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The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel-group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes
BMC Musculoskeletal Disorders volume 18, Article number: 303 (2017)
Psoriatic arthritis (PsA) is a chronic inflammatory arthritis which impacts significantly on the quality of life and work capacity of affected individuals. Recent evidence has shown that early control of inflammation in PsA leads to improved long-term outcomes. It is postulated that prompt intervention after diagnosis using a remission-induction treatment strategy will lead to improved outcomes and optimal disease control of PsA.
The aim of the present study was to compare the clinical efficacy of a treatment strategy in newly diagnosed, treatment naïve PsA subjects, using the combination of golimumab (GOL), methotrexate (MTX) and steroids versus standard care (MTX monotherapy plus steroids).
GOLMePsA is an investigator initiated, phase IIIb, single-centre, randomised, double-blind, placebo-controlled, two-armed, parallel-group, imaging-supplemented study. Eighty-eight PsA patients, diagnosed within 24 months prior to screening and treatment naïve, will be randomised at baseline to receive: (arm 1) the combination of intramuscular/intra-articular prednisolone, MTX and GOL or (arm 2) the combination of intramuscular/intra-articular prednisolone, MTX and placebo for 24 weeks (interventional period). Primary outcome measure is clinical improvement (at least 1 unit difference) in the Psoriatic ArthritiS Disease Activity Score (PASDAS) composite index.
Reflecting a “step down” therapeutic approach, all participants successfully completing the interventional period will be followed up for a further 28 weeks. During this observational period, stable maintenance MTX monotherapy will continue for both arms, unless in case of intolerance or PsA relapse. In the latter case, additional treatment will be provided. Overall, the GOLMePsA study length is planned to be 52 weeks.
The hypothesis underlining this study is that very early treatment with first-line GOL reduces disease activity in PsA, in comparison to conventional therapy.
EudraCT 2013–004122-28. 24/09/2013.
Psoriatic arthritis (PsA) is a polygenic, chronic inflammatory arthritis affecting up to 0.19% of the general population  and 3.2%  to 34%  of individuals with skin psoriasis. The course of PsA is heterogeneous and variable: some patients have mild disease whilst others evolve into a severe arthropathy that is often refractory to conventional treatments. These cases are frequently associated with functional disability and accelerated morbidity [4, 5]. A main hindrance in the treatment of PsA has been the delay to presentation to rheumatology clinics, of up to 9 years from symptoms onset. By that time the majority of affected individuals (67%) has an established, erosive arthropathy with a substantial degree of functional impairment [6,7,8]. However, up to 27% of PsA cases show radiographic damage within 2 years of symptom onset [9, 10]. Even a short delay of 6 months to presentation may lead to permanent work instability .
Over the past two decades, mounting evidence from rheumatoid arthritis (RA) studies has shown that early, aggressive treatment using synthetic and biologic disease-modifying anti-rheumatic drugs (sDMARDs and bDMARDs, respectively) improves the outcome of the disease concerning articular damage and disability . Such a novel therapeutic approach allowed clinical remission to become an achievable goal in many patients treated with bDMARDs, chiefly Tumor Necrosis Factor α (TNFα) inhibitors (TNFi) [13, 14]. As a result, the concepts of “window of opportunity” and “treat-to-target” have become popular in RA treatment. By contrast, data in PsA are still sparse , with only limited evidence on the efficacy of sDMARDs such as methotrexate (MTX)  or leflunomide . To date, only TNFi have shown efficacy on all clinical manifestations of PsA [18,19,20,21] as well as on delaying structural damage . The safety and efficacy of golimumab (GOL) used for reducing signs and symptoms of active PsA and the associated skin and nail disease was evaluated in the GO-REVEAL trial)  with benefits maintained in the long term . Further, in the same trial GOL was associated with inhibition of structural damage (weeks 24 and 52), persistent articular and cutaneous improvements at week 104 and significant improvements in the Patients’ Reported Outcomes (PROs). Currently, GOL, alone or associated with MTX, is indicated to treat active and progressive PsA in adults irresponsive or intolerant to previous sDMARD therapy.
