Tags

Type your tag names separated by a space and hit enter

Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT.
Health Technol Assess. 2018 06; 22(34):1-280.HT

Abstract

BACKGROUND

Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population.

OBJECTIVES

To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy.

DESIGN

Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status.

SETTING

UK outpatient rheumatology departments.

PARTICIPANTS

Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi.

INTERVENTIONS

Alternative TNFi, abatacept or rituximab (and continued background MTX).

MAIN OUTCOME MEASURES

The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity.

LIMITATIONS

Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early.

RESULTS

Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n = 41; abatacept, n = 41; rituximab, n = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity.

FUTURE WORK

The results will add to the randomised evidence base and could be included in future meta-analyses.

CONCLUSIONS

How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative.

TRIAL REGISTRATION

Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151.

FUNDING

This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 34. See the NIHR Journals Library website for further project information.

Authors+Show Affiliations

Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK.Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK.Department of Emergency Medicine, University of Alberta, Edmonton, AB, Canada.Dental Translational and Clinical Research Unit, University of Leeds, Leeds, UK.Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK. National Institute for Health Research Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.Clinical Trials Research Unit, Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK.Academic Unit of Health Economics, Leeds Institute of Health Sciences, University of Leeds, Leeds, UK. National Institute for Health Research Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK.

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29900829

Citation

Brown, Sarah, et al. "Alternative Tumour Necrosis Factor Inhibitors (TNFi) or Abatacept or Rituximab Following Failure of Initial TNFi in Rheumatoid Arthritis: the SWITCH RCT." Health Technology Assessment (Winchester, England), vol. 22, no. 34, 2018, pp. 1-280.
Brown S, Everett CC, Naraghi K, et al. Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT. Health Technol Assess. 2018;22(34):1-280.
Brown, S., Everett, C. C., Naraghi, K., Davies, C., Dawkins, B., Hulme, C., McCabe, C., Pavitt, S., Emery, P., Sharples, L., & Buch, M. H. (2018). Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT. Health Technology Assessment (Winchester, England), 22(34), 1-280. https://doi.org/10.3310/hta22340
Brown S, et al. Alternative Tumour Necrosis Factor Inhibitors (TNFi) or Abatacept or Rituximab Following Failure of Initial TNFi in Rheumatoid Arthritis: the SWITCH RCT. Health Technol Assess. 2018;22(34):1-280. PubMed PMID: 29900829.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alternative tumour necrosis factor inhibitors (TNFi) or abatacept or rituximab following failure of initial TNFi in rheumatoid arthritis: the SWITCH RCT. AU - Brown,Sarah, AU - Everett,Colin C, AU - Naraghi,Kamran, AU - Davies,Claire, AU - Dawkins,Bryony, AU - Hulme,Claire, AU - McCabe,Christopher, AU - Pavitt,Sue, AU - Emery,Paul, AU - Sharples,Linda, AU - Buch,Maya H, PY - 2018/6/15/entrez PY - 2018/6/15/pubmed PY - 2019/4/10/medline SP - 1 EP - 280 JF - Health technology assessment (Winchester, England) JO - Health Technol Assess VL - 22 IS - 34 N2 - BACKGROUND: Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. OBJECTIVES: To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. DESIGN: Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. SETTING: UK outpatient rheumatology departments. PARTICIPANTS: Patients aged ≥ 18 years who were diagnosed with RA and were receiving MTX, but had not responded to two or more conventional synthetic disease-modifying antirheumatic drug therapies and had shown an inadequate treatment response to a first TNFi. INTERVENTIONS: Alternative TNFi, abatacept or rituximab (and continued background MTX). MAIN OUTCOME MEASURES: The primary outcome was absolute reduction in the Disease Activity Score of 28 joints (DAS28) at 24 weeks post randomisation. Secondary outcome measures over 48 weeks were additional measures of disease activity, quality of life, cost-effectiveness, radiographic measures, safety and toxicity. LIMITATIONS: Owing to third-party contractual issues, commissioning challenges delaying centre set-up and thus slower than expected recruitment, the funders terminated the trial early. RESULTS: Between July 2012 and December 2014, 149 patients in 35 centres were registered, of whom 122 were randomised to treatment (alternative TNFi, n = 41; abatacept, n = 41; rituximab, n = 40). The numbers, as specified, were analysed in each group [in line with the intention-to-treat (ITT) principle]. Comparing alternative TNFi with rituximab, the difference in mean reduction in DAS28 at 24 weeks post randomisation was 0.3 [95% confidence interval (CI) -0.45 to 1.05] in the ITT patient population and -0.58 (95% CI -1.72 to 0.55) in the per protocol (PP) population. Corresponding results for the abatacept and rituximab comparison were 0.04 (95% CI -0.72 to 0.79) in the ITT population and -0.15 (95% CI -1.27 to 0.98) in the PP population. General improvement in the Health Assessment Questionnaire Disability Index, Rheumatoid Arthritis Quality of Life and the patients' general health was apparent over time, with no notable differences between treatment groups. There was a marked initial improvement in the patients' global assessment of pain and arthritis at 12 weeks across all three treatment groups. Switching to alternative TNFi may be cost-effective compared with rituximab [incremental cost-effectiveness ratio (ICER) £5332.02 per quality-adjusted life-year gained]; however, switching to abatacept compared with switching to alternative TNFi is unlikely to be cost-effective (ICER £253,967.96), but there was substantial uncertainty in the decisions. The value of information analysis indicated that further research would be highly valuable to the NHS. Ten serious adverse events in nine patients were reported; none were suspected unexpected serious adverse reactions. Two patients died and 10 experienced toxicity. FUTURE WORK: The results will add to the randomised evidence base and could be included in future meta-analyses. CONCLUSIONS: How to manage first-line TNFi treatment failures remains unresolved. Had the trial recruited to target, more credible evidence on whether or not either of the interventions were non-inferior to rituximab may have been provided, although this remains speculative. TRIAL REGISTRATION: Current Controlled Trials ISRCTN89222125 and ClinicalTrials.gov NCT01295151. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 34. See the NIHR Journals Library website for further project information. SN - 2046-4924 UR - https://www.unboundmedicine.com/medline/citation/29900829/Alternative_tumour_necrosis_factor_inhibitors__TNFi__or_abatacept_or_rituximab_following_failure_of_initial_TNFi_in_rheumatoid_arthritis:_the_SWITCH_RCT_ L2 - https://doi.org/10.3310/hta22340 DB - PRIME DP - Unbound Medicine ER -