Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. Effectiveness of antitussives, anticholinergics or honey versus usual care in adults with uncomplicated acute bronchitis: a study protocol of an open randomised clinical trial in primary care Josep M Cots,1 Ana Moragas,2 Ana García-Sangenís,3,4 Rosa Morros,3,5 Ainhoa Gomez-Lumbreras,3 Dan Ouchi,6 Ramon Monfà,6 Helena Pera,3,4 Jesus Pujol,7 Carolina Bayona,8 Mariam de la Poza-Abad,9 Carl Llor 10 To cite: Cots JM, Moragas A, Abstract García-Sangenís A, et al. Strengths and limitations of this study Introduction Despite the frequent use of therapies in acute Effectiveness of antitussives, bronchitis, the evidence of their benefit is lacking, since only anticholinergics or honey ►► Since this is a pragmatic clinical trial evaluating the a few clinical trials have been published, with low sample versus usual care in adults effectiveness of different symptomatic therapies, sizes, poor methodological quality and mainly in children. The with uncomplicated acute masking techniques will not be used. bronchitis: a study protocol of objective of this study is to compare the effectiveness of three ►► A microbiological study will not be carried out as an open randomised clinical symptomatic therapies (dextromethorphan, ipratropium or most cases of acute bronchitis have a viral aetiolo- honey) associated with usual care and the usual care in adults Protected by copyright. trial in primary care. BMJ Open gy, and sputum samples are not routinely collected 2019;9:e028159. doi:10.1136/ with acute bronchitis. in the primary care setting. bmjopen-2018-028159 Methods and analysis This will be a multicentre, ►► The main objective as well as some of the second- pragmatic, parallel group, open randomised trial. Patients ►► Prepublication history for ary objectives of the study are based on information this paper is available online. aged 18 or over with uncomplicated acute bronchitis, provided by the patients themselves in the symptom To view these files, please visit with cough for less than 3 weeks as the main symptom, diaries. However, clinicians will encourage patients the journal online (http://​dx.​doi.​ scoring ≥4 in either daytime or nocturnal cough on a to fill them out appropriately and return them at the org/​10.​1136/​bmjopen-​2018-​ 7-point Likert scale, will be randomised to one of the different follow-up visits scheduled. 028159). following four groups: usual care, dextromethorphan 30 mg ►► Since one-quarter of patients with uncomplicat- three times a day, ipratropium bromide inhaler 20 µg two Received 24 November 2018 ed acute bronchitis still have cough after the first puffs three times a day or honey 30 mg (a spoonful) three Revised 14 March 2019 month, these patients will be followed and called times a day, all taken for up to 14 days. The exclusion Accepted 19 March 2019 2 weeks later. criteria will be pneumonia, criteria for hospital admission, pregnancy or lactation, concomitant pulmonary disease, associated significant comorbidity, allergy, intolerance or contraindication to any of the study drugs or admitted to affect approximately 5% of adults per year, a long-term residence. Sample: 668 patients. The primary and although they occur throughout the year, outcome will be the number of days with moderate-to- the incidence is higher in the autumn and severe cough. All patients will be given a paper-based winter.1 The most frequent of these infections symptom diary to be self-administered. A second visit will is acute bronchitis, which is a self-limiting be scheduled at day 2 or 3 for assessing evolution, with two more visits at days 15 and 29 for clinical assessment, infection of the lower airways that is charac- evaluation of adverse effects, re-attendance and terised by clinical manifestations of cough complications. Patients still with symptoms at day 29 will with or without sputum and the absence of be called 6 weeks after the baseline visit. symptoms or signs of pneumonia. Other © Author(s) (or their Ethics and dissemination The study has been approved symptoms associated with acute bronchitis employer(s)) 2019. Re-use by the Ethical Board of IDIAP Jordi Gol (reference number: include fatigue, wheezing, headache, myal- permitted under CC BY-NC. No commercial re-use. See rights AC18/002). The findings of this trial will be disseminated gias, hoarseness and general discomfort.2 As and permissions. Published by through research conferences and peer-review journals. there are no specific diagnostic criteria for BMJ. Trial registration number NCT03738917; Pre-results. acute bronchitis, the diagnosis is primarily For numbered affiliations see clinical and requires thorough assessment for end of article. differentiation from pneumonia, as well as Correspondence to Background other upper respiratory tract infections such Dr Carl Llor; Lower respiratory tract infections are common as the common cold or sore throat.3 However, ​carles.​llor@​gmail.​com conditions in primary care. These infections cough is not the prominent symptom in the Cots JM, et al. BMJ Open 2019;9:e028159. doi:10.1136/bmjopen-2018-028159 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. latter infections. Conversely, cough constitutes the most on cough associated with acute bronchitis.8 Despite prominent manifestation of acute bronchitis and lasts an being widely used, antihistamines have been evaluated average of 3 weeks, but may persist for more than 1 month primarily in the common cold and were not found to be in 25% of the patients.4 Initially, the cough is non-pro- beneficial to alleviate the symptoms of cough.13 Studies ductive, but after about a week there is an increase in assessing the benefits of Echinacea, Chinese herbs, Pelargo- mucus production, and in the second week, the colour nium sidoides, ivy leaf extracts and other herbal treatments of the sputum often changes from grey-white to purulent. have obtained contradictory results, mainly in patients Despite being a self-limiting condition, most patients with with common cold, with low quality of evidence and some acute bronchitis seek medical advice, mainly because of problems related to safety, and therefore, they are not bothersome cough.5 recommended in patients with acute bronchitis.14–17 Treatment of acute bronchitis is usually symptomatic Most studies that have assessed the benefit of antitus- and is aimed at relieving annoying respiratory symptoms. sives in adults, mainly codeine and dextromethorphan, Treatment should include good hand hygiene, increased have been performed in patients with acute cough in fluid intake, avoidance of smoking and the elimination the context of upper airway infections, thus limiting of environmental cough triggers (for instance, dust), the external validity to patients with acute bronchitis. and the use of vapours, particularly in low-humidity The benefit of dextromethorphan in acute bronchitis is environments, mainly if symptoms include nasal stuff- controversial. A review published by Parvez et al, including iness and nasal discharge. Many general practitioners 451 adults, found that a single dose of dextromethorphan (GPs) prescribe antibiotics, despite evidence of little or 30 mg reduced the number of cough bouts measured no benefit, since up to 90% of acute bronchitis are of with a microphone by between 19% and 36% within the viral aetiology, thereby contributing to the emergence of first 3 hours compared with placebo,18 but a meta-analysis bacterial resistance.6 of six studies in adults with upper airway infections found There are many approaches to the treatment of cough, that a single dose of dextromethorphan was slightly more including analgesics, non-steroidal anti-inflammatory effective than placebo in terms of intensity, effort and drugs (NSAIDs), expectorants, mucolytics, antihista- latency within the first 3 hours after intake (between 12% mines, decongestants, as well as antitussives, β2-agonists or and 17% more effective), although the clinical relevance Protected by copyright. other bronchodilators, alternative therapies and natural of this observation is unclear.19 Studies carried out with treatment.3 In general, these therapies are available as codeine in adults with acute bronchitis have not been over-the-counter medicines in many countries, and their shown to be beneficial.20 In children, dextromethorphan use is very widespread, particularly in southern European has not proven to be more effective than placebo.21 In countries. In a recent observational study conducted in a Scandinavian study conducted in 50 children followed 12 European areas, Catalonia was one of the zones with for 3 days, the average cough score was slightly lower than the highest consumption of mucolytics, bronchodilators placebo, although statistically significant differences were and antitussives.7 not observed between those taking the antitussive and According to the guidelines of the European Respi- those assigned to placebo.22 Despite this, some guide- ratory Society, acute cough can be treated with dextro- lines recommend a short course of antitussives to reduce methorphan or codeine, but mucolytics, antihistamines severe cough during acute illness in adults and children and bronchodilators should not be prescribed in acute over the age of six, but evidence related to their effective- lower respiratory tract infections.1 The reviews carried ness remains unclear.23 out so far conclude that the benefit of these therapies A non-negligible per cent of patients with acute bron- is lacking. In general, the studies performed had small