Are pharmacological randomised controlled clinical trials relevant to real-life asthma populations? A protocol for an unlock study from the ipcrg

INTRODUCTION Asthma has a high prevalence worldwide with a high incidence in primary care settings in many countries.1 It is by definition a variable disease with a broad spectrum of

clinical phenotypes, in which management and treatment can be difficult.2–8 The aim of asthma treatment is optimal control of the disease, which according to Global Initiative for Asthma

(GINA) guidelines implies both symptom control and prevention of exacerbations.1 Despite several treatment options, studies show that about half of the patients have poor asthma control.2,3

When asthma is not controlled, it decreases the quality of life, increases the risk of exacerbations and premature death and is a high cost for the society.2,3 There are concerns that

current asthma treatment is based on research with subjects who are not representative of the patients seen in clinical practice.9 Guidelines for the management of asthma are usually

developed on the basis of the available empirical evidence, and particular emphasis is placed on the conclusions of randomised controlled clinical trials (RCTs) and meta-analyses of RCTs

that have been placed at the top of the evidence hierarchy.10 However, most RCTs have restricted inclusion criteria to obtain a high level of internal validity and usually recruit patients

from secondary health-care settings. The external validity of RCTs, which provides evidence for major clinical guidelines, may be questioned if they are not representative of real-life

populations in primary care.11–15 In the 2007 study by Travers _et al_, only 4% (range 0–36%) of participants with asthma in a population-based survey met the eligibility criteria to be

included in 17 major RCTs cited in the GINA guidelines.14 The same study found that only 6% (range 0–43%) of participants receiving asthma treatment also met the eligibility criteria. The

proportion of patients with asthma from primary care settings that would be eligible for the major RCTs is unknown. If the proportion is similar to that found in the study by Travis _et

al._, then the generalisability of the conclusions and the clinical relevance of major RCTs may be questionable, and they have not been improved in the past decade. There is a need to

explore the external validity of pharmacological RCTs in primary care populations. The UNLOCK (Uncovering and Noting Long-Term Outcomes in COPD and asthma to enhance knowledge) project15 of

the International Primary Care Respiratory Group (IPCRG) covers a broad primary care population that may help clarify the external validity of these RCTs. AIMS AND OBJECTIVES The aim of this

study is to determine whether the inclusion criteria for patients with asthma in the major RTCs supporting GINA guidelines are representative of real-life primary care populations with

asthma. The study will address the following research questions: * 1 What proportion of patients in primary care would be eligible for the major RCTs assessing patients at treatment step two

heading for step three? * 2 What are the clinical characteristics of these patients when compared with participants in major RCT studies? DISCUSSION Asthma is a highly prevalent disease

worldwide with variability and a large range of phenotypes.1–8 The management and treatment of patients with asthma in primary care is a challenge, and many patients still suffer from poor

asthma control.2 The major international clinical guidelines for the prevention and management of asthma are influenced by the empirical evidence and conclusions of RCTs.9–14 However, RCTs

tend to be highly selective in terms of inclusion and exclusion criteria for people with asthma and may under-represent primary care populations with asthma. Smokers, for example, are

usually excluded from registration RCTs assessing inhaled corticosteroids (ICS), as smoking is known to reduce the efficacy of ICS.16 Other common exclusion criteria are pregnancy,

lactation, elderly patients and other chronic diseases such as ischaemic heart disease. A common inclusion criterion is a bronchodilator FEV1 reversibility of 12 or 15%, which is not a

frequent clinical sign in real-life asthma patients, and in the Travers study, 71 (or 76%) of participants with asthma were excluded.14 RCTs are important in establishing the efficacy and

short-term safety of new therapies, but there are limitations in evaluation of effectiveness of the therapies in the real world.17 The assessment of the external validity of asthma RCTs is

therefore needed to better understand the clinical relevance of their conclusions. There should be discussion on the need for effective studies, pragmatic trials and observational studies,

