A Randomised, Single-blind, Sham-controlled, Crossover Pilot Study Assessing the Effect of Non-invasive Vagus Nerve Stimulation (nVNS) on Autonomic Symptoms and Pain Management in Patients With Chronic Musculoskeletal Pain and Autonomic Dysfunction
Phase: NA
Conditions: Chronic Musculoskeletal Pain, Autonomic Dysfunction, Dysautonomia
Sponsor: University of Leeds

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Research Protocol 
(including Statistical Analysis Plan) 
version 2.0 
 
 
A Randomised, Single-blind, Sham-controlled, 
Crossover Pilot Study Assessing the Effect of Non-
invasive Vagus Nerve Stimulation (nVNS) on 
Autonomic Symptoms and Pain Management in 
Patients With Chronic Musculoskeletal Pain and 
Autonomic Dysfunction 
 
Reducing sympathetic tone with nVNS for MSK pain relief 
(RESTORE-MSK)  
 
Norah Almutairi, Darren C Greenwood, Manoj Sivan 
 
NCT number:  
 

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Leeds Institute of Rheumatic and Musculoskeletal Medicine 
Academic Department of Rehabilitation Medicine 
Research Protocol 
 
Version 2.0 
Date: 14-01-2026 
 
Study Short Title: RESTORE-MSK: Reducing Sympathetic Tone with nVNS for MSK Pain Relief 
Study Full Title: A randomised, single-blind, sham-controlled, crossover pilot study assessing 
the effect of non-invasive vagus nerve stimulation (nVNS) on autonomic symptoms and pain 
management in patients with chronic musculoskeletal pain and autonomic dysfunction. 
Sponsor Name: University of Leeds 
Sponsor Number: 2025-NCT57 
 
Details of previous amendments: N/A 
 
 
 

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Key contacts 
 
Sponsor 
University of Leeds 
Medicine and Health Research Governance  
Governance and Compliance  
11-14 Blenheim Terrace  
Leeds  
LS2 9HD  
governance-ethics@leeds.ac.uk  
 
Chief Investigator 
Prof. Manoj Sivan 
Clinical Professor and Consultant in Rehabilitation Medicine  
Leeds Institute of Rheumatic and Musculoskeletal Medicine 
Academic Department of Rehabilitation Medicine 
Level 2, Chapel Allerton Hospital, LS7 4SA 
m.sivan@leeds.ac.uk    
+44(0)113 3922564  
 
Co-Investigator 
Darren C Greenwood BSc MSc PhD 
Senior Lecturer in Biostatistics 
Level 7, LIGHT Laboratories, Clarendon Way, Leeds, LS2 9NL 
 d.c.greenwood@leeds.ac.uk  
+44 (0)113 343 1813 
 
 
Statistician 
Darren C Greenwood BSc MSc PhD 

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Senior Lecturer in Biostatistics 
Level 7, LIGHT Laboratories, Clarendon Way, Leeds, LS2 9NL 
 d.c.greenwood@leeds.ac.uk 
+44 (0)113 343 1813 
 
  
Co-Investigator (PhD Student) 
Mrs Norah Almutairi 
PhD Student 
2nd Floor, Chapel Allerton Hospital Chapeltown Road, Leeds, LS7 4SA  
ml22n2aa@leeds.ac.uk 
+44 (0)1133924396 
 
Trial Co-ordinator  
Ewa Gasior  
Senior Clinical Trials Coordinator / Trauma and Rehab Medicine 
2nd Floor, Chapel Allerton Hospital Chapeltown Road, Leeds, LS7 4SA   
e.a.gasior@leeds.ac.uk  
Tel.: +44 (0)113 39 24734 
 
 

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INVESTIGATOR DECLARATION AND SIGNATURE(S) 
RESTORE-MSK Study, Protocol Version 3, Date: 24/11/2025 
DECLARATION OF PROTOCOL ACCEPTANCE 
I confirm that I am fully informed and aware of the requirements of the protocol and agree 
to conduct the study as set out in this protocol. 
 
 
 
 
 
 
 
  
 
 
 
 
Chief Investigator  
Date 4/12/2025 
 

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Table of Contents 
INVESTIGATOR DECLARATION AND SIGNATURE(S) .......................................................................... 5 
ABBREVIATIONS ................................................................................................................................ 9 
PROTOCOL SYNOPSIS ..................................................................................................................... 10 
SCHEMATIC DIAGRAM  ................................................................................................................... 13 
2. STUDY AIM AND OBJECTIVES ..................................................................................................... 16 
2.1. Study aim ................................................................................................................................. 16 
2.2. Primary objective ..................................................................................................................... 16 
2.3.  Secondary objective(s) ........................................................................................................... 17 
3. STUDY VARIABLES ....................................................................................................................... 17 
3.1. Standard variables ................................................................................................................... 17 
4. STUDY DESIGN ............................................................................................................................ 18 
4.1. 
Study description .......................................................................................................... 18 
4.2. 
Study duration............................................................................................................... 18 
4.3. 
Rationale for the study design ...................................................................................... 18 
5. 
SELECTION AND WITHDRAWAL OF SUBJECTS ...................................................................... 19 
5.1. 
Target population.......................................................................................................... 19 
5.2. 
Estimated number of eligible participants .................................................................... 19 
5.3. 
Eligibility criteria ............................................................................................................ 19 
5.3.1. 
Inclusion criteria ............................................................................................................ 19 
5.3.2. 
Exclusion criteria ........................................................................................................... 19 
5.3.3. 
Exclusions for general safety ......................................................................................... 20 
5.4. 
Withdrawal criteria ....................................................................................................... 20 
6. 
RECRUITMENT, CONSENT AND RANDOMISATION ............................................................... 20 
6.1. 
Recruitment .................................................................................................................. 20 
6.2. 
Consent ......................................................................................................................... 21 
6.3. 
Patients who withdraw consent ................................................................................... 21 
6.4. 
Randomisation process ................................................................................................. 21 
6.5. 
Study blinding ............................................................................................................... 22 
6.6. 
Managing/replacing participants who withdraw early ................................................. 22 
6.7. 
Definition of the end of the trial ................................................................................... 22 
7. 
PATIENT ADVISORY GROUP .................................................................................................. 23 
8. 
DEVICE IMPLEMENTATION AND PARTICIPANT USE .............................................................. 23 
8.1. 
Device training and distribution .................................................................................... 23 
8.2. 
Vagus nerve stimulation ............................................................................................... 23 
8.3. 
Vagus nerve stimulation diary ...................................................................................... 23 

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9. 
METHODS OF ASSESSMENT .................................................................................................. 24 
9.1. 
Subjective assessment variables (Patient Reported Outcomes) .................................. 24 
9.1.1. 
Composite Autonomic Symptom Score (COMPASS-31) ............................................... 24 
9.1.2. 
Brief Pain Inventory – Short Form (BPI-SF) ................................................................... 24 
9.1.3. 
The Hospital Anxiety and Depression Scale (HADS) ...................................................... 24 
9.1.4. 
EuroQol EQ-5D-5L Quality of Life Questionnaire .......................................................... 25 
9.2. 
Objective assessment tests ........................................................................................... 25 
9.2.1. 
NASA 10 Minute lean test ............................................................................................. 25 
9.2.2. 
Theoretical Framework of Acceptability (TFA) / Participant Feedback Questionnaire  25 
10. 
STUDY PROCEDURES BY VISIT ............................................................................................... 26 
10.1. Summary schedule of study assessments ............................................................................. 26 
10.2. Screening visit (Day -x to Day 0) – in person at CAH ............................................................. 27 
10.3. Baseline (Day 0 / Visit 1) - in person at CAH ......................................................................... 27 
10.4. Randomly assigned intervention: GammaCore vagus nerve stimulation / sham vagus nerve 
stimulation (Days 1 – 14) ...................................................................................................................... 27 
10.5. Visit 2 (Day 15, ±2 days) in clinic or remotely (via Teams) in-person or remotely via 
Microsoft Teams ................................................................................................................................... 28 
10.6. Wash-out Period (Day 15–28) ............................................................................................... 28 
10.7. Visit 3 (Day 28, ±2 days) - in person at CAH .......................................................................... 28 
10.8. Randomly assigned intervention: GammaCore vagus nerve stimulation / sham vagus nerve 
stimulation (Day 29-42) ........................................................................................................................ 28 
10.9. Final visit (Day 43, ±2 days in-person or remotely via Microsoft Teams .............................. 28 
10.10. 
Withdrawal .................................................................................................................... 29 
11. 
SAFETY ISSUES ....................................................................................................................... 29 
11.1. 
RISK ASSESSMENT ......................................................................................................... 29 
11.2. 
Defining adverse events (AEs) and serious adverse events (SAEs) ............................... 30 
11.3. 
AEs of special interest ................................................................................................... 30 
11.4. 
Pregnancy ...................................................................................................................... 31 
11.5. 
Defining related and unexpected serious adverse events (RUSAEs) ............................ 31 
11.5.1. 
Recording and reporting of (RU)SAEs ....................................................................... 31 
11.5.2. 
RUSAE reporting requirements ................................................................................. 32 
12. 
URGENT SAFETY MEASURES ................................................................................................. 32 
12.1. 
Serious breaches of protocol ........................................................................................ 33 
13. 
STUDY MANAGEMENT AND ADMINISTRATION .................................................................... 33 
13.1. 
Good clinical practice (GCP) .......................................................................................... 33 
13.2. 
Adherence to protocol .................................................................................................. 33 
13.3. 
Monitoring and audit .................................................................................................... 33 
13.4. 
Study management ....................................................................................................... 33 

