Objectives {7}

The objective of the Multicentre Observational Initiative in Treat to target Outcomes in Psoriatic Arthritis (MONITOR-PsA) cohort is to assess clinical and patient-reported outcomes, as well as costs associated with a pragmatic routine implementation of a T2T approach, and compare those to the outcomes of the TICOPA trial.

The MONITOR-PsA cohort also aims to facilitate recruitment to a number of embedded trials (trials within cohorts (TWiCs) design) to test alternative therapeutic approaches in embedded clinical trials to provide an evidence base for treatment strategy in PsA.

Eligibility criteria {10}

Eligible participants will be as follows: willing and able to give informed consent for the study; male or female; 18years or over; have a clinical diagnosis of PsA confirmed by the ClAsSification of Psoratic ARthritis (CASPAR) criteria [17]; active PsA with ≥ 1 tender or swollen joints or enthesis; not previously had treatment with DMARDs for articular disease; and, in the investigators’ opinion, is able and willing to comply with all study requirements. All potentially eligible participants will be approached for participation in the study by their treating rheumatology team.

Female participants of child bearing potential and male participants whose partner is of child bearing potential must be willing to ensure that they or their partner use effective contraception during potentially teratogenic DMARD treatment and for 3months thereafter (or 2years if received leflunomide unless treated with washout therapy) as in standard practice. Women who are pregnant, nursing or planning pregnancy during the following 12months will only receive DMARDs that are appropriate according to British Society of Rheumatology (BSR) recommendations.

Participants may not enter the study if any of the following apply: Current or previous treatment of arthritis with synthetic DMARDs (including methotrexate, leflunomide or sulfasalazine) or biologic DMARDs (including TNF, IL12/23 or IL17 inhibitor therapies) or targeted synthetic DMARDs (PDE4 of JAK inhibitor therapies); or use of investigational therapies within 1month or 5 biological half-lives of the baseline study visit (whichever is longer).

Who will take informed consent? {26a}

Potential participants will be identified from new referrals to the rheumatology service, particularly those referred to the early arthritis clinic or dedicated PsA clinic. Patients will be identified and approached initially by their clinical care team and will be given brief information about the study. If interested, a full patient information sheet (PIS) and informed consent form (ICF) will be given to them and explained. If they are willing to participate in the observational study, consent can be obtained on the same day. However, they will be allowed as much time as they wish to consider their participation. Written informed consent will then be obtained by means of participant dated signature and dated signature of the person who presented and obtained the Informed Consent. The person who obtained the consent must be suitably qualified and experienced and have been authorised to do so by the chief/principal investigator (CI/PI).

Given the TWiCs design which this cohort underpins, the consent for the cohort includes an optional consent to use participants’ personal details to contact them about future research and explains that a random selection of those eligible for an intervention arm of an embedded treatment study (including clinical trials of medicines) may be invited to participate in these additional embedded studies. Participants are randomised to the offer of an intervention but obviously do not have to consent to participate in these. If participants consent to being approached about further research, they are made aware that their anonymised data may be used as a ‘control arm’ to compare with additional interventional studies.

Intervention description {11a}

Within the cohort, patients will be assessed every 12weeks during the first year of therapy and will be treated in line with current standard step-up care. This will consist of initial therapy with methotrexate alone, then alternative DMARDs for non-response or intolerance, then potentially biologic therapy following NICE recommendations [2].

If an assessment is performed after 12weeks on a new therapy and participants have reached the target of treatment, then this should be continued. If they have not achieved minimal disease activity criteria (MDA) but have shown significant improvement since starting the new therapy (a reduction in tender and swollen joint counts of at least 20%) then treatment should be continued for a further 12weeks before a repeat assessment. If they have not responded significantly, then the next step in the treatment protocol should be offered. For biological and targeted synthetic DMARDs, response must be recorded using the PsA Response Criteria (PsARC) to fulfil NICE guidelines on the prescriptions of these therapies. The timing of this assessment varies by drug (TNF inhibitors 12weeks, apremilast and secukinumab 16weeks, ustekinumab 24weeks). If patients do not achieve a PsARC response, then their treatment should not be continued. Providing that new therapies can be tolerated by the patient and do not cause significant toxicity, such that patients are unwilling to continue with treatment or that treatment must be stopped due to safety concerns, a trial of a minimum of 12weeks therapy should be given before changing or adding an alternative DMARD.

