Digestive System Diseases

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Azithromycin

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

5-day consecutive oral placebo once daily

Tablet - 500 mg azithromycin (as dihydrate)

Azithromycin Pill

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

Placebo

Haggai Bar-Yosef, MD

Anastasia Weis, MD

Doron Schwartz, MD

Baruch Ovadya, MD

Tova Rainis, MD

Ori Segol, MD

Haggai Bar-Yoseph, MD

Eran Israeli, MD

Lior Katz, MD

Ariella Shitrit, MD

Reut Lutski, MD

Iris Dotan

Haim Leibovitzh, MD

This is a randomized placebo-controlled trial in Crohn's 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

Pre-treatment With Azithromycin to Reduce Immunogenicity to to Anti-TNF Agents in Patients With Crohn's Disease

Pre-treatment With Azithromycin to Reduce Immunogenicity to Anti-Tumor Necrosis Factor-α Agents in Patients With Crohn's Disease

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

Crohn's Disease Activity Index (CDAI) ≤150 without systemic corticosteroid therapy

A reduction in CDAI of at least 100 points from baseline.

C-reactive protein (CRP) ≤1.5 upper limit of normal, or fecal calprotectin ≤ 250 mg/kg

Persistent administration of infliximab or adalimumab for 1 year. A 16-week or more interval between infliximab injections, or an 8-week or more interval between adalimumab injections will be considered as treatment cessation. Change in anti-TNF regimen at 26 and 52 weeks defined as increased dosing or decreased dosing interval

- Patient reported outcome (PRO-2) remission at Week 52 (defined as an abdominal pain \[AP\] mean daily score at or below 1 \[AP≤1\] AND a stool frequency \[SF\] mean daily score at or below 3 \[SF≤3\], and no worsening of AP or SF from baseline).

The rate of sustained corticosteroid-free PRO-2 clinical remission at both 14 and 52 weeks, defined as AP≤1 and SF≤3. The rate of clinical response at 14 weeks, defined as a reduction in CDAI of at least 100 points from baseline

The rate of addition of immunomodulator treatment defined as at least one dose of thiopurines or methotrexate

The rate of immunomodulator treatment termination. Termination will be defined in patient treated with azathioprine or 6MP at randomization, as being stopped after at least 14 weeks and not restarting by 52 weeks

Endoscopic improvement defined as a reduction of ≥50% decrement from baseline in SES-CD score

Endoscopic remission defined as SES-CD ≤4

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