Aiming for Remission in Rheumatoid Arthritis (RA) - the ARCTIC Trial (ARCTIC)

Aiming for Remission in Rheumatoid Arthritis: a Randomized Trial Examining the Benefit of Ultrasonography in a Clinical TIght Control Regimen

The ultimate goal of treatment in early rheumatoid arthritis (RA) is remission, i.e. an absence of signs and symptoms of the disease. However, the optimal way of reaching this goal is not known.

Ultrasonography (US) is an imaging modality which application is rapidly growing. It has a number of advantages over other advanced imaging techniques such as magnetic resonance imaging (MRI), including low cost, good accessibility, and ability to scan many joints in a short period of time. However, the additional benefit of using this modality in terms of patient outcomes has not been demonstrated. Thus, clarification is needed if the use of US leads to better care for RA patients.

This study will assess if the use of a treatment strategy incorporating information from ultrasonography assessment will allow for better outcomes of patients with RA, than a strategy based on clinical and laboratory assessments alone.

Study Overview

• Status: Completed
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Device: Ultrasonography

• Study Type: Interventional
• Enrollment (Actual): 238
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Bergen, Norway, 5021
    • Helse Bergen HF, Haukeland University Hospital, Dept. of Rheumatology
  • Drammen, Norway, 3004
    • Vestre Viken HF, Dept. of Rheumatology
  • Haugesund, Norway, 5504
    • HAUGESUND SANITETSFORENING revmatismesykehus
  • Kristiansand, Norway, 4604
    • Sørlandet Sykehus HF, Dept. of Rheumatology
  • Kristiansand, Norway, 4611
    • Revmatologene bendvold/Dovland
  • Oslo, Norway, 0319
    • Diakonhjemmet Sykehus AS, Dept. of Rheumatology
  • Tromsø, Norway, 9038
    • Universitetssykehuset Nord-Norge HF, Dept. of Rheumatology
  • Trondheim, Norway, 7006
    • St Olavs Hospital HF, Dept. of Rheumatology
  • Ålesund, Norway, 6026
    • Helse Sunnmøre HF, Dept. of Rheumatology
  • Bærum
    • Sandvika, Bærum, Norway, 1306
      • Martina Hansens Hospital AS
  • Fredrikstad
    • Moss, Fredrikstad, Norway, 1603
      • Sykehuset Østfold HF, Dept. of Rheumatology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria (all):

• Male or non-pregnant, non-nursing female
• > 18 years of age and < 75 years of age
• Patients classified as having RA (according to new ACR/EULAR criteria)
• Disease duration less than 2 years (defined as time from 1st joint swelling)
• The treating rheumatologist decides the patient requires treatment with a Disease Modifying Anti-Rheumatic Drug (DMARD)
• The patient has taken no prior DMARD
• Patients able and willing to give written informed consent and comply with the requirements of the study protocol

Exclusion Criteria (any):

• Abnormal renal function (serum creatinine > 142 µmol/L in female and > 168 µmol/L in male)
• Abnormal liver function, active or recent hepatitis, cirrhosis
• Major co-morbidities like severe malignancies, severe diabetic mellitus, severe infections, uncontrollable hypertension, severe cardiovascular disease and/or severe respiratory diseases.
• Leukopenia and/or thrombocytopenia
• Inadequate birth control conception, pregnancy, and/or breastfeeding
• Indications of active tuberculosis
• Psychiatric or mental disorders, alcohol abuse or other abuse of substances, 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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Conventional clinical and laboratory assessment
Experimental: Conventional assessment plus ultrasonography	Device: Ultrasonography; Standardized ultrasonographic assessment of 32 joints, assessed for both grey scale synovitis and power doppler signal, at each visit. Dose escalations based on DAS response in combination with change in US score. All joints with US Power Doppler signal are targets for intra articular injections.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete clinical Disease Activity Score (DAS) remission	Specifically, the primary endpoint will be the proportion of patients with all the following criteria met at the end of the study (at 24 months): DAS score < 1.6 at visits 11, 12 and 13 (after 16, 20 and 24 months); Absence of swollen joints at visits 11, 12 and 13 (after 16, 20 and 24 months); No radiological progression between visit 11 (16 months) and visit 13 (24 months)	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Magnetic Resonance Imaging (MRI) of dominant hand	MRIs of dominant hand are scored according to the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) for synovitis, bone marrow edema and erosions, and Haavardsholm tenosynovitis score, as well as a novel joint space narrowing score will be applied.	24 months
American College of Rheumatology (ACR) response	Proportion of patients with ACR20, ACR50, ACR70 and ACR90 response.	24 months
Remission	Various definitions of remission will be calculated, including DAS-remission, ACR-remission, Simplified Diseases Activity Index (SDAI) remission and Clinical Disease Activity Index (CDAI) remission	24 months
European League Against Rheumatism (EULAR) response	EULAR good, moderate and non-response	24 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	24 months
Conventional radiography	Radiographs of hands (posterior/anterior) and foot (anterior/posterior) will be taken at baseline, 3, 6, 12, 16 and 24 months. The modified Sharp van der Heijde Score (vdHSS) will be calculated, including an erosion score and a joint space narrowing score.	24 months
The RA Impact of Disease (RAID) score	The RAID includes seven domains with the following relative weights: pain (21%), functional disability (16%), fatigue (15%), emotional well-being (12%), sleep (12%), coping (12%) and physical well-being (12%).	24 months
EuroQol-5 Dimension (EQ-5D)	EQ-5D is a standardised instrument for use as a measure of health outcome.	24 months
Health Assessment Questionnaire (HAQ-PROMIS)	The HAQ-PROMIS is a questionnaire evaluating the physical function in patients with RA.	24 months
Medical Outcomes Study Short-Form 36-item (SF-36)	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.	24 months
Dual Energy X-ray Absorptiometry (DEXA) of spine and hip	Bone density measurements (DEXA hip and spine, both Z- and T-scores as well as bone mineral density) will be performed at baseline and after 12 and 24 months.	24 months
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	24 months
Ultrasonography (synovitis)	36 joints and 2 tendons will be scored for both grey scale and power doppler synovitis on a 0-3 scale.	24 months
Magnetic Resonance Imaging (MRI) of dominant hand	MRIs of dominant hand are scored according to the Rheumatoid Arthritis Magnetic Resonance Imaging Score (RAMRIS) for synovitis, bone marrow edema and erosions, and Haavardsholm tenosynovitis score, as well as a novel joint space narrowing score will be applied.	12 months
American College of Rheumatology (ACR) response	Proportion of patients with ACR20, ACR50, ACR70 and ACR90 response.	12 months
European League Against Rheumatism (EULAR) response	EULAR good, moderate and non-response	12 months
Remission	Various definitions of remission will be calculated, including DAS-remission, ACR-remission, Simplified Diseases Activity Index (SDAI) remission and Clinical Disease Activity Index (CDAI) remission	12 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
Conventional radiography	Radiographs of hands (posterior/anterior) and foot (anterior/posterior) will be taken at baseline, 3, 6 and 12 months. The modified Sharp van der Heijde Score (vdHSS) will be calculated, including an erosion score and a joint space narrowing score.	12 months
The RA Impact of Disease (RAID) score	The RAID includes seven domains with the following relative weights: pain (21%), functional disability (16%), fatigue (15%), emotional well-being (12%), sleep (12%), coping (12%) and physical well-being (12%).	12 months
Health Assessment Questionnaire (HAQ-PROMIS)	The HAQ-PROMIS is a questionnaire evaluating the physical function in patients with RA.	12 months
Medical Outcomes Study Short-Form 36-item (SF-36)	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
Dual Energy X-ray Absorptiometry (DEXA) of spine and hip	Bone density measurements (DEXA hip and spine, both Z- and T-scores as well as bone mineral density) will be performed at baseline and after 12 and 24 months.	12 months
Ultrasonography (synovitis)	36 joints and 2 tendons will be scored for both grey scale and power doppler synovitis on a 0-3 scale.	12 months
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

Collaborators and Investigators

• Sponsor: Espen A. Haavardsholm
• Collaborators: Oslo University Hospital; Pfizer; Roche Pharma AG; The Research Council of Norway; The Norwegian Rheumatism Association; Abbott; Smerud Medical Research International AS; Innovest; UCB Nordic A/S; MSD Norway AS
• Investigators: Study Director: Tore K Kvien, MD, PhD, Diakonhjemmet Hospital AS

