Characterisation of Pain in Patients With Musculoskeletal Disease: a Prospective, Longitudinal, Observational Study With an Embedded Feasibility Window of Opportunity Sleep Study
Phase: NA
Conditions: Fibromyalgia
Sponsor: University of Oxford

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276  
 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
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Study Title:  Characterisation of Pain in patients with musculoskeletal disease: a prospective, 
Longitudinal, observational study with an Embedded feasibility window of opportunity Sleep Study 
(PAIN-LESS) 
Internal Reference Number / Short title: Pain-LESS 
Ethics Ref: 19/SC/0168  IRAS Project ID 252762 
Trial registration: NCT05962138 
Date and Version No: 7th February 2023, Version 5.0  
 
Chief Investigator: 
Dr Anushka Soni, Senior Clinical Research Fellow, NDORMS, Botnar 
Research Centre, Old Road, OX3 7LD. Anushka.soni@ndorms.ox.ac.uk  
Investigators:  
Dr Eoin Kelleher (eoin.kelleher@ndcn.ox.ac.uk) 
Amanda Wall (amanda.wall@ndcn.ox.ac.uk) 
Dr Ben Seymour (ben.seymour@ndcn.ox.ac.uk) 
Dr Vishvarani Wanigasekera (vishvarani.wanigasekera@ndcn.ox.ac.uk),  
Dr Andrew Segerdahl (andrew.segerdahl@ndcn.ox.ac.uk), 
Professor Irene Tracey (Irene.tracey@ndcn.ox.ac.uk), 
 Wellcome Centre for Integrative Neuroimaging, FMRIB, Nuffield 
Department of Clinical Neurosciences, John Radcliffe Hospital, OX3 9DU.  
Sponsor:  
University of Oxford 
Funder: 
University of Oxford 
Chief Investigator Signature:  
 
There are no conflicts of interest to declare. 
 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the 
Sponsor, the Investigator Team, HRA, host organisation, and members of the Research Ethics Committee, 
unless authorised to do so. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 2 of 32 
TABLE OF CONTENTS 
 
1. 
SYNOPSIS ................................................................................................................................................ 4 
2. 
ABBREVIATIONS...................................................................................................................................... 5 
3. 
BACKGROUND AND RATIONALE ............................................................................................................ 6 
4. 
OBJECTIVES AND OUTCOME MEASURES ............................................................................................... 9 
5. 
STUDY DESIGN ...................................................................................................................................... 10 
6.1 Study Participants............................................................................................................................... 11 
6.2 
Inclusion Criteria .......................................................................................................................... 11 
6.3 
Exclusion Criteria .......................................................................................................................... 12 
7 
STUDY PROCEDURES ............................................................................................................................ 12 
7.1 
Recruitment .................................................................................................................................. 12 
7.2 
Screening and Eligibility Assessment ........................................................................................... 13 
7.3 
Informed Consent......................................................................................................................... 13 
7.4 
Baseline Assessments ................................................................................................................... 14 
7.5 
Subsequent Visits – main study ................................................................................................... 19 
7.6 
Description of procedure ............................................................................................................. 20 
7.7 
Discontinuation/Withdrawal of Participants from Study ............................................................ 21 
7.8 Definition of End of Study .................................................................................................................. 21 
8 
SAFETY REPORTING .............................................................................................................................. 21 
8.1 
Definition of Serious Adverse Events ........................................................................................... 21 
8.2 
Reporting Procedures for Serious Adverse Events ...................................................................... 22 
9 
STATISTICS AND ANALYSIS ................................................................................................................... 22 
9.1 
Description of Statistical Methods ............................................................................................... 22 
9.2 
Number of Participants ................................................................................................................ 23 
9.3 
Analysis of Outcome Measures .................................................................................................... 24 
10 DATA MANAGEMENT ........................................................................................................................... 24 
10.1 
Access to Data .............................................................................................................................. 24 
10.2 
Data Recording and Record Keeping ............................................................................................ 24 
11 QUALITY ASSURANCE PROCEDURES .................................................................................................... 25 
12 ETHICAL AND REGULATORY CONSIDERATIONS ................................................................................... 25 
12.1 
Declaration of Helsinki ................................................................................................................. 25 
12.2 
Guidelines for Good Clinical Practice ........................................................................................... 25 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 3 of 32 
12.3 
Approvals ...................................................................................................................................... 25 
12.4 
Reporting ...................................................................................................................................... 25 
12.5 
Participant Confidentiality ........................................................................................................... 26 
12.6 
Expenses and Benefits .................................................................................................................. 26 
12.7 
Other Ethical Considerations........................................................................................................ 26 
13 FINANCE AND INSURANCE ................................................................................................................... 28 
13.1 
Funding ......................................................................................................................................... 28 
13.2 
Insurance ...................................................................................................................................... 28 
14 PUBLICATION POLICY ........................................................................................................................... 28 
15 INTELLECTUAL PROPERTY..................................................................................................................... 28 
16 REFERENCES ......................................................................................................................................... 29 
17 APPENDIX A:  STUDY FLOW CHART ...................................................................................................... 31 
 
 
 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 4 of 32 
1. SYNOPSIS 
 
Study Title 
Characterisation of Pain in patients with musculoskeletal disease: a 
prospective, Longitudinal, observational study with an Embedded feasibility 
window of opportunity Sleep Study (Pain-LESS)  
Internal ref. no. / short 
title 
. Pain-LESS study 
Study Design 
Prospective, longitudinal, cohort study with embedded feasibility study of 
digital CBT-I. 
Study Participants 
Patients with musculoskeletal disease 
Planned Sample Size 
490 participants with rheumatoid arthritis 
490 participants with fibromyalgia (of which 80 will be included in the 
feasibility study of dCBT-i.  
Planned Study Period 
April 15th 2019 to 30th April 2025 
 
Objectives 
Outcome Measures 
Primary 
 
To investigate whether patients with 
inflammatory arthritis and features of 
centrally driven pain have reduced 
chance of responding to treatment. 
Primary outcome: Percentage 
achieving Disease Activity Score 
<2.6, 6 months after commencing 
anti-rheumatic treatment.  
Secondary outcome: Other 
measures include Disease Activity 
Score reduction of >1.2; simple 
disease activity score <3.3; Clinical 
Disease Activity Index ≤2.8; 
American College of Rheumatology 
(ACR)/European League 
Against Rheumatism (EULAR) 
Boolean (28 tender joint count, 
28 swollen joint count, patient’s 
global assessment (0–10 scale), 
CRP (mg/dL), all ≤1), modified 
DAPSA<4. 
Secondary 
 
To describe the prevalence of 
centrally driven pain in patients with 
other musculoskeletal conditions.  
Scoring according to: Central 
Sensitivity Inventory, Fibromyalgia 
survey criteria, PainDETECT 
questionnaire alongside 
neuroimaging findings. 
Secondary 
To investigate whether digital CBT-I 
can improve quality of life and 
centrally driven symptoms in people 
with FM 
 
 
To determine barriers and facilitators 
to a definitive trial of digital CBT-I in 
people with FM 
SIQR, sleep actigraphy, online 
cognitive assessment at baseline, 
12 weeks, and 24 weeks 
Neuroimaging at baseline and 12 
weeks. 
Focus group at 24 weeks 
 
 
 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 5 of 32 
To evaluate the cost effectiveness of 
digital CBT-I 
 
EQ-5D-5L 
Healthcare usage dairy 
 
 
 
 
Secondary 
To investigate whether maladaptive 
learning in the brain plays a role in 
chronic musculoskeletal pain, and 
from this to predict treatment 
response in fibromyalgia patients  
 
Quantitative Cognitive Testing 
(online games assessing learning 
and decision-making, 
generalisation/avoidance, motor 
decision-making, and 
prediction/metacognition tasks).  
Motor (movement) evaluation - 
video-based assessment 
measuring movement during 
standardised physio-type exercises 
 
 
2. ABBREVIATIONS 
ACR 
American College Rheumatology 
CBT 
Cognitive Behavioural Therapy 
CBT-i 
Cognitive Behavioural Therapy for insomnia 
CDAI 
Clinical Disease Activity Index 
CI 
Chief Investigator 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CSI 
Central Sensitivity Inventory 
CWP 
Chronic Widespread Pain 
DAPSA 
Disease Activity index for Psoriatic Arthritis 
DAS28 
Disease Activity Score 28 
dCBT-i 
Digital Cognitive Behavioural Therapy for insomnia 
EQ-5D-5L 
EuroQuol 5-level health questionnaire 
EULAR 
European League Against Rheumatism  
FM 
Fibromyalgia 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
HRA 
Health Research Authority 
HRV 
Heart Rate Variability 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 6 of 32 
ICF 
Informed Consent Form 
ME 
Motor (Movement) Evaluation 
MRI 
Magnetic Resonance Imaging 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
PDQ 
PainDETECT questionnaire 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
PSA 
Psoriatic Arthritis 
QCAT 
Quantitative Cognitive Aversive Testing 
QMT 
Quantitative Movement Testing 
QST 
Quantitative Sensory Testing 
R&D 
NHS Trust R&D Department 
RA 
Rheumatoid arthritis 
REC 
Research Ethics Committee 
RGEA 
Research Governance, Ethics & Assurance, University of Oxford 
SIQR 
Symptom Impact Questionnaire Revised 
SDAI 
Simple Disease Activity Score 
SOP 
Standard Operating Procedure 
 
