Evaluation of the Efficacy of Azithromycin in Idiopathic Purulent Oedematous Sinusitis in Adults (SOPAZITHRO)

Centre Hospitalier Intercommunal Creteil

Status and phase: Enrolling; Phase 3

Conditions: Sinus Infection Chronic; Sinusitis, Chronic

Treatments: Drug: Placebo; Drug: Azithromycin Oral Tablet

Study type: Interventional

Funder types: Other

Identifiers

NCT05157685

SOPAZITHRO

2020-001227-13 (EudraCT Number)

Details and patient eligibility

About

Purulent Oedematous Sinusitis (POS) is a particular form of chronic rhinosinusitis observed in 2% of the general population. In spite of its heavy impact on the quality of life, There is no established recommendation for the treatment of primary POS. Long-term low-dose macrolides are currently proposed for these forms of chronic rhinosinusitis when conventional treatments (local corticosteroids, saline rinsing, iterative short courses of antibiotics targeted on pathogens, and surgical opening and drainage) have failed. This treatment with macrolides is currently applied off-label.

This study aims to assess the efficacy of macrolides in POS. An extensive workup is fulfilled to exclude other forms of chronic rhinosinusitis (Th2 biased inflammatory diseases, allergic diseases) (allergy, nasosinusal polyposis) or those due to cystic fibrosis or immune deficiency.

Full description

POS is a particular form of chronic rhinosinusitis described in 2% of the general population. They lead to an alteration in the quality of daily life with a significant impact on the professional life of 70% of patients. They can be of idiopathic or of secondary origin. The most frequent secondary forms are those observed in cystic fibrosis and immune deficiencies. The pathophysiology of primary POS remains poorly understood, involving Th1-type inflammation and various bacteria (with Staphylococcus Aureus in the forefront). Bacteria could impair the ciliary beat, perpetuating infection and mucosal inflammation. There is no established recommendation for the treatment of primary POS Long-term low-dose macrolides are currently proposed for these forms of chronic rhinosinusitis when conventional treatments (local corticosteroids, saline rinsing, iterative short courses of antibiotics adapted to the germs found, and surgical drainage) have failed. This treatment with macrolides is currently used off label.

Macrolides are effective on most gram-positive and gram-positive bacteria. Macrolides also have immunomodulatory properties on the Th1 immune response. This effect is maintained even in the presence of macrolide-resistant bacteria. In chronic obstructive pulmonary disease, daily administration of half-dose macrolides over the long term (HDLT) has been shown to be effective in reducing the frequency of infectious exacerbations. Uncontrolled trials have described an improvement in symptom scores in chronic rhinosinusitis with or without polyps. The results observed in randomized trials versus placebo are contradictory. A meta-analysis published in 2013 based on these 2 randomized studies was inconclusive regarding the efficacy of HDLT macrolides. The heterogeneity of the inclusion criteria with rhinosinusitis of a different proTh-2 inflammatory profile corresponding to that usually observed in nasal polyposis could explain this lack of result. A review of the literature published in 2017 on HDLT macrolides based on 52 publications observed a very wide diversity of antibiotic protocols in terms of the molecule chosen, the administration scheme and the duration of treatment (8 to 24 weeks). The number of patients studied was often small, which affected the statistical power of the results obtained. The authors of this review conclude by stressing the need to conduct placebo-controlled studies on large populations of patients selected on the phenotypic level.

This study propose to evaluate the value of HDLT macrolides in this specific etiological setting. This project plans to exclude all chronic rhinosinusitis of Th2 inflammatory origin (allergy, nasosinusal polyposis) or those due to cystic fibrosis or immune deficiency. In addition, the inclusion centers selected in Ile de France have the necessary expertise to evaluate the impact of azithromycin on mucociliary clearance, notably with the development of innovative tools to measure the efficiency of the ciliary beat (high-speed video microscopy and particle tracking).At the same time, the tolerance of HDLT macrolides measured in patients with cystic fibrosis or chronic obstructive pulmonary disease (COPD) is excellent, provided that the well-documented contraindications are respected. No serious adverse effects have been reported, apart from cases of transient or permanent moderate hearing loss requiring audiometric monitoring.

No specific study regarding the treatment of primary POS is available to date, even tough POS is very prevalent and its management is still associated with poor patient-reported outcomes.

Enrollment: 230 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

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

• Persistent intractable purulent rhinosinusitis despite at least 2 antibiotic therapies

• Signed informed consent of the patient

• Membership in a health insurance plan or beneficiary

Exclusion criteria

• Pregnancy or breastfeeding

• PCOS of identified primary cause (identified immune deficiency, cystic fibrosis, HIV)

• 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 sensorineural hearing loss with a mean pure tone threshold in the poorer ear in bone conduction >30 dB across all 3 frequencies (500, 1000 and 2000 Hz) or in only one ear (unilateral deafness).

• 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).The calculation of the corrected QT should be carried out using the Bazett formula.

• 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 drugs

• Patients with severe cholestasis

• Patients under guardianship or curatorship

• 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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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230 participants in 2 patient groups, including a placebo group

Azithromycin oral tablet

Experimental group

Description:

Azithromycin 250 mg once daily morning or evening (with or without meals)

Treatment:

Drug: Azithromycin Oral Tablet

Placebo

Placebo Comparator group

Description:

Placebo once daily morning or evening (with or without meals)

Treatment:

Drug: Placebo