as a complement to RCTs, to evaluate treatment outcomes in real-life clinical settings including the whole asthma population. The main weakness of these studies might be a lower internal

validity, which needs to be addressed in the design of the studies. When developing guideline recommendations in the future, data from both efficacy and effectiveness studies should be

evaluated with the strengths and weaknesses given.18 This study will provide estimates of the proportion of real-life primary care populations that are eligible for RCTs. It will also

present descriptive characteristics of primary care patients compared with patients included in RCTs. This will present relevant information for the adequacy and use of GINA and other major

guidelines in primary health-care settings.16–20 Previous findings suggest that the level of representation of the population with asthma14 and chronic obstructive pulmonary disease (COPD)13

in RCTs may be lower than desirable. This study can inform not only the development of future clinical practice guidelines17–20 but also the way asthma clinical trials are being designed

and implemented.10 The study will tell us more about the patients who are not eligible for these major RCTs, and it may also provide new insights into why the control of asthma in many

patients does not appear to improve in spite of the implementation of the treatment strategies that are recommended in guidelines. MATERIALS AND METHODS STUDY DESIGN The study will use an

observational design for comparing baseline characteristics of asthma patients in primary care databases with the inclusion criteria in the pharmacological RCTs that support major

international guidelines (i.e., GINA). DATA COLLECTION AND INCLUSION CRITERIA Data collection will involve two steps: * 1 Step one will identify the major relevant RCTs used in GINA

guidelines. * 2 Step two will identify the primary care data sets that contain the required variables to assess eligibility for participation in the major RCTs. In step one, a Systematic

Review focusing the search on selected asthma international guidelines (i.e., GINA) will be conducted in order to identify all studies that fit the following criteria: * Randomised

controlled clinical trial * Pharmacological treatment at GINA management step 2 heading for step 3 * RCT sample size _n_>400 * Other criteria (e.g., mainly adult population) The

systematic review will follow the PRISMA21 statement guidelines and follow the steps identified in Figure 1. In step two, members of the IPCRG UNLOCK group will be invited to participate in

the study with primary care data sets that include the variables listed in Table 1. Participants identified in the data sets will remain anonymous. Patient confidentiality will be assured in

the collection and merging of the data sets. DATA ANALYSIS Data will be analysed according the defined criteria for the identification of RCTs. Statistical analysis of the data sets will

provide summary descriptive statistics, means, measures of dispersion and proportions. The statistical analysis will focus on group classification values, and no individual statistical

values will be computed or revealed. ETHICAL APPROVAL All included data sets will require approval by local primary care research ethics committees. REFERENCES * The Global Asthma Report.

Global Asthma Network: Auckland, New Zealand, 2014. http://www.globalasthmanetwork.org/publications/Global_Asthma_Report_2014.pdf. Accessed on September 2015. * Reddel, H. K., Sawyer, S. M.,

Everett, P. W., Flood, P. V., Peters, M. J. Asthma control in Australia: a cross-sectional web-based survey in a nationally representative population. _Med. J. Aust._ 202, 492–497 (2015).

Article  Google Scholar  * Demoly, P. et al. Prevalence of asthma control among adults in France, Germany, Italy, Spain and the UK. _Eur. Respir. Rev._ 18, 105–112 (2009). Article  CAS 

Google Scholar  * Mims, J. W. Asthma: definitions and pathophysiology. _Int. Forum Allergy Rhinol._ 5, S2–S6 (2015). Article  Google Scholar  * Sadowski, C. A., Cor, K., Cave, A. & Banh,

H. L. Administration technique and acceptance of inhaler devices in patients with asthma or COPD. _Ann. Pharmacother._ 49, 639–648 (2015). Article  Google Scholar  * van Boven, J. F.,

Trappenburg, J. C., van der Molen, T. & Chavannes, N. H. Towards tailored and targeted adherence assessment to optimise asthma management. _NPJ Prim. Care Respir. Med._ 25, 15046 (2015).

