Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways
Conditions: Rheumatoid Arthritis
Sponsor: NHS Greater Glasgow and Clyde

 
GLASGOW CLINICAL TRIALS UNIT 
FORM 51.001A 
V7.0 
 
 
 
VERSION V3.1 
Page 1 of 33 
28.10.2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
Probing the Rheumatoid Arthritis Brain to Elucidate Central 
Pain Pathways 
 
 
 
Pro-BEPP 
 
 
 
 
Running Title 
Pro-BEPP  
 
 
 
 
Protocol Version 
V3.1  
 
 
 
 
Protocol Date 
28th October 2022 
 
 
 
 
REC Reference Number 
21/LO/0668 
 
 
 
 
ISRCTN / Clinical Trial.gov 
NUMBER  
 
 
 
 
Sponsor Protocol Number 
GN19RH007 
 
 
 
 
Sponsor 
NHS Greater Glasgow and Clyde  
 
 
 
 
Funder 
Versus Arthritis 
 
 
 
 
 
 
AMENDMENT NUMBER 
DATE 
PROTOCOL VERSION 
 
 
 
 
 
 
1 
02.12.2021 
2.0 – Addition of measures of disease activity at screening 
 
 
 
 
 
 
2 
18.02.2022 
3.0 – Addition of a second screening visit to accommodate 
a screening MRI scan. 
Addition of the option to complete select pre-treatment 
questionnaires remotely, reducing visit duration.  
Changes to follow-up time windows, from +/- 3 days to +/- 
7 days. 
The protocol has been updated to include the above 
additions, and an ultra-high resolution layer specific fMRI 
scan in the post-treatment scanning sequence (section 
6.2.1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be performed according to the UK policy framework for health and social care research 
(version 3.3, 07 November 2017) and WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 1964 (as amended). 
 
 
 
CONFIDENTIAL 
 
 

 
Pro-BEPP – Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways 
 
 
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CHIEF INVESTIGATOR 
 
 
Professor Neil Basu 
 
Senior Clinical Lecturer in Rheumatology 
 
Institute of Infection, Immunity & Inflammation 
 
Sir Graeme Davies Building 
120 University Place 
University of Glasgow  
G12 8TA 
 
 
 
T: 0141 330 1718 
 
E: Neil.Basu@glasgow.ac.uk 
 
 
 
CO-INVESTIGATORS 
 
 
 
Professor Jonathan Cavanagh 
Professor Gregor Thut 
 
 
Professor of Psychiatry 
Professor 
 
 
Institute of Infection, Immunity & Inflammation 
Institute of Neuroscience and Psychology 
 
 
Sir Graeme Davies Building 
Centre for Cognitive Neuroimaging  
 
 
120 University Place 
58 Hillhead Street 
 
 
University of Glasgow 
University of Glasgow  
 
 
G12 8TA 
G18 8QB 
 
 
 
 
 
 
T: 0141 330 7769 
T: 0141 330 3395 
 
 
E: jonathan.cavanagh@glasgow.ac.uk 
E: gregor.thut@glasgow.ac.uk 
 
 
 
 
 
 
 
 
 
Professor Duncan Porter 
 
Dr Graeme Keith 
Honorary Professor of Rheumatology  
Senior Postdoctoral Research Associate 
Gartnavel General Hospital  
Institute of Neuroscience and Psychology 
Dept of Rheumatology 
Centre for Cognitive Neuroscience 
1053 Great Western Rd 
58 Hillhead Street 
Glasgow 
University of Glasgow 
G12 0YN 
G12 8QB 
 
 
 
 
 
 
 
 
 
 
 
 
T: 0141 211 3429 
T:  
 
 
E: duncan.porter@glasgow.ac.uk 
E: graeme.keith@glasgow.ac.uk 
 
 
 
 

 
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Dr Andrew Schrepf 
 
Professor Daniel Clauw 
Research Investigator 
 
Professor of Anaesthesiology, Rheumatology 
and Psychiatry  
 
 
Chronic Pain and Fatigue Research Centre 
Chronic Pain and Fatigue Research Centre 
 
 
24 Frank Lloyd Wright Dr. 
24 Frank Lloyd Wright Dr. 
 
 
Lobby M, Suite 3100 
Lobby M, Suite 3100 
 
 
University of Michigan 
University of Michigan 
 
 
48106-5737 
48106-5737 
 
 
 
 
 
 
T:  
T: 
 
 
E: aschrepf@med.umich.edu 
E: dclauw@med.umich.edu 
 
 
 
 
 
 
 
PROJECT MANAGER / STUDY CO-ORDINATOR 
 
 
 
Maxine Arnott 
 
 
 
Institute of Infection, Immunity & Inflammation 
 
 
 
Sir Graeme Davies Building 
 
 
 
120 University Place 
 
 
 
Glasgow 
 
 
 
G12 8TA 
 
 
 
 
 
 
 
T: 07890059695 
 
 
 
F: N/A 
 
 
 
E: Maxine.arnott@glasgow.ac.uk  
 
 
 
 
 
 
DATA MANAGEMENT 
 
 
 
Institute of Infection, Immunity & Inflammation 
 
 
 
Sir Graeme Davies Building 
 
 
 
120 University Place 
 
 
 
Glasgow 
 
 
 
G12 8TA 
 
 
 
 
 
 
 
 
 
 
 
T:  
 
 
 
F: FAX NUMBER 
 
 
 
E: EMAIL ADDRESS 
 
 
 
 
 

 
Pro-BEPP – Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways 
 
 
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SPONSOR 
 
 
This clinical trial is sponsored by NHS Greater Glasgow and Clyde 
 
 
 
Sponsor’s representative: 
 
 
 
Dr Colette Montgomery Sardar 
  
 
 
Research Governance Officer 
 
 
 
 College of Medical, Veterinary and Life Sciences 
 
 
 
 University of Glasgow  
 
 
 
 Room 327, Wolfson Medical School Building 
 
 
 
 University Avenue 
 
 
 
 Glasgow 
 
 
 
 G12 8QQ 
 
 
 
T: 0141  330 5097 
 
 
 
 
 
E:  colette.montgomerysardar@glasgow.ac.uk 
 
 
 
 
 
 
FUNDING BODY 
 
 
This clinical trial is funded by Versus Arthritis.  
 
Administered by: 
 
 
 
Versus Arthritis   
 
 
 
Copeman House, St Mary’s Court 
St Mary’s Gate,  
Chesterfield 
S41 7TD 
United Kingdom  
 
 
 
 
 
 
 
 
 
T: +44 (0)  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain Pathways 
 
 
 
 
Chief Investigator: 
Prof. Neil Basu 
 
 
 
Institute of Infection, Immunity & Inflammation 
 
 
 
Sir Graeme Davies Building 
 
120 University Place 
 
Glasgow  
 
G12 8TA 
 
 
 
 
 
 
 
 
 
 
Signature: 
 
 
Date: 
28.10.2022 
 
 
  
 
 
Sponsor Representative: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr Colette Montgomery Sardar 
Research Governance Officer 
College of Medical, Veterinary and Life Sciences 
University of Glasgow 
Room 327, Wolfson Medical School Building 
University Avenue 
Glasgow, G12 8QQ 
Tel: 0141 330 5097 
Email: colette.montgomerysardar@glasgow.ac.uk 
 
Signature:  
 
 
Date: 
DATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
 
 
LIST OF ABBREVIATIONS .....................................................................................................................8 
STUDY SYNOPSIS .............................................................................................................................. 10 
1 
STUDY FLOW CHART .................................................................................................................. 12 
2 
SCHEDULE OF ASSESSMENTS ................................................................................................. 13 
3 
INTRODUCTION ........................................................................................................................... 14 
3.1 
BACKGROUND ................................................................................................................... 14 
3.2 
RATIONALE ........................................................................................................................ 14 
3.3 
STUDY HYPOTHESIS ........................................................................................................ 15 
4 
STUDY OBJECTIVES ................................................................................................................... 15 
4.1 
PRIMARY ENDPOINT ........................................................................................................ 15 
4.2 
SECONDARY ENDPOINT(S) ............................................................................................. 15 
5 
STUDY DESIGN ............................................................................................................................ 16 
5.1 
STUDY POPULATION ........................................................................................................ 16 
5.2 
INCLUSION CRITERIA ....................................................................................................... 16 
5.3 
EXCLUSION CRITERIA ...................................................................................................... 16 
5.4 
CONCOMITANT MEDICATION .......................................................................................... 17 
5.5 
IDENTIFICATION OF PARTICIPANTS AND CONSENT ................................................... 17 
5.6 
RANDOMISATION & BLINDING ........................................................................................ 17 
5.7 
WITHDRAWAL OF PARTICIPANTS .................................................................................. 18 
6 
TRIAL PROCEDURES .................................................................................................................. 19 
6.1 
STUDY SCHEDULE ............................................................................................................ 19 
6.1.1 
Screening visit 1 (Day 0) ................................................................................................. 19 
6.1.2 
Screening visit 2 (Day 7) (+/- 7 days) ............................................................................. 19 
6.1.3 
Visit 1 (Day 14) (+/- 7 days) ............................................................................................ 19 
6.1.4 
Visit 2 (Day 28) (+/- 7 days) ............................................................................................ 20 
6.1.5 
Visit 3 (Day 35) (+/- 7 days) ............................................................................................ 20 
6.1.6 
Visit 4 (Day 49) (+/- 7 days) ............................................................................................ 21 
6.2 
BRAIN IMAGING PROTOCOLS ......................................................................................... 21 
6.2.1 
MRI and MRS Protocols ................................................................................................. 21 
6.3 
STUDY OUTCOME MEASURES ....................................................................................... 23 
6.3.1 
Primary Outcome Measure(s) ......................................................................................... 23 
6.3.2 
Secondary Outcome Measure(s) .................................................................................... 23 
6.4 
LABORATORY TESTS ....................................................................................................... 23 
7 
Study Device .................................................................................................................................. 24 
7.1 
TRANSCRANIAL MAGENTIC STIMULATION ................................................................... 24 
7.1.1 
Neuronavigation Scan ..................................................................................................... 24 
7.1.2 
Motor Threshold Assessment ......................................................................................... 25 

 
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7.1.3 
TMS Schedule & Administration ..................................................................................... 25 
7.1.4 
Rationale for Chosen Dose ............................................................................................. 25 
7.1.5 
Sham Procedure ............................................................................................................. 25 
8 
RISK ASSESSMENT AND ADVERSE EVENTS .......................................................................... 26 
8.1 
RISK ASSESSMENT .......................................................................................................... 26 
8.2 
ADVERSE EVENTS (AEs) .................................................................................................. 26 
8.3 
SERIOUS ADVERSE EVENT (SAE) .................................................................................. 27 
8.4 
SERIOUS ADVERSE DEVICE EVENT (SADE) ................................................................. 27 
8.5 
RECORDING AND REPORTING OF ADVERSE EVENTS ............................................... 27 
9 
STATISTICS AND DATA ANALYSIS ............................................................................................ 28 
9.1 
STATISTICAL ANALYSIS PLAN ........................................................................................ 28 
9.2 
SAFETY ANALYSIS ............................................................................................................ 28 
9.3 
SOFTWARE FOR STATISTICAL ANALYSIS ..................................................................... 28 
9.4 
SAMPLE SIZE ..................................................................................................................... 28 
9.5 
MANAGEMENT AND DELIVERY ....................................................................................... 29 
10 TRIAL CLOSURE / DEFINITION OF END OF TRIAL ................................................................... 29 
11 DATA HANDLING .......................................................................................................................... 29 
11.1 
CASE REPORT FORMS / ELECTRONIC DATA RECORD ............................................... 29 
11.2 
RECORD RETENTION ....................................................................................................... 29 
12 TRIAL MANAGEMENT .................................................................................................................. 29 
12.1 
ROUTINE MANAGEMENT OF TRIAL: TRIAL MANAGEMENT GROUP .......................... 29 
13 STUDY AUDIT ............................................................................................................................... 30 
14 PROTOCOL AMENDMENTS ........................................................................................................ 30 
15 ETHICAL CONSIDERATIONS ...................................................................................................... 31 
15.1 
ETHICAL CONDUCT OF THE STUDY ............................................................................... 31 
15.2 
INFORMED CONSENT....................................................................................................... 31 
16 INSURANCE AND INDEMNITY .................................................................................................... 31 
17 FUNDING ...................................................................................................................................... 31 
18 ANNUAL REPORTS ...................................................................................................................... 31 
19 DISSEMINATION OF FINDINGS .................................................................................................. 32 
20 REFERENCES .............................................................................................................................. 33 
 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
 
 
Complete as required, all abbreviations used in the protocol should be defined upon first 
mention and added to this table 
 
 
 
ACR 
American College of Rheumatology 
 
 
 
 
AE 
Adverse Event 
 
 
 
 
ALFF 
Amplitude of Low-Frequency Fluctuations 
 
 
 
 
BOLD 
Blood oxygenation level dependent 
 
 
 
 
CDAI 
Clinical Disease Activity Index 
 
 
 
 
CI 
Chief Investigator 
 
 
 
 
CNORIS 
Clinical Negligence and Other Risks Indemnity Scheme 
 
 
 
 
CNS 
Central Nervous System 
 
 
 
 
CRP 
C-reactive Protein 
 
 
 
 
DMARD 
Disease-Modifying Anti-Rheumatic Drug 
 
 
 
 
eCRF 
Electronic case report form 
 
 
 
 
EL 
Engagement Leads 
 
 
 
 
ELISA 
Enzyme-linked immunosorbent assay 
 
 
 
 
EPR 
Electronic Patient Record 
 
 
 
 
ESR 
Erythrocyte Sedimentation Rate 
 
 
 
 
EULAR 
European League Against Rheumatism 
 
 
 
 
MRI 
Magnetic resonance imaging 
 
 
 
 
GAIN 
Glasgow Arthritis Involvement Network 
 
 
 
 
GluCEST 
Glutamate Chemical Exchange Saturation Transfer 
 
 
 
 
IMID 
Immune-mediated inflammatory diseases 
 
 
 
 
L-IPL 
Left Inferior Parietal Lobule 
 
 
 
 
MRS 
Magnetic Resonance Spectroscopy 
 
 
 
 
MSD 
Meso Scale Discovery 
 
 
 
 
NRS 
Numeric Rating Scale 
 
 
 
 
PPI 
Patient and Public Involvement 
 
 
 
 
PROMIS 
Patient Reported Outcome Measurement Information System 
 
 
 
 
PRP 
Patient Research Partner 
 
 
 
 
R&D 
Research and Development 
 
 
 
 
RA 
Rheumatoid arthritis 
 
 
 
 
RACE 
Research into Inflammatory Arthritis Centre Versus Arthritis 
 
 
 
 

 
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REC 
Research Ethics Committee 
 
 
 
 
ReHo 
Regional Homogeneity 
 
 
 
 
SAE 
Serious Adverse Event 
 
 
 
 
SADE 
Serious Adverse Device Event 
 
 
 
 
SDAI 
Simple Disease Activity Index 
 
 
 
 
7T 
Tesla 
 
 
 
 
TMG 
Trial Management Group 
 
 
 
 
TMS 
Transcranial magnetic stimulation 
 
 
  
 

 
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STUDY SYNOPSIS 
 
 
 
 
Title of Study 
Probing the Rheumatoid Arthritis Brain to Elucidate Central Pain 
Pathways 
 
 
 
 
 
 
 
 
Study Centre 
University of Glasgow/NHS Greater Glasgow and Clyde 
 
 
 
 
Duration of Study 
24 months 
 
 
 
 
 
 
 
 
Primary Objective 
To evaluate changes in neural glutamate, neuronal signal cohesion and 
functional connectivity in RA patients following L-IPL stimulation using TMS 
 
 
 
 
Secondary Objective 
To evaluate changes in pain severity and characterisation, RA disease 
activity, sickness behaviour and peripheral inflammatory markers in RA 
patients following L-IPL stimulation using TMS 
 
 
 
 
Primary Endpoints 
The primary endpoints are 
- Changes in functional connectivity and neuronal signal cohesion after 
TMS/sham therapy, as measured by 7T MRI 
- Changes in glutamate signal in the L-IPL after TMS/sham therapy, as 
measured by 7T MRS 
 
 
 
 
Rationale 
Many patients with rheumatoid joint disease continue to experience 
significant pain despite receiving apparently optimal joint specific therapies. 
We believe this discrepancy relates to the existence of pain sources which 
are supplementary to those present in the joints. In particular, we have been 
among the first to report evidence implicating the brain in the generation of 
this disabling problem. Brain scanning methods have helped us to identify a 
specific region (the left inferior parietal lobule (L-IPL)) which appears to be 
an important link between the characteristic excessive inflammation of RA 
and pain processing.  
We hope to better examine this possible link by employing a safe, non-
invasive technique called transcranial magnetic stimulation (TMS). TMS 
uses a magnet to influence the function of a specific region on the brain 
surface. We will use TMS to target the left inferior parietal lobule and then 
assess participants for changes in aspects of brain biology (which have been 
considered important in other chronic pain disorders), their pain and markers 
of inflammation. Due to the inherent dangers of sampling the brain, we will 
instead use 7T magnetic resonance imaging to make indirect measurements 
of brain biology, including changes in specific chemistry.  
This information will help us to better understand the precise role of the left 
inferior parietal lobule in relation to pain. The results of this modest project 
will inform bigger, more definitive studies and will ultimately deliver 
knowledge that will allow us to address the tremendous shortfall of safe and 
effective pain relief strategies for patients with RA and beyond. 
 
