Stand UP to Rheumatoid Arthritis (SUPRA)

Study Overview
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Brief Summary
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Rheumatoid arthritis is a disabling arthritis that affects young women disproportionately. Although the physicians have some excellent treatments, they do not know which treatment is best for which patient. The investigators want to find ways to identify the right drug for the right patient at the right time. This is what personalized medicine is all about.

Detailed Description
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Rheumatoid arthritis (RA) is a complex, chronic disease of the immune system characterized by disfiguring and disabling arthritis. It affects predominantly women (3:1 ratio with men) and has its peak onset during their most productive years (ages 30-50). RA is associated with serious morbidity (including impaired fertility and pregnancy outcomes, disability, and depression) and premature mortality (particularly from cardiovascular and infectious causes). The Arthritis Alliance of Canada estimates that the cost of RA will exceed $30 billion in Canada in 2040. First-line treatment of RA consists of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) with methotrexate considered as the gold standard. Yet, only 30% of patients will achieve adequate response to methotrexate and the majority will need additional treatment. The development of new biologic and targeted synthetic DMARDs (b/tsDMARDs) in the 20th century has transformed the treatment of RA. Anti-tumour necrosis factor (TNF)-α molecules were the first clinically successful biologic therapies for RA. Drugs targeting other signaling pathways (JAK-STAT, which work downstream of interferons), inflammatory cytokines (IL-6), as well as B cells and T cells have now also become available. Molecules with novel targets (eg. GM-CSF, CD40L) are in clinical trials. Although hailed as 'game-changers' in patient care, the inconvenient truth is that even though nine different b/tsDMARDs are currently available to treat RA, 30% of patients will fail any particular drug. Moreover, physicians have no reliable way of predicting response and guiding treatment decisions. Clinical and genetic predictors have been the subject of intense research but these factors explain only a small portion of the observed variance in treatment response. Using the current trial-and-error approach, patients can cycle through multiple drugs before finally attaining disease control. This means months or years of suboptimal disease control and considerable losses in many domains including physical and emotional well-being, family and social networks, and occupational attainment. The lack of a personalized approach is particularly detrimental in RA because there is a narrow ''window of opportunity'' in the first 3-6 months of onset to control disease and optimize long term outcomes. In addition, failure to personalize treatment may also result in wasted spending on ineffective drugs, that cost up to $20,000 per patient per year, and exposing patients to unnecessary risks of adverse events, in particular serious infections. There is a critical need to 1) transform the current 'trial-and-error' treatment paradigm, 2) explore novel predictors of b/tsDMARD response in RA and, 3) harness the power of advanced analytical strategies to personalize treatment decision-making and optimize outcomes in RA. The investigators propose a multi-pronged solution that combines innovative trial designs, multi-omics and advanced computational prediction to transform clinical care in RA. The investigators propose to develop a new model of care and investigate new avenues, including sex and gender, diet, gut bacteria and environmental exposures, to make treatment decisions. The investigators will also use new methods of analyzing complex information. The highly talented research team has what is needed to transform the care of people living with RA. In preparation for a full-scale study, the investigators propose this feasibility study.

Official Title
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Innovative Trial Designs, Multi-omics and Advanced Computational Prediction to Transform Clinical Care in RA

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: TNFi
* Drug: Anti-IL6
* Drug: JAKi


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years; Arthritis that fulfills the 2010 ACR/EULAR classification criteria for RA; Failure to standard conventional synthetic DMARDs and eligible for second-line b/tsDMARDs (Sub-study 1) or failure to at least one TNF inhibitor and eligible for third-line b/tsDMARDs (Sub-study 2). Exclusion Criteria: Prior b/tsDMARDs for Sub-study 1 or prior b/tsDMARDs other than TNF inhibitors for Sub-study 2; Contraindication to b/tsDMARD therapy, such as active infection or untreated latent TB, current malignancy, severe organ dysfunction, history of VTE (unless anticoagulated), high risk of cardiovascular disease, pregnancy/lactation; Overlap with another inflammatory disease requiring specific immunosuppressive therapy, such as lupus nephritis; Unable to provide consent or complete forms (alone or with assistance) in English or French

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two separate sub-studies will be conducted: Sub-study 1: Subjects who have failed conventional DMARDS will be randomised to receive therapy with TNFi or anti-IL6 using covariate adaptive randomization. Sub-study 2: Subjects who have failed TNFi will be randomised to receive therapy with anti-IL6 or JAKi using covariate adaptive randomization.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sub-study 1 TNFi<br>TNFi - any sub-cutaneous (sc) formulation, namely etanercept (receptor fusion protein), adalimumab (monoclonal antibody), golimumab (monoclonal antibody), or certolizumab (pegylated fragment of a monoclonal antibody) | Drug: TNFi<br>* TNFi - any sub-cutaneous (sc) formulation, namely etanercept (receptor fusion protein) 50 mg sc per week, adalimumab (monoclonal antibody) 40 mg sc every 2 weeks, golimumab (monoclonal antibody) 50 mg sc every month, or certolizumab (pegylated fragment of a monoclonal antibody) 400 mg sc at week 0, 2 and 4, and then 200 mg sc every 2 weeks or 400 mg sc every 4 weeks.<br>* Other names: Certolizumab;|
| Active Comparator: Sub-study 1 Anti-IL6<br>Anti-IL6 receptor monoclonal antibodies - tocilizumab or sarilumab | Drug: Anti-IL6<br>* Anti-IL6 receptor monoclonal antibodies - tocilizumab (if weight <100 kg: 162 mg SC every other week, followed by an increase to weekly based on clinical response; if weight ≥100 kg: 162 mg SC weekly) or sarilumab (200 mg SC once every 2 weeks)<br>* Other names: Sarilumab;|
| Active Comparator: Sub-study 2 Anti-IL6<br>Anti-IL6 receptor monoclonal antibodies - tocilizumab or sarilumab | Drug: Anti-IL6<br>* Anti-IL6 receptor monoclonal antibodies - tocilizumab (if weight <100 kg: 162 mg SC every other week, followed by an increase to weekly based on clinical response; if weight ≥100 kg: 162 mg SC weekly) or sarilumab (200 mg SC once every 2 weeks)<br>* Other names: Sarilumab;|
| Active Comparator: Sub-study 2 JAKi<br>JAKi - tofacitinib (JAK1/3 inhibitor), baricitinib (JAK 1/2 inhibitor) or upadacitinib (JAK1 inhibitor) | Drug: JAKi<br>* JAKi - tofacitinib (JAK1/3 inhibitor) 5 mg po bid, baricitinib 2 mg po qd (JAK 1/2 inhibitor) or upadacitinib 15 mg po qd (JAK1 inhibitor)<br>* Other names: Baricitinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of recruitment at two RA referral centers over 12 months | Feasibility outcome | 12 months | 
| Prompt access to drugs | Feasibility outcome | 4 weeks | 
| Proportion of participants adhering to the allocated treatment | Feasibility outcome | 24 months | 
| Proportion of eligible patients who are invited to participate by their physician | Physician acceptability outcome | 12 months | 
| Proportion of eligible patients who accept to participate | Patient acceptability outcome | 12 months | 
| Proportion of patients reaching SDAI <= 3.3 | Exploratory outcome | 24 months | 
| Proportion of patients reaching DAS28 LDA state | Exploratory outcome | 24 months | 
| Patient-reported outcomes (function, health-related quality of life, fatigue) | Exploratory outcome | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rheumatoid arthritis, Pragmatic trials, Feasibility