Ruiz et al. Trials (2019) 20:740 https://doi.org/10.1186/s13063-019-3727-3 STUDY PROTOCOL Open Access Effectiveness and cost-effectiveness of Improving clinicians’ diagnostic and communication Skills on Antibiotic prescribing Appropriateness in patients with acute Cough in primary care in CATalonia (the ISAAC-CAT study): study protocol for a cluster randomised controlled trial Rafa Ruiz1, Ana Moragas2,3, Marta Trapero-Bertran4, Antoni Sisó5, Anna Berenguera6, Glòria Oliva7, Alícia Borràs-Santos8, Ana García-Sangenís2, Jaume Puig-Junoy9, Josep M. Cots10, Rosa Morros6, Toni Mora4, Anna Lanau-Roig11, Ramon Monfà12, Amelia Troncoso13, Rosa M. Abellana14, Pau Gálvez8, Laura Medina-Perucha6, Lars Bjerrum15, Isabel Amo8, Nieves Barragán16 and Carl Llor17* Abstract Background: Despite their marginal benefit, about 60% of acute lower respiratory tract infections (ALRTIs) are currently treated with antibiotics in Catalonia. This study aims to evaluate the effectiveness and efficiency of a continuous disease-focused intervention (C-reactive protein [CRP]) and an illness-focused intervention (enhancement of communication skills to optimise doctor-patient consultations) on antibiotic prescribing in patients with ALRTIs in Catalan primary care centres. Methods/design: A cluster randomised, factorial, controlled trial aimed at including 20 primary care centres (N = 2940 patients) with patients older than 18 years of age presenting for a first consultation with an ALRTI will be included in the study. Primary care centres will be identified on the basis of socioeconomic data and antibiotic consumption. Centres will be randomly assigned according to hierarchical clustering to any of four trial arms: usual care, CRP testing, enhanced communication skills backed up with patient leaflets, or combined interventions. A cost-effectiveness and cost-utility analysis will be performed from the societal and national healthcare system perspectives, and the time horizon of the analysis will be 1 year. Two qualitative studies (pre- and post-clinical trial) aimed to identify the expectations and concerns of patients with ALRTIs and the barriers and facilitators of each intervention arm will be run. Family doctors and nurses assigned to the interventions will participate in a 2-h (Continued on next page) * Correspondence: carles.llor@gmail.com 17 Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Manso Health Centre, Institut Català de la Salut, Barcelona, Spain Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ruiz et al. Trials (2019) 20:740 Page 2 of 9 (Continued from previous page) training workshop before the inception of the trial and will receive a monthly intervention-tailored training module during the year of the trial period. Primary outcomes will be antibiotic use within the first 6 weeks, duration of moderate to severe cough, and the quality-adjusted life-years. Secondary outcomes will be duration of illness and severity of cough measured using a symptom diary, healthcare re-consultations, hospital admissions, and complications. Healthcare costs will be considered and expressed in 2021 euros (year foreseen to finalise the study) of the current year of the analysis. Univariate and multivariate sensitivity analyses will be carried out. Discussion: The ISAAC-CAT project will contribute to evaluate the effectiveness and efficiency of different strategies for more appropriate antibiotic prescribing that are currently out of the scope of the actual clinical guidelines. Trial registration: ClinicalTrials.gov, NCT03931577. Keywords: Cost-effectiveness, Cost-utility, Effectiveness, Anti-bacterial agents, Prescribing, Acute cough, Respiratory tract infections, Antimicrobial stewardship, Qualitative research, Incremental cost-utility ratio, Primary healthcare Background assessing the effects of interventions targeting clinician anti- Overuse of antibiotics has contributed to the develop- biotic prescribing for ALRTIs in primary care, the reviewers ment of antimicrobial resistance, which represents a found that the most powerful tools for reducing unneces- major threat to human health worldwide [1]. In addition sary antibiotic prescribing are C-reactive protein (CRP) to driving resistance, non-indicated use of antibiotics in- rapid testing, shared decision making, and procalcitonin- curs costs, increases re-consultation for subsequent epi- guided management without compromising outcomes of sodes, medicalizes self-limiting illness, and unnecessarily patient satisfaction and re-consultation, although the meas- exposes individuals to the risk of side effects. Most anti- urement of these outcomes was limited in the trials [9]. biotics are prescribed in primary care, most commonly The antibiotic prescribing behaviour of GPs for acute for acute lower respiratory tract infections (ALRTI), cough in adults is influenced by their perceptions of which