Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant's Mode of Analgesic Action in Rheumatoid Arthritis
Conditions: Rheumatoid Arthritis
Sponsor: NHS Greater Glasgow and Clyde

VERSION NUMBER 1.1 
Page 1 of 35 
VERSION DATE 28.10.2022 
 
 
GLASGOW CLINICAL TRIALS UNIT 
FORM 51.001A 
V7.0 
 
 
 
Exploiting Leading Edge 7T MRI Brain Imaging to Decipher 
Olumiant’s Mode of Analgesic Action in Rheumatoid 
Arthritis 
SOAR 
Running Title 
SOAR 
Protocol Version 
FINAL Ver 1.1 
Protocol Date 
28.10.2022 
REC Reference Number 
21/SW/0077 
ISRCTN / Clinical Trial.gov 
NCT05112120 
Sponsor Protocol Number 
GN19RH319 
Sponsor 
NHS Greater Glasgow and Clyde 
Funder 
Lilly 
AMENDMENT NUMBER 
DATE 
PROTOCOL VERSION 
1 
28.10.2022 
1.1 Change of Trial Manager 
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 

SOAR - Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant’s Mode of Analgesic Action 
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CHIEF INVESTIGATOR 
Dr Neil Basu 
Clinical Senior Lecturer Rheumatology / Honorary Consultant 
Institute of Infection, Immunity & Inflammation 
Sir Graeme Davies Building 
120 University Place 
Glasgow 
G12 8TA 
T: 0141 330 1718 
E: neil.basu@glasgow.ac.uk 
CO-INVESTIGATORS 
Professor Jonathan Cavanagh 
Professor Duncan Porter 
Professor of Psychiatry 
Honorary Professor of Rheumatology 
Institute of Infection, Immunity & Inflammation 
Gartnavel General Hospital 
Sir Graeme Davies Building 
Dept of Rheumatology 
120 University Place 
1053 Great Western Road 
Glasgow 
Glasgow 
G12 8TA 
G12 0YN 
T: 0141 330 7769 
T: 0141 211 3492 
E: Jonathan.Cavanagh@glasgow.ac.uk 
E: duncan.porter@glasgow.ac.uk 
Professor Richard Harris 
Professor Daniel Clauw 
Director of Pain and Fatigue Neuroimaging 
Professor of Anaesthesiology, Rheumatology 
and Psychiatry 
Chronic Pain and Fatigue Research Centre 
Chronic Pain and Fatigue Research Centre 
24 Frank Lloyd Wright Drive 
24 Frank Lloyd Wright Drive 
Lobby M, Suite 3100 
Lobby M, Suite 3100 
University of Michigan 
University of Michigan 
48106-5737 
48106-5737 
T: 
T: 
E: reharris@med.umich.edu 
E: dclauw@med.umich.edu 

SOAR - Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant’s Mode of Analgesic Action 
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Professor David Porter 
Professor Iain McInnes 
Professor in Magnetic Resonance Imaging 
Physics 
Professor of Experimental Medicine 
University of Glasgow 
Institute of Infection, Immunity & Inflammation 
CCNi 
Sir Graeme Davies Building 
58 Hillhead Street 
120 University Place 
Glasgow 
Glasgow 
G12 8QB 
G12 8TA 
T: 
T: 0141 330 8657 
E: David.Porter@glasgow.ac.uk 
E: Iain.McInnes@glasgow.ac.uk 
PROJECT MANAGER / STUDY CO-ORDINATOR 
Miss Maxine Arnott 
Institute of Infection, Immunity & Inflammation 
Sir Graeme Davies Building 
120 University Place 
Glasgow 
G12 8TA 
T: 07890059695 
F: FAX NUMBER 
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 
 
SPONSOR 

SOAR - Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant’s Mode of Analgesic Action 
in Rheumatoid Arthritis 
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FINAL VERSION 1.1 
 
 
 
GLASGOW CLINICAL TRIALS UNIT 
FORM 51.001A 
V7.0 
This clinical trial is sponsored by NHS Greater Glasgow and Clyde 
Sponsor’s representative: 
Emma-Jane Gault 
Research Governance Officer 
Room 327, Wolfson Medical School Building 
University of Glasgow 
Glasgow 
G12 8QQ 
T: 0141 330 5519 
E: emmajane.gault@glasgow.ac.uk 
 
 
FUNDING BODY 
This clinical trial is funded by Lilly. 
Administered by: 
Eli Lilly and Company Limited 
Lilly House 
Priestley Road 
Basingstoke 
Hampshire 
United Kingdom RG24 9NL 
T: +44 (0) 1256 315000 

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GLASGOW CLINICAL TRIALS UNIT 
FORM 51.001A 
V7.0 
Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant’s Mode of Analgesic Action 
in Rheumatoid Arthritis 
Chief Investigator: Dr Neil Basu 
Institute of Infection, Immunity & Inflammation 
Sir Graeme Davies Building 
120 University Place 
Glasgow 
G12 8TA 
Signature: 
 
Date: 28.10.2022 
Sponsor Representative: 
Emma-Jane Gault 
Research Governance Officer 
Room 327, Wolfson Medical School Building 
University of Glasgow 
Glasgow 
G12 8QQ 
Signature: 
Date: DATE 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..................................................................................................................... 8 
STUDY SYNOPSIS ............................................................................................................................... 10 
STUDY FLOW CHART.......................................................................................................................... 12 
SCHEDULE OF ASSESSMENTS ......................................................................................................... 13 
1 
INTRODUCTION ............................................................................................................................ 15 
1.1 
RATIONALE ......................................................................................................................... 15 
1.2 
BACKGROUND ................................................................................................................... 15 
1.3 
STUDY HYPOTHESIS ......................................................................................................... 16 
2 
STUDY OBJECTIVES .................................................................................................................... 16 
2.1 
PRIMARY ENDPOINT ......................................................................................................... 16 
2.2 
SECONDARY ENDPOINT(S) .............................................................................................. 16 
3 
STUDY DESIGN ............................................................................................................................. 17 
3.1 
STUDY POPULATION ......................................................................................................... 17 
3.2 
INCLUSION CRITERIA ........................................................................................................ 17 
3.3 
EXCLUSION CRITERIA ....................................................................................................... 17 
3.4 
IDENTIFICATION OF PARTICIPANTS AND CONSENT .................................................... 17 
3.5 
WITHDRAWAL OF SUBJECTS ........................................................................................... 18 
4 
TRIAL PROCEDURES ................................................................................................................... 19 
4.1 
STUDY SCHEDULE ............................................................................................................ 19 
4.1.1 
Screening & Baseline (Day 0) .......................................................................................... 19 
4.1.2 
VISIT 2 : Week 12 ± 14 days ........................................................................................... 19 
4.2 
BRAIN IMAGING PROTOCOLS .......................................................................................... 20 
4.2.1 
MRI and MRS Protocols .................................................................................................. 20 
4.2.2 
Ultrasound Protocol ......................................................................................................... 21 
4.2.3 
Quantitative Sensory Testing Protocol ............................................................................. 21 
4.3 
STUDY OUTCOME MEASURES ........................................................................................ 22 
4.3.1 
Primary Outcome Measure(s) .......................................................................................... 22 
4.3.2 
Secondary Outcome Measure(s) ..................................................................................... 22 
4.4 
LABORATORY TESTS ........................................................................................................ 23 
5 
Study Medication ............................................................................................................................ 23 
5.1 
OLUMIANT TREATMENT SCHEDULE & ADMINISTRATION ............................................ 23 
5.1.1 
Olumiant Treatment After the Study ................................................................................ 23 
5.2 
CONCOMITANT MEDICINES ............................................................................................. 23 
5.2.1 
Permitted Concomitant Medicines ................................................................................... 23 
5.2.2 
Prohibited Concomitant Medicines................................................................................... 24 

