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

Primary Purpose

Rheumatoid Arthritis

Status

Completed

Phase

Phase 4

Locations

Norway

Study Type

Interventional

Intervention

TNF inhibitors

Synthetic DMARD(s)

Co-medication: Synthetic DMARDs

About this trial

This is an interventional treatment trial for Rheumatoid Arthritis

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Department of Rheumatology, Haukeland University Hospital, Helse Bergen HF
Department of Rheumatology, Drammen Hospital, Vestre Viken HF
Department of Rheumatology, Sykehuset Østfold HF
Department of Rheumatology, Sørlandet Sykehus HF
Revmatismesykehuset AS
Helgelandssykehuset, Mo i Rana
Department of Rheumatology, Diakonhjemmet Hospital
Martina Hansens Hospital AS
Universitetssykehuset Nord-Norge HF
Department of Rheumatology, Helse Møre og Romsdal HF

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Active Comparator

Experimental

Active Comparator

Experimental

Other

Arm Label

Stable dose TNF inhibitor

Stepdown and withdrawal of TNF inhibitor

Stable dose synthetic DMARD

Synthetic DMARD dose reduction

ARCTIC follow-up

Arm Description

Stable dose TNF inhibitor. Any co-medication with synthetic DMARDs kept stable.

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 of synthetic DMARDs, either monotherapy or combination therapy.

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).

Patients are treated according to the ARCTIC treatment schedule based on disease activity.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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

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.

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).

Clinical Disease Activity Index (CDAI)

CDAI includes TCJ28, SJC28, PGA and PhGA.

Swollen joint count

Swollen joint counts are performed on 44 joints, with total joint count ranging from 0 to 44.

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.

Erythrocyte Sedimentation Rate (ESR)

Assessment of ESR in mm/h

C-reactive protein (CRP)

Assessment of CRP in mg/L

Patient's assessment of disease activity (PGA)

PGA is the patient's assessment of disease activity on a VAS 0-100 mm.

Physician's global assessment of disease avtivity (PHGA)

PHGA is the investigator's assessment of disease activity on a VAS 0-100 mm.

Health Assessment Questionnaire (HAQ-PROMIS)

The HAQ-PROMIS is a questionnaire evaluating the physical function in patients with RA.

EuroQol-5 Dimension (EQ-5D)

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

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

Absenteeism (work time missed) Presenteeism (impairment at work / reduced on-the-job effectiveness) Work productivity loss (overall work impairment / absenteeism plus presenteeism) Activity Impairment

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.

Ultrasonography (subclinical synovitis)

36 joints and 2 tendons will be scored for both grey scale and power doppler synovitis on a 0-3 scale.

DAS-remission

Remission is defined as a DAS-score <1.6

DAS28-remission

Remission is defined as a DAS28 score < 2.6

SDAI-remission

Remission is defined as a SDAI score ≤ 3.3

CDAI-remission

Remission is defined as a CDAI score ≤ 2.8

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)

No swollen joint

The percentage of patients with no swollen joints will be assessed

Radiographic outcome

No radiographic progression

Ultrasound outcome

No ultrasound power Doppler signal in any joint.

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.

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.

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.

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.

Full Information

NCT ID

NCT01881308

First Posted

June 17, 2013

Last Updated

April 24, 2022

Sponsor

Diakonhjemmet Hospital

Collaborators

The Research Council of Norway, South-Eastern Norway Regional Health Authority

1. Study Identification

Unique Protocol Identification Number

NCT01881308

Brief Title

Assessing Withdrawal of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

Acronym

ARCTIC REWIND

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2022

Overall Recruitment Status

Completed

Study Start Date

June 17, 2013 (Actual)

Primary Completion Date

January 2020 (Actual)

Study Completion Date

January 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Diakonhjemmet Hospital

Collaborators

The Research Council of Norway, South-Eastern Norway Regional Health Authority

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Rheumatoid Arthritis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

320 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Stable dose TNF inhibitor

Arm Type

Active Comparator

Arm Description

Stable dose TNF inhibitor. Any co-medication with synthetic DMARDs kept stable.

Arm Title

Stepdown and withdrawal of TNF inhibitor

Arm Type

Experimental

Arm Description

Half-dose of TNF inhibitor for the first four months, thereafter withdrawal of TNF inhibitor. Any co-medication with synthetic DMARDs kept stable.

Arm Title

Stable dose synthetic DMARD

Arm Type

Active Comparator

Arm Description

Stable dose of synthetic DMARDs, either monotherapy or combination therapy.

Arm Title

Synthetic DMARD dose reduction

Arm Type

Experimental

Arm Description

Arm Title

ARCTIC follow-up

Arm Type

Other

Arm Description

Patients are treated according to the ARCTIC treatment schedule based on disease activity.

Intervention Type

Drug

Intervention Name(s)

TNF inhibitors

Intervention Type

Drug

Intervention Name(s)

Synthetic DMARD(s)

Intervention Type

Drug

Intervention Name(s)

Co-medication: Synthetic DMARDs

Intervention Description

Synthetic DMARDs given as co-medication for TNF inhibitors as appropriate.

Primary Outcome Measure Information:

Title

Proportion of patients who are non-failures (have not experienced a flare)

Description

Time Frame

12 months

Secondary Outcome Measure Information:

Title

Disease Activity Score (DAS)

Description

Time Frame