Structural abnormalities are insidious in the early disease stages of PsA, rendering radiography a measurable outcome lacking of sensitivity in these patients. Whole body MRI (WB-MRI) allows axial and peripheral multi-joint assessments in one single investigation and is a feasible tool for detection of subclinical inflammation in patients with PsA, particularly for enthesitis and bone marrow oedema (BMO) . Evidence from RA suggests that subclinical BMO is one of the main predictors for on-going radiographic progression, even in the presence of clinical remission . In SpA, there is evidence that BMO may be a predictor of future radiographic axial damage . The ability of WB-MRI and US [27, 28] to identify subclinical inflammation is particularly useful for the quantification of the total inflammatory burden in PsA  and in understanding the features of disease remission after a course of therapy.
To date, there are no data on the role of WB-MRI as an outcome measure in PsA. Further, the use of bDMARDs on treatment naïve, early diagnosed PsA patients has not been addressed in double blind randomized clinical trials. It is therefore postulated that the GOLMePsA study will show that an early aggressive intervention in PsA immediately after diagnosis, using GOL combined with dose escalating MTX protocol and intra-articular or intramuscular corticosteroid, could ameliorate significantly the disease activity and even lead to a state of minimal disease activity (MDA) , or near clinical remission, along with complete ablation of inflammation as shown by WB-MRI at 24 weeks.
The aim of this study is to assess in early diagnosed treatment naïve PsA, the clinical efficacy of a treatment strategy comprising of the combination of GOL plus MTX plus steroids versus standard care (MTX monotherapy plus steroids) using clinical and imaging outcome measures at 24 weeks.
The GOLMePsA trial was designed to address two different hypotheses:
First, that early intervention in recently diagnosed and treatment-näive PsA, through the combination of GOL and MTX plus corticosteroids will lead to clinical improvement reflected by at least 1 unit difference on the scale measured by the Psoriatic ArthritiS Disease Activity Score (PASDAS) [31,32,33,34] at week 24. The improvement will be superior to that shown by the combination of MTX plus placebo plus corticosteroids (conventional therapy).
Secondly, that a subset of PsA patients at presentation have a substantial amount of subclinical articular and/or entheseal inflammation and this can be detected by WB-MRI and US. Using these imaging techniques will allow the identification of subjects whose response to therapy has been successful even at the subclinical level.
The primary objective of this study is to assess whether the combination of GOL with MTX and steroids is superior to standard care (MTX monotherapy plus steroids) in patients with early treatment naïve PsA using the PASDAS score at 24 weeks as the primary outcome measure.
To assess the extent of association between clinical and imaging joint assessments at baseline.
To assess the extent of association between clinical and imaging responses to therapy.
To assess whether responses on imaging outcomes are associated with steroid therapy.
To assess the superiority of combination therapy over standard treatment in improving patient-reported QoL and health status.
To identify baseline variables which may be modifiers of clinical or imaging response (e.g.: symptom duration, immunological parameters).
GOLMePsA is an investigator initiated, phase IIIb, single-centre, randomised, double-blind, placebo-controlled, two-armed, parallel-group, imaging-supplemented study.
A total of 88 patients with PsA, diagnosed within 24 months prior to screening and treatment näive, will be randomised to compare:
The combination of intramuscular/intra-articular prednisolone and MTX plus GOL
The combination of intramuscular/intra-articular prednisolone and MTX plus placebo
The above described interventional period will last 24 weeks. All participants successfully completing this phase will be followed up for other 28 weeks (observational period). Overall, the GOLMePsA study length is planned to be 52 weeks (see Figs. 1 and 2).
The target population is early diagnosed (within 2 years from screening date), treatment naïve PsA cases who satisfy the ClASsification criteria for Psoriatic ARthritis (CASPAR) . A full list of inclusion and exclusion criteria for eligibility and subsequent randomization into this study are detailed in Table 1.
