Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy and safety of single combined (long‐ or short‐acting beta₂ agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma.
Background
Description of the condition
Asthma is the most common chronic respiratory disease, affecting 350 million people worldwide; and it is potentially serious, claiming 400,000 lives per year (GBD Study 2017;GINA 2019). Asthma is recognised as a heterogeneous disease, but common symptoms include wheezing, shortness of breath, chest tightness and cough; these vary over time in their occurrence, frequency and intensity (GINA 2019). Asthma is a clinical diagnosis defined by the history of a constellation of respiratory symptoms that vary over time and in intensity, together with variable expiratory airflow limitation (GINA 2019). Asthma treatment broadly focusses on maintaining daily symptom control and preventing acute worsening of symptoms known as asthma attacks or 'exacerbations'.
The seriousness of asthma varies greatly and severe asthma has attracted significant interest from researchers. Asthma control is the extent to which features of asthma are observed in an individual or have been reduced by treatment. Asthma severity is assessed retrospectively from the level of treatment required to control symptoms and exacerbations (GINA 2019). Globally, prevalence of mild asthma is estimated to be between 45% and 70% of all patients diagnosed with the condition (Rabe 2004; Dusser 2007; Sadatsafavi 2010). Despite being labelled as having mild asthma, this group continues to have severe asthma attacks requiring oral steroids or hospital admission (Bloom 2018), and suffer asthma‐related deaths (Bergström 2008; RCP 2014). Inhaled corticosteroids (ICS) are the most effective preventer drug for adults in achieving overall treatment goals and reducing mortality (Suissa 2000). Intermittence of symptoms in this population often leads to poor inhaler adherence (Taylor 2014). Up to 90% of people with asthma do not take ICS regularly as prescribed (AIHW 2007). Poor adherence to preventer ICS is thought to be a main cause for increase in risk of exacerbations in people with mild asthma (Engelkes 2015).
Description of the intervention
Preventers and relievers
There are over 30 different inhalers now approved for use in asthma. They are usually classified as preventers or relievers. Short‐acting beta agonists (SABA) have been used since the 1970s for rapid relief of asthma symptoms from bronchoconstriction. They lead to rapid improvement of symptoms but do not affect the underlying pathological process (Barnes 1999).
Taking daily preventer steroid inhalers should lead to better asthma control (Chauhan 2013). Adherence to inhaled steroids is often poor, however, for a variety of reasons including fear of side effects, costs and perceptions of asthma severity (Bender 2005). Increasing the daily dose of the preventer ICS therapy during the early phase of an acute exacerbation has also been studied as a way to treat the exacerbation without the need for systemic corticosteroids (Kew 2016), though a benefit from this approach has not been shown. These regimes still depend on the use of a preventer even when the patient feels well; and they are still affected by poor adherence rates (Beasley 2019).
Longer‐acting beta₂ agonists (LABA) are also available. They are generally used as preventer medication and are co‐prescribed with an ICS. Some LABAs have a rapid onset of action and will also rapidly relieve symptoms (Wallin 1993).
Fixed dose combination inhalers
A number of combination inhalers exist. These contain both a steroid and a beta₂ agonist in the same device, thus delivering both treatments at the same time. This has the advantages of simplifying an inhaler regime and ensuring LABA therapy is not taken without ICS. This is important because use of a LABA without an ICS is associated with a significantly increased risk of asthma death (Nelson 2006).
Exacerbations or 'attacks' are thought to be precipitated by external triggers (viral, bacterial, allergen or irritants) leading to an enhanced type 2 inflammatory response in the asthmatic airways (Papi 2018). The prodrome preceding an attack would be a logical time to intervene, especially if these are infrequent. The rapid‐acting beta₂ agonist will act immediately on the smooth muscle to relieve airway narrowing and resultant symptoms. ICS are thought to work by suppressing the type 2 inflammation at the epithelial level (Barnes 2010). Pairing the ICS with the beta₂ agonist therapy, specifically at the time of increased symptoms, could lead to both symptomatic improvement and suppression of the underlying pathological process, and importantly decrease the risk of severe or life‐threatening events (Beasley 2019). In patients with moderate asthma not controlled on medium‐dose ICS or ICS/LABA, fixed‐dose ICS/LABA inhalers used as both maintenance and reliever therapy (MART) is effective in reducing risk of asthma attacks (Cates 2013), but these data cannot necessarily be extrapolated to mild asthma or to use of the combination inhaler as required, without its use also as regular maintenance therapy.