Criteria for discontinuing or modifying allocated interventions {11b}

The step-up treatment within the cohort is based around assessment of the MDA criteria as these are a validated and recommended target of treatment in PsA. If patients do not achieve MDA by 24weeks after initiating therapy (or have not had an improvement of at least 20% in active joint counts after 12weeks on therapy), then treatment should be escalated to the next step.

Strategies to improve adherence to interventions {11c}

This is an observational study embedded within usual clinical practice. Hospital sites will employ their usual strategies to improve adherence to treatment within the cohort. These include counselling on disease-modifying anti-rheumatic drugs by physicians, specialist nurses and pharmacists, follow-up visits for counselling, adherence and monitoring and written support materials given to patients.

Relevant concomitant care permitted or prohibited during the trial {11d}

As this is an observational cohort supporting pragmatic trials, there are no prohibited concomitant care or interventions within this study.

Provisions for post-trial care {30}

Within the MONITOR-PsA cohort, all medications will be prescribed via usual care pathways and patients will be able to continue on their medications at the end of the study as long as they are responding well to treatment. For embedded trials, some medications may not be available beyond the end of the trial period but that will be made clear to participants at the time of consent to the embedded study and alternative therapies will be offered as appropriate in standard rheumatology practice. At the end of any embedded study period, participants return to usual cohort follow-up allowing long-term assessment of the impact of any tested interventions. Insurance is in place via the sponsor and participating NHS sites for any harm resulting from trial participation.

Outcomes {12}

The primary endpoint is the proportion of patients achieving the PsA Disease Activity Score (PASDAS) ‘good’ response [18] at 48weeks. The PASDAS is a composite score including both clinical assessment and patient-reported outcomes [19].

PASDAS responses are calculated as follows:

PASDAS calculation	(((0.18√physician global VAS)+(0.159√patient global VAS)–(0.253 x√SF36−physical component summary score (PCS))+(0.101 x LN (swollen joint count+1))+(0.048 x LN (tender joint count+1))+(0.23 x LN (Leeds enthesitis index+1))+(0.37 LN (tender dactylitis count+1))+(0.102 x LN (C−reactive protein (CRP)+1))+2) x 1.5.
	Improvement
Final PASDAS score	>1.6	≤ 1.6 but >0.8	≤ 0.8
≤ 3.2	Good	Moderate	Poor
>3.2 but <5.4	Moderate	Moderate	Poor
≥ 5.4	Moderate	Poor	Poor

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The results will be discussed in the context of the TICOPA trial [6] (n=206) to see if they are consistent. The patients recruited early in the course of the study who therefore have longer-term follow-up data will enable us to explore durability of the response.

Key secondary endpoints include:

• Time from baseline to first achieving MDA [20] and PASDAS good response [18]

• Proportion achieving PASDAS good response [18] at 24weeks

• Proportion achieving PASDAS moderate response [18] at 24/48weeks

• Healthcare costs and quality adjusted life years (QALYs) (see below)

Exploratory outcomes (not available in TICOPA dataset) will include:

• Change in PsA Impact of Disease (PsAID) score [21] from baseline to 48weeks

• Proportion achieving PsAID participant acceptable symptom state (≤ 4) [21] at 48weeks

• Change in work productivity (WPAI-SHP) [22] (absenteeism, presenteeism and productivity loss) at 24 and 48weeks

• Side effects reported at each time point, combined with the Treatment Satisfaction Questionnaire for Medication (TSQM)

• Outcomes at time points later than 48weeks during the longer-term follow-up of the cohort.