This study is being conducted at the Chapel Allerton Hospital (CAH) Outpatient Department and Research Facility, part of the Leeds Teaching Hospitals National Health Service (NHS) Trust in Leeds, United Kingdom. Potential study candidates may also be identified via rheumatology clinics at Participant Identification Centres (PICs) within the Yorkshire Region (see also acknowledgements section). Potential candidates are provided with verbal and written details about the trial (Participant Information Sheet and Informed Consent Document) before being contacted by the main research team based at CAH. Potential candidates have as long as they need to consider participation. Assenting subjects are invited to provide informed, written consent before being registered into the trial and formally assessed for eligibility.
Consent to the GOLMePsA trial biological sub-study
Eligible subjects are also invited to take part in a Biological Sub-study which collects biological samples (blood and urine) at predefined endpoints. Assenting subjects are asked to sign an additional, specific consent form.
Screening and registration
Following written informed consent and prior to any trial-related procedures, participants are registered in the study enrolment log. All subjects undergo a screening assessment (Figs. 2 and 3) to determine eligibility for the study within 4 weeks prior to the baseline assessments.
The research team keeps a “pre-screening” log with details of all subjects who have been considered for the trial, regardless of final ineligibility or declined participation. These subjects are all referred back to outpatient rheumatology clinics in order to receive standard NHS care.
Following registration, confirmation of eligibility, imaging investigations and completion of baseline assessments and questionnaires, participants are randomised in a 1:1 ratio into one of the two treatment arms. Randomization assignment is performed with a computer-based program which utilizes randomly-permuted block sizes. Randomisation is stratified by the number of clinically involved joints (oligoarticular: ≤4 joints/polyarticular: >4 joints).
Treatment is administered in the two study arms as detailed in Table 2. The planned use of corticosteroids, given as a “bolus” at baseline to all participating subjects, aims to achieve rapid ablation of inflammation. Participants in both arms not achieving at least 30% improvement in the Psoriatic Arthritis Response Criteria (PsARC) [36, 37] at weeks 8 and 12 will receive additional corticosteroid injections. The steroid amount given between both visits will not exceed a maximum of 120 mg methylprednisolone per patient (or comparable amount intra-articularly; unless contraindicated or not tolerated). No further steroids will be allowed between week 12 and week 24. All participants, in both arms, not achieving at least 30% of PsARC improvement beyond week 12 and before week 24 may discontinue the study medication regimen and be treated as clinically indicated. In this case, they may be withdrawn from the treatment part of the study.
All subjects completing the interventional period will continue their MTX and folic acid supplementation unchanged through the observational period if tolerated. During the observational period, in case of increase in disease activity (PsA flare) compared to the previous assessments, the treating physicians will be allowed to consider other available NHS therapeutic options for PsA, such as corticosteroids, sDMARDs or bDMARDs.
After the end of the interventional period and before the end of the trial, intramuscular or intra-articular steroids are not permitted if a clinical or imaging assessment is scheduled within the following 6 weeks.
Assessments, samples and data collection
All protocol-related assessments are recorded on paper source data sheets (SDS) and stored at the research site. These data are then entered onto an electronic case report form (eCRF) specific for the GOLMePsA trial. The trial visits are structured as detailed in Fig. 3.
Biological samples from participants consenting to the GOLMePsA trial Biological Substudy are collected at baseline prior to commencement of trial treatment followed by weeks 12, 24, 36 and 52. In addition, biological samples are collected at the time of early discontinuation (withdrawal visit) if this falls outside the pre-specified time-points (see Fig. 3). Personal details are removed from all biological samples collected as part of the Biological Substudy, after separation into their component parts and before testing. For storage and testing purposes, a pseudo-anonymization unique code will be generated to link the clinical, imaging and laboratory databases. All the biological samples are stored in the central GOLMePsA Trial Biobank in a laboratory at our institution. These samples will be used for a range of studies of direct relevance to the treatment of PsA.