account for one-fourth of all the infectious dis- patient expectations, but sometimes their perceptions do eases treated by general practitioners (GPs). According not match patient views [10]. Patients report lower levels to a study carried out in Catalonia, about 60% of ALRTIs of satisfaction with their consultation if they have an are currently treated with antibiotics [2]. The latest expectation for antibiotics that is not met, and being Cochrane review also suggests that only a slight benefit able to effectively elicit patient views towards shared is achieved from the prescription of antibiotics [3]. Be- decisions is therefore an important skill for clinicians cause no new classes of antibiotics have been developed managing acute cough. Interactive workshops for health- in the last two decades, rationalisation of antibiotic use care professionals and education of patients are likely to in the treatment of ALRTIs in primary care is a key tar- lower the rate of antibiotic prescribing [10]. A Dutch get for influencing the antibiotic-prescribing behaviour study found that the training of physicians in advanced of clinicians [1]. This supports the case for strategies communication skills by seminar role-playing and peer that promote a more prudent use of antibiotics for these feedback on consultation transcripts reduced antibiotic infections. This is even more important in Catalonia, be- prescribing rates by 20% [11]. In a Welsh study a 4% cause this is one of the European Union countries with reduction in global antibiotic use was found after web- the highest rates of antibiotic prescribing, which has based training in advanced communication skills [12]. even slightly increased in the last years [4, 5]. This find- CRP testing has been shown to safely reduce antibiotic ing is also supported by the results of the latest Euroba- prescribing in primary care [13]. In a Dutch study, training rometer on antibiotic use carried out in 2016, in which of physicians in CRP testing lowered the rate of antibiotic 47% of the Spanish respondents admitted having taken prescribing by 20%, but the greatest reduction was ob- an antibiotic in the previous year [6]. served among GPs assigned to CRP testing and enhanced Antibiotic use can be improved by using educational in- communication skills training [11]. In a multinational terventions such as dissemination of printed and audio- study conducted in Europe, which assessed the effects of visual educational materials, group education, personal or internet-based training on antibiotic prescribing for acute group feedback, individual outreach visits, reminders at the respiratory tract infections, both CRP and clinician training time of prescribing, and computer-assisted decision-making in communication skills were effective in reducing anti- systems, among others, but these interventions generally re- biotic prescribing, but the greatest reduction was also seen sult in little change in prescription practices, although the when both the CRP testing and communication skills effect is greater with multi-faceted approaches [7, 8]. In a training interventions were combined [14]. The effect of recent Cochrane review of systematic reviews aimed at the communication skills training was greater in the Dutch Ruiz et al. Trials (2019) 20:740 Page 3 of 9 study, which could be explained mainly by the fact that the inclusion criteria will be given written and verbal informa- intervention was more intense and continuous. In the latter tion about the study and will be asked to provide written study, however, the intervention was limited to a single informed consent. online training lasting approximately 1 h before the trial The inclusion criteria will be age older than 18 years started. In addition, patients were followed for only 4 and first consultation for acute cough (new cough or weeks, whereas approximately 25% of patients still have worsening of a previous cough) of up to 3 weeks’ duration cough after this period, and patients still re-attended their as the predominant symptom, which the clinician believes GPs because full recovery was not accomplished. to be an infectious ALRTI, as defined in other studies [3]. Recent evidence showed that ambulatory antibiotic pre- The exclusion criteria will be a working diagnosis of a scription is associated with a hidden cost of antibiotic re- non-infective disorder, such as heart failure, pulmonary sistance that substantially increases the cost of an antibiotic embolus, oesophageal reflux, or allergy; use of antibiotics prescription [15]. This finding raises concerns regarding the in the previous 2 weeks; immunological deficiencies; and/ magnitude of misalignment between individual and societal or inability to provide informed consent or unable to fol- antibiotic costs. There is a lack of evidence evaluating the low the study procedures. Pneumonia and acute