scholarly journals Placebo comparator group selection and use in surgical trials: the ASPIRE project including expert workshop

2021 ◽  
Vol 25 (53) ◽  
pp. 1-52
Author(s):  
David J Beard ◽  
Marion K Campbell ◽  
Jane M Blazeby ◽  
Andrew J Carr ◽  
Charles Weijer ◽  
...  
Keyword(s):  
Randomised Controlled Trials ◽  
Medical Research Council ◽  
Placebo Control ◽  
Controlled Trials ◽  
Surgical Trials ◽  
Surgical Interventions ◽  
Placebo Controls ◽  
Randomised Controlled ◽  
The Uk ◽  
Future Work

Background The use of placebo comparisons for randomised trials assessing the efficacy of surgical interventions is increasingly being considered. However, a placebo control is a complex type of comparison group in the surgical setting and, although powerful, presents many challenges. Objectives To provide a summary of knowledge on placebo controls in surgical trials and to summarise any recommendations for designers, evaluators and funders of placebo-controlled surgical trials. Design To carry out a state-of-the-art workshop and produce a corresponding report involving key stakeholders throughout. Setting A workshop to discuss and summarise the existing knowledge and to develop the new guidelines. Results To assess what a placebo control entails and to assess the understanding of this tool in the context of surgery is considered, along with when placebo controls in surgery are acceptable (and when they are desirable). We have considered ethics arguments and regulatory requirements, how a placebo control should be designed, how to identify and mitigate risk for participants in these trials, and how such trials should be carried out and interpreted. The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Surgical placebos might be most appropriate when there is poor evidence for the efficacy of the procedure and a justified concern that results of a trial would be associated with a high risk of bias, particularly because of the placebo effect. Conclusions The use of placebo controls is justified in randomised controlled trials of surgical interventions provided that there is a strong scientific and ethics rationale. Feasibility work is recommended to optimise the design and implementation of randomised controlled trials. An outline for best practice was produced in the form of the Applying Surgical Placebo in Randomised Evaluations (ASPIRE) guidelines for those considering the use of a placebo control in a surgical randomised controlled trial. Limitations Although the workshop participants involved international members, the majority of participants were from the UK. Therefore, although every attempt was made to make the recommendations applicable to all health systems, the guidelines may, unconsciously, be particularly applicable to clinical practice in the UK NHS. Future work Future work should evaluate the use of the ASPIRE guidelines in making decisions about the use of a placebo-controlled surgical trial. In addition, further work is required on the appropriate nomenclature to adopt in this space. Funding Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research programme.

scholarly journals Registration and publication of emergency and elective randomised controlled trials in surgery: a cohort study from trial registries

BMJ Open ◽  
2018 ◽  
Vol 8 (7) ◽  
pp. e021700 ◽  
Author(s):  
Rachael L Morley ◽  
Matthew J Edmondson ◽  
Ceri Rowlands ◽  
Jane M Blazeby ◽  
Robert J Hinchliffe
Keyword(s):  
Outcome Measures ◽  
Emergency Surgery ◽  
Randomised Controlled Trials ◽  
Primary Outcome ◽  
Elective Surgery ◽  
Secondary Outcome ◽  
Controlled Trials ◽  
Surgical Trials ◽  
Surgical Interventions ◽  
Randomised Controlled

ObjectivesEmergency surgical practice constitutes 50% of the workload for surgeons, but there is a lack of high quality randomised controlled trials (RCTs) in emergency surgery. This study aims to establish the differences between the registration, completion and publication of emergency and elective surgical trials.DesignThe clinicaltrials.gov and ISRCTN.com trials registry databases were searched for RCTs between 12 July 2010 and 12 July 2012 using the keyword ‘surgery’. Publications were systematically searched for in Pubmed, MEDLINE and EMBASE.ParticipantsResults with no surgical interventions were excluded. The remaining results were manually categorised into ‘emergency’ or ‘elective’ and ‘surgical’ or ‘adjunct’ by two reviewers.Primary outcome measuresNumber of RCTs registered in emergency versus elective surgery.Secondary outcome measuresNumber of RCTs published in emergency versus elective surgery; reasons why trials remain unpublished; funding, sponsorship and impact of published articles; number of adjunct trials registered in emergency and elective surgery.Results2700 randomised trials were registered. 1173 trials were on a surgical population and of these, 414 trials were studying surgery. Only 9.4% (39/414) of surgical trials were in emergency surgery. The proportion of trials successfully published did not significantly differ between emergency and elective surgery (0.46 vs 0.52; mean difference (MD) −0.06, 95% CI −0.24 to 0.12). Unpublished emergency surgical trials were statistically equally likely to be terminated early compared with elective trials (0.33 vs 0.16; MD −0.18, 95% CI −0.06 to 0.41). Low accrual accounted for a similar majority in both groups (0.43 vs 0.46; MD −0.04, 95% CI −0.48 to 0.41). Unpublished trials in both groups were statistically equally likely to still be planning publication (0.52 vs 0.71; MD −0.18, 95% CI −0.43 to 0.07).ConclusionFewer RCTs are registered in emergency than elective surgery. Once trials are registered both groups are equally likely to be published.