How the intervention might work
This review will focus on fixed‐dose combination ICS/rapid onset beta₂ agonist taken as needed — i.e. both treatments in the same inhaler. This is now being considered as a replacement for prescribing people either a SABA or SABA and a separate ICS. The idea is that when people's symptoms are worse they will take their inhaler more often to get symptom relief from the bronchodilator (Wallin 1993); and they will also get more steroid to treat the underlying inflammation (Barnes 2010). This also has the possible benefit of simplification due to the use of a single inhaler as well as reduced issues with adherence, and may in effect titrate the amount of ICS delivered to the individual's symptomatology.
Why it is important to do this review
Several clinical trials of as‐required fixed‐dose combination inhalers have reported in recent years, and have led to a significant change in an international guideline (GINA 2019), which now recommends fixed‐dose ICS/rapid‐acting beta₂ agonist as first line therapy for mild asthma, where the previous guideline recommended use of SABA only. As the majority of economic costs of asthma are related to regular prescribing of preventer medications in primary care (Mukherjee 2016), this recommendation has major cost implications, particularly for public health systems in low‐ to middle‐income countries. There is also the potential for important benefits in improving symptom control, reducing exposure to systemic corticosteroids and reducing admissions — the last of which is a major contributor to the economic burden of asthma (Mukherjee 2016). Therefore an accurate assessment of these benefits using all available randomised clinical trial data is timely, with implications for millions of people with asthma worldwide.
Objectives
To evaluate the efficacy and safety of single combined (long‐ or short‐acting beta₂ agonist plus an inhaled corticosteroid (ICS)) inhaler only used as needed in people with mild asthma.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs). We will include cross‐over designs provided they include an appropriate washout period (a week or more) between interventions. We will include cluster randomised trials if the data have been or can be adjusted for clustering. We will exclude trials of very short duration (an intervention of less than 12 weeks). We will include studies reported in full text, those published as an abstract only and unpublished data.
Types of participants
We will include adults and children (age 6 years and older) with a diagnosis of mild asthma as defined by GINA 2019: asthma that is well controlled with as‐needed controller medication alone, or with low‐intensity maintenance controller treatment. Where GINA definitions are not specified, authors will judge severity using baseline characteristics, requiring an Asthma Control Questionnaire (ACQ) score less than or equal to 1.5 or an Asthma Control Test (ACT) score equal to or more than 16. We will not exclude participants based on non‐respiratory co‐morbidities, provided they also meet the required definition for a diagnosis of asthma. We will exclude participants with chronic obstructive pulmonary disease (COPD), defined by GOLD 2020; and any physician diagnosis of pulmonary fibrosis, bronchiectasis, lung cancer or other respiratory co‐morbidity. To ensure that we are only investigating patients with mild asthma, we will exclude patients taking moderate‐dose ICS daily (defined as greater than or equal to 300 μg per day of beclomethasone equivalent) or higher‐dose ICS daily (defined as greater than or equal to 600 μg per day of beclomethasone equivalent for adults and children aged 12 years or older).
Types of interventions
We will include studies comparing a single fixed‐dose ICS/rapid onset beta₂ agonist inhaler used as needed with at least one of the following comparators.
No treatment
Placebo
As‐required SABA
Regular ICS with as‐required SABA
Regular fixed‐dose combination ICS/LABA, with or without as‐required SABA
Regular fixed‐dose combination ICS/LABA with as‐required ICS/LABA
Separate comparisons will be done comparing single fixed‐dose ICS/rapid onset beta₂ agonist inhaler against each of the comparators listed above. Rapid onset beta₂ agonists include salbutamol (albuterol), terbutaline, and formoterol.
