Surgical interventions are complex. Key elements of this complexity are the surgeon and their learning curve. They pose methodological challenges in the design, analysis and interpretation of ...surgical RCTs. We identify, summarise, and critically examine current guidance about how to incorporate learning curves in the design and analysis of RCTs in surgery.
Current guidance presumes that randomisation must be between levels of just one treatment component, and that the evaluation of comparative effectiveness will be made via the average treatment effect (ATE). It considers how learning effects affect the ATE, and suggests solutions which seek to define the target population such that the ATE is a meaningful quantity to guide practice. We argue that these are solutions to a flawed formulation of the problem, and are inadequate for policymaking in this setting.
The premise that surgical RCTs are limited to single-component comparisons, evaluated via the ATE, has skewed the methodological discussion. Forcing a multi-component intervention, such as surgery, into the framework of the conventional RCT design ignores its factorial nature. We briefly discuss the multiphase optimisation strategy (MOST), which for a Stage 3 trial would endorse a factorial design. This would provide a wealth of information to inform nuanced policy but would likely be infeasible in this setting. We discuss in more depth the benefits of targeting the ATE conditional on operating surgeon experience (CATE). The value of estimating the CATE for exploring learning effects has been previously recognised, but with discussion limited to analysis methods only. The robustness and precision of such analyses can be ensured via the trial design, and we argue that trial designs targeting CATE represent a clear gap in current guidance.
Trial designs that facilitate robust, precise estimation of the CATE would allow for more nuanced policymaking, leading to patient benefit. No such designs are currently forthcoming. Further research in trial design to facilitate the estimation of the CATE is needed.
Simulation offers a simple and flexible way to estimate the power of a clinical trial when analytic formulae are not available. The computational burden of using simulation has, however, restricted ...its application to only the simplest of sample size determination problems, often minimising a single parameter (the overall sample size) subject to power being above a target level. We describe a general framework for solving simulation-based sample size determination problems with several design parameters over which to optimise and several conflicting criteria to be minimised. The method is based on an established global optimisation algorithm widely used in the design and analysis of computer experiments, using a non-parametric regression model as an approximation of the true underlying power function. The method is flexible, can be used for almost any problem for which power can be estimated using simulation, and can be implemented using existing statistical software packages. We illustrate its application to a sample size determination problem involving complex clustering structures, two primary endpoints and small sample considerations.
The power of a large clinical trial can be adversely affected by low recruitment, follow‐up, and adherence rates. External pilot trials estimate these rates and use them, via prespecified decision ...rules, to determine if the definitive trial is feasible and should go ahead. There is little methodological research underpinning how these decision rules, or the sample size of the pilot, should be chosen. In this article we propose a hypothesis test of the feasibility of a definitive trial, to be applied to the external pilot data and used to make progression decisions. We quantify feasibility by the power of the planned trial, as a function of recruitment, follow‐up, and adherence rates. We use this measure to define hypotheses to test in the pilot, propose a test statistic, and show how the error rates of this test can be calculated for the common scenario of a two‐arm parallel group definitive trial with a single normally distributed primary endpoint. We use our method to redesign TIGA‐CUB, an external pilot trial comparing a psychotherapy with treatment as usual for children with conduct disorders. We then extend our formulation to include using the pilot data to estimate the standard deviation of the primary endpoint and incorporate this into the progression decision.
External pilot trials of complex interventions are used to help determine if and how a confirmatory trial should be undertaken, providing estimates of parameters such as recruitment, retention, and ...adherence rates. The decision to progress to the confirmatory trial is typically made by comparing these estimates to pre‐specified thresholds known as progression criteria, although the statistical properties of such decision rules are rarely assessed. Such assessment is complicated by several methodological challenges, including the simultaneous evaluation of multiple endpoints, complex multi‐level models, small sample sizes, and uncertainty in nuisance parameters. In response to these challenges, we describe a Bayesian approach to the design and analysis of external pilot trials. We show how progression decisions can be made by minimizing the expected value of a loss function, defined over the whole parameter space to allow for preferences and trade‐offs between multiple parameters to be articulated and used in the decision‐making process. The assessment of preferences is kept feasible by using a piecewise constant parametrization of the loss function, the parameters of which are chosen at the design stage to lead to desirable operating characteristics. We describe a flexible, yet computationally intensive, nested Monte Carlo algorithm for estimating operating characteristics. The method is used to revisit the design of an external pilot trial of a complex intervention designed to increase the physical activity of care home residents.
Blood for transfusion is a frequently used clinical intervention, and is also a costly and limited resource with risks. Many transfusions are given to stable and non-bleeding patients despite no ...clear evidence of benefit from clinical studies. Audit and feedback (A&F) is widely used to improve the quality of healthcare, including appropriate use of blood. However, its effects are often inconsistent, indicating the need for coordinated research including more head-to-head trials comparing different ways of delivering feedback. A programmatic series of research projects, termed the 'Audit and Feedback INterventions to Increase evidence-based Transfusion practIcE' (AFFINITIE) programme, aims to test different ways of developing and delivering feedback within an existing national audit structure.