The primary outcome in this study is the change in PASDAS score at 24 weeks. The PASDAS is a weighted composite index encompassing joints counts, an assessment of enthesitis and dactylitis, acute phase reactant, QoL, and patients’ and physician’s global assessment by visual analogue scale (VAS). The PASDAS has been shown to perform well in both oligoarticular and polyarticular forms of PsA  and cut-offs for disease activity and response have now been developed and validated using interventional trial data .
Secondary outcomes at weeks 12, 24, 36 and 52 include the Leeds enthesitis index (LEI) , the Leeds dactylitis index basic (LDI-B) [39, 40], the Psoriasis Area and Severity Index (PASI) score , the Body Surface Area (BSA) affected by psoriasis, the modified Nail Psoriasis Severity Index (mNAPSI) , the proportion of subjects achieving MDA, the proportion of subjects achieving the American College of Rheumatology Response Criteria , the proportion of subjects achieving the PASI75 response (defined as having an improvement of at least 75% in the PASI score compared to baseline levels). The proportion of subjects achieving PsARC response is a secondary outcome to be collected at weeks 8, 12, 24, 36 and 52. The Composite Psoriatic Disease Activity Index (CPDAI)  is a secondary outcome to be collected at weeks 24 and 52. The proportion of patients requiring additional steroid therapy, as well as the cumulative steroid dose up to week 12 of this trial, will be also recorded as a secondary outcome.
Imaging measures of disease activity
Systematic WB-MRI scanning of the axial and peripheral skeleton (Table 3) is performed in all suitable subjects (Table 4), using commercially available Siemens MAGNETOM® Verio 3 T scanner with the following sequences: (i) T1-weighted spin echo (SE) before and after an intravenous gadolinium contrast injection; (ii) Short Tau Inversion Recovery (STIR). The estimated scanning time is 60 min. Images are acquired in two phases, allowing patients to mobilize from the scanner for a short time. MRI features of inflammation (ie: synovitis, BMO or osteitis lesions) and damage (erosions, bone formation, fat infiltration, sclerosis and/or ankylosis) will be scored at peripheral joints, entheses and axial skeleton including sacroiliac joints and spine using a novel scoring system.
US scanning of selected joints and entheses of lower and upper limbs (see Table 3), is performed using a multi-planar technique with symmetrical scanning by sonographer blinded to the participant’s clinical characteristics. Articular and entheseal sites will be assessed for the presence of grey scale (GS) abnormalities and power-Doppler (PD) signal. US pathological findings will be identified according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) definitions [45,46,47].
The patients’ overall assessment of PsA activity will be recorded at baseline and then at weeks 12, 24, 36 and 52, using the 100 mm horizontal VAS using the specific wording proposed by Cauli et al.  for PsA. To calculate the PsARC (at weeks 8, 12, 24, 36 and 52), the same assessment will be also recorded on a Likaert scale ranging from 1 to 5. All participants will fill in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)  questionnaire at baseline and then at weeks 12, 24, 36 and 52. The outcomes relating to QoL and health status are: the Health Assessment Questionnaire Disability Index (HAQ-DI)  score; the Dermatology Life Quality Index (DLQI)  score; the Ankylosing Spondylitis Quality Of Life (ASQOL)  score; the Short Form (SF-36)  score. All these questionnaires will be collected at baseline and then at 12, 24, 36 and 52 weeks.
Our null hypothesis (H0) is that the difference between the two treatment arms in the PASDAS score at week 24 is equal to zero. Hence, the alternative hypothesis (H1) is that the difference between the two treatment arms in the PASDAS score at week 24 is not equal to zero. In general, summary statistics (n = number of available measurements; arithmetic mean; standard deviation; median; minimum and maximum) for quantitative variables and absolute and relative frequency tables for qualitative data will be presented. Analyses will be adjusted for the randomisation stratification factor(s) and baseline values of the outcome; 2-tailed tests will be performed and will be considered statistically significant if p < 0.05.
