the start of the intervention for the first participant to the completion of the trial.
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Secondary outcome [16]
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Participant withdrawals
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Assessment method [16]
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Number of withdrawals and percentage out of the total number of participants. This will be calculated by auditing the logs for withdrawals.
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Timepoint [16]
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From the start of the intervention for the first participant to the completion of the trial.
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Secondary outcome [17]
434783
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The percentage of participants experiencing TEAEs
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Assessment method [17]
434783
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percentage of participants who reported TEAEs, out of the total number of participants. During the day 8 and day 15 visits, participants will be verbally asked the open question: "Have you experienced any health problems or had any unusual symptoms or abnormal changes in bodily function in the last week?" If the participant answers yes, they will be asked to list any health problems/symptoms/changes in body function they have experienced, and
a series of follow-up questions will be posed for each problem identified including: "Can you describe it? When did it start? How long did it last for? How frequently did you experience it? Are you still experiencing it? Did it affect your usual daily activities? In what way? Did you seek any medical treatment? If so, what was this?" This information will be used to create a TEAE log and then to classify and grade each TEAE using the Common Terminology Criteria for Coding Adverse Events (CTCAE).
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Timepoint [17]
434783
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From the start of the intervention for the first participant to the completion of the trial.
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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
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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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
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
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Other design features
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Phase
Not Applicable
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Type of endpoint/s
Safety/efficacy
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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.
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Recruitment
Recruitment status
Recruiting
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Date of first participant enrolment
Anticipated
27/05/2024
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Actual
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Date of last participant enrolment
Anticipated
17/03/2025
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Actual
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Date of last data collection
Anticipated
31/03/2025
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Actual
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Sample size
Target
12
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Accrual to date
0
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Final
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Recruitment outside Australia
Country [1]
26245
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New Zealand
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State/province [1]
26245
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Auckland
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Funding & Sponsors
Funding source category [1]
316289
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Commercial sector/Industry
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Name [1]
316289
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Exsurgo Ltd
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Address [1]
316289
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Country [1]
316289
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New Zealand
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Primary sponsor type
Commercial sector/Industry
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Name
Exsurgo Ltd
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Address
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Country
New Zealand
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Secondary sponsor category [1]
318476
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None
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Name [1]
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Address [1]
318476
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Country [1]
318476
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Other collaborator category [1]
283010
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University
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Name [1]
283010
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Auckland University of Technology
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Address [1]
283010
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Country [1]
283010
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New Zealand
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
315105
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Northern A Health and Disability Ethics Committee
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Ethics committee address [1]
315105
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https://ethics.health.govt.nz/about/northern-a-health-and-disability-ethics-committee/
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Ethics committee country [1]
315105
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New Zealand
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Date submitted for ethics approval [1]
315105
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27/10/2023
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Approval date [1]
315105
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08/12/2023
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Ethics approval number [1]
315105
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2023 FULL 18139
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Ethics committee name [2]
315111
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Auckland University of Technology Ethics Committee
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Ethics committee address [2]
315111
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https://www.aut.ac.nz/research/researchethics
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Ethics committee country [2]
315111
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New Zealand
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Date submitted for ethics approval [2]
315111
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22/11/2023
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Approval date [2]
315111
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23/01/2024
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Ethics approval number [2]
315111
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23/370
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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.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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A/Prof David Rice
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Address
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School of Clinical Sciences, Auckland University of Technology, 90 Akoranga Drive, Northcote, Auckland, 0620
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Country
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New Zealand
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Phone
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+64 9 921 7032
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Fax
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Email
133698
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[email protected]
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Contact person for public queries
Name
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David Rice
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Address
133699
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School of Clinical Sciences, Auckland University of Technology, 90 Akoranga Drive, Northcote, Auckland, 0620
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Country
133699
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New Zealand
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Phone
133699
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+64 9 921 7032
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Fax
133699
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Email
133699
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[email protected]
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Contact person for scientific queries
Name
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David Rice
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Address
133700
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School of Clinical Sciences, Auckland University of Technology, 90 Akoranga Drive, Northcote, Auckland, 0620
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Country
133700
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New Zealand
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Phone
133700
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+64 9 921 7032
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Fax
133700
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Email
133700
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[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
Participant consent has not been given. Some of the data may be commercially sensitive.
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What supporting documents are/will be available?
No Supporting Document Provided
Doc. No.
Type
Citation
Link
Email
Other Details
Attachment
22169
Study protocol
387660-(Uploaded-12-04-2024-13-19-34)-Study-related document.pdf
22170
Ethical approval
387660-(Uploaded-23-04-2024-07-28-20)-Study-related document.pdf
22171
Ethical 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.
Download to PDF