Lessening the Impact of Fatigue in Inflammatory Rheumatic Diseases: A Randomised Clinical Trial
Phase: NA
Conditions: Rheumatoid Arthritis, Lupus Erythematosus, Systemic, Axial Spondyloarthritis, Psoriatic Arthritis, Sjogren's Syndrome
Sponsor: University of Aberdeen

Lessening the Impact of Fatigue in IRD 
 
 
 
 
 
 
 
 
 
STUDY PROTOCOL 
 
 
Full Title: 
Lessening the impact of fatigue in inflammatory 
rheumatic diseases: a randomised clinical trial 
Study Acronym: 
LIFT  
Sponsor: 
University 
of 
Aberdeen, 
King's 
College, 
Aberdeen,  AB24 3FX  
Sponsor Reference Number: 
2.049.16 
Funder: 
Arthritis Research UK  
Grant Number: 
21175 
Chief Investigator: 
Co-Chief Investigator 
Prof Gary Macfarlane 
Dr Neil Basu 
IRAS ID: 
216267 
REC Reference Number: 
17/WA/0065 
R&D Reference Number: 
216267/1060155/141467 
Clinicaltrialsgov Number: 
NCT03248518 
Version Number and Date: 
08.10.2020 version 11 

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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................ 2 
PROTOCOL APPROVAL ......................................................................................................... 4 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
SUMMARY ............................................................................................................................... 6 
1 
INTRODUCTION................................................................................................................ 7 
1.1 
BACKGROUND ............................................................................................................. 7 
1.2 
RATIONALE FOR STUDY ................................................................................................. 7 
2 
STUDY OBJECTIVES ..................................................................................................... 10 
2.1 
PRIMARY OBJECTIVE ................................................................................................... 10 
2.2 
SECONDARY OBJECTIVES.............................................................................................. 10 
3 
OUTCOMES .................................................................................................................... 10 
3.1 
PRIMARY OUTCOME ................................................................................................... 10 
3.2 
SECONDARY OUTCOMES .............................................................................................. 10 
3.3 
MEDIATOR/MODERATOR DATA ..................................................................................... 11 
3.4 
QUANTITATIVE PROCESS EVALUATION............................................................................. 11 
3.4.1 
Patient preference .............................................................................................. 11 
3.4.2 
Patient adherence and acceptability ................................................................... 11 
3.5 
QUALITATIVE PROCESS EVALUATION ............................................................................... 12 
3.6 
ECONOMIC EVALUATION.............................................................................................. 12 
3.7 
COLLECTION OF BLOOD SAMPLE FOR FUTURE ETHICALLY APPROVED RESEARCH ......................... 12 
3.8 
STUDY MATRIX.......................................................................................................... 13 
4 
STUDY DESIGN .............................................................................................................. 14 
4.1 
STUDY DESCRIPTION ................................................................................................... 14 
4.2 
STUDY FLOWCHART .................................................................................................... 16 
4.3 
INTERVENTIONS ......................................................................................................... 17 
4.3.1 
Description of interventions................................................................................ 17 
4.3.2 
Treatment protocol ............................................................................................ 18 
4.3.3 
Training of therapists before the study ............................................................... 18 
4.3.4 
Supervision and support of therapists during the study ....................................... 18 
5 
STUDY POPULATION ..................................................................................................... 19 
5.1 
NUMBER OF PARTICIPANTS .......................................................................................... 19 
5.2 
PARTICIPANT SELECTION AND ENROLMENT ...................................................................... 19 
5.2.1 
Identifying Participants ...................................................................................... 19 
5.2.2 
Screening for Eligibility ....................................................................................... 20 
5.2.3 
Inclusion Criteria ................................................................................................ 20 
5.2.4 
Exclusion Criteria ................................................................................................ 20 
5.3 
CONSENTING PARTICIPANTS ......................................................................................... 21 
5.4 
PROCEDURE FOR INELIGIBLE AND NON-RECRUITED PARTICIPANTS.......................................... 21 
6 
RANDOMISATION AND BLINDING ................................................................................ 22 
6.1 
RANDOMISATION DETAILS ........................................................................................... 22 
6.2 
BLINDING ................................................................................................................. 22 
6.3 
WITHDRAWAL PROCEDURES......................................................................................... 22 
7 
STUDY AND SAFETY ASSESSMENTS .......................................................................... 23 
8 
DATA COLLECTION AND MANAGEMENT .................................................................... 23 
8.1 
DATA COLLECTION ..................................................................................................... 23 
8.2 
DATA MANAGEMENT SYSTEM ...................................................................................... 24 

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8.3 
TRANSFER OF DATA .................................................................................................... 24 
9 
LABS AND SAMPLE ANALYSIS .................................................................................... 24 
10 STATISTICS AND DATA ANALYSIS .............................................................................. 25 
10.1 
SAMPLE SIZE CALCULATION .......................................................................................... 25 
10.2 
PROPOSED ANALYSIS .................................................................................................. 25 
10.3 
MISSING DATA .......................................................................................................... 26 
11 TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS ....................................... 26 
11.1 
TRIAL MANAGEMENT GROUP ....................................................................................... 26 
11.2 
STUDY MANAGEMENT ................................................................................................ 26 
11.3 
TRIAL STEERING COMMITTEE ........................................................................................ 27 
11.4 
DATA MONITORING COMMITTEE .................................................................................. 27 
12 INSPECTION OF RECORDS ........................................................................................... 27 
13 GOOD CLINICAL PRACTICE .......................................................................................... 27 
13.1 
ETHICAL CONDUCT OF THE STUDY.................................................................................. 27 
13.1.1 
Confidentiality .................................................................................................... 27 
13.1.2 
Data Protection .................................................................................................. 28 
13.1.3 
Insurance and Indemnity .................................................................................... 28 
14 STUDY CONDUCT RESPONSIBILITIES ......................................................................... 28 
14.1 
PROTOCOL AMENDMENTS, DEVIATIONS AND BREACHES..................................................... 28 
14.2 
STUDY RECORD RETENTION.......................................................................................... 28 
14.3 
END OF STUDY .......................................................................................................... 29 
15 REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS .............................. 29 
15.1 
AUTHORSHIP POLICY .................................................................................................. 29 
15.2 
PUBLICATION ............................................................................................................ 29 
15.3 
PEER REVIEW ............................................................................................................ 29 
16 REFERENCES ................................................................................................................ 29 
APPENDIX 1 SWAT 24 .......................................................................................................... 34 
APPENDIX 2: DELINEATING THE NEURAL MEDIATORS OF INFLAMMATORY RHEUMATIC 
DISEASE (AN OPTIONAL LIFT SUB-STUDY) ....................................................................... 37 
APPENDIX 3: QUALITATIVE EVALUATION (LIFT SUB-STUDY) .......................................... 42 
 
 
 

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PROTOCOL APPROVAL 
 
Lessening the impact of fatigue in inflammatory rheumatic diseases: a 
randomised clinical trial 
 
 
Signatures 
 
By signing this document I am confirming that I have read, understood and approve the 
protocol for the above study. 
 
 
 
 
Prof Gary Macfarlane 
 
 
 
08 October 2020 
Chief Investigator 
 
Signature 
 
Date (dd/mon/yyyy) 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
ASDAS 
Ankylosing Spondylitis Disease Activity Score 
AxSpA 
Axial Spondyloarthritis 
BILAG 
British Isles Lupus Activity Group 
BRAF-MDQ 
Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire 
CBA 
Cognitive Behavioural Approach 
CF 
Chalder Fatigue Scale 
CHaRT 
Centre of Healthcare Randomised Trials 
CI 
Chief Investigator 
CNORIS 
Clinical Negligence and Other Risk Scheme 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CTU 
Clinical Trials Unit 
DAS28 
Disease Activity Score 28 
DMC 
Data Monitoring Committee 
DTI 
Diffusion Tensor Imaging 
eGFR 
Estimated glomerular filtration rate 
ESR 
Erythrocyte Sedimentation Rate 
FA 
Fractional Anisotropy 
FSS 
Fatigue Severity Scale 
GCP 
Good Clinical Practice 
HADS 
Hospital anxiety and depression scale 
ICECAP 
Investigating Choice Experiments for the preference of older people 
CAPability measures for adults 
IRD 
Inflammatory Rheumatic Disease 
MAR 
Missing at random 
MRI 
Magnetic Resonance Imaging 
NHS 
National Health Service 
PA 
Physical Activity 
PASAT 
Paced Auditory Serial Addition Test 
PEP 
Personalised Exercise Programme 
PRoNTo 
Pattern Recognition for Neuroimaging Toolbox 
QALY 
Quality Adjusted Life Years 
QOL 
Quality of Life 
RA 
Rheumatic Arthritis 
RCT 
Randomised Controlled Trial 
REC 
Research Ethics Committee 
RPE 
Rating of Perceived Exertion 
SLE 
Systemic Lupus Erythematosus 
SOP 
Standard Operating Procedure 
S-VLA 
Valued Life Activities short form 
SWAT 
Study Within A Trail 
TDF 
Theoretical Domains Framework 
TSH 
Thyroid Stimulating Hormone 
VBM 
Voxel-based morphometry 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem 

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SUMMARY 
Fatigue is pervasive, disabling and challenging to manage across all inflammatory 
rheumatic diseases (IRDs).  
Primarily, we seek to advance the implementation of fatigue alleviating physical activity 
support programmes and cognitive-behavioural treatments within health services. We 
will individually test these interventions against usual care across multiple, rather than 
single, IRDs to enable improved patient access and resource utilisation. The 
interventions will be delivered centrally, by either telephone or internet-based 
audio/video calls such as Skype or Jabber, with a view to further enhancing cost-
effectiveness.  
The conduct of such a pragmatic study also presents a unique opportunity to a) 
investigate the underlying mechanisms of fatigue in order to optimise future interventions 
and b) identify the moderators of physical activity and cognitive-behavioural therapy 
efficacy so as to inform future stratified studies and patient triage pathways. 
If successful, this study has the potential to unlock widespread access to much needed 
therapies and will provide vital insights into this commonly neglected patient priority. 
 
