The trial was performed between Dec. 30, 2008, and Apr. 28, 2011, at 54 primary care practices (68 family physicians) in Zeeland, a province in the southwestern region of the Netherlands. The study was approved by the medical ethics committee of the University Medical Center Utrecht and the central committee on research involving human subjects of the Netherlands. Neither the family physicians nor the patients received financial reimbursement for participation in the study.
Patients aged 18 years and older who visited their family physician with symptoms of acute rhinosinusitis of at least 5 days’ (maximum 12 weeks’) duration were recruited. We considered patients to have acute rhinosinusitis if they met the criteria for a clinical diagnosis as defined in the European Position Paper on Rhinosinusitis and Nasal Polyps 2007 for primary care.3
Patients had to have at least 2 symptoms: one of either nasal discharge (anterior or posterior nasal drip) or nasal congestion; the other of either facial pain or pressure, or pain when masticating.
We excluded patients with a complicated course of acute rhinosinusitis (i.e., orbital swelling, temperature ≥ 38.5°C after 5 days of symptoms) and those with a history of recurrent rhinosinusitis (≥ 2 episodes in the previous year). Other exclusion criteria were pregnancy, previous head and neck surgery for malignant disease, contraindication for prednisolone, and use of intranasal or oral corticosteroids in the previous 4 weeks.
Sealed blind-sequenced medication containers that held a 7-day supply of either prednisolone 30 mg/d or placebo were distributed to participating practices in randomized blocks of 4. The corticosteroid and placebo drugs, manufactured and tested by the pharmacy department of the University Medical Center Utrecht (independent of the trial team), were identical in taste and appearance. The containers were identifiable only by randomization code number. The pharmacy department created the block randomization sequence using computer-generated random numbers. The randomization code was kept at a locker in the pharmacy department throughout the study and was not broken until data collection was completed and blinded analyses were performed.
After obtaining informed consent, family physicians completed a baseline questionnaire about the participant’s symptoms, comorbidities and consultations for acute rhinosinusitis in the 3 years before the study and performed a basic physical examination.
Each participant was then given a sealed medication container with a 7-day supply of either prednisolone or placebo and a diary to record symptoms for 14 days. The diary included questions about symptoms of asthma and rhinitis in the year before the study,19
the use of trial medication and other medication, their daily activities, and daily entries of 7 symptoms (facial pain or pressure, nasal congestion or blockage, postnasal discharge, runny nose, poor sleep, cough and reduced productivity). In addition, questions regarding disease-specific health-related quality of life from the Sino-Nasal Outcome Test 2020,21
were answered on days 1, 7 and 14. As part of both the daily entries of 7 symptoms and the Sino-Nasal Outcome Test 20, patients were asked to rate the severity of symptoms on a 6-point scale (0 = normal or no problem, 1 = very mild problem, 2 = mild or slight problem, 3 = moderate problem, 4 = severe problem and 5 = problem as bad as it can be).
The participants were allowed to use the following medications for symptom relief: acetaminophen 500 mg (maximum 6 tablets daily) for as long as needed and xylometazoline 0.1% nasal spray for 7 days. Family physicians were allowed to prescribe antibiotics or intranasal corticosteroid treatment but were advised to refrain from doing so as much as possible during the first week of study.
During the initial days of study, a blood sample was taken on a voluntary basis for an allergen-specific IgE test to a panel of common aeroallergens in adults (Phadiatop). The results were classified as positive or negative.
On day 14, patients visited their family physician for a consultation and handed in their symptom diary and medication container. The physician performed a physical examination and completed a questionnaire regarding consultations with the patient in the previous 2 weeks. At 8 weeks, the physicians were asked to complete a final questionnaire about consultations in the past 6 weeks; patients were contacted by telephone by the coordinating investigator to complete a questionnaire including questions from the Sino-Nasal Outcome Test 20.
The primary outcome measure was the proportion of patients with resolution of facial pain or pressure (score of 0 or 1) on day 7. Secondary outcome measures were the proportion of patients with resolution of severe facial pain or pressure (defined as absence of score of 4 or 5 regardless of severity score at baseline) on day 7, the proportion with resolution of other clinically relevant symptoms on day 7, time to resolution of total symptoms (combined symptoms of runny nose, postnasal discharge, nasal congestion, cough and facial pain), median duration of symptoms, health-related quality of life and resumption of daily activities (work or school).
Based on a previous trial,22
we expected 50% of the participants in the placebo group to have resolution of facial pain or pressure on day 7. To detect a clinically important difference in a self-limited condition in a primary care setting, we calculated a sample size of at least 184 patients based on the assumption of a minimum difference of 20% in the primary outcome between groups23,24
(α = 0.05 and β = 0.20).
For dichotomous outcomes, we calculated absolute risk differences, relative risks (RRs) and 95% confidence intervals (CIs). We used binomial logistic regression analysis to adjust for observed differences in baseline characteristics. The Mann–Whitney U test was used to evaluate differences in the median duration of symptoms between the groups. We calculated health-related quality of life by combining individual scores for the items on the Sino-Nasal Outcome Test 20, for a total score ranging from 0 to 100. The Student t test was used to evaluate differences in mean scores between groups at baseline, day 7, day 14 and week 8. We calculated the proportion of patients who resumed daily activities.
In post-hoc analyses, potential modification of the effect of corticosteroids was evaluated by means of binomial logistic regression analyses, including interaction terms for atopic status, allergic rhinitis, chronic nasal symptoms, recurrent rhinosinusitis, duration of symptoms before randomization and baseline severity of symptoms.
We also performed 2 sensitivity analyses: in one, we imputed missing data using multiple imputation;25
in another, we changed the definition of resolution of total symptoms.