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13.4.1. 
Definition of source data .......................................................................................... 33 
13.4.2. 
Source data verification ............................................................................................ 34 
13.4.3. 
Study oversight ......................................................................................................... 34 
13.5. 
Data handling ................................................................................................................ 34 
13.5.1. 
CRF completion ......................................................................................................... 34 
13.5.2. 
Database entry and reconciliation ............................................................................ 34 
13.5.3. 
Screening and enrolment logs .................................................................................. 35 
13.6. 
Archiving and data retention ........................................................................................ 35 
13.7. 
Study suspension, termination and completion ........................................................... 36 
14. DATA EVALUATION ................................................................................................................... 36 
14.1. Responsibilities .................................................................................................................. 36 
14.2. General statistical considerations ..................................................................................... 36 
14.3.  Planned analyses .............................................................................................................. 36 
14.4. Safety analyses .................................................................................................................. 37 
14.5.  Determination of sample size ........................................................................................... 37 
15. ETHICS AND REGULATORY REQUIREMENTS ............................................................................. 37 
15.1. Good Clinical Practice ........................................................................................................ 37 
15.2. Delegation of Investigator duties ...................................................................................... 38 
15.3. Subject information and informed consent ...................................................................... 38 
15.4. Subject confidentiality ....................................................................................................... 39 
15.5. Approval of clinical study protocol and amendments....................................................... 39 
15.6. Protocol amendments ....................................................................................................... 39 
15.7. Ongoing information for Research Ethics Committee ...................................................... 40 
16. FINANCE AND INSURANCE ....................................................................................................... 40 
16.1. Indemnity and insurance ................................................................................................... 40 
16.2. Financial disclosure............................................................................................................ 40 
17. PUBLICATION ............................................................................................................................ 40 
18. 
REFERENCES .......................................................................................................................... 41 
 
 
 
 
 

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ABBREVIATIONS 
Abbreviation 
Term 
AE 
ANS 
AD 
BPI-SF 
Adverse Event 
Autonomic Nervous System 
Autonomic Dysfunction 
Brief Pain Inventory - Short Form 
CI 
CMP 
COMPASS-31 
Chief Investigator 
Chronic Musculoskeletal Pain (CMP) 
Composite Autonomic Symptom Score-31 
CRF 
Case Report Form 
GCP 
Good Clinical Practice 
GP 
HADS 
General Practitioner 
Hospital Anxiety and Depression Scale 
MHRA 
MSK 
NSAID 
nVNS 
TFA 
Medicines And Healthcare Products Regulatory Agency 
Musculoskeletal 
Nonsteroidal Anti-Inflammatory Drug 
Non-invasive Vagus Nerve Stimulation 
Theoretical Framework of Acceptability  
QA 
Quality Assurance 
REC 
RCT 
RUSAEs 
Research Ethics Committee 
Randomized Controlled Trial 
Related and unexpected serious adverse events  
SAE 
Serious Adverse Event 
SD 
Standard Deviation 

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PROTOCOL SYNOPSIS 
GENERAL INFORMATION 
Short Title 
RESTORE-MSK: Reducing Sympathetic Tone with 
nVNS for MSK Pain Relief 
Full Title 
A randomised, single-blind, sham-controlled, crossover 
pilot study assessing the effect of non-invasive vagus 
nerve stimulation (nVNS) on autonomic symptoms 
severity in patients with chronic musculoskeletal pain 
(CMP) with autonomic dysfunction (AD). 
Sponsor 
University of Leeds, Leeds, UK 
Sponsor ID 
2025-NCT57 
MREC No. 
 
Chief Investigator 
Professor Manoj Sivan 
Co-ordinating Centre 
Chapel Allerton Hospital 
National / International 
National 
STUDY INFORMATION 
Phase 
Pilot 
Indication 
chronic musculoskeletal (MSK) pain with autonomic 
dysfunction (AD) 
Design 
a randomised, single-blind, sham-controlled, crossover 
pilot study 
Number of sites 
1 site 
Primary Objective 
• Effect of non-invasive vagus nerve stimulation 
(nVNS) using the GammaCore device on autonomic 
function in patients with chronic musculoskeletal 
(MSK) pain with autonomic dysfunction (AD). 
Secondary Objective(s) 
• Effect of non-invasive vagus nerve stimulation 
(nVNS) using the GammaCore device on pain 
characteristics in patients with chronic 
musculoskeletal (MSK) pain with autonomic 
dysfunction (AD). 
• Effect of non-invasive vagus nerve stimulation 
(nVNS) using the GammaCore device on specific 
AD-related physiological responses, individual's 
quality of life, anxiety, depression, and quality of 
life. 
• Participants' response rate to invitation to 
participate. 
• Acceptability of the intervention. 
Primary Endpoint 
• Severity of autonomic symptoms measured by the 
Composite Autonomic Symptom Score-31 
(COMPASS-31). 

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•  
Secondary Endpoint(s) 
• Physiological response to the lean test, an 
objective measure of autonomic dysfunction 
(scored positive/negative response).  
• Pain severity measured by the Brief Pain Inventory 
- Short Form (BPI-SF). 
• Impact of pain on an individual's life, measured by 
the BPI-SF. 
• Depression and anxiety measured by the Hospital 
Anxiety and Depression Scale (HADS). 
• Quality of life measured by the EQ-5D-5L. 
• Acceptability of the intervention measured by 
Theoretical Framework of Acceptability (TFA) 
based questionnaire (Participant Feedback 
Questionnaire). 
• Response rate to invitation to participate 
measured by number of people consenting divided 
by the number of people invited. 
STUDY TIMELINES 
Expected start date 
02/01/2026 
Subject enrolment phase 
02/01/2026-31/07/2026 
Follow-up duration 
6 weeks 
End of Study Definition 
Last visit of the last participant.  
Expected completion date 
31/7/2026 
STUDY SUBJECT INFORMATION 
Number of study subjects 
12 
Age group of study subjects 
18 years or older 
Inclusion criteria 
a. Individuals diagnosed with musculoskeletal 
(MSK) conditions and currently experiencing 
MSK pain lasting for 12 weeks or longer. 
b. Identified as having autonomic dysfunction (AD) 
if scoring 17 or more on COMPASS-31 
c. Ability to understand and willingness to sign a 
written informed consent document. 

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d. Stated willingness to comply with all study 
procedures and be available for the entire 
duration of the study. 
e. Ability to read and understand English. 
Exclusion criteria 
a. Pregnancy. 
b. Advanced Heart Disease such severe heart 
failure, recent myocardial infarction or ongoing 
investigations for arrhythmias. 
c. Use of another active implantable medical 
device, such as a pacemaker, hearing aid 
implant, or any implanted electronic device. 
d. Use of another muscle stimulating device at the 
same time (e.g., TENS Unit, muscle stimulator) 
or any portable electronic device. 
e. Inability to provide informed consent. 

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SCHEMATIC DIAGRAM  
 
 
 
 

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1. INTRODUCTION 
1.1. Background 
Musculoskeletal pain, often presenting as a chronic condition, affects an estimated 20–33% 
of the global population, according to the World Health Organization (WHO, 2022). This 
equates to approximately 1.75 billion individuals worldwide, with the prevalence continuing 
to increase. In the United Kingdom alone, chronic pain is reported in at least 28 million 
individuals (Fayaz et al., 2016). Chronic musculoskeletal pain (CMP) may arise from various 
etiological factors, including physical injury, muscular overuse, inflammatory processes, or 
degenerative changes. Additionally, CMP is frequently associated with a spectrum of 
comorbid health conditions, such as fibromyalgia, back pain, osteoarthritis, and rheumatoid 
arthritis (Woolf and Pfleger, 2003; Ayis and Dieppe, 2009).  
A growing body of research has highlighted the significant impact of chronic pain as a key 
predictor of functional impairment on a global scale (Rundell et al., 2019; Welsh et al., 2020). 
Moreover, chronic pain constitutes the leading cause of rehabilitation needs worldwide (Cieza 
et al., 2020). According to the Global Burden of Disease Study 2019, several chronic pain 
conditions, including fibromyalgia, neck pain, migraine, osteoarthritis, and other 
musculoskeletal disorders, are among the most significant contributors to years lived with 
disability (YLDs). Among these, chronic low back pain was identified as the single greatest 
cause of YLDs globally (Rice et al., 2016; Anon, 2018).  
Chronic musculoskeletal (MSK) pain is characterised by complex pathophysiology involving 
not only nociceptive and neuropathic mechanisms, but also potential dysregulation of the 
autonomic nervous system (ANS) known as autonomic dysfunction (AD). Emerging evidence 
suggests that autonomic dysfunction (AD), described as altered sympathetic nervous system 
reactivity (either exaggerated or blunted responses to stimuli) has been implicated in the 
pathogenesis of muscle pain (Kalezic, 2006; Yater et al., 2021), linking autonomic 
dysregulation directly to chronic pain. Characterised by symptoms such as orthostatic 
intolerance, palpitations, gastrointestinal dysmotility, and fatigue, autonomic dysfunction 
may co-occur in a significant proportion of patients with chronic MSK pain, further 
exacerbating symptom burden and reducing quality of life (Raj et al., 2000; Furlan et al., 2005; 
Sjors et al., 2009). Given limited evidence on the positive effects of conventional 
pharmacological treatments on managing chronic MSK pain management in patients with 
autonomic dysfunction (Koechlin et al., 2019), non-pharmacological interventions targeting 
central mechanisms of pain modulation are gaining increasing attention. One such modality 
is non-invasive transcutaneous vagus nerve stimulation (nVNS), a form of neuromodulation, 
which has been studied for its analgesic properties based on the electrical stimulation of the 
vagus nerve to modulate autonomic tone and central pain processing. 
Non-invasive vagus nerve stimulation (nVNS) offers a non-pharmacological means to 
influence autonomic tone and central pain processing. With the new development of 
implantable and non-invasive vagus nerve stimulators, recent studies have demonstrated the 

