Azithromycin for Patients With Chronic Rhinosinusitis Failing Medical and Surgical Therapy (AZI-CRS)

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Rhinosinusitis; High-risk Patient
• Intervention / Treatment: Drug: Azithromycin; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 129
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H2W 1T8
      • Centre Hospitalier de l'Université de Montréal (CHUM)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)
• Collaborators: Pfizer
• Investigators: Principal Investigator: Martin Y Desrosiers, MD, FRCSC, CHUM

Publications and helpful links

General Publications

• Desrosiers M, Evans GA, Keith PK, Wright ED, Kaplan A, Bouchard J, Ciavarella A, Doyle PW, Javer AR, Leith ES, Mukherji A, Robert Schellenberg R, Small P, Witterick IJ. Canadian clinical practice guidelines for acute and chronic rhinosinusitis. J Otolaryngol Head Neck Surg. 2011 May;40 Suppl 2:S99-193. English, French.
• Maniakas A, Desrosiers M. Azithromycin add-on therapy in high-risk postendoscopic sinus surgery patients failing corticosteroid irrigations: A clinical practice audit. Am J Rhinol Allergy. 2014 Mar-Apr;28(2):151-5. doi: 10.2500/ajra.2013.27.4017. Epub 2013 Dec 13.
• Desrosiers MY, Kilty SJ. Treatment alternatives for chronic rhinosinusitis persisting after ESS: what to do when antibiotics, steroids and surgery fail. Rhinology. 2008 Mar;46(1):3-14.
• Nader ME, Abou-Jaoude P, Cabaluna M, Desrosiers M. Using response to a standardized treatment to identify phenotypes for genetic studies of chronic rhinosinusitis. J Otolaryngol Head Neck Surg. 2010 Feb;39(1):69-75.
• Renteria AE, Maniakas A, Mfuna LE, Asmar MH, Gonzalez E, Desrosiers M. Low-dose and long-term azithromycin significantly decreases Staphylococcus aureus in the microbiome of refractory CRS patients. Int Forum Allergy Rhinol. 2021 Feb;11(2):93-105. doi: 10.1002/alr.22653. Epub 2020 Jul 26.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2014
• Primary Completion (Actual): August 15, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: November 11, 2014
• First Submitted That Met QC Criteria: December 3, 2014
• First Posted (Estimate): December 4, 2014

Study Record Updates

• Last Update Posted (Actual): January 26, 2018
• Last Update Submitted That Met QC Criteria: January 24, 2018
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Azithromycin; Endoscopic sinus surgery
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Otorhinolaryngologic Diseases; Paranasal Sinus Diseases; Nose Diseases; Sinusitis; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: 14.140