scholarly journals Blinding in trials of interventional procedures is possible and worthwhile

F1000Research ◽  
2018 ◽  
Vol 6 ◽  
pp. 1663 ◽  
Author(s):  
Karolina Wartolowska ◽  
David Beard ◽  
Andrew Carr
Keyword(s):  
Active Treatment ◽  
Randomised Controlled Trials ◽  
Interventional Procedures ◽  
Drop Out ◽  
Placebo Control ◽  
Controlled Trials ◽  
Randomised Controlled

In this paper, we use evidence from our earlier review of surgical randomised controlled trials with a placebo arm to show that blinding in trials of interventional procedures is feasible. We give examples of ingenious strategies that have been used to simulate the active procedure and to make the placebo control indistinguishable from the active treatment. We discuss why it is important to blind of patients, assessors, and caregivers and what types of bias that may occur in interventional trials. Finally, we describe the benefits of blinding, from the obvious ones such as avoiding bias, as well as less evident benefits such as avoiding patient drop out in the control arm.

scholarly journals Surgical interventions for women with stress urinary incontinence: systematic review and network meta-analysis of randomised controlled trials

BMJ ◽  
2019 ◽  
pp. l1842 ◽  
Author(s):  
Mari Imamura ◽  
Jemma Hudson ◽  
Sheila A Wallace ◽  
Graeme MacLennan ◽  
Michal Shimonovich ◽  
...  
Keyword(s):  
Urinary Incontinence ◽  
Stress Urinary Incontinence ◽  
Adverse Events ◽  
Randomised Controlled Trials ◽  
Meta Analysis ◽  
Risk Of Bias ◽  
Controlled Trials ◽  
Surgical Interventions ◽  
Randomised Controlled ◽  
Meta Analyses

Abstract Objectives To compare the effectiveness and safety of surgical interventions for women with stress urinary incontinence. Design Systematic review and network meta-analysis. Eligibility criteria for selecting studies Randomised controlled trials evaluating surgical interventions for the treatment of stress urinary incontinence in women. Methods Identification of relevant randomised controlled trials from Cochrane reviews and the Cochrane Incontinence Specialised Register (searched May 2017), which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Medline In-Process, Medline Epub Ahead of Print, CINAHL, ClinicalTrials.gov, and WHO ICTRP. The reference lists of relevant articles were also searched. Primary outcomes were “cure” and “improvement” at 12 months, analysed by means of network meta-analyses, with results presented as the surface under the cumulative ranking curve (SUCRA). Adverse events were analysed using pairwise meta-analyses. Risk of bias was assessed using the Cochrane risk of bias tool. The quality of evidence for network meta-analysis was assessed using the GRADE approach. Results 175 randomised controlled trials assessing a total of 21 598 women were included. Most studies had high or unclear risk across all risk of bias domains. Network meta-analyses were based on data from 105 trials that reported cure and 120 trials that reported improvement of incontinence symptoms. Results showed that the interventions with highest cure rates were traditional sling, retropubic midurethral sling (MUS), open colposuspension, and transobturator MUS, with rankings of 89.4%, 89.1%, 76.7%, and 64.1%, respectively. Compared with retropubic MUS, the odds ratio of cure for traditional sling was 1.06 (95% credible interval 0.62 to 1.85), for open colposuspension was 0.85 (0.54 to 1.33), and for transobtrurator MUS was 0.74 (0.59 to 0.92). Women were also more likely to experience an improvement in their incontinence symptoms after receiving retropubic MUS or transobturator MUS compared with other surgical procedures. In particular, compared with retropubic MUS, the odds ratio of improvement for transobturator MUS was 0.76 (95% credible interval 0.59 to 0.98), for traditional sling was 0.69 (0.39 to 1.26), and for open colposuspension was 0.65 (0.41 to 1.02). Quality of evidence was moderate for retropubic MUS versus transobturator MUS and low or very low for retropubic MUS versus the other two interventions. Data on adverse events were available mainly for mesh procedures, indicating a higher rate of repeat surgery and groin pain but a lower rate of suprapubic pain, vascular complications, bladder or urethral perforation, and voiding difficulties after transobturator MUS compared with retropubic MUS. Data on adverse events for non-MUS procedures were sparse and showed wide confidence intervals. Long term data were limited. Conclusions Retropubic MUS, transobturator MUS, traditional sling, and open colposuspension are more effective than other procedures for stress urinary incontinence in the short to medium term. Data on long term effectiveness and adverse events are, however, limited, especially around the comparative adverse events profiles of MUS and non-MUS procedures. A better understanding of complications after surgery for stress urinary incontinence is imperative. Systematic review registration PROSPERO CRD42016049339.

