Background/Purpose: Treatment with CTLA4Ig, abatacept (ABA), in early diffuse cutaneous systemic sclerosis (dcSSc; the Phase 2 ASSETtrial) showed evidence of improvements in modified Rodnan skin score (mRSS) and secondary outcome measures at month 12 (2018 ACR abstract submitted); however, statistical significance was not always shown vs. placebo. The CRISS index, a composite outcome measure for trials in SSc¹, 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. We assessed the performance of CRISS, a secondary outcome measure, in ASSET at month12.

Methods: ASSET was an investigator-initiated, multicenter double-blind, randomized placebo-controlled trial. Eligible subjects were randomized in a 1:1 ratio to either 12 months 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 CRISS) prospectively using a case report form. These and all AEs and SAEs were reviewed for cardio-pulmonary and renal involvement by the study PI. Step 2 calculated the 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 CRISS score and its 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 CRISS scores on ABA compared to the PBO at month 12 and the difference was statistically significant (p=0.03; Table). For individual variables, MDGA and HAQ-DI were statistically significant (p=0.004 and p=0.05) favoring ABA. Most variables, except HAQ-DI and PTGA, had statistically significant correlations with the CRISS (Table).

Conclusion: Although the degree of correlation is high between the mRSS and CRISS, there is evidence that CRISS may be more sensitive to clinically meaningful treatment changes than the standard skin score endpoint. This suggests further validation of CRISS as an independent primary endpoint for scleroderma clinical trials.

References:

1. Khanna D. Arthritis Rheumatol. 2016

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evaluation-of-american-college-of-rheumatology-provisional-composite-response-index-in-systemic-sclerosis-in-a-phase-ii-trial-of-abatacept-vs-placebo/