Azithromycin Based Therapy for Induction of Remission in Active Pediatric Crohn's Disease
Information source: Wolfson Medical Center
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Crohn's Disease
Intervention: Azithromycin + Metronidazole (Drug); Metronidazole (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: Prof. Arie Levine Official(s) and/or principal investigator(s): Arie Levine, MD, Study Chair, Affiliation: Pediatric Gastroenterology and Nutrition Unit, The E. Wolfson MC, Tel-Aviv University, Holon, Israel Dan Turner, MD, PhD, Study Director, Affiliation: Pediatric Gastroenterology and Nutrition Unit, The Hebrew University of Jerusalem, Shaare Zedek MC, Jerusalem, Israel Athos Bousvaros, MD, Study Director, Affiliation: Bostons Childrens Hospital Michal Kori, MD, Principal Investigator, Affiliation: Kaplan Medical Center Ron Shaoul, MD, Principal Investigator, Affiliation: Rambam Health Care Campus Eyath Wine, MD, Principal Investigator, Affiliation: Women and Children's Health Research Institute, University of Alberta, Edmonton Jorge Amil Dias, MD, Principal Investigator, Affiliation: Hospital S. Joao, Porto, Porpugal Gigi Wauters Veereman, MD, Principal Investigator, Affiliation: Pedigastro, Antwerpen, Belgium Malgorzata Margaret Sladek, MD, PhD, Principal Investigator, Affiliation: Polish-American Children's Hospital Richard Russell, MD, Principal Investigator, Affiliation: Yorkhill Hospital, Glasgow, Scotland Johanna C. (Hankje) , Escher, MD PhD, Principal Investigator, Affiliation: Erasmus MC-Sophia Children's Hospital
Overall contact: Arie Levine, MD, Phone: 972-3-5028808, Email: alevine@wolfson.health.gov.il
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.
Clinical Details
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.
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Investigator), Primary Purpose: Treatment
Primary outcome: 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)
Secondary outcome: Normalization of CRP ( CRP ≤0.5 mg/dL).Fecal calprotectin at 8 weeks .
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
Minimum age: 5 Years.
Maximum age: 17 Years.
Gender(s): Both.
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.
Locations and Contacts
Arie Levine, MD, Phone: 972-3-5028808, Email: alevine@wolfson.health.gov.il
The E. Wolfson.Medical Center, Holon 58100, Israel; Recruiting Arie Levine, MD, Phone: 972-3-5028808, Email: alevine@wolfson.health.gov.il Arie Levine, MD, Principal Investigator
Additional Information
Starting date: October 2012
Last updated: June 7, 2015
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