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| ID | Type | Description | Link |
|---|---|---|---|
| 2012-005275-14 | EudraCT Number |
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| Name | Class |
|---|---|
| The Research Council of Norway | OTHER |
| South-Eastern Norway Regional Health Authority | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Stable dose TNF inhibitor | Active Comparator | Stable dose TNF inhibitor. Any co-medication with synthetic DMARDs kept stable. |
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| Stepdown and withdrawal of TNF inhibitor | Experimental | Half-dose of TNF inhibitor for the first four months, thereafter withdrawal of TNF inhibitor. Any co-medication with synthetic DMARDs kept stable. |
|
| Stable dose synthetic DMARD | Active Comparator | Stable dose of synthetic DMARDs, either monotherapy or combination therapy. |
|
| Synthetic DMARD dose reduction | Experimental | 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). |
|
| ARCTIC follow-up | Other | Patients are treated according to the ARCTIC treatment schedule based on disease activity. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TNF inhibitors | Drug |
| ||
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Espen A. Haavardsholm, MD PhD | Diakonhjemmet Hospital | Principal Investigator |
| Tore K Kvien, MD PhD | Diakonhjemmet Hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Rheumatology, Helse Møre og Romsdal HF | Ålesund | 6026 | Norway | |||
| Department of Rheumatology, Haukeland University Hospital, Helse Bergen HF |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38583450 | Derived | Kjorholt KE, Sundlisaeter NP, Aga AB, Sexton J, Olsen IC, Fremstad H, Spada C, Madland TM, Hoili CA, Bakland G, Lexberg A, Hansen IJW, Hansen IM, Haukeland H, Ljosa MA, Moholt E, Uhlig T, Kvien TK, Solomon DH, van der Heijde D, Haavardsholm EA, Lillegraven S. Effects of tapering conventional synthetic disease-modifying antirheumatic drugs to drug-free remission versus stable treatment in rheumatoid arthritis (ARCTIC REWIND): 3-year results from an open-label, randomised controlled, non-inferiority trial. Lancet Rheumatol. 2024 May;6(5):e268-e278. doi: 10.1016/S2665-9913(24)00021-3. Epub 2024 Apr 4. | |
| 38216290 |
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The authors commit to making the relevant anonymized patient level data available on reasonable request.
Data will be available within 12 months of study completion.
Data access requests will be reviewed by the study steering committee, and requestors will be required to sign a data access agreement.
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| ID | Term |
|---|---|
| D001172 | Arthritis, Rheumatoid |
| ID | Term |
|---|---|
| D001168 | Arthritis |
| D007592 | Joint Diseases |
| D009140 | Musculoskeletal Diseases |
| D012216 | Rheumatic Diseases |
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| ID | Term |
|---|---|
| D000079424 | Tumor Necrosis Factor Inhibitors |
| ID | Term |
|---|---|
| D000893 | Anti-Inflammatory Agents |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |
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|
| Synthetic DMARD(s) |
| Drug |
|
| Co-medication: Synthetic DMARDs | Drug | Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate. |
|
| 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 |
| 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:
| 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 |
| Bergen |
| 5021 |
| Norway |
| Department of Rheumatology, Drammen Hospital, Vestre Viken HF | Drammen | 3004 | Norway |
| Department of Rheumatology, Sykehuset Østfold HF | Fredrikstad | 1603 | Norway |
| Department of Rheumatology, Sørlandet Sykehus HF | Kristiansand | 4604 | Norway |
| Revmatismesykehuset AS | Lillehammer | 2609 | Norway |
| Helgelandssykehuset, Mo i Rana | Mo i Rana | 8613 | Norway |
| Department of Rheumatology, Diakonhjemmet Hospital | Oslo | 0319 | Norway |
| Martina Hansens Hospital AS | Sandvika | 1306 | Norway |
| Universitetssykehuset Nord-Norge HF | Tromsø | 9038 | Norway |
| Derived |
| Holten K, Paulshus Sundlisaeter N, Sexton J, Nordberg LB, Uhlig T, Kvien TK, Solomon DH, Haavardsholm EA, Lillegraven S, Aga AB; ARCTIC REWIND study group. Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to flares in disease activity. RMD Open. 2024 Jan 12;10(1):e003486. doi: 10.1136/rmdopen-2023-003486. |
| 37607809 | Derived | Lillegraven S, Paulshus Sundlisaeter N, Aga AB, Sexton J, Olsen IC, Lexberg AS, Madland TM, Fremstad H, Hoili CA, Bakland G, Spada C, Haukeland H, Hansen IM, Moholt E, Uhlig T, Solomon DH, van der Heijde D, Kvien TK, Haavardsholm EA. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial. Ann Rheum Dis. 2023 Nov;82(11):1394-1403. doi: 10.1136/ard-2023-224476. Epub 2023 Aug 22. |
| 33944875 | Derived | Lillegraven S, Paulshus Sundlisaeter N, Aga AB, Sexton J, Olsen IC, Fremstad H, Spada C, Madland TM, Hoili CA, Bakland G, Lexberg A, Hansen IJW, Hansen IM, Haukeland H, Ljosa MA, Moholt E, Uhlig T, Solomon DH, van der Heijde D, Kvien TK, Haavardsholm EA. Effect of Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flares in Patients With Rheumatoid Arthritis in Remission: The ARCTIC REWIND Randomized Clinical Trial. JAMA. 2021 May 4;325(17):1755-1764. doi: 10.1001/jama.2021.4542. |
| D003240 |
| Connective Tissue Diseases |
| D017437 | Skin and Connective Tissue Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |