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Background and Aims: Previously published long-term safety data reported a favourable ustekinumab safety profile for the treatment of inflammatory bowel disease [IBD]. We present the final cumulative safety data from pooled ustekinumab IBD phase 2/3 clinical studies through 5 years in Crohn's disease [CD] and 4 years in ulcerative colitis [UC]., Methods: In phase 3 studies, patients received a single intravenous placebo or ustekinumab [130 mg or ~6 mg/kg] induction dose followed by subcutaneous maintenance doses of placebo or ustekinumab [90 mg q8w or q12w]. Analyses included all patients who received one dose of study treatment and included patients who were biologic-naïve and patients with a history of biologic failure. Safety outcomes are summarized and presented using number of events per 100 patient-years of follow-up and corresponding 95% confidence intervals., Results: In this final pooled safety analysis, 2575 patients were treated with ustekinumab with 4826 patient-years of follow-up. Rates of key safety events, including major adverse cardiac events and malignancies, were similar between placebo and ustekinumab or not higher for ustekinumab. Opportunistic infections, including tuberculosis, and malignancies were reported infrequently. Rates of key safety events in the IBD group were no higher in the ustekinumab group than in the placebo group for both patients who were biologic-naïve or who had a history of biologic failure. No lymphomas or cases of posterior reversible encephalopathy syndrome [formerly known as reversible posterior leukoencephalopathy syndrome] were reported., Conclusion: The final cumulative ustekinumab safety data through 5 years in CD and 4 years in UC demonstrated favourable safety compared to placebo and continue to support the well-established safety profile across all approved indications., Clinical Trials.gov Numbers: NCT00265122, NCT00771667, NCT01369329, NCT01369342, NCT01369355, NCT02407236., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background & Aims: Ustekinumab is an effective treatment of Crohn's disease (CD). Of interest to patients is knowing how soon symptoms may improve. We analyzed ustekinumab response dynamics from the ustekinumab CD trials., Methods: Patients with CD received intravenous induction with ustekinumab ∼6 mg/kg (n = 458) or placebo (n = 457). Week 8 ustekinumab responders received subcutaneous ustekinumab 90 mg as the first maintenance dose or as an extended induction dose for nonresponders. Patient-reported symptom changes (stool frequency, abdominal pain, general well-being) within the first 14 days and clinical outcomes through week 44 were evaluated using the CD Activity Index., Results: After ustekinumab infusion, stool frequency improvement was significantly (P < .05) greater than placebo on day 1 and for all patient-reported symptoms by day 10. In patients with no history of biologic failure or intolerance, cumulative clinical remission rates increased from 23.0% at week 3 to 55.5% at week 16 after the subcutaneous dose at week 8. Corresponding cumulative rates for patients with a history of biologic failure or intolerance increased from 12.9% to 24.1%. Neither change from baseline in CD Activity Index score nor week 8 ustekinumab pharmacokinetics were associated with week 16 response. Among all patients who received subcutaneous ustekinumab 90 mg q8w, up to 66.7% were in clinical response at week 44., Conclusions: Ustekinumab induction provided symptom relief by day 1 post-infusion. Following ustekinumab infusion and a subcutaneous 90 mg injection, clinical outcomes continued to increase through week 16 and up to week 44. Regardless of week 8 clinical status or ustekinumab pharmacokinetics, patients should receive additional treatment at week 8., Clinicaltrials: gov numbers, NCT01369329, NCT01369342, and NCT01369355., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: We evaluated the real-world effectiveness and safety of ustekinumab (UST) in patients with Crohn's disease (CD)., Methods: This study used a retrospective, multicenter, multinational consortium of UST-treated CD patients. Data included patient demographics, disease phenotype, disease activity, treatment history, and concomitant medications. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions were assessed using time-to-event analysis, and clinical predictors were assessed by using multivariate Cox proportional hazard analyses. Serious infections and adverse events were defined as those requiring hospitalization or treatment discontinuation., Results: A total of 1,113 patients (51.8% female, 90% prior antitumor necrosis factor exposure) were included, with a median follow-up of 386 days. Cumulative rates of clinical, steroid-free, endoscopic, and radiographic remissions at 12 months were 40%, 32%, 39%, and 30%, respectively. Biologic-naive patients achieved significantly higher rates of clinical and endoscopic remissions at 63% and 55%, respectively. On multivariable analyses, prior antitumor necrosis factor (hazard ratio, 0.72; 95% confidence interval, 0.49-0.99) and vedolizumab exposure (hazard ratio, 0.65; 95% confidence interval, 0.48-0.88) were independently associated with lower likelihoods of achieving endoscopic remission. In patients who experienced loss of remission, 77 of 102 (75%) underwent dose optimization, and 44 of 77 (57%) achieved clinical response. An additional 152 of 681 patients (22.3%) were dose-optimized because of primary nonresponse incomplete response to UST, of whom 40.1% (61 of 152) responded. Serious infections occurred in 3.4% of patients while other noninfectious adverse events (lymphoma [n = 1], arthralgia [n = 6], rash [n = 6], headache [n = 3], hepatitis [n = 3], hair loss [n = 3], neuropathy [n = 1], and vasculitis [n = 1]) occurred in 2.4% of patients., Discussion: UST represents a safe and effective treatment option for CD, with 40% of patients from a highly refractory cohort achieving clinical remission by 12 months. The greatest treatment effect of UST was seen in biologic-naive patients, and dose escalation may recapture clinical response., (Copyright © 2022 by The American College of Gastroenterology.)

