Study design
This randomised, double-blind, placebo-controlled, parallel-group study was conducted in the practices of 3 general practitioners, 2 specialists in pneumology, 1 internal medicine and 1 ENT practice. In accordance with the Helsinki Declaration, the study was approved by the appropriate authorities and ethics committees, responsible for the 7 participating centers. Furthermore, all patients provided an explicit, written consent form, prior to their participation and the commencement of the study.
Patients were randomly assigned to one of the two treatment groups with stratification according to the clinical centers. Patients were then given the necessary dose of capsules, each containing either 200 mg Cineole, or no active ingredient. The dosage for each group amounted to 1 capsule, taken 3 times daily, resulting in a total dose of 600 mg of Cineole per day. The placebo control group received an equal dose of placebo capsules. In order to avoid patients from recognising the smell of Cineole, all patients were instructed to take the capsules with mineral water, half an hour before meals. All capsules, containing either the active substance, or the placebo, were organoleptically identical and sealed in blister stripes. All patients visited the practices at the beginning of the study, as well as in the subsequent 4 and 10 days.
Enrolment of participants
The diagnosis of acute bronchitis was confirmed according to the criteria of Wenzel [7]. The study was limited to adult patients, aged 18 – 70 years, with a diagnosis of acute bronchitis not longer than 7 days. All eligible participants had a Bronchitis-Sum-Score of 7 or higher. Patients were excluded if they had severe medical conditions with relevant influence on the acute bronchitis.
Outcome measures
As primary endpoint a Bronchitis-Sum-Score summarising relevant symptoms of acute bronchitis was defined as multiple criteria composed of the parameters dyspnea, sputum, frequency of cough, thoracic pain, auscultation and lung function – all equally weighted. These were specified for the intensity of dyspnea in scores as 0 = no difficulties in breathing, 1 = minor difficulties in breathing, 2 = moderate difficulties in breathing, 3 = severe difficulties in breathing and 4 = unbearable difficulties in breathing. Quantity of secretion was assessed by scores (0 = no secretion, 1 = < 2 ml (i.e. very modest), 2 = < 5 ml (i.e. modest), 3 = < 10 ml (i.e. moderate), 4 = > 10 ml (i.e. very distinctive). Frequency of coughing fits was documented according to patients diary with the scores 0 = no coughing fits per day, 1 = one coughing fit per day, 2 = 2 – 3 coughing fits per day (i.e. occasionally), 3 = 4–5 coughing fits per day, 4 = 4–9 coughing fits per day (i.e. frequent), 5 = > 15 coughing fits per day (unbearable often). Thoracic pain during coughing was measured by the scores 0 = no, 1 = modest, 2 = moderate, 3 = severe pain, 4 = unbearable pain. Findings of auscultation were measured by the scores 0 = no, 1 = modest, 2 = moderate, 3 = relatively distinctive, 4 = distinctive rales. Impairment of lung function was differentiated by the scores 0 = no, 1 = slight (90 – 99% of predicted value), 2 = moderate (80 – 90% of predicted value), 3 = strong (70 – 79% of predicted value) and 4 = very strong impairment (less than 70% of predicted value).
Additionally, symptom-scores were determined for dyspnea frequency and intensity during rest, as well as after exercise (scores: 0 = caused no problems, 1 = occasional problems, 2 = caused a lot of problems, 3 = the most important problem the patient had). The frequency of dyspnea during the course of a week was also gauged and converted into qualitative scores (scores: 0 = no day was good, 1 = 1–2 days were good, 2 = 3–4 days were good, 3 = nearly every day was good, 4 = every day was good). Additionally, coughing and the propensity to cough were determined, and given by scores (0 = no cough, 1 = in the morning without complaints, 2 = in the morning with complaints, 3 = in the morning and over the day (moderate), 3 = in the morning and over the day (severe), 5 = continuously during whole day (moderate complaints) and 6 = continuously during whole day (relevant complaints).
Visits and randomisation
Randomisation was sequentially assigned in balanced blocks of 4 from a computer-generated list (random, idv Data-Analysis& Study Planning, Krailling, Germany). After the randomisation, the following patient details were recorded: height; weight; age; time from the first diagnosis of asthma symptoms; documentation of allergies; concomitant disease; prescribed medication; assessment of the current maintenance therapy. Control visits were carried out after 4 and 10 days, when adverse events were recorded and compliance with the treatment plan, as well as potential changes to therapy were addressed.
Statistical analysis
The proposed sample size for this study was a total of 240 patients for both treatment groups (nnpar (nonparametric), idv, Data-Analysis & Study Planning, Krailling, Germany). An analysis of efficacy was performed with the intention-to-treat-population including all eligible patients, who received at least one dose of medication and had at least one follow-up visit. The primary outcome measure was composed by a Bronchitis-Sum-Score. The statistical analysis of the data was analysed using the Wilcoxon-Mann–Whitney-U Test, idv, Data-Analysis & Study Planning, Krailing, Germany). All secondary outcome measures were analysed using the Wilcoxon-Mann–Whitney-U Test as well. All data are expressed as mean values (with SD) and all tests were two-tailed. P-values of 0.05 or less were considered to indicate statistical significance.