Protocol for a multicentre randomised controlled parallel-group trial to compare the effectiveness of remotely delivered cognitive-behavioural and graded exercise interventions with usual care alone to lessen the impact of fatigue in inflammatory rheumatic diseases (LIFT)

Introduction Fatigue remains pervasive, disabling and challenging to manage across all inflammatory rheumatic diseases (IRDs). Non-pharmacological interventions, specifically cognitive-behavioural approaches (CBAs) and graded exercise programmes designed to support and increase exercise, are valuable treatments which help patients with IRD to manage their fatigue. Yet, healthcare systems have encountered substantial barriers to the implementation of these therapeutic options. Lessening the Impact of Fatigue in Inflammatory Rheumatic Diseases: a Randomised Trial (LIFT) is designed to give insights into the effectiveness of a remotely delivered standardised intervention for a range of patients with IRD. It will also enable the exploration of putative moderating factors which may allow for the future triage of patients and to investigate the precise mediators of treatment effect in IRD-related fatigue. Methods and analysis LIFT is a pragmatic, multicentre, three-arm randomised, controlled trial, which will test whether adapted CBA and personalised exercise programme interventions can individually reduce the impact and severity of fatigue. This will be conducted with up to 375 eligible patients diagnosed with IRD and interventions will be delivered by rheumatology healthcare professionals, using the telephone or internet-based audio/video calls. Ethics approval and dissemination Ethical approval has been granted by Wales REC 7 (17/WA/0065). Results of this study will be disseminated through presentation at scientific conferences and in scientific journal. A lay summary of the results will be sent to participants. Trial registration number NCT03248518; Pre-results.

Firstly, existing studies -including our own -have only developed bespoke disease-122 specific models of care, which vary in content, structure and method of delivery. 123 Inevitably, this necessitates the development of multiple particular skill sets and 124 duplicated pathways for the care providers if they are to equitably serve their diverse 125 patient populations -a time consuming, costly and inefficient undertaking. 126 Secondly, patients find it challenging to commit to regular face-to-face treatment The timeline for assessment and delivery of interventions is summarised in Figure 2. 179 We anticipate that active CBA and PEP interventions will start between 2 and 8 180 weeks post-randomisation, with an average delay of 4 weeks after randomisation.

181
Follow-up data will be collected from all participants at 10 weeks, 28 weeks and 56 182 weeks after randomisation adjusted for the average delay of 4 weeks, therefore all 183 participants will remain part of the study for 13 months.  In order to be considered eligible for participation in the study they must: Criterion Characteristics of eligible participants 1.
Be male or female aged ≥ 18 years at the time of consent 2.
Have been diagnosed with an IRD such as RA, SLE or AxSpA by a consultant rheumatologist 3. Report fatigue to be a persistent problem as evidenced by answering both questions: Have access to a telephone landline or mobile telephone and/or internet based audio/video calls 5. Give permission for researchers to access their hospital medical notes 6. Have stable disease as evidenced by no change in immunomodulatory therapy within the last three months based Currently be under the care of a secondary care physician Participants will be excluded if: Criterion Characteristics of ineligible participants 1. there are significant abnormalities in thyroid function (TSH levels) in the most recent blood test done within the last three months 2. there is evidence of severe anaemia (haemoglobin levels) in the most recent blood test done within the last three months 3. there is evidence of severe renal dysfunction (eGFR) in the most recent blood test done within the last three months 4. they have a medical condition which would make the proposed interventions unsuitable, e.g. significant heart disease 5. they are pregnant 6. they are unable to understand English sufficiently to take part in the intervention 7. they are unable to provide written informed consent 8. they are not willing to be randomised 9. they are currently participating in an interventional clinical trial participants. If a participant has been identified as potentially eligible s/he will be 202 invited to an appointment for a baseline assessment visit at the local study site.

204
Consenting participants 205 Patients will make a final decision to participate when they attend the local study site 206 for the baseline assessment visit. No study specific procedures will take place before 207 written consent has been obtained. At the baseline assessment visit, a designated 208 member of the local research team will confirm eligibility (including re-confirmation of 209 fatigue state). It will also be determined whether the participant has ever met the  rheumatology team for support to work through the booklet. We will not restrict what 239 usual care may involve, but will monitor the care received for all participants as part 240 of our health economics analysis.

241
Participants randomised to the active treatments will also receive either CBA or PEP.

242
The CBA and PEP treatments are adapted from previous fatigue specific cognitive 243 behavioural [31,32] and exercise interventions [31] to ensure that they are suitable 244 for a remote delivery via telephone or internet-based audio/video call and applicable 245 to the broad spectrum of IRD. Training of therapists before the study 288 Separate CBA and PEP training will be provided for the NHS staff delivering the 289 interventions. This will comprise an intensive 2-day group course delivered by 290 experienced designated investigators supplemented with the therapist manuals. The 291 course will use a range of methods including skills practice with specific feedback 292 using fictitious but typical fatigued cases.

