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4. A randomised phase I study of etrolizumab (rhuMAb β7) in moderate to severe ulcerative colitis

Author

Rutgeerts, Paul J, Fedorak, Richard N, Hommes, Daan W, Sturm, Andreas, Baumgart, Daniel C, Bressler, Brian, Schreiber, Stefan, Mansfield, John C, Williams, Marna, Tang, Meina, Visich, Jennifer, Wei, Xiaohui, Keir, Mary, Luca, Diana, Danilenko, Dimitri, Egen, Jackson, and O'Byrne, Sharon

Subjects
Inflammatory Bowel Disease, Biotechnology, Clinical Trials and Supportive Activities, Clinical Research, Digestive Diseases, Autoimmune Disease, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Aged, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized, Colitis, Ulcerative, Dose-Response Relationship, Drug, Double-Blind Method, Female, Gastrointestinal Agents, Humans, Infusions, Intravenous, Injections, Subcutaneous, Male, Middle Aged, Severity of Illness Index, Treatment Outcome, Young Adult, Etrolizumab, rhuMAb 7, ulcerative colitis, drug development, safety, pharmacokinetics, IBD clinical, IBD basic research, IBD, IBD models, apoptosis, cell cycle, immunology, inflammatory bowel disorders, dendritic cells, Crohn's disease, cytokines, genetics, signal transduction, IBD-genetics, antibody targeted therapy, arthritis, autoimmune disease, integrins, IBD–genetics, rhuMAb β7, Clinical Sciences, Paediatrics and Reproductive Medicine, Gastroenterology & Hepatology
Abstract

ObjectiveEtrolizumab (rhuMAb β7, anti-β7, PRO145223) is a humanised monoclonal antibody targeting the β7 subunit of the heterodimeric integrins α4β7 and αEβ7, which are implicated in leucocyte migration and retention in ulcerative colitis (UC). This randomised phase I study evaluated the safety and pharmacology of etrolizumab in patients with moderate to severe UC.DesignIn the single ascending dose (SAD) stage, etrolizumab (0.3, 1.0, 3.0, 10 mg/kg intravenous, 3.0 mg/kg subcutaneous (SC) or placebo) was administered 4:1 (n=25) in each cohort. In the multiple dose (MD) stage, new patients received monthly etrolizumab (0.5 mg/kg SC (n=4), 1.5 mg/kg SC (n=5), 3.0 mg/kg SC (n=4), 4.0 mg/kg intravenous (n=5)) or placebo (n=5). The pharmacokinetics was studied and Mayo Clinic Score evaluated at baseline, day 29 (SAD), and days 43 and 71 (MD).ResultsIn the SAD stage, there were no dose limiting toxicities, infusion or injection site reactions. Two impaired wound healing serious adverse events occurred in two patients receiving etrolizumab. In the MD stage, there were no dose limiting toxicities, and no infusion or injection site reactions. Headache was the most common adverse event, occurring more often in etrolizumab patients. Antietrolizumab antibodies were detected in two subjects. The duration of β7 receptor full occupancy was dose related. A clinical response was observed in 12/18 patients, and clinical remission in 3/18 patients treated with etrolizumab in the MD stage, compared with 4/5 and 1/5 placebo patients, respectively.ConclusionEtrolizumab is well tolerated in moderate to severe UC. Further investigation is warranted.

Published
2013

6. Metabolomic Profiles Are Gender, Disease and Time Specific in the Interleukin-10 Gene-Deficient Mouse Model of Inflammatory Bowel Disease

Author

Tso, Victor K, Sydora, Beate C, Foshaug, Rae R, Churchill, Thomas A, Doyle, Jason, Slupsky, Carolyn M, and Fedorak, Richard N

Subjects
Medical Biochemistry and Metabolomics, Analytical Chemistry, Biomedical and Clinical Sciences, Chemical Sciences, Autoimmune Disease, Crohn's Disease, Digestive Diseases, Inflammatory Bowel Disease, Aetiology, 2.1 Biological and endogenous factors, Oral and gastrointestinal, Age Factors, Animals, Disease Models, Animal, Female, Inflammatory Bowel Diseases, Interleukin-10, Male, Metabolome, Metabolomics, Mice, Sex Factors, General Science & Technology
Abstract

Metabolomic profiling can be used to study disease-induced changes in inflammatory bowel diseases (IBD). The aim of this study was to investigate the difference in the metabolomic profile of males and females as they developed IBD. Using the IL-10 gene-deficient mouse model of IBD and wild-type mice, urine at age 4, 6, 8, 12, 16, and 20 weeks was collected and analyzed by nuclear magnetic resonance (NMR) spectroscopy. Multivariate data analysis was employed to assess differences in metabolomic profiles that occurred as a consequence of IBD development and severity (at week 20). These changes were contrasted to those that occurred as a consequence of gender. Our results demonstrate that both IL-10 gene-deficient and wild-type mice exhibit gender-related changes in urinary metabolomic profile over time. Some male-female separating metabolites are common to both IL-10 gene-deficient and control wild-type mice and, therefore, appear to be related predominantly to gender maturation. In addition, we were able to identify gender-separating metabolites that are unique for IL-10 gene-deficient and wild-type mice and, therefore, may be indicative of a gender-specific involvement in the development and severity of the intestinal inflammation. The comparison of the gender-separating metabolomic profile from IL-10 gene-deficient mice and wild-type mice during the development of IBD allowed us to identify changes in profile patterns that appear to be imperative in the development of intestinal inflammation, but yet central to gender-related differences in IBD development. The knowledge of metabolomic profile differences by gender and by disease severity has potential clinical implications in the design of both biomarkers of disease as well as the development of optimal therapies.