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analgesic effect of vagal nerve stimulation (VNS) across a range of chronic pain conditions 
including trigeminal allodynia, fibromyalgia, chronic pelvic pain, cluster headache, and 
migraines, with preliminary data indicating potential benefits for alleviating chronic pain and 
associated dysautonomia (Multon and Schoenen, 2005; Chakravarthy et al., 2015; Napadow 
et al., 2012; Garcia et al., 2017). Although the exact mechanism by which VNS modulates 
chronic pain has not yet been clearly established, emerging evidence suggests that its effects 
may be mediated through anti-inflammatory pathways, in combination with modulation of 
both central and peripheral pain processing mechanisms (Shao et al., 2023; Liu et al., 2024). 
These findings have contributed to the growing interest in the therapeutic potential of non-
invasive vagus nerve stimulation (nVNS) leading to the development and commercialization 
of several medical devices in this domain.  
The GammaCore® device (electroCore LLC, Basking Ridge, NJ, USA) is a non-invasive vagus 
nerve stimulator (nVNS) designed to deliver low-voltage electrical stimulation to the cervical 
branch of the vagus nerve. Initially approved in Europe with Conformité Européenne (CE) 
marks for the treatment of primary headaches, GammaCore received FDA clearance in the 
United States for the acute treatment of episodic cluster headache in 2017 and for acute 
migraine in 2018 (Mwamburi et al., 2018). In the UK, the National Institute for Health and 
Care Excellence (NICE) evaluated GammaCore’s clinical effectiveness and cost impact as a 
handheld, patient-controlled device for both the treatment and prevention of cluster 
headache, supporting its use within the NHS for selected patients (O’Connell et al., 2021).  
The efficacy of GammaCore device in managing migraine has been demonstrated in several 
clinical trials. The PRESTO randomized controlled trial (RCT) found that GammaCore 
significantly improved pain-free response rates compared to sham stimulation at 30- and 60-
minutes post-treatment (Tassorelli et al., 2018). In one of the largest randomized sham-
controlled studies for acute cluster headache treatment, nVNS provided significant, clinically 
meaningful, rapid, and sustained benefits for episodic cluster headache (Silberstein et al., 
2016). Additional open-label studies support its analgesic benefit, demonstrating rapid pain 
relief and improved quality-of-life outcomes in both acute and preventive settings (Barbanti 
et al., 2015; Goadsby et al., 2018). Across trials, GammaCore was consistently reported safe 
and well tolerated, with adverse events being mild and involving local discomfort, skin 
irritation, transient muscle stiffness, and pain responsive to the nonsteroidal anti-
inflammatory drug (NSAID) treatment (Chakravarthy et al., 2015; Mwamburi et al., 2018). 
Despite encouraging results in headache and related conditions, the therapeutic potential of 
nVNS in individuals with chronic MSK pain and autonomic dysfunction remains 
underexplored. The aim of this trial is to generate important insights into the potential of 
nVNS as a non-pharmacological treatment option targeting both autonomic and pain-related 
mechanisms. In the proposed study, we hypothesized that a non-invasive vagus nerve 
stimulator (nVNS) with the use of the GammaCore medical device could be effective as a 

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treatment to alleviate pain and improve quality of life in patients with chronic musculoskeletal 
(MSK) pain with autonomic dysfunction (AD).  
Consequently, the primary objective of this study is to evaluate the effect of non-invasive 
vagus nerve stimulation (nVNS) using the GammaCore® device on autonomic function in 
individuals with chronic musculoskeletal (MSK) pain and autonomic dysfunction (AD). 
Secondary objectives include assessing the impact of nVNS on pain characteristics, specific 
AD-related physiological responses, quality of life, anxiety, and depression. Additionally, the 
study aims to determine the response rate to the invitation to participate and evaluate the 
acceptability of the intervention. 
1.2. 
Rationale for the proposed study 
Autonomic dysfunction (AD) is increasingly recognised as a contributing factor in chronic 
musculoskeletal pain (CMP), yet its role remains poorly understood and largely overlooked in 
current treatment approaches. Conventional therapies for CMP often fail to address the 
autonomic component, limiting their effectiveness in patients with coexisting AD. Non-
invasive vagus nerve stimulation (nVNS), delivered via the GammaCore device offers a 
transformative approach based on a novel, dual-target intervention with the potential to 
modulate both autonomic and pain pathways. Investigating this approach may uncover a 
promising therapeutic strategy for a complex and underserved patient population. 
2. STUDY AIM AND OBJECTIVES 
2.1. Study aim 
To evaluate the effect of non-invasive vagus nerve stimulation (nVNS), delivered via the 
GammaCore device, on pain and symptoms of dysautonomia in population of patients with 
chronic musculoskeletal (MSK) pain with autonomic dysfunction (AD), in view of establishing 
feasibility and proof of concept for a larger randomised controlled trial. 
2.2. Primary objective 
To investigate the effect of non-invasive vagus nerve stimulation (nVNS) on autonomic 
function in patients with chronic musculoskeletal (MSK) pain with autonomic dysfunction 
(AD).  
This objective will be achieved through using an adaptive Composite Autonomic Symptom 
Score-31 (COMPASS-31) to assess the severity of autonomic symptoms before and after 
nVNS. 

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2.3.  Secondary objective(s) 
2.3.1. To investigate the physiological response to nVNS in patients with chronic 
musculoskeletal (MSK) pain and autonomic dysfunction (AD) 
This objective will be achieved through using the following methods: 
(1) physiological response to NASA lean test, an objective measure of autonomic 
dysfunction (scored positive/negative response)  
 
2.3.2. Study the impact of Reducing Enduring Sympathetic Tone with nVNS on pain 
characteristics, anxiety and depression level, and quality of life in patients with chronic 
musculoskeletal (MSK) pain and autonomic dysfunction (AD). 
 This objective will be achieved through using the following methods: 
(1a) pain severity measured by the Brief Pain Inventory - short form (BPI-SF),  
(1b) impact of pain on an individual's life, measured by the BPI-SF,  
(2a) anxiety measured by the Hospital Anxiety and Depression Scale (HADS),  
(2b) depression measured by Hospital Anxiety and Depression Scale (HADS),  
(3) quality of life measured by the EQ-5D-5L. 
 
2.3.3. Participants’ response rate to invitation to participate 
This objective will be measured by number of people consenting divided by the 
number of people invited. 
 
2.3.4. Acceptability of the intervention 
This objective will be measured by the Theoretical Framework of Acceptability (TFA) / 
Participant Feedback Questionnaire, which has been developed as a generic 
questionnaire that can be adapted to assess acceptability of any healthcare 
intervention. 
3. STUDY VARIABLES 
3.1. Standard variables 
• COMPASS 31 score 
• Physiological response to NASA Lean Test 
• Pain severity measured by BPI-SF  

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• Impact of pain on individual's life measured by BPI-SF  
• Anxiety measured by HADS 
• Depression measured by HADS 
• Quality of life measured by the EQ-5D-5L 
• Participants’ response rate measured by number of people consenting divided by the 
number of people invited 
• Acceptability of the intervention measured by adapted Theoretical Framework of 
Acceptability (TFA) / Participant Feedback Questionnaire 
• Patient demographics which include (age group, gender, pre-existing conditions and 
comorbidities, medical diagnosis, disease duration, and medication history) 
 
 
4. STUDY DESIGN 
4.1. Study description 
This study is an investigator-initiated, randomised, single-blind, sham-controlled, crossover 
clinical trial assessing the effect of nVNS for pain treatment in patients with chronic 
musculoskeletal (MSK) disease with autonomic dysfunction (AD). The study will be conducted 
at Chapel Allerton Hospital, Leeds from 2nd January 2026 to 31 of July 2026. As active nVNS 
treatment, an FDA approved medical device (GammaCore-S, ElectroCore LLC, Basking Ridge, 
New Jersey, USA) will be used, and the sham devices were identical in appearance 
(ElectroCore LLC, Basking Ridge, New Jersey, USA). 
 
