Patients were eligible to be included in the study if they were ≥18–75 years of age with a Broca Index between 0.75 and 1.30 and evidence of uncomplicated acute bronchitis (≥10 coughing fits during the last day prior to screening visit, Bronchitis Severity Score [BSS] ≥5 points, onset of first symptoms [bronchial mucus production with impaired ability to cough up] within two days before start of treatment, body temperature <39.0 °C; ). Patients were excluded with history or presence of confounding respiratory disease (upper respiratory tract infection within the last 4 weeks, chronic bronchitis, chronic obstructive pulmonary disease [COPD], acute exacerbations thereof bronchiectasis, asthma, suspected pneumonia, cystic fibrosis, lung cancer), active cigarette smoking >10/day, concomitant bacterial infection, elevated body temperature (>39.0 °C sublingual), malignant disease of any origin, known or suspected hypersensitivity to the active substance and/or to any of the excipients. Further exclusion criteria included the following: any need for antibiotic treatment in patients at high risk of serious complications because of pre-existing comorbidity, malignancy other than squamous or basal cell carcinoma of the skin; antibiotic therapy (local or systemic) at any time during the preceding four weeks; need for administration of concomitant local and systemic medications including antibiotics, corticosteroids and antihistaminic agents; immunosuppressive therapy; radiation therapy or chemotherapy within the previous 12 months; pregnancy or breastfeeding; history of alcohol or drug abuse likely to lead to uncooperative behaviour; history of psychiatric and/or neurological illness likely to lead to uncooperative behaviour; participation in a clinical research study within the last 6 weeks; evidence or suspicion of non-compliance; inability to provide informed consent and patients using medication for treatment of common-cold-like symptoms (excluding nasal douche). Apart from saline inhalation no other concomitant medications were allowed for relief of bronchitis symptoms. Participants were recruited by general practitioners, specialists of pneumology or by hospital doctors from pneumology clinics from eight study centres located in Austria (3 centres) and Poland (5 centres).
The study was approved by the responsible Ethics Committees and registered at the European Medicines Agency EudraCT number: 2013-004836-31. All patients provided written informed consent. The trial was conducted according the Declaration of Helsinki, the Good Clinical Practice guidelines of the International Conference on Harmonization, and relevant local national laws and regulations concerning clinical trials. All local legal requirements regarding data protection were adhered to.
The primary objective was the mean difference of a defined total BSS of 25% between the verum group (active substance: Spicae ae.) and the placebo group after 7 days (±1 day in case of prevention) of full medication dose. Secondary objectives evaluated the mean difference of a defined total BSS of 25% between the verum group and the placebo group after 10 days of full medication dose; the global impact of disease on QoL after 7 and 10 days of full medication dosage and the incidence and severity of adverse events and toxicities as reported by the patient or observed by the investigator. Additionally, the progression of the most common accessory symptoms of acute bronchitis (i. e. impairment of general condition, difficulty swallowing, hoarseness, headache, pain in limbs and joints, fatigue, sore throat and acute rhinitis) was assessed in both groups after 7 and 10 days of full medication dosage.
The sample size calculation was based on information from previous trials and taking into account the objectives of this trial. According to the most conservative value observed in a trial published by Matthys and Heger we assumed a standard deviation of 3.2 for the mean change of BSS score from day 0 to day 7 . It was established that a sample size of n = 130 (including a drop-out rate of 20% plus a buffer of n = 21) in each group allows the detection of a minimum difference of 25% in BSS after 7 days of treatment with a power of 90% using the Mann–Whitney test (2-sided, alpha-level 0.05). Statistical programming and analysis were performed using SPSS® version 23.0 (IBM, SPSS, Armonk, NY, USA).
Data were recorded with the aid of case report forms (CRF). One CRF had been filled in by the physician for each patient. Data required in the CRF had to be recorded at the beginning of therapy (day 0), at the second visit after 7 days of treatment and the third visit after 10 days of therapy (end of therapy, EOT).