We will not consider studies investigating other asthma treatments: if required, they would suggest severe asthma. This will include systemic corticosteroids, leukotriene inhibitors, inhaled long‐acting anti‐cholinergics, methylxanthines and monoclonal antibodies.
Types of outcome measures
We will analyse the following outcomes in the review, but we will not use them as a basis for including or excluding studies. Where possible we will analyse outcomes at the 12‐month time point.
Primary outcomes
Exacerbations requiring systemic steroids.
Hospital admissions/emergency department or urgent care visits for asthma.
Measures of asthma control: in order of preference Asthma Control Questionnaire, Asthma Control Test, symptom‐free days.
Secondary outcomes
Measures of lung physiology: in order of preference post‐bronchodilator FEV₁, post‐bronchodilator PEFR, FeNO, then other measures.
Quality of life measures, preferably Asthma Quality of Life Questionnaire, then SF‐36.
Adverse events/side effects.
Total inhaled steroid dose. We will convert inhaled steroid doses to beclomethasone equivalents using the conversion described in Table 1.
Total systemic corticosteroid dose.
Mortality.
1. Inhaled steroid equivalents.
| Drug | Dose considered equivalent to 100 μg beclomethasone dipropionate | Conversion factor |
| Beclometasone | 100 | 1.0 |
| Beclometasone (extra fine particles) | 50 | 2.0 |
| Budesonide | 100 | 1.0 |
| Fluticasone propionate | 50 | 2.0 |
| Fluticasone furoate | 12.5 | 8.0 |
| Mometasone | 50 | 2.0 |
| Ciclesonide | 62.5 | 1.6 |
Search methods for identification of studies
Electronic searches
We will identify studies from searches of the following databases and trial registries.
Cochrane Airways Trials Register (Cochrane Airways 2019), via the Cochrane Register of Studies, all years to date.
Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, via the Cochrane Register of Studies, all years to date.
MEDLINE Ovid SP 1946 to date.
Embase Ovid SP 1974 to date.
US National Institutes of Health Ongoing Trials Register (www.ClinicalTrials.gov).
World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch).
We present the proposed MEDLINE search strategy in Appendix 1. This will be adapted for use in the other databases. The search strategy was developed by the Cochrane Airways Information Specialist in collaboration with the authors, and was peer‐reviewed by another Cochrane Information Specialist using the PRESS checklist (McGowan 2016).
We will search all databases and trials registries from their inception to the present, and we will impose no restriction regarding language or type of publication. We will identify handsearched conference abstracts and grey literature through the Cochrane Airways Trials Register and the CENTRAL database.
Searching other resources
We will check the reference lists of all primary studies and review articles for additional references. We will search relevant manufacturers' websites for study information.
We will search on PubMed for errata or retractions from included studies published in full text, and report the date this was done within the review.
Data collection and analysis
Selection of studies
We plan to use Cochrane’s Screen4Me workflow to help assess the search results. Screen4Me comprises three components: known assessments – a service that matches records in the search results to records that have already been screened in Cochrane Crowd and have been labelled as 'RCT' or 'Not an RCT'; the RCT classifier – a machine learning model that distinguishes RCTs from non‐RCTs; and, if appropriate, Cochrane Crowd (crowd.cochrane.org) – Cochrane’s citizen science platform where 'the crowd' help to identify and describe health evidence. More detailed information about the Screen4Me components can be found in the following publications: McDonald 2017; Thomas 2017; Marshall 2018; Noel‐Storr 2018.
Following this initial assessment, four review authors (ST, FY, MG, AF) will screen the titles and abstracts of the remaining search results independently and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve', with each abstract being screened by at least two authors. We will retrieve the full‐text study reports of all potentially eligible studies and two review authors (two of ST, FY, MG and AF) will independently screen them for inclusion, recording the reasons for exclusion of ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third person/review author (IC or TSCH). We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and 'Characteristics of excluded studies' table (Moher 2009).
Data extraction and management
We will use a data collection form which has been piloted on at least one study in the review for study characteristics and outcome data. Two review authors (SR, GH) will extract the following study characteristics from included studies.