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5.3 
DISCONTINUATION OF STUDY MEDICINES ................................................................... 24 
5.3.1 
Supply of Study Treatment .............................................................................................. 24 
6 
PHARMACOVIGILANCE................................................................................................................ 25 
6.1 
DEFINITIONS OF ADVERSE EVENTS (AEs) ..................................................................... 25 
6.2 
SERIOUS ADVERSE EVENT (SAE) ................................................................................... 25 
6.3 
RECORDING AND REPORTING OF ADVERSE EVENTS ................................................ 25 
7 
STATISTICS AND DATA ANALYSIS ............................................................................................. 27 
7.1 
STATISTICAL ANALYSIS PLAN ......................................................................................... 27 
7.2 
PRIMARY EFFICACY ANALYSIS ....................................................................................... 27 
7.3 
SECONDARY EFFICACY ANALYSIS ................................................................................. 28 
7.4 
SAFETY ANALYSIS ............................................................................................................ 28 
7.5 
SOFTWARE FOR STATISTICAL ANALYSIS ...................................................................... 28 
7.6 
SAMPLE SIZE ..................................................................................................................... 28 
7.7 
MANAGEMENT AND DELIVERY ........................................................................................ 28 
8 
TRIAL CLOSURE / DEFINITION OF END OF TRIAL .................................................................... 29 
9 
DATA HANDLING ...........................................................................................................................29 
9.1 
CASE REPORT FORMS / ELECTRONIC DATA RECORD ................................................ 29 
9.2 
RECORD RETENTION ........................................................................................................ 29 
10 TRIAL MANAGEMENT .................................................................................................................. 30 
10.1 
ROUTINE MANAGEMENT OF TRIAL: TRIAL MANAGEMENT GROUP ............................ 30 
11 STUDY AUDIT ................................................................................................................................ 30 
12 PROTOCOL AMENDMENTS ......................................................................................................... 30 
13 ETHICAL CONSIDERATIONS ....................................................................................................... 31 
13.1 
ETHICAL CONDUCT OF THE STUDY ............................................................................... 31 
13.2 
INFORMED CONSENT ....................................................................................................... 31 
14 INSURANCE AND INDEMNITY ..................................................................................................... 31 
15 FUNDING ....................................................................................................................................... 31 
16 ANNUAL REPORTS ...................................................................................................................... 31 
17 DISSEMINATION OF FINDINGS ................................................................................................... 32 
18 REFERENCES ............................................................................................................................... 33 
19 APPENDIX ..................................................................................................................................... 35 

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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 
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 
DAN 
Dorsal Attention Network 
DAS 
Disease Activity Score 
DMARD 
Disease-Modifying Anti-Rheumatic Drug 
DMN 
Default Mode Network 
DOI 
Digital Object Identifier 
eCRF 
Electronic case report form 
EL 
Engagement Leads 
EPR 
Electronic Patient Record 
EPSI 
Echo-planar Spectroscopic Imaging 
EULAR 
European League Against Rheumatism 
fMRI 
Functional Magnetic resonance imaging 
GAIN 
Glasgow Arthritis Involvement Network 
GluCEST 
Glutamate Chemical Exchange Saturation Transfer 
ICA 
Independent Component Analysis 
IMID 
Immune-mediated inflammatory diseases 
JAK 
Janus Kinase 
JAKi 
Janus Kinase Inhibitor 
LIPL 
Left Inferior Parietal Lobule 
MRS 
Magnetic Resonance Spectroscopy 
NMDA 
N-methyl-d-aspartate 
PPI 
Patient and Public Involvement 
PPT 
Pressure Pain Thresholds 

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PROMIS 
Patient Reported Measurement Information Service 
PRP 
Patient Research Partner 
QST 
Quantitative Sensory Testing 
RA 
Rheumatoid Arthritis 
RACE 
Research into Inflammatory Arthritis Centre Versus Arthritis 
REC 
Research Ethics Committee 
ROI 
Region of Interest 
SAE 
Serious Adverse Event 
SBA 
Seed-Based Correlation Analysis 
SDAI 
Simple Disease Activity Index 
STAT 
Signal Transducer and Activator of Transcription 
7T 
7 Tesla 
TMG 
Trial Management Group 
TNF 
Tumour Necrosis Factor 

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STUDY SYNOPSIS 
Title of Study 
Exploiting Leading Edge 7T MRI Brain Imaging to Decipher Olumiant’s 
Mode of Analgesic Action in Rheumatoid Arthritis 
Lead Study Centre 
University of Glasgow/NHS Greater Glasgow and Clyde 
Duration of Study 
24 months 
Primary Objective 
1) To evaluate the effects of Olumiant on Default Mode Network (DMN)- 
Insula connectivity and insular glutamate levels in rheumatoid arthritis (RA) 
(neurobiological markers of fibromyalgia). 
2) To evaluate the effects of Olumiant on Dorsal Attention Network (DAN)- 
Left Inferior Parietal Lobule (LIPL) connectivity in RA (neurobiological 
marker of peripheral inflammation). 
Secondary Objective 
To explore the relationship between pain, clinical phenotype, peripheral 
immune markers and their change with MRI markers indicative of CNS 
pathway function. 
Primary Endpoints 
The primary neuroimaging metrics of interest are functional connectivity and 
glutamate concentration 
Rationale 
The revolution in rheumatoid arthritis therapeutics has been transformative 
for many patient outcomes. Yet most patients continue to experience life 
disabling pain. Strikingly, even those who achieve full disease remission with 
state-of-the-art anti-tumour necrosis factor (TNF) treatments report 
substantially higher levels of pain when compared to the general population. 
Such disconnect presents one of the greatest contemporary challenges to 
the care of patients with RA. 
Considering the ongoing excess burden of pain in this patient population, 
RA patients receiving Olumiant, a Janus Kinase (JAK) 1/2 inhibitor, report 
superior and more rapid pain improvements in comparison to those 
receiving anti-TNF therapy. However, the majority of this effect could not be 
explained by markers of peripheral inflammation and remains to be 
understood. 
Methodology 
This single-centre, single arm observational cohort study will allow us to 
investigate Olumiant’s mechanism of analgesic action in RA patients. 
Sample Size 
20 participants 
Screening 
Patients with active RA attending clinics in NHS Greater Glasgow and Clyde 
who are scheduled to begin Olumiant as part of their standard NHS clinical 
care will be asked to contribute to this study by their point of care team. 
Inclusion Criteria 
 
