Patients

From October 2008 through December 2010, we evaluated patients at 153 centers in 12 countries (for details, see the Supplementary Appendix, available with the full text of this article at NEJM.org). The protocol was approved by the institutional review board at each study center. The study was conducted and reported in accordance with the protocol and statistical analysis plan, available at NEJM.org. All patients provided written informed consent.

Eligibility criteria included an age of at least 18 years and at least a 3-month history of Crohn's disease with a score of 220 to 450 points on the Crohn's Disease Activity Index (CDAI; scores range from approximately 0 to 600, with higher scores indicating worse disease and a 50-point change indicating the minimal clinically important difference).22,23 All patients met specified criteria for a primary nonresponse, a secondary nonresponse, or unacceptable side effects after receiving a TNF antagonist at an approved dose (Tables S1A through S1D in the Supplementary Appendix).

Patients were permitted to continue receiving stable doses of drugs for the treatment of Crohn's disease, including oral prednisolone (≤40 mg per day) or budesonide (≤9 mg per day), immunomodulators (e.g., azathioprine, mercaptopurine, or methotrexate), mesalamine, and antibiotics, if they had been taking the drugs for at least the prespecified period before study entry of 3 weeks, 4 weeks, 3 weeks, and 3 weeks, respectively. Patients had not received previous therapies specifically targeting interleukin-12 or interleukin-23. Previous treatment with intravenous glucocorticoids, TNF antagonists, or natalizumab was not permitted for the prespecified washout periods of 3 weeks, 8 weeks, and 12 months, respectively.

Excluded were patients who had undergone bowel resection within 6 months before enrollment and those with the short-bowel syndrome, clinically significant stricture that could require surgery or preclude the use of the CDAI to assess the response to therapy, abscess, active tuberculosis, current infection, or other previous or current opportunistic infection or cancer.

Study Design

During the induction phase (weeks 0 to 8), 526 patients were randomly assigned to receive intravenous ustekinumab (Stelara, Janssen Biotech) in doses of 1, 3, or 6 mg per kilogram of body weight or placebo (Fig. S1 in the Supplementary Appendix). During the maintenance phase (weeks 8 to 36), patients who had a response to ustekinumab as induction therapy and those who did not have a response underwent separate randomization to receive subcutaneous ustekinumab (90 mg) or placebo at weeks 8 and 16, with efficacy assessed at week 22. Transition from the induction phase to the maintenance phase occurred at the same visit at week 8.

Patients who had a response to placebo induction received subcutaneous placebo at weeks 8 and 16; those who did not have a response to placebo induction received a subcutaneous injection of ustekinumab (270 mg) at 8 weeks, followed by an injection of 90 mg at 16 weeks. Glucocorticoid tapering was mandated in patients with a clinical response, beginning at 8 weeks. Otherwise, concomitant medications remained constant through week 22. Maintenance end points were assessed at 22 weeks. Patients were followed through 36 weeks for the safety analysis.

We selected intravenous administration (rather than subcutaneous injection) of ustekinumab for the induction phase on the basis of improved clinical outcomes in the phase 2a trial.21 We selected subcutaneous administration for the maintenance phase because a reduced amount of the drug is generally required to maintain efficacy, and subcutaneous administration offers greater convenience for patients.

Adaptive randomization, performed centrally, was used for both phases. In the induction phase, randomization was based on the investigative site and the initial response to a TNF antagonist (i.e., the response to the first TNF antagonist if >1 agent was previously administered). In the maintenance phase, randomization was based on the investigative site and the induction dose; for patients with an initial response to ustekinumab, a third factor was the remission status at 6 weeks.

End Points

The primary end point was a clinical response (≥100-point decrease from the baseline CDAI score) at week 6, which was selected on the basis of the phase 2a trial21 as the optimal timing of separation from placebo for this measure. Patients with a baseline CDAI score of 248 points or less were considered to have a clinical response if the CDAI score was less than 150.22,23 Major secondary end points were clinical remission (CDAI score, <150 points) at week 6, clinical response at week 4, and clinical remission at week 22 among patients with a response to ustekinumab at week 6. Patients who underwent surgery for Crohn's disease, had protocol-prohibited changes in concomitant medications, or had insufficient data for calculation of CDAI scores were considered not to have had a clinical response or remission at that time point, as were patients who discontinued the study drug because of a lack of efficacy during maintenance.

Efficacy and Safety Evaluations

Study visits occurred at weeks 0, 4, 6, 8, 12, 16, 20, 22, 28, and 36. At each visit, we evaluated data for CDAI, adverse events, concomitant medications, and levels of serum ustekinumab and C-reactive protein (CRP). At weeks 0, 22, and 36, we evaluated serum samples for antibodies to ustekinumab, using an antigen-bridging enzyme immunoassay.24 In an endoscopy substudy conducted at selected sites, with separate informed consent obtained from participants, we assessed the degree of mucosal healing at weeks 0, 6, and 22.

Study Oversight

A steering committee comprising academic investigators and representatives of the sponsor (Janssen Research and Development) designed the study, interpreted the data, and contributed to the manuscript. Janssen representatives collected and analyzed the data, and the first author wrote the first draft of the manuscript. All academic authors had full access to the data and vouch for the veracity and completeness of the data and analyses and for the fidelity of this report to the study protocol. All authors made the decision to submit the manuscript for publication. Janssen analyzed and interpreted the pharmacokinetic data. Editorial assistance was provided by employees of the Medical Affairs Publications Group at Janssen Biotech and by another Janssen employee.

Statistical Analysis

We based all sample-size and power calculations on a dose of 6 mg of ustekinumab per kilogram as compared with placebo. We calculated that 496 patients (124 per group) would provide 90% power to detect a 20% difference in clinical response, assuming a response rate of 50% for 6 mg of ustekinumab per kilogram and 30% for placebo.

We analyzed the end points of clinical response at week 6, remission at week 6, and clinical response at week 4 using a two-sided Cochran–Mantel–Haenszel chi-square test at an alpha level of 0.05, with stratification according to the initial response to a TNF antagonist. For patients who had a response to ustekinumab at week 6, we analyzed the proportion of patients in remission at week 22 using the Cochran–Mantel–Haenszel chi-square test, stratified according to the intravenous induction dose and clinical-remission status at week 6. To control for type I error for the primary end point, a prespecified, fixed-sequence-testing procedure was used, beginning with the highest dose. The study was considered to be positive if there was a significant difference in the clinical response at week 6 between the group receiving 6 mg of ustekinumab per kilogram and the group receiving placebo. Testing for clinical remission at week 22 was performed if the comparison between 6 mg of ustekinumab per kilogram and placebo was positive for the primary end point. Analyses of the other secondary end points were not adjusted for multiple comparisons; statements of statistical significance for these end points are based on nominal P values.

To evaluate the consistency of the treatment effect for the clinical response at week 6, we performed 23 prespecified subgroup analyses (Fig. S3 in the Supplementary Appendix). We calculated odds ratios and 95% confidence intervals for the proportions of patients who had a response at week 6 in the group receiving 6 mg of ustekinumab per kilogram and the group receiving placebo.

We used analysis of covariance to evaluate other secondary continuous end points (i.e., change from baseline in the CDAI score and CRP level). Secondary categorical end points (i.e., 70-point response [a decrease from the baseline CDAI score of ≥70 points], sustained 100-point clinical response [a sustained 100-point decrease in the CDAI score], and sustained remission at week 22 among patients who had a response at week 6) were analyzed with the use of a Cochran–Mantel–Haenszel chi-square test. These analyses were not adjusted for multiple comparisons.

Treatment-failure rules were applied to all efficacy end points: baseline (week 0) values were assigned from the time of treatment failure for continuous end points, and dichotomous end points were considered not to have been achieved. If data were missing, dichotomous end points were considered not to have been achieved; the last observation was carried forward for continuous end points. All efficacy analyses were based on the intention-to-treat principle, with data for all patients who underwent randomization included in analyses of induction end points and data for all patients who had a response to ustekinumab at week 6 included in analyses of maintenance end points. Safety analyses were based on actual treatment received.