 
 
 
Methodology 
This randomised, sham-controlled, crossover study will allow us to test the 
hypothesis that systemic inflammation results in haphazard neuronal 
signalling and heightened centralised pain using a single session of non-
invasive TMS. In order to ensure that any observed changes are specific to 
TMS, subjects will be randomised equally to receive an initial single session 
of either active or sham procedure. The latter will employ the same 
equipment but will not generate a magnetic effect. Subjects will be asked to 
return 3 weeks later to receive the alternative procedure. 
 
 
 
 
Sample Size 
20 participants  

 
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Screening 
Patients with active RA attending clinics in NHS Greater Glasgow and Clyde 
will be approached to contribute to this study by the point of care team. 
 
 
Inclusion Criteria 
• 
Adults ≥ 18 years < 75 years. 
• 
Physician diagnosis of RA 
• 
ACR definition of chronic widespread pain 
• 
Able and willing to maintain medication for the 6-week study 
duration 
• 
CRP > 6mg/L or ESR > 20mm/hr 
• 
≥1 swollen joint 
• 
Right-handed (to reduce neuroimaging heterogeneity). 
 
Exclusion Criteria 
 
• 
Inability to provide written informed consent.  
• 
Severe physical impairment (e.g. blindness, deafness, paraplegia). 
• 
Pregnant, planning pregnancy or breast feeding. 
• 
Severe claustrophobia precluding MRI. 
• 
Contraindications to MRI (e.g. metal implants/ pacemaker). 
• 
Contraindications to TMS (e.g. history of seizures). 
• 
Serious infection including sepsis, tuberculosis and opportunistic 
infections such as invasive fungal infections.   
• 
Major confounding neurological disease including Multiple 
Sclerosis, Stroke, Traumatic Brain Injury, Parkinson’s Disease, 
Alzheimer’s Disease 
 
 
Product, Dose, Modes of 
Administration 
A single session of transcranial magnetic stimulation (TMS) of the left 
inferior parietal lobule (L-IPL) will be delivered using a figure of 8 coil at 
10Hz, 90% resting motor threshold intensity and 1200 pulses. The TMS 
pulses will be given in series of 20 trains of 6s duration (with 54s intertrain 
intervals). 
 
 
 
 
Duration of Study 
Participation 
6-8 weeks 
 
 
Statistical Analysis 
1) Descriptive statistics and data visualization. Median values and 
interquartile ranges of primary and secondary outcomes will be generated 
for each of the four time points. Paired plots for raw data and boxplots will 
be generated showing difference scores in the outcomes following sham and 
active TMS. 
2) Hypothesis testing. Paired-difference tests for parametric data (paired 
sample t-tests) will be used to test our hypotheses by comparing the change 
in outcomes following sham TMS to the change in outcomes following 
active TMS. Hypothesis testing will be two-sided with alpha = .05, and 95% 
confidence intervals around the contrast will be generated using 
bootstrapping with 20,000 resamples. 
3) Effect Size: As a simple expression of effect size, the proportion of 
subjects showing greater, equal and lesser reduction in glutamate between 
active and sham conditions will be reported. For the calculation of sample 
size estimates for future studies, the standardized mean difference effect 
size for within-subject designs (d-z) will be calculated. 
4) Outcome inter-relationships: Exploratory correlations will examine the 
relationships between the different outcomes and their change 
 
 
 
 
 
 
 
 

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Study Procedure 
Screening 
Visit 1 
 
Screening 
visit 2† 
Visit 1 
(+/- 7 
days) 
Visit 2 
(+/- 7 
days) 
Visit 3 
(+/- 7 
days) 
Visit 4 
(+/- 7 
days) 
Informed consent 
✓ 
 
 
 
 
 
Inclusion/exclusion criteria 
✓ 
 
 
 
 
 
Neuronavigation Scan 
 
✓ 
 
 
 
 
Motor Threshold Assessment 
 
✓ 
 
 
 
 
7T structural scans 
✓ 
 
 
 
 
 
Randomisation 
✓ 
 
 
 
 
 
Demographics 
✓ 
 
 
 
 
 
BMI 
✓ 
 
 
 
 
 
Family Medical History 
✓ 
 
 
 
 
 
Completion of Symptom Diary††§ 
 
✓ 
✓ 
✓ 
✓ 
 
7T magnetic resonance protocol 
 
 
✓* 
 
✓* 
 
Pain, fatigue, and depression 
severity  
 
 
✓* 
✓ 
✓* 
✓ 
Measure of disease activity 
✓ 
 
✓ 
✓ 
✓ 
✓ 
Sickness Questionnaire 
 
 
✓* 
✓ 
✓* 
✓ 
Pain confounder questionnaires§ 
 
 
✓ 
✓ 
 ✓ 
✓ 
Michigan Body Map Regional Pain§ 
 
 
✓ 
✓ 
✓ 
✓ 
Blood sample for 
immunophenotyping††† 
 
 
✓* 
✓ 
✓* 
✓ 
TMS or sham procedure 
 
 
✓ 
 
✓ 
 
Recording of Adverse Events 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
† Screening visit will be conducted at the Centre for Cognitive Neuroimaging, University of Glasgow 
†† Symptom diary will be completed for the 7 days following each visit 
††† Blood sample schedule outlined in 6.4 LABORATORY TESTS 
* Procedure will be performed twice; before and after TMS/Sham therapy 
§ Option to complete questionnaires remotely to reduce visit length 
 
2 SCHEDULE OF ASSESSMENTS 
 
 

 
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3 INTRODUCTION 
 
 
 
 
3.1 BACKGROUND 
 
 
Rheumatoid arthritis (RA) is a common disease which is characterised by severe joint inflammation and 
chronic pain1. The discovery of new joint specific treatments has transformed patient outcomes and yet 
most patients, even those whose joints respond fully to these treatments, continue to experience 
significant levels of pain2, 3. We therefore believe that RA pain is caused by alternative sources in addition 
to the joints. 
 
Our group are pioneering the investigation of a possible link between the brain and the pain which RA 
patients experience. By employing sophisticated brain scanning methods, we have shown that high 
levels of pain and blood inflammation are associated with changes within a specific region of the brain 
known as the left inferior parietal lobule (L-IPL)4. This region exhibited abnormal connections with other 
brain regions already known to be associated with pain in another chronic pain disorder called 
fibromyalgia. Fibromyalgia is a musculoskeletal condition which is not classically related to high levels 
of blood inflammation, although, interestingly, it is not uncommon for it to co-exist in RA patients5, 6. In 
light of our preliminary brain scan studies, we now think that fibromyalgia in the context of RA may be 
partially influenced by inflammation. 
 
In order to fully understand the precise processes that lead to this potential relationship, it is important 
to characterise the biological abnormalities that underlie our brain scan observations. Previous animal 
experiments have consistently observed abnormalities, such as high levels of the brain chemical 
glutamate and haphazard brain activity, in the context of inflammation. Conducting similar experiments 
in humans is not practical due to the inherent dangers of sampling live brain tissue. Instead, 
neuroscientists commonly use non-invasive methods to manipulate specific parts of the brain in order to 
better understand how they function. In conjunction, the latest scanners are now able to indirectly 
measure the effect of the brain modulation on relevant aspects of brain biology without the need to 
remove tissue7. This information will help us to better understand the relationship between inflammation 
and pain in the RA brain. 
 
 
3.2 RATIONALE 
 
 
Rheumatoid Arthritis-related pain is only partially explained by joint specific inflammation. Despite 
excellent control of peripheral inflammation by contemporary immune modulatory regimes, as many as 
50% of patients continue to report disabling levels of pain, thus comprising an urgent unmet clinical 
need2, 3. 
 
We have been among the first to evidence a contributory role of the central nervous system (CNS) as 
an explanation for this apparent disconnect4, 8. Our cross-sectional neuroimaging studies have 
implicated the left inferior parietal lobule of the brain as a critical interface between inflammation and 
pain. Not only did this region associate with levels of patient reported pain and indicators of systemic 
inflammation, but it was found to be functionally hyperconnected to brain networks established to be pro-
nociceptive in CNS based chronic pain disorders such as fibromyalgia. In parallel, preclinical 
experiments suggest that systemic inflammation leads to heightened glutamate neurotransmission, 
which in turn results in disorganised neuronal signal activity and ultimately altered functional connectivity 
between regions of the brain. In RA patients, we hypothesise that systemic inflammation-related neural 
glutamate 
enhancement 
triggers 
chaotic 
neuronal 
signalling, 
followed 
by 
compensatory 
hyperconnectivity with pro-nociceptive functional brain networks. Thereby, we believe that dysfunctional 
inflammatory processes in RA not only mediate nociception in vulnerable joints but also nociception in 
vulnerable regions of the brain. 