 
 
 
 
 
 

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1 
INTRODUCTION 
1.1 Background 
Despite major advances in the management of inflammatory rheumatic diseases (IRDs), 
patients remain burdened by their disease and cite fatigue as a principal problem. In 
rheumatoid arthritis (RA), for example, as many as 80% of patients report significant 
fatigue [1] and over 70% consider fatigue to be equal to pain in terms of burden [2]. 
Moreover, fatigue is a crucial determinant of impaired quality of life (QOL) [3,4] and a 
predictor of work disability [5,6]. Indeed, over 75% of patients identify fatigue as the main 
barrier to remaining in employment [7]. Studies in other IRDs, such as axial 
spondyloarthritis (AxSpA) and systemic lupus erythematosus (SLE), have reported 
similar fatigue prevalence of 66-85% [8,9] and have found the impact of fatigue on QOL 
and employment to be equally pronounced [10-12]. In spite of these profound 
consequences, patients feel this symptom is clinically ignored [13,14]1,2 and 
rheumatologists admit ignorance regarding its management [15]. 
This situation reflects the poor availability of suitable interventions within modern health 
care systems such as the NHS, but this is not to say that effective treatments do not 
exist. There is now considerable consensus across the health care community that non-
pharmacological interventions, specifically cognitive behavioural approaches (CBA) and 
programmes designed to support increased physical activity, are valuable treatments 
which help IRD patients manage the functional challenges of their disease such as 
fatigue [16,17].  
Our current team has made key contributions to the evidence base, which supports the 
use of these treatments for fatigue in IRDs [18-20].   
However, current health care systems routinely contribute to substantial barriers to the 
implementation of these therapeutic options.   
Firstly, existing studies – including our own – have only developed bespoke disease-
specific models of care, which vary in content, structure and method of delivery. 
Inevitably, this necessitates the development of multiple particular skill sets for the care 
providers if they are to equitably serve their diverse patient populations – a time 
consuming, costly and inefficient undertaking.  
Secondly, patients find it challenging to commit to regular face-to-face treatment 
sessions (a common underpinning of existing CBA and exercise interventions). This is 
often due to a combination of health complications and the time-constrained nature of 
modern life, particularly relevant to those patients still in employment.  
Thirdly, individual patients report substantial variation in their preference and response 
to the distinct interventions of CBA and physical activity [21,22]. 
 
1.2 Rationale for Study 
It has becoming increasingly clear that:  
a) similarities exist across chronic IRD disorders regarding the nature and likely 
mechanisms which maintain fatigue – such as dysfunctional activity behaviours [23-25] 
and illness beliefs [14,26,27], and so the application of standardised generic, rather than 
disease-specific, interventions may prove effective  

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b) alternative, more flexible, methods of remote delivery such as telephone and internet-
based audio/video calls can be just as effective as traditional face to face interventions 
[28,29] and  
c) in the future, the identification of baseline patient preferences and characteristics 
which can predict differential treatment effects (moderators) will be vital to inform a 
personalised triage approach to care [22,30]. 
Therefore, we propose a pragmatic trial, which will use pre-developed cognitive 
behavioural therapy and graded exercise therapy interventions, already considered the 
standard of care in heterogeneous primary fatigue populations. We have adapted them 
to a CBA and personalised exercise programme (PEP) so they may also be generically 
applicable across IRD-fatigue populations. We will now test whether these key non-
pharmacological interventions can individually reduce fatigue, when delivered by the 
rheumatology team, across a mixture of IRDs using telephone or internet-based 
audio/video calls. In doing so, we will be able to explore potential moderating factors 
which may allow for the future triage of patients according to the most suitable 
intervention, but in addition investigate the precise mediators of the effect of treatment 
on IRD-related fatigue. The overall time scale of the LIFT study is summarised in a 
GANTT chart (Figure 1). 
 
 

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Figure 1. GANTT chart of LIFT study, LIFT MRI sub-study and qualitative evaluation sub-study
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Funding (LIFT)
Protocol development
Intervention development
Feedback on intervention documents
Preparation of study documents (PIS)
Establish oversight committees (DMC, TSC, TMG)
Approvals LIFT (Sponsor, REC, R&D)
Approvals LIFT MRI sub-study (Sponsor, REC, R&D)
Study database
Site initiation process and training
Therapist training for intervention (CBA/PEP)
Recruitment phase (LIFT))
Intervention
Study assessment visits 
Recruitment phase (MRI sub-study)
Optional: MRI scan #1 (pre-intervention)
Optional: MRI scan #2 (post-intervention)
Recruitment phase (Qualitative Evaluation sub-study)
Qualitative Evaluation interviews (participants)
Qualitative Evaluation interviews (therapists)
Data entry
Data analysis and statistic
Data processing, analysis and report LIFT MRI sub-study
Publications
protocol
study main outcomes
health economic analysis
qualitative evaluation
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2 
STUDY OBJECTIVES 
2.1 Primary Objective 
Primarily, we seek to test our hypothesis that usual care in addition to either standardised 
CBA or PEP interventions is more effective than usual care alone to lessen the impact 
and severity of fatigue after 56 weeks. 
 
2.2 Secondary Objectives 
We will also explore the underlying moderators (in order to inform future patient triage) 
and mediators (in order to optimise future interventions) of IRD related fatigue. 
 
 
3 
OUTCOMES 
All outcome and mediator data will be assessed at randomisation (baseline) and then, 
on average, 10 weeks, 28 weeks and 56 weeks thereafter (by questionnaire unless 
stated) in all participants. The outcome measures at each time point and their source 
(i.e. questionnaire, medical record, blood sample, diary) are summarised in the study 
matrix (see 3.8).  
 
3.1 Primary Outcome 
The primary outcome fatigue is determined with the Chalder Fatigue Scale (CF) [31] 
using the Likert scoring, assessing the physical and mental symptoms of fatigue, and the 
Fatigue Severity Scale (FSS) [32] assessing the impact of fatigue after 56 weeks. If the 
effect of intervention is positive on the CF, then the FSS outcome will be formally 
analysed. Should the intervention have no effect on the CF, then an explorative analysis 
of the FSS outcome will be performed (details see 10.2). 
 
3.2 Secondary Outcomes 
The secondary outcomes are:  
• 
Fatigue: Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire [33] 
(BRAF-MDQ) assessing physical, living, cognition and emotional aspects of fatigue 
• 
Quality of life & health utility index: Short Form-12 [34] assessing functional health 
and wellbeing from the patient’s perspective 
• 
Pain: Pain numerical rating scale [35] assessing pain intensity  
• 
Anxiety and depression: Hospital anxiety and depression scale (HADS) [36] 
• 
Sleep: Sleep problem scale [37] 
• 
Impact on work: Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem (WPAI:SHP) [38]  
• 
Impact on activities: Valued Life Activities Scale (short form S-VLA) [39] 
• 
Global outcome: change of global health 

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3.3 Mediator/moderator data 
While many outcome measures may also function as mediators, or their baseline values 
as moderators, more detailed cognitive, behavioural, clinical and physical data will be 
important in order to fully characterise these factors.   
Cognitions and behaviours: Brief Illness Perception Questionnaire [40], Behavioural 
Response to Illness Questionnaire [41] 
Clinical: Presence of fibromyalgia [42], serological status, erosive status, disease 
duration, previous and current pharmacological therapies, disease activity: self-reported, 
DAS28 for RA (mandatory), , other disease specific activity measures (non-mandatory), 
inflammation (CRP/ESR), presence of other co-morbidities (Charlson Comorbidity 
Index).  
Physical: Physical activity profiles measured by an activity monitor (activPAL, 
Paltechnologies Ltd, Glasgow). The activPAL will be fitted to the participant at each 
assessment session and participants instructed to remove the device and post it back to 
the research team after seven days in the stamped addressed envelope provided to 
them.  
Quantifying aerobic fitness: we will employ a step test, which involves participants 
wearing a heart rate monitor and stepping onto a 10 inch high box for three minutes at 
different stepping rates (stage 1:17, stage 2:26 and stage 3: 34 steps per minute – guided 
by a metronome). Participants stop the test if the heart reaches 65% of predicted 
maximal heart rate (220-age or 190-age if participant is prescribed beta-blocker) at the 
end of any stage. In addition, values of Borg Rating of Perceived Exertion (RPE) are 
collected. One minute of rest is given between stages and maximal oxygen uptake is 
estimated from heart rate recordings according to established equations [43].  
Neuroimaging data: Participants will have an option to undertake a multi-modal magnetic 
resonance imaging (MRI) brain scan (see Appendix 2) 
 
3.4 Quantitative process evaluation 
3.4.1 Patient preference  
Participants will be given short synopsis of all three treatments, usual care, CBA and 
PEP interventions as treatment for IRD-related fatigue. They will then be asked about 
which treatment they would choose if they had a choice, as well as about their strength 
of preference. 
 
3.4.2 Patient adherence and acceptability 
Patient adherence to the interventions will be monitored via attendance records kept by 
the therapists. In addition, participants receiving the CBA or PEP interventions will be 
contacted by telephone interview by member of trial office Aberdeen at time of session 
4 (approximately week 8) and session 8 (approximately week 26). They will be asked to 
indicate on a scale from 0 (not at all) to 10 (completely), if they think that this treatment 
is the right approach and their willingness to engage and adhere to the intervention. At 
the same time, the therapists will be asked during supervision to what extent they think 
that the participant has engaged with treatment and adhered to the agreed actions and 

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plans. Intervention acceptance by participants will be evaluated in all three treatment 
arms using the Client Satisfaction Questionnaire [44] at 28 weeks.  
 
3.5 Qualitative process evaluation 
We will conduct qualitative evaluations of both participants who received CBA or PEP 
and rheumatology health care professionals who will deliver the interventions (see 
Appendix 3).  
 
3.6 Economic evaluation 
An economic evaluation will be conducted from both a health care system and societal 
perspective. Participants will be asked to record in a diary all types and duration of 
hospital admissions, frequency of visits to hospital for outpatient attendances, and other 
visits to or from relevant health professionals (e.g. general practitioners, nurse 
practitioners, physiotherapists) and specify whether the main reason for the visit was 
fatigue. The participant will be asked to keep the diaries between the baseline and third 
assessment visit (approximately 28 weeks). Furthermore they will be asked to keep 
diaries for two weeks after the third assessment visit and two weeks before they return 
for the last assessment visit. National sources of unit cost data will be applied to value 
resource use (HRG Reference Costs, Unit Costs of Health and Social Care). The costs 
associated with delivery of the interventions will be estimated using records kept by 
therapists of the number and duration of calls per patient. 
Patients will be asked to report any contacts with private practitioners, and the costs of 
over the counter medication/complementary therapies purchased. This also includes 
additional expenses related to their condition or fatigue as well as if there was an impact 
on paid and unpaid work. 
Health-related quality of life data will be collected using the SF-12 and these data will be 
converted to quality of life weights using published tariffs. These data will then be used 
to calculate Quality Adjusted Life Years (QALYs). As the intervention may affect general 
well-being as well as reduce fatigue, we will also collect values for changes in well-being 
data using the ICECAP instrument [45] and changes in life satisfaction [46]. 
 