Adults ≥ 18 years < 75 years. 
 
Clinical diagnosis of RA 
 
Selected to start Olumiant by their usual rheumatology clinical 
team in line with local guidance (previous failure of at least 2 
DMARDs and moderate to severe active disease). 
 
Right-handed (to reduce neuroimaging heterogeneity). 
 
Exclusion Criteria 
 
Inability to provide written informed consent. 

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 
Severe physical impairment (e.g. blindness, deafness, paraplegia). 
 
Pregnant or breast feeding. 
 
Contraindications to MRI (e.g. severe claustrophobia). 
 
Major confounding neurological disease including Multiple 
Sclerosis, Stroke, Traumatic Brain Injury, Parkinson’s Disease, 
Alzheimer’s Disease 
 
Previous targeted synthetic (e.g. Oluminant, tofacitinib) DMARD 
exposure. 
 
Co-morbid medical conditions that may significantly impair physical 
functional status 
 
Medical or psychiatric conditions that in the judgment of study 
personnel would preclude participation in this study (e.g., 
malignancy, psychosis, suicidal ideation) 
 
BMI > 40 or unable to lie comfortably in MRI 
Product, Dose, Modes of 
Administration 
Olumiant will be administered following standard of care guidelines. 
Duration of Study 
Participation 
12 weeks 
Statistical Analysis 
To assess whether treatment with Olumiant results in a reduction in 
functional connectivity (DMN-Insula and DAN-IPL) and glutamate 
quantification, changes in our neuroimaging metrics of interest between time 
points will be evaluated using paired t-tests. Changes in pain, clinical 
phenotyping and immunophenotyping measures will be correlated with 
those significant regions identified from our primary objective. Putative 
confounders will be explored using general linear models. 

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Study Procedure 
Visit 1 - Screening & 
Baseline 
Visit 2 - 12 week 
Inclusion/exclusion criteria 

Informed consent 

EULAR Disease Activity Score (DAS28) 


ACR/EULAR Classification Criteria for RA 

CDAI 


SDAI 


7-Day Symptom Diary (Numeric Rating 
Scale) 


American College of Rheumatology 
Fibromyalgia Scale 


McGill Pain Questionnaire 


Michigan Body Map Regional Pain 


PROMIS-Depression 


PROMIS-Anxiety 


PROMIS-Fatigue 


PROMIS-Sleep related impairment 


PROMIS-Physical functioning short form 


PROMIS-Pain inference 


Pain NRS Pain Number Rating Scale 


FACIT-Fatigue Scale 


Global Impression Of Change (participant) 

Cognitive Failures Questionnaire 


Sickness Questionnaire 



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Demographics 

BMI 

Drug Assessment 


Past Medical History 

Blood sample for immunophenotyping* 


7T magnetic resonance protocol 


Ultrasound of joints** 


Quantitative sensory testing (QST)** 


Recording of Adverse Events 

* Blood sample schedule outlined in 4.4 LABORATORY TESTS 
** Consent to these procedures is optional 

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1 INTRODUCTION 
 
1.1 RATIONALE 
The revolution in rheumatoid arthritis (RA) therapeutics has been transformative for many patient 
outcomes. Yet most patients continue to experience life disabling pain1. Strikingly, even those who 
achieve full disease remission with state-of-the-art anti-TNF treatments report substantially higher levels 
of pain when compared to the general population2. Such disconnect presents one of the greatest 
contemporary challenges to the care of patients with RA. 
 
Considering the ongoing excess burden of pain in this patient population, the RA-BEAM trial presented 
welcome data. RA patients randomised to Olumiant, a JAK1/2 inhibitor, reported superior and more rapid 
pain improvements in comparison to those receiving anti-TNF therapy3. However, the majority of this 
effect could not be explained by markers of peripheral inflammation and remains to be understood4. 
 
1.2 BACKGROUND 
We believe that RA is a mixed pain state i.e. pain pathways exist in addition to established peripheral 
inflammatory nociceptive mechanisms. In particular, the central nervous system (CNS) may have an 
important role in determining RA pain. Recently our group were the first to delineate distinct 
neurobiological pain signatures in the brains of RA patients by employing 3T functional connectivity 
magnetic resonance imaging (fcMRI) – a recent adaptation of functional MRI data that examines the 
synchrony of neural activity which modulates the efficiency and extent of neuronal transmission between 
brain regions. Specifically, we identified and replicated two distinct pain signatures: a) enhanced 
functional connectivity between the Default Mode Network (DMN) and insula which was unrelated to 
levels of peripheral inflammation but, intriguingly, is an established neurobiological marker of fibromyalgia 
(an archetypal CNS determined chronic pain disorder)5 and b) enhanced functional connectivity between 
the Dorsal Attention Network (DAN) and the left inferior parietal lobule (LIPL)6 which was related to levels 
of peripheral inflammation. 
 
Pre-clinical experiments have not only implicated the JAK- signal transducer and activator of transcription 
(STAT) pathway with peripheral immune system functioning but also the brain7, 8. In the CNS, this 
pathway promotes gene expression associated with inflammation which in turn generates pro-nociceptive 
cytokines such as TNFα8. However, there is now also emerging evidence to support the pathway’s direct 
role in synaptic transmission and neurotransmitter receptor modulation. Specifically, the JAK-STAT 
pathway appears important in N-methyl-d-aspartate (NMDA) related synaptic plasticity – a ubiquitous 
glutamate receptor of the human brain. Their induction is selectively blocked by JAK inhibitors and JAK2 
knockdown abolishes NMDA functioning7. Increases in glutamate and subsequent binding to NMDA 
receptors cause chaotic and incoherent neuronal functional activity9. In human studies of fibromyalgia, 
we have consistently evidenced both elevated glutamate levels within the insula and dysfunctional neural 
connectivity10, 11. Moreover, we have shown that fibromyalgia pharmacotherapy (pregablin), considered 
to reduce neural glutamate, rectifies both insular glutamate and pro-nociceptive brain functional 
connectivity (DMN-insula)12. JAK inhibition (JAKi) may facilitate the reduction of glutamate-NMDA binding 
and ultimately pain alleviation by normalising the functional activity of these same neural connections. 
 
