Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain – Study protocol for a randomized double-blind controlled study

Abstract

Background Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. Objectives We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. Methods PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm 3 ; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. Conclusion We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.

Estimating Patient-Specific Relative Benefit of Adding Biologics to Conventional Rheumatoid Arthritis Treatment

“…We screened 1149 records identified by the search and found 11 eligible studies (eFigure 1 in Supplement 1). Among them, we could not access the individual-level data for 6 studies . Hence, we included 5 studies for analysis: RAPID (Rheumatoid Arthritis Prevention of Structural Damage) 1, RAPID 2, REALISTIC (Certolizumab Pegol for the Treatment of Patients With Active Rheumatoid Arthritis), Choy et al, and C-EARLY (Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Combination With Methotrexate in the Treatment of Disease Modifying Antirheumatic Drugs–Naive Adults With Early Active Rheumatoid Arthritis) .…”

“…Patients in 4 studies tended to have longer disease duration compared with the other study. eTable 1 in Supplement 1 presents available characteristics of the 6 eligible studies without available IPD . One study had no results published, and 4 studies were conducted in Asian countries under similar settings with the RAPID trials.…”

“…Among them, we could not access the individual-level data for 6 studies. 35 , 36 , 37 , 38 , 39 , 40 Hence, we included 5 studies for analysis: RAPID (Rheumatoid Arthritis Prevention of Structural Damage) 1, 41 RAPID 2, 42 REALISTIC (Certolizumab Pegol for the Treatment of Patients With Active Rheumatoid Arthritis), 43 Choy et al, 44 and C-EARLY (Multi-center, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Combination With Methotrexate in the Treatment of Disease Modifying Antirheumatic Drugs–Naive Adults With Early Active Rheumatoid Arthritis). 45 In total, 3790 patients (2996 female [79.1%] and 794 male [20.9%]; mean [SD] age, 52.7 [12.3] years; racial categories not provided by the data contributor) were randomized, among whom 2912 were assigned to certolizumab plus csDMARDs and 878 patients to placebo plus csDMARDs.…”

“…eTable 1 in Supplement 1 presents available characteristics of the 6 eligible studies without available IPD. 35 , 36 , 37 , 38 , 39 , 40 One study 38 had no results published, and 4 studies 35 , 37 , 39 , 40 were conducted in Asian countries under similar settings with the RAPID trials. Risk-of-bias assessment for the primary outcome suggested a low risk of bias for all the included studies (eTable 2 in Supplement 1 ).…”

Seasoning to Perfection: How to Optimize Anti-TNF Therapy

“…6 One group is analyzing whether functional brain magnetic resonance imaging could predict the response to the TNF inhibitor, certolizumab, in patients with rheumatoid arthritis. 7 Others have suggested that machine learning could be used to optimize the benefit from TNF inhibitors. 8 Clearly, biomarkers would be valuable in these pursuits.…”