Elsevier

The Lancet

Volume 359, Issue 9317, 4 May 2002, Pages 1541-1549
The Lancet

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Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial*

https://doi.org/10.1016/S0140-6736(02)08512-4Get rights and content

Summary

Background

We did a randomised controlled trial to assess the benefit of maintenance infliximab therapy in patients with active Crohn's disease who respond to a single infusion of infliximab.

Methods

573 patients with a score of at least 220 on the Crohn's disease activity index (CDAI) received a 5 mg/kg intravenous infusion of infliximab at week 0. After assessment of response at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of 5 mg/kg infliximab at the same timepoints (group II), or 5 mg/kg infliximab at weeks 2 and 6 followed by 10 mg/kg (group III). The prespecified co-primary endpoints were the proportion of patients who responded at week 2 and were in remission (CDAI <150) at week 30 and the time to loss of response up to week 54 in patients who responded. Analyses of the co-primary endpoints were by intention to treat.

Findings

335 (58%) patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 of 110 (21%) group I patients were in remission, compared with 44 of 113 (39%) group II (p=0·003) and 50 of 112 (45%) group III (p=0·0002) patients. Thus, patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio 2·7, 95% Cl 1·6–4·6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (IQR 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10–45) for group I (p=0·002 and p=0·0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis. In particular, the incidence of serious infections was similar across treatment groups.

Interpretation

Patients with Crohn's disease who respond to an initial dose of infliximab are more likely to be in remission at weeks 30 and 54, to discontinue corticosteroids, and to maintain their response for a longer period of time, if infliximab treatment is maintained every 8 weeks.

Introduction

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract. Although mild disease can be treated with 5-aminosalicylates, many patients eventually require corticosteroids to control symptoms.1 Once started, acute and in particular chronic use of corticosteroids is associated with well known adverse effects. Moreover, about 45% of patients are unable to discontinue corticosteroid therapy without disease exacerbation.2, 3 The purine antimetabolites and methotrexate are frequently prescribed for patients who are resistant to or dependent on corticosteroids; however, these drugs have a slow onset of action and clinical remission rates of about 40%. Clinical remission is defined by discontinuation of prednisone and a Crohn's disease activity index (CDAI) score of 150 or less after 16 weeks for methotrexate and as a CDAI of less than 175 at 15 months for azathioprine.4, 5 Thus, there is a need for a long-term treatment that maintains clinical remission and reduces exposure to corticosteroids.

Tumour necrosis factor α (TNFα) is a proinflammatory cytokine that has an important role in the pathogenesis of Crohn's disease.6, 7, 8, 9, 10 Infliximab—a chimeric anti-TNFα monoclonal antibody—binds to TNFα with high affinity, thereby neutralising its biological activity.11 When given as a 5 mg/kg intravenous infusion, infliximab induces remission in patients with moderately to severely active Crohn's disease and can reduce corticosteroid requirements.12, 13 Clinical experience has shown that patients can relapse after a single infusion of infliximab.14, 15 In a previous assessment of repeated administration of infliximab (four infusions of 10 mg/kg every 8 weeks) in patients with Crohn's disease, retreatment with infliximab maintained the clinical benefit up to 8 weeks after the last infusion in nearly all patients who responded to an initial dose of treatment.16 However, the results were not statistically significant in that small trial. Further data from a longer study were required to establish the long-term efficacy and safety of repeated doses of infliximab in patients with Crohn's disease who show an initial response to treatment.

In the ACCENT I trial, we aimed to assess the efficacy and safety of repeated infusions of infliximab in patients who improved after an initial infusion. Our hypothesis was that maintenance infliximab treatment is a more effective intervention than a single infusion. Secondary objectives included the assessment of infliximab's corticosteroid-sparing effects and safety in a large number of patients.

Section snippets

Patients

This multicentre, randomised, double-blind trial was carried out at 55 sites in North America, Europe, and Israel. Recruitment of patients took place from Feb 26, 1999, to Jan 24, 2000. For the prespecified 30-week endpoint analysis, the last completed visit was on Aug 30, 2000. For results up to 54 weeks, the last completed visit was on March 15, 2001. The protocol was approved by the institutional review boards at participating sites. Written informed consent was obtained from all patients.

Patients' disposition, baseline characteristics, and previous or concomitant medication

Of 580 patients enrolled, 573 patients at 55 study centres (40 North America, 13 Europe, and two Israel) were started on infliximab 5 mg/kg; 335 (58%) were responders at week 2. These 335 responders were randomly assigned placebo (group I, 110 patients), the 5 mg/kg maintenance regimen (group II, 113 patients), or the 10 mg/kg maintenance regimen (group III, 112 patients) and were assessed in the predefined primary efficacy analyses (figure 1). The 573 patients comprised 239 (42%) men and 334

Discussion

Since previous studies have established that single-dose infliximab is safe and effective for the management of acute Crohn's disease, the primary purpose of ACCENT I was to determine whether maintenance infliximab therapy would provide better long-term efficacy than no further treatment for patients with Crohn's disease who respond to a single infusion of infliximab. The results of this trial indicate that maintenance treatment with infliximab every 8 weeks is better than subsequent placebo

References (27)

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