exacerba- efficiency of different multi-faceted approaches in order to tions of chronic obstructive pulmonary disease will not be decrease the inappropriate prescribing of antibiotics in deemed as exclusion criteria, because they are included in Mediterranean countries. Although CRP point-of-care tests the ALRTI definition. The Standard Protocol Items: Rec- are widely used in a number of European countries for the ommendation for Interventional Trials (SPIRIT) Checklist management of ALRTIs, they are not yet routinely used in is provided as Additional file 1. Catalonia. In addition, these overprescribing actions could lead to inefficiencies of the health system. Sample size calculation To calculate the sample size, we will use a type I error of Methods/design 5% and a power of 80%, and we will assume that antibiotic Objectives prescribing will decrease by at least 15%, from 60% to 45%, This study aims to evaluate the effectiveness and effi- in any one of the three intervention groups. We will also ciency of a continuous (workshop and monthly web- assume a drop-out rate of 12% and an intra-cluster correl- based training) disease-focused intervention (CRP ation coefficient for antibiotic prescribing within practices testing) and a continuous (on-site and monthly online of up to 0.07, based on two recent studies [14, 16]. We esti- training) illness-focused intervention (enhancement mate that a sample of 788 (197 × 4) patients will be needed. of communication skills to optimise doctor-patient Allowance for an inflation factor of 3.73 due to clustering consultations and share decision making with the aid and rounding of numbers for the four subgroups give an of patient-centred leaflets) on antibiotic prescribing overall sample size of 2940 [17]. As a consequence, at least in patients with ALRTIs in Catalan primary care cen- 147 patients will be recruited per centre. tres. An economic evaluation of four strategies for reducing antibiotic prescribing will be performed. Par- ticularly, a cost-effectiveness and cost-utility analysis will Setting and timing be conducted. These interventions will be compared with General practices throughout Catalonia in the localities of the current antibiotic prescribing strategy used in the pri- the study centres (with different socioeconomic levels) will mary care centres. The analysis will be conducted from be approached, and at least three pairs of clinicians (GPs the societal and the national healthcare system perspec- and nurses) in eligible centres will be invited to partici- tives. Two qualitative studies (pre- and post-clinical trial) pate. Eligible centres will be stratified depending on the will be also conducted to inform the development and socioeconomic level and baseline antibiotic consumption, evaluation of the clinical trial. and only those that had not previously used any interven- tion to reduce antibiotic prescribing rates will be selected. Study design They are expected to include 150 patients (75 patients in A cluster randomised, factorial, controlled trial performed each autumn-winter season) in the trial. over a period of 18 months including two autumn-winter seasons will be carried out. A randomised cluster design Trial interventions will be used to keep contamination (influence on partici- The centres will be randomly assigned to four trial arms: pants’ behaviour when another participant or physician usual care, training in the use of a point-of-care CRP test, alters his/her behaviour) within primary care centres to a training in enhanced communication skills, or combined minimum, because three GPs and nurses per centre are training in CRP testing and enhanced communication expected to participate and because a centre-based meet- skills (Fig. 1). Masking of GPs or patients to the interven- ing is part of the intervention. Patients who fulfil the tion itself is not possible. Randomisation of primary care Ruiz et al. Trials (2019) 20:740 Page 4 of 9 Fig. 1 Flowchart of the randomised clinical trial. ALRTI acute lower respiratory tract infection Ruiz et al. Trials (2019) 20:740 Page 5 of 9 centres will be achieved by computer generation of ran- severe cough (i.e., those rating their cough as 3 or more dom numbers. by means of a Likert scale); and the quality-adjusted life- An on-the-spot 2-h training workshop will take place years (QALYs), which will be collected by means of the in the different areas before the inception of the trial. EQ-5D-5L questionnaire within the first 6 weeks This training will be followed by monthly internet-based (Table 1). short training capsules tailored to either of the two Secondary outcome measures are listed in Table 2. interventions measured (clinical cases, medical literature, The duration of symptoms rated moderate to severe will reminders) that GPs allocated to this intervention will also be recorded. Because this study will follow patients have to attend and answer. GPs assigned to both inter- for 6 weeks, we will be able to better define the duration ventions will receive the two training programmes. The of acute cough due to ALRTI. Symptoms will be rated usual care group will assess and manage patients accord- daily as 0 (no problem) to 6 (as bad as it could be) until ing to the practice’s normal procedures. they resolve, and the information will be reported by pa- The CRP group will receive internet training on how to tients in self-completed diaries, similar to what was done target testing (e.g., in cases of clinical uncertainty, such as in in a recent clinical trial on delayed antibiotic prescribing patients with abnormal auscultation, dyspnoea, and impair- carried out in Catalonia [18]. For patients who do not ment of vital signs) and how to negotiate with the patient return diaries, a short form asking about the details of about management decisions. The tests will be carried out the duration and severity of symptoms and whether anti- with Afinion 2 CRP devices (Abbott Diagnostics, Lake For- biotics have been taken or whether the booklet has been est, IL, USA). Clinicians (GPs and nurses) will practise using used will be completed by telephone call to the patient. the device during a run-in period of 2 weeks before data col- The data collection process and the rest of the study lection starts. GPs will be informed about the updated rec- procedures will be supervised. A clinical research associ- ommendations on how to interpret the CRP values and the ate will perform periodic visits to the sites and provide evidence-based management (no antibiotics, delayed anti- online supervision of the data. A data monitoring com- biotic prescribing or immediate antibiotic prescribing). mittee has been deemed not necessary because of the Training in enhanced communication skills will focus on the study characteristics, as well as external audits. Never- gathering of information on patients’ concerns and theless, the coordinating team will hold periodic meet- expectations, exchange of information on symptoms, natural ings, and study procedures will be reviewed. disease course and treatments, agreement of a management plan, red flags, and providing guidance about when to re- Resource use and costs consult and summing up. GPs will also be provided with an Micro-costing techniques will be used to estimate the interactive booklet to use during consultations that includes healthcare costs for patients with acute cough in the dif- information on symptoms, use of antibiotics and antibiotic ferent interventions. The costs will be presented in 2021 resistance, self-help measures, and when to re-consult, and euros (year foreseen to finalize the study). Primary data of the booklet will be given to the patient. This training will be the ISAAC-CAT clinical trial will be used whenever pos- supported by video demonstrations of consultation tech- sible. The costs will include the costs of treatment to con- niques. GPs will also be informed about the updated recom- trol the acute cough and management of these patients. mendations on management of ALRTIs. The cost of treatment will depend on the state of health of the patient but may include the costs of the different ther- Outcome measures apies prescribed, including those recommended to be pur- During the index consultation GPs will document the chased at the pharmacies. The costs of management will duration of the illness, the severity of cough and other include the cost of primary care and secondary care visits symptoms (rated 0, not problematic; to 6, severely prob- within the first 6 weeks as well as any diagnostic tests per- lematic), and the severity of the infections. After ran- formed and the number of days of patient absenteeism. domisation a more detailed case report form (CRF) will The cost of the interventions will cover the continuous be used in the follow-up consultations and will include training, including the workshop and the monthly delivery the same details as the index form plus medical history, of training microcapsules, the cost of the booklets, the current medications, smoking status, findings of struc- cost of the CRP machine, and the reagents used. tured examination, whether CRP is tested, and whether the booklet is used. The primary outcome measures will Cost-effectiveness and cost-utility analyses be antibiotic consumption within the first 6 weeks, as The cost-effectiveness analysis will be conducted com- documented in the CRFs and double-checked by the paring costs and effectiveness/utility, measured in nat- Pharmacy Unit of the Catalan Institute of Health, which ural units and QALYs, respectively, of the different can track if the antibiotic has been dispensed at any of alternatives to usual practice. In most cases the data will the Catalan pharmacies; the duration of moderate to be obtained from the