Screening for Flare After b/tsDMARD Discontinuation in Rheumatoid Arthritis

Study Overview
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Brief Summary
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To evaluate whether stringent follow-up consisting of combined laboratory and ultrasound surveillance is superior to clinical monitoring alone to maintain clinical remission in rheumatoid arthritis.

Detailed Description
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Randomized, controlled, parallel-group, multi-centre study in which patients with rheumatoid arthritis treated with biological/targeted synthetic disease modifying antirheumatic drug (b/tsDMARD) in mono- or combination therapy with conventional synthetic disease modifying antirheumatic drug (csDMARD) in a stable dosage and interval for ≥6 months with low disease activity or remission will receive an power Doppler musculoskeletal ultrasound examination (PDUS) and monitoring of C-reactive protein (CRP) levels at baseline and several timepoints within a 24 month study period (primary endpoint) and within a 48 month long-term extension. At baseline, b/tsDMARD medication will be withdrawn in all patients, who will be randomized in a 1:1 ratio in an Assisted monitoring (arm A) or a Clinical monitoring (arm B) arm respectively. Further stratification for remission vs. low disease activity and mono- vs combination therapy will be implemented in the randomisation process. In arm A, CRP and PDUS information will be made available to the clinical assessors who, at each time-point will use this information along with that from clinical examination, to identify patients experiencing recurrence of inflammation which will then be counted as subclinical flare according to predefined criteria. In arm B the results of CRP and PDUS will be recorded but will not be made available to the clinical assessor who will have to identify clinical flares according to predefined criteria based on information from the clinical examination only.

Official Title
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Screening for Flare After Discontinuation of Biological/Targeted Synthetic Disease Modifying Anti-rheumatic Drug (b/tsDMARD) in Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Other: Discontinuation of biological/targeted synthetic disease modifying anti-rheumatic drug (b/tsDMARD)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism classification criteria biological disease-modifying anti-rheumatic drug (bDMARD) or targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD) treatment in monotherapy or in combination therapy with conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) in a stable dosage and interval for ≥6 months. Previous extension of bDMARD or tsDMARD interval will also be accepted. bDMARDs and tsDMARDs will include all currently available originator and biosimilar compounds, with the exception of rituximab and its biosimilar compounds No swollen joint by 28-joint count at baseline, and screening C-reactive protein of ≤0.5mg/dL at baseline AND history of C-reactive protein >0,5mg/dl related to rheumatoid arthritis activity Clinical disease activity index ≤10 Shared decision between patient and physician to attempt b/tsDMARD withdrawal Willing and able to understand and follow the study procedures Written informed consent Female and male subjects aged ≥ 18 years Exclusion Criteria: History of or current extra-articular manifestation of rheumatoid arthritis, with exception of rheumatoid nodules Systemic glucocorticoid treatment in the past 3 months Intraarticular injection with glucocorticoids in the past 1 month Joint replacement surgery other than total knee or hip arthroplasty or complete joint destruction Power Doppler signal ≥2 in any assessed joint and/or tendon at screening or baseline

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: At baseline, patients will be randomised in a 1:1 ratio in an Assisted monitoring (arm A) or a Clinical monitoring (arm B) arm respectively.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Assisted monitoring<br>In the Assisted monitoring arm, C-reactive protein and musculoskeletal ultrasound information will be made available to the clinical assessors who, at each time-point will use this information, along with information from the clinical examination, to identify patients experiencing recurrence of inflammation which will then be counted as subclinical flare according to predefined criteria. | Other: Discontinuation of biological/targeted synthetic disease modifying anti-rheumatic drug (b/tsDMARD)<br>* The biological/targeted synthetic disease modifying anti-rheumatic drug will be discontinued in both arms at baseline<br>* Other names: b/tsDMARD: Adalimumab, Infliximab, Golimumab, Certolizumab pegol, Tocilizumab, Sarilumab, Etanercept, Anakinra, Filgotinib, Updacitinib, Tofacitinib, Baricitinib;|
| Other: Clinical monitoring<br>In the Clinical monitoring arm, the results of C-reactive protein and musculoskeletal ultrasound information will be recorded but will not be made available to the clinical assessor who at each time-point will make the decision on whether the patient is experiencing or has experienced a clinical flare according to predefined criteria based on information from the clinical examination. | Other: Discontinuation of biological/targeted synthetic disease modifying anti-rheumatic drug (b/tsDMARD)<br>* The biological/targeted synthetic disease modifying anti-rheumatic drug will be discontinued in both arms at baseline<br>* Other names: b/tsDMARD: Adalimumab, Infliximab, Golimumab, Certolizumab pegol, Tocilizumab, Sarilumab, Etanercept, Anakinra, Filgotinib, Updacitinib, Tofacitinib, Baricitinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects without a clinical flare until week 24 | Proportion of subjects without a clinical flare | week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects without a clinical flare | Proportion of subjects without a clinical flare | week 48 | 
| Time to clinical flare (days) | Time to clinical flare (days) | study period | 
| 28 swollen joint count | 28 swollen joint count, scale 0 (best) - 28 (worse) | week 24 | 
| 28 tender joint count | 28 tender joint count, scale 0 (best) - 28 (worse) | week 24 | 
| Proportion of subjects with a clinical flare in the assisted monitoring arm vs. clinical monitoring arm, the latter stratified according to b/tsDMARD reinitiation | Proportion of subjects with a clinical flare in the assisted monitoring arm vs. clinical monitoring arm, the latter stratified according to b/tsDMARD reinitiation | week 24 | 
| Proportion of patients in low disease activity or remission based on simplified disease activity index | Proportion of patients in low disease activity or remission based on simplified disease activity index | week 24 | 
| Proportion of patients in low disease activity or remission based on simplified disease activity index | Proportion of patients in low disease activity or remission based on simplified disease activity index | week 48 | 
| Patient's global assessment | Patient's global assessment, scale 0 (best) - 100 (worst) | week 24 | 
| Evaluator's global assessment | Evaluator's global assessment, scale 0 (best) - 100 (worst) | week 24 | 
| C-reactive protein | C-reactive protein, scale 0 (best) - infinite (worst) | week 24 | 
| Radiographic progression | change in Sharp Van der Heijde score, scale 0 (best) - 488 (worse) | at week 48 weeks from baseline | 
| Health Assessment Questionnaire Disability Index | Health Assessment Questionnaire Disability Index, scale 0 (best) - 3.0 (worse) | week 24 | 
| World Health Organization Quality of Life Questionnaire | World Health Organization Quality of Life Questionnaire, scale 0 (worse) - 100 (best) | week 24 | 
| Morning stiffness | Morning joint stiffness, (minutes), scale 0 (best) - infinite (worst) | week 24 | 
| Fatigue | Fatigue, visual analogue scale, scale 0 (worse) - 100 (best) | week 24 |