Pre-treatment With Azithromycin to Reduce Immunogenicity to Anti-Tumor Necrosis Factor-α Agents in Patients With Inflammatory Bowel Disease (AZITRATIM)

Pre-treatment With Azithromycin to Reduce Immunogenicity to Anti-Tumor Necrosis Factor-α Agents in Patients With Inflammatory Bowel Disease

Pre-treatment With Azithromycin to Reduce Immunogenicity to Anti-Tumor Necrosis Factor-α Agents in Patients With Inflammatory Bowel Disease

This will be a randomized placebo-controlled trial in inflammatory bowel disease patients before initiation of anti-tumor necrosis factor-α (anti-TNF) therapy that aims to test the effect of a pre-treatment short course of azithromycin therapy on immunogenicity

Anti-TNF agents are considered the mainstay of therapy for patients with inflammatory bowel diseases (IBD). Still, its efficacy is hampered by the development of anti-drug antibodies (ADA), which lead to non-responsiveness to this medication. A combination with immunosuppressive agents is currently utilized to reduce ADA development but is accompanied by an increased risk of side effects (i.e. malignancy and infections). The investigators have recently found an epidemiologic link between prior antibiotic use and the development of ADA, and shown an antibiotic-specific effect on ADA development in a mouse model. Macrolide antibiotics were specifically associated with ADA prevention and led to increased durability of the treatment. Since the microbiome has been associated with the response to anti-TNF therapy, the investigators hypothesize that microbial manipulation with azithromycin prior to the initiation of anti-TNF therapy will lower ADA development. the investigators propose a randomized controlled study to test our hypothesis and compare it to matched historical cohorts with available clinical and serological data. The primary outcome will be ADA development at 1 year of therapy.

All consenting adults that fulfil the inclusion criteria will be randomized in a 1:1 ratio and allocated to the azithromycin or placebo arms

Placebo tablet identical in shape and appearance to the azithromycin tablet used in the treatment arm

Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay

Crohn's Disease Activity Index (CDAI) ≤150 or partial Mayo score for ulcerative colitis (UC) of 0-1 without systemic corticosteroid therapy for at least 3 months

A reduction in CDAI of at least 100 points from baseline or a reduction of at least 2.5 points in the partial Mayo score for UC

Persistent administration of infliximab or adalimumab for 1 year. A 16 week or more interval between infliximab injections, or a 8 week or more interval between adalimumab injections will be considered as treatment cessation.

Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay

Inclusion Criteria: All consenting adult (≥18 years) IBD patients starting infliximab or adalimumab therapy. Exclusion Criteria: Inclusion in another interventional study Patients who cannot provide informed consent and do not have a legal guardian Patients with perianal involvement that are expected to require antibiotic therapy for their disease Patients on chronic antibiotic therapy due to any cause Crohn's Disease complication requiring surgical treatment Planned/ongoing methotrexate co-therapy Pregnancy Patients who received azithromycin therapy in the previous year (we will not exclude prior use of other antibiotic therapy)

Gorelik Y, Freilich S, Gerassy-Vainberg S, Pressman S, Friss C, Blatt A, Focht G, Weisband YL, Greenfeld S, Kariv R, Lederman N, Dotan I, Geva-Zatorsky N, Shen-Orr SS, Kashi Y, Chowers Y; IIRN. Antibiotic use differentially affects the risk of anti-drug antibody formation during anti-TNFalpha therapy in inflammatory bowel disease patients: a report from the epi-IIRN. Gut. 2022 Feb;71(2):287-295. doi: 10.1136/gutjnl-2021-325185. Epub 2021 Aug 3.