There are clear practical constraints of sampling fresh human brain tissue in order to interrogate these 
possible mechanisms. Instead, neurobiological surrogate imaging measures may be employed. In 
Glasgow we benefit from the only clinical based ultra-high resolution 7T MRI scanner in the UK. Unlike 
lesser resolutions, 7T can distinguish the resonance of glutamate from other metabolites and so more 
precisely quantify our chemical of interest. Further, the superior spatial resolution of 7T enhances 
capacity to indirectly measure neuronal functional connectivity. 

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1.3 STUDY HYPOTHESIS 
 
We hypothesise that Olumiant’s mechanism of analgesic action is determined by at least two factors. The 
first is related to those pathways seen in fibromyalgia, mediated via DMN-insula connectivity and insular 
glutamate. The second is related to peripheral inflammation, mediated via DAN-LIPL. 
 
2 STUDY OBJECTIVES 
1) To evaluate the effects of Olumiant on DMN-Insula connectivity and insular glutamate levels in RA 
(neurobiological markers of fibromyalgia). 
 
2) To evaluate the effects of Olumiant on DAN-LIPL connectivity in RA (neurobiological marker of 
peripheral inflammation). 
 
3) To explore the relationship between pain, clinical phenotype, peripheral immune markers and their 
change with MRI markers indicative of CNS pathway function. 
 
2.1 PRIMARY ENDPOINT 
The primary endpoints are changes in: 
 
 
brain functional connectivity (DMN-Insula and DAN-LIPL) as measured by 7T MRI 
 
insular glutamate signal as measured by 7T MRS 
Between baseline and visit 2 (week 12) 
 
 
 
Changes in clinical phenotype, pain, depression and anxiety as measured by: 
o 
EULAR Disease Activity Score (DAS28) 
o 
CDAI 
o 
SDAI 
o 
7-Day Symptom Diary (Numeric Rating Scale) 
o 
American College of Rheumatology Fibromyalgia Scale 
o 
McGill Pain Questionnaire 
o 
PROMIS-Depression 
o 
PROMIS-Anxiety 
o 
PROMIS-Fatigue 
o 
PROMIS-Sleep related impairment 
o 
PROMIS-Physical functioning short form 
o 
PROMIS-Pain inference 
o 
Pain Number Rating Scale 
o 
FACIT-Fatigue Scale 
o 
Global Impression of Change (participant) 
o 
Cognitive Failures Questionnaire 
o 
Sickness Questionnaire 
o 
Synovitis score (from joint ultrasound) 
o 
Pain sensitivity variables (from QST measures) 
 
Changes in inflammatory cytokines/chemokines Between baseline and visit 2 (week 12) 
2.2 SECONDARY ENDPOINT(S) 

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3 STUDY DESIGN 
This study will be performed according to the UK policy framework for health and social care research 
(version 3.3, 07 November 2017). 
 
The trial design is detailed below and is summarised in STUDY FLOW CHART and SCHEDULE OF 
ASSESSMENTS. The trial is a single-centre observational cohort study to test the hypothesis that 
Olumiant’s mechanism of analgesic action is determined by at least two factors, the first relating to 
pathways seen in fibromyalgia, and the second relating to peripheral inflammation. 
 
3.1 STUDY POPULATION 
The study will involve participants aged over 18 years with RA who are scheduled to start outpatient 
Olumiant as part of standard clinical practice, who meet the inclusion criteria below and who have none 
of the specified exclusion criteria. All will give full informed consent. 
 
3.2 INCLUSION CRITERIA 
. 
 
Adults ≥ 18 years < 75 years. 
 
Clinical diagnosis of RA 
 
Selected to start Olumiant by their usual rheumatology clinical team in line with local guidance 
(previous failure of at least 2 DMARDs and moderate to severe disease active disease) 
 
Right-handed (to reduce neuroimaging heterogeneity) 
 
3.3 EXCLUSION CRITERIA 
 
 
Inability to provide written informed consent. 
 
Severe physical impairment (e.g. blindness, deafness, paraplegia). 
 
Pregnant or breast feeding. 
 
Contraindications to MRI (e.g. severe claustrophobia). 
 
Major confounding neurological disease including Multiple Sclerosis, Stroke, Traumatic Brain 
Injury, Parkinson’s Disease, Alzheimer’s Disease 
 
Previous targeted synthetic (e.g. Oluminant, tofacitinib) DMARD exposure. 
 
Co-morbid medical conditions that may significantly impair physical functional status 
 
Medical or psychiatric conditions that in the judgment of study personnel would preclude 
participation in this study (e.g., malignancy, psychosis, suicidal ideation) 
 
BMI > 40 or unable to lie comfortably in MRI 
 
3.4 IDENTIFICATION OF PARTICIPANTS AND CONSENT 
 
Patients with active RA attending clinics in NHS Greater Glasgow and Clyde who are scheduled to begin 
Olumiant as part of their standard NHS clinical care will be asked to contribute to this study by their point 
of care team. The direct care team will notify patients of the study, provide a participant information sheet 
and seek their consent for the research team to contact them by telephone. at least 24 hours later to 
gauge their interest in the study and allow them to ask any questions. Eligibility will be confirmed by a 
medically qualified investigator. A record will be kept on the CRF detailing if the telephone call was made, 
if contact was indeed established and the outcome of the telephone call. 

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If the patient is interested and eligible, they will be invited to attend Visit 1 where they will first undertake 
informed consent. At this meeting, subjects will be asked again if they have any questions and those 
who wish to participate will be asked to sign the consent form. Two copies will be signed (one each for 
the participant and the site file) and 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 to 
inform them of their participation in the study. 
Consent will be taken by a member of the research team. 
Reasonable travel expenses will be reimbursed. 
3.5 WITHDRAWAL OF SUBJECTS 
Participants can decide to withdraw from the study at any time without providing a reason. The 
participant needs to request this formally and a withdrawal document will be completed and signed by 
the research staff. They have the option to either withdraw from the study completely or from parts of it. 
Participants will have the option to remain in the study irrespective of stopping treatment. 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, loss of 
capacity for continuous consent, administrative or other reasons. Full details of withdrawal will 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 unless the participant specifies they do not wish this to happen. Any 
stored blood samples that can still be identified as the participants will be destroyed if the participants 
wish this. 