 
3. BACKGROUND AND RATIONALE 
Musculoskeletal conditions and pain both present huge global health problems (1-3). Pain is estimated to 
affect 20% of adults overall, with a recognition that such estimates are likely to be conservative due to 
the lack of a clear definition of pain as a disease entity in its own right (3, 4). Nonetheless, current data 
show that rheumatoid arthritis, osteoarthritis and spinal problems featuring amongst the leading four 
causes of pain (3) highlighting the importance of studies focussing on pain as a primary feature of 
musculoskeletal disease.  
Pain in musculoskeletal conditions was traditionally thought to be mostly due to ongoing peripheral 
nociceptive input, but it is now being recognised that the underlying mechanism of pain is likely to vary 
between individuals with the same disease category. Previous studies, including work from Professor 
Tracey’s group, have suggested features such as centralised pain and neuropathic pain are related to 
outcome following knee arthroplasty for primary knee osteoarthritis (5-7). There is also evidence that a 
central pain component is present in patients with rheumatoid arthritis, for example (8-15). Furthermore 
the concurrent presence of fibromyalgia and rheumatoid arthritis is common and associated with higher 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 7 of 32 
inflammatory arthritis disease activity scores, worsening of functional status, lower levels of synovial 
inflammation and more frequent use of biologic therapy (16-20).  
Accordingly, treatment selection should theoretically reflect the relative contribution of peripherally and 
centrally mediated pain pathways in order to personalise therapeutic strategies with the aim of 
improving response to treatments (21, 22). However, current standard clinical practice does not 
incorporate this approach to the assessment and management of pain in musculoskeletal disease. The 
aims of this study are to: 
1. To investigate whether patients with inflammatory arthritis and features of centrally driven pain 
have reduced chance of responding to treatment. 
2. To describe the prevalence of centrally driven pain in patients with other musculoskeletal 
conditions. 
3. Establish a cohort of patients who would like to be contacted about likely follow-on studies in 
the future. 
 
The prospective, observational cohort study will recruit patients being seen in the Oxford University 
Hospital NHS Trust,  or Connect Health (clinical stakeholder organisation with a responsibility to assess 
and manage patients within the NHS), with a clinical diagnosis of inflammatory arthritis or fibromyalgia. 
The results will be directly generalisable to patients with these same conditions, who are seen in a 
secondary care setting. In addition, some aspects may be applicable to patients with the same conditions 
but who are being managed in primary care. 
The study will follow patients as they receive standard treatments being initiated by their clinical care 
team, who will not be aware of the results of the detailed study pain characterisation. The clinical care of 
the patient will therefore not be influenced or delayed in any way. The patients participating in the 
observational study will not benefit directly, but it is anticipated that the results of this study will help to 
further the goal of personalised patient treatments in the future. As the study does not affect treatment 
of the patients, the risks of the study are limited to those relating to the study assessment procedures as 
detailed below in section seven. 
Feasibility Study of digital CBT-I 
People with FM also commonly suffer from problems with cognition, particularly concentration and 
memory, and disordered sleep (difficulty getting to sleep, frequent waking in the night or waking early). 
There are no standard treatments for these centrally driven symptoms. Psychological therapies include 
cognitive behavioural therapy (CBT), which involves changing unhelpful thought patterns and 
behaviours. However, in-person CBT is costly and difficult to delivery widely. New forms of CBT have 
been developed which can be delivered via the internet. These may overcome limitations posed by in-
person therapy. A type of CBT for insomnia (CBT-I) has improved cognitive symptoms and disordered 
sleep in people with insomnia, and may be useful in treating the centrally driven symptoms of FM. CBT-I 
can be delivered through digital platforms (digital CBT-I, dCBT-I) (26). One such platform is 'Sleepio', a 
validated dCBT-I tool which has demonstrated efficacy in the treatment of insomnia, and has been 
shown to alleviate cognitive symptoms of insomnia (27). This programme involves six 20-minute sessions 
with an animated virtual therapist covering key cognitive and behavioural strategies to improve sleep. 
We will invite a number of participants to take part in a feasibility study where they will be randomised 
to Sleepio or standard care. Participants will be evaluated using online assessment tools of pain, 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 8 of 32 
cognition and sleep. In addition, a selection of participants will undergo sleep actigraphy and/or 
neuroimaging using MRI scans during follow up.  
 
Blood Test  
Previous work has shown that patients with fibromyalgia may also have evidence of dermal nerve fibre 
pathology (23-25). The pathophysiological relevance of this is not clear and it is not known whether 
these findings relate to the pattern of symptoms a patient have, their pain sensitivity (determined using 
QST) or their chance of responding well to specific therapies including those used for neuropathic pain. 
Although it is well recognised that patients with inflammatory arthritis can also develop features 
consistent with fibromyalgia, potential abnormalities in small unmyelinated nerve fibres has not been 
studied in this patient population to date. Some patients with peripheral nerve lesions develop 
neuropathic pain, whereas others do not. It is not currently understood why patients do or do not 
develop neuropathic pain. Also, some patients’ neuropathic pain will improve over time (e.g. with 
treatment or spontaneously), whereas others will continue to have persistent pain. Currently, it cannot 
be predicted who will improve and who will continue to have chronic pain. This may relate to factors 
such as the severity of their neuropathy and the types of nerve fibres involved, psychological factors or 
genetic predisposition. 
Despite the growing evidence for nerve involvement in these pain conditions, its extent and role remains 
controversial. The presence of a sensitive marker confirming a lesion of the nervous system would 
increase the certainty of neuropathic pain. Blood based markers of nerve injury have thus gained 
increasing interest. In particular Neurofilament light chain (NfL) is a consistent diagnostic and prognostic 
biomarker of central nervous system diseases.  
Maladaptive Learning  
Despite its prevalence, it is still not fully understood why some people get chronic pain and others do 
not. One influential idea is that the processes in the brain that normally allow us to adapt to an injury 
and recover from it, are used excessively, meaning that pain is exaggerated and prolonged beyond what 
is necessary. This 'maladaptive brain learning' hypothesis, in its various forms, is a popular model of 
chronic musculoskeletal pain. However, evidence is currently limited by the lack of sufficient tools 
required to measure and quantify learning. This aspect of the study addresses this by implementing a 
novel set of online tools based on a basic science understanding of how learning works in the brain. 
These tools will be used to study outcomes in the fibromyalgia cohort of patients. 
 
 
The aims of this feasibility study are to: 
 
1. To investigate the feasibility of conducting a study of digital CBT-I in patients living with 
fibromyalgia 
2. To investigate the impact of Sleepio (dCBT-I) on quality of life in people with fibromyalgia. 
3. To investigate the impact of Sleepio on centrally driven symptoms including cognition and sleep 
quality in people with fibromyalgia. 
4. To investigate whether patients with features of centrally driven pain have differences in NfL, 
inflammatory markers and genes which can prospectively identify prognostic factors for 
developing neuropathic pain, its persistence and/or its severity.  
5. To investigate whether maladaptive learning in the brain plays a role in chronic musculoskeletal 
pain, and from this to predict treatment response in fibromyalgia patients. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 9 of 32 
In anticipation of likely follow-on and related studies, we will also ask participants if they would like to be 
added to a research database so that they can be contacted for consideration of any future studies being 
undertaken by the research group.  
4. OBJECTIVES AND OUTCOME MEASURES 
 
Objectives 
Outcome Measures  
Timepoint(s) of 
evaluation of this 
outcome measure 
(if applicable) 
Primary Objective 
To investigate whether patients 
with inflammatory arthritis and 
features of centrally driven pain 
have reduced chance of responding 
to treatment. 
Percentage achieving Disease Activity 
Score <2.6. Other measures include 
Disease Activity Score reduction of >1.2; 
simple disease activity score <3.3; Clinical 
Disease Activity Index ≤2.8; American 
College of Rheumatology (ACR)/European 
League Against Rheumatism (EULAR) 
Boolean (28 tender joint count,28 swollen 
joint count, patient’s global assessment 
(0–10 scale),CRP (mg/dL), all ≤1), 
modified DAPSA<4. 
Baseline and at 3, 6 
and 12 months 
after commencing 
therapy. 
Secondary Objectives 
To investigate the features of 
centrally driven pain, detected 
through multi-modal assessment, in 
patients with a range of 
musculoskeletal conditions. 
To investigate whether patients 
with features of centrally driven 
pain have differences in NfL, 
inflammatory markers and genes 
which can prospectively identify 
prognostic factors for developing 
neuropathic pain, its persistence 
and/or its severity 
To investigate whether digital CBT-I 
can improve quality of life and 
centrally driven symptoms in people 
with FM 
 
 
Scoring according to: Central Sensitivity 
Inventory, Fibromyalgia survey criteria, 
PainDETECT questionnaire alongside 
neuroimaging findings. 
 