530
Every effort will be made to ensure data collection is complete. However, we will use 531 statistical techniques for handling missing outcome data. Multiple imputation under a 532 MAR assumption will be used in the first instance, with additional sensitivity analysis 533 if the MAR assumption is not satisfied.

535
Health Economics evaluation 536 An economic evaluation will be conducted from both a health care system and 537 societal perspective. Participants will be asked to record in a diary all types and 538 duration of hospital admissions, frequency of visits to hospital for outpatient 539 attendances, and other visits to or from relevant health professionals (e.g. general 540 practitioners, nurse practitioners, physiotherapists) and specify whether the main 541 reason for the visit was fatigue. The participant will be asked to keep the diaries 542 between the baseline and third assessment visit (approximately 28 weeks).

543
Furthermore they will be asked to keep diaries for two weeks after the third 544 assessment visit and two weeks before they return for the last assessment visit.

545
National sources of unit cost data will be applied to value resource use ( Patients will be asked to report any contacts with private practitioners, and the costs  Health-related quality of life data will be collected using the SF-12 and these data will 554 be converted to quality of life weights using published tariffs. These data will then be 555 used to calculate Quality Adjusted Life Years (QALYs   Availability of data and materials 665 Ownership of the data arising from this study resides with the University of Aberdeen.

666
A clinical study report will be prepared in accordance with ICH authorship guidelines 667 which will be used for publication and presentation at scientific meetings.

668
Investigators have the right to publish orally or in writing the results of the study.

669
There are no plans to place study outcome data in a repository at the current time.  Ethics approval and dissemination 687 The study will be conducted in accordance with the principles of good clinical  and treatment fidelity. Written consent will be obtained to record interviews and to 700 include anonymised statements in publication of the qualitative evaluation outcomes.

702
Trial status 703 The LIFT study began recruitment in August 2017 and will be ongoing until March 704 2019 (anticipated). It is expected that data collection will be completed by April 2020.        if they are also eligible to take part in the MRI sub-study.

871
CBA, cognitive behavioural approach; eGFR, estimated glomerular filtration rate; Hb,  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][2][3]. Moreover, poor recruitment can lead to an underpowered study, which may report clinically relevant effects to be statistically nonsignificant. 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 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

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.

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.      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.

References
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 inflammation 4,5 . 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 nonimprovers-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) 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 a Participant Information Sheet on this substudy. 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 (Glasgow, Edinburgh or Aberdeen) 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.

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 work 6 , 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 or Glasgow. 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.
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 and Edinburgh 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.
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.  Table 1 Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) 9, 16, Figure 1, Figure 2, Figure 3 Page 56 of 58   problem. In rheumatoid arthritis (RA), for example, as many as 80% of patients report 106 significant fatigue [1] and over 70% consider fatigue to be equal to pain in terms of 107 burden [2]. Moreover, fatigue is a crucial determinant of impaired quality of life [3,4] 108 and a predictor of work disability [5,6]. Indeed, over 75% of patients identify fatigue 109 as the main barrier to remaining in employment [7]. Studies in other chronic IRDs,  Firstly, existing studies -including our own -have only developed bespoke disease-127 specific models of care, which vary in content, structure and method of delivery.  interventions, in addition to usual care, is more effective than usual care alone to 164 lessen the impact and severity of fatigue. We will also explore the underlying  The timeline for assessment and delivery of interventions is summarised in Figure 2.

184
We anticipate that active CBA and PEP interventions will start between 2 and 8 185 weeks post-randomisation, with an average delay of 4 weeks after randomisation.

186
Follow-up data will be collected from all participants at 10 weeks, 28 weeks and 56 187 weeks after randomisation adjusted for the average delay of 4 weeks, therefore all 188 participants will remain part of the study for 13 months.  Report fatigue to be a persistent problem as evidenced by answering both questions: Have access to a telephone landline or mobile telephone and/or internet based audio/video calls

