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

doi:10.1053/j.gastro.2008.07.014

Gastroenterology

Volume 135, Issue 4, October 2008, Pages 1130-1141

Data were presented on May 21, 2007 at Digestive Disease Week 2007 (Washington, DC).

https://doi.org/10.1053/j.gastro.2008.07.014 Get rights and content

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.

Section snippets

Patients

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).²⁶ Crohn's colitis, ileitis, or ileocolitis was confirmed by radiography or

Patients

A total of 202 patients were enrolled, of whom 104 and 27 were randomized to treatment in populations 1 and 2, respectively, at 49 centers (Figure 1). Among the 71 patients enrolled but not randomized to treatment, most of these patients did not participate primarily because either screening criteria were not met (49 patients) or consent was withdrawn before randomization (9 patients).

Baseline characteristics generally were similar across treatment groups in populations 1 and 2 (Table 1).

Discussion

Induction of response and remission in patients with active Crohn's disease who fail to respond to conventional therapy (including anti-TNF therapy) is an important unmet clinical need. Inhibition of the interleukin-12/23 inflammation pathways via monoclonal antibody blockade of their common p40 subunit constitutes a unique mechanism of action for Crohn's disease therapy. Although the results of this phase 2, exploratory trial failed to definitively show that induction therapy with ustekinumab

Ustekinumab Crohn's Disease Study Group

The authors wish to thank the Principal Investigators from the Ustekinumab Crohn's Disease Study Group, as listed below in alphabetical order: S. V. Alapati, Gastroenterology Associates LLC, Baton Rouge, LA; F. Anderson, Liver and Intestinal Research Centre, Vancouver, BC, Canada; C. Bernstein, Health Sciences Centre, Winnipeg, MB, Canada; S. J. Bickston, University of Virginia Health System, Division of Gastroenterology & Hepatology, Charlottesville, VA; S. D. Bologna, Troy Gastroenterology,

References (35)

S.B. Hanauer et al.
The Practice Parameters Committee of the American College of GastroenterologyManagement of Crohn's disease in adults
Am J Gastroenterol
(2001)
S.B. Hanauer et al.
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial
Lancet
(2002)
S.B. Hanauer et al.
Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC I trial
Gastroenterology
(2006)
J.F. Colombel et al.
Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial
Gastroenterology
(2007)
P. Rutgeerts et al.
Comparison of scheduled and episodic treatment strategies of infliximab in Crohn's disease
Gastroenterology
(2004)
C.O. Elson et al.
Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice
Gastroenterology
(2007)
C.L. Leonardi 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)
K.A. Papp 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)
W.R. Best et al.
Development of a Crohn's disease activity indexNational Cooperative Crohn's Disease Study
Gastroenterology
(1976)
W.J. Sandborn et al.
A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn's disease
Gastroenterology
(2002)

S. Schreiber et al.

A randomized, placebo-controlled trial of certolizumab pegol (CDP870) for treatment of Crohn's disease

Gastroenterology

(2005)

C. Su et al.

A meta-analysis of the placebo rates of remission and response in clinical trials of active Crohn's disease

Gastroenterology

(2004)

B.E. Sands et al.

Optimal Crohn's disease activity index (CDAI) response criteria is defined by decrease ≥ 100 points

Gastroenterology

(2003)

S.P. Travis et al.

European evidence based consensus on the diagnosis and management of Crohn's disease: current management

Gut

(2006)

S.R. Targan et al.

A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease

N Engl J Med

(1997)

W.J. Sandborn et al.

Certolizumab pegol for the treatment of Crohn's disease

N Engl J Med

(2007)

S. Schreiber et al.

Certolizumab pegol maintenance therapy for Crohn's disease

N Engl J Med

(2007)

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: Some of the results presented in this article were previously published in abstract form in Gastroenterology 2007;132(Suppl 2):A-51.

: Centocor, Inc (Malvern, PA) provided support for this study (C0379T07; clinical trials registration: clinicaltrials.gov #NCT00265122). Marion Blank and Jewel Johanns are employees of Centocor, Inc; William J. Sandborn received research funding in conjunction with the conduct of this study, he also received a research grant (1-UL1-RR024150-01) from the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research and is a consultant to Centocor, Inc (fees paid to the Mayo Clinic); Brian G. Feagan received research funding in conjunction with the conduct of this study, he also received other research grants and is a consultant to Centocor, Inc; Richard N. Fedorak received research funding in conjunction with the conduct of this study; Ellen Scherl received research funding in conjunction with the conduct of this study and other research grants and served as a consultant to Centocor, Inc; Mark R. Fleischer received research funding in conjunction with the conduct of this study and speaker payments, and has served as a consultant to Centocor, Inc; Seymour Katz received research funding in conjunction with the conduct of this study and other research grants from Centocor, Inc; Paul Rutgeerts received research funding in conjunction with the conduct of this study, he also received other research grants and speaker payments, and is a consultant to Centocor, Inc.

: Members of the Ustekinumab Crohn's Disease Study Group are listed at the end of the article.

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

Section snippets

Patients

Patients

Discussion

Ustekinumab Crohn's Disease Study Group

Am J Gastroenterol

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

European evidence based consensus on the diagnosis and management of Crohn's disease: current management

Gut

A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease

N Engl J Med

Certolizumab pegol for the treatment of Crohn's disease

N Engl J Med

Certolizumab pegol maintenance therapy for Crohn's disease

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