ISAAC-CAT clinical study. The Ruiz et al. Trials (2019) 20:740 Page 6 of 9 Table 1 Schedule of enrolment, interventions and assessments for the clinical trial Time point Study period November 4, 2019–April 30, 2021 Day 1 Week 2 Week 6 Enrolment Medical history and physical examination X Explanation of the study and informed consent X Initial CRF X Giving out of the symptom diary, up to week 2 X Interventions CRP rapid test if needed (only among those patients visited X by professionals assigned to the CRP intervention groups)* Use of an interactive booklet (only among those patients X visited by professionals assigned to the enhanced communication skill intervention groups)* Assessments Assessment of the clinical outcome X X Collection and review of the symptom diary X EQ-5D-5L questionnaire X X X Antibiotic consumption X X X Use of drugs other than antibiotics X X X Tests ordered by clinicians X X X Patient satisfaction with care X X Patient perception of the usefulness of the information received X X Patient future consulting intentions X X Absenteeism X X X Evaluation of adverse events X X Number of re-consultations to primary and secondary care and X number of complications regarding the ALRTI Abbreviations: ALRTI acute lower respiratory tract infection, CRF case report form, CRP C-reactive protein, GP general practitioner Randomisation will take place 2 weeks before initiating the clinical trial (October 21, 2019). Workshop for GPs and nurses assigned to any of the three intervention arms at the end of October 2019 *Monthly internet-based short training capsules for GPs and nurses assigned to any of the intervention groups comparison will be performed using the incremental effects of each intervention (e.g., factorial groups with cost-effectiveness ratio and the incremental cost- estimates controlling mutually for each intervention). utility ratio, defined as the ratio of the difference in The analysis will be performed using Stata 15 econometric costs and the difference in effectiveness or utility. software (StataCorp, College Station, TX, USA). The results will be expressed in terms of euros per To study uncertainty, univariate and multivariate de- unit of effectiveness. terministic sensitivity analyses of the relevant parameters considered will be undertaken. Statistical analysis Analyses will be carried out by intention to treat and will Qualitative studies use multilevel logistic regression modelling with differ- There will be two qualitative studies, one pre- and one ent distributions of errors according to the objective post-clinical trial. A phenomenologist framework will be analysed for a factorial study controlled for the baseline applied in both studies. This is a relevant approach be- antibiotic prescribing rate and with allowance for clus- cause the qualitative studies aim to explore the experi- tering by GP and health centre. The effects of various ences of ALRTIs and healthcare in primary care settings potential confounders related to clinical severity will be among participants in their own words and through explored because of the potential for selection bias in an their own interpretations of their realities [19]. Sampling open trial. If interactions between interventions are not will be theoretical and purposive and will include a significant, the results will be presented as the main number of pathways to ensure maximum inclusivity. Ruiz et al. Trials (2019) 20:740 Page 7 of 9 Table 2 Secondary objectives and outcome measures Objectives Outcome measures Time point(s) of evaluation of this outcome measure Number of re-consultations to primary and secondary Re-consultation for new or worsening symptoms, new First 6 weeks post-randomisation care and number of complications regarding the signs, or hospital admission, assessed by review of ALRTI medical notes (practice staff, the local study team, or both using a standard form to report these data), and number of complications regarding the ALRTI Duration of moderate to severe symptoms Number of days until the last day any of the First 6 weeks post-randomisation symptoms is rated 3 or more. Symptoms will be rated daily as 0 (no problem) to 6 (as bad as it could be) until they resolve, and the information will be reported by patients in self-completed diaries. Antibiotic prescription at the baseline visit, Reported in the CRF. The number of patients treated Baseline visit. The dispensing of differentiating immediate and delayed antibiotic with immediate and delayed antibiotic prescribing will antibiotics will be tracked in the prescribing, and antibiotic dispensing at the be evaluated. Dispensing of the antibiotics at the first 6 weeks post-randomisation. pharmacies pharmacies. Drugs other than antibiotics Reported by patients in self-completed diaries First 6 weeks post-randomisation Tests ordered by clinicians Reported in the CRF Baseline visit