1

Introduction

Between 1999 and 2002, there were more than 3 million visits per year to a physician’s office or hospital outpatient or emergency departments for acute rhinosinusitis, with 83% resulting in a prescription for an antibiotic . The distinction between viral and bacterial sinus infection is difficult to make in the primary care setting, and symptoms of acute bacterial sinusitis (ABS) usually resolve on their own. Therefore, several recent publications have questioned the benefit of antibiotic treatment of ABS in a physician practice setting . However, the signs and symptoms of sinusitis can have a significant impact on a patient’s quality of life and productivity , and these outcomes may be improved with earlier symptom resolution.

Recent recommendations for clinical trials of acute sinusitis highlight the importance of symptom resolution as an indicator of treatment efficacy . Draft guidance from the US Food and Drug Administration on the design of future clinical trials of ABS recommends that the primary efficacy end point reflect outcomes that are clinically important to patients. An end point of time to clinical success, defined as the period from the start of study drug administration to complete relief of symptoms, should be used in this setting . However, few antibiotic trials have compared treatments using patient-reported symptom resolution as an end point. One review of antibiotic therapy suggested that antibiotics improve symptom resolution in patients with suspected bacterial disease , whereas a more recent meta-analysis of placebo-controlled trials reported that antibiotics have a minimal impact for most patients who receive them in clinical practice . A recent small, prospective, randomized trial failed to find improvement in symptom resolution rates between amoxicillin and placebo .

A post hoc analysis from a phase III clinical trial showed that significantly more patients receiving a single, 2-g dose of azithromycin extended release had complete resolution of 3 of 4 cardinal symptoms of sinusitis than patients who received levofloxacin 500 mg once daily at a study visit 3 to 5 days after randomization (32.6% vs 23.4%; P = .018) . These findings have not been tested prospectively. Therefore, the objective of this study was to compare early symptom resolution 5 days after patients received either azithromycin extended release or amoxicillin/clavulanate potassium. Secondary objectives were to compare measures of long-term response (antibiotic use and physician visits), symptom resolution over time, sinusitis-related quality of life, and treatment satisfaction.

2

Methods

This was a prospective, randomized, phase IV, multicenter, open-label study in adults (≥18 years) with evidence of acute, uncomplicated, bacterial maxillary sinusitis. Evidence of acute sinusitis was based on signs and symptoms lasting for between 7 and 30 days, to represent a real-world patient population. The signs and symptoms were pain, pressure, and/or tightness associated with 1 or both maxillary sinuses that worsened with movement or percussion, and discolored (yellow-green) nasal discharge or discolored drainage in the posterior pharynx or from the maxillary sinus orifice, together with 2 or more of fever (oral temperature >38°C or tympanic temperature >38.5°C), frequent coughing, nasal congestion, or postnasal drainage. Patients were recruited in the primary care settings of 70 study investigators, and written informed consent from the patient or a legally authorized representative was required. This study is registered on www.clinicaltrials.gov , with the identifying reference of NCT00367120 .

Patients were excluded if they were hypersensitive or intolerant to any macrolide or penicillin compound, had received any systemic antibiotic or used systemic corticosteroids within 30 days before enrollment, or had initiated an inhaled nasal corticosteroid or antifungal therapy within 14 days of the enrollment visit. Other reasons for exclusion included complicated sinusitis, at least 4 episodes of acute sinusitis within the preceding 12 months, or any medical condition or treatment that could interfere with the evaluation of the study drug and/or would make the patient unsuitable for enrollment.

Patients were randomized to receive either a single oral dose of azithromycin extended release (2 g) or 10 days of oral amoxicillin/clavulanate potassium 875 mg/125 mg every 12 hours. For 12 days after enrollment, patients maintained a twice-daily diary to record the occurrence and intensity of symptoms, episodes of diarrhea and abdominal discomfort, treatment compliance, and use of any concomitant symptom relief treatments. Additional information on sinusitis-related quality of life, productivity, adverse events, and use of health resources was gathered through computer-assisted telephone interviews at days 12 and 28 after enrollment. Only patients who completed the first telephone interview were contacted for the second telephone interview.

The intent-to-treat (ITT) population included all eligible patients who were assigned a randomization number. A per-protocol (PP) population was defined as ITT patients who completed the diary and first telephone interview and who reported taking at least 1 dose of the study medication. Because the diary was needed to calculate the primary end point, the PP population was prespecified as the primary analysis population.

The primary end point was self-reported symptom resolution at day 5 in the PP population. Secondary end points included time to resolution of symptoms, sinusitis-related quality of life, resource use (additional physician visits and antibiotic use for sinusitis), treatment success, and treatment satisfaction.

2

Methods

This was a prospective, randomized, phase IV, multicenter, open-label study in adults (≥18 years) with evidence of acute, uncomplicated, bacterial maxillary sinusitis. Evidence of acute sinusitis was based on signs and symptoms lasting for between 7 and 30 days, to represent a real-world patient population. The signs and symptoms were pain, pressure, and/or tightness associated with 1 or both maxillary sinuses that worsened with movement or percussion, and discolored (yellow-green) nasal discharge or discolored drainage in the posterior pharynx or from the maxillary sinus orifice, together with 2 or more of fever (oral temperature >38°C or tympanic temperature >38.5°C), frequent coughing, nasal congestion, or postnasal drainage. Patients were recruited in the primary care settings of 70 study investigators, and written informed consent from the patient or a legally authorized representative was required. This study is registered on www.clinicaltrials.gov , with the identifying reference of NCT00367120 .

Patients were excluded if they were hypersensitive or intolerant to any macrolide or penicillin compound, had received any systemic antibiotic or used systemic corticosteroids within 30 days before enrollment, or had initiated an inhaled nasal corticosteroid or antifungal therapy within 14 days of the enrollment visit. Other reasons for exclusion included complicated sinusitis, at least 4 episodes of acute sinusitis within the preceding 12 months, or any medical condition or treatment that could interfere with the evaluation of the study drug and/or would make the patient unsuitable for enrollment.

Patients were randomized to receive either a single oral dose of azithromycin extended release (2 g) or 10 days of oral amoxicillin/clavulanate potassium 875 mg/125 mg every 12 hours. For 12 days after enrollment, patients maintained a twice-daily diary to record the occurrence and intensity of symptoms, episodes of diarrhea and abdominal discomfort, treatment compliance, and use of any concomitant symptom relief treatments. Additional information on sinusitis-related quality of life, productivity, adverse events, and use of health resources was gathered through computer-assisted telephone interviews at days 12 and 28 after enrollment. Only patients who completed the first telephone interview were contacted for the second telephone interview.

The intent-to-treat (ITT) population included all eligible patients who were assigned a randomization number. A per-protocol (PP) population was defined as ITT patients who completed the diary and first telephone interview and who reported taking at least 1 dose of the study medication. Because the diary was needed to calculate the primary end point, the PP population was prespecified as the primary analysis population.

The primary end point was self-reported symptom resolution at day 5 in the PP population. Secondary end points included time to resolution of symptoms, sinusitis-related quality of life, resource use (additional physician visits and antibiotic use for sinusitis), treatment success, and treatment satisfaction.