Purpose: Ustekinumab, a fully human immunoglobulin G1κ monoclonal antibody that antagonizes human interleukin-12/23p40, is an effective therapy for several immune-mediated inflammatory diseases, including Crohn's disease (CD). This work characterizes the population pharmacokinetic (PK) and exposure-response (E-R) relationships of ustekinumab in patients with CD using data from four Phase IIb/III clinical studies., Methods: Serum ustekinumab concentration-time data from 1673 patients after IV and/or SC administration of ustekinumab were fitted simultaneously using nonlinear mixed effects modeling to develop a population PK model, which was subsequently used to evaluate simulation scenarios. Logistic regression E-R models were used to assess relationships between serum ustekinumab concentrations and clinical remission after induction (n = 1910) and maintenance (n = 387) treatment., Findings: Ustekinumab PK properties are well described by a two-compartment model with first-order absorption and elimination. Typical values of PK parameters for a 70-kg patient were: clearance, 0.192 L/d; volume of distribution at steady state, 4.62 L; and intercompartmental clearance, 0.287 L/d. Ustekinumab terminal elimination t 1/2 was 19 days, and bioavailability after SC administration was 78.3%. Ustekinumab clearance was not affected by coadministration of immunosuppressive agents or corticosteroids. Body weight, serum albumin, and C-reactive protein (CRP) concentrations, tumor necrosis factor (TNF) antagonist failure status, sex, race (Asian vs non-Asian), and anti-ustekinumab antibody status significantly affected ustekinumab disposition; however, the effects of these covariates on ustekinumab exposure were not clinically relevant. The population PK model predicts that a milligram/kilogram dosing approach will result in lower ustekinumab exposure in patients with lower body weight. A positive E-R relationship was established between ustekinumab concentration and efficacy outcomes. The treatment effect of ustekinumab after induction therapy was more pronounced among patients with higher baseline CRP concentrations relative to those with lower values., Implications: In patients with CD, ustekinumab disposition after IV and SC administration was biexponential and consistent with those in patients with ulcerative colitis. Prior treatment with TNF antagonists or the concomitant use of immunosuppressive agents or corticosteroids had no effect on ustekinumab disposition. None of the covariates that affected ustekinumab clearance had a clinically meaningful impact on ustekinumab exposure. E-R models support recommended posology of ustekinumab in adults with CD; however, an ∼6 mg/kg IV induction dose in pediatric patients with lower body weights may not provide exposure that matches that in adult patients., Clinicaltrials: gov identifiers: NCT00771667, NCT01369329, NCT01369342, and NCT01369355., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: While no adverse developmental outcomes were observed in preclinical animal studies, limited data exist regarding effects of ustekinumab on human pregnancies. Previously, no data have been reported for women treated with ustekinumab in inflammatory bowel disease (IBD) clinical trials and corresponding pregnancy outcomes. Here, we present pregnancy outcomes from IBD clinical trials, incorporating 5 years of treatment in Crohn's disease (CD) and 2 in ulcerative colitis (UC)., Methods: All patients in the clinical trials agreed to use adequate birth control and were discontinued from treatment upon pregnancy confirmation. Nonetheless, 39 pregnancies occurred with maternal ustekinumab exposure from 4 CD and 1 UC study. Maternal and neonatal outcomes and data are presented with summary statistics, where available., Results: Of 1289 women who received ≥1 dose of ustekinumab, 39 maternal pregnancies with outcomes were reported (pregnancy cohort). Median maternal age was 28.0 years and median duration of ustekinumab treatment before pregnancy was 63.7 weeks with the last dose of ustekinumab administered prior to or during the first trimester (terminal half-life of ~3 weeks). Outcomes for the 39 pregnancies were: 26 live births (all normal newborns), 8 spontaneous abortions, and 5 elective abortions. No congenital anomalies were reported among normal newborns and no safety signals emerged with neonatal outcomes., Conclusions: Based on this series of 39 pregnancies with outcomes from IBD clinical trials, mothers treated with ustekinumab (limited to up to the first trimester) did not demonstrate a risk of negative outcomes. More data are needed to characterize the safety profile of ustekinumab use during pregnancy., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Background: Active-comparator trials are important to inform patient and physician choice. We aimed to evaluate the efficacy and safety of monotherapy with either ustekinumab or adalimumab in biologic-naive patients with moderately to severely active Crohn's disease., Methods: We conducted a randomised, double-blind, parallel-group, active-comparator, phase 3b trial (SEAVUE) at 121 hospitals or private practices in 18 countries. We included biologic-naive patients aged 18 years or older with moderately to severely active Crohn's disease and a Crohn's Disease Activity Index (CDAI) score of 220-450, who had not responded to or were intolerant to conventional therapy (or were corticosteroid dependent) and had at least one ulcer of any size at baseline endoscopic evaluation. Eligible patients were