Adalimumab Induction Therapy for Crohn Disease Previously Treated with Infliximab

A Randomized Trial

19 June 2007 | Volume 146 Issue 12

Background: 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.

Objective: 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.

Design: 4-week, randomized, double-blind, placebo-controlled trial (November 2004 to December 2005).

Setting: 52 sites in the United States, Canada, and Europe.

Patients: 325 adults 18 to 75 years of age who had 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).

Interventions: Patients were randomly assigned to receive induction doses of adalimumab, 160 mg, and adalimumab, 80 mg, at weeks 0 and 2, respectively, or placebo at the same time points.

Measurements: The primary end point was induction of remission at week 4. Decreases in CDAI by 70 or more and 100 or more points (secondary end points) were also measured.

Results: 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.

Limitations: The trial did not directly compare alternative active treatments and did not evaluate maintenance of response or long-term immunogenicity of adalimumab.

Conclusion: Adalimumab induces remissions more frequently than placebo in adults with Crohn disease who cannot tolerate infliximab or have symptoms despite receiving infliximab therapy.

ClinicalTrials.gov registration number: NCT00105300.

Editors' Notes Context 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? Contribution 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%). Cautions 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. —The Editors

 

Author and Article Information

From the Mayo Clinic, Rochester, Minnesota; Universitaire Ziekenhuizen Leuven, UZ Gasthuisberg, Leuven, Belgium; University of British Columbia, Vancouver, British Columbia, Canada; University of Chicago, Chicago, Illinois; Hopital Claude Huriez and Centre Hospitalier Universitare de Lille, Lille, France; University of Calgary, Calgary, Alberta, Canada; Imelda General Hospital, Bonheiden, Belgium; and Abbott Laboratories, Parsippany, New Jersey, and Abbott Park, Illinois.

Acknowledgments: The authors thank Jennifer Alexander, MS, MBA, of JK Associates Inc. 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 Therapeautics Inc., Ajinomoto Pharmaceuticals, Alba Therapeutics Corporation, Alizyme plc, Alza Corporation, Amgen Inc., AstraZeneca, Atrix Laboratories Inc., Avidia Inc., Berlex, Bexel Pharmaceuticals Inc., BioBalance Corporation, Boehriger-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, Hoffman LaRoche, 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, Millennium Pharmaceuticals Inc., Misshin Kyorin Pharmaceutical Co., Novaritis, NPS Pharmaceuticals, Ocera Therapeutics Inc., Ono Pharma USA, Otsuka American Pharmaceuticals, PDL, Pfizer, 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 Pharmaceuticals, Protein Design Labs, Grunenethal GMBH, Pharmion, UCB, UCB/Celltech, Berlex/Schering, Centocor, Schering-Plough, Elan, Abbott, 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 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, 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 Pharmaceuticals, PDL, Procter & Gamble, Prometheus, Salix Pharmaceuticals Inc., Schering-Plough, Serono, Shire Pharmaceuticals, Targacept Inc., Techlab Inc., Tillots Phara 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 USA, Ferring France, Association Francois Aupetit, Institut national de la santé et de la recherche médicale/L'Institut National de Veille Sanitaire, Institut national de la santé et de la recherche médicale U795, Institut national de la santé et de la recherche médicale/maladies rares, Fonds de Reserche SNFGE, Lille University, International Organisation of Inflammatory Bowel Disease), R. Panaccione (Abbott Laboratories, Schering-Plough, Shire Pharmaceuticals, Millenium, Elan, Procter & Gamble, Bristol-Myers Squibb).

Requests for Single Reprints: William J. Sandborn, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55902; e-mail, sandborn.william{at}mayo.edu.

Current Author Addresses: Dr. Sandborn: Mayo Clinic, 200 First Street South West, 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: Hopital Claude Huriez, CH et U 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 7054.

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.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.

Read all Rapid Responses

To Switch Or Not To Switch TNF Agents In Crohn's Disease

Daniel G. Arkfeld

Annals Online, 19 Jun 2007 [Full text]