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PAZAZ

Personalized AZzithromycin/metronidAZole, in combination with standard induction therapy, to achieve a fecal microbiome community structure and metagenome changes associated with sustained remission in pediatric Crohn’s Disease (CD)

PI: Johan van Limbergen, Francisco Sylvester

Hypothesis

We hypothesize that we can reduce the risk of early flare, after achieving clinical remission using standard-of-care induction therapy, in CD patients with a Proteobacteria-rich signature by using personalized adjuvant-induction therapy with antibiotics (azithromycin/metronidazole).

Study design

We propose a 52 week multi-institutional randomized controlled, open label, clinical pilot trial (n=30) comparing the need of treatment escalation between microbiome-signature informed use of azithromycin/metronidazole during induction therapy (either nutritional or steroid-based) with induction therapy alone. Patients not carrying the Proteobacteria-rich signature will also be followed clinically and through fecal microbiome sampling to assess longitudinal changes in the microbiome associated with ‘standard-of-care’ management. Based on published literature, 50% of children will require repeat induction/treatment escalation by the end of the first year after diagnosis.9-11 25 children carrying the high-risk microbiome signature will need to be randomized to each study arm (10% drop out assumed) in the larger trial following on from this pilot trial, assuming 80% power, to reduce the risk of flaring from 80% to 40%. Methods Eligible children with active, mild-to-moderate CD (PCDAI > 10) will be seen at screening, baseline, 1 month, 3, 6, 9 and 12 months. Patients will start ‘standard-of-care’ induction therapy (either EEN or steroids), pending the results of the fecal microbiome analysis. We propose to randomize a subgroup of patients carrying a Proteobacteria-rich signature to receive either 8 weeks of azithromycin with metronidazole (as elaborated upon below) or only induction therapy with no additional antibiotics. The subgroup of patients who do not carry the Proteobacteria-rich signature will not be randomized and followed as per usual clinical practice (but with 3 monthly fecal microbiome samples) as a separate control arm.

Methods

Eligible children with active, mild-to-moderate CD (PCDAI > 10) will be seen at screening, baseline, 1 month, 3, 6, 9 and 12 months. Patients will start ‘standard-of-care’ induction therapy (either EEN or steroids), pending the results of the fecal microbiome analysis. We propose to randomize a subgroup of patients carrying a Proteobacteria-rich signature to receive either 8 weeks of azithromycin with metronidazole (as elaborated upon below) or only induction therapy with no additional antibiotics. The subgroup of patients who do not carry the Proteobacteria-rich signature will not be randomized and followed as per usual clinical practice (but with 3 monthly fecal microbiome samples) as a separate control arm.

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