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.
OBJECTIVE
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.
Department of Rheumatology, Leiden University Medical Centre, , Leiden, The Netherlands.
D
D
van der Heijde
R
R
Fleischmann
J
J
Wollenhaupt
A
A
Deodhar
D
D
Kielar
F
F
Woltering
C
C
Stach
B
B
Hoepken
T
T
Arledge
P J
PJ
Mease
D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D015535:Arthritis, Psoriatic / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D000068582:Certolizumab Pegol; D018450:Disease Progression; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D011237:Predictive Value of Tests; D011859:Radiography; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D010919:Placebos; D011092:Polyethylene Glycols; D000068582:Certolizumab Pegol
Anti-TNF; Outcomes research; Psoriatic Arthritis