scholarly journals Embedding qualitative research in randomised controlled trials to improve recruitment: findings from two recruitment optimisation studies of orthopaedic surgical trials.

2021 ◽  
Author(s):  
Arabella Scantlebury ◽  
Catriona McDaid ◽  
Stephen Brealey ◽  
Elizabeth Cook ◽  
Arun Ranganathan ◽  
...  
Keyword(s):  
Systematic Review ◽  
United Kingdom ◽  
Mixed Methods ◽  
Randomised Controlled Trials ◽  
Controlled Trials ◽  
Surgical Trials ◽  
Patient Pathways ◽  
Study Results ◽  
Randomised Controlled ◽  
The Impact

Abstract Background: Recruitment of patients is one of the main challenges when designing and conducting randomised controlled trials (RCTs). Trials of rare injuries, or those that include surgical interventions pose added challenges due to the small number of potentially eligible patients and issues with patient preferences and surgeon equipoise. We explore key issues to consider when recruiting to orthopaedic surgical trials from the perspective of staff and patients with the aim of informing the development of strategies to improve recruitment in future research. Design: Two qualitative process evaluations of a United Kingdom-wide orthopaedic surgical RCT (ACTIVE) and mixed methods randomised feasibility study (PRESTO). Qualitative semi-structured interviews were conducted and data was analysed thematically. Setting: NHS secondary care organisations throughout the United Kingdom. Interviews were undertaken via telephone. Participants: 37 trial recruiters (surgeons, physiotherapists, research nurses) and 22 patients were interviewed. Patients included those who agreed to participate in the ACTIVE and PRESTO studies and patients that declined participation in the ACTIVE study. Results: We used a mixed methods systematic review of recruiting patients to randomised controlled trials as a framework for reporting and analysing our findings. Our findings mapped onto those identified in the systematic review and highlighted the importance of equipoise, randomisation, communication, patient’s circumstances, altruism and trust in clinical and research teams. Our findings also emphasised the importance of considering how eligibility criteria are operationalised and the impact of complex patient pathways when recruiting to surgical trials. In particular, the influence of health professionals, who are not involved in trial recruitment, on patients’ treatment preferences by suggesting they would receive a certain treatment ahead of recruitment consultations should not be underestimated. Conclusions: A wealth of evidence exploring factors affecting recruitment to randomised controlled trials exists. A methodological shift is now required to ensure that this evidence is used by all those involved in recruitment and to ensure that existing knowledge is translated into methods for optimising recruitment to future trials. Trial registries: ACTIVE: (ISRCTN98152560) PRESTO: (ISRCTN12094890)

scholarly journals Reducing bias in trials from reactions to measurement: the MERIT study including developmental work and expert workshop

2021 ◽  
Vol 25 (55) ◽  
pp. 1-72
Author(s):  
David P French ◽  
Lisa M Miles ◽  
Diana Elbourne ◽  
Andrew Farmer ◽  
Martin Gulliford ◽  
...  
Keyword(s):  
Systematic Reviews ◽  
Randomised Controlled Trials ◽  
Research Council ◽  
Medical Research Council ◽  
Controlled Trials ◽  
Measurement Reactivity ◽  
Health Related ◽  
Randomised Controlled ◽  
Expert Workshop ◽  
Improve Health