4.2.  Study duration 
The time frame of the study starts from recruiting the participants from the Leeds Teaching 
Hospitals to the final clinic visit of the last recruited participant to apply the Lean Test. 
 
4.3. Rationale for the study design  
This study is a randomised, single-blind, sham-controlled, crossover pilot trial designed to 
evaluate the feasibility and preliminary efficacy of non-invasive vagus nerve stimulation 
(nVNS) using the GammaCore device in individuals with chronic musculoskeletal pain (CMP) 
and co-existing autonomic dysfunction (AD). Autonomic dysregulation has been implicated in 
the pathophysiology of chronic pain, with studies showing altered sympathetic and 
parasympathetic activity, particularly in conditions like fibromyalgia and chronic fatigue 
syndrome (Chakravarthy et al., 2015). Vagus nerve stimulation has been shown to modulate 
autonomic output, reduce inflammation, and influence central pain pathways (Chakravarthy 
et al., 2015; Muthulingam et al., 2023).  
A randomised, sham-controlled design will help to determine the specific effects of nVNS 
beyond placebo and natural symptom fluctuation. The crossover format will allow each 

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participant to serve as their own control, enhancing statistical efficiency and reducing 
between-subject variability—particularly important in small feasibility studies. With the 
adequate washout period, this design aims to minimise carryover effects and is well-suited 
for early-phase investigations. Finally, blinding of participants will minimise expectation bias.  
As a pilot trial, this study aims to assess the feasibility of recruitment and randomisation, the 
acceptability of the intervention in this population and setting, and the completeness of 
outcome data. The study will also explore potential signals of benefit, including changes in 
autonomic symptoms and pain, to determine whether larger-scale evaluation is warranted. 
 
5. SELECTION AND WITHDRAWAL OF SUBJECTS 
5.1. Target population 
Individuals with chronic musculoskeletal pain who have a diagnosed autonomic dysfunction 
(dysautonomia). 
5.2. Estimated number of eligible participants 
We plan to enrol 12 participants in this feasibility study, all of whom have experienced 
musculoskeletal pain on most days for at least 12 weeks, in line with the ICD-11 criteria for 
Chronic Pain (WHO; Treede et al., 2015). Eligible patients must also score ≥ 17 on the 
COMPASS-31 questionnaire to be classified as having autonomic dysfunction (AD). 
5.3. Eligibility criteria 
5.3.1. Inclusion criteria 
A. Individuals diagnosed with musculoskeletal (MSK) conditions and currently 
experiencing MSK pain lasting for 12 weeks or longer. 
B. Identified as having autonomic dysfunction (AD) based on COMPASS 31 score (17 or 
more  
C.  Ability to understand and willingness to sign a written informed consent document. 
D.  Stated willingness to comply with all study procedures and be available for the entire 
duration of the study. 
E.  Ability to read and understand English. 
 
5.3.2. Exclusion criteria 
A. Pregnancy. 
B. People diagnosed with Advanced Heart Disease such severe heart failure, recent 
myocardial infarction or ongoing investigations for arrhythmias. 
C. Unable to provide informed consent. 

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D. Patients who have an active implantable medical device, such as a pacemaker, hearing 
aid implant, or any implanted electronic device. 
E. Are using another device at the same time (e.g., TENS Unit, muscle stimulator) or any 
portable electronic device. 
 
5.3.3. Exclusions for general safety 
None further to the defined exclusion criteria above. 
5.4. Withdrawal criteria 
Participants have the choice to withdraw from the study at any time, without any negative 
impact on their current or future treatment. If they choose to do so, any data already provided 
will be used in the study. No additional data will be collected, and there will be no further 
research procedures carried out on or in relation to the participant. 
 
6. RECRUITMENT, CONSENT AND RANDOMISATION 
6.1. Recruitment 
The Leeds Institute of Rheumatic and Musculoskeletal Medicine will be contacted to provide 
access to their facility and clinics for identification of potential participants. After the approval 
and clinics allocation, summary of the study purpose will be sent to the direct care team in 
each clinic via email, an invitation letter from the research team, the PIS and the consent form 
will be attached to the same email.  
If the participant is identified through a clinic list as a potential participant by clinical 
colleagues based at the site, the clinical team will perform a face-to-face approach in the 
clinic. In the first contact the patient will be provided with a brief explanation of the study. 
This will include detailed information about the rationale, design and personal implications of 
the study. Having been provided with the PIS and verbal information regarding the study 
procedures, patients will have at least 24 hours to consider participation before they will be 
approached by authorised clinician to obtain consent.  
Patients will be contacted by the study team at least 24 hours following the initial approach 
to confirm their interest in the study. If a potential participant expresses interest, they will be 
invited to the clinic, where informed consent will be obtained. On the same visit, the potential 
participant will complete the COMPASS-31 questionnaire, which will be used to assess 
autonomic symptom severity and determine eligibility by categorising participants into high 
or low dysautonomia groups. Eligible participants will then either proceed on the same day 
or be invited for a subsequent visit to complete the study surveys (BPI-SF, HADS, and EQ-5D-
5L) and undergo the NASA Lean Test. They will also receive training on how to use the 
GammaCore device and they will be provided with the device and a stimulation diary.  

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6.2. Consent 
Informed consent will be obtained prior to the participant undergoing any study specific 
procedures. The right of potential participants to refuse consent with or without reason will 
be respected. Consent will be obtained by an authorised clinician who has signed the study 
delegation log. Once consent is obtained, a copy of the consent form will be given to the 
participant, one filed in the study files, and one in the hospital notes.  
6.3. Patients who withdraw consent 
The right of participants to refuse participation without giving reasons will be respected. 
Further, participants will remain free to withdraw from the study at any time without giving 
reasons and without prejudicing any further treatment.  
The investigator may discontinue a participant from the study at any time if the investigator 
considers it necessary for any reason including:  
• Ineligibility (either at the eligibility assessment or arising during the study) 
• Significant protocol deviation 
• Consent withdrawn 
• Death 
If participants withdraw from the study, any data already collected will be retained and be 
used in the study. No further data would be collected, or any other research procedures 
carried out on or in relation to the participant. 
6.4. Randomisation process  
This is a randomised, sham-controlled, crossover pilot study. Each participant will receive 
both the active and sham interventions in a randomly allocated order. Participants will be 
randomly assigned to one of two treatment sequences: 
• Sequence A: Active stimulation followed by sham stimulation. 
• Sequence B: Sham stimulation followed by active stimulation 
A washout period of 2 weeks will be included between treatment periods to minimise 
carryover effects. 
Randomisation will follow a restricted approach with stratification to ensure balanced 
allocation across sequences, and simple randomisation applied within each stratum. 
Stratification will be based on baseline COMPASS-31 autonomic profile score, split into high 
and low dysautonomia group at <40/40+, the median of eligible participants identified in our 
previous study of autonomic dysfunction in people living with chronic MSK pain. The 
randomisation schedule will be generated in advance by the trial statistician using a 
computer-based algorithm and implemented via REDCap, a secure web-based data capture 
system. 

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Following eligibility confirmation and informed consent, participants will be randomised by 
the enrolling research team member using simple randomisation within strata, with strata 
defined by baseline COMPASS-31 score <40 vs 40+, which is the median identified in 
participants meeting the eligibility criteria in our previous study. The randomisation list will 
be generated in Stata. The randomisation list will be concealed from investigators in contact 
with participants and implemented through appropriate software such as the REDCap 
randomisation module. Allocation will remain concealed from the study team until 
randomisation is triggered. 
Metadata related to randomisation (assigned sequence, treatment received) will be collected 
to evaluate feasibility and inform the design of a future definitive trial. 
6.5. Study blinding  
This is a single-blind study, where participants involved in the intervention delivery will be 
blinded to the treatment allocation.  
Blinding will be maintained by Norah Almutairi at clinic visits 1 and 3 by adjusting the device’s 
stimulation amplitude to produce a low-frequency signal. This signal will be perceptible on 
the skin but will not activate the vagus nerve or cause the muscle contractions typically 
associated with higher-intensity active stimulation. Previous studies comparing nVNS 
treatment with a sham device—where the sham was identical in appearance but delivered 
no active signal—have demonstrated that this approach provides an adequate control for 
blinding (Silberstein et al., 2016; Tassorelli et al., 2018). 
To mitigate the risk of unblinding, as participants may notice reduced muscle contraction, a 
blinding assessment will be built into the study. At study completion, participants will be 
asked to indicate whether they believe they received active or sham treatment in each stage 
of the intervention. 
Any incidents of unblinding, intentional or accidental, will be documented and reported. 
To evaluate the success of blinding, participants will be asked to indicate which treatment 
(active or sham) they believe they received. This blinding poll will be completed on the final 
day of treatment and documented in the follow-up CRF. 
6.6. Managing/replacing participants who withdraw early 
Participants who withdraw from the trial early will not be replaced.  
6.7. Definition of the end of the trial 
Study completion will be defined as the time at which the last data item has been locked for 
the last recruited participant. 

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7. PATIENT ADVISORY GROUP 
A Patient Advisory Group was established, comprising patients diagnosed with chronic 
musculoskeletal (MSK) conditions and autonomic dysfunction (AD), identified through Chapel 
Allerton Hospital, the Institute of Rheumatic and Musculoskeletal Medicine, and the 
outpatient clinic. The group reviewed the patient-facing documents (Participant Information 
Sheet and Consent Form), and amendments were made based on their feedback. 
 
8. DEVICE IMPLEMENTATION AND PARTICIPANT USE 
8.1. Device training and distribution 
Following informed consent, eligible participants will either proceed on the same day or be 
invited for a subsequent visit to receive training on how to use the GammaCore device and 
they will be provided with the device and a stimulation diary for home use.  
8.2. Vagus nerve stimulation 
Participants will self-administer the GammaCore® device using a small amount of conduction 
gel applied to the stimulation surfaces. The device is positioned bilaterally under the angle of 
the mandible, guided by the carotid pulse. Each stimulation consists of a two-minute 
application per side. Participants will complete two stimulations per day—morning and 
evening—for two weeks. Afterward, they will have a two-week break. This will be followed 
by additional two weeks of daily use of the device as per the initial schedule. Stimulation is 
painless and may produce a mild buzzing sensation. The stimulation schedule is identical 
across study arms. 
8.3. Vagus nerve stimulation diary 
Participants will be asked to record their compliance to the intervention schedule using a 
stimulation diary. They will indicate their compliance to each stimulation sequence .  Diaries 
will be collected after the first 2 weeks and again following the final stimulation sequence, 
with the data transcribed onto the Follow-up CRF. 
 
 
 
 
 
 

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9. METHODS OF ASSESSMENT 
9.1. Subjective assessment variables (Patient Reported Outcomes) 
9.1.1. Composite Autonomic Symptom Score (COMPASS-31)   
The COMPASS-31 self-administered instrument which commonly employed for evaluating 
and measuring the intensity of autonomic dysfunction symptoms in patients (Sletten et al., 
2012). It consists of 31 items that are categorized into six categories, each indicating a specific 
element of autonomic function. These domains include orthostatic intolerance, vasomotor, 
secretomotor, gastrointestinal, bladder, and pupillomotor symptoms. The questionnaire 
assigns a score to each item based on its severity and frequency, resulting in a total score that 
ranges from 0 to 100. Greater scores suggest a higher degree of autonomic dysfunction (Puri 
& Lee, 2022). It will be used in this study to have an insight into the prevalence and impact of 
autonomic symptoms in various populations.  
 
9.1.2. Brief Pain Inventory – Short Form (BPI-SF) 
The Brief Pain Inventory–Short Form (BPI-SF) is a shortened version of the BPI that requires 
no more than five minutes to complete. It is an essential instrument for evaluating the 
intensity and impact of pain on daily activities. This brief survey requires participants to assess 
their pain level on a scale from 0 (no pain) to 10 (most extreme pain). it captures pain at its 
worst, least, average, and at the moment of completing the survey. In addition to assessing 
pain severity, the BPI-SF evaluates the impact of pain on many aspects of the individual's life 
such as general activity, mood, walking, work, social interactions, sleep, and enjoyment of 
life, using the same 0 to 10 scale. The average of the four pain severity ratings provides a pain 
severity score, and similarly, the average of the seven pain interference ratings offers a pain 
interference score. These averaged scores offer a detailed perspective on the impact of pain 
on an individual's life, assisting healthcare providers in developing customized pain treatment 
strategies.  
 
9.1.3. The Hospital Anxiety and Depression Scale (HADS) 
The HADS is a reliable instrument for identifying depression and anxiety in a general medical 
population of patients (Zigmond & Snaith, 1983). It’s an effective tool that contains only 7 
questions that take roughly 2–5 minutes to complete. Bjelland et al. (2002) conducted a 
review and concluded that HADS enables healthcare professionals to categorize the intensity 
of symptoms related to anxiety and depression in the general population and patients with 
different medical conditions. Individuals scoring below 7 on HADS are known as non-cases, 
while those scoring between 8 and 10 are classified as mild, 11–14 as moderate, and 15–21 
as severe (Bjelland et al., 2002).  
 

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9.1.4. EuroQol EQ-5D-5L Quality of Life Questionnaire 
The EuroQol EQ-5D-5L is a widely validated, standardised instrument developed by the 
EuroQol Group to measure generic health status in clinical and economic evaluations 
(Herdman et al., 2011). The instrument includes five dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension is rated by the 
participant on five levels of severity: no problems, slight problems, moderate problems, 
severe problems, and extreme problems. Participants select one level per domain to describe 
their current health state. Responses are summarised descriptively, with the distribution of 
responses within each domain reported. In addition, domain scores are combined into a five-
digit code representing the participant’s overall health profile (e.g. 12345), which is converted 
into a single index value using the UK EQ-5D-5L value set (Devlin et al., 2018).  
 
9.2. Objective assessment tests 
9.2.1. NASA 10 Minute lean test  
The lean test is a clinical test performed to evaluate Autonomic Nervous System (ANS) 
dysfunction, specifically in the context of diagnosing conditions like Postural Orthostatic 
Tachycardia Syndrome (POTS) or other forms of orthostatic intolerance (Lee et al., 2020). The 
test begins with the participant lying on the exam table or bed. The participant heart rate and 
blood pressure are measured in this position to establish baseline values. Following that, the 
participant asked to stand up without support and remain still. The heart rate and blood 
pressure are reassessed periodically, usually at 2, 5, and 10-minute intervals.  Then, the 
participant is instructed to lean against a wall while keeping heels about 6 inches away from 
it. The back and elbows are allowed to touch the wall. This posture minimizes the muscular 
effort required for standing, which can help isolate the autonomic contribution to standing. 
While leaning, heart rate and blood pressure are continuously monitored. The positive sign 
during the Lean Test is a significant increase in heart rate upon standing, which doesn't 
decrease upon leaning. For a POTS diagnosis, an increase of more than 30 beats per minute 
(or more than 40 beats per minute in adolescents) without a substantial drop in blood 
pressure is generally considered significant. If heart rate increases significantly upon standing 
but decreases or normalizes upon leaning, it may suggest that orthostatic tachycardia is 
related more to other non-autonomic factors.  
 
9.2.2. Theoretical Framework of Acceptability (TFA) / Participant Feedback 
Questionnaire  
The acceptability of the medical device intervention will be measured using an adapted 
version of the Theoretical Framework of Acceptability (TFA) questionnaire developed by 
Sekhon et al. (2022). The TFA is a validated, theory-informed model that defines acceptability 
as a multifaceted construct comprising seven components: affective attitude, burden, 

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ethicality, intervention coherence, opportunity costs, perceived effectiveness, and self-
efficacy. This framework enables assessment of both prospective and retrospective 
acceptability from the perspective of intervention recipients and providers across different 
stages of intervention delivery. A generic TFA-based questionnaire was developed and pre-
validated using a systematic 5-step method, including item generation, discriminant content 
validation, and stakeholder feedback. For this study, the questionnaire will be tailored to 
reflect participant experience of the use of GammaCore medical device. Each construct will 
be assessed using a single-item measure alongside a general acceptability item, using a 5-
point Likert scale. This approach offers a structured yet flexible method to identify potential 
barriers and inform future optimisation of the intervention (Sekhon et al., 2022).  
 
10. STUDY PROCEDURES BY VISIT 
10.1. Summary schedule of study assessments 
Specific Activity       
Duration 
(Minutes) 
Undertaken 
by                      
Day -x  
Day 0 
Days 
1-14 
Day 15  
(+/- 2 
days) 
Days 
15-28 
Day 28  
(+/- 2 
days) 
Days   
29-42 
Day 43 
  
  
  
Screen 
Baseli
ne/ 
Visit 1 
Visit 2  
  
Visit 3 
Final Visit 
 
Identification of 
chronic pain 
participants 
  
Local 
Outpatient 
Staff 
✔ 
 
 
 
 
 
 
 
Approach of 
potential 
participants 
  
Local 
Outpatient 
Staff 
✔ 
 
 
 
 
 
 
 
Check eligibility 
  
Research 
Team 
✔ 
 
 
 
 
 
 
Trial consent 
30 
Research 
Team 
✔ 
 
 
 
 
 
 
COMPASS-31 
questionnaire 
5 
Research 
Team + 
participant 
✔ 
 
 
✔ 
 
 
✔ 
 
 
✔ 
 
Study survey 
(BPI-SF, HADS, 
EQ-5D-5L)  
15 
Research 
Team + 
participant 
 
✔ 
 
✔ 
 
✔ 
 
✔ 
NASA lean test 
10 
Research 
Team + 
participant 
 
✔ 
 
✔ 
 
✔ 
 
✔ 
Theoretical 
Framework of 
Acceptability 
(TFA) / Participant 
Feedback 
Questionnaire 
10 
Research 
Team + 
participant 
 
 
 
 
 
 
 
✔ 
Device training 
20 
Research 
Team 
 
✔ 
 
 
 
 
 
 
Device 
distribution  
- 
Research 
Team 
 
✔ 
 
 
 
 
 
 

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Randomly 
assigned 
intervention 
(GammaCore 
vagus nerve 
stimulation / 
sham vagus nerve 
stimulation) 
2 
Participant  
 
 
✔ 
 
 
 
✔ 
 
Stimulation diary 
2 
Participant  
 
 
✔ 
 
 
 
✔ 
 
Wash-out period 
– 2 weeks 
 - 
Participant  
 
 
 
 
✔ 
 
 
 
 
 
10.2. Screening visit (Day -x to Day 0) – in person at CAH  
During the screening visit, potential participants will be identified as either chronic pain 
patients with dysautonomia or chronic pain patients without dysautonomia. Written 
informed consent will be obtained. Participants will complete Composite Autonomic 
Symptom Score (COMPASS-31) questionnaire. Eligibility will be assessed and confirmed. 
Identification procedures and consent will not be included in the CRF, as they are not intended 
for data analysis; however, the score of COMPASS-31 questionnaire and the eligibility 
assessment will be recorded in the CRF. 
 