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The study will comprise of a total of 2 research visits. 
 
. 
 
Informed consent 
 
Review of inclusion / exclusion criteria 
 
ACR/EULAR Classification Criteria for RA 
 
EULAR Disease Activity Score (DAS28) 
 
CDAI 
 
SDAI 
 
7-Day Symptom Diary (Number Rating Scale) 
 
American College of Rheumatology Fibromyalgia Scale13 
 
McGill Pain Questionnaire14 
 
Michigan Body Map Regional Pain 
 
PROMIS-Depression 
 
PROMIS-Anxiety 
 
PROMIS-Fatigue 
 
PROMIS-Sleep related impairment 
 
PROMIS-Physical functioning short form 
 
PROMIS-Pain inference 
 
Pain Number Rating Scale 
 
FACIT Fatigue Scale 
 
Cognitive Failures Questionnaire15 
 
Sickness Questionnaire16 
 
7T MRI protocol 
 
Ultrasound of joints of interest 
 
Quantitative sensory testing (QST) 
 
Blood draw for immunophenotyping 
 
Demographics 
 
BMI 
 
Drug Assessment 
 
Past Medical History 
 
Estimated visit time 4 hours 
 
 
 
ACR/EULAR Classification Criteria for RA 
 
EULAR Disease Activity Score (DAS28) 
 
CDAI 
 
SDAI 
 
7-Day Symptom Diary (Number Rating Scale) 
 
American College of Rheumatology Fibromyalgia scale 
4 TRIAL PROCEDURES 
4.1 STUDY SCHEDULE 
4.1.1 
Screening & Baseline (Day 0) 
4.1.2 
VISIT 2 : Week 12 ± 14 days 

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 
McGill Pain Questionnaire 
 
Michigan Body Map Regional Pain 
 
PROMIS-Depression 
 
PROMIS-Anxiety 
 
PROMIS-Fatigue 
 
PROMIS-Sleep related impairment 
 
PROMIS-Physical functioning short form 
 
PROMIS-Pain inference 
 
Pain Number Rating Scale 
 
FACIT Fatigue Scale Global Impression of Change (participant) 
 
Cognitive failures questionnaire 
 
Sickness Questionnaire 
 
7T MRI protocol 
 
Ultrasound of joints of interest 
 
Quantitative sensory testing (QST) 
 
Blood draw for immunophenotyping 
 
Drug assessment 
Estimated visit time 3.5 hours 
 
4.2 BRAIN IMAGING PROTOCOLS 
 
4.2.1 
MRI and MRS Protocols 
 
Subjects will be asked to lie supine in the ultra-high resolution 7T multimodal MRI scanner at The Imaging 
Centre of Excellence, based in a comprehensive clinical setting in Glasgow. 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), we will obtain neurobiological surrogate 
measures of functional connectivity and glutamate: 
 
1) Functional connectivity - a resting state BOLD-fMRI scan will be undertaken. Functional connectivity 
MRI (fcMRI) investigations are conducted with subjects resting in the scanner. Ten minutes of whole- 
brain resting state fMRI data will be collected using a simultaneous-multi-slice (SMS) echoplanar-imaging 
(EPI) sequence of factor=3. 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) 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 2017a. 
 
Upon collection of resting state fcMRI data, pre-processing steps will include 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 (DMN-Insula and 
DAN-IPL). 
 
2) 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. A 
20x20 mm3 voxel will be placed in the R posterior insula and shimming of the static magnetic field will be 
performed using advanced methods best suited to MRS acquisition at 7T, such as FASTMAP. Spectra will 
be analysed and quantified in JMRUI or LCModel. 

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In addition, multi-voxel techniques will be employed to provide quantitative maps of glutamate 
concentration across the brain. These will include chemical exchange saturation transfer (CEST) in the 
glutamate-weighted form, or GluCEST, which indirectly measures the glutamate present in tissue by 
measuring the chemical exchange between the glutamate amine spins and the protons present in the 
bulk water. GluCEST will be applied in one axial slice and one sagittal slice, chosen from the T1 
acquisition. The sequence parameters will be slice thickness of 5 mm, field-of-view of 200 x 200 mm2, 
matrix size 192 x 192, TR = 16 s, a saturation pulse train of 10 x 100 ms pulses followed by a FLASH 
readout with flip angle = 10°, TR/TE = 5.5/2.6 ms. 
 
Should any incidental clinically relevant abnormal MRI scan findings be observed that in the opinion of 
the Investigator may put the participant at risk, a referral will be made to the appropriate speciality. Any 
incidental finding review will be managed according to Glasgow Centre for Research Imaging (CRIF) 
processes and Glasgow Clinical Trials Unit (CTU) SOPs. 
 
 
4.2.2 
Ultrasound Protocol 
 
Rheumatoid arthritis is characterised by synovitis with symmetrical involvement. An optional ultrasound 
scan of pre-determined joints and up to 2 symptomatic joints with active disease will be performed at 
baseline and at the 12-week visit. This will provide a robust surrogate measure of peripheral inflammation. 
 
The wrists, MCPs, PIPs joints of hands, knees, MTPs of both feet, and the 2 most symptomatic joints (if 
applicable) will be scanned and graded using the EULAR-OMERACT combined score17. The 
ultrasonographic evaluation will further characterise the synovium involvement in the participants and will 
help to evaluate the response to treatment. 
 
4.2.3 
Quantitative Sensory Testing Protocol 
 
Quantitative Sensory Testing (QST) is a standardised methodology to study pain sensitivity in humans. 
A QST protocol includes a series of noxious and non-noxious stimuli delivered to a patient, followed by 
a semi-objective method for the patient to rate their perception of each stimulus. In this study, participants 
will have the option to complete a fully validated QST battery to characterise pain sensitivity as a sickness 
behaviour variable. All participants who consent to this procedure will undergo familiarisation training 
prior to data collection to reduce QST-related anxiety. 
 
Pressure pain sensitivity (15-20 minutes) will be assessed using a digital algometer with a 1 cm2 rubber 
probe to quantify pressure pain thresholds (PPT) at multiple body sites. Pressure will be manually 
increased at a rate of 50 kPA/s (1000 kPa max). Participants will press a response button to indicate their 
first sensation of pain. Pressure intensity at the time of button press is recorded as the PPT. 
Measurements will be conducted 3 times per site (with 20s intervals) with means used for analysis. 
 