Blood test 
 
 
 
 
 
SIQR, sleep actigraphy, sleep diary, online 
cognitive assessment, self-reported 
cognitive function (British Columbia 
Cognitive Complaints Inventory, BC-CCI) 
Neuroimaging (brain MRI) 
 
Prior to 
commencing 
therapy 
 
 
Baseline 
 
 
 
 
 
Baseline, 12 weeks 
and 24 weeks 
Baseline and 12 
weeks 
 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
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To investigate the cost 
effectiveness of digital CBT-I 
To determine barriers and 
facilitators to a definitive trial of 
CBT-I to alleviate symptoms in 
people with FM 
To investigate whether maladaptive 
learning in the brain plays a role in 
chronic musculoskeletal pain, and 
from this to predict treatment 
response in fibromyalgia patients  
 
EQ-5D-5L 
Healthcare usage dairy 
 
Focus groups of participants 
 
 
 
 
Online games to include learning and 
decision-making, generalisation/ 
avoidance, motor decision-making, and 
prediction/metacognition tasks, and  
motor (movement) evaluation - video-
based assessment measuring movement 
during standardised physio-type exercises 
Baseline, 12 and 24 
weeks 
 
24 weeks  
 
 
 
Baseline, 12 weeks 
 
 
 
5. STUDY DESIGN 
This is a prospective, observational, longitudinal study of patients with a range of musculoskeletal 
conditions being seen in an out-patient setting, with an embedded feasibility study of digital CBT-I.  
Participants will be assessed over a 12 month period from receiving new treatment, alongside their 
routine clinical care. The study assessments will include:  
• 
Confirmation of eligibility to participate in the study (30 minutes) – phone, or in person during 
routine clinical visit 
• 
Pre-treatment assessment (2 hours) –  online questionnaire* and in-person assessment in 
addition to routine patient care visits 
• 
Follow up assessment at 3 months (2 hours) – online questionnaire* and in-person assessment in 
addition to routine patient care visits** 
• 
Follow up assessment at 6 and 12 months post-treatment (30 minutes) – online questionnaire* 
*may be substituted by a shorter telephone administered questionnaire or paper questionnaire if the 
participant prefers this. 
**an additional follow up assessment will be conducted at 1 month in participants receiving treatment 
with biologic agents. This will be the same as the online questionnaire and in-person assessment being 
conducted in all participants 3 months after commencing treatment. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 11 of 32 
If the participant is unable to or does not wish to undertake the MRI component of the main study but is 
willing to complete the rest of the study, the remainder of the assessment will still be conducted as 
detailed above. 
For participants with fibromyalgia, there is approximately a 6 month wait from clinic assessment/ 
diagnosis to receiving standard NHS care of pain rehabilitation treatment. Whist waiting for 
recommended treatment to commence, those with fibromyalgia can choose to also participate in the 
embedded feasibility study of digital CBT-I, as per the diagram below.  
It is estimated that the duration of participant participation in the study will be around 18 months, taking  
into account the lag between a recommended treatment being commenced. Details of data collection            
for each assessment are given in sections 7.3 and 7.4 below.  
 
 
6.0 PARTICIPANT IDENTIFICATION 
6.1 Study Participants 
Participants with a clinical diagnosis of inflammatory arthritis or fibromyalgia, (fibromyalgia only for the 
Maladaptive Learning assessments and Sleep sub study), seen as an out-patient within the Oxford 
University Hospital NHS Trust, or Connect Health (clinical stakeholder organisation with a responsibility 
to assess and manage patients within the NHS) aged 18 or above will be invited to participate in the 
study. Clinic lists will be pre-screened for potentially suitable patients by a member of the clinical care 
team. 
6.2 Inclusion Criteria 
• 
Participant is willing and able to give informed consent for participation in the study. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
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© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
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• 
Male or Female, aged 18 years or above. 
• 
Clinical diagnosis of either inflammatory arthritis or fibromyalgia/chronic widespread pain  
 
• 
Feasibility study of digital CBT-I:  
o 
Concomitant insomnia, frequent waking in the night or early morning waking  
o 
Self-reported difficulties with concentration or memory 
o 
Reliable internet access 
6.3 Exclusion Criteria 
The participant may not enter the study if ANY of the following apply: 
• 
Patients with a poor understanding of English. 
• 
Patients with known neurological or psychiatric conditions (other than depression or anxiety) likely 
to independently affect the results of pain assessment, for example peripheral diabetic 
neuropathy in the opinion of the research team 
 
• 
Feasibility study of digital CBT-I:  
o Major neuropsychiatric disorder (bipolar disorder, schizophrenia or psychotic spectrum 
disorders) 
▪ 
However, participants with depression and anxiety will be eligible 
o Epilepsy 
o Cognitive impairment, dementia or neurodegenerative disorder 
o Recent or planned surgery 
o Current or planned night-time shift work 
o Sleep disorders such as sleep apnoea, restless leg syndrome, circadian rhythm disorder, 
or parasomnia 
o Taking prescribed sleep medications on more than 2 nights in past 2 weeks 
o Currently receiving other psychological therapy for insomnia 
o Pregnant or lactating 
7 STUDY PROCEDURES 
7.1 Recruitment 
Potential participants for all sections of the study (Feasibility study included) will be identified via out-
patient clinics in the Rheumatology and Pain Relief Unit within the Oxford University NHS Trust, or 
Connect Health (clinical stakeholder organisations with a responsibility to assess and manage patients 
within the NHS). Where possible, a member of the clinical care team will pre-screen clinic lists to 
highlight potentially suitable participants in advance of a clinic appointment.  Potential participants will 
be initially approached by their clinical care team and provided with a participant information leaflet. If 
the potential participant agrees, the clinician will also pass on the preferred patient contact details to the 
research team. Posters, with contact details for the research team, will be put up in relevant waiting 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
Clinical Research Protocol Template version 13.0      
 
 
 
 
CONFIDENTIAL 
© Copyright: The University of Oxford and Oxford University Hospitals NHS Foundation Trust 2016 
 
Page 13 of 32 
areas so that potential participants can ask their clinician about the study and/or contact the research 
team directly. 
The research team will arrange to contact all potential participants, either in person, by email or by 
telephone, to give them the opportunity to ask any further questions regarding the study. If the 
participant would like to enrol in the study, the researcher will organise a suitable time for the 
participant to confirm eligibility for the study, and if suitable take informed consent from the participant. 
7.2 Screening and Eligibility Assessment 
Screening for all sections of the study (feasibilityFea study included) will involve confirming the participants 
age, assessment of vulnerability, understanding of English, clinical musculoskeletal diagnosis, and review 
of the general medical history. Additional MRI safety screening will be conducted in participants willing 
to undertake the MRI component of the study. This will include questions regarding their suitability to 
enter an MRI scanner. For the feasibility study additional sleep related screening will be conducted. 
Screening may be done in person if a participant is attending the hospital for a routine appointment, or 
by telephone, email or using Microsoft Forms. The participant will be allowed up to one week to consider 
the information, and the opportunity to question the Investigator, their GP or other independent parties 
to decide whether they will participate in the study. The restriction of one week is due to the fact that if 
the patient is due to start on a new treatment, time will be needed to arrange the baseline assessment 
prior to them starting their new medication. In the case of participants with fibromyalgia who are being 
referred for pain rehabilitation treatment, there will be more time available, as the waiting time for this 
is much longer (often up to 6 months). If confirmation of eligibility to participate in the main study and 
feasibility study is in person, a paper copy of the Participant Information Sheet will be given. If 
confirmation of eligibility to participate is by phone, a paper copy of the Participant Information  Sheet 
can be posted or emailed. MRI safety screening will be repeated on the day of participation prior to 
entering the scanner. 
7.3 Informed Consent 
Written and verbal versions of the Participant Information and Informed Consent will be presented to 
the participants detailing no less than: the exact nature of the study; what it will involve for the 
participant; the implications and constraints of the protocol; the known side effects and any risks 
involved in taking part. It will be clearly stated that the participant is free to withdraw from the study at 
any time for any reason without prejudice to future care, without affecting their legal rights, and with no 
obligation to give the reason for withdrawal. 
The participant will be allowed up to one week to consider the information, and have the opportunity to 
question the Investigator, their GP or other independent parties to decide whether they will participate 
in the study. The restriction is due to the fact that if the patient is due to start on a new treatment, time 
will be needed to arrange the baseline assessment prior to them starting their new medication. In the 
case of participants with fibromyalgia who are being referred for pain rehabilitation treatment , there 
will be more time available for the participants to decide, as the waiting time for this is much longer 
(often up to 6 months). They can choose which of the further assessments they would like to participate 
in, if at all, whilst they are waiting for their pain management treatment. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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Once eligibility and intent to take part in the study have been confirmed by the Chief Investigator or 
delegated study personnel and the potential participant can personally sign and date the latest approved 
version of the Informed Consent form before any study specific procedures are performed, or remote 
consent can be taken over the telephone by the researcher.  The paper consent form or remote consent 
form will be photocopied and a copy given, emailed or posted to the participant for their own records. 
The original will be filed in the study site file and another copy scanned into the participant’s medical 
records. 
At the point of consent, participants with fibromyalgia can choose to additionally participate in the 
feasibility study (see section 7.5).  
7.4 Baseline Assessments 
At the baseline assessment visit, participants will be asked to complete the clinical assessment and 
validated questionnaires described below. This will be done using REDCap, a secure web application 
online portal (redcap) where possible, either with the researcher present or independently according the 
participants preference. If required, a paper format will be used: 
 
