William J. Sandborn, MD; Paul Rutgeerts, MD, PhD; Robert Enns, MD; Stephen B. Hanauer, MD; Jean-Frédéric Colombel, MD; Remo Panaccione, MD; Geert D'Haens, MD; Ju Li, PhD; Marie R. Rosenfeld, BA; Jeffrey D. Kent, MD; Paul F. Pollack, MD
Acknowledgments: The authors thank Jennifer Alexander, MS, MBA, of JK Associates and Michael Nissen, ELS, of Abbott Laboratories for their editorial support during the development of this manuscript.
Grant Support: By Abbott Laboratories.
Potential Financial Conflicts of Interest: Employment: J. Li (Abbott Laboratories), M.R. Rosenfeld (Abbott Laboratories), J.D. Kent (Abbott Laboratories), P.F. Pollack (Abbott Laboratories); Consultancies: W.J. Sandborn (Abbott Laboratories, ActoGeniX NV, AGI Therapeutics Inc., Ajinomoto Pharmaceuticals, Alba Therapeutics Corporation, Alizyme, Alza Corporation, Amgen Inc., AstraZeneca, Atrix Laboratories Inc., Avidia Inc., Berlex, Bexel Pharmaceuticals Inc., BioBalance Corporation, Boehringer Ingelheim, Bristol-Meyers Squibb, Celegene Corporation, Celltech, Centocor, Cerimon Pharmaceuticals Inc., Chemocentryx, Chugai Biopharmaceuticals Inc., CombinatoRx Inc., CoMentis, Corautus Genetics, Cosmo Technologies, CuraGen Corporation, Domantis, Effective Pharmaceuticals Inc., Eisai Medical Research Inc., Elan, Enzo Therapeutics Inc., Eurand, FlexPharm, Genencor International, Genentech, GlaxoSmithKline, H3 Pharma, Hoffmann-La Roche, Human Genome Sciences, Hutchison Medipharma, IDEC Pharmaceuticals Corporation, Inflabloc Pharmaceuticals, Inhale Therapeutics Systems Inc., Inotek Pharmaceutical Corporation, ISIS Pharmaceuticals, Jacobus Pharmaceutical Company, Johnson & Johnson, LigoCyte Pharmaceuticals, McNeil Consumer and Specialty Pharmaceuticals, Medarex Inc., Merck & Co. Inc., Millennium Pharmaceuticals Inc., Nisshin Kyorin Pharmaceutical Co., Novartis, NPS Pharmaceuticals, OCera Therapeutics Inc., Ono Pharma USA, Otsuka America Pharmaceuticals, PDL, Pfizer Inc., Procter & Gamble, Prometheus, Renovis Inc., Salix Pharmaceuticals Inc., SangStat, Schering-Plough, Serono Inc., Shire Pharmaceuticals, Synta Pharmaceuticals Corporation, Targacept, Teva Pharmaceuticals, Therakos, Tularik Inc., UCB, Vela Pharmaceuticals Inc., ViaCell Inc.), P. Rutgeerts (Abbott Laboratories, Centocor, Schering-Plough, Elan, PDL, NovImmune), R. Enns (Schering-Plough), S.B. Hanauer (Abbott Laboratories, Centocor, UCB, Elan), J.-F. Colombel (Boehringer Ingelheim, Otsuka America Pharmaceuticals, Protein Design Labs, Grünenthal GmbH, Pharmion, UCB, UCB/CellTech, Berlex/Schering, Centocor, Schering-Plough, Elan, Abbott Laboratories, Bristol-Myers Squibb, Shire Pharmaceuticals), R. Panaccione (AstraZeneca, Ferring, Abbott Laboratories, Byk Solvay, Schering-Plough, Shire Pharmaceuticals, Centocor, Elan, Prometheus, GlaxoSmithKline, UCB, Procter & Gamble, Bristol-Myers Squibb), G. D'Haens (Centocor, UCB, Abbott Laboratories, Schering-Plough, Elan); Honoraria: W.J. Sandborn (Abbott Laboratories, Axcan, AstraZeneca, Centocor, Elan, Falk Pharma, Otsuka America Pharmaceuticals, PDL, Procter & Gamble, Prometheus, Salix Pharmaceuticals Inc., Schering-Plough, Shire Pharmaceuticals, ICB Pharma), P. Rutgeerts (Abbott Laboratories, Centocor, Schering-Plough, UCB, Elan, PDL, NovImmune), R. Enns (Schering-Plough), S.B. Hanauer (Centocor), J.