The multimodal automated sensory testing (MAST) system18 will be performed. The MAST testing will 
be not be performed in ineligible patients with recent or habitual use of artificial nails. The MAST system 
will apply pressure at the thumbnail in a controlled systematic manner to derive a measure of pressure 
intensity that evokes a moderate level of pain (i.e., Pain = 50/100), as well as PPT and tolerance metrics 
(note inflamed joints will be avoided). The system delivers an ascending series of discrete pressures (5s 
duration; 4 kg/cm2/s ramp rate) at 20s intervals, beginning at 0.25 kg/cm2 and increasing in 0.25-0.50 
kg/cm2 steps. Pain intensity will be rated verbally after each stimulus on a 0-100 numerical rating scale 
(NRS). The test will be terminated at a maximum pressure of 10 kg/cm2 or when subjects reach their 
tolerance. This ascending test will be followed by a random staircase paradigm. MAST pain ratings will 
be used to interpolate Thumb Pain = 50, defined as the pressure intensity that evokes a moderate level 
of pain (i.e., 50/100). Other variables that will also be derived include: 1) thumb-PPT, defined as the first 

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thumb pressure in a series of at least two consecutive thumb pressures that elicited a pain rating > 0, 
and 2) Pressure Pain Tolerance (thumb-TOL), defined as the highest pressure tolerated. 
Cuff algometry (10 minutes) will be used to measure deep muscle tonic pain. This consists of a computer- 
controlled air compressor which delivers varying degrees of pressure to a Velcro-adjusted cuff applied to 
one gastrocnemius muscle. We will conduct a brief calibration procedure to a find a pressure intensity 
that evokes moderate pain and then apply that intensity for 6 minutes. Pain and sensory unpleasantness 
ratings will be obtained every 60s. 
Temporal Summation (4 minutes) is an effect where there is an increase in the perceived intensity of pain 
in response to sequential stimuli of equal physical strength. A 256 or 512 mN pinprick stimulus will be 
applied once to the dominant forearm, followed by a train of 10 identical stimuli (1 Hz). Following the 
single stimulus and the train of 10 stimuli, patients will report the pain intensity of the pinprick sensation 
verbally using a 0-100 NRS. This procedure will be repeated thrice. The mean pain rating of the three 
stimulus trains will be divided by the mean pain rating of the single stimuli to calculate a wind-up ratio 
(WUR); a WUR >1 indicates temporal summation19. 
Aversion to visual stressors (10 minutes) will be used to probe mechanisms of Global Sensory Sensitivity 
that bypass somatic peripheral receptors and the spinal cord. Specifically, participants will be presented 
with a flashing blue/yellow checkerboard pattern (see APPENDIX). Participants will be acclimatised to a 
dark room with their eyes perpendicularly aligned 15-inch away from a 15-inch high-resolution, calibrated 
LED monitor displaying the visual stimulus. Illuminance will be verified using a calibrated light meter. 
Each visual stimulus intensity level and the entire task will be rated on both sensory intensity and 
unpleasantness scales with overall task ratings. 
The MAST system is being used as a Research Tool and not for clinical purposes. 
4.3 STUDY OUTCOME MEASURES 
4.3.1 
Primary Outcome Measure(s) 
The primary outcome measures will be: 
1. brain functional connectivity (DMN-Insula and DAN-LIPL) as measured by 7T MRI 
2. insular glutamate signal as measured by 7T MRS 
Between baseline and visit 2 (week 12) following Olumiant treatment in RA. 
. 
4.3.2 
Secondary Outcome Measure(s) 
The secondary outcome measures will be: 
 
Changes in clinical phenotype, pain, depression and anxiety as measured by 
o 
EULAR Disease Activity Score (DAS28) 
o 
CDAI 
o 
SDAI 
o 
7-Day Symptom Diary (Number Rating Scale) 
o 
American College of Rheumatology Fibromyalgia Scale 
o 
McGill Pain Questionnaire 
o 
Michigan Body Map Regional Pain 
o 
PROMIS-Depression 
o 
PROMIS-Anxiety 

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o 
PROMIS-Fatigue 
o 
PROMIS-Sleep related impairment 
o 
PROMIS-Physical functioning short form 
o 
PROMIS-Pain inference 
o 
Pain Number Rating Scale 
o 
FACIT Fatigue Scale 
o 
Global Impression of Change (Participant)Cognitive Failures Questionnaire 
o 
Sickness Questionnaire 
o 
Synovitis score (from joint ultrasound) 
o 
Pain sensitivity variables (from QST measures) 
 
Changes in inflammatory cytokines/chemokines 
 
from baseline (day 0) to Visit 2 (week 12), following Olumiant treatment in RA. 
 
4.4 LABORATORY TESTS 
 
Sample Type 
Visit 1: Baseline 
Visit 2 (12 weeks) 
SST tube (8.5ml) 


PAXgene RNA tube (2.5ml) 


EDTA tube (2 x 10ml) 


EDTA tubes (4ml) 


 
Blood samples will be processed and analysed as described in the SOAR Lab Protocol. 
 
5 Study Medication 
 
5.1 OLUMIANT TREATMENT SCHEDULE & ADMINISTRATION 
Olumiant (4mg) will be administered in line with standard of care guidance. This is the standard dose in 
line with license for use in active moderate to severe RA. A dose adjustment from 4mg to 2mg is permitted 
during the study depending on side-effects. 
 
 
5.1.1 
Olumiant Treatment After the Study 
At the end of their study involvement, all participants will be returned to NHS standard care. 
Arrangements will be made such that all participants continue NHS standard care with Olumiant without 
interruption. 
 
 
5.2 ONCOMITANT MEDICINES 
 
5.2.1 
Permitted Concomitant Medicines 
 
Concomitant medicines are permitted at the PIs discretion. Maintenance of stable doses of conventional 
synthetic DMARDs, nonsteroidal anti-inflammatory drugs, analgesics, or glucocorticoids (≤10 mg of 
prednisone or the equivalent per day) will be permitted. Intra-articular and intramuscular triamcinolone 
can be used, but not within 8 weeks of the baseline and 12-week assessments. 

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5.2.2 
Prohibited Concomitant Medicines 
 
Biologic disease modifying antirheumatic drug therapy with adalimumab, etanercept, golimumab, 
infliximab, certolizumab, abatacept, tocilizumab, sarilumab, rituximab, tofacitinib, apremilast or 
upadacitinib. 
 
