A Multicenter Randomized Study in Early Rheumatoid Arthritis to Compare Active Conventional Therapy versus Three Biological Treatments: 24 Week Efficacy and Safety Results of the NORD-STAR Trial

Merete Lund Hetland¹, Espen A Haavardsholm ², Anna Rudin ³, Dan Nordström ⁴, Mike Nurmohamed ⁵, Bjorn Gudbjornsson ⁶, Jon Lampa ⁷, Kim Hørslev-Petersen ⁸, Till Uhlig ⁹, Gerdur Grondal ¹⁰, Mikkel Østergaard ¹¹, Marte Heiberg ², Jos Twisk ¹², Kristina Lend ⁷, Simon Krabbe ¹³, Joakim Lindqvist ⁷, Anna-Karin Ekwall ¹⁴, Kathrine Lederballe Grøn ¹⁵, Meliha Kapetanovic ¹⁶, Francesca Faustini ⁷, Riitta Tuompo ¹⁷, Tove Lorenzen ¹⁸, Giovanni Cagnotto ¹⁹, Eva Baecklund ²⁰, Oliver Hendricks ²¹, Daisy Vedder ²², Tuulikki Sokka-isler ²³, Tomas Husmark ²⁴, Maud-Kristine Aga Ljoså ²⁵, Eli Brodin ²⁶, Torkell Ellingsen ²⁷, Annika Söderbergh ²⁸, Milad Rizk ²⁹, Åsa Reckner ³⁰, Line Uhrenholt ³¹, Per Larsson ³², Soeren Just ³³, David Stevens ³⁴, Trine Laurberg ³⁵, Gunnstein Bakland ³⁶, Inge Christoffer Olsen ³⁷, Ronald van Vollenhoven ³⁸ and The NORD-STAR Study Group ³⁹, ¹DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen, Denmark, ²Diakonhjemmet Hospital, Oslo, Norway, ³Dept Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Göteborg, Sweden, ⁴Department of Medicine, ROB-FIN, Helsinki University Hospital and Helsinki University, Helsinki, Finland., Helsinki, Finland, ⁵Amsterdam Rheumatology and immunology Center location Reade and Amsterdam UMC location VU medical center, Amsterdam, Netherlands, ⁶Centre for Rheumatology Research, Landspitali and Faculty of Medicine, University of Iceland, Reykjavik, Iceland, ⁷Karolinska Institutet, Stockholm, Sweden, ⁸Department of Rheumatology, King Christian X's Hospital for Rheumatic Diseases Graasten, Denmark, Graasten, Denmark, ⁹Diakonhjemmet Hospital, Dept. of Rheumatology / University of Oslo, Faculty of Medicine, Oslo, Norway, ¹⁰Department of Rheumatology, Landspitali and Centre for Rheumatology Research, Landspitali, Reykjavík, Iceland, ¹¹Copenhagen Center for Arthritis Research, University of Copenhagen, Copenhagen, Denmark, ¹²Department of Epidemiology and Biostatistics, Amsterdam UMC, Amsterdam, Netherlands, ¹³Rigshospitalet, København, Denmark, ¹⁴University of Gothenburg, Kullavik, Sweden, ¹⁵Rigshospitalt Glostrup, Glostrup, Denmark, ¹⁶Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Section of Rheumatology, Lund and Malmö, Sweden, Lund, Sweden, ¹⁷Helsinki University Hospital, Helsinki, Finland, ¹⁸Reumatologi, Regionshospitalet Silkeborg, Kolding, Denmark, ¹⁹Lund University, Malmö, Sweden, ²⁰Uppsala University, Uppsala, Sweden, ²¹Danish Hospital for Rheumatic Diseases, Sønderborg, Denmark, ²²Amsterdam Rheumatology & immunology Center / Reade, Amsterdam, Netherlands, ²³Jyvaskyla Central Hospital, Jyvaskyla, Finland, ²⁴Rheumatology Clinic, Falun, Sweden, ²⁵Ålesund Hospital Helse Møre og Romsdal HF, Ålesund, Norway, ²⁶Haukeland University Hospital, Bergen, Norway, ²⁷Department of Rheumatology, Odense University Hospital, Denmark, Odense, Syddanmark, Denmark, ²⁸Örebro University Hospital, Ôrebro, Sweden, ²⁹Västmanlands Hospital, Västerås, Sweden, ³⁰Rheumatology Department, Linkoping, Sweden, ³¹Aalborg Universitetshospital, Aalborg, Denmark, ³²Center for Rheumatology, Academic Specialist Center, Stockholm Health Services, Stockholm, Sweden, Stockholm, Stockholms Lan, Sweden, ³³Odense University Hospital, Odense, ³⁴St. Olav's University Hospital, Trondheim, Norway, ³⁵Aarhus University Hospital, Aarhus, Denmark, ³⁶University Hospital of North Norway, Tromsø, Norway, ³⁷Oslo University Hospital, Oslo, Norway, ³⁸Amsterdam Rheumatology and immunology Center, Netherlands., Amsterdam, Netherlands, ³⁹Site investigators in all participating countries, Stockholm, Sweden