• Explore immune response in patients with PsA and how this relates to clinical effectiveness with standard therapies

All outcomes are collected via electronic case report forms (eCRFs). Patient-reported outcomes are inputted directly by the participants using a tablet computer, with a paper version available in case completion on the tablet computer is not possible. A full list of outcome measures and their timings are provided in Table 1.

Table 1

Outcome measures in the MONITOR-PsA cohort study

Procedures	Visits
	Baseline cohort
	Week 0	Week 12	Week 24	Week 36	Week 48	Week 72	Week 96	Annually (after 96weeks)
Informed consent	X
Demographics	X
Medical history	X	X	X	X	X	X	X	X
Medications	X	X	X	X	X	X	X	X
Physical examination	X	X	X	X	X	X	X	X
Routine blood tests (FBC, U&Es, LFTs, CRP and eGFR)	X	X	X	X	X	X	X	X
Immunology (RF, ACPA, ANA)	X
Radiographs of hands/feet/spine	X				X		X	X
Eligibility assessment	X
Adherence		X	X	X	X	X	X	X
68/66 Joint count	X	X	X	X	X	X	X	X
Leeds and SPARCC enthesitis index	X	X	X	X	X	X	X	X
Dactylitis count	X	X	X	X	X	X	X	X
Psoriasis assessment (PASI and BSA)	X	X	X	X	X	X	X	X
Physician VAS	X	X	X	X	X	X	X	X
Metrology with BASMI (if axial involvement)	X				X		X	X
Patient questionnaires (VAS, HAQ, SF36, PsAID, WPAI, BASDAI, BASFI)	X	X	X	X	X	X	X	X
TSQM questionnaire		X	X	X	X	X	X	X
EQ-5D-5L questionnaire	X		X		X	X	X	X
Healthcare utilisation data			X		X	X	X	X
Adverse event assessments	X	X	X	X	X	X	X	X

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All adverse events will not be collected in this study as all the medications used are currently used in PsA and have well documented safety profiles. Only adverse events of special interest (either extra-articular manifestations of the disease or those likely to be related to the therapy used for PsA) occurring during the study will be collected at each study visit by patient questionnaire and physician report as below:

• Patient reported: nausea/vomiting; heartburn/dyspepsia; diarrhoea; fatigue; hair loss; and injection site reactions

• Physician reported: infections; liver function test abnormalities; neutropenia/leucopenia; and uveitis.

Serious adverse events that, in the opinion of the CI, were ‘related’ (resulted from administration of any of the research procedures) and ‘unexpected’ in relation to those procedures will be reported.

Participant timeline {13}

Participants are recruited at or after the time of diagnosis before they start on disease-modifying therapy. Study visits in the cohort will be at 0, 12, 24, 36 and 48weeks, every 6months in year 2 and yearly thereafter in line with routine practice to minimise burden and support retention of participants. In case of treatment escalation at a later time point, visits will be repeated at 12, 24 and 48weeks.

Different embedded trials can be included within this approach either investigating initial treatment (with participants randomised at the MONITOR-PsA baseline visit) or at another specific treatment point in the follow-up period, for example failure of a particular therapy when subsequent treatment is investigated. Study visits for embedded trials will be aligned with those for the cohort wherever possible.

Sample size {14}

We aim to recruit a minimum of 500 participants to the cohort, which may be extended if additional trials are funded. No formal sample size calculations were performed for the cohort. We estimate that around 200 participants will receive the standard treatment within the cohort, which will allow for robust estimation of the primary outcome, i.e. robust confidence intervals around the proportion of participants receiving a PASDAS good response at 48weeks, to be compared to the outcomes observed in the TICOPA trial [6].

Concealment mechanism {16b}

No randomisations are performed as part of the MONITOR-PsA cohort; as such no allocation concealment applies to this study. Embedded trials will randomise participants to their intervention with appropriate allocation concealment. Details of these will be reported in the protocols for the relevant trials.

