Gastroenterology

Gastroenterology

Volume 132, Issue 7, June 2007, Pages 2313-2319
Gastroenterology

Clinical–alimentary tract
Two-Year Combination Antibiotic Therapy With Clarithromycin, Rifabutin, and Clofazimine for Crohn’s Disease

https://doi.org/10.1053/j.gastro.2007.03.031Get rights and content

Background & Aims: Mycobacterium avium subspecies paratuberculosis has been proposed as a cause of Crohn’s disease. We report a prospective, parallel, placebo-controlled, double-blind, randomized trial of 2 years of clarithromycin, rifabutin, and clofazimine in active Crohn’s disease, with a further year of follow-up. Methods: Two hundred thirteen patients were randomized to clarithromycin 750 mg/day, rifabutin 450 mg/day, clofazimine 50 mg/day or placebo, in addition to a 16-week tapering course of prednisolone. Those in remission (Crohn’s Disease Activity Index ≤150) at week 16 continued their study medications in the maintenance phase of the trial. Primary end points were the proportion of patients experiencing at least 1 relapse at 12, 24, and 36 months. Results: At week 16, there were significantly more subjects in remission in the antibiotic arm (66%) than the placebo arm (50%; P = .02). Of 122 subjects entering the maintenance phase, 39% taking antibiotics experienced at least 1 relapse between weeks 16 and 52, compared with 56% taking placebo (P = .054). At week 104, the figures were 26% and 43%, respectively (P = .14). During the following year, 59% of the antibiotic group and 50% of the placebo group relapsed (P = .54). Conclusions: Using combination antibiotic therapy with clarithromycin, rifabutin, and clofazimine for up to 2 years, we did not find evidence of a sustained benefit. This finding does not support a significant role for Mycobacterium avium subspecies paratuberculosis in the pathogenesis of Crohn’s disease in the majority of patients. Short-term improvement was seen when this combination was added to corticosteroids, most likely because of nonspecific antibacterial effects.

Section snippets

Subjects

Patients over 18 years of age diagnosed with Crohn’s disease according to standard criteria and active disease defined as Crohn’s Disease Activity Index (CDAI) ≥200 were enrolled at 20 centers around Australia. Patients with isolated upper gastrointestinal or isolated perianal disease or a stoma were excluded, as were those requiring intravenous corticosteroids at initial assessment and those thought likely to require surgery during the first 4 months of the study. Permitted medications

Subject Disposition and Induction Phase

Between September 1999 and September 2001, 213 patients were enrolled and randomized to receive either antibiotics (n = 102) or placebo (n = 111) (Figure 1). The characteristics of these 2 groups are shown in Table 1. There were no significant differences between them.

There were significantly more patients in the antibiotics arm who went on to the maintenance phase starting at 16 weeks (P = .02). Ninety-one subjects were withdrawn during the prednisolone-induction phase: 35 from the antibiotic

Discussion

This study was designed to show a 40% difference between treatment groups at 24 months, a realistic difference if prolonged combination of clarithromycin, rifabutin, and clofazimine antibiotic therapy was to have a clinically significant impact on Crohn’s disease. Although there was a short-term benefit of the antibiotics at 16 weeks additional to the effect of corticosteroid therapy, the study showed no prolonged advantage of the antibiotic combination either during the 2-year treatment phase

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    Supported by Pharmacia, Pharmacia and Upjohn, and Pfizer Pty Ltd.

    None of the authors has a conflict of interest.

    The Antibiotics in Crohn’s Disease Study Group: Peter Bampton, Flinders Medical Centre, Adelaide; David Hetzel, Royal Adelaide Hospital, Adelaide; Tim Florin, Mater Health Services Adult Hospital, Brisbane; Graham Radford-Smith, Royal Brisbane Hospital, Brisbane; Peter Stephenson, Brisbane Gastroscopy and Colonoscopy, Brisbane; Paul Pavli, The Canberra Hospital, Canberra; Hugh Jackson, Royal Hobart Hospital, Hobart; Brent Mitchell, Launceston General Hospital, Launceston; William Connell, St. Vincent’s Hospital, Melbourne; Brendan Crotty, Austin Health, Melbourne; Peter Gibson, Royal Melbourne Hospital, Melbourne; Steven Kolt, Western Hospital, Melbourne; Michael Merrett, Frankston Hospital, Melbourne; Robert Batey, John Hunter Hospital, Newcastle; Brendan Collins, Royal Perth Hospital, Perth; Hooi Ee, Sir Charles Gairdner Hospital, Perth; Peter Katelaris, Concord Hospital, Sydney; Robert Read, Hornsby Ku-rin-gai Hospital, Sydney; Warwick Selby, Royal Prince Alfred Hospital, Sydney; and Nicholas Talley, Nepean Hospital, Sydney, Australia.

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