Background Measurement can affect the people being measured; for example, asking people to complete a questionnaire can result in changes in behaviour (the ‘question–behaviour effect’). The usual methods of conduct and analysis of randomised controlled trials implicitly assume that the taking of measurements has no effect on research participants. Changes in measured behaviour and other outcomes due to measurement reactivity may therefore introduce bias in otherwise well-conducted randomised controlled trials, yielding incorrect estimates of intervention effects, including underestimates. Objectives The main objectives were (1) to promote awareness of how and where taking measurements can lead to bias and (2) to provide recommendations on how best to avoid or minimise bias due to measurement reactivity in randomised controlled trials of interventions to improve health. Methods We conducted (1) a series of systematic and rapid reviews, (2) a Delphi study and (3) an expert workshop. A protocol paper was published [Miles LM, Elbourne D, Farmer A, Gulliford M, Locock L, McCambridge J, et al. Bias due to MEasurement Reactions In Trials to improve health (MERIT): protocol for research to develop MRC guidance. Trials 2018;19:653]. An updated systematic review examined whether or not measuring participants had an effect on participants’ health-related behaviours relative to no-measurement controls. Three new rapid systematic reviews were conducted to identify (1) existing guidance on measurement reactivity, (2) existing systematic reviews of studies that have quantified the effects of measurement on outcomes relating to behaviour and affective outcomes and (3) experimental studies that have investigated the effects of exposure to objective measurements of behaviour on health-related behaviour. The views of 40 experts defined the scope of the recommendations in two waves of data collection during the Delphi procedure. A workshop aimed to produce a set of recommendations that were formed in discussion in groups. Results Systematic reviews – we identified a total of 43 studies that compared interview or questionnaire measurement with no measurement and these had an overall small effect (standardised mean difference 0.06, 95% confidence interval 0.02 to 0.09; n = 104,096, I 2 = 54%). The three rapid systematic reviews identified no existing guidance on measurement reactivity, but we did identify five systematic reviews that quantified the effects of measurement on outcomes (all focused on the question–behaviour effect, with all standardised mean differences in the range of 0.09—0.28) and 16 studies that examined reactive effects of objective measurement of behaviour, with most evidence of reactivity of small effect and short duration. Delphi procedure – substantial agreement was reached on the scope of the present recommendations. Workshop – 14 recommendations and three main aims were produced. The aims were to identify whether or not bias is likely to be a problem for a trial, to decide whether or not to collect further quantitative or qualitative data to inform decisions about if bias is likely to be a problem, and to identify how to design trials to minimise the likelihood of this bias. Limitation The main limitation was the shortage of high-quality evidence regarding the extent of measurement reactivity, with some notable exceptions, and the circumstances that are likely to bring it about. Conclusion We hope that these recommendations will be used to develop new trials that are less likely to be at risk of bias. Future work The greatest need is to increase the number of high-quality primary studies regarding the extent of measurement reactivity. Study registration The first systematic review in this study is registered as PROSPERO CRD42018102511. Funding Funded by the Medical Research Council UK and the National Institute for Health Research as part of the Medical Research Council–National Institute for Health Research Methodology Research Programme.

scholarly journals A systematic breakdown of the levels of evidence supporting the European Society of Cardiology guidelines

2019 ◽  
Vol 26 (18) ◽  
pp. 1944-1952 ◽  
Author(s):  
Wouter B van Dijk ◽  
Diederick E Grobbee ◽  
Martine C de Vries ◽  
Rolf H H Groenwold ◽  
Rieke van der Graaf ◽  
...  
Keyword(s):  
Expert Opinion ◽  
European Society ◽  
Randomised Controlled Trials ◽  
Class I ◽  
Controlled Trials ◽  
Specific Recommendation ◽  
Level Of Evidence ◽  
Surgical Interventions ◽  
European Society Of Cardiology ◽  
Randomised Controlled

Aims Reviews of clinical practice guidelines have repeatedly concluded that only a minority of guideline recommendations are supported by high-quality evidence from randomised controlled trials. The aim of this study is to evaluate whether these findings apply to the whole cardiovascular evidence base or specific recommendation types and actions. Methods All recommendations from current European Society of Cardiology guidelines were extracted with their class (I, treatment is beneficial; II, treatment is possibly beneficial; III, treatment is harmful) and level of evidence (A, multiple randomised controlled trials/meta-analyses; B, single randomised controlled trials/large observational studies; C, expert opinion/small studies). Recommendations were categorised by type (therapeutic, diagnostic, other) and actions (e.g. pharmaceutical intervention/non-invasive imaging/test). Results In total, 3531 recommendations (median 128, interquartile range 108–150) were extracted from 27 guidelines. Therapeutic recommendations comprised 2545 (72.1%) recommendations, 411 (16.1%) were supported by level of evidence A, 833 (32.7%) by B and 1301 (51.1%) by C. Class I/III (should/should not) recommendations on minimally invasive interventions were most supported by level of evidence A (55/183, 30.1%) (B [70/183, 38.3%], C [58/183, 31.7%]), while class I/III recommendations on open surgical interventions were least supported by level of evidence A (15/164, 9.1%) (B [34/164, 20.7%], C [115/164, 70.1%]). Of all (831, 23.5%) diagnostic recommendations, just 44/503 (8.7%) class I/III recommendations were supported by level of evidence A (B (125/503, 24.9%), C (334/503, 66.4%)). Conclusion Evidence levels supporting European Society of Cardiology guideline recommendations differ widely between recommendation types and actions. Attributing to this variability are different evidence requirements, therapeutic/diagnostic recommendations, different feasibility levels for trials (e.g. open surgical/pharmacological) and many off-topic/policy recommendations based on expert opinion.

