Background/Purpose:

RAPID-PsA (NCT01087788) reports efficacy and safety of certolizumab pegol (CZP), a PEGylated Fc-free anti-TNF, in psoriatic arthritis (PsA).¹ The effect of different imputation methodologies on radiographic progression outcomes is reported.

Methods:

The ongoing 158 week (Wk) RAPID-PsA trial is double-blind and placebo (PBO) controlled to Wk24, dose-blind to Wk48 and then open label to Wk158. Recruited patients (pts) had active PsA and had failed ≥1 DMARD. Pts could have been secondary failures to 1 previous anti-TNF. Pts were randomized 1:1:1 to PBO or 400mg CZP at Wk0, 2 and 4 (loading dose, LD) followed by either 200mg CZP every 2 wks (Q2W) or 400mg CZP every 4 wks (Q4W).¹ Pre-specified analyses included change from baseline (CFB) in modified Total Sharp Score (mTSS) (average scores of 2 independent readers), the primary endpoint, and % non-progressors (mTSS CFB ≤0). In the pre-specified imputation methodology performed in all randomized pts minimum observed baseline (BL) score for missing BL values (0) and maximum observed Wk24 score for missing Wk24 values (356.5) in pts with <2 available x-rays were imputed. Post hoc analyses used alternative methods of imputation for change from BL in mTSS for pts with <2 available x-rays, including no imputation, imputation with the median, mean or maximum CFB in mTSS scores.

Results:

409 pts were randomized. BL demographics were similar between groups. 19.1% and 19.8% of PBO and CZP (combined dose) pts received prior anti-TNF. The pre-specified imputation analysis inappropriately overestimated radiographic progression in all arms including PBO (LS mean 28.9 and 18.3 for PBO and CZP (combined dose) respectively p≥0.05) (Table) as pts with missing Wk24 values were assigned to a change from BL in mTSS of up to 356.5, which is an implausible progression with respect to clinical practice. Significantly more pts were non-progressors in both CZP groups (200mg Q2W and 400mg Q4W) compared with PBO (83.3% and 76.3% vs 34.6%, respectively, p<0.001). Multiple post-hoc analyses showed that CZP effectively inhibited radiographic progression compared to PBO (Table). ACR20 response at Wk12 was significantly higher in both CZP arms (200mg Q2W and 400mg Q4W) vs PBO (58.0% and 51.9% vs 24.3%, respectively, p<0.001). The safety profile was similar to that observed with CZP in RA.

Conclusion:

Conventional radiographic imputation methods showed that CZP effectively inhibited radiographic progression in pts with PsA. Significantly fewer patients had progression with either CZP dose compared to placebo. The highly conservative pre-specified imputation method resulted in an unrealistic assessment of progression in all arms including PBO Differences in methodologies for imputing missing radiographic data can greatly impact assessment and reporting of mean changes from BL in mTSS.

References:

1. Mease PJ. Ann Rheum Dis 2012;71(Suppl3):150