Brian G Feagan1, William J Sandborn1, Christopher Gasink1, Douglas Jacobstein1, Yinghua Lang1, Joshua R Friedman1, Marion A Blank1, Jewel Johanns1, Long-Long Gao1, Ye Miao1, Omoniyi J Adedokun1, Bruce E Sands1, Stephen B Hanauer1, Severine Vermeire1, Stephan Targan1, Subrata Ghosh1, Willem J de Villiers1, Jean-Frédéric Colombel1, Zsolt Tulassay1, Ursula Seidler1, Bruce A Salzberg1, Pierre Desreumaux1, Scott D Lee1, Edward V Loftus1, Levinus A Dieleman1, Seymour Katz1, Paul Rutgeerts1. 1. From Robarts Clinical Trials, Robarts Research Institute, Western University, London, ON (B.G.F.), University of Calgary, Calgary, AB (S.G.), and the Division of Gastroenterology and CEGIIR, University of Alberta, Edmonton (L.A.D.) - all in Canada; University of California, San Diego, La Jolla (W.J.S.), and Cedars-Sinai Medical Center, Los Angeles (S.T.) - both in California; Janssen Research and Development, Spring House (C.G., D.J., Y.L., J.R.F., J.J., L.-L.G., Y.M., O.J.A.), and Janssen Scientific Affairs, Horsham (M.A.B.) - both in Pennsylvania; the Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai (B.E.S., J.-F.C.), and New York University School of Medicine (S.K.) - both in New York; Feinberg School of Medicine, Northwestern University, Chicago (S.B.H.); University Hospitals Leuven, Leuven, Belgium (S.V., P.R.); Stellenbosch University, Stellenbosch, South Africa (W.J.V.); Semmelweis University of Budapest, Budapest, Hungary (Z.T.); the Department of Gastroenterology, Hannover Medical School, Hannover, Germany (U.S.); Atlanta Gastroenterology Specialists, Atlanta (B.A.S.); Hôpital Claude Huriez, Lille, France (P.D.); University of Washington Medical Center, Seattle (S.D.L.); and the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN (E.V.L.).
Abstract
BACKGROUND:Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).
RCT Entities:
BACKGROUND:Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. METHODS: We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). RESULTS: The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. CONCLUSIONS: Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).