randomly assigned (1:1; via an interactive web response system) to receive ustekinumab (approximately 6 mg/kg intravenously on day 0, then 90 mg subcutaneously once every 8 weeks) or adalimumab (160 mg on day 0, 80 mg at 2 weeks, then 40 mg once every 2 weeks, subcutaneously) through week 56. Study treatments were administered as monotherapy and without dose modifications. Patients, investigators, and study site personnel were masked to treatment group assignment. The primary endpoint was the proportion of patients who were in clinical remission (CDAI score <150) at week 52 in the intention-to-treat population (ie, all patients who were randomly assigned to a treatment group). This trial is registered with ClinicalTrials.gov, NCT03464136, and EudraCT, 2017-004209-41., Findings: Between June 28, 2018, and Dec 12, 2019, 633 patients were assessed for eligibility and 386 were enrolled and randomly assigned to receive ustekinumab (n=191) or adalimumab (n=195). 29 (15%) of 191 patients in the ustekinumab group and 46 (24%) of 195 in the adalimumab group discontinued study treatment before week 52. There was no significant difference between the ustekinumab and adalimumab groups in the occurrence of the primary endpoint; at week 52, 124 (65%) of 191 patients in the ustekinumab group versus 119 (61%) of 195 in the adalimumab group were in clinical remission (between-group difference 4%, 95% CI -6 to 14; p=0·42). Safety for both groups was consistent with previous reports. Serious infections were reported in four (2%) of 191 patients in the ustekinumab group and five (3%) of 195 in the adalimumab group. No deaths occurred through week 52 of the study., Interpretation: Both ustekinumab and adalimumab monotherapies were highly effective in this population of biologic-naive patients, with no difference in the primary outcome between the drugs., Funding: Janssen Scientific Affairs., Competing Interests: Declaration of interests BES reports consulting fees from 4D Pharma, AbbVie, Abivax, Allergan, Amgen, Arena Pharmaceuticals, Artugen Therapeutics, AstraZeneca, Baxalta Bioscience India, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Capella Bioscience, Celltrion Healthcare, ClostraBio, Entera, Evommune, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, GossamerBio, Hoffmann-La Roche, HMP Acquisition, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kallyope, Lilly, Merck & Co, MiroBio, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Laboratories, Prometheus Biosciences IBD, Protagonist Therapeutics, Q32 Bio, Redhill Biopharma, Rheos Medicines, Salix Pharmaceuticals, Seres Therapeutics, Shire, Sienna Biopharmaceuticals, Sun Pharma, Surrozen, Takeda, TARGET RWE, Teva, TLL Therapeutics, USWM Enterprises, Viela Bio, Vivelix Pharmaceuticals; grants and consulting fees from Arena Pharmaceuticals, Celgene, and Theravance Biopharma; consulting fees and stock options from Ventyx Biosciences; and stock options from Vivante Health. PMI reports lecture fees from AbbVie, Celgene, Falk Pharma, Ferring, Janssen, MSD, Pfizer, Sapphire Medical, Sandoz, Shire, Takeda, Tillots, and Warner Chilcott; financial support for research from MSD, Pfizer, and Takeda; and advisory fees from AbbVie, Arena, Genentech, Gilead, Hospira, Janssen, Lilly, MSD, Pfizer, Pharmacosmos, Prometheus, Roche, Sandoz, Samsung Bioepis, Takeda, Topivert, VH2, Vifor Pharma, and Warner Chilcott. TH, JLI, L-LG, CG, and AG report employment with Immunology Global Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson or Janssen Scientific Affairs, a wholly owned subsidiary of Johnson & Johnson, and stock ownership in Johnson & Johnson. MA reports consulting or lecture fees from AbbVie, Amgen, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Genentech, Gilead, IQVIA, Janssen, Novartis, Pfizer, Roche, Takeda, and Tillots; and grant support from Innate Pharma, Janssen, Takeda, and Genentech/Roche. SD reports consulting or lecture fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Celgene, Celltrion Healthcare, Enthera, Ferring Pharmaceuticals, Gilead Sciences, Hospira, Inotrem, Janssen, Johnson & Johnson, Lilly, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenix, UCB, and Vifor International. SBH reports grant support and fees for consulting, lectures, and serving on an advisory board from AbbVie, Janssen, and Takeda; consulting or advisory board fees from Allergan, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ferring, Genentech, Gilead, Merck, Novartis, Pfizer, Protagonist, Receptos, Salix, Samsung Bioepis, Seres Therapeutics, TiGenix, and Vhsquared; and grant support from AbbVie, Celgene, Boehringer Ingelheim, Gilead, Janssen, Pfizer, and Takeda. VJ reports consulting fees from AbbVie, Alimentiv, Arena Pharmaceuticals, Asahi Kasei Pharma, Asieris, Bristol Myers Squibb, Celltrion, Ferring, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Lilly, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, and Topivert; and speaker's fees from AbbVie, Ferring, Galapagos, Janssen, Pfizer, Shire, and Takeda. TK reports lecture and consulting fees from AbbVie, Allmiral, Amgen, Arena, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Falk, Gilead, Galapagos, Janssen, Merkle, Pfizer, Takeda, and Tillots. JDL reports consulting fees from Arena Pharmaceuticals, AbbVie, Bridge Biotherapeutics, Bristol Myers Squibb, Entasis Therapeutics, Gilead, Janssen, Lilly, Merck, Nestle Health Science, Pfizer, Protagonist Therapeutics, Samsung Bioepis, Scipher Medicine, and UCB; and research grants from AbbVie, Janssen, and