Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Exploratory outcomes included clinical response, clinical remission, mucosal healing, and change in the Mayo Clinic score at week 32 and histologic remission (Geboes score <2, on a scale from 0 to 5, with higher scores indicating more severe histologic inflammation)21 at weeks 8 and 32. government site. 2022 May;56(5):592-599. doi: 10.1177/10600280211041907. Flexible sigmoidoscopy with colonic biopsy was performed at screening and at weeks 8 and 32. Ozanimod is a small molecule drug that selectively targets S1P receptors 1 and 5 which play a crucial role in lymphocyte trafficking and has been shown to induce a reversible lymphopenia which correlates with response to therapy. and transmitted securely. Overall scores range from 0 to 12 (with each subscore on a scale from 0 to 3), with higher scores indicating greater activity. J Clin Pharmacol 2017;57:988-996. P values reported for analyses other than the primary outcome of clinical remission at week 8 are considered to be nominal and not significant. Rectal bleeding and stool frequency were reported by patients in an electronic diary. Ulcerative colitis is a chronic immune-mediated disease of the colon that is currently treated with mesalamine, glucocorticoids, thiopurines, and biologic agents.1,2 A lack of universal response, the risks of infection and neoplasia, a requirement for parenteral administration, and the development of antidrug antibodies have created a need for safe and effective oral therapies. The time to disease relapse was examined as an exploratory end point. Jain N, Bhatti MT. 15. Lancet 2022 399 ( 10341 ): 2113 - 2128 . The modified intention-to-treat population included all the patients who underwent randomization and received at least one dose of ozanimod or placebo. 4 it is taken orally N Engl J Med 2013;369:699-710, 3. maintenance treatment of acute myeloid leukaemia after induction therapy The formulary will reflect the TAG - NHS England is the responsible commissioner. Ozanimod Treatment for Ulcerative Colitis. Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study. The most common adverse events overall were anemia and headache. Patients without previous TNF antagonist exposure continued to undergo randomization in cohort 1 until enrollment was closed, at which time such patients were assigned to cohort 2. Zeposia. N2 - BACKGROUND Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. / True North Study Group. 27. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). 32. Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Ozanimod is a novel, oral, small-molecule S1P 1 and S1P 5 agonist, mainly S1P 1. NEW! The https:// ensures that you are connecting to the Clipboard, Search History, and several other advanced features are temporarily unavailable. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N Engl J Med. 2022 Sep 8;18:913-927. doi: 10.2147/TCRM.S336139. Moderately to severely active ulcerative colitis (UC) in adults. ); the Feinberg School of Medicine, Chicago (S.B.H. Panel C shows the percentage of patients with mucosal healing (endoscopy subscore of 1 point) at week 8. 26. Prepare to become a physician, build your knowledge, lead a health care organization, and advance your career with NEJM Group information and services. 2022 May;18(5):265-271. Ozanimod (RPC1063) is a new oral S1P1-receptor and S1P5-receptor modulator with no activity on S1P2, S1P3, and S1P4.16 A phase 2 trial of ozanimod in patients with relapsing multiple sclerosis showed a dose-dependent reduction in circulating lymphocytes that was associated with significant reductions in inflammatory and neurodegenerative brain lesions, with minimal effects on heart rate and liver enzymes.17 We evaluated the efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis. NEW! Primary nonresponse was defined as signs and symptoms of persistently active disease despite an adequate trial of induction treatment with an anti-TNF agent. Lamb YN. DOI: 10.1056/NEJMoa1513248, Tap into groundbreaking research and clinically relevant insights. All the authors had full access to the data. The eighth and ninth authors, both employees of the sponsor, vouch for the completeness and accuracy of the data, and the eighth author vouches for the adherence of the trial to the protocol. Adverse events and use of concomitant medications were recorded through 32 weeks. The current study consisted of a 10-week. Federal government websites often end in .gov or .mil. journal = "New England Journal of Medicine". All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. CONCLUSIONS Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. ), VISUAL ABSTRACTOzanimod Therapy for Ulcerative Colitis, Ulcerative colitis is a chronic disease that is characterized by a dysregulated immune response and chronic inflammation in the colonic mucosa.1 Conventional therapies such as aminosalicylates are modestly effective in patients with moderate, but not severe, disease.2 Glucocorticoids have been associated with adverse events and long-term adverse health consequences and are not recommended as maintenance therapy.2-4 Newer agents, including biologic drugs and Janus kinase inhibitors, are not effective in all patients or can lose efficacy with long-term use, and they have been associated with infections, infusion reactions, and cancers.5,6 Thus, the need remains for new oral treatments for ulcerative colitis that are safe and glucocorticoid-sparing and that have durable efficacy.2. U.S. Food and Drug Administration assigned an action date of May 30, 2021. Exploratory Efficacy Outcomes at Week 32 in the Trial of Ozanimod as Maintenance Therapy. 