3.7 Collection of blood sample for future ethically approved research  
Patients will be given the option to provide additional blood samples which will be stored 
in a designated freezer at the University of Aberdeen. These are a maximum of 3 tubes 
per visit of 1x PAXgene RNA (visit 1, 2, 3), 1x PAXgene DNA (visit 1 only), 1x serum 
(visit 1, 2, 3). All samples will be transferred to a designated freezer at the Imaging Centre 
of Excellence, Queen Elizabeth University Hospital in Glasgow and stored until analysis. 
Additional consent for their use in future unspecified studies will be obtained.  
 
 

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3.8 Study Matrix 
 
Source 
Items 
 
Proposed assessment 
[weeks] 
 
 
 
S 
0 
10 
28 
56 
Demographic data 
 
 
 
 
 
 
 
Date of birth, gender, marital status, employment status, level of 
education 
Q 
5 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
Characteristics of study population 
 
 
 
 
 
 
 
Overall health 
Q 
1 
 
✓ 
 
 
 
Physical activity (typical self-reported) 
Q 
1 
 
✓ 
 
 
 
Experience of fatigue for more than 3 month  
Q / CRF 
1 
✓ 
✓ 
 
 
 
Average level of fatigue 
Q / CRF 
1 
✓ 
✓ 
 
 
 
Thyroid function test 
B or MR 
 
 
✓ 
 
 
 
Urea and electrolytes 
B or MR 
 
 
✓ 
 
 
 
Full blood count 
B or MR 
 
 
✓ 
 
 
 
Serological status 
MR 
 
 
✓ 
 
 
 
Erosive status 
MR 
 
 
✓ 
 
 
 
Disease duration  
MR 
 
 
✓ 
 
 
 
Presence of other co-morbidities (Charlson Index) 
MR/CRF 
 
 
✓ 
✓ 
✓ 
✓ 
History of suicide attempts 
MR/CRF 
 
 
✓ 
 
 
 
Inflammation (CRP/ESR)  
B 
 
 
✓ 
✓ 
✓ 
✓ 
Current pharmacological therapies 
MR 
 
 
✓ 
✓ 
✓ 
✓ 
Blood pressure  
 T 
 
 
✓ 
 
 
 
 
 
 
 
 
 
 
 
Primary Outcome 
 
 
 
 
 
 
 
Chalder Fatigue Scale (Likert scoring) 
Q 
11 
 
✓ 
✓ 
✓ 
✓ 
Fatigue Severity Scale (FSS) 
Q 
9 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
Secondary Outcomes 
 
 
 
 
 
 
 
BRAF-MDQ (fatigue) 
Q 
20 
 
✓ 
✓ 
✓ 
✓ 
HADS (anxiety and depression) 
Q 
14 
 
✓ 
✓ 
✓ 
✓ 
Short Form-12 
Q 
12 
 
✓ 
✓ 
✓ 
✓ 
Pain numerical rating scale 
Q 
1 
 
✓ 
✓ 
✓ 
✓ 
Sleep problem scale 
Q 
4 
 
✓ 
✓ 
✓ 
✓ 
Work Productivity and Activity Impairment Questionnaire 
Q 
6 
 
✓ 
✓ 
✓ 
✓ 
Valued Life Activities Scale (short 14 items) 
Q 
14 
 
✓ 
✓ 
✓ 
✓ 
Global outcome 
Q 
1 
 
 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
Additional mediator/moderator data  
 
 
 
 
 
 
 
Cognitions and behaviours 
 
 
 
 
 
 
 
Brief Illness Perception Questionnaire 
Q 
9 
 
✓ 
✓ 
✓ 
✓ 
Behavioural Response to Illness Questionnaire 
Q 
21 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
Clinical 
 
 
 
 
 
 
 
Presence of fibromyalgia 
CRF 
8 
 
✓ 
 
 
✓ 
Disease activity (self-reported) 
CRF  
2 
 
✓ 
✓ 
✓ 
✓ 
Disease activity DAS28 for RA (mandatory), ASDAS, BILAG, 
replaced with disease specific activity measures (non-
mandatory) 
CRF/MR 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
Physical 
 
 
 
 
 
 
 
Physical activity profiles, over a 7 day period  
T 
 
 
✓ 
✓ 
✓ 
✓ 
Quantifying aerobic fitness (step) test (weight, VO2 max and 
Borg Rating of Perceived Exertion) 
T 
 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 

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Source 
Items 
 
Proposed assessment 
[weeks] 
 
 
 
S 
0 
10 
28 
56 
Neuroimaging (optional) 
 
 
 
 
 
 
 
Multi-modal MRI scan 
SC 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
 
Quantitative evaluation 
 
 
 
 
 
 
 
Patient preference 
Q 
2 
 
✓ 
 
 
 
Patient adherence (attendance records) 
SR 
 
 
x 
x 
x 
 
Patient engagement and adherence (telephone call) 
Q 
3 
 
 
x 
x 
 
Patent engagement and adherence (therapist view) 
Q 
2 
 
 
x 
x 
 
Patient acceptability (Client Satisfaction Questionnaire) 
Q 
8 
 
 
 
✓ 
 
 
 
 
 
 
 
 
 
Qualitative process evaluation 
 
 
 
 
 
 
 
Qualitative evaluation in participants (5% sample) 
I 
 
 
 
 
 
 
Qualitative evaluation in therapists (all) 
I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Economic evaluation 
 
 
 
 
 
 
 
Health care costs from participants per diaries 
D 
 
 
✓ 
✓ 
✓ 
✓ 
Additional (personal) costs for participant per diaries 
D 
 
 
✓ 
✓ 
✓ 
✓ 
Cost associated with delivery of therapy 
SR 
 
 
✓ 
✓ 
✓ 
✓ 
Health related quality of life using SF-12 for calculation of QALY 
 
 
 
✓ 
✓ 
✓ 
✓ 
Changes in well-being data using ICECAP  
Q 
5 
 
✓ 
✓ 
✓ 
✓ 
Changes in life satisfaction  
Q 
1 
 
✓ 
✓ 
✓ 
✓ 
 
 
 
 
 
 
 
 
Optional blood sample for future ethically approved research 
 
 
 
 
 
 
1 x PAXgene RNA 
 
 
 
✓ 
✓ 
✓ 
 
1 x PAXgene DNA 
 
 
 
✓ 
 
 
 
1 x serum 
 
 
 
✓ 
✓ 
✓ 
 
 
Key: B, blood sample taken specifically for LIFT; CRF, part of case report form completed by research nurse 
during visit; D, separate diary for participant to keep; I, interviews performed after the last follow-up visit; MR, 
information extracted from medical record; Q, data derived from questionnaire; S, information obtained 
during pre-study invite; SC, Scanner; SR, information extracted from LIFT study records and logs; T, test 
done specifically for LIFT; x, outcome collection at same time frame but separate from assessment visit 
 
 
 
4 
STUDY DESIGN 
The LIFT study is a multi-centre, three-arm randomised controlled trial testing usual care 
alone versus usual care with additional adapted CBA or PEP therapies (see 4.3). 
 
4.1 Study Description 
Eligible participants will be identified from about 3600 patients with IRD attending major 
secondary care rheumatology services in the UK (see also study flow chart under 4.2). 
Potential participants will be identified using local databases/clinic lists and will then be 
mailed or given a pre-study invite, which will include questions about fatigue (see 5.2). 
Potentially eligible participants will be invited to attend a baseline assessment where, if 
appropriate, they will be consented, the eligibility confirmed and randomised. Recruits 
will be randomly assigned to either a course of usual care and CBA or PEP, or usual 
care alone (see 6). Those in the CBA and PEP groups will receive a course of treatment 
involving 7 sessions delivered by telephone/ internet-based audio/video call. A booster 
session will be conducted 22 weeks after the start date of treatment (see 4.3). We expect 
that active CBA and PEP therapy will start at between 2 and 8 weeks post-randomisation, 

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with an average of 4 weeks after baseline. Follow-up data will be collected from all 
participants at 10 weeks, 28 weeks and 56 weeks after randomisation adjusted for the 
average delay of 4 weeks. The timeline for assessment and delivering of interventions is 
summarised in Figure 2 below.  
 
 
 
Figure 2. Study time line 
 
The primary outcome measures will be fatigue severity and impact (see 3.1). Secondary 
outcome measures will include those on quality of life, pain, psychological distress and 
work ability (see 3.2). Additional clinical, physical activity and psycho-social data will be 
collated to enable the identification of moderators and mediators (see 3.3 and 3.4). A 
subgroup of participants will be invited to take part in a nested qualitative evaluation 
study after they completed the follow-up (see Appendix 3). A subgroup will be invited to 
take part in an optional nested mechanistic observational MRI sub-study (Appendix 2). 
The main effectiveness analysis will be via intention-to treat including all participants (see 
10).  
 
 

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4.2 Study Flowchart 
 
 
 
 
 

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4.3 Interventions 
All participants will receive the usual care intervention and will be posted an Arthritis 
Research UK education booklet. Participants randomised to the active treatments will 
also receive either CBA or PEP. The CBA and PEP treatments are adapted from 
previous fatigue specific cognitive behavioural [47,48] and physical activity interventions 
[47]  to ensure that they are suitable for a remote delivery via telephone or internet-based 
audio/video call and applicable the broad spectrum of IRD.  
 
4.3.1 Description of interventions 
Usual care: Due to issues of treatment access, patient education using Arthritis Research 
UK’s information booklet for self-management of fatigue [49] represents usual care in 
almost all UK rheumatology centres and is freely available. The leaflet covers the major 
relevant topics (including fatigue validation, energy management, priorities, sleep, 
stress, and assertiveness) underpinned by goal-setting and self-monitoring of activity. It 
encourages, at several key points that the patient asks their rheumatology team for 
support to work through the booklet. We will not restrict what usual care may involve, but 
will monitor the care received for all participants as part of our health economics analysis 
(see 3.6).   
 