chitis present exaggerated bronchial responsiveness, sample sizes and methodological flaws that make their which is mainly reported when the infection is caused comparison difficult.8 It should be considered that over- by viruses and atypical germs.24 However, a recent review the-counter preparations contain different drugs with a does not support the routine use of β2-adrenergic variety of modes of action that can make them difficult inhalers in patients with acute bronchitis.25 On the other to compare.9 Most clinicians recommend the use of hand, in one of the clinical trials included in this review a analgesics to alleviate mainly fever, headache, myalgia significant improvement in symptom scores was observed and chest pain. NSAIDs are also frequently prescribed in adults who received fenoterol 0.2 mg four times a day in patients with lower respiratory infections, mainly for for 7 days when there was bronchial hyper-reactiveness, relieving cough. However, two recent randomised clin- wheezing or a decrease in the forced expiratory volume ical trials have shown that the number of days with cough in one second compared with the same group of patients among patients taking NSAIDs is not significantly lower who had received placebo. This effect, however, was not than placebo.10 11 Some trials with inhaled corticosteroids observed among patients not presenting airflow obstruc- have also shown a very marginal benefit, but the number tion.26 This same effect has been described with inhaled of patients included in these studies was small.12 The anticholinergics, such as ipratropium and tiotropium clinical efficacy of other symptomatic drugs is also ques- alone or associated with β2-agonists, but these studies tionable. For example, trials assessing the effect of expec- were primarily conducted in patients with cough due to torants and mucolytics have not shown favourable effects upper airway infections.27 28 The release of acetylcholine 2 Cots JM, et al. BMJ Open 2019;9:e028159. doi:10.1136/bmjopen-2018-028159 Open access BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. in the airways by parasympathetic stimulation could degree of bronchial hyper-reactiveness measured with trigger hyper-reactiveness and increase mucosal secre- peak-flow and also (8) to evaluate the utilisation of anti- tion on the walls of the airways, and this might explain biotics and different symptomatic treatments in the four the possible antitussive properties of inhaled anticholin- arms, (9) to evaluate the number of days of absence from ergic drugs.29 Other drugs such as leukotriene inhibitors work in the four study arms, (10) to assess the number have not shown to be useful in acute cough.30 Despite all of times patients re-attend for symptoms related to the these limitations, the guidelines recommend that bron- episode of acute bronchitis, (11) to assess the number of chodilators can only be used in patients with bronchial complications related to the episode of acute bronchitis, hyper-reactiveness, outweighing the adverse effects, such (12) to assess patient satisfaction in the four study arms as tremors or nervousness, that these drugs can cause.31 and (13) to assess the number of adverse events in the In recent years, some studies using honey in children four study arms. have found favourable results on the frequency of cough, patient quality of life and the quality of sleep of both parents and children. In a recent meta-analysis, including Methods and analysis six clinical trials and a total of nearly 900 children, honey Trial design alleviated cough symptoms compared with no treatment This study is a phase IV, multicentre, pragmatic, parallel or diphenhydramine, but was not found to be more group, open randomised trial. effective than dextromethorphan. Apart from the limita- tions of the small sample sizes of these studies, most chil- Study arms dren received active treatment (different types of honey Once the patients are included in the trial, they will be depending on the studies) for only one night, and studies randomised into one of the four treatment groups: (1) evaluating their use in adult population are lacking.32 usual clinical practice group, (2) usual clinical prac- There is no clear evidence that some types of honey have tice +dextromethorphan (15 mg unit), one 15 mg tablet superior antimicrobial properties to others as described three times a day up to a maximum of 14 days, (3) usual in some papers.33 34 clinical practice +ipratropium bromide (20 µg each puff), Therefore, we believe that this clinical trial is justi- two puffs three times a day up to a maximum of 14 days, Protected by copyright. fied, since evidence of the benefit of these treatments in and (4) usual clinical practice +30 g of honey (one table- adults with acute