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.
Bibliographical noteFunding Information:
Dr. Feagan reports receiving fees for serving on advisory boards from AbbVie, Allergan, Amgen, AstraZeneca, Avaxia Biologics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Elan–Biogen, Ferring, Genentech–Roche, Janssen–Johnson & Johnson, Merck, Millennium, Nestlé, Novo Nordisk, Novartis, Pfizer, Prometheus, Protagonist, Receptos, Salix, Sigmoid Pharma, Takeda, Teva, TiGenix, Tillotts Pharma, and UCB Pharma, consulting fees from AbbVie, Actogenix, Akros, Albireo Pharma, Allergan, Amgen, AstraZeneca, Avaxia Biologics, Avir Pharma, Axcan, Baxter Healthcare, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan–Biogen, EnGene, Ferring, Genentech–Roche, GiCare Pharma, Gilead Sciences, Given Imaging, GlaxoSmithKline, Ironwood, Janssen Biotech–Centocor, Janssen–Johnson & Johnson, Kyowa Hakko Kirin, Eli Lilly, Merck, Mesoblast Pharma, Millennium, Nestlé, Novo Nordisk, Novartis, Pfizer, Prometheus, Protagonist, Re-ceptos, Salix, Sanofi, Shire, Sigmoid Pharma, Synergy Pharma, Takeda, Teva, TiGenix, Tillotts Pharma, UCB Pharma, Vertex, VHsquared, Wyeth, Zealand, and Zygenia, lecture fees from Ab-bVie, Janssen–Johnson & Johnson, Takeda, and UCB Pharma, and grant support from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Janssen Biotech–Centocor, Janssen–Johnson & Johnson, Pfizer, Receptos, Sanofi, and Takeda, and being an employee of Robarts Clinical Trials; Dr. Sandborn, receiving consulting fees from Kyowa Hakko Kirin, Millennium, Celgene, Prometheus, Santarus, AbbVie, Catabasis, Vertex, Warner Chil-cott, Gilead Sciences, Cosmo Pharmaceuticals, Ferring, Sigmoid Pharma, Tillotts Pharma, and Am Pharma; Dr. Gasink, Dr. Jacob-stein, Ms. Lang, Drs. Friedman, Blank, Johanns, and Gao, and Mr. Miao and Mr. Adedokun, being employees of Janssen; Ms. Lang, Dr. Blank, and Dr. Johanns, holding stock or stock options in Johnson & Johnson; Dr. Sands, receiving personal fees from AbbVie, Bristol-Myers Squibb, Boehringer Ingelheim, Akros Pharma, Arena, Celgene, Forward Pharma, Immune Pharmaceuticals, Eli Lilly, Synergy Pharma, Theravance, Pfizer, Receptos, Takeda, Millennium, TiGenix, TopiVert Pharma, Forest Research Institute, Luitpold Pharmaceuticals, MedImmune, Prometheus, Salix, Amgen, Vedanta Biosciences, Vindico Medical Education, UCB Pharma, Rockpointe, JK Associates, Focus Medical Communications, Imedex, Med-IQ, Strategic Consultants International, American Academy of CME, Catrille and Associates, and Huntsworth Health North America, and grant support from AbbVie, Celgene, Pfizer, Takeda, Millennium, MedImmune, Prometheus, and Amgen; Dr. Hanauer, receiving grant support and fees for consulting, lectures, and serving on an advisory board from Janssen; Dr. Vermeire, receiving consulting fees from Merck Sharp and Dohme, Pfizer, Mundipharma, Hospira, Genentech– Roche, and Galapagos, lecture fees from Merck Sharp and Dohme, Pfizer, Mundipharma, and Hospira, and grant support from Merck Sharp and Dohme, AbbVie, and Takeda; Dr. Targan, receiving consulting fees from Janssen; Dr. Ghosh, receiving fees for serving on steering committees for Janssen, AbbVie, Pfizer, Receptos, Aerpio, and Novartis, fees for serving on a drug-monitoring committee for Janssen, and fees for lectures and serving on advisory boards for AbbVie and Takeda; Dr. Co-lombel, receiving personal fees from AbbVie, Amgen, Boehringer Ingelheim, Celgene, Celltrion, Enterome, Ferring, Genen-tech, Janssen–Johnson & Johnson, MedImmune, Merck, Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda, Theradiag, and PPM Services, receiving grant support from AbbVie, Jans-sen–Johnson & Johnson, and Takeda, and holding stock options in Genfit and Intestinal Biotech Development; Dr. Seidler, receiving personal fees from Merck Sharp and Dohme and travel support from Takeda and Merck Sharp and Dohme, and serving as a principal investigator in trials sponsored by Pfizer, Boehringer Ingelheim, Roche, Salix–Celgene, Mitsubishi, and Gilead Sciences; Dr. Salzberg, receiving consulting fees from Janssen, Takeda, and AbbVie and lecture fees from Janssen and Takeda; Dr. Loftus, receiving personal fees from Janssen, Takeda, AbbVie, UCB Pharma, Genentech, Celgene, Amgen, Bristol-Myers Squibb, Eli Lilly, Mesoblast, Theradiag, Sun Pharma, and Seres Therapeutics and grant support from Janssen, Takeda, AbbVie, UCB Pharma, Genentech, Amgen, Bristol-Myers Squibb, Pfizer, Re-ceptos, Gilead Sciences, and Robarts Clinical Trials; Dr. Diele-man, receiving fees for serving on advisory boards from Jans-sen, AbbVie, Shire, and Ferring; Dr. Katz, receiving lecture fees, paid to his institution, from AbbVie, Takeda, and UCB Pharma, and that his institution has served as a recruitment center for trials sponsored by Janssen, Celgene, Arena, Atlantic, Genentech, and Biogen Idec; and Dr. Rutgeerts, consulting fees from Johnson & Johnson, Merck Sharp and Dohme, AbbVie, UCB Pharma, Bristol-Myers Squibb, Amgen–MedImmune–AstraZeneca, Pfizer, Tillotts Pharma, Falk Pharma, and Takeda, lecture fees from Johnson & Johnson, Merck Sharp and Dohme, AbbVie, and UCB Pharma, and personal fees from Robarts Clinical Trials. No other potential conflict of interest relevant to this article was reported.
Supported by Janssen Research and Development.
© 2016 Massachusetts Medical Society.
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