Takeda. EVL Jr reports consulting fees from AbbVie, Amgen, Arena, Boehringer Ingelheim, Bristol Myers Squibb, Calibr, Celgene, Genentech, Gilead, Gossamer Bio, Iterative Scopes, Janssen, Lilly, Morphic, Ono Pharma, Pfizer, Protagonist, Scipher Medicine, Sun Pharma, Surrozen, Takeda, and UCB; and research support from AbbVie, Bristol Myers Squibb, Celgene, Genentech, Gilead, Gossamer Bio, Janssen, Pfizer, Receptos, Robarts Clinical Trials, Takeda, Theravance, and UCB. EM reports participation as an investigator in trials sponsored by Janssen. RP reports consulting fees from AbbVie, Abbott, Alimentiv, Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Celltrion, Cosmos Pharmaceuticals, Eisai, Elan, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Satisfai Health, Sandoz, Schering-Plough, Shire, Sublimity Therapeutics, Theravance, UCB, and Takeda; speaker fees from AbbVie, Arena, Celgene, Ferring, Gilead Sciences, Janssen, Lilly, Merck, Pfizer, Roche, Sandoz, Shire, and Takeda; research or educational support from AbbVie, Ferring, Janssen, Pfizer, and Takeda; and has served on advisory boards for AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Celltrion, Ferring, Galapagos, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Merck, Mylan, Oppilan Pharma, Pandion Pharma, Pfizer, Sandoz, Shire, Sublimity Therapeutics, Theravance, and Takeda. ES reports grant support from AbbVie, AstraZeneca, Celgene, Crohn's and Colitis Foundation, Genentech, Janssen Research & Development, New York Crohn's Foundation, Pfizer, Seres Therapeutics, and UCB; consulting fees from AbbVie, Abgenomics, Crohn's and Colitis Foundation, Evidera, GI Health Foundation, Janssen, Protagonist, Seres, and Takeda; stock ownership in Gilead; and speaker fees from GI Health Foundation and Prime Therapeutics. OBS reports participation as an investigator in trials sponsored by Janssen. WJS reports grants from AbbVie, Aviva, Arena Pharmaceuticals, Boehringer Ingelheim, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen, Lilly, Pfizer, Prometheus Biosciences, Seres Therapeutics, Shire, Takeda, and TheraVance Biopharma; consulting fees from AbbVie, Abivax, Admirx, Alfa sigma, Alimentiv, Alivio Therapeutics, Allakos, Allergan, Amgen, Applied Molecular Transport, Arena Pharmaceuticals, Avexegen Therapeutics, Bausch Health (Salix), BeiGene, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celgene, Celltrion, Cellularity, Conatus, Cosmo Pharmaceuticals, Equillium, Escalier Biosciences, Ferring, Forbion, Genentech/Roche, Gilead Sciences, Glenmark Pharmaceuticals, Gossamer Bio, Immunic (Vital Therapies), Incyte, Index Pharmaceuticals, Intact Therapeutics, Janssen, Kyowa Kirin Pharmaceutical Research, Kyverna Therapeutics, Landos Biopharma, Lilly, Miraca Life Sciences, Nivalis Therapeutics, Novartis, Nutrition Science Partners, Oppilan Pharma (acquired by Ventyx Biosciences), Otsuka, Pandion Therapeutics, Paul Hastings, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonists Therapeutics, Provention Bio, Reistone Biopharma, Ritter Pharmaceuticals, Seres Therapeutics, Shanghai Pharma Biotherapeutics, Shire, Shoreline Biosciences, Sienna Biopharmaceuticals, Sigmoid Biotechnologies, Sterna Biologicals, Sublimity Therapeutics, Surrozen, Takeda, Theravance Biopharma, Thetis Pharmaceuticals, Tigenix, Tillotts Pharma, UCB Pharma, Vendata Biosciences, Ventyx Biosciences, Vimalan Biosciences, Vivelix Pharmaceuticals, Vivreon Biosciences, and Zealand Pharma; stock or stock options from Allakos, BeiGene, Gossamer Bio, Oppilan Pharma (acquired by Ventyx Biosciences), Prometheus Biosciences, Prometheus Laboratories, Progenity, Shoreline Biosciences, Ventyx Biosciences, Vimalan Biosciences, and Vivreon Biosciences; and employment at Shoreline Biosciences., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background & Aims: The IM-UNITI study and long-term extension (LTE) evaluated the long-term efficacy, safety, and immunogenicity of subcutaneous ustekinumab maintenance therapy in patients with Crohn's disease. Here, we report the final results of IM-UNITI LTE through 5 years., Methods: Patients completing safety and efficacy evaluations at week 44 of the maintenance study were eligible to participate in the LTE and continue the treatment they were receiving. Unblinding occurred after completion of maintenance study analyses (August 2015), and patients receiving placebo were discontinued from the study after unblinding. No dose adjustment occurred in the LTE. Efficacy assessments were conducted every 12 weeks until unblinding and at dosing visits thereafter through week 252. Serum ustekinumab concentrations and antidrug antibodies were evaluated through weeks 252 and 272, respectively., Results: Using an intent-to-treat analysis of all patients randomized to ustekinumab at maintenance baseline, 34.4% of patients in the every-8-weeks group and 28.7% in the every-12-weeks group were in clinical remission at week 252. Corresponding remission rates among patients who entered the LTE were 54.9% and 45.2%. Overall, adverse event rates (per 100 patient-years) from maintenance week 0 through the final visit generally were similar in the placebo and combined ustekinumab groups for all adverse events (440.3 vs 327.6), serious adverse events (19.3 vs 17.5), infections (99.8 vs 93.8), and serious infections (3.9 vs 3.4). Serum ustekinumab concentrations were maintained throughout the LTE. Antidrug antibodies occurred in 5.8% of patients who received ustekinumab during induction and maintenance and continued in the