bronchitis, with cough as a predomi- spoon) three times a day up to a maximum of 14 days, two nant symptom, is unclear. We prioritise the use of dextro- 750 mg bottles of wildflower honey (the most frequent methorphan, as this antitussive is recommended by type of honey used in our country) will be provided and clinical guidelines at the usual dose of 15 mg three times patients will be recommended to add the honey to a cup a day in the adult population, and ipratropium bromide of lemon or thyme juice, milk herbal tea, yoghourt, herbal inhalers, since the majority of studies carried out so teas, etc. All the drugs and products used in this study are far have considered β2-agonists, with very poor results already marketed, and therefore, the manufacturers are on effectiveness, and the fact that anticholinergics are responsible for the elaboration and control of samples. frequently used in primary care in our country. In our The study drugs will be provided free to the participants study, we want to evaluate the effectiveness of honey at the by the sponsor. The provision, secondary conditioning recommended dose of 30 g three times a day in the adult and distribution of the study drugs and products will population, since their benefit has only been explored in be performed by the Barcelona primary care pharmacy paediatrics. Unlike most published studies, these treat- service. All the study drugs as well as the honey will be ments will be recommended for a maximum of 14 days, kept at room temperature. To improve compliance, because as discussed earlier the average duration of symp- participants will be asked to record their daily dosage in toms with cough due to acute bronchitis is 3 weeks. the symptom diary. Sample size Objectives For the sample size calculation, a recent publication The main aim of the trial is to evaluate the clinical effec- about delayed antibiotic prescribing carried out in Spain tiveness of adding three symptomatic treatments (dextro- using the same symptom diaries with specific data from methorphan, ipratropium bromide or honey) to usual the group of patients with acute bronchitis has been care in reducing days with moderate-to-severe cough considered, from which an average duration of 5.5 days compared with usual care. The secondary objectives are of moderate-to-severe cough was obtained, with a SD of aimed at evaluating the clinical effectiveness of adding 4.5 days.35 Considering a reduction of 1.5 days as a clin- three symptomatic treatments to usual care compared with ically relevant outcome, a sample of 167 patients per usual care in the reduction of days: (1) with cough, (2) group is estimated (a total of 668). The power to detect with moderate-to-severe daytime cough, (3) with moder- the difference was assumed to be 0.8, with a two-sided ate-to-severe nocturnal cough, (4) severe or moderate significance level of 0.05. The allocation ratio of subjects symptoms, (5) severe symptoms, (6) until the complete into the groups is 1:1:1:1. We expect a 15% of loss to resolution of symptoms, (7) according to the baseline follow-up. Calculations have been performed with the aid Cots JM, et al. BMJ Open 2019;9:e028159. doi:10.1136/bmjopen-2018-028159 3 Open access BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. of GRANMO software, V.7.12 April 2012 (https://www.​ institutions and (12) difficulty in conducting scheduled imim.​cat/​ofertadeserveis/​software-​public/​granmo/). follow-up visits. Following the usual clinical practice, participating GPs Recruitment may prescribe the concomitant therapy they consider The trial will be conducted in different primary care appropriate, including analgesics such as NSAIDs or centres in Catalonia, Spain. A large geographical area of paracetamol, mucolytics, expectorants, antihistamines practices throughout Catalonia will be invited to partic- and also antibiotics. However, they will not be allowed to ipate to maximise the generalisability of the sample prescribe antitussives, including codeine, anticholinergic of adults with uncomplicated acute bronchitis and to inhalers and they will not be allowed to recommend the avoid saturation of research studies in some practices. use of honey, including honey candies, tablets or infu- The recruiting GPs will commence the study in January sions with honey. All drug information (name of product, 2019 and will attempt to recruit all eligible patients until purpose of administration, dosage, duration of adminis- October 2020. Provided the necessary sample is met tration, etc) will be recorded on the patient case report before this date, the recruitment period will end at the form (CRF) and patients will fill out any other treatment time of the inclusion of the last patient. The sponsor they obtain or purchase from the pharmacy in their reserves the right to prematurely discontinue this trial symptom diaries. at any time in case (1) the expected inclusion objectives are not met or (2) new information appears regarding Randomisation the efficacy or safety of any of the study medications that Patients will be assigned sequentially as they enter the could significantly affect the continuation of the trial or study. Randomisation of patients will be performed by overrules the previous positive evaluation of the bene- registering the patient in an electronic CRF during the fit-risk ratio. index visit. Patients will be stratified based on the previous duration of symptoms (≤1 week, >1 week). Once a patient Participants is included in the trial and the randomisation has been Inclusion criteria centrally made, the investigator will provide the assigned Potential participants who meet the following criteria treatment and record the dispensing and medication Protected by copyright. will be included in this trial: (1) age 18 years or older, code in the electronic CRF. Since this is a multicentre (2) symptoms of acute bronchitis, defined as an acute study, a block procedure will be performed to assign lower-respiratory-tract infection with cough as the patients to each of the health centres at a 1:1:1:1 ratio. predominant symptom, starting within 3 weeks before Blinding study inclusion, (3) patients who score ≥4 in either the This is an open study. Neither physicians nor patients will daytime and/or nocturnal cough on a 7-point Likert scale be blind to the patient's assignment to the study group. and (4) patients who consent to participate. The open nature of the clinical trial ensures that the results obtained in this study are very close to the reality Exclusion criteria of primary care, considering that both the participating Patients with any of the following criteria will be excluded GPs and the patients with uncomplicated acute bron- from this trial: (1) suspected pneumonia; if the profes- chitis will be aware of the treatment given. However, the sional suspects pneumonia, a chest X-ray will be recom- main outcome will be assessed by the patients themselves. mended and the patient will be randomised if this diagnosis is discarded, (2) criteria for hospital admission Outcome measures (impaired consciousness, respiratory rate >30 breaths/ Primary outcome min, pulse >125 beats/min, systolic blood pres- Duration (days) of moderate-to-severe cough in days. sure <90 mm Hg or diastolic blood pressure <60 mm Hg, Each symptom will be scored by the patient on a 7-point temperature >40°C or oxygen saturation <92%), (3) preg- Likert scale (0 = not affected, 1 = very little problem, nancy or breast feeding, (4) baseline respiratory disease 2 = slight problem, 3 = moderately bad, 4 = bad, such as chronic obstructive pulmonary disease, asthma, 5 = very bad, 6 = as bad as it could be). The number of days tuberculosis or bronchiectasis, (5) associated significant until the last day the patient scores 3 in either daytime comorbidity, such as moderate-to-severe heart failure, cough or nocturnal cough in the paper-based symptom dementia, acute myocardial infarction/recent cerebral diary will be considered for the main outcome. We will vascular accident (<3 months), severe liver failure, severe use validated questionnaires, which have also been used renal failure, (6) immunosuppression, such as chronic in a previous study.36 infection by HIV, transplanted, neutropenic, or patients receiving immunosuppressive treatment, (7) active Secondary outcomes neoplasm, (8) terminal illness, (9) history of intolerance Different secondary outcomes will be taken into account: or allergy to any of the study treatments, (10) patients (1) duration of symptoms (number of days until the last in whom, in the opinion of the investigator, treatment day the patient scores 2 in any of the symptoms), (2) with dextromethorphan, ipratropium bromide or honey duration of moderate-to-severe daytime cough (number is contraindicated, (11) patients living in long-term of days until the last day the patient scores 3 in daytime 4 Cots JM, et al. BMJ Open 2019;9:e028159. doi:10.1136/bmjopen-2018-028159 Open access BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. cough), (3) duration of moderate-to-severe nocturnal be conducted via periodic on-site/online visits, and all cough (number of days until the last day the patient the patients recruited will be monitored following a risk scores 3 in nocturnal cough), (4) duration of cough approach monitoring plan. (number of days until the last day the patient scores 2 in either daytime or nocturnal cough), (5) duration of Ascertainment of visits severe symptoms (number of days until the last day the The patients will be randomised to one of the four treat- patient scores 5 in any of the symptoms), (6) duration of ment strategies. To standardise data collection, all of the moderate-to-severe symptoms (number of days until the participating GPs will be trained by the coordinating last day the patient scores 3 in any of the symptoms), (7) centre. The patients will receive information on the duration of moderate-to-severe cough in days according study by the participating GPs, and if they are interested to the basal degree of bronchial hyper-reactiveness at the in participating, they will be provided with an informed baseline visit, measured with peak flow (the greatest of consent form to read and sign. A maximum length of three determinations will be considered), (8) utilisation 10 to 15 min is expected for the interview, randomisation of antibiotics and other symptomatic therapies within the and the introduction of the data. The participating GPs first 4 weeks, (9) duration of work or school absenteeism will explain the study scheme and the visit programme due to the episode of acute bronchitis, (10) number of to the patient (table 1). After randomisation, informa- re-attendances to any doctor regarding the episode of tion on the strategy to which they have been allocated acute bronchitis within the first 4 weeks, (11) number will be given to the participants, and they will be given of complications related to the episode of acute bron- the free study medication and will be informed as to the chitis within the first 4 weeks, such as pneumonias, visits appropriate measures to take in case of worsening or no to emergency departments, hospital admissions, (12) improvement of their condition. In addition, they will patient satisfaction and (13) adverse reactions. be given a paper-based diary to be completed by them- selves on a daily basis. The information collected in the Withdrawal diary includes: times in which study medication is taken, Patients will be free to withdraw from the study at any concomitant treatments used and a questionnaire of time for any reason without prejudice to future care, and symptoms, which has been previously used in other Protected by copyright. with no obligation to provide the reason for withdrawal. studies.35 Patients will complete the diary while symptoms In addition, the investigator may withdraw a participant related to the respiratory condition are present. from the trial at any time if deemed necessary by any of GPs will call patients 2 to 3 days after their inclusion in the following reasons: (1) intercurrent process or illness the study to monitor their progress and resolve possible that in the opinion of the investigator requires the with- doubts regarding the completion of the diary. Patients drawal of the patient's treatment, (2) the presence of an will be scheduled for a second visit at day 15 (2 weeks after adverse event that requires the withdrawal of the patient’s the patient inclusion) to evaluate their clinical evolu- treatment, (3) those who require a concomitant treat- tion. Depending on the patient’s clinical evolution, the ment not allowed during study participation (antitussives, follow-up will be different: (1) clinical cure, defined as anticholinergic inhalers, honey) or (4) protocol violation. absence of symptoms; the diary will be collected and they During the trial, patients will be asked to inform about will be called 2 weeks later to check if they have sought any signs of worsening symptoms, and investigators will medical advice again due to the episode of acute bron- evaluate appropriate measures if they need additional chitis, (2) clinical improvement, defined as the persistence therapy. Since this is a pragmatic trial, patients who of symptoms but with improvement with respect to the decide interrupting the study drug treatment but want to index visit. Patients will be given a new symptom diary to continue with the study procedures, will be followed in be completed in the following 14 days and will be asked to the same way as the other patients. return at day 29 to evaluate their condition. Participating GPs may prescribe any of the medications allowed by the Data management and monitoring study protocol, the same treatment as that which was previ- The investigators will follow the standard operating ously received by the patient, or nothing if not necessary. procedures of the trial for better quality of assessment and If the doctor deems it necessary to prescribe any of the outcome data collection. The investigators who evaluate therapies under study (with the exception of the arm in outcome measures should be restricted to only those GPs which the patient is located), the patient will discontinue who have attended the training meetings. All assessment the trial and follow the usual clinical practice, (3) failure, data and case reports will be collected at baseline (day when the patient is worse or presents the same symptoms 1) and at the various follow-up visits in the intervention as those presented at the index visit; patients will be with- arms and control group. Collected documents and data drawn from the study and will be managed according to will be managed by electronic CRF. Only the principal the clinician’s best judgement. At day 29, patients who investigator or those who have permission will be able to improved at day 15 will be similarly categorised as (1) access the data. The CRFs and other documents will be clinical cure, (2) improvement or (3) failure. Patients stored at a separate and secure location for 25 years after with clinical cure or improvement will be contacted again trial completion. Multicentre clinical trial monitoring will at day 43 (6 weeks after the baseline visit) to record if they Cots JM, et al. BMJ Open 2019;9:e028159. doi:10.1136/bmjopen-2018-028159 5 Open access BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. Table 1 Timetable of study period Day Day 1 Day 2 to 4 Day 15 Day 29* Day 43† Visit Visit 1 Phone visit 1 Visit 2 Visit 3 Phone visit 2 Phone visit 3 Visit at the centre X X X‡ Medical history and physical examination X Explanation of the study and informed consent X Initial CRF X Randomisation X Dispensing the study treatment X Peak flow determination X Giving out of the first symptom diary, up to day 15 X Assessment of the clinical outcome X X X X X Adherence to the study drug X X Evaluation of adverse events X X X X X Collection of the first symptom diary and giving out of the X second symptom diary from day 16 to day 29§ Collection of the second symptom diary X Evaluation of re-attendance to healthcare services due to X X X X X infectious condition Evaluation of complications X X X X X *Final visit if the symptoms have disappeared. †Only if the visit at day 29 is at the centre and a cure or improvement is recorded. ‡Phone visit if a cure is recorded at day 15. Protected by copyright. §Only if the patient still has symptoms of infection (improvement). CRF, case report form. have consulted with a professional regarding the episode the different strategies with the usual treatment, we will of cough and to assess safety (figure 1). use the chi-square tests for categorical variables and the Student t-test and variance analysis for continuous vari- Statistical analysis ables. Effectiveness evaluation will be primarily based The characteristics of the study population will be on intention-to-treat (ITT) analysis in such a way that described using frequencies for categorical variables any event in any patient will be included in the group to and mean and SD for quantitative variables. To compare which the patient was randomised, and per protocol (PP) Figure 1 Study scheme. GPs, general practitioners . 6 Cots JM, et al. BMJ Open 2019;9:e028159. doi:10.1136/bmjopen-2018-028159 Open access BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. analysis will be used as a secondary analysis. ITT analysis protection of personal data. This is a clinical trial based will be conducted in all subjects randomised, and PP anal- on the outpatient setting, and neither patients nor ysis will be conducted in those who complete the entire researchers will receive any monetary compensation. trial without violating the protocol. To avoid the effect of potential confounders, the Adverse events and serious adverse events effectiveness of each treatment with respect to the This is a low intervention clinical trial meaning that the usual clinical practice will be analysed through Cox drugs administered are used in accordance with the proportional risk survival analysis, reporting both terms of the marketing authorisation with a well-known crude and adjusted relative risk. The effect of the treat- safety profile and that the intervention on the patient ment will be adjusted for variables collected at baseline, poses no additional risk to the subject compared with such as age, gender, ethnicity, smoking status, alcohol usual clinical practice. The study medications used in this consumption, peak-flow measurement, previous treat- clinical trial have been widely prescribed and consumed ment, previous vaccination, comorbidity and previous for a long time, and the safety profile of these drugs is number of acute bronchitis. well-documented. Censoring and missing data: Those who discontinue, Adverse events will be recorded and followed if they are miss follow-up or, for whatever reason, are not evaluated found to be serious or/and related to the study drug. The for the main variable will be considered censored at the occurrence of this kind of adverse events will be moni- last follow-up date. In addition, patients who do not show