Plans to promote participant retention and complete follow-up {18b}

Study visits in the cohort are deliberately aligned to usual clinical care. Given that most DMARD therapies can take up to 12weeks to work, assessment in early arthritis is often at approximately 3-month intervals. Once patients are stable, appointments are generally gradually spaced out to minimise disruption to patients’ lives. Therefore, follow-up will be every 12weeks in year one, every 6months in year 2 and annually thereafter. If participants change therapy later in the course of their disease, additional study visits will be performed at weeks 12, 24 and 48 after any treatment change. This will allow development of embedded trials testing alternative treatment strategies in more established disease.

Following the development of the COVID-19 pandemic in 2020, some remote follow-up had to take place to ensure ongoing safety on treatment and subsequently this was permitted (particularly at week 36) under a specific COVID-19-related amendment. The primary endpoint of the study requires physical assessments by a clinician but during lockdown, limited information was collected via remote follow-up when physician visits were not possible.

As the cohort itself is non-interventional, participants who withdraw will withdraw completely, including withdrawal from follow-up. If they consent, their data up to the point of withdrawal will be retained and utilised in any analysis. Participants in embedded trials will be able to withdraw from the intervention protocols but remain in the cohort for follow-up.

Data management {19}

All information concerning the data management procedures of the MONITOR-PsA cohort and embedded studies are included in study specific data management plans. Access to the study database is limited to authorised personnel using individual log-ins. The study database is stored on secure University of Oxford servers with appropriate backup. In some other study sites, data are collected using their local secure databases supporting existing database projects, before being transferred securely to Oxford for amalgamation.

To ensure high-quality data, databases also include multiple data validations, including checks for plausible ranges, and valid date ranges. Additional data checks are routinely performed by the study statistician. The calculation of composite scores will be verified before any analysis.

Confidentiality {27}

All data will be processed in compliance with applicable data protection legislation, and all documents will be stored safely in confidential conditions. On all study-specific documents, other than the signed ICF and patient contact details, the participant will be referred to by the study participant number/code, not by name. Identifiable contact information will be stored separately from study data and held at the local research site and by the central coordinating team. For central monitoring purposes, completed consent forms will be reviewed by the coordinating trials unit, but these will be transferred via secure data transfer to ensure personal details are secure at all times.

Interim analyses {21b}

No formal interim analyses are planned for the MONITOR-PsA cohort ahead of the primary analysis. The Data Safety and Monitoring Committee may see interim descriptive summaries of accumulating data in confidence.

Additional analyses of the longer-term follow-up are planned to take place after the primary analysis of this cohort. Subsets of the cohort including participants enrolled in the embedded trials may also be analysed throughout the duration of the cohort.

Methods for additional analyses (e.g. subgroup analyses) {20b}

Supplementary analyses will be undertaken to explore the many baseline prognostic factors in order to examine which patients most benefit from this treatment and whether important subgroups can be defined. These analyses will be exploratory and utilise descriptive summaries and logistic regression models.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}

Missing data will be minimised by careful study conduct and data management. Missing data will be described with reasons given where available; the number and percentage of individuals in the missing category will be presented.

The nature and mechanism for missing variables and outcomes will be investigated, and if appropriate multiple imputation will be used. Sensitivity analyses will be undertaken assessing the underlying missing data assumptions, if appropriate.

Economic analysis

An economic evaluation, in the form of a cost-effectiveness analysis, is not planned as part of the MONITOR PsA study. Instead, the analysis will be presented in a descriptive and informative way so as to establish comparisons in costs and QALYs estimates with the predecessor of MONITOR, the TICOPA trial.

Data will be collected on the health resources used by participants during the study period. At 24, 48 and 96weeks post-randomisation participants and health professionals will be asked to complete economic questionnaires in relation to hospital admission, medication, outpatient visits and community health care. Unit cost data will be obtained from national databases such as the BNF [26] and PSSRU costs of health and social care [27].

