Clinical trial NCT01881308: Assessing Withdrawal of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis
Official title: REmission in Rheumatoid Arthritis - Assessing WIthrawal of Disease-modifying Antirheumatic Drugs in a Non-inferiority Design
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Rheumatoid Arthritis
Lead sponsor: Diakonhjemmet Hospital
Sponsor class: OTHER
Collaborators: name: The Research Council of Norway
name: South-Eastern Norway Regional Health Authority
First posted: 2013-06-19
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of patients who are non-failures (have not experienced a flare)
timeFrame: 12 months
Secondary outcomes:
measure: Disease Activity Score (DAS)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Disease Activity Score in 28 joints (DAS28)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Simplified Disease Activity Index (SDAI)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Clinical Disease Activity Index (CDAI)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Swollen joint count
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Tender joint count
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Erythrocyte Sedimentation Rate (ESR)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: C-reactive protein (CRP)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Patient's assessment of disease activity (PGA)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Physician's global assessment of disease avtivity (PHGA)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Health Assessment Questionnaire (HAQ-PROMIS)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: EuroQol-5 Dimension (EQ-5D)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Medical Outcomes Study Short-Form 36-item (SF-36) Physical and Mental Component Summary Score
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Work performance
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Radiographic joint damage
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Ultrasonography (subclinical synovitis)
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: DAS-remission
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: DAS28-remission
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: SDAI-remission
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: CDAI-remission
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: ACR/EULAR Boolean remission
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: No swollen joint
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Radiographic outcome
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Ultrasound outcome
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: American College of Rheumatology (ACR) response
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: The European League Against Rheumatism (EULAR) response
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: The Food and Drug Administration (FDA) major clinical response
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
measure: Medication
timeFrame: 12 months, with subsequent long-term analyses after 24 months and 36 months
Other outcomes:
Locations:
city: Bergen
country: Norway
facility: Department of Rheumatology, Haukeland University Hospital, Helse Bergen HF
city: Drammen
country: Norway
facility: Department of Rheumatology, Drammen Hospital, Vestre Viken HF
city: Fredrikstad
country: Norway
facility: Department of Rheumatology, Sykehuset Østfold HF
city: Kristiansand
country: Norway
facility: Department of Rheumatology, Sørlandet Sykehus HF
city: Lillehammer
country: Norway
facility: Revmatismesykehuset AS
city: Mo i Rana
country: Norway
facility: Helgelandssykehuset, Mo i Rana
city: Oslo
country: Norway
facility: Department of Rheumatology, Diakonhjemmet Hospital
city: Sandvika
country: Norway
facility: Martina Hansens Hospital AS
city: Tromsø
country: Norway
facility: Universitetssykehuset Nord-Norge HF
city: Ålesund
country: Norway
facility: Department of Rheumatology, Helse Møre og Romsdal HF
Study officials:
affiliation: Diakonhjemmet Hospital
name: Espen A. Haavardsholm, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Diakonhjemmet Hospital
name: Tore K Kvien, MD PhD
role: STUDY_DIRECTOR
References:
citation: 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.