Personalised azithromycin+metronidazole (PAZAZ), in combination with standard induction therapy, to achieve a faecal microbiome community structure and metagenome changes associated with sustained remission in paediatric Crohn's disease (CD): protocol of a pilot study.

introductionEarly relapse in Crohn's disease (CD) is associated with a more severe disease course. The microbiome plays a crucial role, yet strategies targeting the microbiome are underrepresented in current guidelines. We hypothesise that early manipulation of the microbiome will improve clinical response to standard-of-care (SOC) induction therapy in patients with a relapse-associated microbiome profile. We describe the protocol of a pilot study assessing feasibility of treatment allocation based on baseline faecal microbiome profiles. METHODS AND ANALYSIS: This is a 52-week, multicentre, randomised, controlled, open-label, add-on pilot study to test the feasibility of a larger multicontinent trial evaluating the efficacy of adjuvant antibiotic therapy in 20 paediatric patients with mild-to-moderate-CD (10<PCDAI≤37.5; PCDAI, Pediatric Crohn's Disease Activity Index). SOC induction treatment will be Crohn's Disease Exclusion Diet+Partial Enteral Nutrition (CDED+PEN). Relapse-associated microbiome signatures will be evaluated using 16S rRNA gene sequencing and a previously generated Bayesian predictive model (BioMiCo) based on baseline stool. At week 4, patients in remission with relapse-associated signatures (group A) will be randomised to CDED+antibiotics (A2) or CDED+PEN alone (A1). Patients in remission without this signature will continue CDED+PEN alone (B). Patients not in remission will receive CDED+antibiotics regardless of their microbiome signature (C). Subjects in group A2 or C will receive a combination of azithromycin 7.5 mg/kg (weeks 4-8: 5 days/week; weeks 9-12: 3 days/week) with metronidazole 20 mg/kg/day (weeks 4-12). Primary outcomes will assess feasibility of treatment allocation and possible efficacy to sustain remission (PCDAI≤10, no need for reinduction). Exploratory outcomes will include changes in PCDAI, inflammatory markers and patient-reported outcomes. We will additionally explore changes in faecal microbiome taxonomic composition between groups. ETHICS AND DISSEMINATION: This study was approved by METC-AMC and CCMO (Netherlands) and IWK Health Centre (Canada). The first version of this protocol was approved by North Carolina Children's Hospital (USA), Wolfson Medical Centre (Israel). The FDA (USA), Health Canada and Ministry of Health (Israel) have reviewed and approved the protocol. Results will be published in international peer-reviewed journals and summaries will be provided to the funders and participants. TRIAL REGISTRATION NUMBER: NCT04186247.