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

Phase 2

Recruiting

• Conditions: Crohn's Disease Relapse; Biological Substance; Adverse Effect
• Interventions: Drug: Azithromycin Pill; Other: Placebo

• Registration Number: NCT05599347
• Lead Sponsor: Rambam Health Care Campus

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.

Study Timeline

• Study First Submitted: 2022-09-14
• Study First Submitted QC: 2022-10-25
• Study First Posted: 2022-10-31
• Study Start: 2023-04-24
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-19
• Last Update Posted: 2023-11-22
• Primary Completion: 2025-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 180

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.

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Azithromycin	Azithromycin Pill	5-day consecutive treatment with oral azithromycin 500 mg once daily
Control	Placebo	5-day consecutive oral placebo once daily

Primary Outcome Measures

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

Secondary Outcome Measures

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

Trial Locations

Locations (11)

el Aviv Sourasky Medical Center - Ichilov; 🇮🇱 Tel Aviv, Israel

Wolfson Medical Center; 🇮🇱 H̱olon, Israel

Hillel Yaffe Medical Center; 🇮🇱 Hadera, Israel

Hadassah Medical Center; 🇮🇱 Jerusalem, Israel

Rabin Medical Center; 🇮🇱 Petah Tikva, Israel

Shaare Zedek; 🇮🇱 Jerusalem, Israel

Bnei Zion; 🇮🇱 Haifa, Israel

Carmel Medical Center; 🇮🇱 Haifa, Israel

Rambam Health Care Campus; 🇮🇱 Haifa, Israel

Soroka University Medical Center; 🇮🇱 Be'er Sheva, Israel

Zvulun; 🇮🇱 Kiryat Bialik, Israel