Slide 1: Evaluation of ACR CRISS in Systemic Sclerosis in a Phase 3 Randomized Controlled Trial
2938 Evaluation of American College of Rheumatology Provisional Composite Response Index in Systemic Sclerosis (ACR CRISS) in a Phase 3 Randomized Controlled Trial D. Khanna,1 C. J. F. Lin,2 H. Spotswood,3 J. Siegel,2 A. Jahreis,2 C. Denton,4 D.E. Furst5 1University of Michigan, Ann Arbor, MI; 2Gene
Slide 2: Disclosures
Disclosures • D. Khanna is a consultant to AbbVie, Roche/Genentech, Actelion, GlaxoSmithKline, Sanofi-Aventis, Inventiva, CSL Behring, Boehringer- Ingelheim, and Bayer; receives research grants from Bayer, BMS, and Pfizer; and owns stock in Eicos Sciences, Inc • C.J.F. Lin, J. Siegel, and A. Jahreis
Slide 3: Background
Background • SSc is a rare autoimmune connective tissue disease characterized by microvascular damage and fibrosis of the skin and internal organs1 • focuSSced is a phase 3 trial evaluating the safety and efficacy of TCZ in patients with SSc2 – The primary outcome did not meet statistical significan
Slide 4: focuSSced Is a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Tocilizumab in SSc
focuSSced Is a Randomized, Double-Blind, Placebo-Controlled Phase 3 Trial of Tocilizumab in Patients With SSc Screening Double-Blind Treatment Period Open-Label Treatment Period (40 days) (48 weeks) (48 weeks) Baseline Week 48 Week 96 TCZ 162 mg SC QW Randomization 1:1 n=105 Adult patients with syst
Slide 5: Outcome Measures
Outcome Measures1,2 • Outcome measures could be clinically meaningful end points that are direct measures of how patients feel, function, and survive • Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, are often
Slide 6: ACR CRISS Is a Composite End Point That Is a 2-Step Process
ACR CRISS Is a Composite End Point That Is a 2-Step Process • Composite end Cardio-pulmonary-renal point that captures worsening? overall well-being1 • Assessed in a 2-step process1 • Preliminary evidence of validation in a Yes No phase 2 trial2 PROCEED to CRISS score=0.00 Step 2 CRISS, Composite Re
Slide 7: Step 1: Expert Consensus on Definition of a Patient Whose Condition Has Not Improved
Step 1: Expert Consensus on Definition of a Patient Whose Condition Has Not Improved During a Trial • During Step 1, clinically meaningful decline in cardio-pulmonary-renal involvement with a probability of zero is assessed • Patient’s condition is considered not improveda if he/she develops any one
Slide 8: The ACR CRISS Score
The ACR CRISS Score • CRISS calculates the probability 25 Placebo or of improvement for each patient ineffective drug ranging from 0.0 (no 20 Effective drug improvement) to 1.0 (marked improvement) Density 20 10 Distribution of ACR CRISS in 5 a hypothetical trial 0 0 0.2 0.4 0.6 0.8 1.0 Probability
Slide 9: focuSSced Step 1: Summary of ACR CRISS Events Identified by Medical Review
focuSSced Step 1: Summary of ACR CRISS Events Identified by Medical Review PBO TCZ • Overall, 19 patients n=106 n=104 experienced events of renal or Renal crisis 0 1 cardiopulmonary New-onset LVEF involvement that 2 1a (EF <45%) required treatment Significant ILD (%pFVC <80%, %pFVC reduction 11 4 •
Slide 10: Step 2: Computation of the Predicted Probability of Improvement for Each Patient
Step 2: Computation of the Predicted Probability of Improvement for Each Patient • mRSS = surrogate for skin • FVC% = surrogate for lung involvement • HAQ-DI = direct measure of function • Patient global assessment = direct measure of feel • MD global assessment = surrogate of patient overall diseas
Slide 11: Step 2: focuSSced Study Results at Week 48
Step 2: focuSSced Study Results at Week 48 PBO TCZ Nominal n=106 n=104 p Value mRSS, 0-51a -4.41 -6.14 0.0983 %pFVC -3.91 -0.60 0.0015 Week 48 HAQ-DI, 0-3a -0.06 -0.11 0.4489 Patient global assessment, 0-10a -0.77 -1.01 0.4339 Physician global assessment, 0-10a -2.00 -2.45 0.4378 Full efficacy and s
Slide 12: focuSSced ACR CRISS Scores at Week 48
focuSSced ACR CRISS Scores at Week 48 • In the remaining patients who did not score zero at Step 1, there was a shift toward higher ACR CRISS scores in favor of TCZ versus PBO at week 48 • More patients in the TCZ arm than in the PBO arm achieved improvement in CRISS scores of ≥0.601 PBO TCZ Differe
Slide 13: Spearman Correlations Between CRISS Score and Individual Scores/Variables at 48 Weeks
Spearman Correlations Between CRISS Score and Individual Scores/Variables in CRISS at 48 Weeksa PBO TCZ n=106 n=104 mRSS, 0-51b -0.79 -0.88 %pFVC 0.43 0.28 HAQ-DI, 0-3b -0.58 -0.60 Patient global assessment, 0-10b -0.62 -0.43 Physician global assessment, 0-10b -0.66 -0.40 aIncluding both Step 1 and
Slide 14: Conclusions
Conclusions • In this analysis of patient-level data from the focuSSced trial, more patients had cardio-pulmonary-renal involvement in the PBO group than in the TCZ group (captured by Step 1) • ACR CRISS score Step 2 distinguished TCZ from PBO • The focuSSced study validates the ACR CRISS end point
Slide 15: focuSSced Investigators
focuSSced Investigators Country Investigators Country Investigators Argentina Lucero, Pons-Estel, Tate, Barriera, Savio Lithuania Bukauskiene, Butrimiene Belgium Smith, Westhovens Mexico Ramos Remus, Rodriquez Reyna, Medrano Ramirez Bulgaria Stoilov, Rashkov, Batalov, Goranov Netherlands Huizinga, V