Health Related Quality of life will be estimated using the EuroQol EQ-5D 5L for self-completion at baseline, 24, 48 and 96weeks post-randomisation. As per the NICE position statement, the responses to the EQ-5D-5L will be converted into multi-attribute utility scores using the approved ‘cross-walk’ to the 3L instrument using the mapping function developed by van Hout et al. [28] and the converted responses will be valued using the established time trade-off utility algorithm for the UK [29]. QALYs will be calculated as the area under the utility curve of utility scores from baseline, 24, 48 and 96weeks, data using the trapezoidal rule [30].

The economic analysis will be conducted from a UK NHS and Personal Social Services perspective (PSS) using the cohort data.

Composition of the data monitoring committee, its role and reporting structure {21a}

The DSMC is a group of independent experts external to the study who assess the progress, conduct, participant safety and, if required critical endpoints of a clinical trial. The DSMC has agreed and adopted an appropriate charter that defines its terms of reference and operation in relation to oversight of the study. They will not be asked to perform any formal interim analyses of effectiveness. They will, however, review accruing data, summaries of the data presented by treatment group, and will assess the screening algorithm against the eligibility criteria. They will also consider emerging evidence from other related research and review related SAEs that have been reported. They may advise the chair of the Trial Steering Committee at any time if, in their view, the study (or embedded trial) should be stopped for ethical reasons, including concerns about participant safety. DSMC meetings will be held at least annually during the recruitment phase of the study. Full details including names will be included in the DSMC charter. The TSC and DSMC for the study will also cover any embedded trials within the cohort to allow cohesive review of any safety issues.

Adverse event reporting and harms {22}

As the cohort supports clinical trials of investigational medicinal products (IMPs), considerable thought has been given to safety reporting. Within the cohort, only serious adverse events (SAE) occurring to a participant where in the opinion of the CI the event was ‘related’ (resulted from administration of any of the research procedures) and ‘unexpected’ in relation to those procedures will be reported. However, for participants in the embedded trials, SAEs will be reported according to the individual trial protocols.

All non-serious adverse events will not be collected in the cohort or current trials as all the IMPs are licenced, currently used in PsA and have well documented safety profiles. Only adverse events of special interest (either extra-articular manifestations of the disease or those likely to be related to the therapy used for PsA) occurring during the study will be collected at each study visit by patient questionnaire and physician report.

The following information will be recorded: severity, assessment of relatedness to trial medication and action taken. The severity of events will be assessed on the following scale: 1=mild, 2=moderate, 3=severe. Follow-up information will be provided as necessary.

Frequency and plans for auditing trial conduct {23}

The study may be monitored, or audited in accordance with the current approved protocol, Good Clinical Practice (GCP), relevant regulations and standard operating procedures. A Monitoring Plan will be developed according to OCTRU’s standard operating procedures (SOPs) which involves a risk assessment. The monitoring activities are based on the outcome of the risk assessment and may involve central monitoring and on-site monitoring.

The study coordinator will be responsible for ensuring adherence to the trial protocols at the trial sites. Quality assurance checks will be undertaken by OCTRU to ensure integrity of study entry procedures and data collection. OCTRU has a quality assurance team who will audit this study by conducting (at least once in the lifetime of the study, more if deemed necessary) review of the Trial Master File (TMF). Furthermore, the processes of consenting, registration, provision of information and provision of treatment will be monitored. Written reports will be produced for the TSC, informing them if any corrective action is required.

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}

Any significant amendments to the protocol will be reviewed by the sponsor and the approving ethics committee prior to any implementation. If any new safety data becomes available, or there is a significant change to the study design that would impact on patients, then participants would be given an updated patient information leaflet and where appropriate asked to reconsent.

The MONITOR study team also acknowledge the support of Patrick Julier in IT development for the MONITOR study.