Treatment assignment and masking
In this double-blind trial, patients were assigned via a computer-generated random number list to receive 500 mg amoxicillin 3 times a day or placebo for 10 days. The trial medication was supplied in numbered uniform cardboard boxes, each containing 30 capsules of the same size, color, and shape for active and placebo treatment. The randomization list, kept at the pharmacy of GUH, was accessible to the participating FPs only in case of a serious adverse event.
To assess the effectiveness of masking, patients and their FPs guessed the treatment group at 10-day follow-up. Data were encoded and entered without knowledge of treatment allocation. Compliance was assessed by counting leftover medication. All patients were allowed to use xylometazoline 1% nose drops and paracetamol or ibuprofen to alleviate symptoms; these data were registered.
Assessment of potential recruitment bias caused by exclusion
First, we compared the characteristics of patients enrolled by high-recruiting FPs (at least 14 patients recruited) with those of patients from low recruiters (at most 5 patients recruited). Second, we asked all participating FPs to complete a short questionnaire over a 6-week period on all patients eligible for the trial but not included in it (sex, age, body temperature, severity of nasal discharge and pain, reason for non-recruitment). Third, to estimate the proportion of sinusitis cases among included patients, all patients were invited for an optional radiologic examination of the maxillary sinuses (single Waters view).28 Radiographs were taken in the nearest radiology unit, collected centrally, and evaluated by a radiologist of the GUH who specialized in the ear, nose, and throat.
Baseline measurements
Randomized patients completed an extensive questionnaire and were physically examined by their FP. To evaluate the symptoms, we used the 20 items of the sinonasal outcome test (SNOT-20)29,30 supplemented by 3 questions about pain. Symptoms were scored on a 6-category (0-5) Likert scale. Patients were also asked to indicate which of their symptoms (no more than 5) were most troublesome.
Follow-up
During 10 days of treatment, all patients recorded their daily drug intake (trial medication and symptomatic medication); their general feeling of illness; the presence of nasal discharge, pain, and cough; body temperature; the occurrence of presumed adverse drug effects; and absence from work or school. On day 10 they underwent a second physical examination and completed the symptom questionnaire again. In case of insufficient recovery, the FP was then at liberty to prescribe an open antibiotic course (we recommended amoxicillin clavulanate) without revealing the previous treatment phase. Patients who had recovered on day 10 did not have to return on day 15. Any patient with poor recovery on day 10 was asked, regardless of open antibiotic treatment, to continue writing in the diary and to come back on day 15 if complaints were still present.
The 2 primary endpoints were the therapy success rate on day 10 and the duration of general illness, pain, and purulent rhinorrhea as recorded in the diary. Treatment was considered successful when all symptoms that the patient had included in the list of “most important item affecting my health” scored 0 (absent) or 1 (very mildly present) after 10 days of treatment. Secondary endpoints were the mean change in severity score between day 1 and 10 on the various symptoms, incidence of unfavorable evolution, incidence of side effects, intake of analgesics, and duration of sick leave. The number of patients needed to demonstrate a difference in the therapy success rate of 15% at day 10 (α = 0.05, β = 0.20) was 168 per treatment group.31 This determination assumed a success rate of 50% in the placebo group.11,12
Statistics
Data were analyzed with SPSS-7. Differences in proportions are presented as relative risks with 95% confidence intervals and tested by chi-square test. The duration of symptoms is presented by Kaplan-Meier survival plots. Differences in duration are tested by the log rank test. Other continuous variables are tested by Student’s t test or the nonparametric Mann-Whitney U test.
Results
Participant flow and follow-up
Of 416 patients enrolled in the study, 8 were excluded after randomization. Of the 408 patients remaining, 202 received amoxicillin and 206 placebo; 34 patients (8%) withdrew from the trial. Their personal characteristics and clinical conditions at inclusion were not different from those of patients with follow-up. Figure 1 lists reasons for exclusion or withdrawal. The treatment code was broken once for a suspected allergic reaction and once because of an exacerbation of symptoms. In accordance with the intention-to-treat principle, all enrolled patients were included in the analyses in the groups to which they were originally randomized. Patients who had withdrawn because of side effects were also included in the analysis of side effects.