Published
2013

9. The Probiotic VSL#3 Has Anti-inflammatory Effects and Could Reduce Endoscopic Recurrence After Surgery for Crohn's Disease

Author

Fedorak, Richard N., Feagan, Brian G., Hotte, Naomi, Leddin, Des, Dieleman, Levinus A., Petrunia, Denis M., Enns, Robert, Bitton, Alain, Chiba, Naoki, Paré, Pierre, Rostom, Alaa, Marshall, John, Depew, William, Bernstein, Charles N., Panaccione, Remo, Aumais, Guy, Steinhart, A. Hillary, Cockeram, Alan, Bailey, Robert J., Gionchetti, Paolo, Wong, Cindy, and Madsen, Karen

Published
2015
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12. Methotrexate in Combination With Infliximab Is No More Effective Than Infliximab Alone in Patients With Crohn's Disease

Author

Feagan, Brian G., McDonald, John W.D., Panaccione, Remo, Enns, Robert A., Bernstein, Charles N., Ponich, Terry P., Bourdages, Raymond, MacIntosh, Donald G., Dallaire, Chrystian, Cohen, Albert, Fedorak, Richard N., Paré, Pierre, Bitton, Alain, Saibil, Fred, Anderson, Frank, Donner, Allan, Wong, Cindy J., Zou, Guangyong, Vandervoort, Margaret K., Hopkins, Marybeth, and Greenberg, Gordon R.

Published
2014
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18. Clinical Experience with Infliximab for Crohn’s Disease: The First 100 Patients in Edmonton, Alberta

Author

Clifford Sample, Robert J Bailey, Dennis Todoruk, Daniel Sadowski, Gramlich Leah, Mario Milan, Raeleen Cherry, Mang Ma, Eoin Lalor, John McKaigney, Richard Sherbaniuk, Kata Matic, Connie Switzer, and Fedorak Richard N

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

OBJECTIVE: To determine whether the clinical efficacy and safety of infliximab in diverse clinical referral practices was similar to that seen in the randomized, controlled clinical trials.

Published
2002
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39. Novel Microbial-Based Immunotherapy Approach for Crohn's Disease

Author

Sutcliffe, Simon, primary, Kalyan, Shirin, additional, Pankovich, Jim, additional, Chen, Jenny M. H., additional, Gluck, Rashieda, additional, Thompson, Darby, additional, Bosiljcic, Momir, additional, Bazett, Mark, additional, Fedorak, Richard N., additional, Panaccione, Remo, additional, Axler, Jeffrey, additional, Marshall, John K., additional, Mullins, David W., additional, Kabakchiev, Boyko, additional, McGovern, Dermot P. B., additional, Jang, Julie, additional, Coldman, Andrew, additional, Vandermeirsch, Gillian, additional, Bressler, Brian, additional, and Gunn, Hal, additional

Published
2019
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45. Association of Genetic Variants in NUDT15 With Thiopurine-Induced Myelosuppression in Patients With Inflammatory Bowel Disease

Author

Walker, Gareth J., Harrison, James W., Heap, Graham A., Voskuil, Michiel D., Andersen, Vibeke, Anderson, Carl A., Ananthakrishnan, Ashwin N., Barrett, Jeffrey C., Beaugerie, Laurent, Bewshea, Claire M., Cole, Andy T., Cummings, Fraser R., Daly, Mark J., Ellul, Pierre, Fedorak, Richard N., Festen, Eleonora A. M., Florin, Timothy H., Gaya, Daniel R., Halfvarson, Jonas, Hart, Ailsa L., Heerasing, Neel M., Hendy, Peter, Irving, Peter M., Jones, Samuel E., Koskela, Jukka, Lindsay, James O., Mansfield, John C., McGovern, Dermot, Parkes, Miles, Pollok, Richard C. G., Ramakrishnan, Subramaniam, Rampton, David S., Rivas, Manuel A., Russell, Richard K., Schultz, Michael, Sebastian, Shaji, Seksik, Philippe, Singh, Abhey, So, Kenji, Sokol, Harry, Subramaniam, Kavitha, Todd, Anthony, Annese, Vito, Weersma, Rinse K., Xavier, Ramnik, Ward, Rebecca, Weedon, Michael N., Goodhand, James R., Kennedy, Nicholas A., Ahmad, Tariq, Walker, Gareth J., Harrison, James W., Heap, Graham A., Voskuil, Michiel D., Andersen, Vibeke, Anderson, Carl A., Ananthakrishnan, Ashwin N., Barrett, Jeffrey C., Beaugerie, Laurent, Bewshea, Claire M., Cole, Andy T., Cummings, Fraser R., Daly, Mark J., Ellul, Pierre, Fedorak, Richard N., Festen, Eleonora A. M., Florin, Timothy H., Gaya, Daniel R., Halfvarson, Jonas, Hart, Ailsa L., Heerasing, Neel M., Hendy, Peter, Irving, Peter M., Jones, Samuel E., Koskela, Jukka, Lindsay, James O., Mansfield, John C., McGovern, Dermot, Parkes, Miles, Pollok, Richard C. G., Ramakrishnan, Subramaniam, Rampton, David S., Rivas, Manuel A., Russell, Richard K., Schultz, Michael, Sebastian, Shaji, Seksik, Philippe, Singh, Abhey, So, Kenji, Sokol, Harry, Subramaniam, Kavitha, Todd, Anthony, Annese, Vito, Weersma, Rinse K., Xavier, Ramnik, Ward, Rebecca, Weedon, Michael N., Goodhand, James R., Kennedy, Nicholas A., and Ahmad, Tariq