Planned efficacy analyses
The primary endpoint will be assessed on an intention-to-treat (ITT) basis. Analysis of covariance by multiple linear regression will be used to compare PASDAS between the two treatment groups at week 24. Binary secondary endpoints will be analysed using multiple binary logistic regression. Continuous interval outcomes will be analysed using multiple linear regression. Severely skewed or ordinal outcomes will be analysed using quantile regression. Planned subgroup analyses will investigate differences in treatment response according to oligo/polyarthritis status, immunological status, disease duration at baseline. A per protocol analysis will also be performed.
The frequency of all Serious Adverse Events (SAEs) during the study period in patients who received at least 1 dose of study treatment will be presented for each treatment group separately. The data will be displayed as number of subjects experiencing the SAEs, percentage of subjects, and number of SAEs. Data will also be corrected for exposure by 100 patient-years.
Handling of dropouts and missing data
For patients who withdraw early, data from the withdrawal visit will be imputed for subsequent visits for continuous outcomes, and non-response will be imputed for binary outcomes. For all other instances of missing data, multiple imputation will be used. A number of sensitivity analyses testing robustness of conclusions under different missing data mechanisms will be conducted.
Determination of sample size
Using in-house unpublished data, we estimated the minimum clinically important difference to be 0.7 units on the PASDAS; this is similar to a published value for smallest detectable difference of 0.8 units . We will aim to detect a difference of at least 1 unit between the treatment arms in this study. The standard deviation of PASDAS in the Tight Control of Psoriatic Arthritis (TICOPA)  MTX rapid escalation arm at 24 weeks (restricted to patients who remained on methotrexate throughout) was 1.57. Assuming δ = 1, σ = 1.57, at alpha = 0.05 and 1-Beta = 0.8 this would require 78 patients; accounting for 10% drop-out we will aim to recruit a total of 88 (44 per group).
PsA is a costly disease both for the individual and the society. Current treatment guidelines and treat-to-target strategies are based on a step-up approach with sDMARDs being the main staple of treatment, despite limited data supporting their efficacy. The GOLMePsA study aims to test the hypothesis that rapid control of disease activity by aggressive abrogation of inflammation with bDMARDs (GOL) in early diagnosed PsA will lead to better outcomes at 24 weeks when compared to sDMARD. Observing both arms up to 52 weeks will allow us to investigate whether the anticipated benefit of early use of bDMARDs leads to sustained response while on MTX monotherapy and better disease control at the end of the observational period. In addition, rapid optimization of disease management is expected to lead to significant improvements in QoL of affected individuals. A recent post-hoc analysis of the PRESTA trial provided some evidence on the superior efficacy of early bDMARD use in PsA by showing that subjects treated within 2 years of clinical onset had greater improvements in disease activity outcomes and PROs  than those with a longer disease duration. Data from an observational Swedish cohort  have highlighted the link between shorter symptom duration at presentation and a favourable outcome at 5 year follow-up. The GOLMePsA study was conceived in parallel to the running of the TICOPA trial in our institution and before any results from the latter were available. Recent evidence published since from the TICOPA trial  supports the notion that early and intensive treatment ameliorates disease activity effectively. These findings support our initial hypothesis that shortening the time from symptom onset to diagnosis, coupled with an aggressive therapeutic approach, should provide a window of opportunity for optimal management of PsA. The GOLMePsA trial will compare two different treatment combination strategies for PsA (single corticosteroid injection plus MTX plus bDMARD versus single corticosteroid injection plus MTX). This translates into both treatment arms receiving active medication (MTX and corticosteroids). These interventions will allows us to gather more data concerning the efficacy of early intensive treatment strategies in PsA and to characterize the role of bDMARD therapy early in the course of the disease. This study design will also provide important insights concerning the efficacy and safety of a “step down” strategy with bDMARDs followed by MTX maintenance in contrast to a more cautionary “step up” approach (bDMARDs following sDMARDs failure or intolerance). The effect of adding sDMARDs to MTX in early PsA patients stepping down from bDMARDs will also be explored.