LTE., Conclusions: Patients receiving subcutaneous ustekinumab maintained clinical remission through 5 years. No new safety signals were observed. ClinicalTrials.gov number NCT01369355., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Ustekinumab is currently approved globally in Crohn's disease (CD) and psoriatic diseases. Recent phase 3 data demonstrate safety/efficacy in ulcerative colitis (UC). Crohn's disease and UC phase 3 programs had similar study designs, facilitating integrated safety analyses., Methods: Data from 6 ustekinumab phase 2/3 CD and UC studies were pooled, and safety was evaluated through 1 year. Patients received 1 placebo or ustekinumab (generally 130 mg or ~6 mg/kg) intravenous induction, then subcutaneous (90 mg) maintenance every 8/12 weeks. Analyses incorporated all patients who received ≥1 ustekinumab dose. Safety outcomes are presented as percentages of patients (induction) and as number of patients with events per 100 patient-years of follow-up (through 1 year). For key safety events, 95% confidence intervals (CIs) are provided, as appropriate. Hazard ratios with 95% CIs from time-to-event analyses for serious adverse events and serious infections were also performed., Results: Through 1 year, 2574 patients received ustekinumab (1733 patient-years of follow-up). The number of patients with adverse events per 100 patient-years (placebo 165.99 [95% CI, 155.81-176.67] vs ustekinumab 118.32 [95% CI, 113.25-123.55]), serious AEs (27.50 [95% CI, 23.45-32.04] vs 21.23 [95% CI, 19.12-23.51]), infections (80.31 [95% CI, 73.28-87.84] vs 64.32 [95% CI, 60.60-68.21]), serious infections (5.53 [95% CI, 3.81-7.77] vs 5.02 [95% CI, 4.02-6.19]), and malignancies excluding nonmelanoma skin cancer (0.17 [95% CI, 0.00-0.93] vs 0.40 [95% CI, 0.16-0.83]) were similar between placebo and ustekinumab., Conclusions: The safety profile of ustekinumab across the pooled inflammatory bowel disease population through 1 year was favorable and generally comparable to placebo. These data are consistent with the established safety profile of ustekinumab across indications., Clinicaltrials.gov Numbers: NCT00265122; NCT00771667; NCT01369329; NCT01369342; NCT01369355; NCT02407236., (© 2020 Crohn’s & Colitis Foundation. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation.)

Background and Aims: Following induction/maintenance treatment in the UNITI/IM-UNITI studies of ustekinumab for Crohn's disease, patients entered a long-term extension for up to 5 years from induction. Efficacy through 152 and safety through 156 weeks are reported., Methods: At IM-UNITI Week 44, 567 ustekinumab-treated patients entered the long-term extension and continued to receive blinded subcutaneous ustekinumab on their assigned dose interval, without any subsequent dose adjustment. Placebo-treated patients discontinued after study unblinding [after IM-UNITI Week 44 analyses]. Efficacy data in the long-term extension [LTE] were collected every 12 weeks [q12w] before unblinding and then at q12w/q8w dosing visits., Results: Through Week 156, 29.6% of ustekinumab-treated patients discontinued. In an intent-to-treat analysis of randomised patients from IM-UNITI Weeks 0-152, 38.0% of ustekinumab induction responders receiving the drug q12w and 43.0% q8w were in remission at Week 152. Among patients entering the long-term extension in their original randomised groups, 61.9% of q12w and 69.5% of q8w patients were in remission at Week 152. Across all ustekinumab-treated patients [randomised and non-randomised] entering the long-term extension, remission rates at Week 152 were 56.3% and 55.1% for q12w and q8w, respectively. Safety events [per 100 patient-years] were similar among all ustekinumab-treated patients entering the long-term extension and placebo [overall adverse events 389.70 vs 444.17; serious adverse events, 18.97 vs 19.54; serious infections, 4.21 vs 3.97]. Rates of antibodies to ustekinumab through Week 156 remained low, 4.6% in all randomised ustekinumab-treated patients; lowest among patients in the original randomised q8w group [2/82, 2.4%]., Conclusions: Continued treatment with subcutaneous ustekinumab maintained clinical response and remission through 3 years in a majority of patients who responded to induction therapy and was well-tolerated. ClinicalTrials.gov number NCT01369355., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Although ustekinumab is an effective therapy for moderate to severe Crohn's disease (CD), its effects on the microscopic manifestations of CD are unknown., Methods: We evaluated the effects of ustekinumab on histologic CD activity in an analysis of data from 251 participants in phase 3 induction and maintenance studies. Two endoscopic biopsy samples were collected at weeks 0, 8, and 44 from the ileum, splenic flexure, and rectum (18 biopsy samples from each patient). Histologic activity was assessed based on global histology activity scores (GHASs)., Results: At week 8, the mean GHAS was significantly reduced after ustekinumab induction treatment (from 10.4 ± 7.0 to 7.1 ± 5.9; P < .001) but not in patients who received placebo (from 9.2 ± 6.4 to 7.8 ± 6.2). At week 44 in the randomized maintenance therapy population, the mean GHAS remained reduced from week 8 in patients who received subcutaneous ustekinumab (90 mg every 8 weeks; from 7.4 ± 7.7 to 6.1 ± 4.7) but not every 12 weeks (from 5.3 ± 3.9 to 8.7 ± 4.1) or placebo (from 9.2 ± 3.8 to 10.9 ± 7.1). In the pooled (randomized and nonrandomized) maintenance therapy population, histologic improvement