The Cognitive behavioural approach (CBA) is a structured psychological intervention, 
which explicitly aims to replace unhelpful beliefs and behaviours with more adaptive 
ones. In this study, the CBA will target a number of unhelpful behavioural patterns such 
as ‘activity avoidance’ and ‘all or nothing’. These can lead to negative mood states, which 
enhance the perception of fatigue even further. Following a brief assessment of individual 
patients beliefs and behaviours surrounding fatigue, the aim of the treatment is to change 
unhelpful beliefs and behavioural factors through the application of patient-centred 
strategies and behavioural activities, which are supported by written materials and 
regular consultations with rheumatology health care professionals. The participants will 
receive additional key leaflets and diaries to assist them with making changes to manage 
fatigue. The times and duration of keeping the diary as well as the exchange of content 
will be set individually for each patient following assessment and in collaboration with the 
allocated therapist. For example the participant may be asked to keep the rest and 
activity dairy for up to two weeks before a session with the therapist and they will talk 
about it via video call where the participant shows the diary to the therapist. 
 
The Personalised Exercise Programme (PEP) is theoretically based on the premise that 
chronic fatigue relates to PA intolerance, supported by unhelpful illness beliefs (such as 
fear avoidance) and deconditioning, with a consequent increased perception of effort. 
PEP aims to disrupt this vicious cycle by a graded exposure behaviour therapy, which is 
symptom contingent, to gradually optimise patients levels of PA with view to modifying 
their altered perception of effort, improve their tolerance of PA, fitness and function, 
reverse the deconditioning and ultimately reduce the severity and impact of fatigue. 
Participants will receive an individually tailored graded exercise programme, initially 
delivered according to their physical capacity and gradually increased in duration and 
then intensity. The participants will receive additional information and diaries to assist 

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with the intervention. The times and duration of keeping the diary as well as the exchange 
of content will be subject to change based on the instructions of the allocated therapist. 
The intervention will utilise pedometers and/or heart rate monitors for goal-setting and to 
enhance motivation.  
 
4.3.2 Treatment protocol 
Both interventions will be delivered by trained rheumatology health care professionals, 
such as rheumatology nurses, occupational therapists and physiotherapists, with a pre-
existing understanding of IRDs. Participants will be offered seven one-to-one telephone 
or internet-based audio/video call (based on patient preference) sessions (up to 45 
minutes) of CBA or PEP interventions with a trained rheumatology health care 
professional. The first session of the PEP intervention, however, will be delivered face-
to-face. PEP may be delivered by a rheumatology specialist physiotherapist and CBA 
may be delivered by a rheumatology nurse or alternatively an equally qualified and 
trained allied health professional. A booster session will be conducted at 22 weeks after 
start of therapy by the relevant rheumatology health care professionals.  
 
4.3.3 Training of therapists before the study 
Separate CBA and PEP training will be provided for the rheumatology nurses and 
physiotherapists. This will comprise an intensive 3-day group course delivered by 
experienced designated investigators (see delegation log in Trail Management File, 
TMF) supplemented with the modified therapist manuals. The course will utilise a range 
of methods including skills practice with specific feedback using fictitious but typical 
fatigued cases.  
 
4.3.4 Supervision and support of therapists during the study 
Supervision will be provided by designated investigators (see delegation log in TMF) on 
a fortnightly basis, as required, to the rheumatology health care professionals either face 
to face or by telephone depending on feasibility and preference. Some of the sessions 
will be recorded and used in supervision to provide feedback to rheumatology health 
care professionals and to ensure treatment fidelity. We aim to take a 5% sample of 
sessions from individuals who agree to be recorded which is based on a random sample 
generated from an algorithm that takes into account session number, therapist, site 
location, patient gender. 5% of total number of sessions for those in CBA and PEP is 89 
recordings, however this will be subject to participant agreeing to be recorded and 
treatment adherence (no sessions completed).  
In addition, support will be available in cases where a rheumatology health care 
professional requires assistance with respect to a particular participant. In addition to 
direct contact option with the supervisor, we will have a notification system incorporated 
in the database provided and maintained by CHaRT (see 8.2). After secure log-in, the 
rheumatology health care professional is able to log a report with details about the issue 
using the participant ID number but no further identifying details included. The database 
will, if requested, notify the designated investigator or nominated deputy if unavailable 
as summarised in the delegation log in the TMF, who will provide clinical input if 
necessary or identify either designated supervisor to provide support if an intervention 

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specific issue is raised. We will aim to arrange for the rheumatology health care 
professional to be contacted within 24 h (based on normal working hours) regarding the 
issue and agreement reached on the required action to be taken and by whom.  
 
5 
STUDY POPULATION 
 
5.1 Number of Participants 
Based on the sample size calculation (see 10.1), 100 evaluable participants per 
treatment are required. The data of participants are evaluable when outcomes at the 56 
weeks follow-up are available. Based on our own previous studies, we estimate a 
dropout rate of 20% and therefore we anticipate recruiting 125 participants in each 
treatment group, or 375 participants previously diagnosed with IRD (e.g. RA, SLE and 
AxSpA, psoriatic arthritis, vasculitis or Sjogren’s Syndrome).  
 
5.2 Participant Selection and Enrolment 
Local procedures at the participating study sites are different and the recruitment process 
may vary in order to accommodate the specific circumstances at each site. Study posters 
and leaflets will be available at NHS premises of study sites and displayed on websites 
and social media to increase awareness of the study. Patients are asked to contact their 
Rheumatology team if they are interested in the study as enrolment is by invitation only. 
All potential participants will undergo a two-step screening process consisting on a pre-
study invite and an assessment of their medical notes to identify potentially eligible 
participants. All participants will provide written informed consent before they undergo 
the baseline assessment visit and randomisation to one of the three intervention groups 
(see 4.3.1).  
 
5.2.1 Identifying Participants 
A nurse who is a member of the direct care team will identify potential participants using 
established databases and/or by searching of clinic lists at each study site. Patients with 
rheumatologist diagnosed IRDs (e.g. RA, SLE and AxSpA, psoriatic arthritis, vasculitis 
or Sjogren’s Syndrome) will be selected. Each potential participant will be contacted by 
the direct care team on behalf of the local Principal Investigator first. They will receive a 
pre-study invite either by post or at the time of a rheumatology appointment consisting 
of a cover letter (see Appendix 1 for details on SWAT Study within a Trial), study 
information and a few questions to explore interest and eligibility. They will also be asked 
to give permission for the local research personnel to access their hospital medical notes 
to further screen for eligibility and for permission to be contacted by the study team (local 
and central). 
If a participant has been identified as potentially eligible a member of the local research 
team will contact the potential participant within a week to invite him/her to an 
appointment for a baseline assessment visit at the local study site. 
 

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5.2.2 Screening for Eligibility 
After return of the pre-study invite, the research personnel at each study site will assess 
their medical notes to determine eligibility based on the inclusion and exclusion criteria 
summarised in 5.2.3 and 5.2.4. A trained rheumatology research nurse will review and 
confirm eligibility. In addition, the local rheumatology consultant will have the opportunity 
to withdraw (see 6.3) or exclude participants. 
 
5.2.3 Inclusion Criteria 
In order to be considered eligible for participation in the study they must: 
• 
be ≥ 18 years at the time of consent 
• 
have been diagnosed by a rheumatologist with an IRD such as RA, SLE or AxSpA  
• 
report fatigue to be a persistent problem as evidenced by answering both 
questions: 
▪ 
Have you had problems with fatigue for more than three months? (Yes) 
▪ 
Please circle the number that shows your average level of fatigue during 
the past 7 days. (≥ 6 based on a scale of 0 (no fatigue) to 10 (totally 
exhausted)) 
• 
have access to a telephone landline or mobile telephone and/or internet based 
audio/video calls 
• 
give permission for researchers to access their hospital medical notes 
• 
currently be under the care of a secondary care physician  
• 
have stable disease as evidenced by no change in immunomodulatory therapy 
within the last three months based on the hospital medical record 
 
5.2.4 Exclusion Criteria 
Participants will be excluded if:  
• 
there are significant abnormalities of thyroid function (TSH levels) on the most 
recent blood test done within the last three months 
• 
there is evidence of severe anaemia (haemoglobin levels) on the most recent 
blood test done within the last three months 
• 
there is evidence of severe renal dysfunction (eGFR) on the most recent blood 
test done within the last three months  
• 
they have a medical condition which would make the proposed interventions 
unsuitable, e.g. significant heart disease  
• 
they are pregnant  
• 
they are unable to understand English sufficiently to take part in the intervention 
• 
they are unable to provide written informed consent 
• 
they are not willing to be randomised 
• 
they are currently participating in an interventional clinical trial 
 
 
 

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5.3 Consenting Participants 
The potential volunteers will make a decision to participate when they attend the local 
study site for the baseline assessment visit. An appropriately trained member of the 
research personnel at each site will obtain informed written consent from the participants. 
During the first baseline assessment visit, a designated member of the local research 
team will determine interest in participating and confirm potential eligibility (including re-
confirmation of fatigue state). He/she will explain the study and answer any questions, 
which the patient has but will also raise issues of feasibility of use of telephone and, if 
necessary, investigate whether they have for example a hands-free option on their 
telephone. If a suitable option is not available, a telephone with hands-free function 
(owned and maintained by the LIFT study team) will be loaned for the intervention period.  
No study specific procedures will take place before written consent has been obtained. 
Once the participant is ready to provide informed written consent, the patient will 
complete the baseline assessment forms, have clinical information recorded and will be 
screened for other treatable causes of fatigue. Therefore, the research nurse will take a 
blood sample to measure thyroid function, haemoglobin and renal function, if these have 
not been assessed within past three months. Should the person become ineligible as 
result of the blood test, we will follow the procedure for ineligible participants. In addition, 
a blood sample is taken to measure CRP and ESR as well as blood samples (1 x 
PAXgene RNA, 1 x PAXgene DNA, 1 x serum) for storage for future ethically approved 
research. Procedures for reporting all study blood results will be in place (see also 9). 
Participation in the LIFT study will be recorded by the nurse in the hospital medical 
records together with a copy of the signed consent form.  
The research nurse will also determine whether the participant has ever met the relevant 
classification criteria for RA (mandatory), or other IRDs (non-mandatory):  
1) RA (2010 American College of Rheumatology/European League Against Rheumatism 
RA criteria [50] or 1987 American College of Rheumatology RA criteria [51]),  
2) SLE (1997 American College of Rheumatology SLE criteria [52]) and 
3) AxSpA, (Assessment of Spondyloarthritis (ASAS) criteria for AxSpA [53]).  
 