Assessment 
Purpose 
Clinical history 
This will include disease duration, current and 
previous treatments including those for pain 
management specifically, and other past medical 
history 
Disease activity score measure 
Used in routine clinical practice to capture 
disease activity specific to a condition. For 
example: disease activity score-28 in rheumatoid 
arthritis, psoriatic response criteria in psoriatic 
arthritis, Bath ankylosing spondyloarthritis 
disease activity index in ankylosing 
spondyloarthritis, fibromyalgia impact 
questionnaire in fibromyalgia) 
MRI safety questionnaire 
Assess whether participant is safe to undergo MRI 
scanning 
Euroqol-5D (EQ5D)/HAQ 
Standardised measure of health-related quality of 
life 
Musculoskeletal Health Questionnaire (MSK-HQ) 
Supplementary measure of health status 
designed to be used across a range of 
musculoskeletal conditions in order to monitor 
progress over time and response to treatment 
Beck depression and anxiety inventories 
To assess and describe psychological comorbidity 
and its impact on symptoms and treatment 
response 
PainDETECT questionnaire 
To assess for features of neuropathic pain 
Central sensitivity inventory 
To indirectly assess centralised sensitisation 
Insomnia severity index 
To assess sleep disturbance, an important factor 
in pain experience 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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Fibromyalgia survey criteria 
To assess for concurrent fibromyalgia in those 
with inflammatory arthritis, which may impact 
treatment outcome 
Fibromyalgia Impact Questionnaire Revised*       
To assess the overall impact of symptoms and 
quality of life in those with FM in Sleep sub-study 
Chalder Fatigue Scale* 
 
To assess self-reported fatigue in Sleep sub-study  
Behavioural inhibition system/Behavioural 
activation system (BIS/BAS) scale 
To assess reward responsiveness which may be 
impaired in chronic pain and impact on treatment 
responsiveness 
The Multidimensional Assessment of 
Interoceptive Awareness (MAIA) 
To assess interoception which may be impaired in 
patients with chronic pain 
Locus of control 
To quantify the degree to which participant feels 
they have control over outcome of life events 
which is likely to be particularly relevant to 
response to rehabilitation 
Credibility Expectancy Questionnaire 
To assess expectations of treatment so can adjust 
for this effect 
Tampa scale for kinesophobia 
To assess fear of movement which may impact 
response to treatment 
British Columbia Cognitive Complaints Inventory 
(BC-CCI)* 
To assess self-reported cognition in Sleep sub-
study 
Multiple Ability Self-Report Questionnaire 
(MASQ) * 
 
This is a measure of self-perceived cognitive 
difficulties that is more widely used in the 
fibromyalgia literature to explore subjective 
cognitive difficulties (i.e. Fibro-fog). The BC-CCI 
(outlined above) is used in the sleep literature to 
explore subjective cognitive difficulties. Using 
both will allow us to compare our results to 
previous work in both the fibromyalgia and sleep 
fields 
Pittsburgh Sleep Quality Index (PSQI)* 
Provides quantitative sleep parameters, such as 
total sleep time, wake-after-sleep onset 
Epworth Sleepiness Scale (ESS)* 
A measure of subjective sleepiness 
Sleep Disorders Questionnaire* 
 
To screen for sleep disorders which may be an 
exclusion for participation, such as obstructive 
sleep apnoea, restless leg syndrome etc (these 
are already outlined in the exclusion criteria 
(section 6.3)) 
* Additional questionnaires if participant consent to the feasibility study 
Tasks 
Participants will undergo quantitative sensory testing outside the scanner in accordance with the 
established protocol developed by Rolke and the German Research Group on Neuropathic pain.  
Quantitative sensory testing is a standard technique used to determine skin sensitivity to thermal, touch, 
and vibration stimuli. Testing will be conducted over an area which is primarily affected by the 
musculoskeletal condition of interest (e.g. metacarpophalangeal joints in rheumatoid arthritis), as well as 
control areas that are not directly involved (e.g. sternum). The exact protocol and test sites will be 
refined following pilot work in up to 5 participants, in order to ascertain which modalities and test sites 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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will be practical to assess in this patient population. For those with fibromyalgia, heart rate variability 
(HRV) will also be measured using the validated Camera HRV app on either the researchers phone or a 
dedicated device to be used for the study. The participant will hold their index finger to the device 
camera for 5 minutes and the app will record the HRV. The app was developed by and is owned by a 
health technology scientist Marco Altini. The camera-based HRV analysis has been validated and used in 
clinical research and sports training. No personal details are entered into the app - for the purposes of 
this project, the app simply monitors heart rate for 5 minutes and calculates HRV, providing a value 
which is documented by the researcher, like any of the other QST instruments. The app is purely a 
research tool and will have no influence on medical treatment. 
Imaging 
Participants who are willing and able to take part in the imaging component of the study, will undergo 
standard brain MRI scans including protocols to image central nervous system structure and function 
scans, alongside physiological noise monitoring.  
Blood Test  
Participants will also be invited to have an additional blood sample taken. Blood samples will be assessed 
for potential biomarkers that can shed a light into mechanisms for the development of neuropathic pain 
(e.g. cellular, molecular or humoral analysis depending on the type of neuropathy). DNA can show how 
gene variants may modify the risk of a person developing a neuropathy and/or the severity of 
neuropathic pain.  
Blood sample 
The Chief Investigator, or any other trained investigator, will draw max 30mls blood via venepuncture as 
per the World Health Organisation (WHO) guidelines on drawing blood. The appropriate equipment, 
including tourniquet, latex/nitrilegloves, vacutainers, sterile needles, cotton wool, alcohol wipes, 
plasters, clean equipment trays and medical tape will be available in the clinical testing room within the 
MRI scanning research facility. The room has a comfortable chair for participants with a 
cushion/pillow/arm rest to support participants’ arms while blood is being drawn, and a clinical 
examination bed where the participant can lie down (with their legs raised if necessary) should they feel 
faint. Lastly, basic facilities for dealing with participants who faint (or feel faint) during phlebotomy will 
be provided—somewhere they can lie down and equipment for monitoring blood pressure. There will 
always be another member of staff in the building whilst this procedure is being performed. There is an 
appropriate sharps disposal bin in the room. The facility has a needle stick policy in place. The sample will 
be taken labelled with the participants’ ID number. After the participant’s appointment, the sample will 
be taken to the laboratory and will be either processed immediately and/or stored at in a locked freezer 
at -80 or -20 degrees, in compliance with The Human Tissues Act. Although taking blood is a very 
standard procedure, common risks are pain during the procedure and bruising (with associated pain 
afterwards); these will usually disappear within a few days. In the event that a participant reports 
symptoms of an infection (local redness, swelling, pain or discharge of pus) or other complications, they 
should be referred to their GP or to A&E urgently.The time required for taking the blood sample is 3 
minutes. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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Overall, the Baseline Assessment visit will take around 2 hours. Participants will be able to stop at any 
point and continue after they have had a rest. 
Feasibility Study 
Recruitment into the feasibility sub-study will be as the procedure described in section 7.1. At the point 
of consent, participants with fibromyalgia who have chosen to additionally take part in the feasibility 
study, will be randomised 1:1 to Sleepio or Standard Care, using the Sealed Envelope randomisation 
software (www.sealedenvelope.com). 
 
The baseline assessment will be the same as for the main study, with a very short QST protocol lasting up 
to 5 minutes only. In addition, participants will be asked to complete a vigilance task using the study 
device and the research team will help the participant to capture video data for motor evaluation. 
Motor evaluation 
Video data of participants doing simple physio exercises, to quantify how they move doing 
standardised movements. This is done using a smart-phone / tablet camera, which people can set up in 
their home or attend for a separate study visit. The participant (face included) is recorded doing a list of 
exercises - marching on the spot holding onto a chair for support, hip and knee extension, squats and 
heel lifts with chair for support. These typically involve 3 to 4 repetitions and takes a few minutes, after 
which the video will be uploaded to a secure cloud-server. Motion capture analysis will use inhouse 
software, owned by the University of Oxford but based on Detectron2 
(https://github.com/facebookresearch/detectron2), that allows quantification of movement angles and 
speeds at different joints, as a metric of physical ability, which can be used to quantify pain related 
changes in movement; these will be visually inspected for validation. The videos themselves will not be 
stored but the computer generated skeletal poses will be stored as 2D/3D coordinate time series in pkl 
or h5 files (see Reconstruction, Figure 1).  
Participants will be given information on how to access the maladaptive learning games and cognitive 
tests, which they can complete at home at their convenience. 
Patients will be given an activity watch to wear, and a sleep diary to complete, for 7 days before and 
after undergoing the Sleepio programme or standard care. 
After the visit, participants will then be randomised to standard care or given access to the online CBT-I 
programme, Sleepio. Participants will be given a web link and activation code to Sleepio. They will be 
required to complete a daily sleep diary for the duration of the programme. The programme involves six 
personalised 20-minute video sessions over 10 weeks. It uses evidence-based cognitive and behavioural 
interventions, sleep hygiene education, and relaxation exercises to target unhelpful behaviours and 
thoughts in order to reduce symptoms of poor sleep. Participants may use Sleepio in their own time at 
home via a web browser or smartphone app. Standard care involves provision of written materials 
produced by the charity Versus Arthritis, with evidence-based advice on sleep hygiene.  
 
