Azithromycin Based Therapy for Induction of Remission in Active Pediatric Crohn's Disease
Condition: Crohn's Disease
MeSH terms: Crohn Disease
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to evaluate effectiveness of 2 months antibiotic course of
      Azithromycin combined with Metronidazole compared with 2 months antibiotic course of
      Metronidazole alone.
    

Detailed description: 
      Background: Recent reviews and guidelines no longer recommend antibiotic therapy for
      induction of remission in Crohn's disease (CD) due to studies showing lack of efficacy.
      Genetic and microbiological findings have demonstrated that CD is characterized by a
      defective innate immune response to bacteria and defective apoptosis of T cells. Bacteria
      have been shown to reside on, and invade epithelial cells, are present in granulomas and to
      replicate inside macrophage phagolysosomes in susceptible individuals. A defect in bacterial
      triggering from the luminal epithelial and intracellular compartments, while simultaneously
      trying to induce apoptosis, has never been explored. Azithromycin is an antibiotic with
      excellent intracellular penetration, high luminal concentrations, and is also effective
      against biofilms which have been described in CD. It is a potent activator of apoptosis of T
      cells. Preliminary data in pediatric patients with short duration of disease have shown a
      remission rate of 60% and normalization of CRP in about 50% of patients treated with
      azithromycin and metronidazole in combination. The investigators hypothesize that a 2-month
      antibiotic course of azithromycin combined with metronidazole is effective for inducing
      remission in active pediatric Crohns disease (CD). The investigators also hypothesize that
      remission will be accompanied by normalization of CRP in a high proportion of patients with
      active CD. The goal of the present study is to evaluate the efficacy of this combination in a
      randomized controlled trial (RCT).

      Methods: This will be a single blinded multicenter randomized controlled trial in children
      with mild to moderate active CD (PCDAI≥10 ≤40) and elevated CRP, involving the terminal ileum
      and/or colon , comparing two arms over 8 weeks of therapy:

      Group 1: Oral Azithromycin 7.5 mg/kg once daily (maximum 500mg) 5 consecutive days a week for
      the first 4 weeks and 3 consecutive days a week for the last 4 weeks +metronidazole 10mg/kg
      X2/day (maximum 1000mg) for 8 weeks .Group 2: Oral metronidazole 10mg/kg X2/day (maximum
      1000mg) for 8 weeks . Four visits will take place at enrolment, and at 4, 8, and 12 weeks
      thereafter. In addition, there will be a telephone visit at 48 hours after commencement of
      therapy. Patients will be evaluated for PCDAI, Physicians Global Assessment (PGA) and CRP at
      each visit. The primary endpoint will be response rate at 8 weeks defined as a drop in PCDAI
      of at least 12.5 points (or remission). Secondary end points will include : 1.Remission rate
      at 8 weeks. 2. Normalization of CRP (CRP ≤0.5 mg/dL), 3. Fecal calprotectin at 8 weeks and 4.
      Corticosteroid free remission at 12 weeks.

      Importance and anticipated outcomes: The investigators believe that high dose azithromycin
      will be associated with a high remission rate in early disease. If azithromycin based therapy
      is validated in an appropriate RCT, it would strengthen the premise that bacteria could, and
      possibly should be a therapeutic target in CD early in the disease. At a practical level an
      additional treatment that does not involve corticosteroids and does not suppress the immune
      system would be available for induction of remission. On a translational level, the
      underlying hypothesis which led to this treatment regimen, namely that bacteria in all
      compartments and apoptosis need to be targeted simultaneously, might have ramifications for
      how the disease should be treated. Theoretically, CD may be a chronic disease because the
      investigators do not simultaneously treat the two triggers for persistent inflammation
      (bacterial triggering and defective apoptosis), and ongoing inflammation allows continuous
      bacterial penetration.
    

Intervention name(s): Azithromycin + Metronidazole; Metronidazole
Intervention type(s): Drug; Drug
Intervention description(s): Azithromycin 7.5 mg/kg once daily (maximum 500mg) 5 consecutive days a week for the first 4 weeks and 3 consecutive days a week for the next 4 weeks +metronidazole 10mg/kg X2/day (maximum 1000mg) for 8 weeks.; Oral metronidazole 10mg/kg X2/day (maximum 1000mg) for 8 weeks.
Other intervention name(s): Azanil; Flagyl; Flagyl
Intervention MeSH terms: Azithromycin; Metronidazole
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment
Keywords: Pediatric; Crohn's disease; Azithromycin; Metronidazole; Mild to moderate Crohn's Disease