 
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3.3 STUDY HYPOTHESIS 
 
 
 
We believe that the left inferior parietal lobule of the brain is a key region where inflammation and pain 
communicate in RA. Specifically, we hypothesise that inflammation leads to high levels of glutamate in 
the left inferior parietal lobule and subsequent haphazard functioning of this area. This then leads to 
abnormal communication with other regions of the brain such as those known to be important to pain 
processing in fibromyalgia. Ultimately, we expect these processes to alter patients’ overall experience 
of pain.  
If correct, we would expect a normalisation of left inferior parietal lobule activity to reduce glutamate 
levels and rebalance the functioning of the proposed pain systems in 'inflamed' RA patients. 
 
 
Changes in components of sickness behaviour, pain severity, disease activity and inflammation after 
TMS/sham therapy as follows:  
• 
Pain severity as measured by the Michigan Body Map Regional Pain and NRS-Pain 
• 
RA disease activity as measured by SDAI, CDAI 
• 
Sickness behaviour as measured by the Sickness Questionnaire 
 
Given the clear practical constraints of sampling fresh human brain tissue, we propose to test our 
hypothesis by combining state-of-the-art non-invasive brain modulatory techniques alongside leading-
edge neurobiological surrogate imaging measures. Transcranial magnetic stimulation (TMS) is the 
neural modulatory probe of choice for neuroscientists seeking to infer causality of specific brain cortical 
regions9, 10. Ultra-high resolution 7T MRI enables measurement of functional connectivity and haphazard 
neuronal signal activity at significantly superior spatial resolution compared to standard 3T approaches 
and can uniquely assess regional glutamate. 
 
As a critical first step, this feasibility study aims to pilot a transcranial magnetic stimulation (TMS) protocol 
designed to target the L-IPL in RA. We will evaluate its effect employing ultra-high resolution 7T 
functional and glutamate measures. This novel project will inform a larger study which will aim to provide 
more robust evidence for the proposed neural pain interface between systemic inflammation and pain. 
Such knowledge could potentially support the analgesic testing of existing compounds e.g. 
alternative/augmented immunosuppressants or neural glutamate modulatory agents; and reverse 
translated in order to more precisely dissect the culprit mechanisms which in turn may inform the 
development of novel pain therapeutics. Both represent core aims of Versus Arthritis and address critical 
priorities among the patient populations that we serve. 
 
 
4 STUDY OBJECTIVES 
 
 
1) Determine the effects of L-IPL TMS on functional connectivity and neuronal signal cohesion. 
2) Determine the effects of TMS on MRS Glutamate signal in the L-IPL. 
3) Determine the effects of TMS on pain severity and disease activity in RA patients. 
 
 
4.1 PRIMARY ENDPOINT 
 
 
• 
Changes in functional connectivity and neuronal signal cohesion after TMS/sham therapy, as 
measured by 7T MRI 
• 
Changes in glutamate signal in the L-IPL after TMS/sham therapy, as measured by 7T MRS 
 
 
4.2 SECONDARY ENDPOINT(S) 
 
 

 
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• 
Putative pain confounders as measured by PROMIS-Fatigue, PROMIS-Depression, PROMIS-
Anxiety, PROMIS-Sleep Related Impairment, PROMIS-Physical functioning short form, PROMIS-
Pain interference and ACR Fibromyalgia Scale 
• 
Blood protein levels of inflammatory cytokines/chemokines  
 
 
 
5 STUDY DESIGN 
 
 
 
The study design is detailed below and is summarised in the STUDY FLOW CHART and Error! 
Reference source not found.. The trial is a single-centre, randomised sham-controlled crossover study 
to test the hypothesis that normalisation of left inferior parietal lobule activity using TMS will reduce 
glutamate levels and rebalance the functioning of the proposed pain systems in 'inflamed' RA patients.  
 
All of the study research data/ indices including the outcomes of study measures and samples will be 
shared with our collaborators in the University of Michigan.  No personal data will be exported to our co-
investigators at University of Michigan, but non-personal information may be transferred. The data 
transferred to the University of Michigan will include the study code/age/gender and questionnaire data.  
The University of Michigan will not have access to the pseudoanonymised key which will be kept within 
NHS GG&C only, therefore data will be anonymised to the University of Michigan investigators and 
pseudoanonymised to NHS GG&C/University of Glasgow investigators.  The University of Michigan will 
undertake collaborative analyses; an appropriate Data Transfer Form and Controller to Controller 
Agreement will be completed. 
 
 
5.1 STUDY POPULATION 
 
 
The study will involve participants aged over 18 years with active inflammatory RA who meet the inclusion 
criteria below and who have none of the specified exclusion criteria. All will give full informed consent.  
Rheumatoid arthritis patients attending secondary care clinics in NHS GG&C and in NHS Lanarkshire 
will be screened for eligibiity. NHS Lanarkshire will act as a participant identification centre ( PIC ) and 
all study participants will undertake study procedures at the University of Glasgow and the Queen 
Elizabeth University Hospital(NHS GG&C).   
 
 
5.2 INCLUSION CRITERIA 
 
 
• 
Adults ≥ 18 years < 75 years. 
• 
Physician diagnosis of RA 
• 
ACR definition of chronic widespread pain 
• 
Able and willing to maintain usual/ medication for the 6-week study duration 
• 
CRP > 6mg/L or ESR > 20mm/hr 
• 
≥1 swollen joint 
• 
Right-handed (to reduce neuroimaging heterogeneity) 
 
 
5.3 EXCLUSION CRITERIA 
 
 
• 
Inability to provide written informed consent.  
• 
Severe physical impairment (e.g. blindness, deafness, paraplegia). 
• 
Pregnant, planning pregnancy or breast feeding. 
• 
Severe claustrophobia precluding MRI. 
• 
Contraindications to MRI (e.g. metal implants/ pacemaker). 
• 
Contraindication to TMS (e.g. history of seizures). 

 
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• 
Serious infection including sepsis, tuberculosis and opportunistic infections such as invasive 
fungal infections.   
• 
Major confounding neurological disease including Multiple Sclerosis, Stroke, Traumatic Brain 
Injury, Parkinson’s Disease, Alzheimer’s Disease 
 
 
 
5.4 CONCOMITANT MEDICATION 
 
 
All Rheumatoid Arthritis therapies (including DMARDs/steroids/biologics) are permitted but must stay 
constant for the duration of the study. In exceptional circumstances, intra-articular/ intra-muscular steroids 
will be permitted according to investigator discretion. 
 
 
5.5 IDENTIFICATION OF PARTICIPANTS AND CONSENT 
 
 
Patients with active RA attending rheumatology outpatient clinics in NHS Greater Glasgow and Clyde 
and in NHS Lanarkshire will be notified of the study by the direct care team and will be provided with a 
patient information sheet. The patient will be asked to consent to a member of the research team 
contacting them by phone at least 24 hours later to gauge their interest in the study and allow them to 
ask any questions. This verbal agreement to be contacted by researchers will be documented by the 
direct care team in clinical record. Eligibility will be confirmed by a medically qualified doctor who is part 
of both the clinical/research team. 
Contact details of interested patients will be shared by the clinical team with the research team via NHS 
to NHS email.  
 
If the patient assents, they will be contacted by phone by a member of the research team to go through 
basic screening, address any queries, verify right hand dominance and check for MRI and significant 
medical condition contraindications. At this stage, potential participants will be invited to attend screening 
and consent visits that will be conducted at the Imaging Centre of Excellence (ICE) at the Queen 
Elizabeth University Hospital and the Centre for Cognitive Neuroimaging at the University of Glasgow. At 
these meetings, subjects will be asked again if they have any questions. Participants will undergo 
informed consent where two copies of the consent form will be signed (one each for the participant and 
the site file). A copy of the signed consent form will be inserted into the patient’s record or scanned into 
the electronic patient record (EPR). A letter will be sent to the patient’s GP informing them of their 
participation in the study.  
 
Eligibility will be confirmed by a medically qualified investigator and consent will be taken by a member 
of the research team. 
 
The research team comprises individuals who help to coordinate and perform the study in addition to 
individuals from the direct clinical care team.  In addition to the clinical team, the research team requires 
access to the patient's medical record to be able to comprehensively collect necessary clinical 
characterization e.g blood results and validate patient reports. 
 