10.3. Baseline (Day 0 / Visit 1) - in person at CAH  
 At baseline, participants will complete the study survey, which consists of: 
• Brief Pain Inventory – Short Form (BPI-SF) 
• Hospital Anxiety and Depression Scale (HADS) 
• EuroQol EQ-5D-5L Quality of Life Questionnaire 
They will also undergo the NASA Lean Test. These assessments will be recorded in the CRF 
and used for data analysis. Device training and distribution will take place during this visit; 
however, these are procedural activities only and will not be recorded in the CRF. 
 
10.4. Randomly assigned intervention: GammaCore vagus nerve stimulation 
/ sham vagus nerve stimulation (Days 1 – 14)  
Participants will perform twice daily vagus nerve stimulation using the GammaCore device 
and will record their use in a stimulation diary. Both activities will be captured in the CRF and 
included in the data analysis. 
 

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10.5. Visit 2 (Day 15, ±2 days) in clinic or remotely (via Teams) in-person or 
remotely via Microsoft Teams 
At this visit, participants will complete the COMPASS-31 questionnaire and the study surveys 
(BPI-SF, HADS, and EuroQol EQ-5D-5L).  
For in-person visits: Questionnaires can be completed online via REDCap before the 
appointment or on paper at the clinic. The NASA Lean Test will be performed at the clinic 
under researcher supervision. 
For remote visits: Participants will receive a secure REDCap link to complete the 
questionnaires online prior to the Microsoft Teams appointment. Participants will perform 
the NASA Lean Test at home using the blood pressure monitor provided at baseline, guided 
by the researcher via video call. 
All assessments will be recorded in the CRF for data analysis. 
10.6. Wash-out Period (Day 15–28) 
 A two-week wash-out period will follow, during which no study interventions will be 
undertaken. This period is procedural only and will not be recorded in the CRF.  
 
10.7. Visit 3 (Day 28, ±2 days) - in person at CAH  
At this visit, participants will complete the COMPASS-31 questionnaire and the study 
surveys (BPI-SF, HADS, and EuroQol EQ-5D-5L). Questionnaires can be completed online via 
REDCap before the appointment or on paper at the clinic. Participants will also repeat the 
NASA Lean Test at the clinic under researcher supervision. 
The GammaCore device will be adjusted by the researcher to the alternate setting (active or 
sham) for the second treatment phase to maintain blinding. This visit must be conducted in 
person at Chapel Allerton Hospital to allow for device adjustment. 
All assessments will be recorded in the CRF for data analysis.. 
 
10.8. Randomly assigned intervention: GammaCore vagus nerve stimulation 
/ sham vagus nerve stimulation (Day 29-42) 
Participants will perform twice daily sham vagus nerve stimulation and record usage in a 
stimulation diary. All procedures will be documented in the CRF and included in the analysis. 
 
10.9. Final visit (Day 43, ±2 days in-person or remotely via Microsoft Teams 

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At the final visit, participants will complete the COMPASS-31 questionnaire and the study 
surveys (BPI-SF, HADS, and EuroQol EQ-5D-5L). In addition, they will complete the Theoretical 
Framework of Acceptability (TFA) / Participant Feedback Questionnaire and a blinding 
assessment questionnaire. 
For in-person visits: Questionnaires can be completed online via REDCap before the 
appointment or on paper at the clinic. The NASA Lean Test will be performed at the clinic 
under researcher supervision. 
For remote visits: Participants will receive a secure REDCap link to complete the 
questionnaires online prior to the Microsoft Teams appointment. Participants will perform 
the NASA Lean Test at home using the blood pressure monitor provided at baseline, guided 
by the researcher via video call. 
All assessments will be recorded in the CRF for data analysis. 
 
10.10. Withdrawal  
 In the event of withdrawal, participants will be asked to complete the same assessments 
scheduled for the completion visit, that is COMPASS-31 questionnaire, study survey (BPI-SF, 
HADS, EuroQol EQ-5D-5L), the NASA Lean Test, and the Theoretical Framework of 
Acceptability (TFA) / Participant Feedback Questionnaire. Data from these assessments will 
be recorded in the CRF and included in the analysis. 
 
11. SAFETY ISSUES 
11.1. RISK ASSESSMENT 
 
Risk  
Likelihood  
Severity  
Mitigation strategy  
Device-related 
adverse events 
(tingling, skin 
redness, headache, 
dizziness) 
Moderate 
Low 
• Comprehensive device training at baseline 
• Written instructions provided 
• Daily diary to monitor symptoms 
• Contact details provided for concerns 
Incorrect device use 
Low 
Low 
• Face-to-face training with demonstration 
• Written instructions  
• Practice session at baseline 
• Follow-up at Visit 2 to check technique 
NASA Lean Test - 
dizziness or fainting 
Low 
Low 
• Test performed under supervision at 
baseline 
• Participants can stop at any time 
• For home tests: participants instructed to 

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have support nearby 
• Clear stopping criteria provided 
Distress from 
questionnaires 
(HADS - mental 
health questions) 
Low 
Low 
• Participants informed in PIS about 
questionnaire content 
• Can decline to answer any question 
• Can withdraw at any time 
• Contact details provided for concerns 
11.2. Defining adverse events (AEs) and serious adverse events (SAEs) 
An adverse event (AE) refers to any untoward medical occurrence in a participant, which does 
not necessarily have a causal relationship with the research procedure. 
A serious adverse event (SAE) is an adverse event which is defined as serious, i.e. that it: 
• Results in death. Death may occur as a result of the basic disease process. 
Nevertheless, all deaths occurring within 30 days of the patient’s final research clinic 
appointment must be treated as an SAE and reported as such. All deaths which may 
be considered as related to the trial agent, regardless of the interval, must be treated 
as a SAE and reported as such. 
• Is life-threatening. 
• Requires inpatient (overnight) hospitalization or prolongation of an existing 
hospitalization. 
• Results in a persistent or significant disability or incapacity. 
• Results in a congenital anomaly or birth defect. 
• Additionally, important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered SAEs when, based on 
appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  
• Any other significant clinical event, not falling into any of the criteria above, but 
which in the opinion of the Investigator requires reporting. 
11.3. AEs of special interest 
Only relevant adverse events (AEs) will be recorded in the (e)CRF. The following are 
examples of AEs that are NOT considered relevant and will NOT be recorded: 
• Pre-existing condition that does not worsen. 
• Planned hospitalisations for pre-existing conditions. 
• Events that happen before a participant gives informed consent. 
• Medical events related to the chronic MSK condition that do not put the patient at 
risk (e.g., severe back pain). 
• Any abnormal lab results related to co-morbidities the participant has. 

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11.4. Pregnancy 
As pregnancy is an exclusion criterion for this study, participants who become pregnant 
during the trial will be withdrawn immediately. All pregnancies will be followed up until birth. 
Should there be a congenital anomaly or birth defect, this will be reported as an SAE to the 
main REC and Sponsor if, in the opinion of the chief investigator, the congenital anomaly or 
birth defect is related to the research treatment or procedure. 
11.5. Defining related and unexpected serious adverse events (RUSAEs) 
A serious adverse event suspected to have a reasonable causal relationship to the study 
treatment or procedure which is unexpected i.e. where the nature or severity is inconsistent 
with the available information relating to the treatment or procedure or is not listed in this 
protocol as an expected occurrence is subject to expedited reporting.  
11.5.1. 
Recording and reporting of (RU)SAEs 
Relevant adverse events (AEs) will be collected and recorded on the eCRF from the signing of 
the informed consent form until 30 days after the final study appointment. AEs will be 
assessed and recorded at every study visit. 
Determination of SAEs should be based on signs or symptoms detected during physical 
examination and clinical evaluation of the participant. Signs and symptoms must be recorded 
using standard medical terminology. Participants considered incapable of giving consent will 
not be included in this study. 
SAEs will be collected from the signing of the informed consent form until 30 days after the 
final study appointment. The Investigator must instruct participants to report all AEs and SAEs 
during this time period. Participants will be required to promptly report any suspected serious 
adverse events (SAEs) to an investigator via telephone. In the event of a suspected SAE, the 
participant will be requested to return to the study site for further clinical evaluation and 
appropriate management. 
During the time period specified above, the investigator will: 
• Record all AEs and SAEs on source documents 
• Record all AEs and SAEs in the eCRF for participants who are not screen failures 
• Report all RUSAEs on a 'Serious Adverse Event report form for non-CTIMPs', available 
from the NRES website, and send to the main REC for the trial 
All SAEs and RUSAEs will be reviewed by the Chief Investigator within 24 hours. 
The following will be collected and reported to the Sponsor office (governance-
ethics@leeds.ac.uk) within 1 working day of the research team becoming aware of the 
event:    
• 
Full details in medical terms    
• 
Event duration (start and end dates, if applicable)   

