Study of Antibiotics in the Treatment of Colonic Crohn's Disease
Crohn's disease (CD) is a form of inflammatory bowel disease that can affect any part of the digestive system. Symptoms of this chronic illness include abdominal pain, bloating, nausea, vomiting, and diarrhea. CD also causes bowel wall ulcers, strictures (narrowings of a hollow structure due to scar tissue and swelling), and fistulae (abnormal passages from the intestines to another organ or to the skin).
CD is thought to arise from a combination of inherited (genetic) factors and some undefined environmental factor(s). One environmental factor that has been shown to be intimately involved with the development of CD is the presence of bacteria that normally inhabit the intestines. As a result, some physicians have tried to alter the normal bacterial population as a means of controlling the inflammation (swelling) in the intestines of individuals with CD. Among such strategies is the use of a combination of metronidazole and ciprofloxacin. These broad-spectrum antibiotics control CD symptoms by acting on the intestinal bacteria that can contribute to chronic inflammation. More investigation is needed to firmly establish the usefulness of this therapy because previous clinical trials have given mixed results, although they have suggested that antibiotics can be particularly useful in cases of Crohn's colitis (CD that primarily affects the large intestine). Because these earlier studies have lacked a large enough patient population with colonic involvement, a trial focusing on this CD subgroup with a sufficient number of subjects will help to clarify the value of combining metronidazole and ciprofloxacin.
The proposed study will test the hypothesis that combination antibiotic therapy is effective in the treatment of CD involving the colon. The study will compare the use of combination therapy consisting of metronidazole and ciprofloxacin with placebo (dummy tablets) and will examine the results of treatment at the end of 8 weeks of treatment.
Drug: Metronidazole placebo
Drug: ciprofloxacin placebo
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Metronidazole and Ciprofloxacin in the Treatment of Colonic Crohn's Disease: The MACINTOCC Trial.|
- Complete response to therapy defined as a reduction of the CDAI score to below 150 points with a reduction of at least 70 points from baseline. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
- Partial response (improvement) will be analyzed as a secondary outcome measure and will be defined as a reduction of the CDAI score by 70 points or more but with a final value of 150 points or greater. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
|Study Start Date:||May 2006|
|Study Completion Date:||July 2008|
|Primary Completion Date:||July 2008 (Final data collection date for primary outcome measure)|
Placebo Comparator: I
Ciprofloxacin placebo and Metronidazole placebo
|Drug: Metronidazole placebo Drug: ciprofloxacin placebo|
Ciprofloxacin 500 mg bid po Metronidazole - total daily dose dependent on body weight
500 mg bid po
Other Name: CiproDrug: metronidazole
250 mg bid po / 250 mg tid po / 500 mg bid po depending on body weight
Other Name: Flagyl
The role of bacteria and microbial agents in the pathogenesis of Crohn's disease has been suggested and is supported by animal models of inflammatory bowel disease (IBD) in which the presence of normal gut flora is required for the initiation and full expression of the inflammatory reaction. In human Crohn's disease, antibiotics are commonly used even though the evidence to support this practice is not strong. Several studies have indicated that antibiotics have some biological activity in Crohn's disease and that this activity may be most pronounced in the subset of patients with colonic involvement.
In order to better justify the use of antibiotics in the treatment of Crohn's disease, the Antibiotics for Colonic Crohn's Disease trial has been designed to determine if ciprofloxacin and metronidazole combination therapy is effective in the treatment of active Crohn's disease of the colon. This two arm, multi-centre, randomized, double-blind, parallel-group, placebo-controlled study will involve 136 patients with mild to moderate active Crohn's disease of the colon (with or without ileal involvement), as defined by a Crohn's Disease Activity Index (CDAI) score between 220 and 450.
Eligible patients will be randomly assigned to receive one of two treatment regimens: (1) ciprofloxacin (500 mg po bid; provided as
1 x 500 mg tablets) and metronidazole (<50 kg, 250 mg po bid; 50-75 kg, 250 mg po tid; >75 kg, 500 mg po bid; all doses provided as 1 x 250 mg tablets) or (2) placebo. Treatment will be continued for a period of 8 weeks.
Treatment success will be defined as a complete response to therapy at the end of eight weeks. Complete response (remission) will be defined as a reduction of the CDAI score to below 150 points with a reduction of at least 70 points from baseline. Partial response (improvement) will be analyzed as a secondary outcome measure and will be defined as a reduction of the CDAI score by 70 points or more but with a final value of 150 points or greater. Patients who experience a persistent rise in their CDAI scores of 100 points or more on two consecutive visits or a rise in their CDAI score to 400 points or more at any visit will be considered to be treatment failures and will be withdrawn from the study.
The primary analysis will be an intent-to-treat comparison of the proportion of patients achieving remission by 8 weeks in the ciprofloxacin/metronidazole and placebo groups. Secondary outcome measures will evaluate partial response and adverse event rates.
|Mount Sinai Hospital|
|Toronto, Ontario, Canada, M5G 1X5|
|Principal Investigator:||A. Hillary Steinhart, M.D.||Mount Sinai Hospital, New York|