12. Elevated liver aminotransferase levels were more common with ozanimod. Safety was also assessed. These data should be interpreted cautiously given that the usefulness of these markers is highly dependent on clinical context.22. At week 10, the percentage of patients with clinical remission was significantly higher in the ozanimod group than in the placebo group (18.4% vs. 6.0%, P<0.001) (, Among the 457 patients who had a response to ozanimod during the induction period and underwent subsequent randomization in the maintenance period, 37.0% in the ozanimod group and 18.5% in the placebo group had clinical remission at week 52 (P<0.001) (, Treatment-effect sizes in patients with TNF antagonist exposure were similar to those in patients without such exposure. Aliment Pharmacol Ther 2020;52:1008-1016. Lancet Gastroenterol Hepatol. Sphingosine-1 Phosphate Receptor Modulators: The Next Wave of Oral Therapies in Inflammatory Bowel Disease. With respect to the advantages, the convenience of oral administration is attractive to patients and providers. Endoscopic improvement was defined as a mucosal endoscopy subscore of 1 or less, without friability. Clinical remission was defined as a rectal-bleeding subscore of 0, a stool-frequency subscore of 1 or less (plus a 1-point reduction from baseline), and a mucosal endoscopy subscore of 1 or less, without friability. The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. The sponsor and the steering committee interpreted the data jointly. government site. 25. 1. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician's global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). Nat Immunol 2007;8:1295-1301, 7. Cohort 2 was included to increase the number of patients with a response who would be available for randomization in the maintenance phase of the trial. Cohen JA, Arnold DL, Comi G, et al. The site is secure. The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Lancet Gastroenterol Hepatol 2020;5:819-828. Federal government websites often end in .gov or .mil. S6 and S7). and Feagan, {Brian G.} and Geert D'Haens and Wolf, {Douglas C.} and Igor Jovanovic and Hanauer, {Stephen B.} RVT-3101 has been evaluated in an earlier Phase 2 study (TUSCANY) in 50 patients, and is being evaluated in a large global Phase 2b study (TUSCANY-2) in 245 adult participants with moderate to severe ulcerative colitis. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). Affiliations. The order of testing was the primary-outcome comparison of remission rates at week 8 in the group that received 1 mg of ozanimod with the placebo group, followed by the comparison of remission rates at week 8 in the group that received 0.5 mg of ozanimod with the placebo group if the result of the primary analysis was significant (two-sided P<0.05), followed by each major secondary outcome in order (clinical response, change in Mayo Clinic score from baseline, and mucosal healing), with comparisons for the 1-mg dose preceding those for the 0.5-mg dose. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. 2022 Nov 7;28(41):5893-5909. doi: 10.3748/wjg.v28.i41.5893. Bookshelf (%). Gastroenterology. Am J Gastroenterol 2015;110:802-819, May 5, 2016N Engl J Med 2016; 374:1754-1762 The most advanced way to teach, practice, and assess clinical reasoning skills. N Engl J Med 2010;362:387-401, 9. Background: Inference and missing data. The members of the steering committee designed the trial in collaboration with the sponsor (Bristol Myers Squibb). Sandborn WJ, Feagan BG, Wolf DC, et al. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. EP. 2015 Inderscience Enterprises Ltd.. All rights reserved. Cohen JA, Comi G, Selmaj KW, et al. The primary outcome was clinical remission (Mayo Clinic score 2, with no subscore >1) at 8 weeks. Methods: Squamous-cell carcinoma of the skin developed in one patient who received 1 mg of ozanimod; this patient had previously been treated with mercaptopurine for more than 2 years. Would you like email updates of new search results? title = "Ozanimod as induction and maintenance therapy for ulcerative colitis". Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. Epub 2021 Nov 17. Abnormal liver-function tests led to the discontinuation of ozanimod therapy in 3 of 796 patients (0.4%) in the induction period and in 1 of 230 patients (0.4%) in the maintenance period. Rubin DB. N Engl J Med. The overall incidence of nonserious infection with ozanimod therapy was similar to that with placebo during the induction period but was higher than that with placebo during the maintenance period (Table 2). 