FRI0327\u2005EVALUATION OF AMERICAN COLLEGE OF RHEUMATOLOGY PROVISIONAL COMPOSITE RESPONSE INDEX IN SYSTEMIC SCLEROSIS IN A PHASE II TRIAL OF ABATACEPT VS. PLACEBO

Abstract

Background Treatment with CTLA4Ig, abatacept (ABA), in early diffuse systemic sclerosis (dcSSc; a Phase 2 ASSET trial) showed evidence of improvements in modified Rodnan skin score (mRSS) and secondary outcome measures at month 121; however, statistical significance was not always shown vs. placebo. The ACR CRISS index, a composite outcome measure for trials in SSc2, is a 2-step process that assigns a probability of improvement for each subject ranging from 0 [no improvement] to 1 [marked improvement]. Step 1 assesses clinically meaningful decline in cardio-pulmonary-renal involvement with a probability of 0. For remaining subjects, probability of improvement is based on 5 variables: changes from baseline to month 12 in FVC%, mRSS, patient (PTGA) and physician global assessments (MDGA), and HAQ-DI. Objectives We assessed the performance of ACR CRISS, a secondary outcome measure, in ASSET at month12. Methods ASSET was a multicenter double-blind, randomized placebo-controlled trial. Eligible subjects were randomized in a 1:1 ratio to either 12 months of 125 mg SC ABA or matching placebo, stratified by duration of dcSSc (≤18 vs >18 to ≤36 months). Investigators reported SSc end organ involvement (Step 1 for ACR CRISS) prospectively using a case report form. All AEs and SAEs were reviewed for cardio-pulmonary and renal involvement by the study PI. Step 2 calculated the ACR CRISS index as previously defined. Treatment differences, adjusted for duration of dcSSc, in the CRISS score were assessed by the non-parametric Van Elteren test and by ANCOVA for individual CRISS components. We calculated Spearman’s correlation coefficients to assess the relationship between the ACR CRISS score and individual components. Multiple imputation was used for analysis, creating 25 complete datasets with estimates, standard errors and p-values pooled over each imputed dataset. Results 88 subjects (44 ABA, 44 PBO) were randomized; 63 (72%) had complete data for all relevant outcomes at month 12. 5 PBO and 5 ABA subjects met the pre-defined definition of worsening cardio-pulmonary-renal involvement (Step 1) and were given a score of 0. There is evidence of improved ACR CRISS scores on ABA compared to the PBO at month 12 and the difference was statistically significant (p=0.03; Table). Most variables, except HAQ-DI and PTGA, had statistically significant correlations with the ACR CRISS (Table). Conclusion In ASSET trial, the ACR CRISS was more sensitive to clinically meaningful treatment changes than the skin score and provides further validation of ACR CRISS as an independent primary endpoint for clinical trials. References [1] Khanna D. ACR Presentation 2018 [2] Khanna D. Arthritis Rheumatol. 2016 Acknowledgement This project was supported by NIH/NIAID Clinical ACE grant (5UM1AI110557-05) and an investigator-initiated grant by Bristol-Myers Squibb Disclosure of Interests Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Cathie Spino: None declaredTable Spearman Correlations between CRISS and individual components at 12 months and Comparison of ABA and PBO using CRISS index and individual components at 12 months; Outcome ABAN=44 PBON=44 Treatment Difference (ABA-PBO) P-value^ ACR CRISS (0.0-1.0) median (IQR) 0.68 (1.00) 0.01 (0.86) 0.03 Spearman Correlation LS mean (SE) LS mean (SE) LS mean(SE) P-value^^ ΔmRSS (0-51) -0.75* -6.7 (1.30) -3.8 (1.23) -2.9 (1.75) 0.10 ΔFVC% predicted 0.36* -1.4 (1.30) -3.1 (1.20) 1.7 (1.72) 0.32 ΔPTGA (0-10) -0.17 -0.50 (0.392) -0.30 (0.385) -0.20 (0.557) 0.73 ΔMDGA (0-10) -0.47* -1.34 (0.282) -0.18 (0.284) -1.16 (0.403) 0.004 ΔHAQ-DI (0-3) -0.21 -0.11 (0.079) 0.11 (0.076) -0.22 (0.108) 0.05 p-value for treatment comparisons based on Van Elteren test^^p-value for treatment comparisons based on ANCOVA model with treatment, duration of SSc and baseline value as covariates*p< 0.01 using Spearman correlation coefficientNegative score denotes improvement, except for FVC% where negative score denotes worsening; LS mean = least squares mean; SE = standard error