Maladaptive Learning 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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Patients with fibromyalgia can choose to participate in a battery of online learning games that can be 
played on tablet or smart phone on a separate day. These are validated experimental tasks that probe 
how people learn and make decisions for rewards (e.g. winning points in a game) and punishments (e.g. 
losing points in a game). The different games probe different aspects of learning, and each takes around 
20 minutes; the score is revealed at the end. The games are as follows: 
1i) Balloon popping game (Instrumental learning task). Coloured balloons rise up on the screen, and on 
each go, participants choose one which balloon they want to pop by touching it on the screen. When a 
balloon pops it will either give them points, or take away points, or do nothing. Participants can learn 
which coloured balloons are good and which are bad, but the tricky thing is that this changes continually 
through the game, so they need to constantly keep track and relearn which ones are good. We analyse in 
detailed the learning process by looking at people's choices and response times. 
ii) 'Road sign check' game (Generalization task). People imagine they are driving through a dangerous 
mountain road and pass road signs which are symbols on a sign background - the signs mean that it is 
either safe, or that there is a danger they need to avoid by pressing a button. The problem is that the 
signs are very similar and can be hard to tell which ones are safety and which are danger signs. 
Furthermore, you lose points for pressing the 'avoid' button. Therefore you need to look very carefully 
and only press 'avoid' when you think the sign is a danger sign. The task itself involves a blending of 
visual features of two exemplar signs, and allows us to assess how people generalise across perceptual 
space. 
iii) Screen touching game (Motor decision-making). Two 'target zones' appear on a screen - a green 
target, and a red target. If you touch inside the green target you win points, if you touch inside the red, 
you lose points. The participant needs to touch as quickly as possible, as the targets only appear for a 
very short time. The problem is that the two targets often overlap, and are often very small, meaning 
that you need to be both very quick and very accurate - typically trying to touch within the green target 
that does not overlap with the red, which might only be a slither of the target. We analyse how people's 
movement actions are affected by the proximity of the red target, given their overall level of accuracy. 
iv) Ball balancing game (Motor adaptation). In this game, participants need to hold their phone/tablet 
horizontally to balance a virtual ball on the screen and stop it rolling off. To make things difficult, there is 
a constant moving tilt to the screen which they can't see, so they need to concentrate and constantly 
adjust the way they hold the phone/tablet to stop it rolling off. We analyse how they adjust their 
movements to different tilts. 
v) Prediction games. There are two version of the games: a pain prediction game and a control task, a 
stockmarket prediction game. In the pain prediction game, participants are required to continuously rate 
their spontaneous level of pain on a visual analogue scale. Intermittently they will be asked to predict how 
much pain they expect to feel in the near future, again using another visual analogue scale. Participants 
are asked to rate the confidence in their estimates. In the control stockmarket task, participants are asked 
to predict the value of shares changing over time, as in the real-life stockmarket. Again, we will collect 
confidence ratings for the prediction estimates. The first task evaluates how pain evolves over time, in 
each subject, and the ability of participants to consciously anticipate pain flare-ups. The control task is 
used to assess whether there are specific difficulties in anticipating uncertain events involving rewards 
and losses. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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7.5 Subsequent Visits – main study 
 
Participants will be followed up at up to four timepoints, as shown in the flowchart in section 5. The 
questionnaire component can be completed using REDCap, a secure web application, or paper format as 
preferred by the patient. If the participant is unable to attend for an in-person visit, the questionnaire 
component of the assessment will be completed either by telephone, using REDCap, or the 
questionnaires may also be posted to the participant for completion, if this is preferred by the 
participant. Follow up visits at T2 (10-14 weeks after commencing therapy) and T3 (22-26 weeks after 
commencing therapy) will be identical, as detailed below: 
Follow-up T2 and T3* 
The following assessments will be conducted**:  
• 
Repeat eligibility check 
• 
Assessment of disease activity measures and other validated questionnaires listed in baseline 
assessment 
• 
Update of medical history, medications, and any other therapeutic strategies being used 
• 
QST/brain imaging if conducted at baseline  
 
A further follow-up visit T4 will be conducted at 50-54 weeks after commencing treatment this will include. 
The following assessments will be conducted**:  
• 
Repeat eligibility check 
• 
Assessment of disease activity measures and other validated questionnaires listed in baseline 
assessment 
• 
Update of medical history, medications, and any other therapeutic strategies being used 
 
*In patients with inflammatory arthritis, commencing a biologic therapy, an additional follow up 
assessment will be conducted at 1 month. This will be identical to the one conducted at follow-up T2 and 
T3. 
 
**If the participant is unable to attend for an in-person visit, a telephone appointment will be offered in 
order to complete the questionnaires. The questionnaires may also be posted to the participant for 
completion, if this is preferred by the participant.  

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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Subsequent Visits – Feasibility study 
The follow up at T3 can be conducted remotely. Questionnaires, cognitive testing and maladaptive 
learning assessments will be completed online and the activity watches will be administered and 
returned by recorded delivery post. Participants will also be invited by telephone or email to attend a 
follow up research visit in person, which will be the same as the baseline assessment. 
 
