Adalimumab dose tapering in patients with rheumatoid arthritis who are in long-standing clinical remission: results of the phase IV PREDICTRA study

Abstract

Objective: To investigate the association between baseline disease activity and the occurrence of flares after adalimumab tapering or withdrawal in patients with rheumatoid arthritis (RA) in sustained remission.

Methods: The PREDICTRA phase IV, randomised, double-blind (DB) study (ImPact of Residual Inflammation Detected via Imaging TEchniques, Drug Levels, and Patient Characteristics on the Outcome of Dose TaperIng of Adalimumab in Clinical Remission Rheumatoid ArThritis (RA) Patients) enrolled patients with RA receiving adalimumab 40 mg every other week who were in sustained remission ≥6 months. After a 4-week, open-label lead-in (OL-LI) period, patients were randomised 5:1 to DB adalimumab taper (every 3 weeks) or withdrawal (placebo) for 36 weeks. The primary endpoint was the association between DB baseline hand and wrist MRI-detected inflammation with flare occurrence.

Results: Of 146 patients treated during the OL-LI period, 122 were randomised to taper (n=102) or withdrawal (n=20) arms. Patients had a mean 12.9 years of active disease and had received adalimumab for a mean of 5.4 years (mean 2.2 years in sustained remission). Overall, 37 (36%) and 9 (45%) patients experienced a flare in the taper and withdrawal arms, respectively (time to flare, 18.0 and 13.3 weeks). None of the DB baseline disease characteristics or adalimumab concentration was associated with flare occurrence after adalimumab tapering. Approximately half of the patients who flared regained clinical remission after 16 weeks of open-label rescue adalimumab. The safety profile was consistent with previous studies.

Conclusions: Approximately one-third of patients who tapered adalimumab versus half who withdrew adalimumab experienced a flare within 36 weeks. Time to flare was numerically longer in the taper versus withdrawal arm. Baseline MRI inflammation was not associated with flare occurrence.

Trial registration number: NCT02198651, EudraCT 2014-001114-26.

Keywords: DMARDs (biologic); anti-TNF; disease activity; rheumatoid arthritis.

Conflict of interest statement

Competing interests: PE has received research grants and/or consulting fees from AbbVie, Bristol-Myers Squibb, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz and UCB. GRB has received research grants and/or consulting fees from AbbVie, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz and UCB. EN has received speaker fees from AbbVie, Roche, Bristol-Myers Squibb, Pfizer, UCB, Lilly, Novartis, Janssen and Celgene GmbH, and consulting fees from AbbVie. LS has received speaker fees from AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly and Roche. IL and FK are full-time employees of AbbVie and may hold AbbVie stock or stock options. PGC has received speakers' bureau or consulting fees from AbbVie, Bristol-Myers Squibb, Lilly, Novartis, Pfizer and Roche.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Patient disposition. *Two patients entered the DB period but were not treated during the OL-LI period. During the OL-LI period, five patients were not in remission; of these, two patients did not continue into the DB period, whereas three patients were randomised into the DB period in error (all were due to the baseline DAS28 score being entered incorrectly). †One patient discontinued after withdrawal of consent and was not treated during the OL-LI period. ‡ Other reasons included MRI refusal/not performed/problems, n=8; elevated DAS28/flare, n=4; did not meet randomisation criteria, n=1, protocol violation, n=1, family emergency, n=1; moved, n=1, patient request, n=1. §Other reasons included protocol violation, n=1; patient request after serious AE, n=1; patient unable to attend visits, n=1; final visit mistakenly reported as premature discontinuation, n=1. |1 patient was incorrectly entered and treated in the open-label rescue period. ¶Other reason was patient request. AE, adverse event; DAS28, 28-joint Disease Activity Score; DB, double-blind; OL-LI, open-label, lead-in.

Figure 2

(A) Percentage of patients who flared and time from DB baseline to flare in the taper and withdrawal arms, and (B) percentage of patients who regained disease control and time from flare to regain of disease control in the taper and withdrawal arms. Last observation carried forward analysis. Flare was defined as either DAS28(ESR) >2.6 and DAS28(ESR) increase >0.6 from DB baseline or DAS28(ESR) increase ≥1.2 from DB baseline, irrespective of absolute DAS28(ESR). Regain of disease control was defined as DAS28(ESR) 1.2 if DAS28(ESR)

Figure 3

DB baseline parameters and occurrence of flare among patients in the taper arm. *Excluding adalimumab. ACPA, anticitrullinated peptide antibody; bDMARDs, biologic disease-modifying antirheumatic drugs; BME, bone marrow oedema; CRP, C reactive protein; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; DAS28(ESR), 28-joint Disease Activity Score based on erythrocyte sedimentation rate; DB, double-blind; HAQ-DI, Health Assessment Questionnaire Disability Index; RAMRIS, Rheumatoid Arthritis MRI Score; RF, rheumatoid factor.