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

NCT ID: NCT05599347

Last Updated: 2025-04-04

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 180 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-04-24
• Study Completion Date: 2026-12-31

Brief Summary

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

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.

Conditions

Crohn's Disease Relapse; Biological Substance; Adverse Effect

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: QUADRUPLE

Study Groups

Azithromycin

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

Group Type: EXPERIMENTAL

Azithromycin Pill

Intervention Type: DRUG

Tablet - 500 mg azithromycin (as dihydrate)

Control

5-day consecutive oral placebo once daily

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

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

Interventions

Azithromycin Pill

Tablet - 500 mg azithromycin (as dihydrate)

Intervention Type: DRUG

Placebo

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

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• Ability to provide written informed consent prior to any study procedures and willing and able to attend all study visits, comply with the study procedures, read and write in order to complete questionnaires, and be able to complete the study period.
• Aged 18 to 80 years of age, inclusive, at the time of signing the informed consent.
• Diagnosis of CD with an onset of symptoms for a minimum of 3 months prior to Screening as determined by the investigator based on clinical history, exclusion of infectious causes, and characteristic endoscopic and histologic findings.
• Prior decision of starting infliximab or adalimumab therapy (including biosimilar drugs).
• Thiopurine and corticosteroid co-therapy will be permitted.

Exclusion Criteria

• Inclusion in another interventional study
• Patients who cannot provide informed consent and do not have a legal guardian
• Patients with perianal involvement who are expected to require antibiotic therapy for their disease
• Patients on chronic antibiotic therapy due to any cause
• Patients with ongoing fluid collection/abscess either internal or perianal
• Known history of allergy to the study intervention formulation or any of its excipients or components of the delivery device
• Prolonged QTc interval or conditions leading to additional risk for QT prolongation
• Chronic kidney disease stage 5 (GFR < 10)
• Crohn's Disease complication requiring surgical treatment
• Planned/ongoing methotrexate co-therapy
• Fecal microbiota transplantation within 8 weeks prior to randomization
• Participant has any disorder that, in the opinion of the investigator, may compromise the ability to participate in the study
• Pregnancy
• Patients who received azithromycin therapy in the previous year (we will not exclude prior use of other antibiotic therapy)
• Patients who received any antibiotic treatment within 4 weeks prior to randomization
• Re-induction of the same anti-TNF medication
• Patients who are on chronic therapy which cannot be withheld in one of these medications: colchicine, phenytoin, and digoxin

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rambam Health Care Campus

OTHER

Sponsor Role: lead

Responsible Party

Haggai Bar-Yoseph MD

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Soroka University Medical Center

Beersheba, , Israel

Site Status: RECRUITING

Bnei Zion

Haifa, , Israel

Site Status: RECRUITING

Carmel Medical Center

Haifa, , Israel

Site Status: RECRUITING

Rambam Health Care Campus

Haifa, , Israel

Site Status: RECRUITING

Wolfson Medical Center

Holon, , Israel

Site Status: RECRUITING

Hadassah Medical Center

Jerusalem, , Israel

Site Status: RECRUITING

Shaare Zedek

Jerusalem, , Israel

Site Status: RECRUITING

Zvulun

Kiryat Bialik, , Israel

Site Status: RECRUITING

Rabin Medical Center

Petah Tikva, , Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Haggai Bar-Yosef, MD

Role: CONTACT

h_bar-yoseph@rmc.gov.il

050-2064878

Anastasia Weis, MD

Role: CONTACT

A_WEIS@rambam.health.gov.il

Facility Contacts

Doron Schwartz, MD

Role: primary

Tova Rainis, MD

Role: primary

Ori Segol, MD

Role: primary

Haggai Bar-Yoseph, MD

Role: primary

Eran Israeli, MD

Role: primary

Lior Katz, MD

Role: primary

Ariella Shitrit, MD

Role: primary

Reut Lutski, MD

Role: primary

Iris Dotan

Role: primary

References

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.

Reference Type: RESULT

PMID: 34344783 (View on PubMed)

Other Identifiers

0432-22-RMB

Identifier Type: -

Identifier Source: org_study_id