title: Head-to-head comparison of aggressive conventional therapy and three biological treatments and comparison of two de-escalation strategies in patients who respond to treatment: study protocol for a multicenter, randomized, open-label, blinded-assessor, phase 4 study.
abstract: New targeted therapies and improved treatment strategies have dramatically improved the outcomes of patients with rheumatoid arthritis (RA). However, it is unknown whether different early aggressive interventions can induce stable remission or a low-active disease state that can be maintained with conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy, and whether they differ in efficacy and safety. The Nordic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) study will assess and compare (1) the proportion of patients who achieve remission in a head-to-head comparison between csDMARD plus glucocorticoid therapy and three different biological DMARD (bDMARD) therapies with different modes of action and (2) two de-escalation strategies in patients who respond to first-line therapy.
  
  
  
  In a pragmatic, 80-160-week, multicenter, randomized, open-label, assessor-blinded, phase 4 study, 800 patients with early RA (symptom duration less than 24 months) are randomized 1:1:1:1 to one of four different treatment arms: (1) aggressive csDMARD therapy with methotrexate + sulphasalazine + hydroxychloroquine + i.a. glucocorticoids (arm 1A) or methotrexate + prednisolone p.o. (arm 1B), (2) methotrexate + certolizumab-pegol, (3) methotrexate + abatacept, or (4) methotrexate + tocilizumab. The primary clinical endpoint is the proportion of patients reaching Clinical Disease Activity Index (CDAI) remission at week 24. Patients in stable remission over 24 consecutive weeks enter part 2 of the study earliest after 48 weeks. Patients not achieving sustained CDAI remission over 24 consecutive weeks, exit the study after 80 weeks. In part 2, patients are re-randomized to two different de-escalation strategies, either immediate or delayed (after 24 weeks) tapering, followed by cessation of study medication. All patients remain on stable doses of methotrexate. The primary clinical endpoint in part 2 is the proportion of patients in remission (CDAI ≤2.8) 24 weeks after initiating treatment de-escalation. Radiographic assessment will be performed regularly throughout the trial, and blood and urine samples will be stored in a biobank for later biomarker analyses.
  
  
  
  NORD-STAR is the first investigator-initiated, randomized, early RA trial to compare (1) csDMARD and three different bDMARD therapies head to head and (2) two different de-escalation strategies. The trial has the potential to identify which treatment strategy to apply in early RA to achieve the best possible outcomes for both patients and society.
  
  
  
  NCT01491815 and NCT02466581 . Registered on 8 December 2011 and May 2015, respectively. EudraCT: 2011-004720-35.
authors.affiliation: Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Nordre Ringvej 57, DK-2600, Glostrup, Denmark. daniel.glinatsi@gmail.com.
authors.forename: Daniel
authors.identifier: 0000-0003-0452-8200
authors.initials: D
authors.lastname: Glinatsi
authors.affiliation: Department of Rheumatology, Diakonhjemmet Hospital, Box 23 Vinderen, 0219, Oslo, Norway.
authors.forename: Marte S
authors.initials: MS
authors.lastname: Heiberg
authors.affiliation: Clinical Rheumatology Research Centre, Sahlgrenska University Hospital, Gröna Stråket 14, 413 45, Gothenburg, Sweden.|Department of Rheumatology and Inflammation Research, The Sahlgrenska Academy at Gothenburg University, Box 480, 405 30, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Rudin
authors.affiliation: Helsinki University Central Hospital and University of Helsinki, Division of Internal Medicine, Stenbäcksgatan 9 A, FIN-00290, Helsinki, Finland.
authors.forename: Dan
authors.initials: D
authors.lastname: Nordström
authors.affiliation: Department of Rheumatology, Diakonhjemmet Hospital, Box 23 Vinderen, 0219, Oslo, Norway.
authors.forename: Espen A
authors.initials: EA
authors.lastname: Haavardsholm
authors.affiliation: Centre for Rheumatology Research, University Hospital, v/Hringbraut, 101, Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Gudbjornsson
authors.affiliation: Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Nordre Ringvej 57, DK-2600, Glostrup, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mikkel
authors.initials: M
authors.lastname: Østergaard
authors.affiliation: National Advisory Unit for Rehabilitation in Rheumatology, Department of Rheumatology, Diakonhjemmet Hospital, Box 23 Vinderen, 0319, Oslo, Norway.
authors.forename: Till
authors.initials: T
authors.lastname: Uhlig
authors.affiliation: Department of Rheumatology, University Hospital, Fossvogur, 101, Reykjavik, Iceland.
authors.forename: Gerdur
authors.initials: G
authors.lastname: Grondal
authors.affiliation: Department of Rheumatology, King Christian 10th Hospital for Rheumatic Diseases, Toldbodgade 3, 6300, Graasten, Denmark.|Institute of Regional Health Research, University of Southern Denmark, Graasten, Denmark.
authors.forename: Kim
authors.initials: K
authors.lastname: Hørslev-Petersen
authors.affiliation: Unit for Clinical Therapy Research, Inflammatory Diseases, The Karolinska Institutet, 171 76, Stockholm, Sweden.
authors.forename: Ronald
authors.initials: R
authors.lastname: van Vollenhoven
authors.affiliation: Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Nordre Ringvej 57, DK-2600, Glostrup, Denmark.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Merete L
authors.initials: ML
authors.lastname: Hetland
mesh_terms: D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy*; D001688:Biological Products / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000652:urine; D002985:Clinical Protocols; D004359:Drug Therapy, Combination; D005938:Glucocorticoids / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D012042:Registries; D012074:Remission Induction; D012107:Research Design; D012537:Scandinavian and Nordic Countries; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D001688:Biological Products; D015415:Biomarkers; D005938:Glucocorticoids
keywords: Aggressive conventional treatment; Biological treatment; De-escalation strategy; Early treatment; Rheumatoid arthritis; Sustained remission