Assessing Withdrawal of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Study Overview
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Brief Summary
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The purpose of this study is to assess the effect of disease-modifying anti-rheumatic drugs (DMARDs) dose reduction in patients with rheumatoid arthritis (RA). Remission is the treatment target in RA, but knowledge about the best way to treat RA patients who achieve sustained remission is limited. DMARDs have potential serious adverse events, and biologic DMARDs are costly to the society. The objectives for ARCTIC REWIND are to assess the effect of tapering and withdrawal of DMARDs on disease activity in RA patients in sustained remission, to study predictors for successful tapering and withdrawal of DMARDs in this patient group, and to study cost-effectiveness of different treatment options in RA remission. ARCTIC REWIND is a randomized, open, controlled, parallel-group, multicenter, phase IV, non-inferiority strategy study. Patients with less than five years of disease duration and stable remission for at least 12 months are randomized to either continued stable treatment or tapering and withdrawal of DMARDs, including tumor necrosis factor (TNF) inhibitors and synthetic DMARDs. Patients are assessed by clinical examination, patient reported outcome measures, ultrasonography, MRI and X-ray, and monitored for adverse events. The primary endpoint of the study is the proportion of patients who are non-failures (have not experienced a flare) at 12 months. Secondary endpoints include composite disease activity scores and remission criteria, joint damage and inflammation assessed by various imaging modalities, work participation, health care resource use and health related quality of life.

Official Title
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REmission in Rheumatoid Arthritis - Assessing WIthrawal of Disease-modifying Antirheumatic Drugs in a Non-inferiority Design

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: TNF inhibitors
* Drug: Synthetic DMARD(s)
* Drug: Co-medication: Synthetic DMARDs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Rheumatoid arthritis according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria Male or non-pregnant, non-nursing female >18 years of age and <80 years of age Patient in the TNF-inhibitor group: Any disease duration. Patient in the synthetic DMARD group: RA diagnosis after 01.01.2010. Sustained remission for ≥12 months according to DAS or Disease Activity Score based on 28 joints (DAS28), with documented remission status at a minimum of 2 consecutive visits during the last 18 months OR participation in the first ARCTIC trial DAS <1.6 and no swollen joints at inclusion OR participation in the first ARCTIC trial Unchanged treatment with TNF inhibitors and/or synthetic DMARDs during the previous 12 months, with a stable or reduced dose of glucocorticosteroids OR participation in the first ARCTIC trial Subject capable of understanding and signing an informed consent form Provision of written informed consent Exclusion Criteria: Abnormal renal function, defined as serum creatinine >142 μmol/L in female and >168 μmol/L in male, or a glomerular filtration rate (GFR) <40 mL/min/1.73 m2 Abnormal liver function (defined as aspartate transaminase (ASAT)/alanine aminotransferase (ALAT) >3x upper normal limit), active or recent hepatitis, cirrhosis Major co-morbidities, such as severe malignancies, severe diabetic mellitus, severe infections, uncontrollable hypertension, severe cardiovascular disease (NYHA class 3 or 4) and/or severe respiratory diseases Leukopenia and/or thrombocytopenia Inadequate birth control, pregnancy, and/or breastfeeding Indications of active tuberculosis Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers or other factors which makes adherence to the study protocol impossible.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stable dose TNF inhibitor<br>Stable dose TNF inhibitor. Any co-medication with synthetic DMARDs kept stable. | Drug: TNF inhibitors<br> <br> Drug: Co-medication: Synthetic DMARDs<br>* Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.<br>|
| Experimental: Stepdown and withdrawal of TNF inhibitor<br>Half-dose of TNF inhibitor for the first four months, thereafter withdrawal of TNF inhibitor. Any co-medication with synthetic DMARDs kept stable. | Drug: TNF inhibitors<br> <br> Drug: Co-medication: Synthetic DMARDs<br>* Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.<br>|
| Active Comparator: Stable dose synthetic DMARD<br>Stable dose of synthetic DMARDs, either monotherapy or combination therapy. | Drug: Synthetic DMARD(s)<br> <br> |
| Experimental: Synthetic DMARD dose reduction<br>Half-dose synthetic DMARDs (monotherapy or combination therapy) for the first 12 months of the study. Patients classified as non-failures are re-randomized at 12 months to either continue half-dose synthetic DMARD(s) or withdraw all DMARD(s). | Drug: Synthetic DMARD(s)<br> <br> |