Focus groups 
Three groups of 6 participants (18 in total) will be invited to participate in a focus group at T3 (24 weeks). 
This will be a part of the consent process for this feasibility-study, and participants may opt not to take 
part. The focus groups will be approximately 3 hours in length, and participants will be reimbursed for 
their time in accordance with INVOLVE guidelines. These focus groups will be carried out online, using 
Microsoft Teams, and the recording will be transcribed using MS Teams inbuilt transcription software. 
Participants in these focus groups will be asked about their views of the study process, with the aim to 
identify barriers and facilitators to a future definitive trial of the intervention.  
7.6 Description of procedure  
MRI 
Imaging interventions: Once contraindications to magnetic resonance imaging are excluded by use of the 
facility’s screening forms, the risks of undergoing a scan are minimal.  A trained scanner operator or 
radiographer will go through a list of possible risks with the participant before scanning.  The MRI 
scanner consists of a large powerful magnet.  Magnetic resonance imaging uses no ionising radiation.  
There are, however, potential hazards associated with MRI and the scanning of participants including the 
presence of surgical implants, participants’ clothing, jewellery (such as body piercings) bodily habitus, or 
medical conditions.  A comprehensive list of potential risks has been compiled, and the participant 
should be checked against this by the operator, prior to entering the controlled areas of the MRI 
scanners. As per standard scanning procedure, participants will be invited to get changed into provided 
scrubs prior to scanning in order to minimise risk. During the actual scanning procedure, the scanner 
produces loud banging noises, and the participant will be given suitable hearing protection (earplugs – 
these will be fitted correctly).  The participant will be attached to physiological monitors (i.e. pulse and 
respiration). Where necessary (i.e. in the case of glasses being removed), vision will be corrected using 
MR-compatible optical frames. There is a small mirror that will allow them to see out of the scanner.  
During the experiment, the participant will be able to communicate with the operator in the control 
room.  In addition, they will be given a call button, which allows them to alert the operator at any time.  
People with a history of claustrophobia may be excluded from participation in the study.  All participants 
will still be introduced carefully to the scanner and allowed to leave at any stage, should they wish to do 
so.  Once in the scanner, participants will be able to indicate immediately if they wish the scanning to 
cease by pressing a call button in their hands. 
Once the participant is comfortable to begin scanning, the radiographer will begin the relevant scan 
protocol which consists of different MR sequences aimed at imaging different structural and functional 
properties of the CNS before, during and after the application of different nociceptive stimuli. In some 
instances, participants will also be presented with innocuous ‘control’ sensations like visual stimuli (e.g. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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flashing chequerboards, colourful images) or auditory stimuli (e.g. white noise) matched in terms of 
saliency to the painful stimuli.  
Immediately following the scan session, the participant will be taken out of the scanner and led to an 
adjacent, private examination room so that they can change back into their own clothes. 
Participants will be thanked and have a follow up visit booked prior to leaving.  
The study intervention is online cognitive behavioural therapy for insomnia (CBT-I) through a 
commercially available programme, Sleepio. The programme involves 6 sessions of automated CBT-I with 
an automated, virtual professor and access to a daily online sleep diary. Participants may also interact 
with an online community and library of resources. 
7.7 Discontinuation/Withdrawal of Participants from Study 
Each participant has the right to withdraw from the study at any time.  In addition, the Investigator may 
discontinue a participant from the study at any time if the Investigator considers it necessary for any 
reason including: 
• 
Ineligibility (either arising during the study or retrospectively having been overlooked at screening) 
• 
Significant protocol deviation 
• 
Significant non-compliance with treatment regimen or study requirements 
• 
Withdrawal of Consent 
• 
Loss to follow up 
Withdrawal from the study may result in exclusion of the data from that participant from analysis, if 
required by the participant.  
The sample size for the study takes into account attrition over the course of the study and so withdrawn 
participants will not need to be directly replaced.  
The reason for withdrawal will be recorded in the CRF. 
7.8 Definition of End of Study 
The end of study is the date of the last postal or online questionnaire/ telephone follow up of the last 
participant. If the participant has consented to be contacted for consideration of future studies, their 
name, contact details and musculoskeletal diagnosis will be retained on the research database for a 
period of 10 years after the end of the study. 
8 SAFETY REPORTING  
8.1 Definition of Serious Adverse Events 
A serious adverse event is any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires inpatient hospitalisation or prolongation of existing hospitalisation 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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• 
results in persistent or significant disability/incapacity 
• 
consists of a congenital anomaly or birth defect. 
Other ‘important medical events’ may also be considered serious if they jeopardise the participant or 
require an intervention to prevent one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers to an event in which the 
participant was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
8.2 Reporting Procedures for Serious Adverse Events 
A serious adverse event (SAE) occurring to a participant should be reported to the REC that gave a 
favourable opinion of the study where in the opinion of the Chief Investigator the event was ‘related’ 
(resulted from administration of any of the research procedures) and ‘unexpected’ in relation to those 
procedures. Reports of related and unexpected SAEs should be submitted within 15 working days of the 
Chief Investigator becoming aware of the event, using the HRA report of serious adverse event form (see 
HRA website). 
9 STATISTICS AND ANALYSIS 
9.1 Description of Statistical Methods 
Non-imaging data will be analysed using statistical software packages such as Stata. Initially descriptive 
statistics will be used to describe the results of demographic, disease activity and psychophysical 
assessments conducted across the difference conditions being studied. Statistical approaches used will 
include chi-squared tests of association, correlation, Student’s t-test, and univariable linear regression 
models. Further analyses will explore whether pre-treatment pain characteristics, in particular the 
presence of centralises pain, predict response to treatment, measured by reduction in disease activity. 
This will be done using univariable regression analysis. We will also examine whether there are clusters 
or sub-groups of patients within the cohort, using data driven methods such as cluster analysis. 
All imaging data will be analysed using standard methods within FSL (FMRIB Software Library). The first 5 
subjects will be analysed as a first checkpoint to check data quality and other measures of quality. For 
the maladaptive learning assessments, the results from the online panel of games will be fitted from 
simulated data, based on pilot studies in patients/controls, for power analysis where parameters of 
interests will be highlighted with significant differences. The accuracy of model fitting will improve as 
more data is added i.e. the framework becomes more powerful as more data is added (intrinsic 
sustainability). 
 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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Figure 1. This illustrates what the output data looks like, shown here as the full parameter distributions, 
but can be simplified to basic summary statistics of the key learning parameters. 
 
For the Sleep sub study, quantitative feasibility outcomes will be summarised descriptively. Qualitative 
data will be coded using inductive thematic analysis to examine participants’ views and experiences of 
the recruitment process, intervention, and trial process, including MRI assessments. Themes that emerge 
will be discussed with the patient research partners. 
9.2 Number of Participants 
 
Previous work, using the ratio of tender to swollen joints as an indirect marker of central sensitization in 
patients with either RA or PSA, has shown that on average  43% of patients with low levels of likely 
central sensitization achieved remission (using DAS-28 remission criteria) compared to 23% in those with 
high levels of central sensitisation when being treated with either methotrexate or an anti-TNF agent. 
However a data simulation study showed that, for machine-learning methods, a sample size of 70 times 
the number of variables allows accurate identification of the data structure (36). Using the seven main 
variables of pain, fatigue, sleep disturbance, dyscognition, depression, anxiety and function, data for 490 
participants, for each condition would be needed, including the feasibility study.  
For the feasibility study 80 participants will be recruited in total, with 40 being assessed using MRI. 
Participants will be randomised on a 1:1 ratio to the intervention and standard care groups. This should 
provide a large enough sample to inform the practicalities of delivering dCBT-I, MRI assessments, and 
provide information on recruitment, uptake, and attrition, which will inform the design of the definitive 
trial. A moderate effect size (Cohen’s d >0.3) would be sufficient to accept the result as worth 
investigating, in order to achieve a meaningful clinical benefit for patients, and in keeping with similar 
effects of CBT-I on cognitive outcomes in insomnia.  
All participants in the Sleep sub-study will be invited to participate in the focus groups. However, it is 
envisioned that 18 (three groups of six participants) will take part, owing to the time commitment 
involved.  

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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9.3 Analysis of Outcome Measures  
All participant data will be used in the analysis of primary and secondary outcome measures, unless a 
participant has specified when withdrawing consent that they do not want data already collected to be 
analysed.  
The participants will be divided into those with and without centralised pain, determined by the 
centralised sensitivity inventory. The difference between achieving remission will be assessed using the 
standardised DAS -28 criteria at 6 months, in line with the primary outcome measure. Regression 
analyses will be used to investigate any significant differences in outcome for the two groups, including 
univariate analyses followed by multivariate analyses adjusting for known predictors of outcome such as 
age, sex and baseline pain/disease activity severity.   
Correlation analyses will be used to assess for any associations between different measures of central 
sensitization across the different musculoskeletal measures. This will be done for the group as a whole, 
as well for individual diagnoses to evaluate any differences in the relationships for the different 
conditions. 
10 DATA MANAGEMENT 
10.1 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor and host institution for 
monitoring and/or audit of the study to ensure compliance with regulations. 
10.2 
Data Recording and Record Keeping 
Data will be collected using REDCap, a secure web-based application, which can be used to directly 
capture data or in conjunction with paper-based questionnaires where this approach is preferred by the 
participant. Data will be entered onto an electronic database and stored on a password protected, 
encrypted University of Oxford computer. REDCap is frequently utilised within the department and there 
is an established track history in the context of other HRA approved studies.  Participant data will be 
anonymised by allocating an individual reference number. All hard copies of the information will be 
stored in a locked filing cabinet within swipe and security code access at the Botnar Research Centre.  
No personal data needs to be entered onto the Camera HRV app on the study device. The HRV value will 
be deleted from the device immediately after the value has been recorded on the password protected, 
secure research database on the university server, using a secured internet connection. 
For the Maladaptive Learning component of the study, the videos of participants’ movements will be 
uploaded to a secure cloud server where inhouse software will convert the videos into the computer 
generated skeletal poses, which will be stored as 2D/3D coordinate time series in pkl or h5 files (see 
Reconstruction, Figure 1). The original videos will then be deleted. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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The Sleepio app collects some identifiable data (such as participants’ email address) which is stored on 
Sleepio’s secure servers which researchers will be allowed access to. Sleepio data is stored in data 
centres, hosted by AWS (Amazon) in the United States. They have HIPAA BAA and EU Model Clause 
agreements with Amazon, requiring them to adhere to the appropriate EU and US regulations for 
protecting data.  They use consent as their legal basis for processing, and do not generally delete data 
automatically after a specific amount of time. However, if a user requests a deletion, they will delete 
within 30 days.  All data is encrypted in transit and at rest. Personal data gathered by the Sleepio system 
is accessible to a limited number of Big Health employees, including members of the engineering & 
infrastructure, research & clinical, product, commercial, and customer service teams.  Any personal data 
being shared with other organization requires a HIPAA BAA (and EU Model Clauses if appropriate), and 
requires data to be sent encrypted. 
In addition, the online focus groups will be conducted over Microsoft Teams. The Live Transcription 
feature in Teams will create a transcript of the meeting as it happens. Although the transcription 
software will use participants’ names for identification and accuracy of transcribing, no one at Microsoft 
ever sees the meeting’s content, and the transcripts are automatically deleted immediately after each 
meeting. Microsoft does not use this data for its own purpose. As no transcription service can be 
guaranteed to be 100% accurate, the meeting will be recorded. A member of the research team will 
cross check the transcripts for quality control and the recording will be deleted as soon as transcript 
verification is complete. Each focus group will be a maximum of 3 hours in length. 
11 QUALITY ASSURANCE PROCEDURES 
The study may be monitored, or audited in accordance with the current approved protocol, GCP, 
relevant regulations and standard operating procedures. 
12 ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
Declaration of Helsinki 
The Investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki.  
12.2 
Guidelines for Good Clinical Practice 
The Investigator will ensure that this study is conducted in accordance with relevant regulations and with 
Good Clinical Practice. 
12.3 
Approvals 
The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to an appropriate Research Ethics Committee (REC), and HRA for written 
approval. 
12.4 
Reporting 
 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
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The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. The CI shall submit once a year throughout 
the study, or on request, an Annual Progress report to the REC Committee, HRA (where required) host 
organisation and Sponsor. In addition, an End of Study notification and final report will be submitted to 
the same parties. 
 