Meeting: 2019 ACR/ARP Annual Meeting

Date of first publication: October 23, 2019

Keywords: Abatacept, certolizumab pegol, drug treatment, Late-Breaking 2019, Tocilizumab

Session Information

Date: Tuesday, November 12, 2019

Title: Late-Breaking Abstracts ePoster

Session Type: Late-Breaking Abstract Poster Session

Session Time: 9:00AM-11:00AM

Background/Purpose: The optimal first-line treatment of patients (pts) with early rheumatoid arthritis (RA) is yet to be established. The primary aim was to assess and compare the proportion of pts who achieved remission with active conventional therapy (ACT) and with three different biologic therapies after 24 wks. Secondary aims were to assess and compare other efficacy measures and safety.

Methods: The investigator-initiated NORD-STAR trial (NCT01491815) was conducted in Sweden, Denmark, Norway, Finland, The Netherlands and Iceland. In this multicenter, randomized, open-label, blinded-assessor, phase 4 study pts with early RA (ACR/EULAR 2010 criteria, 18+ years old, < 24 months’ symptom duration, disease activity score (C-reactive protein, CRP (DAS28)) >3.2, ≥2 (of 66) swollen and ≥2 (68) tender joints, rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) positive or CRP >10mg/L)) were recruited and randomized 1:1:1:1 (stratified by country, gender and ACPA). All received methotrexate (25 mg/week after one month). To this was added: Arm 1 (ACT): either oral prednisolone (tapered from 20 mg/d to 5 mg/d in 9 wks); or: sulphasalazine (2 g/day), hydroxychloroquine (35mg/kg/wk) and mandatory intra-articular (IA) triamcinolone hexacetonide (TCH) in ≤4 swollen joints (≤80 mg/visit up to wk 20); Arm 2 (CZP): certolizumab (CZP) 200 mg EOW SC (400 mg at 0, 2 and 4 wks); Arm 3 (ABA): abatacept 125 mg/wk SC; Arm 4 (TCZ): tocilizumab 8 mg/kg/4wks IV or 162 mg/wk SC. IA TCH was allowed in all arms up to wk 20. Primary outcome was clinical disease activity index remission (CDAI≤2.8) at wk 24 (ITT analysis). Dichotomous outcomes were analyzed by adjusted (stratification variables, age, body mass index (BMI) and baseline DAS28) logistic regression with non-responder imputation (NRI). Non-inferiority analyses (per protocol population) had a pre-specified margin of 15%.

Results: In total, 812 pts were randomized. At baseline age was 54.3±14.7 yrs (mean±SD), 31.2% were male, DAS28 5.0±1.1, 74.9% were RF positive and 81.9% ACPA positive, BMI 26.2±5.1 kg/m2, time since diagnosis 7 (1-18) days (median, IQR). Crude CDAI remission rates (ITT) were: ACT: 42.0%, CZP: 47.8%, ABA: 52.5%, TCZ: 41.0%. Figure 1 shows the estimated remission rates with 95% CI. Table 1 shows the primary and key secondary outcomes (ITT population). With ACT as the reference, the absolute difference in adjusted remission rate (delta) was 9% (95%CI: 0.1 to 19%) for ABA, 4% (-5 to 13%) for CZP and -1% (-10 to 9%) for TCZ. Differences in remission rates with CZP and TCZ, but not with ABA, remained within the pre-defined non-inferiority margin versus ACT (per-protocol population), Figure 2. Total numbers of (serious) adverse events (SAEs/total AEs) across ACT, CZP, ABA, TCZ were 13/552, 20/530, 10/527, 10/653, respectively.

Conclusion: High remission rates were found across all four treatment arms at 24 wks. Higher CDAI remission rate was observed for ABA versus ACT (delta 9%) and for CZP (4%), but not for TCZ (-1%). With the predefined 15% margin, ACT was non-inferior to CZP and TCZ, but not to ABA. These results underscore the efficacy and safety of active conventional therapy based on MTX combined with glucocorticoids and may guide future treatment strategies for early RA.

Figure 1.

Figure 2.

Disclosure: M. Lund Hetland, Abbvie, 2, AbbVie, 2, Biogen, 2, BMS, 2, CellTrion, 2, 9, MSD, 2, Novartis, 2, Orion, 2, Pfizer, 2, Samsung, 2, UCB, 2; E. Haavardsholm, None; A. Rudin, None; D. Nordström, AbbVie, 5, 8, BMS, 5, 8, Celgene, 5, 8, Lilly, 5, 8, MSD, 2, 4, 8, Novartis, 5, 8, Pfizer, 2, 5, 8, Roche, 2, 5, 8, UCB, 5, 8; M. Nurmohamed, AbbVie, 2, 8, BMS, 2, 8, Celgene, 2, 8, Eli Lilly, 2, 8, Janssen, 2, 8, Merck, 2, 8, Pfizer, 2, 8, Roche, 2, 8, UCB, 2, 8; B. Gudbjornsson, Actavis, 8, Amgen, 8, Novartis, 8, Pfizer, 8; J. Lampa, None; K. Hørslev-Petersen, AbbVie, 2, Pfizer, 9; T. Uhlig, None; G. Grondal, None; M. Østergaard, AbbVie, 2, 8, 9, Abbvie, 2, 5, 8, Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, UCB, 5, 8, Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, and UCB, 5, 8, Abbvie, Celgene, Centocor, Merck, and Novartis, 2, Abbvie, Celgene, Centocor, Merck, Novartis, 2, BMS, 2, 5, 8, 9, Boehringer Ingelheim, 5, 8, Boehringer-Ingelheim, 2, 8, Boehringer-ingelheim, 9, Celgene, 2, 5, 8, Centocor, 2, Eli Lilly, 5, 8, 9, Eli Lilly and Company, 5, 8, Eli-Lilly, 2, 8, Hospira, 2, 5, 8, Janssen, 2, 5, 8, 9, Merck, 2, 5, 8, 9, Novartis, 2, 5, 8, Novo, 2, 5, 8, Novo Nordisk, 5, 8, Orion, 2, 5, 8, Pfizer, 2, 5, 8, 9, Regeneron, 2, 5, 8, Roche, 2, 5, 8, roche, 9, Sandoz, 2, 8, Sanofi, 2, 8, UCB, 2, 5, 8; M. Heiberg, None; J. Twisk, None; K. Lend, None; S. Krabbe, None; J. Lindqvist, None; A. Ekwall, AbbVie, 1, Pfizer, 1; K. Lederballe Grøn, BMS, 1; M. Kapetanovic, Abbvie, 5, Pfizer, 2; F. Faustini, None; R. Tuompo, Roche, 1, Novartis, 1; T. Lorenzen, None; G. Cagnotto, Novartis, 1; E. Baecklund, None; O. Hendricks, LILLY, 1, ABBVIE, 1, Novartis, 1; D. Vedder, None; T. Sokka-isler, None; T. Husmark, None; M. Ljoså, None; E. Brodin, None; T. Ellingsen, None; A. Söderbergh, None; M. Rizk, AbbVie, 1; Å. Reckner, None; L. Uhrenholt, None; P. Larsson, None; S. Just, None; D. Stevens, None; T. Laurberg, Abbvie, 1, UCB Nordic, 1; G. Bakland, Novartis, 1; I. Olsen, None; R. van Vollenhoven, None.

To cite this abstract in AMA style:

Lund Hetland M, Haavardsholm E, Rudin A, Nordström D, Nurmohamed M, Gudbjornsson B, Lampa J, Hørslev-Petersen K, Uhlig T, Grondal G, Østergaard M, Heiberg M, Twisk J, Lend K, Krabbe S, Lindqvist J, Ekwall A, Lederballe Grøn K, Kapetanovic M, Faustini F, Tuompo R, Lorenzen T, Cagnotto G, Baecklund E, Hendricks O, Vedder D, Sokka-isler T, Husmark T, Ljoså M, Brodin E, Ellingsen T, Söderbergh A, Rizk M, Reckner Å, Uhrenholt L, Larsson P, Just S, Stevens D, Laurberg T, Bakland G, Olsen I, van Vollenhoven R, NORD-STAR Study Group. A Multicenter Randomized Study in Early Rheumatoid Arthritis to Compare Active Conventional Therapy versus Three Biological Treatments: 24 Week Efficacy and Safety Results of the NORD-STAR Trial [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/a-multicenter-randomized-study-in-early-rheumatoid-arthritis-to-compare-active-conventional-therapy-versus-three-biological-treatments-24-week-efficacy-and-safety-results-of-the-nord-star-trial/. Accessed .

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