 
5.6 RANDOMISATION & BLINDING 
 
 
This is a randomised, sham-controlled, crossover study. Once participants have given consent and been 
fully screened for study eligibility, they will be randomised to receive either a single session of active TMS 
procedure to the L-IPL or a TMS sham procedure which will not modulate the brain. Provided the first 
session causes no reason to withdraw the participant, they will return 3 weeks later to receive the 
alternative TMS procedure to that they had undergone originally.  
 

 
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In order to optimise participant blinding, we will employ a sham coil which mimics the clicking and scalp 
sensations. 
 
 
 
5.7 WITHDRAWAL OF PARTICIPANTS 
 
 
 
The patient can decide to withdraw from the clinical trial at any time for no reason. The Chief Investigator 
(CI) or co-investigators also have the right to withdraw patients from the study if deemed in the best 
interests of the patient or in the event of Adverse Events (AEs), protocol violations, administrative or other 
reasons. Full details of withdrawal should be recorded on the electronic Case Report Form (eCRF).  
 
Participants may decide to withdraw their initial consent for this study, at this point no further information 
regarding the participant will be collected. Data relating to the patient that has been collected up to the 
point of withdrawal will still be used. Any stored blood samples that can still be identified as the 
participants will be destroyed.  
 
 
  
 

 
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6 TRIAL PROCEDURES 
 
 
 
6.1 STUDY SCHEDULE 
 
 
The study will comprise of a total of 6 research visits.  
 
 
 
6.1.1 
Screening visit 1 (Day 0) 
 
. 
This screening visit will be conducted at the  Queen Elizabeth University Hospital. 
  
• 
Informed consent  
• 
Review of inclusion / exclusion criteria 
• 
Disease activity (SDAI / CDAI) 
• 
7T structural scans 
• 
Randomisation 
• 
Demographics 
• 
BMI 
• 
Medical History 
 
Estimated visit time 1 hour 
 
 
 
6.1.2 
Screening visit 2 (Day 7) (+/- 7 days)  
 
 
This screening visit will be conducted at the Centre for Cognitive Neuroimaging, University of Glasgow. 
 
• 
Neuronavigation scan 
• 
Motor threshold assessment 
• 
Completion of symptom diary (to be done at home, Days 8-14) 
 
Estimated visit time 1 hour 
 
 
 
6.1.3 
Visit 1 (Day 14) (+/- 7 days) 
 
 
Visit 1 will be conducted at the Queen Elizabeth University Hospital  
• 
 7T Neuroimaging protocol* 
• 
 Michigan Body Map Regional Pain§ 
• 
 NRS for pain, fatigue, and depression*  
• 
 McGill Pain Questionnaire§ 
• 
 Disease activity (SDAI / CDAI) 
• 
 Sickness Questionnaire* 
• 
 Pain confounder questionnaires§: 
o 
PROMIS-Fatigue (16-items)§ 
o 
PROMIS-Depression (8 items)§ 
o 
PROMIS-Anxiety (8 items)§ 
o 
PROMIS-Sleep Related Impairment (8 items)§ 
o 
PROMIS-Physical Functioning Short Form (8-items)§ 
o 
PROMIS-Pain Interference (8-item)§ 

 
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o 
ACR Fibromyalgia Scale§ 
• 
Venous blood sample for peripheral immunophenotyping* 
• 
TMS or sham procedure 
• 
Completion of symptom diary (to be done at home, Days 15-21) 
*will be conducted before and after TMS/sham procedure 
§has the option to be completed remotely to reduce visit time 
 
Estimated visit time 4 hours 
 
 
 
6.1.4 
Visit 2 (Day 28) (+/- 7 days) 
 
 
Visit 2 will be conducted at the Queen Elizabeth University Hospital  
 
• 
Michigan Body Map Regional Pain§  
• 
NRS for pain, fatigue, and depression 
• 
McGill Pain Questionnaire§ 
• 
Disease activity (SDAI / CDAI) 
• 
Sickness Questionnaire 
• 
Pain confounder questionnaires§: 
o 
PROMIS-Fatigue (16-items)§ 
o 
PROMIS-Depression (8 items)§ 
o 
PROMIS-Anxiety (8 items)§ 
o 
PROMIS-Sleep Related Impairment (8 items)§ 
o 
PROMIS-Physical Functioning Short Form (8-items)§ 
o 
PROMIS-Pain Interference (8-item)§ 
o 
ACR Fibromyalgia Scale§ 
• 
Venous blood sample for peripheral immunophenotyping 
• 
Completion of symptom diary (to be done at home, Days 29-35) 
§has the option to be completed remotely to reduce visit time 
 
Estimated visit time 1.5 hours 
 
 
 
6.1.5 
Visit 3 (Day 35) (+/- 7 days) 
 
 
Visit 3 will be conducted at the Queen Elizabeth University Hospital  
 
• 
7T Neuroimaging protocol* 
• 
Michigan Body Map Regional Pain§ 
• 
NRS for pain, fatigue, and depression* 
• 
McGill Pain Questionnaire§ 
• 
Disease activity (SDAI / CDAI) 
• 
Sickness Questionnaire* 
• 
 Pain confounder questionnaires§: 
o 
PROMIS-Fatigue (16-items)§ 
o 
PROMIS-Depression (8 items)§ 
o 
PROMIS-Anxiety (8 items)§ 
o 
PROMIS-Sleep Related Impairment (8 items)§ 
o 
PROMIS-Physical Functioning Short Form (8-items)§ 
o 
PROMIS-Pain Interference (8-item)§ 
o 
ACR Fibromyalgia Scale§ 
• 
Venous blood sample for peripheral immunophenotyping* 
• 
TMS or sham procedure 

 
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• 
Completion of symptom diary (to be done at home, Days 36-42) 
*will be conducted before and after TMS/sham procedure 
§has the option to be completed remotely to reduce visit time 
 
Estimated visit time 4 hours 
 
 
 
6.1.6 
Visit 4 (Day 49) (+/- 7 days) 
 
 
Visit 4 will be conducted at the Queen Elizabeth University Hospital  
 
• 
Michigan Body Map Regional Pain§  
• 
NRS for pain, fatigue, and depression  
• 
McGill Pain Questionnaire§ 
• 
Disease activity (SDAI / CDAI) 
• 
Sickness Questionnaire 
• 
Pain confounder questionnaires§: 
o 
PROMIS-Fatigue (16-items)§ 
o 
PROMIS-Depression (8 items)§ 
o 
PROMIS-Anxiety (8 items)§ 
o 
PROMIS-Sleep Related Impairment (8 items)§ 
o 
PROMIS-Physical Functioning Short Form (8-items)§ 
o 
PROMIS-Pain Interference (8-item)§ 
o 
ACR Fibromyalgia Scale§ 
• 
Venous blood sample for peripheral immunophenotyping 
§has the option to be completed remotely to reduce visit time 
 
Estimated visit time 1.5 hours 
 
 
6.2 BRAIN IMAGING PROTOCOLS  
 
   
 
6.2.1 
MRI and MRS Protocols 
 
 
The 7T multimodal MRI brain scanner is housed within the Imaging Centre of Excellence at the QEUH, 
Glasgow. An ultra-high resolution 7T multimodal MRI brain scan using a MAGNETOM Terra 7T scanner 
(Siemens Healthcare, Erlangen, Germany) and a single channel transmit, 32 channel receive 
radiofrequency head coil (Nova Medical, Wilmington, MA) will obtain neurobiological surrogate measures 
of structure, functional connectivity, neural signal cohesion and glutamate: 
 
Screening (screening visit 1): 
a) Structural MRI scan - A whole-brain T1-weighted images will be collected using a twice 
magnetization-prepared rapid gradient echo (MP2RAGE) sequence, with a scanning time of 10 
minutes. The scan will be processed to parcellate the brain and mark the region of interest (left 
IPL). 
b) Spectroscopy voxel scan - A magnetic resonance scan will be undertaken to identify the voxel 
of interest for spectroscopic imaging. A single voxel sequence will be employed with semi-LASER 
preparation. An approximately 20x20x20 mm3 voxel will be placed in the L-IPL, taking 
approximately 5 minutes. 
 