Methods: study design, total duration of study, details of any 'run‐in' period, number of study centres and location, study setting, withdrawals and date of study.
Participants: N, mean age, age range, gender, severity of condition, diagnostic criteria, baseline lung function, smoking history, inclusion criteria and exclusion criteria.
Interventions: intervention, comparison (including types and doses of beta agonist and corticosteroid), concomitant medications, prior medications and excluded medications.
Outcomes: primary and secondary outcomes specified and collected, and time points reported.
Notes: funding for studies and notable conflicts of interest of trial authors.
Two review authors (SR, GH) will independently extract outcome data from included studies. We will note in the 'Characteristics of included studies' table if outcome data were not reported in a usable way. We will resolve disagreements by discussion or by involving a third person/review author (IC or TSCH) to reach consensus. One review author (IC) will transfer data into the Review Manager 5 file (Review Manager 2014). We will double‐check that data are entered correctly by comparing the data presented in the systematic review with the study reports. A second review author (TSCH) will spot‐check study characteristics for accuracy against the study report.
Assessment of risk of bias in included studies
Two review authors (SR, GH) will assess risk of bias independently for each study using the criteria outlined in version 5.1 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreements by discussion or by involving another author (IC or TSCH). We will assess the risk of bias according to the following domains.
Random sequence generation
Allocation concealment
Blinding of participants and personnel
Blinding of outcome assessment
Incomplete outcome data
Selective outcome reporting
Other bias
We will judge each potential source of bias as high, low or unclear risk and provide a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary (e.g. for unblinded outcome assessment, risk of bias for all‐cause mortality may be very different than for a patient‐reported pain scale). Where information on risk of bias relates to unpublished data or correspondence with a trialist, we will note this in the 'Risk of bias' table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assessment of bias in conducting the systematic review
We will conduct the review according to this published protocol and justify any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will analyse dichotomous data as odds ratios (OR) or (where appropriate) rate ratios (RR) and continuous data as the mean difference (MD) or standardised mean difference (SMD). If data from rating scales are combined in a meta‐analysis, we will ensure they are entered with a consistent direction of effect (e.g. lower scores always indicate improvement).
We will undertake meta‐analyses only where this is meaningful: that is, if the treatments, participants and the underlying clinical question are similar enough for pooling to make sense.
We will describe skewed data narratively (for example, as medians and interquartile ranges for each group).
Where multiple trial arms are reported in a single study, we will include only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) are combined in the same meta‐analysis, we will either combine the active arms or halve the control group to avoid double‐counting.
If adjusted analyses are available (ANOVA or ANCOVA) we will use these as a preference in our meta‐analyses. If both change from baseline and endpoint scores are available for continuous data, we will use change from baseline unless there is low correlation between measurements in individuals. If a study reports outcomes at multiple time points, we will use 12 months preferentially, with 3 months as a 'second choice'.
We will use intention‐to‐treat (ITT) or 'full analysis set' analyses where they are reported (i.e. those where data have been imputed for participants who were randomly assigned but did not complete the study) instead of completer or per protocol analyses
Unit of analysis issues
For outcomes involving event counts where participants may have multiple events (exacerbations, hospitalisations) and 3 or 12 month incidence rates are available, we will use events primarily as the unit of analysis rather than participants. For other dichotomous outcomes and where incidence rate ratios are not available, we will use participants, rather than events, as the unit of analysis (i.e. number of children admitted to hospital, rather than number of admissions per child). We will only meta‐analyse data from cluster‐RCTs if the available data have been adjusted (or can be adjusted) to account for the clustering.
Where possible, we will include data from paired analyses of any identified cross‐over studies.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as an abstract only). Where this is not possible, and the missing data are thought to introduce serious bias, we will take this into consideration in the GRADE rating for affected outcomes.
Assessment of heterogeneity
We will use the I² statistic to measure heterogeneity among the studies in each analysis. If we identify substantial heterogeneity we will report it and explore the possible causes by prespecified subgroup analysis.