continued in patients given ustekinumab every 8 weeks (from 7.1 ± 6.2 to 5.2 ± 4.2; P < .0001) but not in those given ustekinumab every 12 weeks (from 6.1 ± 5.7 to 7.2 ± 5.1) or placebo (from 8.2 ± 4.2 to 8.9 ± 6.8). A significantly greater proportion of patients achieved histologic response (≥50% decrease in GHAS from baseline) at week 44 if they received ustekinumab every 8 weeks (50% in the randomized maintenance population and 54% in the pooled maintenance population) compared with every 12 weeks (17% and 39% in the randomized and pooled populations, respectively) or placebo (0% and 22% in the randomized and pooled populations, respectively) (P = .0137 for every 8 weeks vs placebo and P = .3529 for every 12 weeks vs placebo in the randomized population; P = .0168 for every 8 weeks vs placebo and P = .3069 for every 12 weeks vs placebo in the pooled population). Regional and overall mean GHASs correlated with the simple endoscopic score for CD (r = .6255, P < .0001). Multivariate analysis found an association between histologic improvement and endoscopic or histologic burden at baseline., Conclusions: In an analysis of data from participants in phase 3 induction and maintenance trials, we found histologic improvement in a greater proportion of patients given ustekinumab vs placebo. The largest improvements occurred in patients who received ustekinumab maintenance therapy every 8 weeks. ClinicalTrials.gov nos. NCT01369329, NCT01369342, and NCT01369355., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Among immunosuppressive- and biologic-naïve patients with moderately-to-severely active Crohn's disease (CD), a higher proportion of those treated with the combination of infliximab and azathioprine achieved corticosteroid-free remission at week 26 (CSFR26) than those given infliximab monotherapy; patients given the combination therapy also had higher serum concentrations of infliximab. Enhanced benefit of combination therapy may occur through synergistic modes of action or the influence of azathioprine on infliximab pharmacokinetics., Methods: We analyzed data from 206 patients from whom week 30 serum samples were available: 97 received infliximab monotherapy (5 mg/kg, n = 97) and 109 received combination therapy (2.5 mg/kg/day; n = 109). Proportions of patients achieving CSFR26 and mucosal healing (absence of ulcers) at week 26 were calculated for each quartile of serum concentrations of infliximab, and exposure-response relationships were compared., Results: Within quartiles of serum concentrations of infliximab, CSFR26 did not differ significantly between patients who received combination therapy vs monotherapy. However, among patients in the lowest quartile of serum concentration of infliximab, twice as many patients who received infliximab monotherapy achieved CSFR26 vs combination therapy. Anti-drug antibodies were detected only in the lowest quartile of serum concentrations of infliximab-in 35.9% of patients given monotherapy and 8.3% of patients given combination therapy., Conclusion: Among patients with CD and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. Combination therapy with azathioprine appears to improve efficacy by increasing pharmacokinetic features of infliximab. ClinicalTrials.gov, NCT00094458., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: Theoretical risks of biologic agents remain under study., Objective: The aim of this study was to integrate 1-year safety data from 12 ustekinumab registrational trials., Methods: Patients had moderate-to-severe plaque psoriasis, active psoriatic arthritis (PsA) (± methotrexate), or moderate-to-severe Crohn's disease (CD; failed/intolerant of immunomodulators/corticosteroids). Psoriatic patients received subcutaneous ustekinumab 45/90 mg or placebo, generally at week 0, week 4, then every 12 weeks thereafter, while those with CD received a single intravenous ustekinumab dose (130 mg or weight range-based dosing of approximately 6 mg/kg) or placebo induction dose at week 0, followed by subcutaneous ustekinumab 90 mg at week 8 and every 8/12 weeks thereafter. The incidence rates of a priori-defined safety events were integrated post hoc (adjusted for duration of follow-up, reported per 100 patient-years [PYs])., Results: Among 6280 enrolled patients, 5884 ustekinumab-treated patients (psoriasis: 3117; PsA: 1018; CD: 1749) contributed 4521 PYs versus 674 PYs in placebo-treated patients through year 1 (829 PYs and 385 PYs during 8- to 16-week controlled periods). Combined across diseases among ustekinumab- versus placebo-treated patients, respective incidences/100 PYs (95% confidence intervals) of infections were 125.4 (122.2-128.7) versus 129.4 (120.9-138.3) through year 1, and not meaningfully increased in patients who did versus those who did not receive methotrexate (92.5 [84.2-101.5] vs. 115.3 [109.9-121.0]), or significantly increased in patients who did versus those who did not receive corticosteroids (116.3 [107.3-125.9] vs. 107.3 [102.0-112.8]) at baseline. Major adverse cardiovascular events (0.5 [0.3-0.7] vs. 0.3 [0.0-1.1]), malignancies (0.4 [0.2-0.6] vs. 0.2 [0.0-0.8]), and deaths (0.1 [0.0-0.3] vs. 0.0 [0.0-0.4]) were rare across indications., Conclusions: Ustekinumab demonstrated a favorable and consistent safety profile across registrational trials in approved indications., Trial Registrations: ClinicalTrials.gov identifier: NCT00320216, NCT00267969, NCT00307437, NCT00454584, NCT00267956, NCT01009086, NCT01077362, NCT00265122, NCT00771667, NCT01369329, NCT01369342, and NCT01369355.