5.4 Procedure for ineligible and non-recruited participants 
The research nurse or other member of the research team will complete the relevant 
section of the case report form (CRF) for each person and the reasons for ineligibility will 
be recorded. If the reason for ineligibility is reversible with appropriate treatment, e.g. 
change in immunomodulatory therapy, thyroid disorder or anaemia, the potential 
participant may be contacted at a later stage and, if appropriate, re-invited for 
assessment including re-consenting and new participant ID. Patients who selected 5 for 
their average level of fatigue may be re-sent an invitation after 3 months, if appropriate. 
The collected anonymised data will be stored in the designated database for evaluation 
but no further data will be collected from the participant unless the person specifically 
requests to destroy all collected, questionnaires and data during the formal withdrawal 
procedure (see 6.3). 
 

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6 
RANDOMISATION AND BLINDING 
6.1 Randomisation Details 
After the patient has provided written consent to participate in the study and eligibility 
has been confirmed, the member of the local research team will randomise the 
participant via the Clinical Trials Unit (CTU). The CTU is the Centre for Healthcare 
Randomised Trials (CHaRT) based within the University of Aberdeen. The CTU provides 
a 24 h randomisation web based service. Using a computer generated sequence, 
participants will be allocated to receive either of the two treatments or usual care (1:1:1 
ratio). Randomisation will be minimised by diagnosis (RA, SLE, AxSpA or other IRD) and 
the presence/absence of depressive symptoms (Hospital Anxiety & Depression Scale 
(HADS) depression subscale >10) and will include a random element set at 20%. That 
is, 20% of all the allocated randomisations will be randomly re-allocated 50:50 to the 
remaining two treatment options.  
Randomised participants will be contacted by the study co-ordinator (or designated 
deputy if unavailable) by post, email and/or telephone with information about their 
intervention and details of their allocated therapist, if applicable. All personal contact 
details will be only accessible in the password protected study database (see 8.2).  
 
6.2 Blinding 
Full blinding will not be possible due to the need to engage people in behavioural change. 
However, to reduce detection bias, we will aim to blind research personnel undertaking 
outcome assessments to participants’ treatment allocation. To facilitate blinding we will 
remind participants to refrain from discussing (and subsequently revealing) their 
treatment allocation at follow-up assessments with the research personnel. Finally, data 
will be analysed blind to allocation. 
 
6.3 Withdrawal Procedures 
Participants will have the option to withdraw at any time during the study period of 13 
months. The participant needs to request this formally and a withdrawal document will 
be completed and signed by the designated research staff at the local sites. They have 
the option to either withdraw from the study completely or from parts of it (pre-study 
invite, treatment or follow-up). If participants withdraw from the study completely or from 
follow-up assessments, they will not receive further invitations but we will use the data 
collected prior to the withdrawal (depending on permission). Those withdrawing from the 
treatment only will continue to be sent invitations to attend and complete follow-up 
assessment visits, unless they request to withdraw completely later on. Failure of any 
participant to complete a follow-up at any particular time-point will not be counted as a 
withdrawal unless the participant formally requests to withdraw. In addition, a participant 
can also be withdrawn by others, for example the local PI or primary consultant, should 
the need arise at any stage throughout the study period. This also includes loss of 
capacity for continuous consent.  
 

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7 
STUDY AND SAFETY ASSESSMENTS 
There are unlikely to be major safety issues with our proposed non-pharmacological 
interventions. However, if the rheumatology healthcare professional delivering CBA and 
PEP or any study personnel have any safety concerns, we will follow a specific Standard 
Operating Procedure (SOP) for adverse events in non-CTIMP studies. In brief, they will 
use a standard template after secure log-in into the study database. A designated 
investigator with rheumatology background and/or designated experienced investigators 
responsible for the training of therapists as summarised in the delegation log in the TMF 
will then assess and categorise events according to the SOP to determine if the event is 
expected, related and/or serious. There will be access to independent clinicians (both 
rheumatology and psychology), if required. We will make every effort to report all 
confirmed related serious adverse events to the sponsor within 24 working hours after 
the CI has been made aware of them. 
 
8 
DATA COLLECTION AND MANAGEMENT 
8.1 Data Collection 
Case Report Forms (CRF), including medical outcomes, and questionnaires as indicated 
under 3 and 3.8, respectively, are completed during the assessment visits at the local 
study site either on paper or online in the database. All participants will have the option 
to complete the questionnaires and diaries online in the database (requires a valid email 
address) or on paper depending on personal preference. There will be the option to 
complete the questionnaire at home, if the participant requests this. Paper 
questionnaires will then be returned via pre-paid envelopes to the study centre. If the 
participant opted for online entry, he/she will receive secure access limited to own data 
in the database via a link sent to a provided email address and/or log-in code. Paper 
health economic diaries which are filled by the participant throughout the study will also 
be returned either in person to the local study site or by pre-paid envelope to the study 
centre Aberdeen. If a participant is entirely unable (e.g. due to mobility issues) to attend 
a follow-up visit at 10, 28 or 56 weeks in person, but is still happy to continue with the 
follow-up, the data collection (except blood samples, step test, DAS28) will be done by 
phone and post. The option for remote data collection will only be used in selected cases 
at the discretion of the PI/CI/Co-CI if an assessment visit at the local site would be 
delayed for at least 3 weeks. In case of a participant unable to attend a follow-up visit, 
the paper questionnaire, diaries and ActivPAL will be sent out by post and will be returned 
via pre-paid envelopes to either the study centre or the local study site. In case of a local 
site unable to perform a follow-up visit, the Trial Office staff will perform the remote visit 
instead. Information from medical records will be taken retrospectively once the local site 
is in a position again to continue. Any participants who do not return a questionnaire at 
the 56 weeks follow-up visit will be telephoned and asked some questions over the phone 
about fatigue (i.e. Chalder Fatigue Scale, Fatigue Severity Scale), Patient Global 
Impression of Change, Disease activity and intensity of pain. Personal data, including 
postal address, phone numbers (landline and mobile), email addresses, and anonymised 
data files for study outcomes are stored in locked filing cabinets (hard copy) and in a 
bespoke database provided and maintained by CHaRT (see 8.2) as well as secured 
shared drives with access via password controlled computers (university and NHS 
networks) by study staff only (electronic data) (see also 13.1.1 and 13.1.2). Participants 
will have the option to undertake a multi-modal MRI brain scan (see Appendix 2). A 

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subgroup of participants and all therapists will have the option to take part in an interview 
as part of the Qualitative Evaluation sub-study (see Appendix 3). 
 
8.2 Data Management System 
A study specific database will be established and maintained by CHaRT. The access to 
the database is password controlled with personal access rights (see also 13.1.1 and 
13.1.2). The structure and content of the database will be individualised based on the 
protocol, the study outcome questionnaires and CRF. Individual requirements such as 
screening log and report functions for continuous monitoring of recruitment, 
randomisation and follow-up will also be incorporated. There will be a read-only role 
which allows access to the system for audit and monitoring. 
 
8.3 Transfer of Data 
Personal data including signed consent forms (original hard copy) will be held at to local 
study site for the duration of the study before they are transferred by tracked surface mail 
service to the study centre/study team in Aberdeen for archiving or destroyed. Copies of 
signed consent forms and anonymised study outcomes (hard copy) will be transferred to 
the study centre/study team in Aberdeen by tracked surface mail service for monitoring 
purposes and data input, respectively. All electronic data is password protected and 
accessible via the secure database by the study staff from each study site as described 
in 8.2. 
 
 
9 
LABS AND SAMPLE ANALYSIS 
This multi-centre study involves a number of standard blood investigations, i.e. TSH, 
haemoglobin, serum creatinine, CRP and ESR, routinely processed by local NHS 
laboratories. Blood samples for CRP and ESR analysis and sample storage for future 
ethically approved research will be taken at each assessment as specified in the study 
matrix by trained personnel only following established procedures. Blood samples for 
TSH, haemoglobin and serum creatinine analysis will only be taken at baseline to confirm 
eligibility, if required. Sample coding, preparation, storage, analysis and transfer of 
results and optional blood samples for long-term storage at the trial centre will be 
performed according to the analytical protocol based on national laboratory guidelines. 
The exact logistic and procedure will be agreed on with each site before the start of the 
study and we will make every effort to standardise the workflow across sites to reduce 
bias. Additional optional blood samples will be stored for future ethically approved 
research). All study blood results (abnormal or otherwise) will also be directed towards 
the local PI who can determine locally how these will be handled. 
 
 

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10 STATISTICS AND DATA ANALYSIS 
10.1 Sample Size Calculation 
Our planned primary intention to treat analyses will compare PEP + usual care versus 
usual care alone, and CBA + usual care versus usual care alone separately. We base 
our calculations on a standardised effect size of 0.50 (considered credible in other 
pragmatic effectiveness studies), which would equate to being powered to detect a 
minimal important clinical difference of 2 units in the CF Scale, assuming a common 
standard deviation across the randomised groups of 4 units. Assuming an overall 
significance level of 5% (by calculating the two pre-specified randomised groups 
comparisons, PEP + usual care vs. usual care alone and CBA + usual care vs usual care 
alone, at 2.5%, to maintain an overall level of not more than 5%) and a power of 90%, 
we require 100 evaluable participants in each of the three groups.   
 
10.2 Proposed Analysis 
All statistical analyses will be governed by a comprehensive Statistical Analysis Plan, 
which will be authored by the study statistician and approved by the Trial Steering 
Committee and the Data Monitoring Committee before the main study outcome data are 
examined. All analyses will be carried out using Stata. In accordance with CONSORT 
guidelines, we will report all participant flow. Descriptive statistics of recruitment, drop-
out and completeness of interventions will be provided.  
 
Effectiveness Analysis: The main effectiveness analysis will be via intention-to-treat 
including all participants, with no planned interim analysis for early termination for either 
overwhelming evidence of effectiveness or abandoning for futility. Baseline 
characteristics will be presented by randomised group without formal statistical tests. We 
will test the primary hypothesis for between-group change in the primary outcome for 
each of the two pre-specified comparisons (CBA + usual care vs usual care alone and 
PEP + usual care vs usual care alone) using repeated measures mixed model, with 
subject as a random effect, and a suitably specified covariance structure (e.g. 
Autoregressive [1] (AR[1]), rheumatology healthcare professional as a random effect (to 
adjust for any clustering by rheumatology healthcare professional), with baseline 
outcome measure, and any other strongly predictive baseline measures, including the 
minimisation factors of presence/absence of depression and centre, and diagnosis. 
Treatment and its interaction with time will be fitted as fixed effects, and we apply 
standard regression diagnostics. The analysis will use statistical techniques for handling 
missing outcome data using multiple imputation under a missing at random (MAR) 
assumption. The secondary outcomes will be analysed using an analogous method. The 
main estimate of treatment effect will focus on the 56 weeks after baseline. 
 
Mediation analysis: We will use modern causal inference methods to investigate the set 
of mediator measures. If the effectiveness analysis shows significant between group 
differences in the mediators then we will use parametric regression models to test for 
effect of mediator on outcome, and the residual direct effect of treatment on outcome. 
Since all the measures are continuous, the indirect effects are calculated by multiplying 
relevant pathways and bootstrapping is used to produce valid standard errors for the 

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indirect effects. All analyses will adjust for baseline measures of the mediators, outcome 
and putative measured confounders, and be tested for moderation by diagnosis. 
Mediation analyses are potentially biased by measurement error in mediators and hidden 
confounding between mediators and outcomes; we will build on our previous 
methodological and applied work in this context to include repeated measurement of 
mediators and outcomes to account for classical measurement error and baseline 
confounding. We will investigate the sensitivity of the estimates to these problems and 
that of unmeasured confounding using instrumental variable (IV) methods with baseline 
covariate by randomisation interactions as potential instruments. 
 
Moderation analysis: We will examine differential treatment effects using the set of 
moderator measures by extending the intention to treat analysis models to include an 
interaction term between treatment and each of the moderators separately. We will use 
bias correction/cross-validation methods to identify robust evidence for individual 
moderation and for a moderation index, both on the overall effect and also along the 
steps of the mediation pathway. 
  
10.3 Missing Data 
Every effort will be made to ensure data collection is complete. However, we will use 
statistical techniques for handling missing outcome data. Multiple imputation under a 
MAR assumption will be used in the first instance, with other methods employed if the 
MAR assumption is not satisfied. 
 
 
11 TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
11.1 Trial Management Group 
The study will be co-ordinated by a Trial Management Group, consisting of the grant 
holder (CI), a rheumatology consultant (Co-CI), additional members of the Epidemiology 
group, a study co-ordinator and a representative from CHaRT. The members of the Trial 
Management Group and their responsibilities are summarised in the delegation log in 
the TMF. In addition, the names and responsibilities of all co-investigators are also 
summarised in the delegation log in the TMF.  
 
11.2 Study Management 
A Study co-ordinator (or designated deputy) will be responsible for the overall day-to-day 
management of the study and will be accountable to the CI, the Co-CI and investigators. 
He/she will ensure that personal and confidential information is restricted to those entitled 
to know it, will assist in the compliance with research and clinical governance guidelines, 
data protection and ethical requirements. 
A Study co-ordinator (or designated deputy) will establish and maintain procedures to 
ensure adherence to study protocols, SOPs and administrative requirements. He/she will 
be responsible for training and monitoring the study staff at the local sites involved in 

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recruitment and assessment of the participants. He/she will assist in monitoring the study 
progress to ensure compliance with and adherence to the project plan and identify, 
evaluate and rectify problems. He/she will be responsible for checking the outcome 
documents for completeness, plausibility and consistency. However, this remains the 
overall responsibility of the CI. Any queries will be resolved by the CI or delegated 
member of the study team.  
 
11.3 Trial Steering Committee 
A Trial Steering Committee (TSC) has been established to oversee the conduct and 
progress of the study. The TSC comprises an independent chair who has expertise in 
trials and other members, both independent and study investigators, with background 
relevant to IRD or type of interventions including user representatives, who have lived 
experience of IRD related fatigue, and a clinician working with people with IRD. The 
members of the TSC are documented in the TMF at the study centre Aberdeen. 
 
11.4 Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) has been established to oversee 
study progress. The members of the IDMC are summarised in the TMF at the study 
centre Aberdeen. 
 
12 INSPECTION OF RECORDS 
Investigators and institutions involved in the study permit study related monitoring and 
audits on behalf of the sponsor, NHS R&D and REC. In the event of an audit or 
monitoring, the Investigator agrees to allow the representatives of the sponsor direct 
access to all study records and source documentation. 
 
13 GOOD CLINICAL PRACTICE 
13.1 Ethical Conduct of the Study 
The study will be conducted in accordance with the principles of good clinical practice 
(GCP). In addition to Sponsorship approval, a favorable ethical opinion will be obtained 
from the appropriate REC and appropriate NHS R&D approval(s) will be obtained prior 
to commencement of the study. A collaboration agreement and site agreements will be 
signed between The University Court Of The University Of Aberdeen and the included 
parties and study sites, respectively. 
 
13.1.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified 
using unique participant ID numbers to maintain participant confidentiality. All records 
will be kept in a secure storage area with limited access to study staff only. Clinical 
information will not be released without the written permission of the participant, except 
as necessary for monitoring and auditing by the Sponsor or its designee. The 
investigators and study staff involved with this study will not disclose or use for any 

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purpose other than performance of the study, any data, record, or other unpublished, 
confidential information disclosed to those individuals for the purpose of the study.  
 
13.1.2 Data Protection  
All Investigators and study staff involved with this study will comply with the requirements 
of the Data Protection Act 2018 with regard to the collection, storage, processing and 
disclosure of personal information and will uphold the Act’s core principles. The 
investigators and study staff will also adhere, if appropriate, to the current version of the 
NHS Scotland Code of Practice on Protecting Patient Confidentiality. Access to collated 
participant data will be restricted to the CI and appropriate study staff as needed. 
Computers used to collate the data will have limited access measures via user names 
and passwords, and such documents will be password protected and stored on secure 
University or NHS servers. Published results will not contain any personal data that could 
allow identification of individual participants. 
 
13.1.3 Insurance and Indemnity 
Where the study involves University of Aberdeen staff undertaking clinical research on 
NHS patients, such staff will hold honorary contracts with Grampian Health Board, which 
means they will have cover under Grampian’s membership of the CNORIS scheme. 
 
14 STUDY CONDUCT RESPONSIBILITIES 
14.1 Protocol Amendments, Deviations and Breaches 
The CI will seek approval for any amendments to the Protocol or other study documents 
from the Sponsor, REC and NHS R&D Office(s). Amendments to the protocol or other 
study documents will not be implemented without these approvals. It is the responsibility 
of the sponsor to designate amendments as substantial or non-substantial. 
In the event that a CI needs to deviate from the protocol, the nature of and reasons for 
the deviation will be recorded in the CRF, documented and submitted to the Sponsor. If 
this necessitates a subsequent protocol amendment, this will be submitted to the 
Sponsor for approval and then to the appropriate REC and lead NHS R&D Office for 
review and approval.  
In the event that a serious breach of GCP is suspected, this will be reported to the 
Sponsor immediately using the “Breach Report Form”.  
 
14.2 Study Record Retention 
All study documentation (hard copy and electronic) will be kept for a minimum of 5 years 
from the protocol defined end of study point in the University of Aberdeen archive. When 
the minimum retention period has elapsed, study documentation will not be destroyed 
without permission from the sponsor.  
 

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14.3 End of Study 
The end of study is defined as last data collection of either the qualitative evaluation 
study phase or during the last follow-up visit at 56 weeks from the last participant after 
CBA/PEP intervention or usual care start date – whichever comes last. 
 
15 REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS 
15.1 Authorship Policy 
Ownership of the data arising from this study resides with the University of Aberdeen. 
On completion of the study, the study data will be analysed and tabulated, and a clinical 
study report will be prepared in accordance with ICH authorship guidelines.  
 
15.2 Publication 
The clinical study report will be used for publication and presentation at scientific 
meetings. Investigators have the right to publish orally or in writing the results of the 
study. 
 
15.3 Peer Review 
The initial study proposal was peer reviewed extensively within the system of the 
University of Aberdeen, as well as experts in the field before the grant application was 
submitted to Arthritis Research UK. Furthermore, representatives of the National 
Rheumatoid Arthritis Society, the National Ankylosing Spondylitis Society and Lupus UK 
significantly influenced the study design. In addition, the proposal underwent review from 
the funding agency (Arthritis Research UK). Any documents created as part of this 
project will undergo peer review internally within the research team, and representatives 
of the National Rheumatoid Arthritis Society, the National Ankylosing Spondylitis Society 
or Lupus UK.  
 
 
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[53] M Rudwaleit, R Landewé, D Van Der Heijde, J Listing, J Brandt, J Braun, et al. The 
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uncertainty appraisal, Ann.Rheum.Dis. 68 (2009) 770-776. 
 

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Appendix 1 SWAT 24 
 
Background 
Recruiting and retaining participants for randomised trials can be extremely difficult.  It is 
likely that less than 50% of trials meet their recruitment target, or meet their target without 
extending the length of the trial [1-3]. Moreover, poor recruitment can lead to an 
underpowered study, which may report clinically relevant effects to be statistically non-
significant. A non-significant finding increases the risk that an effective intervention will 
be abandoned before its true value is established, or that there will be a delay in 
demonstrating this value while more studies or meta-analyses are done. Moreover, if 
non-responses to the study invitation differ between the patients with diagnosis of RA, 
SLE and AxSpA, a systematic bias may be introduced that may undermine confidence 
in the results of the trial. Finally, poor recruitment and subsequently retention can lead 
to a trial being extended, increasing costs. 
Trialists recognise the challenge and use many interventions to improve recruitment and 
retention but it is generally difficult to predict their effect. The Cochrane systematic review 
of strategies to improve recruitment [4] and the Cochrane review of strategies it improve 
retention [5] both found only a handful of interventions with high quality evidence of 
benefit. Given how central recruitment and retention are to all trials, it is crucial that more 
rigorous evaluations of recruitment and retention interventions are done. 
 
Rationale for SWAT 
One way of doing this is to do a Study Within a Trial (SWAT) [6]. A SWAT provides a 
protocol for the evaluation of an intervention to improve some part of the trial process, 
such as recruitment or retention. This evaluation is then embedded within a host trial, 
such as LIFT. Several teams can follow the same SWAT protocol, meaning the results 
can be combined in a meta-analysis. This coordinated and collaborative approach 
means trialists will have faster access to high-quality evidence to inform their trial design, 
conduct, analysis and reporting decisions.   
The SWAT 24 which describes the use of a theory-based cover letter was initially 
developed to increase response rates of questionnaires sent during follow-up to collect 
outcome data direct from participants. A low response rate to these questionnaires puts 
the validity and generalisability of the trial results in jeopardy. Since returning the 
questionnaire is a behaviour, this opens up the possibility of designing a behaviour 
change intervention to influence the willingness of participants to do that behaviour. We 
propose to use SWAT 24 in LIFT to improve response rates to the pre-study invitation 
letter used to make initial contact with potential participants identified as described in the 
main protocol (see 5.2.1) to explore interest and eligibility. The SWAT 24 study is part of 
the Trial Forge initiative to improve trial efficiency [7]. 
 