Assessment of reporting biases
If we are able to pool more than 10 studies, we will create and examine a funnel plot to explore possible small‐study and publication biases.
Data synthesis
We will use a random‐effects model and perform a sensitivity analysis with a fixed‐effect model.
'Summary of findings' table
We will create a 'Summary of findings' table using the following outcomes.
Exacerbations requiring systemic steroids
Hospital admissions/emergency department or urgent care visits for asthma
Asthma control, preferably measured by the Asthma Control Questionnaire
Inhaled steroid dose
Total systemic steroid dose
Adverse events
We will use the five GRADE considerations (risk of bias; consistency of effect; imprecision; indirectness; and publication bias) to assess the quality of a body of evidence as it relates to the studies that contribute data for the prespecified outcomes. We will use the methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019), using GRADEpro software (GRADEpro GDT). We will justify all decisions to downgrade the quality of studies using footnotes and we will make comments to aid the reader's understanding of the review where necessary.
Subgroup analysis and investigation of heterogeneity
We plan to carry out the following subgroup analyses.
Adults and adolescents vs children (i.e. 12 years and over vs under 12 years) in keeping with GINA 2019 definitions
High vs low eosinophils (for trials where this is reported, using the trialists' definition of high and low)
High vs low FeNO (where reported, using the trialists' definition of high and low)
By inhaler component drugs (i.e. by each inhaled steroid drug and by short‐ or long‐acting beta agonist)
We will use the following outcomes in subgroup analyses.
Exacerbations requiring oral steroid
Hospital admissions/emergency department or urgent care visits for asthma
Measures of asthma control
We will use the formal test for subgroup interactions in Review Manager 5 (Review Manager 2014).
Sensitivity analysis
We plan to carry out sensitivity analyses, removing the following from the primary outcome analyses.
Trials deemed at high risk of bias in at least one domain
Cross‐over (as opposed to parallel group) trials
Trials in which asthma severity is not explicitly stated, but only derived from baseline characteristics
We will compare the results from a fixed‐effect model with the random‐effects model.
Acknowledgements
The authors would like to thank the Cochrane Airways Editorial team, particularly Rebecca Fortescue, Emma Dennett and Emma Jackson for their help defining the clinical question and methods and Liz Stovold for the search strategy.
The authors and Airways' Editorial Team are grateful to the following peer reviewers for their time and comments.
Amnuayporn Apiraksakorn MD, Khon Kaen Hospital, Thailand;
David JW Evans, Lancaster Medical School, UK;
Gabriel Tafdrup Notkin (consumer peer reviewer), Denmark;
Hebatullah M Abdulazeem (consumer peer reviewer), Technical University of Munich, Germany;
Kayleigh Kew, BMJ Technology Assessment Group (BMJ‐TAG), UK;
Olatokunbo Sanwo, East Kent Hospitals University NHS Foundation Trust, UK
Dr PA Marsden, Manchester University NHS Foundation Trust and Manchester University, UK;
Dr Robin G Carr, retired GP, UK; and
Dr Simon S Craig, Monash University and Monash Medical Centre, Australia.
The Background and Methods sections of this protocol are based on a standard template used by Cochrane Airways.
This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Airways. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.
Appendices
Appendix 1. Database search strategy
Ovid MEDLINE(R) ALL <1946 to September 13, 2019>
# Searches
1 exp Asthma/
2 asthma$.ti,ab.
3 1 or 2
4 Fluticasone/
5 Budesonide/
6 Beclomethasone/
7 exp Triamcinolone/
8 fluticasone.tw.
9 beclomethasone.tw.
10 budesonide.tw.
11 triamcinolone.tw.
12 flunisolide.tw.
13 ciclesonide.tw.
14 (flixotide or flovent).tw.
15 (becotide or beclofort or becodisk or QVAR or vanceril).tw.
16 pulmicort.tw.
17 (kenalog or azmacort).tw.
18 bronalide.tw.
19 Alvesco.tw.
20 Mometasone Furoate/
21 mometasone.tw.
22 (inhal$ adj3 (steroid$ or corticosteroid$ or glucocorticoid$)).tw.
