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

Official title

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

Overview

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.

Interventions

• Drug Azithromycin Pill
  Tablet - 500 mg azithromycin (as dihydrate)
• Other Placebo
  Placebo tablet identical in shape and appearance to the azithromycin tablet used in the treatment arm

Primary outcome measures

• Anti-drug antibody development [Time frame: 1 year after the initiation of therapy]

Secondary outcome measures (12)

• Sustained corticosteroid-free clinical remission [Time frame: At both 3 months and a 1 year after the initiation of therapy]
• Clinical response [Time frame: 1 year after the initiation of therapy]
• Sustained corticosteroid-free biochemical remission [Time frame: at both 6 months and a 1 year after the initiation of therapy]
• Treatment durability [Time frame: at both 6 months and a 1 year after the initiation of therapy]
• Anti-TNF drug levels [Time frame: At 6 weeks, 26 weeks and a 1 year after the initiation of therapy]
• Early anti-drug antibody development [Time frame: At 6 weeks, 26 weeks and a 1 year after the initiation of therapy]
• PRO-2 remission at Week 52 [Time frame: 1 year after the initiation of therapy]
• Sustained corticosteroid-free PRO-2 clinical remission [Time frame: At both 14 and a 1 year after the initiation of therapy]
• Addition of immunomodulator treatment [Time frame: At any time during the study]
• Immunomodulator treatment termination [Time frame: At 14 weeks and not restarting by 1 year after the initiation of therapy]
• Endoscopic improvement [Time frame: At 26 weeks]
• Endoscopic remission [Time frame: At 26 and 52 weeks]

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Prevention

Study locations

Israel · 9 centers

• Rambam Health Care Campus — Haifa
• Soroka University Medical Center — Beersheba
• Bnei Zion — Haifa
• Carmel Medical Center — Haifa
• Wolfson Medical Center — Holon
• Hadassah Medical Center — Jerusalem
• Shaare Zedek — Jerusalem
• Zvulun — Kiryat Bialik
• … and 1 more center

Publications

• 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. d PMID 34344783

Identifiers

NCT: NCT05599347 · 0432-22-RMB

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