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Azithromycin Based Therapy for Induction of Remission in Active Pediatric Crohn's Disease

This study is currently recruiting participants.
Verified December 2012 by Wolfson Medical Center
Sponsor:
Information provided by (Responsible Party):
Prof. Arie Levine, Wolfson Medical Center
ClinicalTrials.gov Identifier:
NCT01596894
First received: April 12, 2012
Last updated: December 13, 2012
Last verified: December 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Crohn's Disease
 Drug: Azithromycin + Metronidazole
Drug: Metronidazole
 Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (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.

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Wolfson Medical Center:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Normalization of CRP ( CRP ≤0.5 mg/dL). [ Time Frame: At week 8 ] [ Designated as safety issue: No ]
  • Fecal calprotectin at 8 weeks . [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

Estimated Enrollment: 70
Study Start Date: October 2012
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Other Names:
  • Azanil
  • Flagyl
Active Comparator: Metronidazole
Oral metronidazole 10mg/kg X2/day (maximum 1000mg) for 8 weeks.
 Drug: Metronidazole
Oral metronidazole 10mg/kg X2/day (maximum 1000mg) for 8 weeks.
Other Name: Flagyl

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.

  Eligibility

Ages Eligible for Study:   5 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Children 5-17 years of age.
  2. Diagnosis of active Crohn's Disease.4. Patients with a PCDAI≥10 ≤40 (mild to moderate disease).
  3. Have involvement of the colon and/or terminal ileum.
  4. Disease defined as L1, L2, L3 or any of the above and may have gastric, duodenal or esophageal disease (L4a) according to the Paris classification for site of disease.
  5. The CRP ≥ 0.6 mg/dL.
  6. Duration of disease since diagnosis < 3 years.
  7. Negative stool culture, Clostridium Difficile Toxin from current flare.

Exclusion Criteria:

  1. Duration of disease since diagnosis > 3 years.
  2. Positive stool culture or O&P last 30 days.
  3. Presence of clostridium difficile toxin in stool.
  4. Azithromycin or Metronidazole allergy or known intolerance.
  5. Diagnosis of IBD -U.
  6. Presence of macroscopic disease involving the proximal ileum or jejunum (L4b).
  7. Continuous macroscopic disease of the colon appearing as typical ulcerative colitis and Crohns diagnosed only by focality or granuloma on biopsies.
  8. Presence of extraintestinal manifestations (such as arthritis, uveitis, or sclerosing cholangitis).Apthous lesions of mouth can be included.
  9. Presence of fibrostenotic disease (strictures with prestenotic dilatation).
  10. Presence of penetrating disease (fistulas or abscess).
  11. Presence of current perianal disease defined as fistula or abscess.
  12. Patients receiving concurrent corticosteroids or biologics.
  13. Patients who have received steroids in the past 14 days.
  14. Immune deficiency (CGD, GSD1, IL10R etc).
  15. Known allergy or intolerance to any of the study medications.
  16. Concurrent diseases such as hepatitis, ALT >2 times UNL, renal failure.
  17. Pregnancy.
  18. Patients with known heart disease.
  19. Prolonged QTc by E.C.G at baseline.
  20. Patient after surgical resection.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01596894

Contacts
Contact: Arie Levine, MD 972-3-5028808 alevine@wolfson.health.gov.il

Locations
Israel
The E. Wolfson.Medical Center Recruiting
Holon, Israel, 58100
Contact: Arie Levine, MD     972-3-5028808     alevine@wolfson.health.gov.il    
Principal Investigator: Arie Levine, MD            
Sponsors and Collaborators
Prof. Arie Levine
Investigators
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: Javier Martín De Carpi, MD Hospital Sant Joan de Déu
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
  More Information

No publications provided

Responsible Party: Prof. Arie Levine, Director, Pediatric Gastroenterology and Nutrition unit., Wolfson Medical Center
ClinicalTrials.gov Identifier: NCT01596894     History of Changes
Other Study ID Numbers: 0035-12-WOMC
Study First Received: April 12, 2012
Last Updated: December 13, 2012
Health Authority: Israel: Ministry of Health

Keywords provided by Wolfson Medical Center:
Pediatric
Crohn's disease
Azithromycin
Metronidazole
Mild to moderate Crohn's Disease

Additional relevant MeSH terms:
Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Metronidazole
Azithromycin
 Radiation-Sensitizing Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Infective Agents
Therapeutic Uses
Antiprotozoal Agents
Antiparasitic Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on May 16, 2013