5.
Give permission for researchers to access their hospital medical notes there is evidence of severe anaemia (haemoglobin levels) in the most recent blood test done within the last three months 3. there is evidence of severe renal dysfunction (eGFR) in the most recent blood test done within the last three months 4. they have a medical condition which would make the proposed interventions unsuitable, e.g. significant heart disease 5.
they are pregnant 6. they are unable to understand English sufficiently to take part in the intervention 7. they are unable to provide written informed consent 8. they are not willing to be randomised 9. they are currently participating in an interventional clinical trial   Both CBA and PEP interventions will be delivered by health care professionals. PEP Supervision and support of therapists during the study 300 Supervision will be provided by designated investigators on a fortnightly basis, or as 301 required, to the therapists either face-to-face or by telephone depending on feasibility 302 and preference. In addition, support will be available in cases where a therapist Some of the intervention sessions will be recorded and used in supervision to provide 309 feedback to therapists and to ensure treatment fidelity. We aim to take a 5% sample   Furthermore, participants will be given the option to provide additional blood samples 376 which will be stored in a designated freezer at the University of Aberdeen. These will 377 be a maximum of 3 tubes per visit of 1x PAXgene DNA (visit 1 only), 1x PAXgene  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59 1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  this approach acknowledges that both participants and therapists will have been 407 involved in a remotely delivered intervention. All interviews will be audio recorded, 408 anonymised during transcription, and checked for accuracy.

534
Every effort will be made to ensure data collection is complete. However, we will use 535 statistical techniques for handling missing outcome data. Multiple imputation under a 536 MAR assumption will be used in the first instance, with additional sensitivity analysis 537 if the MAR assumption is not satisfied.

539
Health Economics evaluation 540 An economic evaluation will be conducted from both a health care system and 541 societal perspective. Participants will be asked to record, in a diary, all types and 542 duration of hospital admissions, frequency of visits to hospital for outpatient 543 attendances, and other visits to or from relevant health professionals (e.g. general 544 practitioners, nurse practitioners, physiotherapists) and specify whether the main 545 reason for the visit was fatigue. Each participant will be asked to keep the diaries 546 between the baseline and third assessment visit (approximately 28 weeks).

547
Furthermore they will be asked to keep diaries for two weeks after the third 548 assessment visit and two weeks before they return for the last assessment visit.

549
National sources of unit cost data will be applied to value resource use (HRG

550
Reference Costs, Unit Costs of Health and Social Care). The costs associated with was an impact on paid and unpaid work.

557
Health-related quality of life data will be collected using the SF-12 and these data will 558 be converted to quality of life weights using published tariffs. These data will then be 559 used to calculate Quality Adjusted Life Years (QALYs). As the intervention may affect  All study documentation will be kept for a minimum of 5 years from the protocol 601 defined end of study point in the University of Aberdeen archive. When the minimum 602 retention period has elapsed, study documentation will not be destroyed without 603 permission from the sponsor.  problem will be considered, either through database screening or manual screening 631 by research nurses, and invited to take part in the trial. Participants will be asked to 632 provide information about fatigue, our primary outcome, at baseline and weeks 10,  Ethics approval and dissemination 651 The study will be conducted in accordance with the principles of good clinical  Consent will be sought for recording of interventions sessions for quality assurance 663 and treatment fidelity. Written consent will be obtained to record interviews and to 664 include anonymised statements in publication of the qualitative evaluation outcomes.

665
Ownership of the data arising from this study resides with the University of Aberdeen.

666
A clinical study report will be prepared in accordance with ICH authorship guidelines 667 which will be used for dissemination of findings via publication and presentation at 668 scientific meetings. Investigators have the right to publish orally or in writing the 669 results of the study.
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 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

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
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 inflammation 4,5 . 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 nonimprovers-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) 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).  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 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 a Participant Information Sheet on this substudy. 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 (Glasgow, Edinburgh or Aberdeen) 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 (i.e. specific to this substudy) on attendance at the imaging centre prior to the MRI assessment and then conduct a final MRI safety screen.

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 work 6 , 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 or Glasgow. 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 approximately 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.
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 and Edinburgh 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.
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.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59   Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities 30 5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)

Methods: Participants, interventions, and outcomes
Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained 9 Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

9-11
Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered 13-16 11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease) n/a 11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests) 16, 19 11d Relevant concomitant care and interventions that are permitted or prohibited during the trial 13 Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended 16-20, Supplement Table 1 Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure) 9, 16, Figure 1,   1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  o n l y   3   Sample size  14  Estimated number of participants needed to achieve study objectives and how it was determined, including  clinical and statistical assumptions supporting any sample size calculations   22   Recruitment  15 Strategies for achieving adequate participant enrolment to reach target sample size 9

Methods: Assignment of interventions (for controlled trials)
Allocation: Sequence generation 16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions 12 Allocation concealment mechanism 16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned 12 Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions 12 Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how 12-13 17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant's allocated intervention during the trial n/a

Methods: Data collection, management, and analysis
Data collection methods 18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

16-21 18b
Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) 25

Methods: Monitoring
Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed 26-27 21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial n/a

Harms 22
Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct 21 Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor n/a How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial 27