Evaluation of American College of Rheumatology Provisional Composite Response Index in Systemic Sclerosis (CRISS) in the Fasscinate Trial

Dinesh Khanna¹, Veronica J. Berrocal², Christopher Denton³, Angelika Jahreis⁴, Helen Spotswood⁵, Celia J. F. Lin⁴, Jeffrey Siegel⁶ and Daniel E. Furst⁷, ¹University of Michigan, Ann Arbor, MI, ²Div of Rheumatology, University of Michigan, Ann Arbor, MI, ³Department of Rheumatology, University College London, Royal Free Hospital, London, United Kingdom, ⁴Genentech, South San Francisco, CA, ⁵Roche Products Ltd., Welwyn Garden City, CA, United Kingdom, ⁶Roche Products Ltd., Welwyn Garden City, United Kingdom, ⁷University of California, Los Angeles, David Geffen School of Medicine, Los Angeles, CA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: clinical trials, outcome measures and systemic sclerosis

Session Information

Date: Wednesday, November 8, 2017

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's – Clinical Aspects and Therapeutics III

Session Type: ACR Concurrent Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Treatment with Interleukin-6R inhibitor, tocilizumab (TCZ), in early progressive systemic sclerosis (SSc; the faSScinate trial) resulted in consistent, but not statistically significant, improvements in skin sclerosis at wks 24 and 48¹. The 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 0.0 [no improvement] to 1.0 [marked improvement]. Step 1 assesses clinically meaningful decline in cardio-pulmonary-renal involvement with a probability of 0.0. For remaining subjects, probability of improvement examined 5 variables: FVC%, Rodnan skin score (mRSS), patient (PTGA) and physician global assessments (MDGA), and HAQ-DI. We assessed the performance of CRISS in the faSScinate at wks 24 and 48.

Methods: Pts ≥18 y with active SSc were randomized 1:1 to TCZ 162 mg or placebo (PBO) subcutaneously wkly for 48 wks. Step 1 for CRISS was captured using review of serious adverse event data. Step 2 calculated the CRISS index as previously defined. Non-parametric Wilcoxon test and proportion z-tests were used to assess whether significant differences exist between the CRISS score in both its continuous and binary form in TCZ and PBO. Analyses utilized all subjects, with missing data imputed using the best-fitting linear mixed model determined through Chi-square significance test on the deviance. The linear mixed models selected included a subject-specific random intercept, an indicator for treatment and a function of time. PD Protocol WA27788 Amendment 4 p.50-53,101

Results: 87 pts (43 TCZ, 44 PBO) were enrolled. 14.10.15_CSR WA27788 (Week 24), pg51-54 4 subjects in the PBO and none in TCZ met the pre-defined definition of worsening cardio-pulmonary-renal involvement (Step 1) thus given a score of 0.0. Using the CRISS as a continuous measure, the median scores statistically significantly favored TCZ compared to the PBO at wks 24 and 48 (p=0.01 and 0.002; Table).

Conclusion: In this post-hoc analysis using patient-level data from FaSScinate, CRISS discriminated TCZ from PBO, supporting its validity in an independent cohort from its development cohort.

References: 1. Khanna. Lancet. 2016

2. Khanna. Arthritis Rheumatol. 2016

Table: Comparison of TCZ and PBO using CRISS index and individual variables at 24 and 48 weeks.
	TCZ, N=43	PBO, N=40Õ	P value
CRISS (0.0-1.0), median [IQR] at 24 weeks	0.19 [0.006; 0.92]	0.0006 [0.0001; 0.13]	0.01*
CRISS (0.0-1.0), median [IQR] at 48 weeks	0.32 [0.01; 0.93]	0.001 [0.0002; 0.16]	0.002*
mRSS (0-51), mean change at 24 weeks	-4.19	-2.65	0.28
mRSS (0-51), mean change at 48 weeks	-5.26	-3.0	0.12
FVC% predicted, mean change at 24 weeks	-0.66	-4.20	<0.01
FVC% predicted, mean change at 48 weeks	-2.21	-6.5	<0.01
PT GA (0-10), mean change at 24 weeks	-0.36	-0.06	0.51
PT GA (0-10), mean change at 48 weeks	-0.85	-0.36	0.33
MD GA (0-10), mean change at 24 week	-1.92	-1.79	0.82
MDGA (0-10), mean change at 48 weeks	-3.18	-1.88	0.03
HAQ-DI (0-3), mean change at 24 weeks	0.17	0.18	0.93
HAQ-DI (0-3), mean change at 48 weeks	0.15	0.23	0.53
*Using Wilcoxon test as CRISS data is not normally distributed Õ 4 subjects in the placebo met step 1 thus given a score of 0.0. The data were not imputed for these subjects when calculating individual measures over time. The linear mixed model was expressed either as a categorical variable for week-visit number (HAQ-DI and FVC), or as a polynomial of degree 1 in week-visit used as a continuous variable (PT and MD GA) or as a 2 degree polynomial in week-visit (mRSS). The model for HAQ-DI and FVC included also the interaction of treatment and week-visit number

Disclosure: D. Khanna, Actelion, Bayer, BoehringerIngelheim, Chemomab, Corbus, Covis, Cytori,Eicos, EMD Serono, Genentech/Roche, Gilead, GSK, Sanofi-Aventis,UCB Pharma, 5,NIH/NIAMS, NIH/NIAID,Bayer, BMS, Genentech/Roche, Pfizer, 2,Eicos, 4; V. J. Berrocal, None; C. Denton, Bayer, CSL Behring, 2,Genentech-Roche, Actelion, GlaxoSmithKlein, Bayer, Sanofi-Aventis, Inventiva, Boehringer Ingelheim, 5; A. Jahreis, Genentech Inc, 3; H. Spotswood, Roche Products Ltd, 3,Roche Products Ltd, 1; C. J. F. Lin, Genentech Roche, 3; J. Siegel, Genentech, Inc., 3; D. E. Furst, None.

To cite this abstract in AMA style:

Khanna D, Berrocal VJ, Denton C, Jahreis A, Spotswood H, Lin CJF, Siegel J, Furst DE. Evaluation of American College of Rheumatology Provisional Composite Response Index in Systemic Sclerosis (CRISS) in the Fasscinate Trial [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/evaluation-of-american-college-of-rheumatology-provisional-composite-response-index-in-systemic-sclerosis-criss-in-the-fasscinate-trial/. Accessed .

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