The evaluation will comprise two linked 2×2 factorial, cross-sectional cluster-randomised controlled trials. Each trial will estimate the effects of two feedback interventions, 'enhanced content' and 'enhanced follow-on support', designed in earlier stages of the AFFINITIE programme, compared to current practice. The interventions will be embedded within two rounds of the UK National Comparative Audit of Blood Transfusion (NCABT) focusing on patient blood management in surgery and use of blood transfusions in patients with haematological malignancies. The unit of randomisation will be National Health Service (NHS) trust or health board. Clusters providing care relevant to the audit topics will be randomised following each baseline audit (separately for each trial), with stratification for size (volume of blood transfusions) and region (Regional Transfusion Committee). The primary outcome for each topic will be the proportion of patients receiving a transfusion coded as unnecessary. For each audit topic a linked, mixed-method fidelity assessment and cost-effectiveness analysis will be conducted in parallel to the trial.
AFFINITIE involves a series of studies to explore how A&F may be refined to change practice including two cluster randomised trials linked to national audits of transfusion practice. The methodology represents a step-wise increment in study design to more fully evaluate the effects of two enhanced feedback interventions on patient- and trust-level clinical, cost, safety and process outcomes.
http://www.isrctn.com/ISRCTN15490813.
The quality of care for people with dementia in care homes is of concern. Interventions that can improve care outcomes are required.
To investigate the clinical effectiveness and cost-effectiveness ...of Dementia Care Mapping™ (DCM) for reducing agitation and improving care outcomes for people living with dementia in care homes, versus usual care.
A pragmatic, cluster randomised controlled trial with an open-cohort design, follow-up at 6 and 16 months, integrated cost-effectiveness analysis and process evaluation. Clusters were not blinded to allocation. The primary end point was completed by staff proxy and independent assessors.
Stratified randomisation of 50 care homes to the intervention and control groups on a 3 : 2 ratio by type, size, staff exposure to dementia training and recruiting hub.
Fifty care homes were randomised (intervention,
= 31; control,
= 19), with 726 residents recruited at baseline and a further 261 recruited after 16 months. Care homes were eligible if they recruited a minimum of 10 residents, were not subject to improvement notices, had not used DCM in the previous 18 months and were not participating in conflicting research. Residents were eligible if they lived there permanently, had a formal diagnosis of dementia or a score of 4+ on the Functional Assessment Staging Test of Alzheimer's Disease, were proficient in English and were not terminally ill or permanently cared for in bed. All homes were audited on the delivery of dementia and person-centred care awareness training. Those not reaching a minimum standard were provided training ahead of randomisation. Eighteen homes took part in the process evaluation.
Two staff members from each intervention home were trained to use DCM and were asked to carry out three DCM cycles; the first was supported by an external expert.
The primary outcome was agitation (Cohen-Mansfield Agitation Inventory), measured at 16 months. Secondary outcomes included resident behaviours and quality of life.
There were 675 residents in the final analysis (intervention,
= 388; control,
= 287). There was no evidence of a difference in agitation levels between the treatment arms. The adjusted mean difference in Cohen-Mansfield Agitation Inventory score was -2.11 points, being lower in the intervention group than in the control (95% confidence interval -4.66 to 0.44;
= 0.104; adjusted intracluster correlation coefficient: control = 0, intervention = 0.001). The sensitivity analyses results supported the primary analysis. No differences were detected in any of the secondary outcomes. The health economic analyses indicated that DCM was not cost-effective. Intervention adherence was problematic; only 26% of homes completed more than their first DCM cycle. Impacts, barriers to and facilitators of DCM implementation were identified.
The primary completion of resident outcomes was by staff proxy, owing to self-report difficulties for residents with advanced dementia. Clusters were not blinded to allocation, although supportive analyses suggested that any reporting bias was not clinically important.
There was no benefit of DCM over control for any outcomes. The implementation of DCM by care home staff was suboptimal compared with the protocol in the majority of homes.
Alternative models of DCM implementation should be considered that do not rely solely on leadership by care home staff.
Current Controlled Trials ISRCTN82288852.
This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in
; Vol. 24, No. 16. See the NIHR Journals Library website for further project information.
Introduction
Haemarthrosis is a clinical feature of haemophilia leading to haemarthropathy. The ankle joint is most commonly affected, resulting in significant pain, disability and a reduction in ...health‐related quality of life. Footwear and orthotic devices are effective in other diseases that affect the foot and ankle, such as rheumatoid arthritis, but little is known about their effect in haemophilia.
Aims
To review the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia.
Methods
A systematic literature review was conducted. Two review authors independently screened studies for inclusion and appraised methodological quality using Joanna Briggs Institute Critical Appraisal checklists. A narrative analysis was undertaken.
Results
Ten studies involving 271 male participants were eligible for inclusion. All studies were quasi‐experimental; three employed a within‐subject design. Two studies included an independent comparison or control group. A range of footwear and orthotic devices were investigated. Limited evidence from non‐randomised studies suggested that footwear and orthotic devices improve the number of ankle joint bleeding episodes, gait parameters and patient‐reported pain.