Pharmazeutische Fabrik Montavit Ges.m.b.H., Austria, conducted the study and provided study medication. Verum capsules (batch no. 13449501) with gastroresistant coating contained 150 mg Spicae aetheroleum (Tavipec®, manufacturer: Pharmazeutische Fabrik Montavit Ges.m.b.H., Absam, Austria) as the active ingredient; placebo capsules (batch no. 11536401) with gastroresistant coating were filled with medium-chain triglycerides (manufacturer: Catalent®, Eberbach, Germany). Spicae ae. is a herbal medicinal product containing the essential oil obtained by steam distillation of the flowering tops and stalks of Lavandula latifolia as the active ingredient. Its main constituents are linalool, 1,8-cineole and camphor in concentrations of 34–50%, 16–39% and 8–16%, respectively, as sourced from the European Pharmacopoeia 8th edition (http://online6.edqm.eu/ep800/). Spicae ae. is authorised to the market in Austria since 1959 but not yet authorised in Poland.
The administration route for all study medications was oral application. Study participants were assigned to swallow 2 capsules three times daily every day as a whole with some liquid, 30 min before a meal (breakfast, lunch, dinner) for 10 days. The dose schedule was planned according to the summary of product characteristics (SmPC) recommendations and the same for all patients. The investigational medicinal products (IMPs) were supplied in a double blind way according to a randomization list prepared by computer (random permuted blocks, confidential block size) via Rancode Professional® (IDV Gauting, Germany). Each patient was provided capsules for 10 days (+2 days in case of weekend). Both, verum and placebo were indistinguishable with regard to capsule size and outer appearance, smell, packaging and labelling. Adherence was tracked by counting the number of remaining capsules from each individual patient, both by the study nurse and the study monitor (four eye principle). As a characteristic ethereal taste may be perceptible during therapy with Spicae ae., Austrian participants to the study had to be naïve to Spicae ae. in order to avoid unblinding by the patient.
Data required in the CRF had to be recorded at the beginning of therapy, at the second visit after 7 days of treatment and the third visit after 10 days of therapy (end of therapy, EOT). Efficacy was recorded using the BSS, derived by summing responses to five major symptoms (i. e. cough, sputum, rales/rhonchi, chest pain during coughing, dyspnoea) with higher scores indicating more severe symptomatology, rated from 0 to 4 (0 = absent, 1 = mild, 2=moderate, 3 = severe, 4 = very severe). Further signs and symptoms of acute bronchitis (i. e. impairment of general condition, difficulty swallowing, hoarseness, headache, pain in limbs and joints, fatigue, sore throat and acute rhinitis) were assessed by verbal rating from 0 to 3 with higher scores indicating more severe symptomatology (0 = none, 1 = slight, 2 = moderate, 3 = severe). The global impact of disease on QoL was verbally assessed by the question “How troublesome are your symptoms of bronchitis?” At any visit, patients should assess their condition on a 10-point scoring system ranging from “Not troublesome” (= 0) to “Worst thinkable troublesome” (= 10). Scores from 0–3, 4–7, and 8–10 indicated mild, moderate and severe impact, respectively. Adverse events were either reported by the patient or observed by the investigator (recorded at each visit). As far as possible, each adverse event was described by its duration (start and end dates), its severity (mild, moderate, severe), its relationship to the study medication (not related, unlikely, possibly, probably, definitely), whether this influenced the course of the study medication (continued per protocol, reduced, interrupted, discontinued, therapy change), or whether it required specific therapy. No interim analysis was planned or performed.
All patients who completed the defined course of treatment for the primary (7 days) and secondary endpoints (10 days) were eligible for the efficacy analysis. All subjects included into the study, who had received at least one dose of medication and who provided at least one post-baseline safety information were considered evaluable for safety analysis (Intent to treat [ITT] principle). For efficacy parameters, all analyses were done for the per-protocol (PP) population of the secondary endpoint (10 days). The main efficacy variable was quantitative, however, not necessarily normally distributed; therefore a two-sided (α = 5%) Mann–Whitney test (rank-sum test) was applied. The differences in scores for the secondary endpoints were analysed with the Mann–Whitney test analogously. All secondary parameters were summarized using descriptive statistics, i. e. number (%) of patients for categorical variables and mean, SD (standard deviation), median, minimum/maximum for continuous variables. Descriptive statistics were produced by treatment group.