Effect of different imputation approaches on the evaluation of radiographic progression in patients with psoriatic arthritis: results of the RAPID-PsA 24-week phase III double-blind randomised placebo-controlled study of certolizumab pegol

D van der Heijde, R Fleischmann, J Wollenhaupt, A Deodhar, D Kielar, F Woltering, C Stach, B Hoepken, T Arledge, P J Mease, D van der Heijde, R Fleischmann, J Wollenhaupt, A Deodhar, D Kielar, F Woltering, C Stach, B Hoepken, T Arledge, P J Mease

Abstract

Objectives: To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials.

Methods: The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated.

Results: 409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses.

Conclusions: Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.

Keywords: Anti-TNF; Outcomes research; Psoriatic Arthritis.

Figures

Figure 1
Figure 1
Cumulative probability plots of modified Total Sharp Score (mTSS) total change, with data from patients with fewer than two available radiographs (A) imputed using prespecified imputation method, (B) not imputed, (C) imputed using median mTSS change from baseline of observed patients, (D) imputed using mean mTSS change from baseline of observed patients, (E) imputed using maximum mTSS change from baseline of observed patients and (F) imputed using maximum mTSS change from baseline by treatment group. CZP, certolizumab pegol; Q2W, every 2 weeks; Q4W, every 4 weeks.

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Source: PubMed

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