Conclusion
This review demonstrates a lack of robust evidence regarding the efficacy and effectiveness of footwear and orthotic devices in the management of ankle joint haemarthrosis and haemarthropathy in haemophilia. Methodological heterogeneities and limitations with the study designs, small sample sizes and limited follow‐up of participants exist. Future studies utilising randomised designs, larger sample sizes, long‐term follow‐up and validated patient‐reported outcome measures are needed to inform the clinical management of ankle joint haemarthrosis and haemarthropathy.
Early phase trials of complex interventions currently focus on assessing the feasibility of a large randomised control trial and on conducting pilot work. Assessing the efficacy of the proposed ...intervention is generally discouraged, due to concerns of underpowered hypothesis testing. In contrast, early assessment of efficacy is common for drug therapies, where phase II trials are often used as a screening mechanism to identify promising treatments. In this paper, we outline the challenges encountered in extending ideas developed in the phase II drug trial literature to the complex intervention setting. The prevalence of multiple endpoints and clustering of outcome data are identified as important considerations, having implications for timely and robust determination of optimal trial design parameters. The potential for Bayesian methods to help to identify robust trial designs and optimal decision rules is also explored.
Two accepted designs exist for parallel-group cluster-randomised trials (CRTs). Closed-cohort designs follow the same individuals over time with a single recruitment period before randomisation, but ...face challenges in settings with high attrition. (Repeated) cross-sectional designs recruit at one or more timepoints before and/or after randomisation, collecting data from different individuals present in the cluster at these timepoints, but are unsuitable for assessment of individual change over time. An 'open-cohort' design allows individual follow-up with recruitment before and after cluster-randomisation, but little literature exists on acceptability to inform their use in CRTs.
To document the views and experiences of expert trialists to identify: a) Design and conduct challenges with established parallel-group CRT designs,b) Perceptions of potential benefits and barriers to implementation of open-cohort CRTs,c) Methods for minimising, and investigating the impact of, bias in open-cohort CRTs.
Qualitative consultation via two expert workshops including triallists (n = 24) who had worked on CRTs over a range of settings. Workshop transcripts were analysed using Descriptive Thematic Analysis utilising inductive and deductive coding.
Two central organising concepts were developed. Design and conduct challenges with established CRT designs confirmed that current CRT designs are unable to deal with many of the complex research and intervention circumstances found in some trial settings (e.g. care homes). Perceptions of potential benefits and barriers of open cohort designs included themes on: approaches to recruitment; data collection; analysis; minimising/investigating the impact of bias; and how open-cohort designs might address or present CRT design challenges. Open-cohort designs were felt to provide a solution for some of the challenges current CRT designs present in some settings.
Open-cohort CRT designs hold promise for addressing the challenges associated with standard CRT designs. Research is needed to provide clarity around definition and guidance on application.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Depression is common in dementia but the evidence base for appropriate drug treatment is sparse and equivocal. We aimed to assess efficacy and safety of two of the most commonly ...prescribed drugs, sertraline and mirtazapine, compared with placebo. Methods We undertook the parallel-group, double-blind, placebo-controlled, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial in participants from old-age psychiatry services in nine centres in England. Participants were eligible if they had probable or possible Alzheimer's disease, depression (lasting ≥4 weeks), and a Cornell scale for depression in dementia (CSDD) score of 8 or more. Participants were ineligible if they were clinically critical (eg, suicide risk), contraindicated to study drugs, on antidepressants, in another trial, or had no carer. The clinical trials unit at King's College London (UK) randomly allocated participants with a computer-generated block randomisation sequence, stratified by centre, with varying block sizes, in a 1:1:1 ratio to receive sertraline (target dose 150 mg per day), mirtazapine (45 mg), or placebo (control group), all with standard care. The primary outcome was reduction in depression (CSDD score) at 13 weeks (outcomes to 39 weeks were also assessed), assessed with a mixed linear-regression model adjusted for baseline CSDD, time, and treatment centre. This study is registered, number ISRCTN88882979 and EudraCT 2006-000105-38. Findings Decreases in depression scores at 13 weeks did not differ between 111 controls and 107 participants allocated to receive sertraline (mean difference 1·17, 95% CI −0·23 to 2·58; p=0·10) or mirtazapine (0·01, −1·37 to 1·38; p=0·99), or between participants in the mirtazapine and sertraline groups (1·16, −0·25 to 2·57; p=0·11); these findings persisted to 39 weeks. Fewer controls had adverse reactions (29 of 111 26%) than did participants in the sertraline group (46 of 107, 43%; p=0·010) or mirtazapine group (44 of 108, 41%; p=0·031), and fewer serious adverse events rated as severe (p=0·003). Five patients in every group died by week 39. Interpretation Because of the absence of benefit compared with placebo and increased risk of adverse events, the present practice of use of these antidepressants, with usual care, for first-line treatment of depression in Alzheimer's disease should be reconsidered. Funding UK National Institute of Health Research HTA Programme.
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