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

Sponsor

Rambam Health Care Campus (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05599347

Collaborator

(none)

180

Enrollment

Location

Arms

Anticipated Duration (Months)

3.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Inflammatory Bowel Diseases Biological Substance; Adverse Effect	Drug: Azithromycin Pill Other: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

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

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Jan 1, 2023

Anticipated Primary Completion Date :

Dec 31, 2025

Anticipated Study Completion Date :

Dec 31, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Azithromycin 5-day consecutive treatment with oral azithromycin 500 mg once daily	Drug: Azithromycin Pill Tablet - 500 mg azithromycin (as dihydrate)
Placebo Comparator: Control 5-day consecutive oral placebo once daily	Other: Placebo Placebo tablet identical in shape and appearance to the azithromycin tablet used in the treatment arm

Arm

Intervention/Treatment

Experimental: Azithromycin

5-day consecutive treatment with oral azithromycin 500 mg once daily

Drug: Azithromycin Pill

Tablet - 500 mg azithromycin (as dihydrate)

Placebo Comparator: Control

5-day consecutive oral placebo once daily

Other: Placebo

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

Outcome Measures

Primary Outcome Measures

Anti-drug antibody development [1 year after the initiation of therapy]
Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay

Secondary Outcome Measures

Sustained corticosteroid-free clinical remission [1 year after the initiation of therapy]
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
Clinical response [1 year after the initiation of therapy]
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
Sustained corticosteroid-free biochemical remission [1 year after the initiation of therapy]
C-reactive protein (CRP) ≤1.5 upper limit of normal, or fecal calprotectin ≤ 250 mg/kg
Treatment durability [1 year after the initiation of therapy]
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.
Anti-TNF drug levels [1, 6, and 12 months after the initiation of therapy]
Levels at various timepoints
Early anti-drug antibody development [1, and 6 months after the initiation of therapy]
Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)