Abstract

Importance: Use of thiopurines may be limited by myelosuppression. TPMT pharmacogenetic testing identifies only 25% of at-risk patients of European ancestry. Among patients of East Asian ancestry, NUDT15 variants are associated with thiopurine-induced myelosuppression (TIM). Objective: To identify genetic variants associated with TIM among patients of European ancestry with inflammatory bowel disease (IBD). Design, Setting, and Participants: Case-control study of 491 patients affected by TIM and 679 thiopurine-tolerant unaffected patients who were recruited from 89 international sites between March 2012 and November 2015. Genome-wide association studies (GWAS) and exome-wide association studies (EWAS) were conducted in patients of European ancestry. The replication cohort comprised 73 patients affected by TIM and 840 thiopurine-tolerant unaffected patients. Exposures: Genetic variants associated with TIM. Main Outcomes and Measures: Thiopurine-induced myelosuppression, defined as a decline in absolute white blood cell count to 2.5 × 109/L or less or a decline in absolute neutrophil cell count to 1.0 × 109/L or less leading to a dose reduction or drug withdrawal. Results: Among 1077 patients (398 affected and 679 unaffected; median age at IBD diagnosis, 31.0 years [interquartile range, 21.2 to 44.1 years]; 540 [50%] women; 602 [56%] diagnosed as having Crohn disease), 919 (311 affected and 608 unaffected) were included in the GWAS analysis and 961 (328 affected and 633 unaffected) in the EWAS analysis. The GWAS analysis confirmed association of TPMT (chromosome 6, rs11969064) with TIM (30.5% [95/311] affected vs 16.4% [100/608] unaffected patients; odds ratio [OR], 2.3 [95% CI, 1.7 to 3.1], P = 5.2 × 10-9). The EWAS analysis demonstrated an association with an in-frame deletion in NUDT15 (chromosome 13, rs746071566) and TIM (5.8% [19/328] affected vs 0.2% [1/633] unaffected patients; OR, 38.2 [95% CI, 5.1 to 286.1], P = 1.3 × 10-8), which was replicated in a differen, Funding Agencies:International Serious Adverse Events Consortium Crohn's Colitis UK Wellcome Trust WT097835MF National Institutes of Health P01DK046763

Published
2019
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46. A Systematic Review for the Development of a Core Outcome Set for Ulcerative Colitis Clinical Trials

Author

Ma, Christopher, Panaccione, Remo, Fedorak, Richard N., Parker, Claire E., Nguyen, Tran M., Khanna, Reena, Siegel, Corey A., Peyrin-Biroulet, Laurent, D'Haens, Geert, Sandborn, William J., Feagan, Brian G., Jairath, Vipul, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology

Abstract

Advances in drug development for ulcerative colitis (UC) have been paralleled by innovations in trial design. Development of a core outcome set (COS) to standardize outcome definitions and reporting in clinical trials is desirable. We aim to systematically review the efficacy and safety outcomes reported in UC placebo-controlled RCTs. We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017 for placebo-controlled RCTs in adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were extracted and stratified by decade of publication. Eighty-three RCTs (68 induction, 15 maintenance) were included, enrolling 17,737 patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the Ulcerative Colitis Disease Activity Index (UCDAI) and the Mayo Clinic Score (MCS) were commonly used tools for assessing clinical response/remission. Remarkably, substantial variability in the definition of clinical or composite-clinical endpoints was observed with over 50 definitions of response or remission utilized. Endoscopic, histologic, and fecal/serum biomarker outcomes were reported in 83.1% (69/83), 24.1% (20/83), and 24.1% (20/83) of RCTs, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints exists. Patient-reported efficacy and quality of life outcomes were described in 25 RCTs (30.1%) and safety outcomes were reported in 77 RCTs (92.8%). Despite recent advances in clinical trials methodology, important heterogeneity in reporting and variability in endpoint definitions still remains. A need exists to develop and validate a COS for UC clinical trials

Published
2018

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