Article  Google Scholar  * Fischer, J., Wimmer, A. & Mahlich, J. Medication adherence in asthma therapy--a structured review. _Pneumologie_ 67, 406–414 (2013). * Sheehan, W. J. &

Phipatanakul, W. Difficult-to-control asthma: epidemiology and its link with environmental factors. _Curr. Opin. Allergy Clin. Immunol._ 15, 397–401 (2015). Article  CAS  Google Scholar  *

Wong, G. W., Miravitlles, M., Chisholm, A. & Krishnan, J. A. Respiratory guidelines—which real world? _Ann. Am. Thorac. Soc._ 11(Suppl 2): pp S85–S91 (2014). * Harbour, R. & Miller,

J. A new system for grading recommendations in evidence based guidelines. _BMJ_ 323, 334–336 (2001). Article  CAS  Google Scholar  * Williams, B. A. Perils of evidence-based medicine.

_Perspect. Biol. Med._ 53, 106–120 (2010). Article  Google Scholar  * Herland K., Akselsen J.-P., Skjønsberg O. H. & Bjermer L. How representative are clinical study patients with asthma

or COPD for a larger “real life” population of patients with obstructive lung disease?. _Respir. Med._ 99, 11–19 (2005). * Kruis, A. L. et al. Primary care COPD patients compared with large

pharmaceutically-sponsored COPD studies: an UNLOCK validation study. _PLoS ONE_ 9, e90145 (2014). Article  Google Scholar  * Travers, J. et al. External validity of randomised controlled

trials in asthma: to whom do the results of the trials apply? _Thorax_ 62, 219–223 (2007). Article  Google Scholar  * Chavannes, N. et al. UNLOCK: uncovering and noting long-term outcomes in

COPD to enhance knowledge. _Prim. Care Respir. J._ 19, 408 (2010). Article  Google Scholar  * Roche, N. et al. Quality standards for real-world Research. Focus on observational database

studies of comparative effectiveness. _Ann. Am. Thorac. Soc._ 11(Suppl 2): S99–S104 (2014). Article  Google Scholar  * Price, D. et al. Real-world research and its importance in respiratory

medicine. _Breathe (Sheff)_ 11, 26–38 (2015). Article  Google Scholar  * Price, D., Hillyer, E. & van der Molen, T. Efficacy versus effectiveness trials: informing guidelines for asthma

management. _Curr. Opin. Allergy Clin. Immunol._ 13, 50–57 (2013). Article  Google Scholar  * Lalloo, U. G. et al. Asthma programmes in diverse regions of the world: challenges, successes

and lessons learnt. _Int. J. Tuberc. Lung Dis._ 15, 1574–1587 (2011). Article  CAS  Google Scholar  * Reddel, H. K. & Levy, M. L. The GINA asthma strategy report: what’s new for primary

care? _Npj Prim. Care Respir. Med._ 25, 15050 (2015). Article  Google Scholar  * Moher D., Liberati A., Tetzlaff J., Altman D. G. The PRISMA Group Preferred reporting items for systematic

reviews and meta-analyses: the PRISMA Statement. _J. Clin. Epidemiol._ 151, 264–269 (2009). Download references ACKNOWLEDGEMENTS FUNDING The IPCRG provided funding for this research project

as an UNLOCK Group study for which the funding was obtained through an unrestricted grant by Novartis AG, Basel, Switzerland. Novartis has no role in study design, data collection and

analysis, decision to publish or preparation of the manuscript. This study will include data from the Optimum Patient Care Research Database and is undertaken in collaboration with Optimum

Patient Care and the Respiratory Effectiveness Group. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Public Health and Caring Science, Family Medicine and Preventive Medicine,

Uppsala University, Uppsala, Sweden Karin Lisspers & Björn Ställberg * ICVS/3B's - PT Government Associate Laboratory, Life and Health Sciences Research Institute (ICVS), School of

Health Sciences, University of Minho, Braga, Portugal Pedro Teixeira * Department of Primary and Community Care, Radboud University Nijmegen, Nijmegen, The Netherlands Coert Blom *

