Non-inferiority of dose reduction versus standard dosing of TNF-inhibitors in axial spondyloarthritis

Abstract

Objective: The objective was to determine if dose reduction is non-inferior to full-dose TNFi to maintain low disease activity (LDA) in patients already in remission with TNFi, in axial spondyloarthritis.

Methods: Randomized, parallel, non-inferiority, open-label multicentre clinical trial. Patients were eligible if they had axial spondyloarthritis and had been in clinical remission for ≥ 6 months with any available TNFi (adalimumab, etanercept, infliximab, golimumab) at the dose recommended by product labelling. Patients were randomized by automated central allocation to continue the same TNFi dose schedule, or to reduce the dose by roughly half according to the protocol. The main outcome was the proportion of subjects with LDA after 1 year. Serious adverse reactions or infections were recorded.

Results: The trial stopped due to end of the funding period, after 126 patients were randomized; 113 patients (84.1% male, mean age (SD) 45.6 (13.0) years) were included in the main per-protocol subset. Non-inferiority was concluded for LDA at 1 year (47/55 (83.8%) patients in the full-dose and 48/58 (81.3%) patients in the reduced-dose arm, adjusted difference (95% CI) - 2.5% (- 16.6% to 11.7%)). Serious adverse reactions or infections were reported in 7/62 patients (11.3%) assigned to full dose and 2/61 patients (3.3%) assigned to reduced dose (p value = 0.164).

Conclusion: In patients with ankylosing spondylitis in clinical remission for at least 6 months, dose reduction is non-inferior to full TNF inhibitor doses to maintain LDA after 1 year. Serious adverse events may be less frequent with reduced doses.

Trial registration: EU Clinical Trials Registry, EudraCT 2011-005871-18 and ClinicalTrials.gov, NCT01604629 .

Keywords: Dose-tapering; Non-inferiority; Spondyloarthritis; TNF inhibitors.

Conflict of interest statement

Ethics approval and consent to participate

The trial was performed according to the study protocol and protocol amendments, which were approved by the Ethics Committee for Clinical Research of the participating sites and by the Spanish Agency for Medicines and Health Products, and complied with the ethical principles of biomedical research, Good Clinical Practice [35] and applicable Spanish legislation. Two amendments to the protocol reflected in the clinical trial registration sites were implemented after recruitment was initiated, which referred to inclusion of new investigators and recruiting sites, and to allow collection of blood samples for measurement of inflammatory mediators, drug plasma measurements and ADA.

Consent for publication

All authors have read and approved the final version and consent to publication.

Competing interests

No author has received any private funding, nor has any been influenced in the preparation of the manuscript. The following authors declare that they have no competing interests: CP, FT, CAS, AV and GC. In the past 2 years, JG has received grants to attend congresses and educational courses, has obtained fees for scientific consultancies and has received speaking fees and fees for participation in educational programmes from the following companies: Roche, MSD, Pfizer, AbbVie, Janssen Cilag, UCB Pharma, Novartis and Celgene. EdM has received grant/research support from AbbVie and Pfizer, honorarium as a speaker from Abbvie, MSD and Novartis and consultant fees from Abbvie and Novartis. JS has obtained grants to attend congresses, speaking fees and fees for participation in educational programmes from Abbvie, Pfizer, MSD, Roche, UCB and Menarini. XJ has attended advisory board meetings of Celgene, has received investigational grants from Abbvie and Pfizer and has received fees for participation in educational programmes from MSD, Pfizer and Abbvie. RS has received speaking fees and fees for attending advisory boards from Abbott/Abbvie, Bristol-Myers Squibb, MSD, Roche, UCB and Pfizer, investigational grants from Bristol-Myers Squibb, MSD, Roche, UCB, Pfizer, FER and SCR and funding for educational projects from MSD, Bristol-Myers Squibb and Abbvie.

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Figures

Fig. 1

Disposition of patients. FAS, full analysis; PPS, per-protocol main analysis set; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CRP, C-reactive protein. *Not meeting inclusion criteria for remission (BASDAI ≤ 2 and CRP ≤ upper limit of normality)

Fig. 2

Proportion of patients with low disease activity and clinical remission at 12 months. a Proportion of subjects with low disease activity and clinical remission at 12 months, per-protocol subset (main analysis). b Proportion of subjects with low disease activity and clinical remission at 12 months, intention-to-treat subset. c Adjusted differences between groups and non-inferiority testing for low disease activity and clinical remission, per-protocol subset (main analysis). d Adjusted differences between groups and non-inferiority testing for low disease activity and clinical remission, intention-to-treat subset. Low disease activity was defined by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 4 and Physician Global Assessment < 4, Patient Global Assessment < 4 and axial pain at night < 4. Clinical remission was defined by BASDAI ≤ 2, Physician Global Assessment ≤ 2 and Patient Global Assessment ≤ 2