-F. Colombel (Centocor, Schering-Plough, Abbott Laboratories, Elan, Ferring, UCB), R. Panaccione (Ferring, Axcan, Jansen, Schering-Plough, Shire Pharmaceuticals, Procter & Gamble), G. D'Haens (Centocor, UCB, Abbott Laboratories, Schering-Plough, Elan); Stock ownership or options (other than mutual funds): J. Li (Abbott Laboratories), M.R. Rosenfeld (Abbott Laboratories), J.D. Kent (Abbott Laboratories), P.F. Pollack (Abbott Laboratories); Expert testimony: S.B. Hanauer (Prometheus); Grants received: W.J. Sandborn (Abbott Laboratories, Bristol-Meyers Squibb, Centocor, Chemocentryx, Elan, Otsuka America Pharmaceuticals, PDL, Procter & Gamble, Prometheus, Salix Pharmaceuticals Inc., Schering-Plough, Serono, Shire Pharmaceuticals, Targacept, Techlab Inc., Tillotts Pharma AG, UCB), P. Rutgeerts (Abbott Laboratories, Centocor, Schering-Plough, UCB), S.B. Hanauer (Abbott Laboratories, Centocor, UCB, Elan, Prometheus), J.-F. Colombel (Giuliani, AstraZeneca, Danisco, Sanofi, Ferring, Association Francois Aupetit, Institut National de la Santé et de la Recherche Médicale, Fonds de Recherche Société Nationale Française de Gastroentérologie, Lille University, International Organisation of Inflammatory Bowel Disease), R. Panaccione (Abbott Laboratories, Schering-Plough, Shire Pharmaceuticals, Millennium Pharmaceuticals Inc., Elan, Procter & Gamble, Bristol-Myers Squibb).
Requests for Single Reprints: William J. Sandborn, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Sandborn: Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
Dr. Rutgeerts: University Hospital, Herestraat 49, 3000 Leuven, Belgium.
Dr. Enns: St. Paul's Hospital, 770-1190 Hornby Street, Vancouver, British Columbia V6Z 2A5, Canada.
Dr. Hanauer: Division of Gastroenterology, University of Chicago Hospital, 5841 South Maryland Avenue, Box 400, Chicago, IL 60637.
Dr. Colombel: Hôpital Claude Huriez, Centre Hospitalier et Universitaire de Lille, 59037 Lille, Cedex, France.
Dr. Panaccione: University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta T2N 4N1, Canada.
Dr. D'Haens: Imelda General Hospital, Imelda GI Clinical Research Center, Imeldalaan 9, 2820 Bonheiden, Belgium.
Drs. Li, Kent, and Pollack and Ms. Rosenfeld: Abbott Laboratories, 300 Interpace Parkway, Parsippany, NJ 07054.
Author Contributions: Conception and design: W.J. Sandborn, P. Rutgeerts, S.B. Hanauer, J. Li, P.F. Pollack.
Analysis and interpretation of the data: W.J. Sandborn, P. Rutgeerts, R. Enns, S.B. Hanauer, J.-F. Colombel, R. Panaccione, G. D'Haens, M.R. Rosenfeld, J.D. Kent, P.F. Pollack.
Drafting of the article: W.J. Sandborn, P. Rutgeerts, S.B. Hanauer, R. Panaccione, J.D. Kent, P.F. Pollack.
Critical revision of the article for important intellectual content: W.J. Sandborn, P. Rutgeerts, R. Enns, S.B. Hanauer, J.-F. Colombel, R. Panaccione, G. D'Haens, J. Li, M.R. Rosenfeld, J.D. Kent, P.F. Pollack.
Final approval of the article: W.J. Sandborn, P. Rutgeerts, R. Enns, S.B. Hanauer, J.-F. Colombel, R. Panaccione, G. D'Haens, J. Li, M.R. Rosenfeld, J.D. Kent, P.F. Pollack.
Provision of study materials or patients: W.J. Sandborn, P. Rutgeerts, S.B. Hanauer, J.-F. Colombel, J.D. Kent, G. D'Haens.
