Azithromycin for Patients With Chronic Rhinosinusitis Failing Medical and Surgical Therapy

Study Overview
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Brief Summary
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Justification: Chronic rhinosinusitis (CRS) is one of the most common inflammatory diseases with an incidence and prevalence superior to 10%. Unfortunately, more than 30% of patients do not respond to standard medical and surgical treatment, thus continuously increasing the symptomatologic and socio-economic burden of this disease. Hypothesis: The investigators believe that the addition of azithromycin (AZI) to the treatment regimen of patients with refractory CRS failing conventional medico-surgical treatment will be beneficial in a symptomatologic and endoscopic level. Primary objective: 1- To evaluate whether Azithromycine 250 mg PO three times weekly is effective in controlling signs and symptoms of CRS in high-risk patients unresponsive to standard management after endoscopic sinus surgery (ESS) with budesonide irrigations. Secondary objectives: i) Validate a simple and concise treatment algorithm for patients refractory to standard CRS treatment of ESS and BUDI, with the addition of low-dose AZI. ii) Characterise and define the population deemed high-risk for standard CRS treatment failure by evaluating: 1) demographics, 2) inflammatory states and 3) the nasal flora microbiome of patients at the different follow-up points of this study. iii) Explore the mechanisms of AZI by assessing the changes in inflammatory states and the nasal flora microbiome associated with successful AZI therapy. Methods: Inclusion of all patients admitted for endoscopic sinus surgery (ESS) for CRS operated by the same surgeon (MD). Following their first postoperative visit (2 weeks), all patients will receive nasal irrigations with budesonide (BUDI) twice daily for 4 months and will be re-evaluated. If there is a failure of treatment, patients eligible to receive AZI will be randomized in to two groups, AZI 250mg or a placebo three times a week for 4 months. At every follow-up, complete endoscopic exams will be performed, along with sinus cultures and brush cytology. Population: All patients deemed high-risk with CRS admitted for ESS between October 2014 and October 2015.

Official Title
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Azithromycin as add-on Therapy in Patients Failing Medical and Surgical Treatment for Chronic Rhinosinusitis: a Double-blind, Randomized, Placebo-controlled Trial

Conditions
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Chronic Rhinosinusitis, High-risk Patient

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with ≥1 of the following criteria: history of sinus surgery, first sinus surgery at ≤38 years of age, an absolute eosinophilia of ≥500 cells/mm, serum IgE levels of >150 kIU/L, a Gram negative bacteria in a sinus culture, the presence of intra-operative eosinophilic mucin. Exclusion Criteria: Patients with cystic fibrosis, inverted papillomas, osteomata, mucoceles or other lesions of the base of skull will be excluded. Patients with an elevated cardiovascular disease risk will be excluded from the randomized clinical trial part of this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Azithromycin<br>Patients will receive the active study drug, azithromycin, as well as sinus irrigations with budesonide. | Drug: Azithromycin<br>* The drug will be taken three times a week for four months.<br>* Other names: Zithromax;|
| Placebo Comparator: Placebo<br>Patients will receive a placebo as well as sinus irrigations with budesonide. | Drug: Placebo<br>* The placebo will be taken three times a week for four months.<br>* Other names: No other name;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Signs and symptoms outcome to Azithromycin | Evaluate if Azithromycin 250mg by mouth, three times a week for four months will be effective in controlling signs and symptoms of chronic rhinosinusitis patients at a high-risk of recurrence following standard medical and surgical treatment. Disease level is evaluated through nasal endoscopy. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment algorithm validation | Validate a simple and concise treatment algorithm for patients refractory to standard CRS treatment of ESS and BUDI, with the addition of low-dose AZI. | 8 months | 
| High-risk population | Characterise and define the population deemed high-risk for standard CRS treatment failure by evaluating: The demographics of this population The inflammatory state of patients at the different follow-ups (serum biomarkers) The microbiome of the nasal flora of patients at the different follow-ups (microbial cultures) | 12 months | 
| Azithromycin mechanism of action | Explore the mechanisms of action of AZI by assessing the changes in inflammatory states (serum biomarkers and epithelium inflammation) and the nasal flora microbiome (microbial cultures) associated with successful AZI therapy. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Azithromycin, Endoscopic sinus surgery