Objective for SWAT 24 
To assess the effects of a theory-based cover letter on response rate to a pre-study invite 
to explore interest and eligibility 
 

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Outcome 
Primary outcome:  
Response rate 
 
Secondary outcomes:  
Response time 
Consent rate 
Study retention  
Intervention adherence 
 
Intervention 
The Theoretical Domains Framework (TDF) is a tool for identifying theoretical targets for 
behaviour change interventions [8]. The TDF and behaviour change techniques were 
used by the IQuaD trial team [9] to produce a template that trial teams can use to 
structure a theory-informed cover letter. 
 
Comparator 
A standard cover letter 
 
Method for allocating to intervention or comparator 
Participating study centres will be randomly allocated to send the standard letter or the 
theory-informed letter. 
 
Analysis plan 
The primary analysis is the difference in primary and secondary outcomes between those 
receiving the theory-based cover letter and those receiving the standard cover letter. 
 
 
References 
[1] Ben G O Sully, Julious SA, Nicholl J. A reinvestigation of recruitment to randomised, controlled, 
multicenter trials: a review of trials funded by two UK funding agencies. Trials 2013, 14: 166.  
[2] McDonald AM, Knight RC, Campbell MK, Entwistle VA, Grant AM, Cook JA, Elbourne DR, 
Francis D, Garcia J, Roberts I, Snowdon C. What influences recruitment to randomised controlled 
trials? A review of trials funded by two UK funding agencies. Trials 2006;7:9. 
[3] Foy R, Parry J, Duggan A, Delaney B, Wilson S, Lewin-van den Broek NTh, Lassen A, Vickers 
L, Myres P. How evidence-based are recruitment strategies for randomized controlled trials in 
primary care? Experience from seven studies. Family Practice 2003;20:83-92. 

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[4] Treweek S, Mitchell E, Pitkethly M, Cook J, Kjeldstrøm M, Johansen M, Taskila TK, Sullivan 
F, Wilson S, Jackson C, Jones R, Lockhart P. Strategies to improve recruitment to randomised 
controlled trials. Cochrane Database of Systematic Reviews 2010, Issue 4. Art. No.: MR000013. 
DOI: 10.1002/14651858.MR000013.pub5. 
[5] Brueton VC, Tierney J, Stenning S, Harding S, Meredith S, Nazareth I, Rait G. Strategies to 
improve retention in randomised trials. Cochrane Database of Systematic Reviews 2013, Issue 
12. Art. No.: MR000032. DOI: 10.1002/14651858.MR000032.pub2. 
[6] Smith V, Clarke M, Devane D, Begley C, Shorter G, Maguire L. SWAT 1: what effects do site 
visits by the principal investigator have on recruitment in a multicentre randomized trial? Journal 
of Evidence-based Medicine 2013; 6:136–7.  
[7] Treweek S, Altman DG, Bower P, Campbell M, Chalmers I, Cotton S, et al. Making randomised 
trials more efficient: report of the first meeting to discuss the Trial Forge platform. Trials 2015; 
16:261. 
[8] Michie et al. Making psychological theory useful for implementing evidence based practice. 
Qual &Safety in Health Care 2005; 14:26–33 
[9] Jan E Clarkson, Craig R Ramsay, Paul Averely, D Bonetti, Dwayne Boyers, Louise Campbell, 
Graham R Chadwick, Anne Duncan, Andrew Elders, Jill Gouick, Nigel B Pitts, Marjon van der 
Pol, David Nj Ricketts, Margaret K Ross, James G Steele, Moira Swan, Martin Tickle, Pauline D 
Watt, Helen V Worthington, Linda Young. IQuaD dental trial; improving the quality of dentistry: a 
multicentre randomised controlled trial comparing oral hygiene advice and periodontal 
instrumentation for the prevention and management of periodontal disease in dentate adults 
attending dental primary care. BMC Oral Health 10/2013; 13(1):58. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 2: Delineating the neural mediators of inflammatory 
rheumatic disease (An optional LIFT sub-study) 
 
Background 
One of the objectives of the LIFT trial is to understand the mediators of treatment effect 
which will enable optimising of interventions and inferences to be made regarding the 
mechanisms of fatigue. We are collecting putative patient reported, clinical and physical 
activity profile mediator data. In addition we would like to provide the option for 
participants to provide their neuroimaging data by undertaking additional MRI scans of 
their brain.Neuroimaging has provided consistent mechanistic insights into fatigue, 
reinforcing our epidemiological investigations of RA related fatigue which have identified 
strong associations with central factors such as mental health and cognitive dysfunctions 
but not peripheral measures of inflammation4,5. We were the first to test these methods 
in a fatigued chronic inflammatory disease cohort. We identified multiple neural 
correlates of fatigue in patients with vasculitis using different structural and functional 
magnetic resonance imaging (MRI) modes 6,7 and we have since observed similar fatigue 
specific findings in RA.  
Our original studies were small (n=12) and cross-sectional but did implicate a potential 
role for a striato-thalamo-frontal network. Among fatigued vasculitis patients, we 
observed an apparent overuse of the cingulum and fornix white matter tracts, as 
identified by Diffusion Tensor Imaging (DTI), which coincided with the high functional 
activity within some of their source and destination grey matter structures, specifically 
the thalamus, medial globus pallidus, medial frontal and cingulate gyri and paracentral 
lobule.  
Our most recent pilot was larger and although uncontrolled included a repeat multi-modal 
scan at 6 months that enabled the longitudinal evaluation of fatigue in the context of 
standard care (which did not include fatigue specific therapy). Of those n=54 completing 
follow up, n=22 reported modest, albeit clinically relevant, improvements in their fatigue. 
Interestingly, widespread reductions in cortical grey matter volumes were measured, 
using voxel-based morphometry (VBM), among the non-improvers at follow-up however 
no such volume changes were observed among improvers. In contrast, sub-cortical grey 
matter volumes exhibited large significant increases in non-improvers. The sub-cortical 
grey matter volumes of improvers also increased, although the changes were small in 
comparison.           
In terms of white matter integrity, as measured by DTI, widespread abnormalities were 
observed among improvers. Within this group, significantly reduced fractional anisotropy 
(FA) was measured at follow-up compared to baseline in major white matter tracts. 
Strikingly, no significant longitudinal FA changes were measured within the non-
improvers group. Similarly, improvers- and not non-improvers- evidenced widespread 
imbalances in functional connectivity imbalance over time. 
Overall, these data strongly associate central neural pathways in RA related fatigue.  
Although the different MRI metrics provide complementary evidence which implicate 
frontal networks, a targeted approach (e.g. with non-invasive neuromodulation devices) 

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will demand much greater knowledge of the precise culprit frontal regions, moreover 
several non-frontal regions seem also to be relevant.  Until now, no studies have been 
adequately designed to pin-point those brain regions which mediate changes in fatigue 
(and so demonstrate causal potential). 
The problem with our existing studies is that they were either cross-sectional, or 
longitudinally followed individuals who had spontaneous changes in their fatigue (thus 
the changes in fatigue from one time point to the next were modest). We propose that 
the best way to identify which of these brain regions are most important in mediating 
fatigue is to perform controlled longitudinal imaging studies in individuals prior to and 
then following an intervention that reliably improves fatigue in most individuals.   
This Lessening the Impact of Fatigue Trial (LIFT) sub-study provides a timely opportunity 
to address this research void. 
 
Sub-study objective 
• 
Which functional and structural brain mediators best explain fatigue improvement 
and are they potentially trans-cranially accessible? 
 
Study design 
An optional nested mechanistic observational sub-study within the Lessening the Impact 
of Fatigue Trial (LIFT).  
 
Participants 
All consenting LIFT participants will be invited to participate in this optional sub-study 
which involves an additional MRI brain scan prior to and 26 weeks after their first 
treatment session (if CBA or PEP) or within 8 weeks of randomisation and 6 months 
thereafter if usual care. The only additional exclusion criteria is any contra-indications to 
MRI scanning (e.g. pacemaker). 
 
Participant selection 
At the baseline visit, all participants will be provided an information sheet on this sub-
study. The research team will then contact the participants a few days later to establish 
interest and the absence of MRI contraindications. If suitable and interested, the 
participant will be offered an appointment to attend their nearest participating MRI 
research facility (Edinburgh, Aberdeen or Glasgow) within a month. A research team 
member, recorded in the Delegation Log and with GCP training, will be responsible for 
taking additional full written informed consent (specific to this sub-study) on attendance 
at the imaging centre prior to the MRI assessment and then conduct a final MRI safety 
screen. 
 

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Participant withdrawal 
All participants will be free to withdraw at any time from the MRI sub-study, without giving 
reasons and without prejudicing further treatment or their participation in the LIFT trial.  
 
MRI assessment 
Prior to entering the scanner, subjects will have the opportunity to practice a cognitive 
task required for the standard fMRI aspect of analysis. As with our previous work6, the 
validated PASAT will be employed to transiently fatigue the subject. The task is a 
measure of cognitive function; specifically auditory processing, calculation, working 
memory and attention. Participants will be asked to listen to a series of numbers ranging 
from 1 to 9. They are required to sum consecutive numbers (i.e. the first to the second, 
the second to the third etc.) and to record, via a button press, every occasion two 
consecutive numbers sum to the number 10. Concurrently, they will be asked to focus 
on a computer screen displaying three boxes containing random, rapidly changing 
numbers. This visual stimulus is intended to distract the participants from the auditory 
task and hence increase difficulty. They will be instructed not to process the visual 
numbers in any way.   
Participants will then be asked to lie supine in the 3T Phillips Achieva X-series MRI 
scanner in Aberdeen or the equivalent scanner in Edinburgh. The multi-modal MR will 
consist of structural and functional sequences: 
Structural- We will collect images to allow volumetric analysis. We will also acquire 
images to allow determination of white matter hyperintensity lesion load and measures 
of white matter structural integrity (e.g. DTI).  
Functional Imaging- Images sensitive to BOLD contrast will be acquired during rest to 
investigate metrics such as intrinsic network connectivity as well as during the PASAT 
task (3x3minute periods interspersed by 30s rest periods). 
In total these can will take approximately 45 minutes to conduct and will be repeated at 
approx. 6 months (when we predict to observe the greatest effect from the interventions). 
 
Analysis 
Following pre-processing of the MRI data the following analysis will be undertaken which 
will integrate data which will have been collected as part of the parent trial: 
Longitudinal comparisons (paired t-tests as implemented by SPSS for ROI based 
variables and Freesurfer for voxel based variables) of structural and functional change 
indices in relation to subjects’ change in fatigue will be performed. Putative confounders 
will be individually introduced as co-variates of interest. The individual analyses will focus 
upon those regions of interest previously identified by our studies, but since we recognise 
that these are not comprehensive we will also conduct agnostic (data-driven) whole brain 
analyses. All analyses will be adjusted for multiple testing. 

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Having identified and validated key neural areas, group differences in mediators of 
treatment effects on outcomes will be assessed via mediation analysis methods in order 
to tackle the secondary objective. These involve causal inference methods, such as 
structural equation modelling, to account for measurement error in the imaging data, and 
repeated measures to allow for the inclusion of all available data. Those resultant neural 
mediators which are common to both interventions and accessible to non-invasive 
neuromodulation will serve as our future therapeutic targets.  
Finally we will be using whole brain statistical pattern recognition techniques on the 
neuroimaging data and mediation effects identified in answer to the previous objective. 
In the Pattern Recognition for Neuroimaging Toolbox (PRoNTo) brain scans are treated 
as spatial patterns and statistical learning models are used to identify statistical 
properties of the data that can be used to discriminate between, or classify, experimental 
groups of subjects. 
 
Sample size 
We aim to recruit 120 participants (who will have been randomised to receive either usual 
care alone, CBA in addition to usual care or PEP in addition to usual care in the parent 
trial). 
 
Data handling 
MRI scan data will be stored in an anonymised format in the University of Aberdeen, 
Edinburgh and Glasgow imaging archive system on the university drive, with a back-up 
disc stored in a fireproof safe. The code for the images will be held on a separate 
computer relating the patient information to the participant ID. The participant ID will be 
used on the MRI images. Images may be stored on disc in anonymised format for 
research team discussions out-with the imaging department. 
 
Safety assessments 
The MRI scanner is very safe and does not expose participants to any harmful radiation. 
Given its reliance on a strong magnetic field, it is essential that certain metallic 
instruments/objects are not taken into the scan room.  
 
This is avoided by: 
1) All participants are clothed in 'theatre greens' so to avoid the danger of concealed 
metal objects within clothes. 
2) Patients will be screened for absolute exclusion to MRI scanning.  
In addition, all participants must undertake a strict and comprehensive checklist prior to 
scanning. This includes questions about heart valves, pacemakers and other potential 
metallic implants. 

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If a participant becomes distressed during the MRI scan, he/she will be able to access 
to a “panic button” which will immediately terminate the procedure. 
 
Sub-study matrix 
The study connects to the 1-year LIFT recruitment phase which will begin in August 2017 
(month 0). 
Study steps 
-3-0 m 0-6 m 
6-12 m 
12-18 m 
18-24 m 
24-30 m 
Governance 
approvals 
 
 
 
 
 
 
RA Subject 
recruitment 
 
 
 
 
 
 
MRI scan #1 
(pre-intervention) 
 
 
 
 
 
 
MRI scan #2 
(post-intervention) 
 
 
 
 
 
 
Data processing, 
analysis & report 
 
 
 
 
 
 
 
 
References 
1. 
Hewlett S, Cockshott Z, Byron M, et al. Patients' perceptions of fatigue in rheumatoid 
arthritis: 
overwhelming, 
uncontrollable, 
ignored. 
Arthritis 
and 
rheumatism. 
2005;53(5):697-702. 
2. 
Davies H, Brophy S, Dennis M, Cooksey R, Irvine E, Siebert S. Patient perspectives of 
managing fatigue in Ankylosing Spondylitis, and views on potential interventions: a 
qualitative study. BMC Musculoskelet Disord. 2013;14:163. 
3. 
Patton MQ, Patton MQQe, research m. Qualitative research & evaluation methods. 3rd 
ed. ed. Thousand Oaks, Calif. ; London: Sage; 2002. 
4. 
Druce KL, Jones GT, Macfarlane GJ, Basu N. Determining pathways to improvements in 
fatigue in rheumatoid arthritis: results from the British Society for Rheumatology Biologics 
Register for Rheumatoid Arthritis. Arthritis & Rheumatology. 2015;67:2303-2310. 
5. 
Druce KL, Jones GT, Macfarlane GJ, Basu N. The changes in pain which mediate 
Reductions in fatigue likely reflect central not peripheral mechanisms: Results from the 
BSRBR-RA. Arthritis Care & Research. 2016. 
6. 
Basu N, Murray AD, Jones GT, Reid DM, Macfarlane GJ, Waiter GD. Neural correlates 
of fatigue in granulomatosis with polyangiitis: a functional magnetic resonance imaging 
study. Rheumatology. 2014;53:2080-2087. 
7. 
Basu N, Murray AD, Jones GT, Reid DM, Macfarlane GJ, Waiter GD. Fatigue-related 
brain white matter changes in granulomatosis with polyangiitis. Rheumatology. 
2013:ket135. 
 
 
 

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Appendix 3: Qualitative Evaluation (LIFT sub-study) 
 
Background 
Qualitative studies nested within trials offer the opportunity to investigate the views and 
experiences of participants. They can generate insights into unexpected or unanticipated 
outcomes of the trial, as well as provide detailed, personal accounts that can aid 
understanding and implementation of the research.  
 
Sub-study Objectives 
To understand patients’ experiences and views of taking part in the CBA and PEP 
interventions as part of the LIFT trial. 
To explore patients’ experiences and views that may have led to participants not 
engaging with the allocated intervention.   
To understand rheumatology health care professionals’ (therapists’) experiences and 
views of being trained in and delivering the CBA and PEP interventions as part of the 
LIFT trial. 
 
Study design 
An optional nested qualitative process evaluation sub-study with participants and 
therapists who have taken part in the Lessening the Impact of Fatigue Trial (LIFT). 
 
Participants 
A subgroup of LIFT study participants randomised to either CBA or PEP will be invited if 
they have given consent to be contacted after they have completed or stopped their 
treatment. 
All therapists (both PEP and CBA) who were trained and delivered the interventions will 
receive additional information.  
To ensure integrity, participants will be invited to take part once they have left or 
completed the intervention phase (see Figure 1 main protocol).  
 
Participant identification and sample size 
We will use a maximum variation sampling strategy [1] to identify participants with a 
range of IRDs, gender, age, disease duration and primary outcomes in the main RCT. 
To achieve this, a minimum of 40 interviews (20 per intervention arm) is required. We 
will aim to invite all study therapists from both intervention arms across all study sites. 
They will be invited once they have delivered the intervention to their last allocated study 
participant or once they are suitably experienced based on how long they have been 
delivering the intervention at the time of interview – whichever comes first. 
The study team at the Trial Office will send an invitation consisting of a cover letter, study 
information, copy of the consent form and reply slip to each potential participant who has 

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given permission to be contacted after the LIFT study. Participants will be invited after 
they attended assessment visit 4 at 56 weeks or if they have withdrawn during the follow-
up phase. The study team at the Trial Office will also send invitations to all study 
therapists. 
Participants willing to take part can return the completed Participant Reply Slip sent with 
the invitation letter directly to the designated study site at the Bristol Royal Infirmary. 
Therapists willing to take part will get in touch with the designated member of the local 
study team as per site delegation log by phone or email.  
A designated member of the local study team as per site delegation log at the designated 
study site will contact the potential participant/therapist to discuss the study and arrange 
a date and time for the interview. 
 
Consenting participants and therapists 
Once contacted for the interview, at the beginning of the call, the purpose and process 
of the interview will be explained again, before potential participants are asked to 
consent. Verbal consent will only considered to have been given at this point and will be 
recorded on a digital voice recorder. Participants and therapists will have received the 
wording of the consent as part of their invitation to take part. 
 
Interviews and data collection 
Data will be collected through semi-structured interviews conducted by telephone or by 
internet-based audio/video calls. In addition to the practical considerations of offering 
these options, this approach acknowledges that both participants and therapists will have 
been involved in a remotely delivered intervention. All interviews will be audio recorded, 
anonymised during transcription, and checked for accuracy. 
 
Participant/therapist withdrawal 
Participants/therapists are free to withdraw at any time, and with no explanation. If they 
withdraw before the findings are written up, we will not include any of their data. 
 
Analysis 
Participant experiences and views of the interventions will be analysed using a 
framework analysis [2] to assess the content, mode of delivery, acceptability, barriers 
and facilitators, helpfulness and subsequent impact of the interventions on their daily 
lives. 
Experiences and views of the therapists of intervention training and delivery, including 
challenges and benefits of learning and using new skills, and barriers and facilitators to 
supporting patients remotely will be analysed using inductive thematic analysis [3]. 
 
 
 

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Data handling 
The study specific database (see 8.2 in main protocol) will be used. Personal contact 
details will be made available to the designated member of the local study team as per 
site delegation log at the study site only when the participants have given their 
permission to be contacted. 
Recorded consent will be stored as essential digital documents in a bespoke database 
provided and maintained by CHaRT (see 8.2 in main protocol ) as well as secured shared 
drives with access via password controlled computers (university) by study staff only 
(electronic data). At the end of the project, they will be archived in the University of 
Aberdeen archive (see 14.2 in main protocol). 
 
Safety assessments 
We do not anticipate any side-effects of taking part in an interview. However, if the 
interview makes participants feel worried about their fatigue or health, the designated 
member of the local study team as per site delegation log will arrange for them to see 
their clinical nurse specialist or rheumatologist. 
 
Sub-study matrix 
See Figure 1 GANTT chart 
 
References 
[1] MQ Patton, Qualitative research & evaluation methods, 3rd ed., Sage Publications, 
Thousand Oaks, California, 2002. 
[2] NK Gale, G Heath, E Cameron, S Rashid, S Redwood. Using the framework method for the 
analysis of qualitative data in multi-disciplinary health research, BMC Med.Res.Methodol. 13 
(2013). 
[3] V Braun, V Clarke. Using thematic analysis in psychology, Qual.Res.Psychol. 3 (2006) 77-
101.