| Other: ARCTIC follow-up<br>Patients are treated according to the ARCTIC treatment schedule based on disease activity. | Drug: TNF inhibitors<br> <br> Drug: Synthetic DMARD(s)<br> <br> Drug: Co-medication: Synthetic DMARDs<br>* Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients who are non-failures (have not experienced a flare) | Flare is defined as composite measure: (1) An increase in disease activity score (DAS) to >1.6 AND (2) a change in DAS of at least 0.6 AND (3) > 1 swollen joint. If a patient does not fulfill this formal definition, but experiences a clinically significant flare according to the investigator and patient, this is treated as a flare. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Activity Score (DAS) | The DAS is a composite score that includes the Ritchie articular index (RAI), the 44- swollen joint counts (SJC-44), the Erythrocyte Sedimentation Rate (ESR) and a general health (GH) assessment on a Visual Analogue Scale (VAS). The DAS is calculated as follows: DAS = 0.54*sqrt(RAI) + 0.065*(SJC-44) + 0.33*Ln(ESR) + 0.0072*GH | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Disease Activity Score in 28 joints (DAS28) | The 28-joint Disease Activity Score (DAS28) includes the 28- tender joint counts (TJC28), 28-swollen joint counts (SJC28), Erythrocyte Sedimentation Rate (ESR) and Patient Global Assessment (PGA) on a VAS. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Simplified Disease Activity Index (SDAI) | SDAI includes TCJ28, SJC28, PGA, physician's global assessment of disease activity on a VAS 0-100 mm (PhGA) and C-reactive protein (CRP). | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Clinical Disease Activity Index (CDAI) | CDAI includes TCJ28, SJC28, PGA and PhGA. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Swollen joint count | Swollen joint counts are performed on 44 joints, with total joint count ranging from 0 to 44. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Tender joint count | Tender joints is assessed by Ritchie Articular Index which assesses tenderness of 26 joint regions, based on summation of joint responses after applying firm digital pressure. The index ranges from 0 to 3 for individual measures and the sum 0 to 78 overall. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Erythrocyte Sedimentation Rate (ESR) | Assessment of ESR in mm/h | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| C-reactive protein (CRP) | Assessment of CRP in mg/L | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Patient's assessment of disease activity (PGA) | PGA is the patient's assessment of disease activity on a VAS 0-100 mm. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Physician's global assessment of disease avtivity (PHGA) | PHGA is the investigator's assessment of disease activity on a VAS 0-100 mm. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Health Assessment Questionnaire (HAQ-PROMIS) | The HAQ-PROMIS is a questionnaire evaluating the physical function in patients with RA. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| EuroQol-5 Dimension (EQ-5D) | EQ-5D is a standardised instrument for use as a measure of health outcome. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Medical Outcomes Study Short-Form 36-item (SF-36) Physical and Mental Component Summary Score | The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based physical and mental health summary measures and a preference-based health utility index. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Work performance | Absenteeism (work time missed) Presenteeism (impairment at work / reduced on-the-job effectiveness) Work productivity loss (overall work impairment / absenteeism plus presenteeism) Activity Impairment | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Radiographic joint damage | Radiographs of hands (posterior/anterior) and foot (anterior/posterior) will be taken at baseline, 12, 24 and 36 months. The modified Sharp van der Heijde Score (vdHSS) will be calculated, including an erosion score and a joint space narrowing score. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Ultrasonography (subclinical synovitis) | 36 joints and 2 tendons will be scored for both grey scale and power doppler synovitis on a 0-3 scale. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| DAS-remission | Remission is defined as a DAS-score <1.6 | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| DAS28-remission | Remission is defined as a DAS28 score < 2.6 | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| SDAI-remission | Remission is defined as a SDAI score ≤ 3.3 | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| CDAI-remission | Remission is defined as a CDAI score ≤ 2.8 | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| ACR/EULAR Boolean remission | The patient must satisfy all of the following in order to achieve ACR/EULAR remission: RAI ≤ 1 SJC44 ≤ 1 CRP ≤ 1 PGA ≤ 1 (on a scale 0-10, in this study ≤ 14 on a scale 0-100) | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| No swollen joint | The percentage of patients with no swollen joints will be assessed | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Radiographic outcome | No radiographic progression | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Ultrasound outcome | No ultrasound power Doppler signal in any joint. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| American College of Rheumatology (ACR) response | If a patient has experienced a flare, and treatment has been escalated, the ACR 2050/70/90 response will be calculated. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| The European League Against Rheumatism (EULAR) response | If a patient has experienced a flare, and treatment has been escalated, the EULAR response will be calculated. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| The Food and Drug Administration (FDA) major clinical response | If a patient has experienced a flare, and treatment has been escalated, the FDA major clinical response will be calculated. | 12 months, with subsequent long-term analyses after 24 months and 36 months | 
| Medication | The number of patients on different conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologic therapy. Dose of DMARDs in users will be recorded, prednisolone usages and number of intraarticular injections. | 12 months, with subsequent long-term analyses after 24 months and 36 months |