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
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
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
QUADRUPLE
Enrollment
180
Tablet - 500 mg azithromycin (as dihydrate)
Placebo tablet identical in shape and appearance to the azithromycin tablet used in the treatment arm
Soroka University Medical Center
Beersheba, Israel
RECRUITINGBnei Zion
Haifa, Israel
RECRUITINGCarmel Medical Center
Haifa, Israel
Anti-drug antibody development
Percent of patients developing anti-drug antibodies defined as measurable antibodies using an anti-lambda ELISA assay
Time frame: 1 year after the initiation of therapy
Sustained corticosteroid-free clinical remission
Crohn's Disease Activity Index (CDAI) ≤150 without systemic corticosteroid therapy
Time frame: 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.
Time frame: 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
Time frame: 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
Time frame: at both 6 months and a 1 year after the initiation of therapy
Anti-TNF drug levels
Levels at various timepoints
Time frame: 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
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Rambam Health Care Campus
Haifa, Israel
RECRUITINGWolfson Medical Center
Holon, Israel
RECRUITINGHadassah Medical Center
Jerusalem, Israel
RECRUITINGShaare Zedek
Jerusalem, Israel
RECRUITINGZvulun
Kiryat Bialik, Israel
RECRUITINGRabin Medical Center
Petah Tikva, Israel
RECRUITINGTime frame: 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).
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: At 26 weeks
Endoscopic remission
Endoscopic remission defined as SES-CD ≤4
Time frame: At 26 and 52 weeks