Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01881308
Recruitment Status : Active, not recruiting
First Posted : June 19, 2013
Last Update Posted : September 16, 2020
Sponsor:
Collaborators:
The Research Council of Norway
South-Eastern Norway Regional Health Authority
Information provided by (Responsible Party):
Espen A. Haavardsholm, MD PhD, Diakonhjemmet Hospital

Tracking Information
First Submitted Date  ICMJE June 17, 2013
First Posted Date  ICMJE June 19, 2013
Last Update Posted Date September 16, 2020
Actual Study Start Date  ICMJE June 17, 2013
Actual Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 19, 2013)
Proportion of patients who are non-failures (have not experienced a flare) [ Time Frame: 12 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 17, 2013)
Proportion of patients who are non-failures (have not experienced a flare) [ Time Frame: 12 months ]
Flare is defined as a combination of: (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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2019)
  • Disease Activity Score (DAS) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    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
  • Disease Activity Score in 28 joints (DAS28) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    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.
  • Simplified Disease Activity Index (SDAI) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    SDAI includes TCJ28, SJC28, PGA, physician's global assessment of disease activity on a VAS 0-100 mm (PhGA) and C-reactive protein (CRP).
  • Clinical Disease Activity Index (CDAI) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    CDAI includes TCJ28, SJC28, PGA and PhGA.
  • Swollen joint count [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    Swollen joint counts are performed on 44 joints, with total joint count ranging from 0 to 44.
  • Tender joint count [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    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.
  • Erythrocyte Sedimentation Rate (ESR) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    Assessment of ESR in mm/h
  • C-reactive protein (CRP) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    Assessment of CRP in mg/L
  • Patient's assessment of disease activity (PGA) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    PGA is the patient's assessment of disease activity on a VAS 0-100 mm.
  • Physician's global assessment of disease avtivity (PHGA) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    PHGA is the investigator's assessment of disease activity on a VAS 0-100 mm.
  • Health Assessment Questionnaire (HAQ-PROMIS) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    The HAQ-PROMIS is a questionnaire evaluating the physical function in patients with RA.
  • EuroQol-5 Dimension (EQ-5D) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    EQ-5D is a standardised instrument for use as a measure of health outcome.
  • Medical Outcomes Study Short-Form 36-item (SF-36) Physical and Mental Component Summary Score [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    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.
  • Work performance [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    1. Absenteeism (work time missed)
    2. Presenteeism (impairment at work / reduced on-the-job effectiveness)
    3. Work productivity loss (overall work impairment / absenteeism plus presenteeism)
    4. Activity Impairment
  • Radiographic joint damage [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    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.
  • Ultrasonography (subclinical synovitis) [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    36 joints and 2 tendons will be scored for both grey scale and power doppler synovitis on a 0-3 scale.
  • DAS-remission [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    Remission is defined as a DAS-score <1.6
  • DAS28-remission [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    Remission is defined as a DAS28 score < 2.6
  • SDAI-remission [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    Remission is defined as a SDAI score ≤ 3.3
  • CDAI-remission [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    Remission is defined as a CDAI score ≤ 2.8
  • ACR/EULAR Boolean remission [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    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)
  • No swollen joint [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    The percentage of patients with no swollen joints will be assessed
  • Radiographic outcome [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    No radiographic progression
  • Ultrasound outcome [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    No ultrasound power Doppler signal in any joint.
  • American College of Rheumatology (ACR) response [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    If a patient has experienced a flare, and treatment has been escalated, the ACR 2050/70/90 response will be calculated.
  • The European League Against Rheumatism (EULAR) response [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    If a patient has experienced a flare, and treatment has been escalated, the EULAR response will be calculated.
  • The Food and Drug Administration (FDA) major clinical response [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    If a patient has experienced a flare, and treatment has been escalated, the FDA major clinical response will be calculated.
  • Medication [ Time Frame: 12 months, with subsequent long-term analyses after 24 months and 36 months ]
    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.
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Assessing Withdrawal of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis
Official Title  ICMJE REmission in Rheumatoid Arthritis - Assessing WIthrawal of Disease-modifying Antirheumatic Drugs in a Non-inferiority Design
Brief Summary

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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Rheumatoid Arthritis
Intervention  ICMJE
  • Drug: TNF inhibitors
  • Drug: Synthetic DMARD(s)
  • Drug: Co-medication: Synthetic DMARDs
    Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.
Study Arms  ICMJE
  • Active Comparator: Stable dose TNF inhibitor
    Stable dose TNF inhibitor. Any co-medication with synthetic DMARDs kept stable.
    Interventions:
    • Drug: TNF inhibitors
    • Drug: Co-medication: Synthetic DMARDs
  • 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.
    Interventions:
    • Drug: TNF inhibitors
    • Drug: Co-medication: Synthetic DMARDs
  • Active Comparator: Stable dose synthetic DMARD
    Stable dose of synthetic DMARDs, either monotherapy or combination therapy.
    Intervention: 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).
    Intervention: Drug: Synthetic DMARD(s)
  • ARCTIC follow-up
    Patients are treated according to the ARCTIC treatment schedule based on disease activity.
    Interventions:
    • Drug: TNF inhibitors
    • Drug: Synthetic DMARD(s)
    • Drug: Co-medication: Synthetic DMARDs
Publications * Lillegraven S, Paulshus Sundlisæter N, Aga AB, Sexton J, Olsen IC, Fremstad H, Spada C, Madland TM, Høili CA, Bakland G, Lexberg Å, Hansen IJW, Hansen IM, Haukeland H, Ljoså 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 17, 2013)
360
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 2022
Actual Primary Completion Date January 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Norway
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01881308
Other Study ID Numbers  ICMJE DIA2012-1/ver4_1
2012-005275-14 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: The authors commit to making the relevant anonymized patient level data available on reasonable request.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: Data will be available within 12 months of study completion.
Access Criteria: Data access requests will be reviewed by the study steering committee, and requestors will be required to sign a data access agreement.
Responsible Party Espen A. Haavardsholm, MD PhD, Diakonhjemmet Hospital
Study Sponsor  ICMJE Diakonhjemmet Hospital
Collaborators  ICMJE
  • The Research Council of Norway
  • South-Eastern Norway Regional Health Authority
Investigators  ICMJE
Principal Investigator: Espen A. Haavardsholm, MD PhD Diakonhjemmet Hospital
Study Director: Tore K Kvien, MD PhD Diakonhjemmet Hospital
PRS Account Diakonhjemmet Hospital
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP