Evaluation of Azithromycin Efficacy in Idiopathic Purulent Oedematous Sinusitis in Adults: A Multicentre Randomised Controlled Trial

Trial ID: 2024-517239-33-00
Protocol: SOPAZITHRO
Sponsor: Centre Hospitalier Intercommunal Creteil

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Diseases & Conditions

Sinusitis bacterial Chronic sinusitis

Objectives

The primary objective of this study is to assess the evolution of the specific quality of life score, measured by the **Sino-Nasal Outcome Test 22 (SNOT 22)**, from inclusion to the end of a 3-month treatment period in patients with idiopathic purulent oedematous sinusitis. This evaluation is clinically relevant as it provides insight into the impact of azithromycin treatment on the quality of life in individuals suffering from this condition, potentially guiding therapeutic decisions.

Secondary objectives include: - Comparing the efficacy of azithromycin to placebo over 3 months on various parameters such as the number of infectious rhinosinus exacerbations, antibiotic courses, intensity of functional symptoms, endoscopic examination results, CT score of rhinosinus opacities, ciliary beat, degree of nasal inflammation, bacterial colonization, general quality of life, and absenteeism from work. - Evaluating the compliance and tolerance of the treatment, both clinically and biologically. - Assessing the remanence of the treatment at 6 months concerning quality of life, symptomatology, nasal endoscopy, and bacteriological sampling. - Identifying clinico-biological predictive factors of response to treatment.

Participants

The clinical trial involves participants diagnosed with **chronic rhinosinusitis**, a condition categorized under **ear, nose, and throat diseases**. The study population includes both male and female subjects, aged between 18 and 70 years. Participants are required to be in general good health, with the exception of their chronic rhinosinusitis condition, which must have persisted for more than 12 weeks and meet specific endoscopic and CT criteria. The trial does not include a vulnerable population. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria. The sponsor has not provided information regarding the total number of participants in the study. Key inclusion criteria include a history of persistent purulent rhinosinusitis that has not responded to at least two antibiotic therapies, as per current recommendations. Participants must have signed informed consent and be members or beneficiaries of a health insurance plan. The selection process ensures a representative sample of the target demographic, focusing on individuals with a rebellious form of the condition.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of a 3-month continuous extended treatment with **azithromycin** in adults with idiopathic purulent oedematous sinusitis. This is a multicentre, randomized, controlled trial with a double-blind design to ensure unbiased results. The trial is expected to run from November 21, 2022, to December 21, 2025, with participant involvement lasting approximately three months. The primary objective is to assess the evolution of the specific quality of life score, Sino-Nasal Outcome Test 22 (SNOT 22), from inclusion to the end of the treatment period. Secondary endpoints include the number of infectious rhinosinus exacerbations, courses of antibiotics used, and various symptom scales and quality of life assessments.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (18-70 years), diagnosis of chronic rhinosinusitis, and previous treatment history. Following successful screening, participants will be randomized to receive either azithromycin or a placebo. The treatment will be administered orally, with a maximum daily dose of 250 mg. Follow-up visits will be scheduled to monitor the participants' progress, adherence to the treatment regimen, and any adverse events. The end-of-study visit will occur at the conclusion of the three-month treatment period, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or withdraw consent. The trial aims to provide valuable insights into the treatment of chronic sinusitis, contributing to the understanding of its management and potential therapeutic strategies.

Treatment

The clinical trial involves the administration of **Azithromycin**, an antibacterial agent, as the experimental medication. Azithromycin is provided in a pharmaceutical form identified as PHF00230MIG. The active substance, azithromycin, is of chemical origin and is classified under the ATC code J01FA10. The medication is administered orally at a dosage of 250 mg per day. The treatment period extends for a maximum of three months, with the total daily dose not exceeding 250 mg. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to the experimental treatment, a placebo, referred to as **Azithromycin placebo**, is utilized as a comparator in the study. The placebo is designed to mimic the experimental medication in appearance and administration route, which is oral. The placebo does not contain any active pharmaceutical ingredients and serves to provide a control for evaluating the efficacy of the experimental treatment. The administration schedule for the placebo mirrors that of the azithromycin, ensuring consistency in the trial's design.

Efficacy

Efficacy in the clinical trial titled "SOPAZITHRO: Evaluation of the Efficacy of 3-month Continuous Extended Treatment With Azithromycin in Idiopathic Purulent Oedematous Sinusitis in Adults" will be assessed using both primary and secondary endpoints. The primary endpoint is the comparison of the **Sinonasal Outcome Test (SNOT) 22** specific quality of life score averages between inclusion and the end of the 3-month treatment period. This endpoint will measure the intra-individual difference in quality of life related to sinonasal symptoms.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of efficacy. These include the number of infectious rhinosinus exacerbations, the number of courses of antibiotics used, visual analog scales of symptoms, semi-quantitative symptom scales, semi-quantitative nasal endoscopy scores, and quantitative Lund MacKay CT scores. Additional secondary endpoints involve nasal inflammation flow, general quality of life assessed by the Short Form-36 (SF-36), days off work, olfactory scores, and the presence of bacteria on protected nasal swabs. The trial will also evaluate the number of participants with clinical and biological adverse events as assessed by compliance, and the residual effects of the treatment using various scales and questionnaires, including the SNOT 22, SF-36, VAS score, semi-quantitative symptom scale, nasal endoscopy, and bacteriological samples. Furthermore, the quantitative and qualitative aspects of the ciliary beat will be assessed.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient older than 18 years and less than 70 years of age
Chronic rhinosinusitis (> 12 weeks of evolution) meeting the definition published in the European Paper Position2012 (1) and corresponding exclusively to the following endoscopic and CT criteria: Nasal endoscopy showing bilateral and diffuse involvement associating edema of the mucosa of the nasal cavities and meatus with the presence of mucopurulent secretions in these areas Nasosinus CT scan showing diffuse and bilateral pansinus opacities involving at least the maxillary sinuses and the anterior and posterior ethmoids
Rebellious form of persistent purulent rhinosinusitis despite at least 2 antibiotic therapies prescribed according to HAS recommendations in force for ethmoid sinusitis
Signed informed consent of the patient
Membership in a health insurance plan or beneficiary

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Exclusion Criteria

Pregnancy or breastfeeding
PCOS of identified primary cause (identified immune deficiency, cystic fibrosis)
Chronic non-purulent rhinosinusitis (nasosinusal polyposis, allergic rhinosinusitis)
Localized chronic suppurative rhinosinusitis (single sinus, unilateral, frontal or maxillary or sphenoidal)
Severe hepatic insufficiency (factor V level < 50%)
Severe renal insufficiency (stage 4 (GFR < 30 ml/min/1.73 m2) and/or creatinine < 40 ml/min)
Severe heart failure (old age, ischemic heart disease, episode of recurrent cardiac arrest; hypotension, NYHA functional stage III-IV; widened QRS, complex ventricular arrhythmias; hyponatremia (Na <135mmol/l); stage 4 renal failure (GFR < 30 ml/min/1.73 m2); severely depressed LVEF (< 30%)
Documented moderate pre-existing hearing loss (>30dB) or single ear (unilateral cophosis)
Major cognitive impairment or lack of French language skills preventing completion of SNOT-22 and SF-36 questionnaires
Patient with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases)
Patient with peanut or soy allergy
Patient allergic to macrolides
Patients who are intolerant or allergic to any of the excipients of azithromycin or placebo
Treatment with azithromycin in the previous 3 months
Long QT on ECG ((>440ms for male and >450ms for female) or cardiac arrhythmia or bradycardia (<60btm)
Hypokalemia or hypomagnesemia on blood ionogram
Confirmed or suspected atypical mycobacteriosis
Contraindicated drug combinations with macrolides (K-vitamins or drugs containing cisapride, colchicine, ergotamine or dihydroergotamine
Cautionary drug combinations (non-inclusion criteria) Atorvastatin (Increased risk of concentration-dependent rhabdomyolysis-type adverse events due to decreased hepatic metabolism of the cholesterol-lowering drug. Ciclosporin (risk of increased ciclosporin blood levels and creatinine levels) Digoxin (increase in digoxemia due to increased absorption of digoxin), Drugs likely to cause torsades de pointes, in particular class IA (e.g. quinidine) and class III (e.g. amiodarone, sotalol) antiarrhythmics, antipsychotics (e.g. phenothiazines, pimozide), tricyclic antidepressants (e.g. citalopram), certain fluoroquinolones (e.g. moxifloxacin, levofloxacin) (increased risk of ventricular rhythm disturbances) Simvastatin (increased risk of rhabdomyolysis-type adverse effects (concentration-dependent), due to decreased hepatic metabolism of the cholesterol-lowering agent) Ivabradine (increased risk of ventricular rhythm disorders), Hypokalemic drugs Bradycardia drug
Patients with severe cholestasi
Patients under guardianship or curatorsh
Patients with hematologic malignancies who have undergone hematopoietic stem cell transplantation
History of facial radiotherapy
History of rhinosinus cancer
Participation in other category 1 research at the time of inclusion or in the month prior to inclusion