 
 
5.3 DISCONTINUATION OF STUDY MEDICINES 
 
The study medication should be permanently and immediately discontinued in case of the following 
situations: 
1. Serious infection requiring hospitalisation, including sepsis, tuberculosis and opportunistic 
infections such as invasive fungal infections, which rule out the continuation of the study drug if 
determined so by the Investigator 
2. Clinically significant abnormal laboratory result(s) or AE(s), which rule out continuation of the 
study drug, as determined by the Investigator 
3. The Investigator believes it is in the best interest of the subject. 
4. The participant requests withdrawal from the study. 
5. Commencement of prohibited medicines. 
6. Any other potentially serious condition as judged by the investigator which may place the 
participant at additional risk should they continue within the study. 
Participants may also be withdrawn from the study in the event they are significantly non-compliant with 
study procedures to the extent that the participant would be at risk for continued participation in the trial as 
determined by the investigator. 
At the end of their study involvement, all participants will be returned to NHS standard care. Arrangements 
will be made such that all participants continue with NHS standard care treatment with Olumiant without 
interruption. 
 
 
5.3.1 
Supply of Study Treatment 
. 
The study site will be responsible for procurement of all Olumiant via usual NHS supply mechanisms for 
medicines. 

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6 PHARMACOVIGILANCE 
 
6.1 DEFINITIONS OF ADVERSE EVENTS (AEs) 
Any untoward medical occurrence in a subject to whom a medicinal product has been administered, 
including occurrences which are not necessarily caused by or related to that product. 
 
 
 
6.2 SERIOUS ADVERSE EVENT (SAE) 
Any adverse event or adverse reaction that: 
a) Results in death 
b) Is life threatening 
c) Requires hospitalisation or prolongation of existing hospitalisation 
d) Results in persistent or significant disability or incapacity 
e) Consists of a congenital anomaly or birth defect 
f) 
Is otherwise considered medically significant by the investigator 
g) Important adverse events/reactions that are not immediately life-threatening or do not result in 
death or hospitalisation but may jeopardise the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above 
 
 
6.3 RECORDING AND REPORTING OF ADVERSE EVENTS 
Reports of Serious Adverse Events (SAE), drug exposure during pregnancy, non-serious Adverse 
Events (AE) and misuse and abuse of the study drug, other medication errors and uses outside of what 
is foreseen in the protocol (irrespective if a clinical event has occurred) should be submitted to the 
Research Ethics Committee (REC) using the Non-CTIMP safety report to REC form. 
 
Only reports of SAEs and non-serious AEs that are 1. related to the study (i.e. they resulted from 
administration of any of the research procedures) and 2. unexpected (i.e. not listed in the protocol as an 
expected occurrence) 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. 
 
Related Unexpected Serious Adverse Event (RUSAE) 
Any SAE thought to be related to a trial specific procedure performed on that subject that is thought to 
be unexpected; that is the event is not listed within the protocol or would not be expected to occur when 
carrying out the trial specific procedure in normal clinical practise. 
Recording and reporting of adverse events 
 
The study is considered to be of low risk and is primarily an observational study. The MRI scanning 
procedure is the principal trial specific procedure and safety reporting will be focussed around this 
procedure 
 
Adverse events and serious adverse events will be collected only during the period of time the participant 
attends clinic for their MRI scan i.e. from the time the participant begins preparation for the scan until 24 
hours post scan. 

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In addition to Sponsor requirements the investigators have a contractual agreement with the MAH to 
report any SARs suspected to be related to olumiant within 15 days of investigator awareness. These 
events should be recorded and reported in line with the manufacturers requirements. 
 
Recording of adverse events 
 
AEs occurring during this timeframe must be recorded, assessed, reported, analysed and managed in 
accordance with the UK Policy Framework for Health and Social Care Research and the study protocol. 
All AEs must be assessed for seriousness. 
 
Recording and reporting of serious adverse events 
 
Where an SAE requires recording; full details including the nature of the event, start and stop dates, 
severity, relationship to research product and/or trial procedures, and the outcome of the event will be 
recorded in the patient’s medical notes and CRFs.). These events will be monitored and followed up 
until satisfactory resolution and stabilization. 
 
SAEs should be assessed to determine if the event is related to the MRI scanning procedures and 
assessed for expectedness against the list of expected events detailed below. 
 
Where an event meets the criteria of an SAE and is both: 
 
Related: that is, it resulted from administration of study medicines or any of the research procedures, 
And 
Unexpected: that is against the procedure events listed below as an expected occurrence. 
 
The SAE is considered a Related and Unexpected Serious Adverse Event (RUSAE) and must be 
reported to the Sponsor. 
 
The assessment of causality and expectedness must be carried out by an authorised clinician. 
Expected events related to the MRI scanning procedure 
The MRI procedure is painless and not uncomfortable. The primary risks known to occur from MRI are 
due to the magnet’s ability to pull metal objects towards it. This pull can cause metal objects in the body 
(e.g. surgical clips or staples) to move and cause bleeding or disruption of surrounding tissue. Metal 
objects carried or worn by a person (e.g. jewellery, hair clips, tools) can be pulled towards the magnet 
and, if free to fly through the air, could strike an individual. The MRI can cause pacemakers or stimulators 
implanted in the body to malfunction. There may be some slight discomfort from noise produced by the 
MRI machine. 
Prior to inclusion in the study, the presence of potential MR risks, such as pacemakers, surgical clips or 
metallic surgical devices will be excluded by medical and surgical history using a standard review form. 
Participants will be asked to complete and sign a safety screening form and will be instructed to bring or 
wear clothing without metal fasteners, and remove jewelry and any other metal objects from their body. 
Participants will wear foam earplugs or headphones to reduce the loud noises made by the scanner. 
During the performance of MRI, the volunteers will be monitored at all times by research personnel 
associated with the project. They will be able to communicate with the examiner and, if needed, can 
terminate or take a break from the procedure at any time 
 
Reporting to the Sponsor 
 
All RUSAEs must be reported to the Pharmacovigilance Office immediately (within 24 hours) using the 
generic non-CTIMP SAE form which is available from http://www.glasgowctu.org/data/SAE_non- 

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CTIMP.pdf. The SAE form should be completed and signed by appropriately delegated staff. The form 
should be faxed or e-mailed to the PV Office (pharmacovig@glasgowctu.org) and a copy placed in the 
Study Site File. If necessary a verbal report can be given by contacting the PV Office on 0141 330 4744. 
This must be followed up as soon as possible with a signed written (or electronic) report. 
 
If all of the required information is not available at the time of initial reporting, the investigator must ensure 
that any missing information is forwarded to the PV Office as soon as this becomes available. The report 
should indicate that this information is follow-up information for a previously reported event. 
 
The Sponsor in liaison with the CI will carry out an assessment of expectedness prior to submission of 
the event to the REC. 
 