Neuroimaging Protocol (visit 1 and visit 3): 
a) Functional connectivity and neuronal signal cohesion data – a resting state BOLD-fMRI 
scan will be undertaken. Functional connectivity MRI (fcMRI) investigations are conducted with 
subjects resting in the scanner. Approximately ten minutes of whole-brain resting state fMRI data 

 
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will be collected using a simultaneous-multi-slice (SMS) echoplanar- imaging (EPI) sequence of 
factor=4, with echo time (TE) = 25ms, repetition time (TR) = 1500ms, flip angle (FA) = 65°, field 
of view=192 × 192mm2 with 96 slices of 1.5mm isotropic resolution. A whole-brain T1- weighted 
structural image will also be collected using a twice magnetization-prepared rapid gradient echo 
(MP2RAGE) sequence. During the resting state, subjects will be instructed not to undertake any 
particular task and to stay awake with their eyes open on a fixation cross. Whole brain coverage 
will be performed. Data will be pre-processed and analysed using software such as statistical 
parametric mapping (SPM) software package version 12 (SPM12, Wellcome Department of 
Cognitive Neurology, London, United Kingdom) and the Conn (Cognitive and affective 
neuroscience laboratory, MIT, Cambridge, USA) functional connectivity toolbox, all running on 
MATLAB. Upon collection of resting state fcMRI data, the pre-processing steps necessary for 
each analysis will be included such as the removal of physiological artefacts, motion correction, 
realignment, registration, normalization and smoothing. Connectivity indices will be generated 
from matrices informed by our a priori determined regions of interest and standard grey matter 
atlases. Moreover, layer-dependant connectivity and network comparison will be performed. 
 
Regarding BOLD oscillatory markers of neural signalling cohesion: Regional homogeneity (ReHo) and 
Amplitude of Low-Frequency Fluctuations (ALFF) are two complementary methods used to study the 
regional neural activity. They can be estimated using MATLAB based software such as REST 
(http://restfmri.net/forum/index.php?q=rest). The ReHo analysis is a voxel-based measure of the 
similarity using Kendall’s coefficient concordance between the BOLD time-series of a given voxel and its 
nearest neighbours. The ReHo measures the synchrony of adjunct regions and can be used to evaluate 
the consistency of local functional activities in a brain area. While the ALFF approach measures the total 
power of the BOLD signal within the low-frequency range between 0.01 and 0.1 Hz. ALFF has been 
proven to be a valuable parameter to reflect the power of regional spontaneous neuronal activity. 
 
b) Glutamate Imaging – a magnetic resonance spectroscopy scan will be undertaken in order to 
detect the glutamate concentration. A single voxel sequence will be employed with semi-LASER 
preparation. An approximately 20x20x20 mm3 voxel will be placed in the L-IPL and shimming of 
the static magnetic field will be performed using advanced methods best suited to MRS 
acquisition at 7T, such as FASTESTMAP. Spectra will be preprocessed in the MATLAB based 
tool MRspa, then analysed and quantified using LCModel. 
 
In addition, experimental multi-voxel techniques will be explored to investigate the utility of quantitative 
maps of glutamate concentration across the brain. This will be in the form of the Accelerated magnetic 
resonance SPectroscopic Imaging using REadout Segmentation (ASPIRES) technique. This is a multi-
voxel spectroscopic technique which has been developed in-house, building on previous work, and is 
based on the well-known Echo-Planar Spectroscopic Imaging (EPSI) method. ASPIRES uses readout 
segmentation to nullify the spectral bandwidth limitations of standard EPSI methods at 7T and 
undersampling schemes with advance compressed sensing reconstruction to allow for significantly 
shorter, clinically viable acquisition times. 
 
c) Layer Specific fMRI scan - a laminar based resting-state fMRI will be collected using A C2P 
sequence with multiband from CMRR (University of Minnesota) with spin-echo excitation 
sequence. Sub-millimetre fMRI data will be analysed using BrainVoyager software. Pre-
processing and analysis pipeline will include segmentation of the cortical layers, motion 
correction, filtering and up-sampling functional data, co-registration with anatomical data, 
estimation the interaction across cortical layers within the IPL and between IPL layers and other 
ROIs.  
 
 
 
 
 
 
 

 
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6.3 STUDY OUTCOME MEASURES 
 
 
 
6.3.1 
Primary Outcome Measure(s) 
 
 
The primary outcome measures will be: 
 
1. Changes in functional connectivity and neuronal signal cohesion as measured by 7T MRI 
2. Changes in glutamate signal in the L-IPL as measured by 7T MRS  
 
before and after TMS/sham procedure. 
 
. 
 
6.3.2 
Secondary Outcome Measure(s) 
 
 
The secondary outcome measures will be: 
 
1. Changes in pain severity as measured by the Pain NRS  
2. Changes from the Michigan Body Map Regional Pain 
3. Changes in RA disease activity as measured by SDAI, CDAI 
4. Changes in putative pain confounders as measured by PROMIS-Fatigue, PROMIS-Depression, 
PROMIS-Anxiety, PROMIS-Sleep Related Impairment, PROMIS-Physical functioning short 
form, PROMIS-Pain Interference and ACR Fibromyalgia Scale  
5. Changes in blood protein levels of inflammatory cytokines/chemokines  
 
before and after TMS/sham procedure (1) and (5).  
before TMS/sham procedure (2), (3) and (4).  
 
 
 
6.4 LABORATORY TESTS 
 
 
Sample Type 
Screening 
visit 1 
Screening 
visit 2 
Visit 1† 
Visit 2 
Visit 3† 
Visit 4 
SST tube (8.5ml) 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
EDTA tube (4ml) 
 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
EDTA tube (10ml x 
2) 
 
 
✓ 
✓ 
 
✓ 
✓ 
 
PAXgene RNA Tube 
(2.5ml)* 
 
 
✓ 
✓ 
 
✓ 
✓ 
 
† Blood samples will be collected before and after TMS/sham procedure at these visits.  
* This blood sampling will be optional at the discretion of the CI. 
 
Blood samples will be processed and analysed as described in the Pro-BEPP Lab Protocol.  Blood samples 
will be obtained and RNA measured for cytokines, chemokines and other proteins in order to help us 
measure different disturbances of the immune system in relation to rheumatoid arthritis and how they relate 
to the brain’s pain centres.   
 
At the end of the study, samples will be transferred to the auspices of the accredited NHS Greater Glasgow 
and Clyde Biorepository and stored for up to 10 years and disposed of after storage in accordance with the 
Human Tissue Authority's Code of Practice. 
 
  
 

 
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7 Study Device  
 
 
Participants who are eligible for the study will receive transcranial magnetic stimulation using a 70 mm 
Double Coil connected to Super-Rapid magnetic stimulator, Magstim Co., UK. The coil and stimulator 
are developed and manufactured in accordance with ISO 13485:2003 and are CE marked under the 
Medical Device Directive (93/42/EEC). 
 
  
 
Further detail of the device and schedule is given below.  
 
 
 
7.1 TRANSCRANIAL MAGENTIC STIMULATION  
 
 
 
7.1.1 
Neuronavigation Scan 
 
 
 
As part of  screening visit 2, and in preparation of the transcranial magnetic stimulation/scanning session, 
we will identify the optimal spot on the participants head to position the stimulation coil. For precise TMS 
coil positioning, TMS neuronavigation will be used (Brainsight®). This is to optimize stimulation accuracy 
in order to reach the area of the brain where stimulation is likely to have the best effect. To do so, the 
participant will be asked to wear a headband and head cap while sitting on a chair in a room.We will use 
an individual structural brain scan (the 7T scan performed at screening visit 1) and an optical system 
(camera, sensors and a digital pen) that will allow us to identify the spot on their head that is above the 
area in the brain that we will stimulate. We will then write on the head cap the stimulation spot, to be used 
in the next session. The procedure is non-invasive, painless and safe and there are no known or 
foreseeable risks or side effects. The TMS target site will be identified using MNI coordinates (group 
averaged) from our original fMRI connectivity work on RA patients. 
 
 
Figure 1. Magstim Super-Rapid magnetic stimulator and 70 mm Double Coil 

 
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7.1.2 
Motor Threshold Assessment 
 
 
Screening visit 2 will also include assessment of the resting motor threshold. This will be used to 
standardise the intensity of active TMS used in a subsequent session. As is normal practice, single pulse 
TMS will be used to stimulate the left motor cortex, which will be located with the aid of neuronavigation. 
The motor threshold is the minimum intensity required to elicit a motor evoked potential in the 
contralateral hand in at least 50% of trials. This threshold is affected by individual differences in anatomy 
and cortical excitability, and therefore varies between participants. 
 
 
 
7.1.3 
TMS Schedule & Administration 
 
 
Active TMS will consist of a single session of 20 minutes. A figure of 8 coil will be used at 10Hz, 90% 
resting motor threshold intensity and 1200 pulses. The TMS pulses will be given in series of 20 trains of 
6s duration (with 54s intertrain intervals).  
 
 
 
7.1.4 
Rationale for Chosen Dose 
 
 
 
The high-frequency repetitive TMS (rTMS) protocol has been extensively used to interfere with parietal 
lobe network activity. In healthy participants, high frequency (10Hz) rTMS interacts with large-scale 
oscillatory network activity of the parietal lobe in the alpha band, causing changes in perceptual 
thresholds across multiple sensory modalities. Likewise, in healthy participants, high-frequency rTMS 
over the L-IPL reconfigures cortico-cortical network properties as revealed by fMRI. And in chronic pain 
patients, high frequency rTMS appears to relieve pain. Furthermore, there is evidence of analgesic 
efficacy in patients with fibromyalgia where high frequency rTMS has been applied to nonmotor areas. 
 