23 or/4‐22
24 exp Adrenergic beta‐2 Receptor Agonists/
25 exp Albuterol/
26 Terbutaline/
27 Formoterol Fumarate/
28 Salmeterol Xinafoate/
29 (Salbutamol or albuterol).tw.
30 Terbutaline.tw.
31 Bambuterol.tw.
32 (formoterol or eformoterol).tw.
33 Indacaterol.tw.
34 Olodaterol.tw.
35 salmeterol.tw.
36 or/24‐35
37 Fluticasone‐Salmeterol Drug Combination/
38 Budesonide, Formoterol Fumarate Drug Combination/
39 Mometasone Furoate, Formoterol Fumarate Drug Combination/
40 Fostair.tw.
41 Symbicort.tw.
42 DuoResp Spiromax.tw.
43 Fobumix.tw.
44 Seretide.tw.
45 Relvar.tw.
46 Ventide.tw.
47 Aerocort.tw.
48 Salbair.tw.
49 or/37‐48
50 23 and 36
51 3 and (49 or 50)
52 (controlled clinical trial or randomized controlled trial).pt.
53 (randomized or randomised).ab,ti.
54 placebo.ab,ti.
55 dt.fs.
56 randomly.ab,ti.
57 trial.ab,ti.
58 groups.ab,ti.
59 or/52‐58
60 Animals/
61 Humans/
62 60 not (60 and 61)
63 59 not 62
64 51 and 63
Contributions of authors
SR and TSCH wrote the protocol background. IC wrote the Methods section based on a standard Cochrane template with contributions from all the authors.
Contributions of editorial team
Rebecca Fortescue (Co‐ordinating Editor): edited the protocol; advised on methodology.
Chris Cates (Co‐ordinating Editor): checked the planned methods, approved the protocol prior to publication.
Emma Dennett (Managing Editor): co‐ordinated the editorial process; advised on content; edited the protocol.
Emma Jackson (Assistant Managing Editor): conducted peer review; edited the references.
Elizabeth Stovold (Information Specialist): designed the search strategy; arranged for peer review of the search strategy.
Sources of support
Internal sources
-
National Institute for Health Research, UK.
TSC Hinks, S Ramakrishnan and G Hynes were supported by the NIHR Oxford Biomedical Research Centre
External sources
-
Wellcome Trust, UK.
TSC Hinks was supported by a Wellcome Trust Career Development Fellowship 211050/Z/18/Z
Declarations of interest
I Crossingham works in a clinically relevant speciality. He has been involved in recruitment for a GlaxoSmithKline‐sponsored trial of inhaled nemiralisib for COPD, but did not directly receive funding for this. In February 2017 Hamilton Medical paid for his travel and accommodation to attend training on their ventilators as part of a post‐sales package to his institution. Ventilation is a potential supportive therapy for acute severe asthma but not directly relevant to this review.
TSC Hinks has received research funding from the Wellcome Trust (4 February 2015 to 31 July 2018, 3 December 2018 ‒ ongoing), NIHR (1 May 2019 ‒ ongoing), and the Beit Guardians (3 December 2018 ‒ ongoing). He has received speaker fees from AstraZeneca in June 2019, Boehringer Ingelheim (March 2019) and his research team have received funding from Sanofi (September 2019 ‒ ongoing).
G Hynes has a joint research fellowship from the University of Oxford and UCB. He has attended educational events sponsored by Sanofi (September 2019), Teva (2018) and AstraZeneca (2016 and 2017), and has received an honorarium from Teva in 2018 for producing educational materials over which Teva had no editorial control.
F Yasmin has no relevant conflicts of interest.
A Fries works in a clinically relevant speciality.
S Ramakrishnan is undertaking a PhD supported by an unrestricted research grant from AstraZeneca. He has attended educational events sponsored by AstraZeneca (2019). He also works in a clinically relevant specialty.
M Gowell has no relevant conflict of interest.
S Turner reports money for travel from Novartis in 2019 for an educational event.
A Choudhry works in a clinically relevant speciality.
New
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