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• 
Action taken   
• 
Outcome   
• 
Seriousness criteria   
• 
Causality (i.e. relatedness to research investigation), in the opinion of the 
investigator whether the event would be considered expected.   
The Sponsor will maintain detailed records of the SAEs reported by an investigator in 
accordance with good clinical practice and applicable local regulations. 
The Investigator will follow up on all SAEs until the events have subsided, returned to baseline, 
or, in case of permanent impairment, until the condition has stabilized. SAEs that are (or 
develop into) chronic conditions will be followed up until it is established that the condition 
is chronic at which point no further follow-ups will be made since the condition will unlikely 
resolve.  
11.5.2. 
RUSAE reporting requirements 
All SAEs identified by the local Investigator as both likely to be related to protocol-treatment 
and unexpected will be reviewed by the Chief Investigator (CI). The CI, local PI or other 
qualified and delegated individual may declare an SAE a RUSAE. This may be downgraded in 
discussion with the CI but if no agreement can be made or in the absence of the CI the event 
should be reported as a RUSAE. A RUSAE once reported can be downgraded at a later date 
upon the receipt of new information.  
Identifiable patient data, other than linked anonymised data required by the NRES non-CTIMP 
SAE form, must not be included when reporting RUSAEs. 
The CI will then inform the Research Ethics Committee (REC) that gave the favourable opinion 
for the study of RUSAEs within the required expedited reporting timescales. RUSAEs must be 
reported to the REC within 15 calendar days of the CI (or their research team) being informed 
of the event.  
RUSAEs will be reported in accordance with the principles of GCP and the UK Policy 
Framework for Health and Social Care Research 2017. They will all be signed off by the 
Principal Investigator or, in their absence, by a delegated individual. 
12. URGENT SAFETY MEASURES 
If the research team becomes aware of information affecting the risk/benefit balance of the 
trial, they may take immediate action to ensure patient safety. Urgent safety measures 
deemed necessary must be reported immediately or within 1 working day of research team 
awareness to the Sponsor (governance-ethics@leeds.ac.uk). The  principle Investigator must 
also notify the main Research Ethics Committee (REC) within 3 days of implementing any 

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urgent safety measures, providing details of the measures taken and the reasons for taking 
them.  
12.1. Serious breaches of protocol 
A serious breach is a breach which is likely to effect to a significant degree either: 
• The safety or physical or mental integrity of the subjects of the trial; or 
• The scientific value of the trial 
Serious breaches of GCP will be reported to the Sponsor (governance-ethics@leeds.ac.uk) 
within 24 hours (same day, except weekends) from the time the research team becomes 
aware of the incident. 
13. STUDY MANAGEMENT AND ADMINISTRATION 
13.1. Good clinical practice (GCP)  
This clinical trial will be run in accordance with the Good Clinical Practice (GCP) and the UK 
Policy Framework for Health and Social Care Research 2017. 
13.2. Adherence to protocol 
The Investigator should not deviate from the protocol. In medical emergencies, the 
Investigator may use his/her medical judgment and may remove a study participant from 
immediate hazard before notifying the Sponsor and the REC in writing regarding the type of 
emergency and the course of action taken. 
13.3. Monitoring and audit 
The Sponsor reserves the right to audit any site involved in the trial and authorisation for this 
is given via the study contract or agreement. A site may be audited by DRMD or an 
independent contractor working for DRMD, and the Investigator should allow direct access to 
trial documentation. 
13.4. Study management 
13.4.1. 
Definition of source data 
Source documents are original records in which raw data are first recorded. These may 
include, e.g. hospital/clinic/general practitioner records, charts, diaries, laboratory results, 
printouts, care records, ECG or other printouts, completed scales, or Quality of Life 
Questionnaires. Source documents should be kept in a secure, limited access area. 
Some data will be recorded directly in the CRF and will not appear in a source document as 
defined in the Source Data Verification form. 

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13.4.2. 
Source data verification 
Source data verification ensures accuracy and credibility of the data obtained. The 
Investigator will review the reported data to ensure they are accurate, complete, and 
verifiable from source documents (e.g. subject files, recordings from automated instruments, 
ECG tracings, x-ray films, laboratory notes). All data reported on the CRF should be supported 
by source documents, unless otherwise specified in section 13.4.1. Data Verification and will 
be carried out by the Investigator(s) and members of the study team who will check the case 
report forms for completeness and clarity, and crosscheck them with source documents. 
13.4.3. 
Study oversight 
This study is part of a PhD and will be regularly reviewed with the supervisors. 
 
13.5. Data handling 
13.5.1. 
CRF completion 
The research team is responsible for prompt reporting of accurate, complete, and legible data 
in the CRFs and in all required reports. Any change or correction to the CRF should be dated, 
initialled, and explained (if necessary) and should not obscure the original entry. Use of 
correction fluid is not permitted. Screen failure data will not be entered in the (e)CRF. The 
Investigator should maintain a list of personnel authorized to enter data into the eCRF. 
Detailed instructions will be provided in the CRF Instructions. 
13.5.2. 
Database entry and reconciliation 
All clinical and participant-reported data will be recorded and managed on Leeds Teaching 
Hospitals NHS Trust (LTHT) systems, specifically the REDCap database, up to and including the 
point of data lock.  Identifiable data, including participant contact details and the code link 
document, will be stored separately in a locked filing cabinet at Leeds Institute of Rheumatic 
and Musculoskeletal Disease (LIRMM), with access restricted to authorised personnel only. 
Clinical and research data will be stored in anonymised form on the REDCap database, linked 
only by the unique study ID code. Identifiable data will be stored separately from clinical and 
research data to ensure participant confidentiality. Once data collection is complete and the 
database has been locked, an export of the anonymised research dataset will be securely 
transferred to the University of Leeds's nominated statistician for analysis. A copy of this final 
dataset, alongside all outputs, tables, and code from statistical analyses, will be stored 
securely on University of Leeds server space managed by LIRMM for the duration of the 
required retention period. Data will only be shared between the clinical site (Chapel Allerton 
Hospital) and the Sponsor site (University of Leeds LIRMM Department, located within the 
same building at Chapel Allerton Hospital). No identifiable data will be transferred 
electronically or physically outside of these premises, minimising any risk of confidentiality 
breaches. Regular backups of electronic data will be performed. 

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13.5.3. 
Screening and enrolment logs 
Subject’s Screening will be recorded in the Subject Screening Log. 
The Investigator will keep a list containing all subjects enrolled into the study. This list remains 
with the Investigator and is used for unambiguous identification of each subject. The list 
contains the subject identification number, full name, date informed consent signed, date of 
screening, and the hospital number or National Health Security number, if applicable. 
The subject’s consent and enrolment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation. 
 
13.6. Archiving and data retention 
Although not required by law for non-CTIMPs, in line with the principles of GCP essential study 
documents will be retained for a minimum of 5 years following the completion of the study. 
Arrangements for confidential destruction will then be made. If a patient withdraws consent 
for their data to be used, it will be confidentially destroyed immediately. No records/study 
documentation/data may be destroyed without first obtaining written permission from the 
Sponsor. 
Essential documents include (this list is not exhaustive): 
• Signed informed consent documents for all subjects. 
• Subject identification code list, screening log (if applicable) and enrolment log. 
• Record of all communications between the Investigator, the REC and the Sponsor. 
• Composition of the REC, and the Sponsor (or other applicable statement as described 
in section 14.5. 
• List of sub-investigators and other appropriately qualified persons to whom the 
Investigator has delegated significant trial-related duties, together with their roles in 
the study and their signatures. 
• Copies of case report forms and documentation of corrections for all subjects. 
• All other source documents (subject medical records, hospital records, laboratory 
records, etc.). 
Normally, these records will be held in the Investigator's archives. If the Investigator is unable 
to meet this obligation, he or she must ask the Sponsor for permission to make alternative 
arrangements. Details of these arrangements should be documented. 
 

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13.7. Study suspension, termination and completion 
Suspension or termination of the study may occur at any time for any reason, following 
discussion between the Investigator and the Sponsor. Upon study completion, the 
Investigator will provide the Sponsor with final reports and summaries as required by 
regulations and will be responsible for completing a premature end of study report to the 
Research Ethics Committee (REC) within 15 days.  
Study completion will be defined as the time at which the last data item has been locked for 
the last recruited participant. 
 