29. A total of 9 of 67 patients in the group that received 1 mg of ozanimod had grade 3 reductions in the lymphocyte count, and no patient in either ozanimod group had grade 4 lymphopenia (Table S6 in the Supplementary Appendix). C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. Epub 2021 Dec 8. Feagan BG, Sandborn WJ, Danese S, et al. ACG clinical guideline: ulcerative colitis in adults. Please enable it to take advantage of the complete set of features! (%), Laboratory assessments no./total no. Sandborn WJ, Feagan BG, D'Haens G et al (2022) Ozanimod as induction and maintenance therapy for ulcerative colitis. Ustekinumab as induction and maintenance therapy for ulcerative colitis. For the primary analysis, as well as for the analyses of all secondary outcomes that were defined as proportions, patients who had missing data were classified as not having had a response. the efficacy of ozanimod for induction and maintenance for moderately to severely active uc was examined in the phase 2 touchstone trial. Patients underwent dose escalation during the first week after randomization; thereafter, the patients received the randomly assigned dose for 8 weeks (see the Supplementary Appendix). All the authors had full access to the data. Third, ozanimod treatment resulted in large reductions from baseline in absolute lymphocyte counts, with most patients in the group that received 1 mg having counts below the lower limit of the normal range at week 8 a finding that is consistent with the mechanism of the drug. In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. METHODS We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. First-degree atrioventricular block and sinus bradycardia developed on day 8 in one patient who was treated with ozanimod. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. "Ozanimod is an oral, sphingosine-1-phosphate (S1P) receptor modulator . The three-component Mayo score is defined as the sum of the rectal-bleeding subscore, the stool-frequency subscore, and the endoscopy subscore. Ozanimod: first approval. Drugs. Studies of other agents, notably monoclonal antibodies directed toward adhesion molecules, have previously shown that interference with lymphocyte trafficking is an effective therapeutic approach for patients with ulcerative colitis. One patient in the 0.5-mg ozanimod group who had evidence of preexisting bradycardia (heart rate of 50 beats per minute and a PR interval of 198 msec before ozanimod treatment was initiated) had first-degree atrioventricular block and sinus bradycardia on day 8 (heart rate, 46 beats per minute; PR interval, 201 msec [upper limit of the normal range, 200 msec]); this event was asymptomatic and transient and resolved without intervention. By week 10, 18.4% and 6.0% of the ozanimod and placebo groups achieved clinical remission while on stable corticosteroids, respectively (P <.0001).In the re-randomized maintenance population, 37.0% of the 230 patients in the ozanimod group and 18.5% of the 227 patients in the placebo group achieved clinical . A total of 91 of the 103 patients who entered the maintenance phase (88%) completed the trial. Annu Rev Biochem 2009;78:743-768, 4. Brinkmann V, Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. The overall incidence of adverse events was higher in the ozanimod group than in the placebo group during the maintenance period and was similar among the groups during the induction period. T1 - Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med 1987;317:1625-1629, 19. Panel A shows the primary end point (shaded area) and key secondary end points from the induction period (cohort 1) at week 10, and Panel B the primary end point (shaded area) and key secondary end points from the maintenance period at week 52. 83 A phase 2 trial (TOUCHSTONE) evaluated the induction and maintenance treatment of ozanimod in 197 moderate to severe UC patients. PMC Am J Gastroenterol 2019;114:384-413. This trial was not large enough or of sufficiently long duration to assess safety. Clinical remission was defined as follows: a rectal-bleeding subscore of 0; a stool-frequency subscore of 1 or less, with a decrease of at least 1 point from baseline; and an endoscopy subscore of 1 or less (all on scales from 0 [none] to 3 [most severe]).19. 24. The .gov means its official. The time to disease relapse (an exploratory end point) during the maintenance period is shown in Figure S4. Clinical response was defined as a reduction of at least 3 points and of at least 30% from baseline in the total Mayo score or a reduction of at least 2 points and of at least 35% from baseline in the three-component Mayo score, plus a reduction of at least 1 point in the rectal-bleeding score or an absolute rectal-bleeding score of no more than 1 point. 2022 May;18(5):265-271. FOIA Additional details regarding the statistical analysis are provided in the Supplementary Appendix. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. Multiple post hoc subgroup analyses were also performed (see the Supplementary Appendix). One patient in the placebo group and one in the group assigned to receive 0.5 mg of ozanimod did not receive the assigned regimen and were excluded from the analysis. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. Methods We conducted a phase 3, multicenter,. Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. Methods: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Efficacy analyses were based on all patients who underwent randomization and received at least one dose of ozanimod or placebo (modified intention-to-treat population). The plan specified that formal testing would stop if the results were not significant, and all subsequent analyses would be considered to be exploratory and the corresponding P values nominal. NEW! ); and Northwestern University, Evanston, IL (S.B.H.). RESULTS In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. Sandborn et al. Treatment-effect sizes in patients with TNF antagonist exposure were similar to those in patients without such exposure. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.). In the maintenance period, cancer was diagnosed in 4 patients (basal-cell carcinoma and rectal adenocarcinoma in 1 patient each who received ozanimod during the induction and maintenance periods, and adenocarcinoma of the colon and breast cancer in 1 patient each who received ozanimod during the induction period and placebo during the maintenance period) (see the Supplementary Appendix). N Engl J Med 2021; 385 (14) 1280-1291 From December 2012 through April 2015, we conducted this randomized, double-blind, placebo-controlled phase 2 trial of induction and maintenance therapy at 57 centers in 13 countries. Background: Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. The primary outcome was clinical remission (Mayo Clinic score 2, with no subscore >1) at 8 weeks. Scott FL, Clemons B, Brooks J, et al. A complete list of investigators in the TOUCHSTONE trial is provided in the Supplementary Appendix, available at NEJM.org. Mehling M, Brinkmann V, Antel J, et al. (%), Had a secondary nonresponse no./total no. Epub 2022 Aug 22. 2. Other prespecified end points included histologic remission and clinical remission in subgroups defined according to demographic and disease-based characteristics. Presented at the Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis, Stockholm, September 1113, 2019. abstract. Gordon JP, McEwan PC, Maguire A, Sugrue DM, Puelles J. Characterizing unmet medical need and the potential role of new biologic treatment options in patients with ulcerative colitis and Crohns disease: a systematic review and clinician surveys. Finding a way out: lymphocyte egress from lymphoid organs. Gastroenterol Hepatol (N Y). Stange EF, Travis SPL, Vermeire S, et al. Our trial had some limitations. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. Efficacy Outcomes at Week 8 in the Trial of Ozanimod as Induction Therapy. Safety was also assessed. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, Finally, the trial was limited to patients receiving ozanimod as monotherapy or in combination with glucocorticoids or aminosalicylates. Data were compiled by the sponsor; Pharmaceutical Product Development provided assistance with statistical programming. Significant improvements with ozanimod as compared with placebo were also observed with regard to the three ranked key secondary end points of clinical response, endoscopic improvement, and mucosal healing (P<0.001 for all comparisons). The sphingosine-1-phosphate (S1P) subtype 1 (S1P1) receptor is a member of a family of five widely expressed receptors (S1P1 through S1P5) that are responsible for regulating multiple immunologic and cardiovascular effects.3,4 Cell-surfaceassociated S1P1 receptor plays a crucial role in the trafficking of lymphocytes from lymphoid organs.5,6 S1P1-receptor agonists induce internalization and degradation of the S1P1 receptor, rendering B and T lymphocytes incapable of migrating from secondary lymphoid organs, which leads to a reversible reduction in circulating lymphocytes in the blood.4,5,7, Patients treated with fingolimod (Gilenya, Novartis), a S1P-receptor modulator that has been approved for the treatment of relapsing multiple sclerosis,8,9 have a decrease from baseline of 70 to 80% in the peripheral-blood lymphocyte count owing to lymph-node sequestration of naive and central memory lymphocytes. Selmaj KW, Steinman L, Comi G, et al. 16. N Engl J Med. First, in cohort 1, patients were randomly assigned in a 2:1 ratio to receive ozanimod hydrochloride at a dose of 1 mg per day (equivalent to 0.92 mg of ozanimod; referred to hereafter as ozanimod) or matched placebo once daily in a double-blind manner. This site needs JavaScript to work properly. Affiliations. Gastroenterology. Clinical response was defined as a reduction in the three-component Mayo score of at least 2 points and at least 35% from baseline, as well as a reduction in the rectal-bleeding subscore of at least 1 point or an absolute rectal-bleeding subscore of 1 or less. Mandala S, Hajdu R, Bergstrom J, et al. RESULTS In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. Elevated liver aminotransferase levels were more common with ozanimod. both in California; Robarts Clinical Trials, Robarts Research Institute, and the Department of Medicine, Western University, London, ON (B.G.F. Editorial support was provided by the sponsor and by Robarts Clinical Trials (funded by the sponsor). Ozanimod induction and maintenance treatment for ulcerative colitis. Ozanimod as induction and main-tenance therapy for ulcerative colitis. Gastroenterol Hepatol (N Y). Rates of clinical remission at week 32 and clinical response and mucosal healing at weeks 8 and 32 were analyzed similarly. FOIA Decker A, Schauer F, Lazaro A, Monasterio C, Schmidt AR, Schmitt-Graeff A, Kreisel W. World J Gastroenterol. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Gut 2000;47:404-409. Neurology 2010;75:403-410, 12. N Engl J Med 1987;317:1625-1629. 17. Clin Gastroenterol Hepatol 2020;18(11):2510.e5-2517.e5. The incidence. Address reprint requests to Dr. Sandborn at the Division of Gastroenterology, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0956, or at [emailprotected]. Editorial assistance was funded by Bristol Myers Squibb. Abnormal liver-function tests led to the discontinuation of ozanimod therapy in 3 of 796 patients (0.4%) in the induction period and in 1 of 230 patients (0.4%) in the maintenance period. Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. 2021;385:1280-1291. Ozanimod effective as induction, maintenance therapy for ulcerative colitis A once-daily oral formulation of ozanimod, a selective sphingosine-1-phosphate (S1P) receptor modulator, outdid placebo as induction and maintenance t. Etrolizumab for maintenance therapy in patients with moderately to severely active ulcerative colitis (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Vedolizumab as induction and maintenance therapy for ulcerative colitis. Kappos L, Radue E-W, OConnor P, et al. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. 8. 19 this was a double-blind, placebo-controlled trial. Five patients who had a clinical response did not enter the maintenance phase (Table S7 in the Supplementary Appendix). Background: Only one head-to-head comparison of advanced treatments in moderately to severely active ulcerative colitis (UC) has been published; therefore, there remains a need for further comparisons. All the patients had documented presence of varicellazoster virus IgG antibody or complete varicellazoster vaccination at screening. (%), Serious adverse event related to ozanimod or placebo no. Macular edema occurred in 3 patients receiving ozanimod; all cases resolved after treatment discontinuation (, Presented at the Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis, Presented at the Triennial Joint Meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (MSVirtual2020), Case Records of the Massachusetts General Hospital, Talquetamab, a T-CellRedirecting GPRC5D Bispecific Antibody for Multiple Myeloma, A Covid-19 Milestone Attained A Correlate of Protection for Vaccines, A Step toward Interoperability of Health IT, Breakthrough Infections after Postexposure Vaccination against Mpox, Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma, Case 37-2022: A 55-Year-Old Man with Fatigue, Weight Loss, and Pulmonary Nodules, Brief Report: In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompes Disease, NEJM Catalyst Innovations in Care Delivery, Time since diagnosis of ulcerative colitis yr, Had a primary nonresponse no./total no. Figueroa, Gabriela; Forster, Erin . The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P 1 and S1P 5 receptors, is approved in the United States and European Union for the treatment of ulcerative colitis (UC) [, , ].The pathogenesis of inflammatory bowel disease (IBD) is mediated in part by lymphocyte trafficking to and from inflamed tissues in the gut []. The trial included blinded induction and maintenance periods and an optional open-label period (Fig. Glucocorticoid-free remission was defined as clinical remission at 52 weeks without receipt of glucocorticoids for at least 12 weeks. Blood samples were obtained at each visit for clinical chemical and hematologic studies and for the measurement of the C-reactive protein concentration. At week 8, a total of 30% of the patients in the group that received 0.5 mg of ozanimod and 53% of those in the group that received 1 mg of ozanimod had absolute lymphocyte counts that were below the lower limit of the normal range, with the majority of patients in each ozanimod group having grade 1 or grade 2 reductions in the lymphocyte count. Sandborn WJ1, Feagan BG1, Wolf DC1, D'Haens G1, Vermeire S1, Hanauer SB1, Ghosh S1, Smith H1, Cravets M1, Frohna PA1, Aranda R1, Gujrathi S1, Olson A1, TOUCHSTONE Study Group Collaborators (101) Sparrow M, Vermeire S, Churchev J, Kotzev I, Takov D, Dragomirov B, Vladimirov B, The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). The authorized source of trusted medical research and education for the Chinese-language medical community. 2022 Jun;162(7):2104-2106. doi: 10.1053/j.gastro.2022.01.033. Eligible patients were 18 to 75 years of age and had ulcerative colitis, with a Mayo Clinic score18 of 6 to 12 and an endoscopic subscore of 2 or 3, as determined by blinded central read. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. After a screening period of up to 5 weeks, patients entered a 10-week induction period. Croft NM, Faubion WA Jr, Kugathasan S, Kierkus J, Ruemmele FM, Shimizu T, Mostafa NM, Venetucci M, Finney-Hayward T, Sanchez Gonzalez Y, Bereswill M, Lazar A, Turner D. Lancet Gastroenterol Hepatol. Ozanimod treatment was shown to be more effective at inducing clinical remission than placebo for patients with ulcerative colitis. Would you like email updates of new search results? We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. doi: 10.1056/NEJMc1607287. TA830: Pembrolizumab for A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. This potent. Nature 2004;427:355-360. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. Cohort 2 (with a planned sample of 300 patients) was used to ensure that the trial would have an enrollment of 400 patients in the maintenance period, with the trial having 90% power for the primary end point. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. *Plusminus values are means SD. Patients receiving biologic agents or azathioprine, mercaptopurine, or methotrexate were required to discontinue these agents 5 half-lives before starting the trial regimen and 4 weeks before their screening endoscopy, respectively. Elevated liver aminotransferase levels were more common with ozanimod. METHODS We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Together they form a unique fingerprint. Ozanimod is a small molecule drug that selectively targets S1P receptors 1 and 5 which play a crucial role in lymphocyte trafficking and has been shown to induce a reversible lymphopenia which correlates with response to therapy. Biometrika 1976;63:581-592. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 30. 2022 Nov 22. doi: 10.1007/s12035-022-03137-2. We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the . A documented presence of varicellazoster virus IgG antibody or complete varicellazoster vaccination at least 30 days before randomization was also required. All patients included had to have failed prior treatment for ulcerative colitis, and were generally not allowed to be on other ulcerative colitis treatments during the trial. N1 - Funding Information: At week 8, clinical remission occurred in 11 of 67 patients (16%) who received 1 mg of ozanimod and in 9 of 65 patients (14%) who received 0.5 mg of ozanimod, as compared with 4 of 65 (6%) who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo) (Figure 1A). Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Background: ); the Inflammatory Bowel Disease Center, Academic Medical Center, Amsterdam (G.D.); the Center for Crohns Disease and Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta (D.C.W. Additional information about the methods is provided in the Supplementary Appendix. RESULTS In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. Intest Res 2018;16:26-42. Gastroenterology 2007;132:763-786, 21. 1. Ozanimod for treating moderately to severely active ulcerative colitis (TA828) Evidence-based recommendations on ozanimod (Zeposia) for treating moderately to severely active ulcerative colitis in adults when conventional or biological . At the end of the 10-week induction period, ozanimod outperformed placebo on every measure of clinical effectiveness: clinical remission (23.4% vs. 8.9%), clinical response (53.7% vs. 30.7%), endoscopic improvement (35.6% vs. 14.9%) and mucosal healing (18% vs. 5%). Accessibility A total of 184 patients (80.0%) who had been assigned to receive ozanimod and 124 (54.6%) who had been assigned to receive placebo completed the maintenance period. Randomization was conducted by means of a centralized interactive voice- and Web-based activated response system (IxRS). Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. The absolute lymphocyte count decreased by a mean of approximately 54% from baseline to week 10 in patients who received ozanimod. A total of 199 patients were randomly assigned to the trial groups, of whom 197 received placebo or ozanimod (Fig. Nat Rev Drug Discov 2009;8:297-307, 5. 2016 May 5;374(18):1754-62. doi: 10.1056/NEJMoa1513248. Treatment with ozanimod was shown to have a significantly higher clinical response during induction and maintenance of ulcerative colitis. Conclusions: Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. N Engl J Med 2010;362:402-415, 10. In this phase 2 trial involving patients with moderately or severely active ulcerative colitis, treatment with ozanimod at a once-daily oral dose of 1 mg resulted in slightly higher rates of clinical remission at week 8 than those with placebo (16% vs. 6%, P=0.048). The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). The emerging role of histologic disease activity assessment in ulcerative colitis. We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. 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