Assessing Withdrawal of Disease-Modifying Antirheumatic Drugs in Rheumatoid Arthritis

NCT01881308 | Completed Phase 4

• 2 other identifiers: DIA2012-1/ver4_12012-005275-14
• Study Type: interventional
• Target: 320
• Locations: 1 country
• Sites: 10

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.

Conditions

Rheumatoid Arthritis

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (28)

• Disease Activity Score (DAS)

  12 months, with subsequent long-term analyses after 24 months and 36 months

• Disease Activity Score in 28 joints (DAS28)

  12 months, with subsequent long-term analyses after 24 months and 36 months

• Simplified Disease Activity Index (SDAI)

  12 months, with subsequent long-term analyses after 24 months and 36 months

• Clinical Disease Activity Index (CDAI)

  12 months, with subsequent long-term analyses after 24 months and 36 months

• Swollen joint count

  12 months, with subsequent long-term analyses after 24 months and 36 months

Study Arms (5)

Stable dose TNF inhibitor

ACTIVE COMPARATOR

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

Drug: TNF inhibitors; Drug: Co-medication: Synthetic DMARDs

Stepdown and withdrawal of TNF inhibitor

EXPERIMENTAL

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

Stable dose synthetic DMARD

ACTIVE COMPARATOR

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

Drug: Synthetic DMARD(s)

Synthetic DMARD dose reduction

EXPERIMENTAL

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)

ARCTIC follow-up

OTHER

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

Drug: TNF inhibitors; Drug: Synthetic DMARD(s); Drug: Co-medication: Synthetic DMARDs

Interventions

TNF inhibitors DRUG

ARCTIC follow-up; Stable dose TNF inhibitor; Stepdown and withdrawal of TNF inhibitor

Synthetic DMARD(s) DRUG

ARCTIC follow-up; Stable dose synthetic DMARD; Synthetic DMARD dose reduction

Co-medication: Synthetic DMARDs DRUG

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

ARCTIC follow-up; Stable dose TNF inhibitor; Stepdown and withdrawal of TNF inhibitor

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Diakonhjemmet Hospital: lead
• The Research Council of Norway: collaborator
• South-Eastern Norway Regional Health Authority: collaborator

Study Sites (10)

Department of Rheumatology, Helse Møre og Romsdal HF

Ålesund, 6026, Norway

Location

Department of Rheumatology, Haukeland University Hospital, Helse Bergen HF

Bergen, 5021, Norway

Location

Department of Rheumatology, Drammen Hospital, Vestre Viken HF

Drammen, 3004, Norway

Location

Department of Rheumatology, Sykehuset Østfold HF

Fredrikstad, 1603, Norway

Location

Department of Rheumatology, Sørlandet Sykehus HF

Kristiansand, 4604, Norway

Location

Revmatismesykehuset AS

Lillehammer, 2609, Norway

Location

Helgelandssykehuset, Mo i Rana

Mo i Rana, 8613, Norway

Location

Department of Rheumatology, Diakonhjemmet Hospital

Oslo, 0319, Norway

Location

Martina Hansens Hospital AS

Sandvika, 1306, Norway

Location

Universitetssykehuset Nord-Norge HF

Tromsø, 9038, Norway

Location

Related Publications (4)

• Kjorholt KE, Sundlisaeter NP, 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, Kvien TK, Solomon DH, van der Heijde D, Haavardsholm EA, Lillegraven S. Effects of tapering conventional synthetic disease-modifying antirheumatic drugs to drug-free remission versus stable treatment in rheumatoid arthritis (ARCTIC REWIND): 3-year results from an open-label, randomised controlled, non-inferiority trial. Lancet Rheumatol. 2024 May;6(5):e268-e278. doi: 10.1016/S2665-9913(24)00021-3. Epub 2024 Apr 4.

  PMID: 38583450 DERIVED

• Holten K, Paulshus Sundlisaeter N, Sexton J, Nordberg LB, Uhlig T, Kvien TK, Solomon DH, Haavardsholm EA, Lillegraven S, Aga AB; ARCTIC REWIND study group. Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to flares in disease activity. RMD Open. 2024 Jan 12;10(1):e003486. doi: 10.1136/rmdopen-2023-003486.

  PMID: 38216290 DERIVED

• Lillegraven S, Paulshus Sundlisaeter N, Aga AB, Sexton J, Olsen IC, Lexberg AS, Madland TM, Fremstad H, Hoili CA, Bakland G, Spada C, Haukeland H, Hansen IM, Moholt E, Uhlig T, Solomon DH, van der Heijde D, Kvien TK, Haavardsholm EA. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial. Ann Rheum Dis. 2023 Nov;82(11):1394-1403. doi: 10.1136/ard-2023-224476. Epub 2023 Aug 22.

  PMID: 37607809 DERIVED

• 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.

  PMID: 33944875 DERIVED

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Tumor Necrosis Factor Inhibitors

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Anti-Inflammatory Agents; Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• Espen A. Haavardsholm, MD PhD

  Diakonhjemmet Hospital

  PRINCIPAL INVESTIGATOR

• Tore K Kvien, MD PhD

  Diakonhjemmet Hospital

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD PhD, Head of Department

Study Record Dates

• First Submitted: June 17, 2013
• First Posted: June 19, 2013
• Study Start: June 17, 2013
• Primary Completion: January 1, 2020
• Study Completion: January 1, 2022
• Last Updated: April 26, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

NO (10)