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

Background: 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.

Methods/design: 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.

Discussion: 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.

Trial registration: NCT01491815 and NCT02466581 . Registered on 8 December 2011 and May 2015, respectively. EudraCT: 2011-004720-35.

Keywords: Aggressive conventional treatment; Biological treatment; De-escalation strategy; Early treatment; Rheumatoid arthritis; Sustained remission.

Fig. 1

Flow chart of the phases in treatment part 1 (TP1) of the NORD-STAR study

Fig. 2

Flow chart of the phases in treatment part 2 (TP2) of the NORD-STAR study

Fig. 3

Overview of the NORD-STAR study, treatment part 1. Abbreviations: TP1 treatment part 1, ACT aggressive conventional synthetic disease-modifying antirheumatic therapy, TNF tumor necrosis factor, ABA abatacept, TCZ tocilizumab, W week

Fig. 4

Overview of the NORD-STAR study, treatment parts 2 A and B. Abbreviations: TP2 treatment part 2, DR dose reduction, W week, MTX methotrexate, BL baseline

Fig. 5

Schedule of enrollment, interventions and assessments in the NORD-STAR study, treatment part 1. *This visit may be replaced by a telephone contact. **Measured if clinically indicated. ***Blinding of joint-assessor is not necessary since the patient has not been randomized to a treatment arm at screening. ****If tocilizumab is given intravenously, the weight is measured at all visits. Abbreviations: ET early termination, MTX methotrexate, SSZ sulphasalazine, HCQ hydroxychloroquine, i.a. intra-articular, CZP certolizumab-pegol, ABA abatacept, TCZ tocilizumab, RA rheumatoid arthritis, SJC swollen joint count, TJC tender joint count, RF rheumatoid factor, ACPA anti-citrullinated protein antibodies, ANA anti-nuclear antibody, PPD purified protein derivate, VAS Visual Analogue Scale, HAQ Health Assessment Questionnaire, WPAI, Work Productivity Activity Impairment, EQ5D EuroQol 5 dimensions, PASS, Patient Acceptable Symptom State, FACIT Functional Assessment of Chronic Illness Therapy, SF36 Short Form 36, CDAI Clinical Disease Activity Index, DAS Disease Activity Score

Fig. 6

Schedule of enrollment, interventions and assessments in the NORD-STAR study, treatment part 2A. *This visit may be replaced by a telephone contact. **Measured if clinically indicated. ***If tocilizumab is given intravenously, the weight is measured at all visits. Abbreviations: ET early termination, SJC swollen joint count, TJC tender joint count, RF rheumatoid factor, ACPA anti-citrullinated protein antibodies, ANA anti-nuclear antibody, VAS Visual Analogue Scale, HAQ Health Assessment Questionnaire, WPAI Work Productivity Activity Impairment, EQ5D EuroQol 5 dimensions, PASS Patient Acceptable Symptom State, FACIT Functional Assessment of Chronic Illness Therapy, SF36 Short Form 36, CDAI Clinical Disease Activity Index, DAS Disease Activity Score

Fig. 7

Schedule of enrollment, interventions and assessments in the NORD-STAR study, treatment part 2B. *This visit may be replaced by a telephone contact. **Measured if clinically indicated. ***If tocilizumab is given intravenously, the weight is measured at all visits. Abbreviations: ET early termination, SJC swollen joint count, TJC tender joint count, RF rheumatoid factor, ACPA anti-citrullinated protein antibodies, ANA anti-nuclear antibody, VAS Visual Analogue Scale, HAQ Health Assessment Questionnaire, WPAI Work Productivity Activity Impairment, EQ5D EuroQol 5 dimensions, PASS Patient Acceptable Symptom State, FACIT Functional Assessment of Chronic Illness Therapy, SF36 Short Form 36, CDAI Clinical Disease Activity Index, DAS Disease Activity Score