12.5 
Participant Confidentiality 
The study will comply with the UK General Data Protection Regulation (GDPR) and Data Protection Act 
2018, which require data to be de-identified as soon as it is practical to do so. All information which is 
collected about participants during the course of the research will be kept strictly confidential and 
coded, stored securely under the responsibility of Dr Anushka Soni. Identifiable information will be 
removed from the information we collect as soon as it is possible to do so. All hard copies of the 
information will be stored in a locked filing cabinet within swipe and security code access at the Botnar 
Research Centre. Computerised data will be stored on a password protected, encrypted University of 
Oxford computer. Data collected via the secured web application will be anonymised at the point of 
entry to REDCap and stored on a password protected, secured university server at NDORMS: data are 
collected through a secured internet connection. The information will be stored for a period of 10 years 
and then will be destroyed securely. 
Responsible members of the University of Oxford and the Oxford University Hospital NHS Trust may be 
given access to data for monitoring and/or audit of the study to ensure that the research is complying 
with applicable regulations. 
12.6 
Expenses and Benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts, or a mileage allowance provided as appropriate. In addition, participants in the focus group for 
the Sleep sub-study for cognitive symptoms will be given a small reimbursement to compensate them for 
their time. This will be in line with INVOLVE guidance. 
12.7 
Other Ethical Considerations 
 
Comfort:  
i) Certain MRI sequences can be very noisy so subjects will be given earplugs.  
ii) The enclosed space of the scanner can induce feelings of claustrophobia. Any subject with a history of 
claustrophobia will be excluded. Other subjects will be introduced carefully to the scanner and allowed 
to leave at any stage. Whilst in the scanner subjects have easy access to a call button should they wish to 
stop the scan or speak with the operator. 
iii) Lying on the scanner table for prolonged times can induce lower back pain. This will be minimised by 
means of comfortable padding and positioning. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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iv) Some patients may be asked to delay taking some of their pain related medications, such as 
paracetamol and non-steroidal anti-inflammatory medications, around the time of the brain scan, as it 
can affect the results of the MRI. However, this will not preclude a patient from participating in the study 
if it is not possible to do so. 
Ferromagnetic Objects: 
Ferromagnetic Objects can be attracted to the scanner and could injure the participant. Magnetic objects 
in or around the magnet will be tightly secured or MRI compatible in all cases to preclude projectile risks. 
All researchers entering the magnet environment have undergone annual MRI safety testing to ensure 
maximal awareness and safety around the scanner and for each research volunteer. 
Incidental findings: 
In the unlikely event of seeing any structural abnormalities on an MRI scan, the scan will be checked by a 
clinical specialist.  If the specialist feels that the abnormality was medically important, they will discuss 
the implications with the participant and arrange for further investigations as necessary.  Participants will 
not be informed unless the specialist considers the finding has clear implications for their current or 
future health.  It is important to note that scans are not carried out for diagnostic purposes, and 
therefore the scans are not a substitute for a clinical appointment. Rather, the scans are intended for 
research purposes only. 
It is known that some inherited genes increase the risk of certain health conditions, for instance heart 
disease or rare forms of cancer. In people whose risk is known to be higher than average, medical action 
may be taken to reduce the risk of these conditions developing or causing problems in the future. From 
the blood samples and skin biopsies collected for the sub study, it is possible that genetic changes may be 
found by chance (incidental findings), which may increase the risk of the individual developing one of these 
conditions. Each participant can decide on the consent form whether or not they want to be informed 
about such medically actionable findings. If a medically actionable finding is identified and the participant 
opted to be informed, then a clinically qualified member of the research team will arrange an appointment 
with the participant to discuss the findings.  
Experimental pain stimuli: 
All stimuli that are used to experimentally induce pain have been safely used as part of our pain research 
programme in ethically approved projects (see IDREC Approved Protocol 19, v4 “STUDIES 
INVESTIGATING EXPERIMENTALLY INDUCED PAIN IN ADULT HEALTHY VOLUNTEERS”). The minimal 
intensity of noxious stimuli necessary to achieve goals of the study is established. The stimulation 
intensity does not exceed the individual tolerance level. Participants are always able to terminate a 
painful stimulus at will. The exact test paradigm will be optimised through a period of pilot work in and 
outside the scanner in order to best mimic the clinical pain being experienced.  
1. Mechanical Stimuli: 
Sensation-related touch, including a sharp pinprick, can be elicited using Von Frey hairs and punctuate 
stimuli specifically designed to deliver a constant force to the skin surface. Vibration can also be 
delivered using specially designed Vibro-Tactile pads on the surface of the skin. None of these devices 
penetrate the skin. The maximum force delivered will be 512 mN for punctate probes.  
2. Thermal Stimuli: 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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Thermal stimulations including hot and cold sensations can be elicited using thermode devices 
specifically designed to deliver thermal sensations to the skin surface. Thermal temperature can also be 
maintained or modulated by the use of warm/cold compresses (e.g. water bottles) that can be placed on 
the surface of the skin. The absolute temperature range delivered will be between 0 and 55 degrees 
Celsius (see IDREC Approved Protocol 19, v4 “STUDIES INVESTIGATING EXPERIMENTALLY INDUCED PAIN 
IN ADULT HEALTHY VOLUNTEERS”). 
There are no known side effects to any of these stimulations. These have been approved in earlier NHS 
ethics applications for use in the FMRIB pain laboratory and can be used in conjuncture with one another 
and in MR environments (see Approved Protocol 19). 
The Sleep sub-study does not pose any ethical concerns relating to the intervention, Sleepio. Participants 
will be randomised to a standard care control, and their usual care will not be influenced or delayed in 
any way. Sleepio is an online NICE-accredited cognitive behavioural therapy for insomnia tool, which has 
previously been validated as effective and safe in insomnia. The use of Sleepio poses minimal risks to 
participants. 
13 FINANCE AND INSURANCE 
13.1 
Funding 
The study is fully funded by the Oxford-UCB prize fellowship. 
13.2 
Insurance 
The University has a specialist insurance policy in place which would operate in the event of any 
participant suffering harm as a result of their involvement in the research (Newline Underwriting 
Management Ltd, at Lloyd’s of London).  NHS indemnity operates in respect of the clinical treatment that 
is provided. 
14 PUBLICATION POLICY 
The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and 
any other publications arising from the study.  Authors will acknowledge that the study was funded by 
the Oxford-UCB Prize Fellowship. Authorship will be determined in accordance with the ICMJE guidelines 
and other contributors will be acknowledged. 
15 INTELLECTUAL PROPERTY 
 
