Azithromycin Based Therapy for Induction of Remission in Active Pediatric Crohn's Disease
|Crohn's Disease||Drug: Azithromycin + Metronidazole Drug: Metronidazole||Phase 4|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Primary Purpose: Treatment
|Official Title:||A Randomized, Single Blinded, Controlled, Multi Center Phase 4 Study for Induction of Remission in Active Pediatric Crohn's Disease, Using 2 Months Antibiotic Course of Azithromycin Combined With Metronidazole vs. Metronidazole Alone.|
- Response rate at 8 weeks defined as a drop in PCDAI (Pediatric Crohn's Disease Activity Index ) of at least 12.5 points (or remission without steroids, intention to treat principle) [ Time Frame: 8 weeks ]
- Normalization of CRP ( CRP ≤0.5 mg/dL). [ Time Frame: At week 8 ]
- Fecal calprotectin at 8 weeks . [ Time Frame: 8 weeks ]
- Remission at week 8 [ Time Frame: 8 weeks ]
|Study Start Date:||October 2012|
|Study Completion Date:||December 2015|
|Primary Completion Date:||December 2015 (Final data collection date for primary outcome measure)|
Experimental: Azithromycin + Metronidazole
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.
Drug: Azithromycin + Metronidazole
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.
Active Comparator: Metronidazole
Oral metronidazole 10mg/kg X2/day (maximum 1000mg) for 8 weeks.
Oral metronidazole 10mg/kg X2/day (maximum 1000mg) for 8 weeks.
Other Name: Flagyl
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01596894
|The E. Wolfson.Medical Center|
|Holon, Israel, 58100|
|Study Chair:||Arie Levine, MD||Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel|
|Study Director:||Dan Turner, MD, PhD||Pediatric Gastroenterology and Nutrition Unit, The Hebrew University of Jerusalem, Shaare Zedek MC, Jerusalem, Israel|
|Study Director:||Athos Bousvaros, MD||Bostons Childrens Hospital|
|Principal Investigator:||Michal Kori, MD||Kaplan Medical Center|
|Principal Investigator:||Ron Shaoul, MD||Rambam Health Care Campus|
|Principal Investigator:||Eyath Wine, MD||Women and Children's Health Research Institute, University of Alberta, Edmonton|
|Principal Investigator:||Jorge Amil Dias, MD||Hospital S. Joao, Porto, Porpugal|
|Principal Investigator:||Gigi Wauters Veereman, MD||Pedigastro, Antwerpen, Belgium|
|Principal Investigator:||Malgorzata Margaret Sladek, MD, PhD||Polish-American Children's Hospital|
|Principal Investigator:||Richard Russell, MD||Yorkhill Hospital, Glasgow, Scotland|
|Principal Investigator:||Johanna C. (Hankje) , Escher, MD PhD||Erasmus MC-Sophia Children's Hospital|