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

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

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

Study Overview

• Status: Recruiting
• Conditions: Biological Substance; Adverse Effect; Crohn's Disease Relapse
• Intervention / Treatment: Drug: Azithromycin Pill; Other: Placebo

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 Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Haggai Bar-Yosef, MD; Phone Number: 050-2064878; Email: h_bar-yoseph@rmc.gov.il
• Study Contact Backup: Name: Anastasia Weis, MD; Email: A_WEIS@rambam.health.gov.il

Study Locations

• Israel
  • Be'er Sheva, Israel
    • Not yet recruiting
    • Soroka University Medical Center
    • Contact: Doron Schwartz, MD
  • Hadera, Israel
    • Not yet recruiting
    • Hillel Yaffe Medical Center
    • Contact: Baruch Ovadya, MD
  • Haifa, Israel
    • Recruiting
    • Rambam Health Care Campus
    • Contact: Haggai Bar-Yoseph, MD
  • Haifa, Israel
    • Recruiting
    • Carmel Medical Center
    • Contact: Ori Segol, MD
  • Haifa, Israel
    • Recruiting
    • Bnei Zion
    • Contact: Tova Rainis, MD
  • H̱olon, Israel
    • Not yet recruiting
    • Wolfson Medical Center
    • Contact: Eran Israeli, MD
  • Jerusalem, Israel
    • Not yet recruiting
    • Hadassah Medical Center
    • Contact: Lior Katz, MD
  • Jerusalem, Israel
    • Recruiting
    • Shaare Zedek
    • Contact: Ariella Shitrit, MD
  • Kiryat Bialik, Israel
    • Not yet recruiting
    • Zvulun
    • Contact: Reut Lutski, MD
  • Petah Tikva, Israel
    • Recruiting
    • Rabin Medical Center
    • Contact: Iris Dotan
  • Tel Aviv, Israel
    • Not yet recruiting
    • el Aviv Sourasky Medical Center - Ichilov
    • Contact: Haim Leibovitzh, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-drug antibody development	Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay	1 year after the initiation of therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sustained corticosteroid-free clinical remission	Crohn's Disease Activity Index (CDAI) ≤150 without systemic corticosteroid therapy	At both 3 months and a 1 year after the initiation of therapy
Clinical response	A reduction in CDAI of at least 100 points from baseline.	1 year after the initiation of therapy
Sustained corticosteroid-free biochemical remission	C-reactive protein (CRP) ≤1.5 upper limit of normal, or fecal calprotectin ≤ 250 mg/kg	at both 6 months and a 1 year after the initiation of therapy
Treatment durability	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	at both 6 months and a 1 year after the initiation of therapy
Anti-TNF drug levels	Levels at various timepoints	At 6 weeks, 26 weeks and a 1 year after the initiation of therapy
Early anti-drug antibody development	Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay	At 6 weeks, 26 weeks and a 1 year after the initiation of therapy
PRO-2 remission at Week 52	- 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).	1 year after the initiation of therapy
Sustained corticosteroid-free PRO-2 clinical remission	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	At both 14 and a 1 year after the initiation of therapy
Addition of immunomodulator treatment	The rate of addition of immunomodulator treatment defined as at least one dose of thiopurines or methotrexate	At any time during the study
Immunomodulator treatment termination	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	At 14 weeks and not restarting by 1 year after the initiation of therapy
Endoscopic improvement	Endoscopic improvement defined as a reduction of ≥50% decrement from baseline in SES-CD score	At 26 weeks
Endoscopic remission	Endoscopic remission defined as SES-CD ≤4	At 26 and 52 weeks

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus

Publications and helpful links

General 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. doi: 10.1136/gutjnl-2021-325185. Epub 2021 Aug 3.

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2023
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: September 14, 2022
• First Submitted That Met QC Criteria: October 25, 2022
• First Posted (Actual): October 31, 2022

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 19, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: immunogenicity; adalimumab; Crohn's disease; infliximab; azithromycin
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: 0432-22-RMB

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No