Patient satisfaction with care Reported in the symptom diaries First 6 weeks post-randomisation Patient perception of the usefulness of the Collected in the symptom diaries First 6 weeks post-randomisation information received Patient future consulting intentions Collected in the symptom diaries First 6 weeks post-randomisation Serious adverse events Assessed by review of medical notes (practice staff, the First 6 weeks post-randomisation local study team, or both using a standard form to report these data) Number of days of sick leave (absenteeism) Collected in the CRFs First 6 weeks post-randomisation ALRTI acute lower respiratory tract infection, CRF case report form Pre-clinical trial study recruited. Recruitment will be carried out as for the pre- Semi-structured individual interviews (n = 30) and a group clinical trial study. The methods of data collection will be dif- discussion (n = 8–12 participants) will be conducted with ferent for healthcare professionals and patients. Healthcare patients diagnosed with an ALRTI in the pre-clinical trial professionals will be asked to take part in a World Café [20], study. This qualitative pre-clinical trial study will aim to and patients will be recruited for individual semi-structured explore past experiences with ALRTIs, expectations and interviews as for the pre-intervention study. Through World preferences of treatment, patients’ understanding of the Café we will generate GP and nurse collective knowledge symptoms of ALRTIs, the relationship with healthcare about what are the preferences, needs, experiences, strengths professionals, and perceived communication skills of and limitations in reducing inappropriate antibiotic prescrib- healthcare professionals. Data collection will take place in ing for adults with ALRTIs. the primary care clinics where participants are recruited. The interviews will take 45–60 min, and the group discus- Data analyses sion will last about 90 min. They will all take place in the A thematic content analysis will be performed on the primary care centres. The semi-structured interviews and basis of information obtained in the interviews and group discussion will be audio-recorded and transcribed World Café. The data will be analysed in the following systematically and verbatim. All data collection will be manner. After successive readings of the transcribed in- conducted by the same technical expert from the research terviews, the researchers will attain some pre-analytical team. The topic guide for the group discussion will be de- insight into the data. Next, four researchers will conduct veloped on the basis of findings from the interviews. All the following analytical steps: interviews will be conducted in the two official languages (Spanish and Catalan). 1. Identification of the relevant subjects and texts 2. Fragmentation of the text into units of meaning Post-clinical trial study 3. Text codification with emerging codes from the data The aim of this study will be to investigate the satisfaction, 4. Creation of categories by grouping the codes based pros, and cons of GPs, nurses, and patients assigned to the on the criterion of similarity different intervention trial arms. For this study, 35 healthcare 5. Analysis of each category professionals (GPs and nurses) and 30 patients will be 6. Elaboration of new text with the results Ruiz et al. Trials (2019) 20:740 Page 8 of 9 These results will subsequently be discussed among the Authors’ contributions research team members until a consensus is reached (tri- MTB, AS, and CL are co-chief investigators of this trial and act as guarantors of the study in its entirety. AM, MTB, AS, GO, AGS, RMor, AT, and CL led the angulation). The analysis will be performed using NVivo development of the research question and the study design and obtained software (QSR International, Doncaster, Australia). the funding. CL drafted the manuscript. MTB, JPJ, and TM provided health economics input. AB and LMP are leading the qualitative studies. RR, JMC, ALR and RMon are in charge of the selection of the participants for the clin- Discussion ical trial. ABS, PG, and IA provided input from the patient’s perspective. RMA is in charge of the statistical analysis. AM, AS, JMC and NB are responsible for ALRTIs are very prevalent diseases and one of the most fre- the training process. LB provided expertise on the implementation strategies. quent causes of medical visits in primary care [21]. Despite All authors listed provided critical review and final approval of the most of these infections’ being self-limiting conditions, manuscript. most patients feel ill, and many do not perform their usual Authors’ information activities. Patients often return to their physician or seek Not applicable. other medical help because the symptoms may persist, mainly cough, which may be very bothersome for some Funding [22]. Furthermore, patients