Background & Aims: We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn's disease (CD)., Methods: We performed an endoscopy substudy of 334 patients with moderate to severe CD participating in 3 randomized controlled phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline time point of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomly assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary end point was change in the Simplified Endoscopic Activity Score for Crohn's Disease (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy., Results: Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline time point until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P = .012). Results were similar among patients in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P = .176 and for every 8 weeks, a reduction of 3.1; P = .107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis., Conclusions: In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab. (ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355)., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Aims: We assessed the effect of ustekinumab on health-related quality of life [HRQOL] in adults with Crohn's disease [CD]., Methods: Patients with moderately to severely active CD and inadequate response or intolerance to tumour necrosis factor antagonists [UNITI-1, n = 741], or conventional therapy [UNITI-2, n = 627] were randomised to placebo, ustekinumab 130 mg, or 6 mg/kg intravenous induction therapy. At Week 8, ustekinumab-treated responders (Crohn's Disease Activity Index [CDAI] reduction ≥100 or CDAI <150 points) were re-randomised to subcutaneous maintenance therapy [IM-UNITI, n = 388] with placebo, ustekinumab 90 mg every 12 weeks [q12w], or ustekinumab 90 mg every 8 weeks [q8w], for 44 additional weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and 36-item Short Form Health Survey [SF-36] physical component summary [PCS] and mental component summary [MCS] scores were completed at induction baseline and Week 8, and at maintenance Weeks 20 and 44. Clinically meaningful improvement in IBDQ and PCS and MCS scores were evaluated. For all HRQOL outcomes, each ustekinumab dose and placebo were compared., Results: Induction baseline mean values of IBDQ, PCS, and MCS were similar across groups, but impaired relative to general population norms. At Week 8, ustekinumab induced greater improvement than placebo in both HRQOL scores. Significantly greater proportions of patients receiving ustekinumab 6 mg/kg or 130 mg had clinically meaningful IBDQ improvement [UNITI-1: 54.8%, 46.9% versus 36.5%, respectively; UNITI-2: 68.1%, 58.7% versus 41.1%, respectively; p <0.05, all comparisons]. Similarly, greater proportions of ustekinumab-treated patients in both studies had clinically meaningful improvements in PCS and MCS as compared with placebo. At Week 44, improvements in IBDQ, PCS, and MCS scores were maintained with ustekinumab., Conclusions: Ustekinumab improved HRQOL in patients with moderately to severely active CD.

Background: In Phase 3 studies of ustekinumab, a fully human monoclonal IL-12/23p40 antibody approved for moderate-to-severe Crohn's disease, patients entered a long-term extension after completing 8 weeks of induction and 44 weeks of maintenance treatment. Efficacy through 92 weeks and safety through 96 weeks of IM-UNITI maintenance are reported., Methods: UNITI-1 (TNF-antagonist failures) and UNITI-2 (conventional therapy failures) patients (N = 1281) entered IM-UNITI, including 397 ustekinumab intravenous induction responders randomised to subcutaneous ustekinumab 90 mg every 12 weeks, every 8 weeks, or placebo and 884 nonrandomised patients. Dose-adjustment to 90 mg every 8 weeks occurred in patients randomised to 90 mg every 12 weeks and placebo patients with loss of response (Weeks 8-32). All Week 44 completers could enter the long-term extension without further dose adjustment. Placebo patients discontinued following study unblinding., Results: A total of 718 patients (all treated) entered the long-term extension (298 randomised and 420 not randomised). Overall, 86.5% (621/718) completed Week 96. The proportions of randomised patients in clinical remission were generally maintained from Week 44 through 92 in ustekinumab 90 mg every 12 weeks (77.4% to 72.6%), every 8 weeks (84.1% to 74.4%), and prior dose adjustment groups (63.4% to 53.5%). At Week 92, the proportions of patients in clinical remission were similar in the ustekinumab 90 mg every 12 weeks and every 8 weeks groups and lower in patients with prior dose adjustment. Proportions of patients in clinical remission at Week 92 for all treated every 8 weeks (64.4%) and every 12 weeks (64.3%) groups were lower than randomised every 8 weeks (74.4%) and every 12 weeks (72.6%) groups, but similarly maintained. Safety events (per hundred patient-years) were similar among all placebo and ustekinumab patients (Week 0-96), including adverse events (484.39 vs 447.76), serious adverse events (19.24 vs 18.82), and serious infections (4.09 vs 4.02). No dose effect was observed., Conclusions: Subcutaneous ustekinumab maintained clinical response and remission through Week 92. No new safety signals were observed. ClinicalTrials.gov number NCT01369355., (© 2018 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background & Aims: Ustekinumab is a monoclonal antibody that binds with high affinity to the p40 subunit of human interleukin 12 (IL12 and IL23) that has been approved for treatment of patients with moderate to severe Crohn's disease (CD). However, there are few data on its pharmacokinetic properties or the relationship between drug exposure levels and patient response. We collected data from 2 Phase 3 induction studies and 1 maintenance study to determine ustekinumab's pharmacokinetic features, relationship between exposure and response, and optimal serum concentrations for efficacy., Methods: We collected data on serum concentrations of ustekinumab and efficacy from induction studies of patients with moderate to severe CD given ustekinumab for 8 weeks following a single intravenous dose (either 130 mg or approximately 6 mg/kg). We collected the same data from a maintenance study of patients with a response to ustekinumab in the induction study who then received subcutaneous injections (90 mg) every 8 or 12 weeks for 44 weeks. At week 44 of the maintenance study (52 weeks after treatment began), patients were evaluated for the primary endpoint of clinical remission (defined as a CD activity index score below 150 points), endoscopic markers of efficacy, and serum level of C-reactive protein. Ustekinumab concentration data were categorized into quartiles and relationships between exposure and response were assessed. Optimal concentration cutoff values were evaluated using receiver operating characteristic curve analysis., Results: Serum concentrations of ustekinumab over time were proportional to dose and did not differ significantly between the induction studies. In the maintenance study, ustekinumab concentration reached the steady state by the second maintenance dose; the median trough concentration was approximately threefold higher in patients given ustekinumab at 8-week intervals compared with 12-week intervals. Ustekinumab serum concentrations associated with rates of clinical remission and endoscopic efficacy endpoints, correlated inversely with level of C-reactive protein, and did not associate with use of immunomodulators. Trough concentrations of ustekinumab of 0.8 (or even up to 1.4 μg/mL) or greater were associated with maintenance of clinical remission in a higher proportion of patients than patients with lower trough concentrations., Conclusions: In an analysis of data from Phase 3 studies of patients with moderate to severe CD, we found serum concentrations of ustekinumab to be proportional to dose and associate with treatment efficacy. Concentrations of ustekinumab did not seem to be affected by cotreatment with immunomodulators. Clinicaltrials.gov no. NCT01369329 (UNITI 1), NCT01369342 (UNITI 2), and NCT01369355 (IM-UNITI)., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Informative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn's disease, where a commonly used composite endpoint Crohn's Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and other response driven dose adjustments. This manuscript illustrates the complexities of exposure-response modeling of such composite endpoint data through a latent-variable based Indirect Response model framework for CDAI scores using data from three phase III trials of ustekinumab in patients with moderate-to-severe Crohn's Disease. Visual predictive check was used to evaluate model performance. Potential impacts of the study design on model development and evaluation of the E-R relationship in the induction and maintenance phases of treatment are discussed. Certain biases appeared difficult to overcome, and an autocorrelated residual error model was found to provide improvement.