scholarly journals A survey of instructions to authors in surgical journals on reporting by CONSORT and PRISMA

2012 ◽  
Vol 94 (7) ◽  
pp. 468-471 ◽  
Author(s):  
S Shantikumar ◽  
J Wigley ◽  
W Hameed ◽  
A Handa
Keyword(s):  
Systematic Reviews ◽  
Randomised Controlled Trials ◽  
Trial Registration ◽  
Controlled Trials ◽  
Clinical Trial Registration ◽  
Journal Citation Reports ◽  
Randomised Controlled ◽  
The Uk ◽  
Meta Analyses ◽  
Surgical Journals

INTRODUCTION Guidance has been published on how best to report randomised controlled trials (Consolidated Standards of Reporting Trials – CONSORT) and systematic reviews (Preferred Reporting Items for Systematic Reviews and Meta-Analyses – PRISMA). The aim of this study was to establish to what extent surgical journals formally endorse CONSORT and PRISMA in the respective reporting of randomised controlled trials and systematic reviews. METHODS Overall, 136 surgical journals indexed in Journal Citation Reports® were studied. Author guidelines were scrutinised for the following guidance: conflict of interests (COI), the Uniform Requirements for Manuscripts (URM), clinical trial registration, CONSORT and PRISMA. RESULTS The frequency of guidance endorsement was found to be as follows: COI 82%, URM 62%, trial registration 32%, CONSORT 29% and PRISMA 10%. Journals with a higher impact were more likely to adopt trial registration, CONSORT and PRISMA. Journals with editorial offices in the UK were more likely to insist on disclosure of COI and to endorse CONSORT. CONCLUSIONS Guidelines produced to improve publication practice have not been implemented widely by surgical journals. This may contribute to an overall poorer quality of published research. Editors of surgical journals should uniformly endorse reporting guidance and update their instructions to authors to reflect this.

scholarly journals Determining the Feasibility of Ambulance-Based Randomised Controlled Trials in Patients with Ultra-Acute Stroke: Study Protocol for the “Rapid Intervention with GTN in Hypertensive Stroke Trial” (RIGHT, ISRCTN66434824)

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Sandeep Ankolekar ◽  
Gillian Sare ◽  
Chamila Geeganage ◽  
Michael Fuller ◽  
Lynn Stokes ◽  
...  
Keyword(s):  
Acute Stroke ◽  
Functional Outcomes ◽  
Randomised Controlled Trials ◽  
Controlled Trial ◽  
Trial Registration ◽  
Controlled Trials ◽  
Stroke Study ◽  
Registration Number ◽  
Randomised Controlled ◽  
The Uk

Background. Time from acute stroke to enrolment in clinical trials needs to be reduced to improve the chances of finding effective treatments. No completed randomised controlled trials of ambulance-based treatment for acute stroke have been reported in the UK, and the practicalities of recruiting, consenting, and treating patients are unknown.Methods. RIGHT is an ambulance based, single-blind, randomised controlled trial with blinded-outcome assessment. The trial will assess feasibility of using ambulance services to deliver ultra-acute stroke treatments; a secondary aim is to assess the effect of glyceryl trinitrate (GTN) on haemodynamic variables and functional outcomes. Initial consent, randomisation, and treatment are performed by paramedics prior to hospitalisation. Patients with ultra-acute stroke (≤4 hours of onset) are randomised to transdermal GTN (5 mg/24 hours) or gauze dressing daily for 7 days. The primary outcome is systolic blood pressure at 2 hours. Secondary outcomes include feasibility, haemodynamics, dependency, and other functional outcomes. A nested qualitative study is included.Trial Status. The trial has all relevant ethics and regulatory approvals and recruitment started on February 15, 2010. The trial stopped recruitment in December 2011 after 41 patients were recruited.Trial Registration. The trial registration number is ISRCTN66434824 and EudraCT number is 2007-004766-40.

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