Ownership of IP generated by employees of the University vests in the University.  The protection and 
exploitation of any new IP is managed by the University’s technology transfer office, Oxford University 
Innovations. 
 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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16 REFERENCES 
1. 
Murray CJ, Lopez AD. Measuring the global burden of disease. N Engl J Med. 2013;369(5):448-57. 
2. 
Smith E, Hoy DG, Cross M, Vos T, Naghavi M, Buchbinder R, et al. The global burden of other 
musculoskeletal disorders: estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis. 
2014;73(8):1462-9. 
3. 
Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011;11:770. 
4. 
Raffaeli W, Arnaudo E. Pain as a disease: an overview. J Pain Res. 2017;10:2003-8. 
5. 
Brummett CM, Urquhart AG, Hassett AL, Tsodikov A, Hallstrom BR, Wood NI, et al. 
Characteristics of fibromyalgia independently predict poorer long-term analgesic outcomes following 
total knee and hip arthroplasty. Arthritis Rheumatol. 2015;67(5):1386-94. 
6. 
A. Soni NKA, The COASt Study Group, A.J. Price, I. Tracey, M. Javaid. Neuropathic pain as a 
predictor of short and long-term outcome following knee replacement surgery. Osteoarthritis and 
Cartilage. 2016;24:S420–S1. 
7. 
Kurien T, Arendt-Nielsen L, Petersen KK, Graven-Nielsen T, Scammell BE. Preoperative 
Neuropathic Pain Like Symptoms and Central Pain Mechanisms in Knee Osteoarthritis Predicts Poor 
Outcome 6 Months After Total Knee Replacement Surgery. J Pain. 2018. 
8. 
Leffler AS, Kosek E, Lerndal T, Nordmark B, Hansson P. Somatosensory perception and function 
of diffuse noxious inhibitory controls (DNIC) in patients suffering from rheumatoid arthritis. Eur J Pain. 
2002;6(2):161-76. 
9. 
Edwards RR, Wasan AD, Bingham CO, 3rd, Bathon J, Haythornthwaite JA, Smith MT, et al. 
Enhanced reactivity to pain in patients with rheumatoid arthritis. Arthritis Res Ther. 2009;11(3):R61. 
10. 
Lee YC, Chibnik LB, Lu B, Wasan AD, Edwards RR, Fossel AH, et al. The relationship between 
disease activity, sleep, psychiatric distress and pain sensitivity in rheumatoid arthritis: a cross-sectional 
study. Arthritis Res Ther. 2009;11(5):R160. 
11. 
Meeus M, Vervisch S, De Clerck LS, Moorkens G, Hans G, Nijs J. Central sensitization in patients 
with rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2012;41(4):556-67. 
12. 
Lee YC, Lu B, Edwards RR, Wasan AD, Nassikas NJ, Clauw DJ, et al. The role of sleep problems in 
central pain processing in rheumatoid arthritis. Arthritis Rheum. 2013;65(1):59-68. 
13. 
Lee YC, Bingham CO, 3rd, Edwards RR, Marder W, Kristine P, Bolster MB, et al. Pain Sensitization 
is Associated with Disease Activity in Rheumatoid Arthritis Patients: A Cross-Sectional Study. Arthritis 
Care Res (Hoboken). 2017. 
14. 
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 Rheumatol. 
2018;70(7):1000-7. 
15. 
Wartolowska K, Hough MG, Jenkinson M, Andersson J, Wordsworth BP, Tracey I. Structural 
changes of the brain in rheumatoid arthritis. Arthritis Rheum. 2012;64(2):371-9. 
16. 
Lee YC, Lu B, Boire G, Haraoui BP, Hitchon CA, Pope JE, et al. Incidence and predictors of 
secondary fibromyalgia in an early arthritis cohort. Ann Rheum Dis. 2013;72(6):949-54. 
17. 
Duran J, Combe B, Niu J, Rincheval N, Gaujoux-Viala C, Felson DT. The effect on treatment 
response of fibromyalgic symptoms in early rheumatoid arthritis patients: results from the ESPOIR 
cohort. Rheumatology (Oxford). 2015;54(12):2166-70. 
18. 
Lage-Hansen PR, Chrysidis S, Lage-Hansen M, Hougaard A, Ejstrup L, Amris K. Concomitant 
fibromyalgia in rheumatoid arthritis is associated with the more frequent use of biological therapy: a 
cross-sectional study. Scand J Rheumatol. 2016;45(1):45-8. 
19. 
Mian AN, Chaabo K, Wajed J, Subesinghe S, Gullick NJ, Kirkham B, et al. Rheumatoid arthritis 
patients with fibromyalgic clinical features have significantly less synovitis as defined by power Doppler 
ultrasound. BMC Musculoskelet Disord. 2016;17(1):404. 
20. 
Kim H, Cui J, Frits M, Iannaccone C, Coblyn J, Shadick NA, et al. Fibromyalgia and the Prediction of 
Two-Year Changes in Functional Status in Rheumatoid Arthritis Patients. Arthritis Care Res (Hoboken). 
2017;69(12):1871-7. 
21. 
Clauw DJ. Diagnosing and treating chronic musculoskeletal pain based on the underlying 
mechanism(s). Best Pract Res Clin Rheumatol. 2015;29(1):6-19. 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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CONFIDENTIAL 
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22. 
Geenen R, Overman CL, Christensen R, Asenlof P, Capela S, Huisinga KL, et al. EULAR 
recommendations for the health professional's approach to pain management in inflammatory arthritis 
and osteoarthritis. Ann Rheum Dis. 2018;77(6):797-807.                                                                                       
23.  
Uceyler N, Zeller D, Kahn AK, Kewenig S, Kittel-Schneider S, Schmid A, et al. Small fibre pathology 
in patients with fibromyalgia syndrome. Brain. 2013;136(Pt 6):1857-67.                                                                
24.  
Evdokimov D, Frank J, Klitsch A, Unterecker S, Warrings B, Serra J, et al. Reduction of skin 
innervation is associated with a severe fibromyalgia phenotype. Ann Neurol. 2019;86(4):504-16.                    
25.  
Evdokimov D, Dinkel P, Frank J, Sommer C, Uceyler N. Characterization of dermal skin 
innervation in fibromyalgia syndrome. PLoS One. 2020;15(1):e0227674.  
26.  
Luik A, Marsden A, Emsley R, Henry A, Stott R, Miller C, Espie C. Long-term benefits of digital 
cognitive behavioural therapy for insomnia: Follow-up report from a randomized clinical trial. J Sleep 
Res. 2020;29(4):e13018 
27.  
Kyle S, Hurry M, Emsley R, Marsden A, Omlin X, et al., The effects of digital cognitive behavioral 
therapy for insomnia on cognitive function: a randomized controlled trial. Sleep. 2020; 43(9):1                                              
28.  
Themistocleous, A.C., et al., The Pain in Neuropathy Study (PiNS): a cross-sectional observational 
study determining the somatosensory phenotype of painful and painless diabetic neuropathy. Pain, 
2016;157(5):1132-45.                                                                                                                                                       
29.  
Schmid, A.B., et al. The relationship of nerve fibre pathology to sensory function in entrapment 
neuropathy. Brain, 2014;137(Pt 12):3186-99.                                                                                                        
30.  
Quattrini, C., et al. Surrogate Markers of Small Fiber Damage in Human Diabetic Neuropathy. 
Diabetes, 2007;56(8):2148-2154.                                                                                                                             
31. 
Zhou, L., et al. Correlates of epidermal nerve fiber densities in HIV-associated distal sensory 
polyneuropathy. Neurology, 2007;68(24):2113-2119.                                                                                           
32. 
Polydefkis, M., et al., Skin biopsy as a tool to assess distal small fiber innervation in diabetic 
neuropathy. Diabetes Technol Ther, 2001;3(1):23-28.                                                                                           
33.  
Lauria, G., et al., EFNS guidelines on the use of skin biopsy in the diagnosis of peripheral 
neuropathy. European Journal of Neurology, 2005;12(10):747-58.                                                                     
33.  
Dawes, J.M., et al., CXCL5 mediates UVB irradiation-induced pain. Sci Transl Med, 2011;3(90): 
90ra60.                                                                                                                                                                                     
35.  
Joint Task Force of the European Federation of Neurological Societies/Peripheral Nerve Society 
Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. J Peripher Nerv Syst, 
2010;15(2):79-92. 
36.  
Dolnicar, S. G., B; Leisch, F; Schmidt, K, Required Sample Sizes for Data-Driven Market 
Segmentation Analyses in Tourism.Journal of Travel Research 2013 
 
 
 
 
 
 
 

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with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
2023. REC ref. 19/SC/0168. IRAS Project ID 25276 
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17 APPENDIX A:  STUDY FLOW CHART 
 
APPENDIX B:  AMENDMENT HISTORY 
 
Amendment 
No. 
Protocol 
Version 
No. 
Date 
issued 
Author(s) of changes 
Details of Changes made 
1 
 
2 
7th 
October 
2020 
Dr Anushka Soni 
Inclusion of sub-study (blood 
test and skin biopsy), updated 
PIL and electronic consent form  
 
2 
 
 
 
3 
10th 
January   
2022 
Dr Anushka Soni 
Additional investigators; 
amendment of planned study 
size from 200 to 490; extension 
of planned study end date to 30 
April 2025; inclusion of 
Maladaptive Learning 
assessments within main study 
and Sleep sub-study, updated 
consent forms, PIL and separate 
Sleep study consent form and 
PIL  
3 
4 
23 
September 
2022 
Dr Anushka Soni 
Clarification of planned sample 
size. Additional movement 
analysis for the Maladaptive 

Characterisation of Pain in patients with musculoskeletal disease: a prospective, Longitudinal, observational study 
with an Embedded feasibility window of opportunity Sleep Study (PAIN-LESS).  Protocol version 5.0, 7th February 
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Learning assessments, 
recruitment from Connect 
Health, updated outcome 
measure questionnaires for 
Sleep sub-study,  updated study 
flowchart, new study 
documents - remote consent 
forms, research invitation letter, 
maladaptive learning sub study 
email.  
4 
 
 
 
 
5 
07 
February 
2023 
Dr Anushka Soni 
Updated study name. 
Amendment of sample size 
from 100 to 80 for those with 
fibromyalgia. Sleep Disorders 
Questionnaire administered via 
email or Microsoft Forms for 
fibromyalgia sleep screening. 
Addition of the British Colombia 
Cognitive Complaints Inventory, 
EQ-5D-5L and healthcare 
useage questions added to 
REDCap. Option to record heart 
rate variability on an ipad. 
Simplification and alignment of 
study arms for fibromyalgia, 
including: renaming sleep sub-
study as a feasibility study; 
reordering of paragraphs in 
protocol for clarity, rewording 
of secondary objectives of 
study, removal of skin biopsy 
from study protocol and 
associated documents, 
incorporation of the seperate 
sleep sub-study Patient 
Information Sheet and Consent 
Forms into main study 
documentation and updated 
study flow diagram. Addition of 
Sleepio instructions and paper 
copy of sleep diary. Study 
posters for clinicians and 
patients. Removal of 
Healthshare from Participating 
Organisations. Revised inclusion 
criteria and removal of option 
of MS Forms Consent Form.