Clinical trial NCT05599347: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Crohn's Disease Relapse
Biological Substance; Adverse Effect
Keywords: Crohn's disease
infliximab
adalimumab
azithromycin
immunogenicity
Lead sponsor: Rambam Health Care Campus
Sponsor class: OTHER
First posted: 2022-10-31
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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 arms
Primary purpose: PREVENTION

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.

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

Primary outcomes:
measure: Anti-drug antibody development
timeFrame: 1 year after the initiation of therapy
Secondary outcomes:
measure: Sustained corticosteroid-free clinical remission
timeFrame: At both 3 months and a 1 year after the initiation of therapy
measure: Clinical response
timeFrame: 1 year after the initiation of therapy
measure: Sustained corticosteroid-free biochemical remission
timeFrame: at both 6 months and a 1 year after the initiation of therapy
measure: Treatment durability
timeFrame: at both 6 months and a 1 year after the initiation of therapy
measure: Anti-TNF drug levels
timeFrame: At 6 weeks, 26 weeks and a 1 year after the initiation of therapy
measure: Early anti-drug antibody development
timeFrame: At 6 weeks, 26 weeks and a 1 year after the initiation of therapy
measure: PRO-2 remission at Week 52
timeFrame: 1 year after the initiation of therapy
measure: Sustained corticosteroid-free PRO-2 clinical remission
timeFrame: At both 14 and a 1 year after the initiation of therapy
measure: Addition of immunomodulator treatment
timeFrame: At any time during the study
measure: Immunomodulator treatment termination
timeFrame: At 14 weeks and not restarting by 1 year after the initiation of therapy
measure: Endoscopic improvement
timeFrame: At 26 weeks
measure: Endoscopic remission
timeFrame: At 26 and 52 weeks
Other outcomes:
Locations:
city: Be'er Sheva
country: Israel
facility: Soroka University Medical Center
city: Haifa
country: Israel
facility: Bnei Zion
city: Haifa
country: Israel
facility: Carmel Medical Center
city: Haifa
country: Israel
facility: Rambam Health Care Campus
city: H̱olon
country: Israel
facility: Wolfson Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek
city: Kiryat Bialik
country: Israel
facility: Zvulun
city: Petah Tikva
country: Israel
facility: Rabin Medical Center
Study officials:
References:
citation: 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.