14. DATA EVALUATION 
14.1. Responsibilities 
Norah Almutairi will be responsible for data evaluation under the supervision of Dr. Darren 
Greenwood and Professor Manoj Sivan. Data analysis will be performed collaboratively, with 
oversight provided by the supervisors. The final reports will be written by Norah Almutairi, 
with input, review, and approval from Dr. Darren and Professor Manoj.  
14.2. General statistical considerations 
In general, summary statistics [n (number of available measurements), arithmetic mean and 
standard deviation, median and interquartile range] for quantitative variables and absolute 
and relative frequency tables for qualitative data will be presented, as appropriate. 
Estimates will be presented with 95% confidence intervals and two-tailed tests used 
throughout. Results will be taken to be statistically significant at two-tailed P<0.05. 
No adjustment will be made for the stratifying factor as the treatment comparison is within-
person. No corrections for multiple comparisons are planned. 
Wherever possible the trial will be reported in accordance with the recommendations of the 
CONSORT (Consolidated Standards of Reporting Trials) statement, including CONSORT 
recommendations for presentation of crossover trials. 
14.3.  Planned analyses 
Statistical analysis will be performed in Stata (StataCorp 2023, Release 18 or higher, Texas, 
United States).  
Exploration of the effect of the intervention on daily the primary outcome (COMPASS-31 
score) and continuous secondary outcomes (BPI-SF pain severity, BPI-SF, impact of pain, HADS 
depression and anxiety scores, EQ-5D-5L quality of life, TFA-based Participant Feedback 
Questionnaire) will be evaluated using the pkcross package in Stata, to implement the 
appropriate ANOVA model. The secondary outcome of physiological response to the lean test 

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(scored positive/negative response) will be evaluated using the equivalent mixed-effects 
logistic regression model.  
The models will take sequence, period and intervention (active or sham) as covariates. 
Response rate to invitation to participate will be summarised as above using descriptive 
statistics. 
 14.4. Safety analyses 
Line listings of all SAEs will be provided in the end of trial report. The frequency of all SAEs 
recorded during the study period will be presented. The data will be displayed as number of 
subjects experiencing the SAEs, percentage of subjects, and number of SAEs. Data will also be 
corrected for exposure by 100 patient-years.14.5. Handling of dropouts and missing data 
Based on our previous work with the COMPASS-31 questionnaire and the NASA lean test in 
the same population, we do not anticipate substantial losses to follow-up. The primary 
analysis will therefore be on a complete case basis. However, were necessary, we will use 
linear mixed-effects models rather than ANOVA, as they handle missing data more effectively. 
14.5.  Determination of sample size  
Sample size determination is based on Senn (2002). Based on our previous study of autonomic 
function in people living with chronic MSK pain, we assume a standard deviation of the 
COMPASS-31 score is approximately 20. A minimal clinically important difference (MCID) has 
not been established for COMPASS-31 in people living with chronic MSK pain, so we assume 
an MCID of 0.5 standard deviations, i.e. 10 points on the COMPASS-31 score. In addition, 
based on previous literature, the intraclass correlation for COMPASS-31 across a range of 
populations and conditions is consistently between 0.8 and 0.9 (Tresister et al., 2015; Drulovic 
et al., 2017; Ahn et al., 2021; Is et al., 2021), so we assume the intraclass correlation is 0.85. 
This indicates how similar the repeated compass-31 measures are across the time periods. 
Based on these figures, to achieve 80% power to detect a difference in COMPASS-31 scores 
between tVNS and sham of 10 points, at two-tailed P<0.05, needs complete data on n=12 
participants in total, receiving both interventions in random order. 
While we expect dropout to be minimal in this study, it is sensible to plan for some 
uncertainty. To provide flexibility, we may recruit up to 16 participants, ensuring that 
complete data are available for at least 12. 
 
15. ETHICS AND REGULATORY REQUIREMENTS 
15.1. Good Clinical Practice 
This study will be conducted in accordance with applicable laws and regulations including, but 
not limited to, the Good Clinical Practice (GCP) and the recommendations guiding ethical 

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research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, 
Finland, 1964, amended at the 48th General Assembly, Somerset West Republic of South 
Africa, October 1996. The Research Ethics Committee (REC) must review and approve the 
protocol and informed consent form before any subjects are enrolled. Before any protocol-
required procedures are performed, the subject must sign and date the REC-approved 
informed consent form. The right of a patient to refuse participation without giving reasons 
must be respected. The patient must remain free to withdraw at any time from the study 
without giving reasons and without prejudicing his/her further treatment. The study will be 
submitted to and approved by a main Research Ethics Committee (REC) and the appropriate 
regulatory authorities prior to entering patients into the study. 
15.2. Delegation of Investigator duties 
The Investigator should ensure that all persons assisting with the trial are adequately qualified 
and informed about the protocol, any amendments to the protocol, the study treatments, 
and their trial related duties and functions. 
The Investigator should maintain a delegation log of co-investigators and other appropriately 
qualified persons to whom he or she has delegated significant trial-related duties. 
15.3. Subject information and informed consent 
Before being enrolled in the study, subjects must consent to participate after the nature, 
scope, and possible consequences of the study have been explained in a form understandable 
to them. 
An informed consent document (Patient Information Leaflet) that includes both information 
about the study and the consent form will be prepared and given to the subject at least 24 
hours prior to the screening visit. This document will contain all the elements required by the 
Good Clinical Practice and any additional elements required by local regulations.  
At the screening visit, patients will be given the opportunity to ask questions, and the nature 
and objectives of the study will be explained by the study doctor responsible for the informed 
consent discussions.  
After reading the informed consent document, the subject must give consent in writing. The 
subject's consent must be confirmed at the time of consent by the personally dated signature 
of the subject and by the personally dated signature of the person conducting the informed 
consent discussions, the study doctor. 
The original signed consent document will be retained in the study files. Other copies of the 
consent form are required: 
• One copy of the informed consent document will be kept in the patient’s clinical 
notes. 
• One copy will be given to the patient. 

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Consent is an ongoing process and will be reassessed at each study visit. 
The Investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained. 
The Investigator must inform the subject’s primary physician about the subject’s participation 
in the trial if the subject has a primary physician and if the subject agrees to the primary 
physician being informed. 
15.4. Subject confidentiality 
Only the subject number will be recorded in the case report form, and if the subject name 
appears on any other document (e.g. laboratory report), it must be obliterated on the copy 
of the document to be supplied to anyone outside the clinical care team. The subjects will be 
informed that representatives of the Sponsor, Research Ethics Committee (REC) or regulatory 
authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence. 
All information collected during the course of the trial will be kept strictly confidential.  
Information will be held securely on paper and electronically.  
The study will comply with all aspects of the Data Protection Act 2018. 
15.5. Approval of clinical study protocol and amendments 
Before the start of the study, the clinical study protocol, informed consent document, and 
any other appropriate documents will be submitted to the REC and the Sponsor with a cover 
letter or a form listing the documents submitted, their dates of issue, and the site (or region 
or area of jurisdiction, as applicable) for which approval is sought.  
Before the first subject is enrolled in the study, all ethical and legal requirements must be 
met, including approval of the study by the NHS, the Sponsor Research and Development 
department and the REC. 
Amendments must be evaluated to determine whether formal approval must be sought and 
whether the informed consent document should be revised, thus all protocol amendments 
and administrative changes must first be discussed with and approved by the Sponsor before 
being submitted to the REC, in accordance with legal requirements. Amendments must be 
evaluated to determine whether formal approval must be sought and whether the informed 
consent document should be revised. 
The Investigator must keep a record of all communication with the REC and the Sponsor.  
15.6. Protocol amendments 
Requests for any amendments to the study must be sent to the Sponsor by the Chief 
Investigator. The Sponsor will determine whether said amendments are substantial or non 
substantial prior to their submission to the appropriate bodies for approval. Patients should 

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be reconsented to the study if the amendments affect the information they have received, 
patient safety, or if the change alters the type or quality of the data collected for the study. 
Patients should only be re-consented AFTER an amendment has been fully approved. 
15.7. Ongoing information for Research Ethics Committee 
Unless otherwise instructed by the REC and the Sponsor, the Investigator must submit to the 
REC and the Sponsor: 
• Information on serious adverse events that are unexpected and related to study 
procedures (RUSAEs) from the Investigator’s site, within 15 calendar days of the 
research team becoming aware of them. 
• Expedited safety reports, as soon as possible. 
• The NRES Declaration of End of Study form. 
 
16. FINANCE AND INSURANCE 
16.1. Indemnity and insurance 
The University when acting as sponsor, has insurance cover in force, which meets claims 
arising from death or injury, which are brought against the University and where those claims 
arise from the Universities own negligence in its role and activities relating to the study (and 
which is subject to the terms, conditions and exceptions of the relevant policy).  Clinical 
negligence indemnification will rest with the participating NHS Trust under standard NHS 
arrangements. 
16.2. Financial disclosure 
None of the Investigators or members of the research team have any financial involvement 
with the sponsorship or funding bodies or will receive personal benefits, incentives or 
payment over and above normal salary. 
 
17. PUBLICATION 
The results of this study will be disseminated through: Peer reviewed scientific journals, 
internal report, conference presentation, publication on website, thesis and others. 
The personal data gathered will be anonymised as soon as it is practical to do so (right after 
the experiment is completed by the participant). This means that all identifiable data will be 
destroyed. When publishing occurs, all data will be anonymous and be non-identifiable.  
Participants will be given the option of receiving a summary of the results obtained from the 
research. If they are interested in receiving this information, they will be requested to provide 
contact details (email or postal address) that will not be linked in any way to the data they 

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have provided in the study. Once the data is analysed and results are obtained from the study 
a lay summary of the conclusions will be sent to the contact details provided by participants.  
 
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