A Randomized Trial of Ustekinumab, a Human Interleukin-12/23 Monoclonal Antibody, in Patients With Moderate-to-Severe Crohn's Disease

Background & Aims: Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23. Methods: We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn's disease (population 1). Patients were given subcutaneous placebo at weeks 0–3, then ustekinumab at weeks 8–11; subcutaneous ustekinumab at weeks 0–3, then placebo at weeks 8–11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). Results: In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo. Conclusions: Ustekinumab induced a clinical response in patients with moderate-to-severe Crohn's disease, especially in patients previously given infliximab. Background & Aims: Interleukin-12 and interleukin-23 are inflammatory cytokines implicated in Crohn's disease pathophysiology. Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin-12/23. Methods: We performed a double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with moderate-to-severe Crohn's disease (population 1). Patients were given subcutaneous placebo at weeks 0–3, then ustekinumab at weeks 8–11; subcutaneous ustekinumab at weeks 0–3, then placebo at weeks 8–11; intravenous placebo at week 0, then ustekinumab at week 8; or intravenous ustekinumab at week 0, then placebo at week 8. Furthermore, an open-label trial evaluated the effects of 4 weekly subcutaneous injections or 1 intravenous infusion of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). Results: In population 1, clinical response rates for the combined groups given ustekinumab and placebo were 53% and 30% (P = .02), respectively at weeks 4 and 6, and 49% and 40% (P = .34), respectively at week 8. In a subgroup of 49 patients who were previously given infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than the group given placebo (P < .05) through week 8. In population 2, the clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43% and 54%, respectively. There was no increase in the number of adverse or serious adverse events in patients given ustekinumab through week 8 compared with placebo. Conclusions: Ustekinumab induced a clinical response in patients with moderate-to-severe Crohn's disease, especially in patients previously given infliximab. See Maser EA et al on page 1112 in CGH. See Maser EA et al on page 1112 in CGH. Conventional therapy for moderate-to-severe Crohn's disease includes corticosteroids and immunosuppressive therapy with azathioprine, 6-mercaptopurine, or methotrexate.1Hanauer S.B. Sandborn W. 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Ustekinumab is a fully human IgG1 monoclonal antibody that targets the interleukin 12/23 shared p40 subunit. Anti–interleukin-12/23 therapy with ustekinumab has shown efficacy in psoriasis22Leonardi C.L. Kimball A.B. Papp K.A. et al.Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 1).Lancet. 2008; 371: 1665-1674Abstract Full Text Full Text PDF PubMed Scopus (1400) Google Scholar, 23Papp K.A. Langley R.G. Lobwohl M. et al.Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, placebo-controlled trial (PHOENIX 2).Lancet. 2008; 371: 1675-1684Abstract Full Text Full Text PDF PubMed Scopus (1255) Google Scholar, 24Krueger G.G. Langley R.G. Leonardi C. et al.A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis.N Engl J Med. 2007; 356: 580-592Crossref PubMed Scopus (702) Google Scholar and has been evaluated in multiple sclerosis.25Kasper L.H. Everitt D. Leist T.P. et al.A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis.Curr Med Res Opin. 2006; 22: 1671-1678Crossref PubMed Scopus (41) Google Scholar Here we report the results of a randomized, placebo-controlled, phase 2a induction trial of ustekinumab in patients with moderate-to-severe Crohn's disease. This trial was conducted between May 2004 and October 2006. The protocol was approved by the institutional review board at each center. All patients gave written informed consent. Eligible patients were adults with moderate-to-severe Crohn's disease of at least 6 weeks' duration and a Crohn's disease activity index (CDAI) score of 220–450 points (range, 0–600 points; greater scores indicate more severe disease).26Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3035) Google Scholar Crohn's colitis, ileitis, or ileocolitis was confirmed by radiography or endoscopy. Ineligible patients were those testing positive for a tuberculin skin test and patients with short-bowel syndrome, an ostomy, obstructive symptoms with strictures, current or recent opportunistic infection or abscess, cancer, recent treatment with any investigational agent or an anti-TNF agent including infliximab within the past 16 weeks. Concomitant use of 5-aminosalicylates, antibiotics, prednisolone at a maximum daily dose of 20 mg, azathioprine, 6-mercaptopurine, or methotrexate was permitted. Concomitant medication doses remained constant, except corticosteroids, which could be tapered by 2.5 mg/wk after week 8. Two populations were studied. Population 1 had received at least one of the following: 5-aminosalicylates, antibiotics, corticosteroids, azathioprine, 6-mercaptopurine, or methotrexate; submaximal infliximab doses or regimens (ie, only 1–2 induction doses of infliximab 5 mg/kg, or maintenance doses of infliximab 5 mg/kg every 8 weeks without shortening the dosing interval or escalating to infliximab 10 mg/kg, or infliximab intolerance); or other anti-TNFα agents. Population 2 comprised nonresponders to a 3-dose induction of infliximab 5 mg/kg (primary nonresponders) or initial responders who lost response during every-8-week maintenance therapy, despite dose escalation to 10 mg/kg (secondary nonresponders), as determined by the investigator. This was a double-blind, placebo-controlled, parallel-group, cross-over study. Cross-over to the alternate therapy occurred at week 8. Patients were randomly assigned (1:1:1:1) to 1 of 4 groups: subcutaneous placebo at weeks 0, 1, 2, and 3, then 90 mg ustekinumab at weeks 8, 9, 10, and 11; subcutaneous 90 mg ustekinumab at weeks 0, 1, 2, and 3, then placebo at weeks 8, 9, 10, and 11; intravenous placebo at week 0, then 4.5 mg/kg ustekinumab at week 8; or intravenous 4.5 mg/kg ustekinumab at week 0, then placebo at week 8. This was an open-label study. Patients were assigned randomly (1:1) to either subcutaneous 90 mg ustekinumab at weeks 0, 1, 2, and 3, or intravenous 4.5 mg/kg ustekinumab at week 0. No additional treatment was administered at week 8. Randomization in both study populations was performed centrally using an adaptive randomization procedure that was stratified by investigative site. Clinical response was defined as a reduction of at least 25% and 70 points in the CDAI score from week 0.4Hanauer S.B. Feagan B.G. Lichtenstein G.R. et al.Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.Lancet. 2002; 359: 1541-1549Abstract Full Text Full Text PDF PubMed Scopus (3629) Google Scholar, 27Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar Clinical remission was defined as an absolute CDAI score of less than 150 points, and 100-point response was defined as a reduction of at least 100 points from week 0 in the CDAI score.26Best W.R. Becktel J.M. Singleton J.W. et al.Development of a Crohn's disease activity index National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (3035) Google Scholar, 27Sandborn W.J. Feagan B.G. Hanauer S.B. et al.A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease.Gastroenterology. 2002; 122: 512-530Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar Patients in both populations were followed up for safety and efficacy through week 28. Data for CDAI scores were collected from patient diaries; clinical assessments, adverse events, and concomitant medications were recorded; and laboratory tests, including assessment of the C-reactive protein concentration, were performed throughout the study. Blood samples were drawn at weeks 0, 16, 28, and 54 for assessment of antibodies to ustekinumab using an antigen-bridging enzyme immunoassay. The primary end point was clinical response at week 8 in population 1, defined as a reduction of 25% or more and 70 points or more from the baseline CDAI score. Secondary end points included clinical response at weeks 4 and 6, and clinical remission and 100-point response at weeks 4, 6, and 8. Other end points included clinical response, 100-point response, and clinical remission at week 16, a time point 8 weeks after the first dose of ustekinumab in patients who initially had been assigned to placebo from week 0 through week 8. Patients who had a prohibited change in their concomitant Crohn's disease medication, a Crohn's disease–related surgery, or who discontinued study medication for lack of therapeutic effect were considered not to have achieved clinical response, clinical remission, or 100-point response from the time of event onward. Patients with insufficient data to calculate their CDAI score were considered not to have achieved clinical response, clinical remission, or 100-point response at that time point. The intent-to-treat population included all randomized patients. Comparisons between the placebo (subcutaneous and intravenous combined) and ustekinumab (subcutaneous and intravenous combined) groups were made for each end point using a 2-sided, 0.05-level Cochran–Mantel–Haenszel chi-square test, stratified by route of administration. Comparisons of each end point through week 8 by route of administration were made between placebo and ustekinumab using a 2-sided, 0.05-level Fisher's exact test. Prespecified subgroup analyses were as follows: baseline bodyweight (<60 kg, ≥60 to <75 kg, or ≥75 kg); Crohn's disease duration (≤5 y, >5 to ≤15 y, or >15 y); C-reactive protein (<0.6 mg/dL or ≥0.6 mg/dL); and previous use (yes, no) or concomitant use (yes, no) of corticosteroids, 5-aminosalicylate compounds, azathioprine, 6-mercaptopurine, methotrexate, anti-TNF agents, or antibiotics. Odds ratios and corresponding 95% confidence intervals were determined to compare the proportion of patients in clinical response at week 8 in the combined ustekinumab and combined placebo groups. Summaries of adverse events and antibodies to ustekinumab were based on data for all patients who received at least one dose of study medication and were based on the actual treatment received. For the primary end point of clinical response at week 8 in population 1, we planned to recruit 25 patients each into the subcutaneous and intravenous ustekinumab and placebo groups, yielding a total sample size of 100 patients. Combining the subcutaneous and intravenous routes of administration for both the ustekinumab and placebo groups, 100 patients would provide 82% power to detect a difference in clinical response rates of 30% assuming a 70% rate of clinical response for ustekinumab and a 40% rate of clinical response for placebo. No power calculations were performed for population 2. The steering committee of academic investigators and Centocor contributors designed this study. Centocor bioanalytic staff created the clinical database and performed the statistical analyses. All authors interpreted the data, and prepared and approved the report for submission.