with bronchitis miss an average The research is being funded by a grant from the Fundació La Marató de TV3 (reference no. 201820). of 2–3 days of work per episode [23]. In addition, many pa- tients are prescribed antibiotics unnecessarily. Availability of data and materials Rapid testing, such as CRP testing, has been widely The datasets generated and/or analysed during the current study are promoted for improving the care of with ALRTIs [1]. available in the Scientia repository (http://scientiasalut.gencat.cat). Most evaluations of diagnostic devices consider analytic performance without evaluating impact on patient out- Ethics approval and consent to participate Central ethical approval from the Research Ethics Committee Investigació comes or costs. However, new tests should not be intro- Clínica de la IDIAP Jordi Gol (reference approval no. P18/227) has been duced into routine clinical care if they do not improve confirmed, and we will not begin recruitment at other centres of the trial outcomes that matter to patients individually or to soci- until ethical approval has been obtained. The coordinating team will ensure that this study is conducted in accordance with the principles of the ety, including consideration of impact on recovery and Declaration of Helsinki and good clinical practice. Informed consent will be quality of life, antibiotic prescribing, and antibiotic re- obtained from all study participants. There are no additional consent sistance [24]. Efficiency is also a relevant criterion for provisions, because no ancillary studies are planned. health decision making. The enhancement of clinician Consent for publication communication skills with the provision and discussion Not applicable. of leaflets targeted to the population has also demon- strated a powerful tool to reduce inappropriate antibiotic Competing interests prescribing. However, the continuous training in these AM and CL report having received research grants from Abbott Diagnostics. interventions has never been investigated. The other authors declare that they have no competing interests. Author details 1 Institut Català de la Salut, Barcelona, Spain. 2Fundació Institut Universitari Trial status per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Recruitment opened on 18 November 2019 and is expected Barcelona, Spain. 3Universitat Rovira i Virgili, Jaume I Health Centre, Institut to continue to 30 April 2021. Català de la Salut, Tarragona, Spain. 4Research Institute for Evaluation and Public Policies (IRAPP), Universitat Internacional de Catalunya, Barcelona, Spain. 5Fundació Atenció Primària, Barcelona, Spain. 6Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina Supplementary information (IDIAPJGol), Universitat Autònoma de Barcelona, Bellaterra, Cerdanyola del Supplementary information accompanies this paper at https://doi.org/10. Vallès, Spain. 7Ministry of Health, Government of Catalonia, Barcelona, Spain. 1186/s13063-019-3727-3. 8 Institut Universitari de Pacients (Patients’ University Institut), Universitat Internacional de Catalunya, Barcelona, Spain. 9Pompeu Fabra University Additional file 1. Standard Protocol Items: Recommendations for (UPF)-Barcelona School of Management, Barcelona, Spain of Economics and Interventional Trials (SPIRIT) 2013 checklist: recommended items to Business, Barcelona, Spain. 10Universitat de Barcelona, La Marina Health address in a clinical trial protocol and related documents. Centre, Institut Català de la Salut, Barcelona, Spain. 11La Marina Health Centre, Institut Català de la Salut, Associació d’Infermeria Familiar i Comunitària de Catalunya, Barcelona, Spain. 12Fundació Institut Universitari Abbreviations per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), ALRTI: Acute lower respiratory tract infection; CRF: Case report form; CRP: C- UICEC de IDIAP Jordi Gol – Plataforma SCReN, Universitat Autònoma de reactive protein; EQ-5D-5L: 5-level EuroQol 5 dimensions questionnaire; Barcelona, Bellaterra, Cerdanyola del Vallès, Spain. 13Àrea de Suport al GP: General practitioner; ISAAC-CAT: Effectiveness of Improving Diagnostic Medicament i Servei de Farmàcia Barcelona, Institut Català de la Salut, and Communication Skills on Antibiotic Prescribing Appropriateness in Acute Barcelona, Spain. 14Biostatistics, Department of Basic Clinical Practice, Cough; QALY: Quality-adjusted life-year Universitat de Barcelona, Barcelona, Spain. 15Centre for General Practice, Department of Public Health, University of Copenhagen, Copenhagen, Denmark. 16Catalan Society of Family Medicine, Group on Communication, Acknowledgements Health Centre Vallcarca, Barcelona, Spain. 17Fundació Institut Universitari per In addition to the authors, the ISAAC-CAT study team includes Enriqueta a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Pujol and Joan Lozano. 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