Publications and helpful links

General Publications

• Sundin U, Aga AB, Skare O, Nordberg LB, Uhlig T, Hammer HB, van der Heijde D, Kvien TK, Lillegraven S, Haavardsholm EA; ARCTIC study group. Conventional versus ultrasound treat to target: no difference in magnetic resonance imaging inflammation or joint damage over 2 years in early rheumatoid arthritis. Rheumatology (Oxford). 2020 Sep 1;59(9):2550-2555. doi: 10.1093/rheumatology/kez674.
• Paulshus Sundlisaeter N, Olsen IC, Aga AB, Hammer HB, Uhlig T, van der Heijde D, Kvien TK, Lillegraven S, Haavardsholm EA; ARCTIC study group. Predictors of sustained remission in patients with early rheumatoid arthritis treated according to an aggressive treat-to-target protocol. Rheumatology (Oxford). 2018 Nov 1;57(11):2022-2031. doi: 10.1093/rheumatology/key202.
• Jonsson MK, Hensvold AH, Hansson M, Aga AB, Sexton J, Mathsson-Alm L, Cornillet M, Serre G, Lillegraven S, Fevang BS, Catrina AI, Haavardsholm EA. The role of anti-citrullinated protein antibody reactivities in an inception cohort of patients with rheumatoid arthritis receiving treat-to-target therapy. Arthritis Res Ther. 2018 Jul 13;20(1):146. doi: 10.1186/s13075-018-1635-7.
• Paulshus Sundlisaeter N, Aga AB, Olsen IC, Hammer HB, Uhlig T, van der Heijde D, Kvien TK, Lillegraven S, Haavardsholm EA; ARCTIC study group. Clinical and ultrasound remission after 6 months of treat-to-target therapy in early rheumatoid arthritis: associations to future good radiographic and physical outcomes. Ann Rheum Dis. 2018 Oct;77(10):1421-1425. doi: 10.1136/annrheumdis-2017-212830. Epub 2018 Jun 22.
• Nordberg LB, Lillegraven S, Aga AB, Sexton J, Lie E, Hammer HB, Olsen IC, Uhlig T, van der Heijde D, Kvien TK, Haavardsholm EA. The Impact of Ultrasound on the Use and Efficacy of Intraarticular Glucocorticoid Injections in Early Rheumatoid Arthritis: Secondary Analyses From a Randomized Trial Examining the Benefit of Ultrasound in a Clinical Tight Control Regimen. Arthritis Rheumatol. 2018 Aug;70(8):1192-1199. doi: 10.1002/art.40494. Epub 2018 Jun 29.
• Jonsson MK, Sundlisaeter NP, Nordal HH, Hammer HB, Aga AB, Olsen IC, Brokstad KA, van der Heijde D, Kvien TK, Fevang BS, Lillegraven S, Haavardsholm EA. Calprotectin as a marker of inflammation in patients with early rheumatoid arthritis. Ann Rheum Dis. 2017 Dec;76(12):2031-2037. doi: 10.1136/annrheumdis-2017-211695. Epub 2017 Aug 16.
• Aga AB, Berner Hammer H, Christoffer Olsen I, Uhlig T, Kvien TK, van der Heijde D, Fremstad H, Madland TM, Lexberg AS, Haukeland H, Rodevand E, Hoili C, Stray H, Noraas AL, Widding Hansen IJ, Bakland G, Lillegraven S, Lie E, Haavardsholm EA. Development of a feasible and responsive ultrasound inflammation score for rheumatoid arthritis through a data-driven approach. RMD Open. 2016 Dec 16;2(2):e000325. doi: 10.1136/rmdopen-2016-000325. eCollection 2016.
• Haavardsholm EA, Aga AB, Olsen IC, Lillegraven S, Hammer HB, Uhlig T, Fremstad H, Madland TM, Lexberg AS, Haukeland H, Rodevand E, Hoili C, Stray H, Noraas A, Hansen IJ, Bakland G, Nordberg LB, van der Heijde D, Kvien TK. Ultrasound in management of rheumatoid arthritis: ARCTIC randomised controlled strategy trial. BMJ. 2016 Aug 16;354:i4205. doi: 10.1136/bmj.i4205.
• Nordberg LB, Lillegraven S, Lie E, Aga AB, Olsen IC, Hammer HB, Uhlig T, Jonsson MK, van der Heijde D, Kvien TK, Haavardsholm EA; and the ARCTIC working group. Patients with seronegative RA have more inflammatory activity compared with patients with seropositive RA in an inception cohort of DMARD-naive patients classified according to the 2010 ACR/EULAR criteria. Ann Rheum Dis. 2017 Feb;76(2):341-345. doi: 10.1136/annrheumdis-2015-208873. Epub 2016 Apr 19.
• Aga AB, Hammer HB, Olsen IC, Uhlig T, Kvien TK, van der Heijde D, Fremstad H, Madland TM, Lexberg AS, Haukeland H, Rodevand E, Hoili C, Stray H, Bendvold AN, Soldal DM, Bakland G, Lie E, Haavardsholm EA. First step in the development of an ultrasound joint inflammation score for rheumatoid arthritis using a data-driven approach. Ann Rheum Dis. 2016 Aug;75(8):1444-51. doi: 10.1136/annrheumdis-2015-207572. Epub 2015 Jun 17.

Study record dates

Study Major Dates

• Study Start: September 1, 2010
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: September 16, 2010
• First Submitted That Met QC Criteria: September 20, 2010
• First Posted (Estimate): September 21, 2010

Study Record Updates

• Last Update Posted (Estimate): April 16, 2015
• Last Update Submitted That Met QC Criteria: April 15, 2015
• Last Verified: April 1, 2015

More Information

Terms related to this study

• Keywords: rheumatoid arthritis; remission; ultrasonography; imaging remission; tight control; treat to target
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid
• Other Study ID Numbers: DIA2010-1