Background/aims: Efficacy and safety of ustekinumab were evaluated in a Japanese subpopulation with moderately to severely active Crohn's disease (CD) in UNITI-1, UNITI-2 and IM-UNITI studies and results were compared with the overall population., Methods: Overall, patients in UNITI-1 (Japan, n=56; failed response to tumor necrosis factor antagonist) and UNITI-2 (Japan, n=26; failed response to prior conventional therapy) were randomized to placebo or ustekinumab intravenous induction (130 mg or ~6 mg/kg) at week 0. Responders to ustekinumab induction therapy (Japan, n=21) were randomized to placebo or ustekinumab (90 mg, subcutaneous) maintenance (every 12 weeks [q12w] or 8 weeks [q8w]) in IM-UNITI. The primary endpoint was clinical response at week 6 for induction studies and clinical remission at week 44 for maintenance study., Results: Percentage of patients achieving clinical response at week 6 was greater in ustekinumab 130 mg and ~6 mg/kg groups than in the placebo group (UNITI-1: 36.8% and 31.6% vs. 27.8%, respectively, for Japanese; 34.3% and 33.7% vs. 21.5%, respectively, for overall; UNITI-2: 37.5% and 55.6% vs. 11.1%, respectively, for Japanese; 51.7% and 55.5% vs. 28.7%, respectively, for overall). Clinical remission rate at week 44 during maintenance was greater in the ustekinumab 90 mg SC q12w and q8w groups than in the placebo group (50.0% and 55.6% vs. 25.0%, respectively, for Japanese; 48.8% and 53.1% vs. 35.9%, respectively, for overall). Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population., Conclusions: Ustekinumab could be considered as a new therapeutic option for moderately to severely active CD in Japanese patients. Both ustekinumab induction and maintenance treatments were generally well tolerated (Clinical Trial Registration: NCT01369329, NCT01369342, NCT01369355)., Competing Interests: Conflict of interest: Yuya Imai, Yoko Murata, Nobuko Matsushima, and Richuan Zheng are employees of Janssen Pharmaceutical K.K., Japan. Dr. Christopher Gasink is an employee of Janssen Research & Development, LLC, United States. Dr. Toshifumi Hibi is a consultant for Janssen Pharmaceutical K.K., Japan.

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 .).

Background: In patients with Crohn's disease, the efficacy of ustekinumab, a human monoclonal antibody against interleukin-12 and interleukin-23, is unknown., Methods: We evaluated ustekinumab in adults with moderate-to-severe Crohn's disease that was resistant to anti-tumor necrosis factor (TNF) treatment. During induction, 526 patients were randomly assigned to receive intravenous ustekinumab (at a dose of 1, 3, or 6 mg per kilogram of body weight) or placebo at week 0. During the maintenance phase, 145 patients who had a response to ustekinumab at 6 weeks underwent a second randomization to receive subcutaneous injections of ustekinumab (90 mg) or placebo at weeks 8 and 16. The primary end point was a clinical response at 6 weeks., Results: The proportions of patients who reached the primary end point were 36.6%, 34.1%, and 39.7% for 1, 3, and 6 mg of ustekinumab per kilogram, respectively, as compared with 23.5% for placebo (P=0.005 for the comparison with the 6-mg group). The rate of clinical remission with the 6-mg dose did not differ significantly from the rate with placebo at 6 weeks. Maintenance therapy with ustekinumab, as compared with placebo, resulted in significantly increased rates of clinical remission (41.7% vs. 27.4%, P=0.03) and response (69.4% vs. 42.5%, P<0.001) at 22 weeks. Serious infections occurred in 7 patients (6 receiving ustekinumab) during induction and 11 patients (4 receiving ustekinumab) during maintenance. Basal-cell carcinoma developed in 1 patient receiving ustekinumab., Conclusions: Patients with moderate-to-severe Crohn's disease that was resistant to TNF antagonists had an increased rate of response to induction with ustekinumab, as compared with placebo. Patients with an initial response to ustekinumab had significantly increased rates of response and remission with ustekinumab as maintenance therapy. (Funded by Janssen Research and Development; CERTIFI ClinicalTrials.gov number, NCT00771667.).