Assessing Withdrawal of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis (ARCTIC REWIND)

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

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.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: TNF inhibitors; Drug: Co-medication: Synthetic DMARDs; Drug: Synthetic DMARD(s)

• Study Type: Interventional
• Enrollment (Actual): 320
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Department of Rheumatology, Haukeland University Hospital, Helse Bergen HF
  • Drammen, Norway, 3004
    • Department of Rheumatology, Drammen Hospital, Vestre Viken HF
  • Fredrikstad, Norway, 1603
    • Department of Rheumatology, Sykehuset Østfold HF
  • Kristiansand, Norway, 4604
    • Department of Rheumatology, Sørlandet Sykehus HF
  • Lillehammer, Norway, 2609
    • Revmatismesykehuset AS
  • Mo i Rana, Norway, 8613
    • Helgelandssykehuset, Mo i Rana
  • Oslo, Norway, 0319
    • Department of Rheumatology, Diakonhjemmet Hospital
  • Sandvika, Norway, 1306
    • Martina Hansens Hospital AS
  • Tromsø, Norway, 9038
    • Universitetssykehuset Nord-Norge HF
  • Ålesund, Norway, 6026
    • Department of Rheumatology, Helse Møre og Romsdal HF

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Stable dose TNF inhibitor; Stable dose TNF inhibitor. Any co-medication with synthetic DMARDs kept stable.	Drug: TNF inhibitors; Drug: Co-medication: Synthetic DMARDs; Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.
Experimental: Stepdown and withdrawal of TNF inhibitor; 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; Drug: Co-medication: Synthetic DMARDs; Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.
Active Comparator: Stable dose synthetic DMARD; Stable dose of synthetic DMARDs, either monotherapy or combination therapy.	Drug: Synthetic DMARD(s)
Experimental: Synthetic DMARD dose reduction; 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)
Other: ARCTIC follow-up; Patients are treated according to the ARCTIC treatment schedule based on disease activity.	Drug: TNF inhibitors; Drug: Co-medication: Synthetic DMARDs; Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.; Drug: Synthetic DMARD(s)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Diakonhjemmet Hospital
• Collaborators: The Research Council of Norway; South-Eastern Norway Regional Health Authority
• Investigators: Principal Investigator: Espen A. Haavardsholm, MD PhD, Diakonhjemmet Hospital; Study Director: Tore K Kvien, MD PhD, Diakonhjemmet Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2013
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): January 1, 2022

Study Registration Dates

• First Submitted: June 17, 2013
• First Submitted That Met QC Criteria: June 17, 2013
• First Posted (Estimate): June 19, 2013

Study Record Updates

• Last Update Posted (Actual): April 26, 2022
• Last Update Submitted That Met QC Criteria: April 24, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Anti-Inflammatory Agents; Tumor Necrosis Factor Inhibitors; Antirheumatic Agents
• Other Study ID Numbers: DIA2012-1/ver4_1; 2012-005275-14 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The authors commit to making the relevant anonymized patient level data available on reasonable request.
• IPD Sharing Time Frame: Data will be available within 12 months of study completion.
• IPD Sharing Access Criteria: Data access requests will be reviewed by the study steering committee, and requestors will be required to sign a data access agreement.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)