Statistical expertise: J. Li.
Administrative, technical, or logistic support: M.R. Rosenfeld, P.F. Pollack.
Collection and assembly of data: W.J. Sandborn, P. Rutgeerts, R. Panaccione, J. Li, P.F. Pollack.
Adalimumab, a fully human tumor necrosis factor (TNF) antagonist, is an effective treatment for patients with Crohn disease who are naive to the chimeric TNF antagonist, infliximab. No anti-TNF agent has been evaluated prospectively in patients with Crohn disease who had responded to another anti-TNF agent and then lost that response or were intolerant of the agent.
To determine whether adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who have symptoms despite infliximab therapy or who cannot take infliximab because of adverse events.
4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005).
52 sites in the United States, Canada, and Europe.
325 adults 18 to 75 years of age who had a history of Crohn disease for 4 months or more that was moderate to severe at baseline (Crohn's Disease Activity Index [CDAI] score, 220 to 450 points).
Patients were randomly assigned to receive induction doses of adalimumab, 160 mg and 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points.
The primary end point was induction of remission at week 4. Decreases in CDAI score by 70 or more and 100 or more points (secondary end points) were also measured.
A total of 301 patients completed the trial. Twenty-one percent (34 of 159) of patients in the adalimumab group versus 7% (12 of 166) of those in the placebo group achieved remission at week 4 (P < 0.001). The absolute difference in clinical remission rates was 14.2 percentage points (95% CI, 6.7 to 21.6 percentage points). A 70-point response occurred at week 4 in 52% (82 of 159) of patients in the adalimumab group versus 34% (56 of 166) of patients in the placebo group (P = 0.001). The absolute difference in 70-point response rates was 17.8 percentage points (CI, 7.3 to 28.4 percentage points). Two of 159 patients in the adalimumab group and 4 of 166 patients in the placebo group discontinued treatment because of adverse events. No patients in the adalimumab group and 4 of 166 patients in the placebo group had a serious infection.
The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab.
Adalimumab induces remissions more frequently than placebo in adult patients with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy.
ClinicalTrials.gov registration number: NCT00105300.
Can adalimumab, an anti–tumor necrosis factor (anti-TNF) agent, induce remission in patients with Crohn disease who do not respond to or cannot tolerate another anti-TNF agent?
This double-blind, placebo-controlled trial included 325 adults with Crohn disease who had symptoms despite treatment with infliximab or who could not tolerate infliximab because of adverse events. At 4 weeks, more patients randomly assigned to the adalimumab group achieved remission than did those in the placebo group (21% vs. 7%).
The trial did not directly compare efficacy of different anti-TNF agents and did not assess maintenance of response or the long-term immunogenicity of adalimumab.
Study flow diagram.
*Patients with missing Crohn's Disease Activity Index scores were assumed to have had treatment failure.
Table 1. Baseline Characteristics*
Table 2. Patients Achieving Remission at Each Visit*
Mean Crohn's Disease Activity Index (CDAI) score at each visit.
Remission was defined as a decrease in the CDAI score to <150.
Summary of subgroup efficacy results.
Differences are reported in percentage points, and error bars represent 95% CIs. Interaction P values were 0.88 for concomitant immunosuppressive therapy (azathioprine, 6-mercaptopurine, and methotrexate), 0.01 for concomitant corticosteroid therapy, 0.52 for previous loss of response to infliximab, 0.28 for previous intolerance of infliximab, 0.17 for previous loss of response to and intolerance of infliximab, 0.36 for presence of antibodies to infliximab at screening, and 0.67 for C-reactive protein (CRP) concentration ≥10 mg/L at week 0. *Missing data for 1 patient in the placebo group. †Missing data for 7 patients in the placebo group and 6 patients in the adalimumab group.
Table 3. Summary of Safety and Immunogenicity Analyses for All Randomly Assigned Patients*
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Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Colombel J, Panaccione R, et al. Adalimumab Induction Therapy for Crohn Disease Previously Treated with Infliximab: A Randomized Trial. Ann Intern Med. ;146:829–838. doi: 10.7326/0003-4819-146-12-200706190-00159
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Published: Ann Intern Med. 2007;146(12):829-838.
Gastroenterology/Hepatology, Inflammatory Bowel Disease.
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