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      Adalimumab for the treatment of fistulas in patients with Crohn’s disease

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          Abstract

          Objective:

          To evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn’s disease (CD).

          Design:

          A phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites.

          Patients:

          A subgroup of adults with moderate to severely active CD (CD activity index 220–450) for ⩾4 months who had draining fistulas at baseline.

          Interventions:

          All patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension.

          Main Outcome Measures:

          Complete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression.

          Results:

          Of 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis).

          Conclusions:

          In patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial.

          ClinicalTrials.gov Identifier: NCT00077779 and NCT00195715.

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          Most cited references 13

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          Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial.

          This study evaluated the efficacy and safety of adalimumab, a fully human, anti-tumor necrosis factor monoclonal antibody administered subcutaneously, in the maintenance of response and remission in patients with moderate to severe Crohn's disease (CD). Patients received open-label induction therapy with adalimumab 80 mg (week 0) followed by 40 mg (week 2). At week 4, patients were stratified by response (decrease in Crohn's Disease Activity Index > or =70 points from baseline) and randomized to double-blind treatment with placebo, adalimumab 40 mg every other week (eow), or adalimumab 40 mg weekly through week 56. Co-primary end points were the percentages of randomized responders who achieved clinical remission (Crohn's Disease Activity Index score <150) at weeks 26 and 56. The percentage of randomized responders in remission was significantly greater in the adalimumab 40-mg eow and 40-mg weekly groups versus placebo at week 26 (40%, 47%, and 17%, respectively; P < .001) and week 56 (36%, 41%, and 12%, respectively; P < .001). No significant differences in efficacy between adalimumab eow and weekly were observed. More patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (6.9% and 4.7% in the 40-mg eow and 40-mg weekly groups, respectively). Among patients who responded to adalimumab, both adalimumab eow and weekly were significantly more effective than placebo in maintaining remission in moderate to severe CD through 56 weeks. Adalimumab was well-tolerated, with a safety profile consistent with previous experience with the drug.
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            Infliximab for the treatment of fistulas in patients with Crohn's disease.

            Enterocutaneous fistulas are a serious complication of Crohn's disease and are difficult to treat. Infliximab, a chimeric monoclonal antibody to tumor necrosis factor alpha, has recently been developed as a treatment for Crohn's disease. We conducted a randomized, multicenter, double-blind, placebo-controlled trial of infliximab for the treatment of fistulas in patients with Crohn's disease. The study included 94 adult patients who had draining abdominal or perianal fistulas of at least three months' duration as a complication of Crohn's disease. Patients were randomly assigned to receive one of three treatments: placebo (31 patients), 5 mg of infliximab per kilogram of body weight (31 patients), or 10 mg of infliximab per kilogram (32 patients); all three were to be administered intravenously at weeks 0, 2, and 6. The primary end point was a reduction of 50 percent or more from base line in the number of draining fistulas observed at two or more consecutive study visits. A secondary end point was the closure of all fistulas. Sixty-eight percent of the patients who received 5 mg of infliximab per kilogram and 56 percent of those who received 10 mg per kilogram achieved the primary end point, as compared with 26 percent of the patients in the placebo group (P=0.002 and P=0.02, respectively). In addition, 55 percent of the patients assigned to receive 5 mg of infliximab per kilogram and 38 percent of those assigned to 10 mg per kilogram had closure of all fistulas, as compared with 13 percent of the patients assigned to placebo (P=0.001 and P=0.04, respectively). The median length of time during which the fistulas remained closed was three months. More than 60 percent of patients in all the groups had adverse events. For patients treated with infliximab, the most common were headache, abscess, upper respiratory tract infection, and fatigue. Infliximab is an efficacious treatment for fistulas in patients with Crohn's disease.
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              Infliximab maintenance therapy for fistulizing Crohn's disease.

              Infliximab, a monoclonal antibody against tumor necrosis factor, is an effective maintenance therapy for patients with Crohn's disease without fistulas. It is not known whether infliximab is an effective maintenance therapy for patients with fistulas. We performed a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least three months' duration. Patients received 5 mg of infliximab per kilogram of body weight intravenously on weeks 0, 2, and 6. A total of 195 patients who had a response at weeks 10 and 14 and 87 patients who had no response were then randomly assigned to receive placebo or 5 mg of infliximab per kilogram every eight weeks and to be followed to week 54. The primary analysis was the time to the loss of response among patients who had a response at week 14 and underwent randomization. The time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, P<0.001). At week 54, 19 percent of patients in the placebo maintenance group had a complete absence of draining fistulas, as compared with 36 percent of patients in the infliximab maintenance group (P=0.009). Patients with fistulizing Crohn's disease who have a response to induction therapy with infliximab have an increased likelihood of a sustained response over a 54-week period if infliximab treatment is continued every 8 weeks. Copyright 2004 Massachusetts Medical Society
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                Author and article information

                Journal
                Gut
                gut
                Gut
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0017-5749
                1468-3288
                2009
                July 2009
                5 February 2009
                5 February 2009
                : 58
                : 7
                : 940-948
                Affiliations
                [1 ]Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, Lille, France
                [2 ]Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
                [3 ]Mayo Clinic, Rochester, Minnesota, USA
                [4 ]St Vincent’s Hospital and University of Melbourne, Melbourne, Australia
                [5 ]Imelda Ziekenhuis, Bonheiden, Belgium
                [6 ]University Hospital of Gathuisberg, Leuven, Belgium
                [7 ]St Paul’s Hospital, University of British Columbia, Vancouver, British Columbia, Canada
                [8 ]University of Calgary, Calgary, Alberta, Canada
                [9 ]Christian-Albrechts University, Kiel, Germany
                [10 ]Abbott Laboratories, Parsippany, New Jersey, USA
                [11 ]Abbott Laboratories, Abbott Park, Illinois, USA
                Author notes

                ▸ Competing interests: Declared (the declaration can be viewed on the Gut website at http://gut.bmj.com/content/vol58/issue7)

                Correspondence to: Dr J-F Colombel, Hôpital Claude Huriez, Centre Hospitalier Universitaire de Lille, Rue Michel Polonovski, Lille, France 59037; jfcolombel@ 123456chru-lille.fr
                Article
                gt159251
                10.1136/gut.2008.159251
                2689393
                19201775
                © Colombel et al 2009

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Categories
                Inflammatory Bowel Disease
                1506
                1507

                Gastroenterology & Hepatology

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