Reporting of RUSAEs to the Ethics Committee 
 
The PV office will report all RUSAEs to the ethics committee within 15 days of the PV office becoming 
aware of the event, via the ‘report of serious adverse event form’ for non-CTIMPs published on the Health 
Research 
Authority 
web 
site. 
http://www.hra.nhs.uk/documents/2015/02/safety-report-form-non- 
ctimp.docx. The form will be completed by the Sponsor and will be signed by the Chief Investigator prior 
to submission. 
 
Reporting of SAEs related to olumiant to the MAH 
 
The investigators must report all serious adverse events that are suspected to be related to olumiant 
within 15 days of becoming aware of the event. SAEs can be submitted using the Sponsors generic SAE 
reporting form that can be downloaded from the following location https://glasgowctu.org/Home/00- 
safety-reporting/. 
 
 
 
7 STATISTICS AND DATA ANALYSIS 
 
7.1 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).. To assess whether treatment with 
Olumiant results in a reduction in functional connectivity (DMN-Insula and DAN-IPL) and glutamate 
quantification, changes in our neuroimaging metrics of interest between time points will be evaluated 
using paired t-tests. Changes in pain, clinical phenotyping and immunophenotyping measures will be 
correlated with those significant regions identified from our primary objective. Putative confounders will 
be explored using general linear models. 
 
7.2 PRIMARY EFFICACY ANALYSIS 
 
The primary outcomes are changes in brain functional connectivity (DMN-Insula and DAN-LIPL) and 
changes in insular glutamate signal from baseline (day 0) to Visit 2 (week 12), following Olumiant 
treatment in RA. 
 
Resting state fMRI data will be pre-processed to control transient head movements and parcellated into 
cortical areas and subcortical nuclei before estimation of a functional connectivity matrix for each subject 
under each treatment condition. Topological analysis of weighted graphs derived from these matrices 
will estimate brain network properties such as weighted nodal degree and modular community structure, 

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which are known to be sensitive to the effects of peripheral CRP and are hypothetically expected to be 
indicative also of the effects of Olumiant treatment on functional brain networks. 
Objective 1 and 2: To assess whether treatment with Olumiant results in a reduction in functional 
connectivity (DMN-Insula and DAN-IPL) and glutamate levels, changes in our neuroimaging metrics of 
interest between time points will be evaluated using paired t-tests. 
7.3 SECONDARY EFFICACY ANALYSIS 
The secondary outcomes are changes in pain, clinical phenotype, peripheral immune markers and their 
change with MRI markers indicative of CNS pathway function from baseline (day 0) to Visit 2 (week 12), 
following Olumiant treatment in RA. 
Changes in pain, clinical phenotyping and immunophenotyping measures will be correlated with those 
significant regions identified from our primary objectives. Putative confounders will be explored using 
general linear models. 
7.4 SAFETY ANALYSIS 
The safety data (serious adverse events) – both numbers of subjects and events – will be summarised 
overall using descriptive statistics. 
7.5 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 3.2.4 (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. 
7.6 SAMPLE SIZE 
Based on the only previous study to examine and evidence fMRI changes pre- and post- RA treatment 
(n=10)20 and our previous MRS study in fibromyalgia (n=17)12 we estimate that a group sample size of 
n=20 will be sufficient to detect significant neuroimaging changes (n=3 dropout). Moreover, the enhanced 
sensitivity of 7T and our capacity to apply hypothesis-based region of interest analysis, based on our 
recent work, will afford greater reserves of power which in turn will enable testing of putative confounders. 
A sample size of n=17 should be sufficent to measure changes in our optimal outcomes (fMRI and MRS) 
7.7 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. All statistical analyses will be 
conducted according to a pre-specified Statistical Analysis Plan. 

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8 TRIAL CLOSURE / DEFINITION OF END OF TRIAL 
The end of the study is defined as database lock after the last data collection. The end of the study will be 
reported to the Sponsor and REC within 90 days, or 15 days if the study is terminated prematurely. 
 
 
9 DATA HANDLING 
 
9.1 CASE REPORT FORMS / ELECTRONIC DATA RECORD 
Case Report Forms (CRF), including medical outcomes, and questionnaires are completed during the 
assessment visits at the local study site either on paper or online in the secure database. All participants 
will have the option to complete the questionnaires online in the database or on paper depending on 
personal preference. Completed paper pain diaries will be returned either by pre-paid envelope, phone 
or online. 
 
Personal data, including postal address, phone numbers (landline and mobile), email addresses, and 
anonymised data files for study outcomes will be stored in locked filing cabinets (hard copy) and in a 
NHS GGC approved database as well as secured shared drives with access via password controlled 
computers (university and NHS networks) by study staff only (electronic data). 
 
A study-specific, NHS GGC approved, eCRF will be established. 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 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 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). 
 
 
9.2 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. In line with the 
University of Glasgow’s Code of Good Research Practice study data will be retained for a minimum of 
10 years. 
Archive coded information will be retained for a maximum of 10 years after the end of this trial and for its 
transmission outside the European Economic Area. 

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10 TRIAL MANAGEMENT 
10.1 ROUTINE MANAGEMENT OF TRIAL: TRIAL MANAGEMENT GROUP 
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. 
 
11 STUDY AUDIT 
This study may be selected randomly for audit by NHS Greater Glasgow and Clyde governance team 
following the annual audit plan. 
 
 
12 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). Amendments to the protocol 
or other study documents will not be implemented without these approvals. 

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13 ETHICAL CONSIDERATIONS 
 
13.1 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. 
 
The CI will be responsible for updating the REC of any new information related to the study. 
 
 
13.2 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 or study treatment at any time. 
Participants will be asked to provide permission to allow their de-identified data to be transferred out of 
the European Economic Area or United Kingdom. 
Anonymised data will be transferred between the University of Glasgow and the University of Michigan. 
 
14 INSURANCE AND INDEMNITY 
 
The SOAR study is sponsored by NHS Greater Glasgow and Clyde. The sponsor will be liable for 
negligent harm caused by the design of the trial. NHS indemnity is provided under the Clinical Negligence 
and Other Risks Indemnity Scheme (CNORIS). 
 
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. 
 
 
15 FUNDING 
The study is supported by an Investigator Initiated grant from Lilly “Exploiting Leading Edge 7T MRI Brain 
Imaging to Decipher Olumiant’s Mode of Analgesic Action in Rheumatoid Arthritis ”. 
 
 
 
 
16 ANNUAL REPORTS 

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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. 
 
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. 

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Figure 1. Flashing blue/yellow checkerboard pattern presented to patients for the ‘Aversion to Visual 
Stimulus’ component of the QST protocol.