Further, the GOLMePsA trial is collecting data from several clinical manifestations of PsA (articular and cutaneous involvement, entheses, dactylitis and nail disease). The choice of PASDAS as primary outcome will contribute to explore issues of multidimensionality in a heterogeneous condition like PsA. From the regulatory/ethic point of view, however, PsARC was chosen to manage efficacy decisions at weeks 8–12 as a reflection of current treatment guidelines in the UK.
Further, more evidence will become available on the efficacy of high-dose MTX as initial agent in the treatment of the early phases of PsA. Previous studies exploring this issue have reported promising results [16, 56], although they could have potentially underestimated the presence of a dose effect. One of the main findings from the TICOPA trial was the apparently higher number of side effects reported on the tight control arm. The main difference between the GOLMePsA study and the TICOPA trial is the earlier exposure to bDMARDs as part of an aggressive combination strategy also incorporating methotrexate and steroids. This could lead to higher toxicity than the conventional treatment arm, although our experience, with nearly 25% of the GOLMePsA subjects recruited, has not raised such concerns so far.
Finally, GOLMePsA uses an imaging package comprising WB-MRI and US to assess the overall burden of inflammation in early PsA. This will allow for the characterization of bulk of subclinical disease as a possible biomarker of treatment response and prognosis at 24 and 36 weeks.
The first patient was enrolled in GOLMePsA in November 2015 with recruitment planned to end in April 2018. There are an estimated 4–6 eligible subject per month seen in our Early Arthritis and Spondyloarthritis clinics, yielding a possible 48 eligible patients per year. Since opening, the trial has undergone minor protocol amendments (current version 4.0). All these are reflected in the present paper.
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Participant Identification Centres (PICs) within the Yorkshire Region:
• Bradford Teaching Hospitals NHS Foundation Trust;
• Airedale NHS Foundation Trust;
• The Mid Yorkshire Hospitals NHS Trust (Clayton, Dewsbury and District, Pinderfields, and Pontefract);
• Harrogate and District NHS Foundation Trust;
• Calderdale and Huddersfield NHS Foundation Trust (Calderdale Royal Hospital and Huddersfield Royal Infirmary).
The GOLMePsA study is funded by Janssen. The study sponsor is the Leeds Teaching Hospitals NHS Trust, UK.
Availability of data and materials
Ethics approval and consent to participate
Ethical and governance approval for the GOLMePsA study was obtained from the Research Ethics Committee of the Leeds Teaching Hospitals NHS Trust (14/EM/0124). All participants provide informed, written consent to take part in the study. The progress of the trial is monitored by an independent Trial Steering Committee (TSC).
Consent for publication
HMO has received honoraria, consultancy fees and/or grant funding from Abbvie, Celgene, Janssen, MSD, Novartis, Pfizer and UCB.
PH, DMG and PE have received honoraria, consultancy fees and/or grant funding from Abbvie, Bristol-Myers-Squibb, MSD, Lilly, Novartis, Pfizer, Roche-Chugai and UCB.
LCC has received honoraria, consultancy fees and/or grant funding from Abbvie, Bristol-Myers-Squibb, Celgene, Janssen, MSD, Lilly, Novartis, Pfizer, and UCB.
GDM and EMAH have no disclosures.
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De Marco, G., Helliwell, P., McGonagle, D. et al. The GOLMePsA study protocol: an investigator-initiated, double-blind, parallel-group, randomised, controlled trial of GOLimumab and methotrexate versus methotrexate in early diagnosed psoriatic arthritis using clinical and whole body MRI outcomes. BMC Musculoskelet Disord 18, 303 (2017) doi:10.1186/s12891-017-1659-1
- Psoriatic arthritis
- Early diagnosis
- Minimal disease activity