Department of General Practice, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands Janwillem Kocks * GRIAC Research Institute Groningen, University of

Groningen, University Medical Center Groningen, Groningen, The Netherlands Janwillem Kocks * Division of Applied Health Sciences, Academic Primary Care, University of Aberdeen, Aberdeen, UK

David Price * Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands Niels Chavannes Authors * Karin Lisspers View author publications You can also search

for this author inPubMed Google Scholar * Pedro Teixeira View author publications You can also search for this author inPubMed Google Scholar * Coert Blom View author publications You can

also search for this author inPubMed Google Scholar * Janwillem Kocks View author publications You can also search for this author inPubMed Google Scholar * Björn Ställberg View author

publications You can also search for this author inPubMed Google Scholar * David Price View author publications You can also search for this author inPubMed Google Scholar * Niels Chavannes

View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Karin Lisspers. ETHICS DECLARATIONS COMPETING INTERESTS JK, BS and

NC are Associate Editors of _npj Primary Care Respiratory Medicine_, but were not involved in the editorial review of, nor the decision to publish this article. KL has received honoraria

for educational activities and lectures from AstraZeneca, GlaxoSmithKline, Novartis, MEDA and Takeda, and has served on advisory boards arranged by MEDA and Novartis. BS has received

honoraria for educational activities and lectures from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Novartis, MEDA and TEVA, and has served on advisory boards arranged by AstraZeneca,

Novartis and Boehringer Ingelheim. DBP has Board Membership with Aerocrine, Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis and Teva.

Consultancy: Almirall, Amgen, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Meda, Mundipharma, Napp, Novartis, Pfizer, Teva and Zentiva; grants/grants pending with UK National

Health Service, British Lung Foundation, Aerocrine, AstraZeneca, Boehringer Ingelheim, Chiesi, Eli Lilly, GlaxoSmithKline, Meda, Merck, Mundipharma, Novartis, Orion, Pfizer, Respiratory.

Effectiveness Group, Takeda, Teva and Zentiva; payments for lectures/speaking: Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Kyorin, Meda, Merck, Mundipharma,

Novartis, Pfizer, SkyePharma, Takeda and Teva; payment for manuscript preparation: Mundipharma and Teva; patents (planned, pending, or issued): AKL; payment for the development of

educational materials: GlaxoSmithKline, Novartis; stock/stock options: shares in AKL that produces phytopharmaceuticals and owns 80% of Research in Real-Life and its subsidiary social

enterprise Optimum Patient Care; received payment for travel/accommodations/meeting expenses from Aerocrine, Boehringer Ingelheim, Mundipharma, Napp, Novartis, and Teva; funding for patient

enrollment or completion of research: Almirall, Chiesi, Teva and Zentiva; peer reviewer for grant committees: Medical Research Council (2014), Efficacy and Mechanism Evaluation programme

(2012), HTA (2014); and received unrestricted funding for investigator-initiated studies from Aerocrine, AKL, Almirall, Boehringer Ingelheim, Chiesi, Meda, Mundipharma, Napp, Novartis,

Orion, Takeda, Teva and Zentiva. The remaining authors declare no conflict of interest. RIGHTS AND PERMISSIONS This work is licensed under a Creative Commons Attribution 4.0 International

License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is

not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit

http://creativecommons.org/licenses/by/4.0/ Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Lisspers, K., Teixeira, P., Blom, C. _et al._ Are pharmacological randomised

controlled clinical trials relevant to real-life asthma populations? A protocol for an UNLOCK study from the IPCRG. _npj Prim Care Resp Med_ 26, 16016 (2016).

https://doi.org/10.1038/npjpcrm.2016.16 Download citation * Received: 21 November 2015 * Revised: 13 January 2016 * Accepted: 26 January 2016 * Published: 14 April 2016 * DOI:

https://doi.org/10.1038/npjpcrm.2016.16 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not

currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative