Predictors of Maintenance of Long-term Remission in Crohn’s Disease Patients Treated With Certolizumab Pegol: Multivariate and Univariate Analyses From the PRECiSE 3 Study

Introduction: Maintenance of remission in Crohn’s disease (CD) may be optimized by identifying factors that influence long-term treatment outcomes. Demographic, genetic, and clinical factors have been identified as short-term predictors of treatment efficacy and disease progression 1-3 and of relapse prevention 4. The PRECiSE 3 (P3) 7-year trial is the first opportunity to study predictors of maintenance of long-term remission in patients with CD treated with certolizumab pegol (CZP). Methods: Patients who completed double-blind, placebo-controlled studies (P1/P2) enrolled in P3, were followed prospectively, and received open-label CZP 400 mg every 4 weeks up to 7 years. Baseline (BL) factors for testing for association with time to loss of remission (Harvey-Bradshaw index [HBI] score >4) were identified based on clinical relevance, variables in the literature, age, C-reactive protein (CRP), HBI, disease duration, disease location and behavior (Montreal classification), smoking status, prior IBD surgery, BMI, fecal calprotectin, albumin, hematocrit, prior infliximab use, immunomodulator, and corticosteroid (CS) use (BL of P1/P2). Predictors that were significant by univariate analysis were confirmed by multivariate Cox regression and reduced stepwise multivariate Cox regression and were compared with each other to determine independence. Results: Of 594 patients in P3, 453 had sufficient data for univariate and multivariate analyses. Nonsignificant BL predictors of the time to loss of remission by included age, CRP, disease duration, disease behavior, BMI, fecal calprotectin, immunosuppressant, and CS use. Significant BL predictors included serum albumin concentrations (<35 g/L vs. ≥35 g/L), smoking (current vs. other), hematocrit (low <40%/<38% for males/females vs. normal ≥40%/≥38%, respectively), prior IBD surgery (yes vs. no), and entry HBI (<8 vs. ≥8; p<0.05 for all). All of these significant predictors were confirmed with Cox regression models and their influence was determined by the reduced stepwise multivariate Cox regression model (Table). Correlations between predictors were low. Conclusion: These analyses identified several key factors as influential for long-term remission of CD with CZP treatment. The BL factors described are being used to build an algorithm for predicting the success of long-term response to CZP. ClinicalTrials.gov: NCT00160524. Disclosure - William Sandborn - Consulting fees: Abbott Laboratories, ActoGeniX NV, AGI Therapeutics, Inc., Alba Therapeutics Corporation, Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Astellas Pharma, Athersys, Inc., Atlantic Healthcare Limited, Axcan Pharma (now Aptalis), BioBalance Corporation, Boehringer -Ingelheim Inc, Bristol Meyers Squibb, Celgene, Celek Pharmaceuticals, Cellerix SL, Cerimon Pharmaceuticals, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle Pharmaceuticals, Eisai Medical Research Inc., Elan Pharmaceuticals, EnGene, Inc., Eli Lilly, Enteromedics, Exagen Diagnostics, Inc., Ferring Pharmaceuticals, Flexion Therapeutics, Inc., Funxional Therapeutics Limited, Genzyme Corporation, Genentech (now Roche), Gilead Sciences, Given Imaging, Glaxo Smith KlineGlaxoSmithKline, Human Genome Sciences, Ironwood Pharmaceuticals (previously Microbia Inc.), Janssen (previously Centocor), KaloBios Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Lycera Corporation, Meda Pharmaceuticals (previously Alaven Pharmaceuticals), Merck Research Laboratories, MerckSeronoMerck Serono, Millennium Pharmaceuticals (subsequently merged with Takeda), Nisshin Kyorin Pharmaceuticals Co., Ltd., Novo Nordisk A/S, NPS Pharmaceuticals, Optimer Pharmaceuticals, Orexigen Therapeutics, Inc., PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb Limited, Purgenesis Technologies, Inc., Receptos, Relypsa, Inc., Salient Pharmaceuticals, Salix Pharmaceuticals, Inc., Santarus, Schering Plough Corporation (acquired by Merck), Shire Pharmaceuticals, Sigmoid Pharma Limited, Sirtris Pharmaceuticals, Inc. (a GSK company), S.L.A. Pharma (UK) Limited, Targacept, Teva Pharmaceuticals, Therakos, Tillotts Pharma AG (acquired by Zeria Pharmaceutical Co., Ltd), TxCell SA, UCB Pharma, Viamet Pharmaceuticals, Vascular Biogenics LimitedLtd. (VBL), Warner Chilcott UK Limited, and Wyeth (now Pfizer). Speakers fees: Abbott Laboratories, Bristol Meyers Squibb, and Janssen (previously Centocor). Financial support for research: Abbott Laboratories, Bristol Meyers Squibb, Genentech, Glaxo Smith Kline (now Roche), GlaxoSmithKline, Janssen (previously Centocor), Millennium Pharmaceuticals (now Takeda), Novartis, Pfizer, Procter and Gamble Pharmaceuticals, Shire Pharmaceuticals, and UCB Pharma. CR: Ironwood Pharmaceuticals, Forest Labs, Santarus Pharmaceuticals, Salix Pharmaceuticals, Boston Scientific, Takeda, Prometheus, UCB, Janssen, and Santarus. Stefan Schreiber - Consulting Fee/Advisory Board: Abbvie, MSD, Jansen, Takeda, Hospira, UCB, Federal Funding: German Government, EU Funding, NIH. Corey Siegel - Consultant/Advisory Board: Abbvie, BiolineRX, Given Imaging, Lilly, Janssen, Salix, Millenium, Pfizer, Prometheus, Takeda, UCB, Speaker for CME activities: Abbvie, Janssen, Merck, Grant support: CCFA, AHRQ (1R01HS021747-01) Abbvie, Janssen, Salix, Warner-Chilcott, UCB, Intellectual property - Dartmouth-Hitchcock Medical Center and Cedars-Sinai Medical Center have a patent pending for a “System and Method of Communicating Predicted Medical Outcomes”, filed 3/34/10. Dr. Corey Siegel and Dr. Lori Siegel are inventors. Gil Melmed - Consultant for: abbvie, ucb, given imaging, luktpold pharma, Research grant: shire, Prometheus. Dermot McGovern - Salary from Foundation Source: The Leona M. and Harry B. Helmsley Charitable Trust, Crohns and Colitis Foundation of America, Consulting Fee/Advisory Board: UCB, Merck, Ferring, NovoNordisk, Genentech, Eli Lilly, Federal Funding: NIH, European Union. Bosny Pierre-Louis, Gordana Kosutic, and Marshall Spearman are employees of UCB Pharma and have stocks and stock options.Table 1: Predictors of Maintenance of Long-term Remission, the Influence of Covariates on the Time to Loss of Remission (Years) Starting From the BL of P1/P2 (Reduced Stepwise Multivariate Cox Regression Model)

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