 
 
7.1.5 
Sham Procedure 
 
 
 
Sham TMS will be applied for the exact same duration with the identical pulse sequence but using a 
sham TMS coil (Magstim Co., UK). This is a replica of the active figure of 8 coil and produces similar 
peripheral effects to the active coil (such as TMS coil clicks) but does not produce electromagnetic fields 
penetrating the skull.  
 
 
 
  
 

 
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8 RISK ASSESSMENT AND ADVERSE EVENTS 
 
 
 
 
8.1 RISK ASSESSMENT 
 
 
Transcranial magnetic stimulation has been used in a growing number of laboratories worldwide since 
1984, however there are some potential adverse effects from TMS. Contraindications will be excluded 
through careful screening. All precautionary measures will be taken to avoid adverse events and safety 
guidelines will be rigorously followed. TMS is considered safe for studies in both healthy participants 
and patients when applied within the safety guidelines and is regarded as having a less than minimal 
risk to study participants. All contraindications and potential adverse effects will be disclosed to the 
participants in the Participant Information Sheet. 
 
Common adverse effects: 
 
Headaches and/or Neck Pain:  Up to 10% of subjects undergoing TMS experience headaches or neck 
pain, which are believed to be due to muscle tension. All prior cases of headaches induced by TMS 
have promptly resolved with a single dose of paracetamol or aspirin. In some cases, TMS may cause 
facial discomfort on the same side of stimulation. 
 
Hearing Problems: TMS produces a loud clicking sound when the current is passed through the 
stimulation coil. The peak sound pressure associated with the TMS pulse has been measured in a 
safety study. At a distance of 10cm and with maximum TMS intensity (100% stimulator output), the 
TMS pulse creates very brief (< 300 micro-sec) peak sound pressure levels of 110 dB (duration of bi-
phasic TMS pulse: 300 micro-sec). Given that the threshold limits of impact noise would be reached 
only after 1’000-10’000 pulses per day (based on American Conference of Governmental Industrial 
Hygienists), the risk of TMS noise is considered small even without hearing protection.  
 
Rare adverse effects: 
 
Syncope: Fainting can occur due to anxiety and psycho-physical discomfort during testing and 
treatment with TMS. Subjects will be monitored for feeling any signs or symptoms of a pending 
syncopal event (i.e. feeling “dizzy, lightheaded or going to pass out”). If this is the case, TMS will 
immediately be stopped and the participant will be assisted.  
 
Seizures: TMS can cause a seizure; however, this is an extremely rare problem. Fewer than 25 cases 
have been reported from the thousands of studies conducted internationally and the risk of a seizure 
from repeated courses of TMS is substantially less than one in a thousand. To make the participants’ 
risk as small as possible, the investigators will follow all precautions that are recommended by the 
International Society for Transcranial Stimulation and mentioned in the 2008 updated safety guidelines 
of The Safety of TMS Consensus Group. 
 
Memory: TMS could induce transient and weak changes in memory, attention and other cognitive and 
mental functions up to maximally an hour after TMS. This is a rare risk. 
 
 
 
8.2 ADVERSE EVENTS (AEs) 
 
 
An adverse event is any untoward medical occurrence, unintended disease or injury, or untoward clinical 
signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not related 
to the investigational medical device. 
 
Note 1 to entry: This definition includes events related to the investigational medical device or the 
comparator. 

 
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Note 2 to entry: This definition includes events related to the procedures involved. 
Note 3 to entry: For users or other persons, this definition is restricted to events related to the use of 
investigational medical devices. 
 
 
8.3 SERIOUS ADVERSE EVENT (SAE)  
 
 
An adverse event that led to any of the following: 
a) death, 
b) serious deterioration in the health of the subject, users or other persons as defined by one or 
more of the following: 
1) a life-threatening illness or injury, or 
2) a permanent impairment of a body structure or a body function including chronic 
diseases, or 
3) in-patient or prolonged hospitalisation, or 
4) medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function, 
c) foetal distress, foetal death or a congenital abnormality or birth defect including physical or 
mental impairment 
 
Note 1 to entry: Planned hospitalisation for a pre-existing condition, or a procedure required by the CI 
without serious deterioration in health, is not considered a serious adverse event. 
 
 
 
8.4 SERIOUS ADVERSE DEVICE EVENT (SADE)  
 
 
A serious adverse device effect (SADE) is any adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. A SADE may be anticipated or unanticipated. 
 
Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or 
outcome has been identified in the risk analysis report.  
 
 
Unanticipated serious adverse device effect (USADE) is a serious adverse device effect which by its 
nature, incidence, severity or outcome has not been identified in the current version of the risk analysis 
report. 
 
 
8.5 RECORDING AND REPORTING OF ADVERSE EVENTS 
 
 
Reports of non-serious Adverse Events (AE), Serious Adverse Events (SAE), serious adverse device 
events (SADE) or other errors outside of what is foreseen in the protocol (irrespective if a clinical event 
has occurred)  will be reported to the CI and will be submitted to the Research Ethics Committee (REC) 
using the Non-CTIMP safety report to REC form. 
 
Only reports of SAEs, non-serious AEs or SADEs that are 1. related to the study (i.e. they resulted from 
administration of any of the research procedures) and 2. unexpected (USADE) should be submitted.  
 
These should be sent within 15 days of the CI becoming aware of the event. There is no requirement for 
annual safety reports in addition to the information provided through the annual progress report. 
 
 
 
 
 

 
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9 STATISTICS AND DATA ANALYSIS 
 
 
 
 
9.1 STATISTICAL ANALYSIS PLAN 
 
 
The study will have a comprehensive Statistical Analysis Plan, which will govern all statistical aspects of 
the study, and will be agreed by the Trial Management Group (TMG) before any unblinded data is seen. 
 
The primary outcomes measures are changes in functional connectivity and neuronal signal cohesion 
as measured by 7T MRI and changes in glutamate signal in the L-IPL as measured by 7T MRS, before 
and after TMS/sham procedure in patients with RA. 
 
The secondary outcome measures are changes in pain severity, changes in RA disease activity, 
changes in putative pain confounders and changes in inflammatory cytokines/chemokines before and 
after TMS/sham procedure in patients with RA. 
 
1) Descriptive statistics and data visualization. Median values and interquartile ranges of primary 
and secondary outcomes will be generated for each of the four time points. Paired plots for raw data and 
boxplots will be generated showing difference scores in the outcomes following sham and active TMS. 
 
2) Hypothesis testing. Paired-difference tests for parametric data (paired sample t-tests) will be used 
to test our hypotheses by comparing the change in outcomes following sham TMS to the change in 
outcomes following active TMS. Hypothesis testing will be two-sided with alpha = .05, and 95% 
confidence intervals around the contrast will be generated using bootstrapping with 20,000 resamples. 
 
3) Effect Size: As a simple expression of effect size, the proportion of subjects showing greater, equal 
and lesser reduction in glutamate between active and sham conditions will be reported. For the 
calculation of sample size estimates for future studies, the standardized mean difference effect size for 
within-subject designs (d-z) will be calculated (Reference 40). 
 
4) Outcome inter-relationships: Exploratory correlations will examine the relationships between the 
different outcomes and their change 
 
 
9.2 SAFETY ANALYSIS 
 
 
The safety data (serious adverse events) – both numbers of subjects and events – will be summarised 
overall using descriptive statistics.  
 
 
 
9.3 SOFTWARE FOR STATISTICAL ANALYSIS 
 
 
The statistical software to be used will be specified in the Statistical Analysis Plan. It is likely to be either 
SAS 9.4 for Windows, Cary, NC, USA or R version 4.0 (R Core Team (2016). R: A language and 
environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. 
https://www.R-project.org/.) or higher versions of those programs. 
 
 
 
9.4 SAMPLE SIZE 
 
 
Although inadequately powered to investigate the specific relationship between pain and the MRI 
metrics, changes in glutamate concentration and functional connectivity pre- and post-TMS have 

 
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previously been measured at 3T in sample sizes of n<20. Likewise, changes in pain experience after 
rTMS have been reported in studies with sample sizes of n<20. 
 
 
9.5 MANAGEMENT AND DELIVERY 
 
 
All files will receive a Digital Object Identifier (DOI), with associated metadata being listed in the 
University of Glasgow Research Data Registry and the DataCite metadata store. The DOI of each 
dataset will be included in any publication reporting it, allowing each dataset to be identified and 
accessed by researchers reading the publication. DOIs will also be linked with appropriate records in the 
University’s publication repository to enhance visibility of datasets 
 
 
 
10 TRIAL CLOSURE / DEFINITION OF END OF TRIAL 
 
 
The trial will end once last participant has completed the last visit. 
 