tored. The rest of the adverse events will be treated as symptoms of improvement along the study will also be they are during the normal clinical practice, but will not censored at the last day of follow-up. We do not plan to be collected in the CRF. make imputation of missing data. Sub-analysis: To assess the consistency of the data Dissemination collected by telephone (in subjects not attending the visit A range of dissemination activities are planned at of the 15th and 29th), a sub-analysis will be carried out national and international conferences. At the end of using only the data from the diary. A sub-analysis with the the trial, we will publish the final report in an open patients taking antibiotics will also be studied. access peer-review journal even in the case of negative Protected by copyright. All the analyses will be done with the statistical software results, and the study results will also be disseminated R (V.3.2 or higher) and the level of significance will be via conference presentations. A summary of the findings 0.05. will be sent to the participating practices on completion of the acute bronchitis 4 treatments (AB4T) study, and Patient and public involvement the participants will also be informed of the results. Patients and the public are not actively involved in the process of this study. However, the participants will be informed of the study results at the end of the trial. Discussion Acute bronchitis is the most common respiratory tract infection seen in outpatient departments as approx- Ethics and dissemination imately 5% of the general population develop this Ethical issues infectious condition. Despite problems associated with The trial will be conducted in accordance with the antibiotic overuse in Western countries and the substan- Declaration of Helsinki and Good Clinical Practice tial economic burden associated with acute bronchitis, guidelines and Consolidated Standards of Reporting currently no definitive medication is recommended. Trials guidelines. If the protocol needs relevant modi- There are many studies exploring the efficacy of symp- fications, the investigators are required to inform the tomatic therapies, but different systematic reviews eval- institutional review board (IDIAP Jordi Gol, Barce- uating the effectiveness of antitussives, bronchodilators, lona, Spain) and the Spanish Agency of Medicines and herbs and natural remedies found that there was insuf- Healthcare Products as well as participants and receive ficient evidence to support the use of these treatments reapproval. Before the trial, investigators are required because of the high risk of bias, small sample sizes and the to provide all information related to the clinical trial heterogeneity of the patients included in these studies to every patient, including the possible benefits and as many of these patients had an infection other than harms, other therapeutic choices and right to withdraw, acute bronchitis. This study is a multicentre, pragmatic, via a written consent form approved by the institutional parallel group, open randomised placebo-controlled review board. After being provided with enough time trial to evaluate the efficacy and safety of usual care plus and opportunity to ask questions and decide whether three different symptomatic treatments that are widely or not to participate, written informed consent will consumed by patients with acute cough due to an uncom- be obtained from all participants before study inclu- plicated lower respiratory tract infection in a rigorous sion. Data confidentiality will be ensured at all times, and adequately powered study. as stated in the researcher's commitment sheet, as will There are some limitations to this protocol. A micro- compliance with the current legislation regarding the biological study is not carried out, but since nearly 90% Cots JM, et al. BMJ Open 2019;9:e028159. doi:10.1136/bmjopen-2018-028159 7 Open access BMJ Open: first published as 10.1136/bmjopen-2018-028159 on 16 May 2019. Downloaded from http://bmjopen.bmj.com/ on November 17, 2020 at Univesity Autonomous of Barcelona. of the episodes of acute bronchitis are of viral aetiology, properly cited, appropriate credit is given, any changes made indicated, and the use treatment with antibiotics is not indicated and the micro- is non-commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. biological study is therefore not necessary, similar to the usual practice in primary care, in which this procedure is not routinely performed. In addition, the study is prag- References 1. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management matic and replicates current primary care. It is an open of adult lower respiratory tract infections--full version. 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