Model-Based Meta-Analysis Compares DAS28 Rheumatoid Arthritis Treatment Effects and Suggests an Expedited Trial Design for Early Clinical Development

A nonlinear mixed effects modeling approach was used to conduct a model-based meta-analysis (MBMA) of longitudinal, summary-level, baseline-corrected 28-joint Disease Activity Score (Delta DAS28) clinical trial data from seven approved rheumatoid arthritis (RA) drugs (abatacept, adalimumab, certolizumab, etanercept, rituximab, tocilizumab, and tofacitinib), representing 130 randomized clinical trials in 27,355 patients. All of the drugs except tocilizumab were found to have relatively similar Delta DAS28 time courses and efficacy (baseline-corrected and placebo-corrected) at 24 weeks and beyond of approximately 0.87-1.3 units in the typical RA patient population. Tocilizumab was estimated to have a differentially greater response of 1.99 at 24 weeks, likely due to its disproportionate effect on the acute-phase cytokine interleukin-6. Baseline DAS28, disease duration, percentage of male participants, and the year of conduct of the trial were found to have statistically significant effects on the timing and/or magnitude of Delta DAS28 in the control arms. Clinical trial simulations using the present MBMA indicated that abatacept, certolizumab, etanercept, tocilizumab, and tofacitinib would be expected to have a greater than 70% probability of showing a statistically significant difference vs. control at Week 6 with a sample size of similar to 30 patients per arm. In future RA clinical trials, an interim analysis conducted as early as 6 weeks after treatment initiation, with relatively small sample sizes, should be sufficient to detect the Delta DAS28 treatment effect vs. placebo.

Automated summary

This study conducted a model-based meta-analysis of RA drugs and found that most drugs had similar effects on Delta DAS28 in typical RA patient population, except tocilizumab which showed a significantly greater response at 24 weeks possibly due to its effect on interleukin-6. Factors like baseline DAS28, disease duration, percentage of male participants, and year of trial conduct had significant effects on the timing and magnitude of Delta DAS28 in control arms. Clinical trial simulations suggested that several drugs would have a high probability of showing a significant difference vs. control at Week 6 with small sample sizes.