 
 
12 TRIAL MANAGEMENT 
 
 
 
 
12.1 ROUTINE MANAGEMENT OF TRIAL: TRIAL MANAGEMENT GROUP 
 
 
 
11 DATA HANDLING 
 
 
 
 
11.1 CASE REPORT FORMS / ELECTRONIC DATA RECORD 
 
 
An eCRF will be used to collect study data. The eCRF will be developed by the study team using Castor 
and access to the eCRF will be restricted, with only authorised, site-specific personnel able to make 
entries or amendments to their participants’ data. It is the investigator’s responsibility to ensure 
completion and to review and approve data captured in the eCRF. 
 
Data will be validated at the point of entry into the eCRF and at regular intervals during the study. Data 
discrepancies will be flagged to relevant members of the research team and any data changes will be 
recorded in order to maintain a complete audit trail (e.g. reason for change, date change made, who 
made change). 
 
 
 
11.2 RECORD RETENTION 
 
 
To enable evaluations and/or audit from regulatory authorities, the investigator agrees to keep records, 
including the identity of all participating subjects (sufficient information to link record), all original signed 
informed consent forms, serious adverse event forms, source documents, and detailed records of 
treatment disposition in accordance with ICH GCP, local regulations, whichever is longer.  The University 
of Glasgow as per its Code of Good Research Practice will keep pseudonymised research data for 10 
years after the study ends. 
 

 
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The trial will be co-ordinated by the Trial Management Group (TMG). The TMG normally includes those 
individuals responsible for the day-to-day management of the trial, such as the CI, statistician, project 
manager, research nurse, and research fellow. The role of the group is to monitor all aspects of the 
conduct and progress of the trial, ensure that the protocol is adhered to and take appropriate action to 
safeguard participants and the quality of the trial itself. 
 
 
  
 
 
13 STUDY AUDIT 
 
 
This study may be selected randomly for audit by NHS Greater Glasgow and Clyde governance team 
following the annual audit plan.  
 
14 PROTOCOL AMENDMENTS 
 
 
Any change in the study protocol will require an amendment. Any proposed protocol amendments will 
be initiated by the CI following discussion with the TMG and any required amendment forms will be 
submitted to the REC and sponsor.  
 
The CI will liaise with the study sponsor to determine whether an amendment is non-substantial or 
substantial. All amended versions of the protocol will be signed by the CI and sponsor representative.  
 
Before the amended protocol can be implemented, favourable opinion/approval must be sought from the 
original reviewing REC, and Research and Development (R&D) office(s). 

 
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15 ETHICAL CONSIDERATIONS 
 
 
 
15.1 ETHICAL CONDUCT OF THE STUDY 
 
 
The study will be carried out in accordance with the World Medical Association Declaration of Helsinki 
(1964) and its revisions (Tokyo [1975], Venice [1983], Hong Kong [1989], South Africa [1996], Edinburgh 
[2000], Seoul [2008] and Fortaleza [2013]). 
 
Favourable ethical opinion will be sought from a REC before participants are recruited into this clinical 
study. Participants will only be allowed to enter the study once they have provided written informed 
consent or their next of kin have provided written informed assent (if required). 
 
The CI will be responsible for updating the REC of any new information related to the study. 
 
 
 
15.2 INFORMED CONSENT 
 
 
 
Written informed consent will be obtained from each study participant.  
 
The research nurse or investigator will explain the exact nature of the study in writing, provision of 
participant information sheet, and verbally. This will include the known side-effects that may be 
experienced, and the risks of participating in this study. Participants will be informed that they are free to 
withdraw their consent from the study at any time. 
 
 
16 INSURANCE AND INDEMNITY 
 
 
 
The Pro-BEPP study is sponsored by NHS Greater Glasgow and Clyde. The sponsor will be liable for 
negligent harm caused by the management of the trial. As employers of the protocol authors, both NHS 
GG&C and the University of Glasgow will be liable for negligent harm caused by the design of the study.  
NHS GG&C, as the site of the study, will be responsible for harm caused by the conduct of the study.  
NHS indemnity is provided under the Clinical Negligence and Other Risks Indemnity Scheme (CNORIS).  
University of Glasgow clinical trials insurance will apply. 
 
The NHS has a duty of care to patients treated, whether or not the patient is taking part in a clinical trial, 
and the NHS remains liable for clinical negligence and other negligent harm to patients under its duty of 
care. 
 
 
17 FUNDING 
 
 
 
18 ANNUAL REPORTS 
 
 
Annual progress reports will be submitted to REC on the anniversary of the ethics favourable opinion. A 
copy of this report will also be sent to the Sponsor. 
 The study is supported by Versus Arthritis “Probing the Rheumatoid Arthritis Brain to Elucidate Central 
Pain Pathways ”. 

 
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19 DISSEMINATION OF FINDINGS 
 
 
In addition to the traditional academic routes of communication and dissemination via peer reviewed 
publication and national and international conferences, we will also use Research into Inflammatory 
Arthritis Centre Versus Arthritis (RACE) and Glasgow Arthritis Involvement Network (GAIN) Patient 
Research Partner (PRP) networks to develop local patient and public involvement (PPI) groups. 
Supported by Engagement Leads (EL) already in place at each institution, RACE PRPs will form a key 
part of our communications programme. A PRP member from each institution already attends quarterly 
centre meetings, accompanied by institutional ELs. 
 
We aim to communicate to the student body in our University via PRP-Student Mentor/Buddy system. 
Newly appointed PhD students in areas related to this project will be paired with a local PRP volunteer 
for the duration of their project, ensuring the patient remains at the core of the research and giving the 
students the opportunity to develop insight and the required skills to communicate their ideas and impact 
of their work with members of the public. 
 
Local PRP Forum Membership. We will join the local RACE scientific meetings, affording local PRPs the 
opportunity to interact with the wider RACE community. 
 
Communications support. We will provide lay summaries of the project to the IMID community, as well 
as contributing to the RACE website. Study Summary results will be available via newsletter.  We will 
ask participants to consent to give their contact details ( home /email address) for the purpose of study 
communication including the dissemination of  a newsletter.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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1. 
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med 2011; 365(23): 2205-
2219. 
 
2. 
Conaghan PG, Strand V, Alten R, Sullivan E, Blackburn S, Huneault L et al. OP0107 Pain still 
remains a high unmet need among psoriatic arthritis patients receiving existing biologic treatment: 
results from a multi national real-world survey, vol. 762017, 96.92-97pp. 
 
3. 
Rifbjerg-Madsen S, Christensen AW, Christensen R, Hetland ML, Bliddal H, Kristensen LE et al. 
Pain and pain mechanisms in patients with inflammatory arthritis: A Danish nationwide cross-
sectional DANBIO registry survey. PLoS One 2017; 12(7): e0180014. 
 
4. 
Schrepf A, Kaplan CM, Ichesco E, Larkin T, Harte SE, Harris RE et al. A multi-modal MRI study of 
the central response to inflammation in rheumatoid arthritis. Nature Communications 2018; 9(1): 
2243. 
 
5. 
Boyden SD, Hossain IN, Wohlfahrt A, Lee YC. Non-inflammatory Causes of Pain in Patients with 
Rheumatoid Arthritis. Current Rheumatology Reports 2016; 18(6): 30. 
 
6. 
Basu N, Kaplan CM, Ichesco E, Larkin T, Harris RE, Murray A et al. Neurobiologic Features of 
Fibromyalgia Are Also Present Among Rheumatoid Arthritis Patients. Arthritis & Rheumatology 
2018; 70(7): 1000-1007. 
 
7. 
Cai K, Haris M, Singh A, Kogan F, Greenberg JH, Hariharan H et al. Magnetic resonance imaging 
of glutamate. Nature Medicine 2012; 18(2): 302-306. 
 
8. 
Basu N, Murray AD, Jones GT, Reid DM, Macfarlane GJ, Waiter GD. Neural correlates of fatigue 
in granulomatosis with polyangiitis: a functional magnetic resonance imaging study. Rheumatology 
2014; 53(11): 2080-2087. 
 
9. 
Eldaief MC, Halko MA, Buckner RL, Pascual-Leone A. Transcranial magnetic stimulation modulates 
the brain's intrinsic activity in a frequency-dependent manner. Proc Natl Acad Sci U S A 2011; 
108(52): 21229-21234. 
 
10. 
Lefaucheur JP, André-Obadia N, Antal A, Ayache SS, Baeken C, Benninger DH et al. Evidence-
based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS). Clin 
Neurophysiol 2014; 125(11): 2150-2206. 
 
 
 
20 REFERENCES