Facilitating Activity and Self-management for people with Arthritic knee, hip or lower back pain (FASA): A cluster randomised controlled trial.

BACKGROUND: Chronic musculoskeletal pain including osteoarthritis (OA) can significantly limit the functional independence of individuals. The spine and hip and knee are predominantly affected; management guidelines for each recommend exercise and education to support self-management. OBJECTIVES: This study investigated the effectiveness of a generic exercise and self-management intervention for people over-50 with hip/knee OA and/or lower back pain compared to continued GP management. DESIGN: Single blind, cluster randomised controlled trial. METHOD: Participants who had previously consulted with hip/knee OA and/or chronic lower back pain were recruited from 45 GP practices in SW England. Practices were randomly allocated to receive continued GP care (control) or continued GP care and a 6-week group exercise and self-management intervention facilitated by a physiotherapist and located in a community-based physiotherapy department. The primary outcome measure was the Dysfunction Index of the Short Musculoskeletal Functional Assessment (DI-SMFA) measured at six month post-rehabilitation. RESULTS: 349 participants were recruited and allocated to the intervention (n = 170) or control (n = 179) arms; the attrition rate was 13% at the 6 month primary end-point. One minor adverse event in the intervention group that required no medical input was reported. Intervention arm participants reported better function at 6 months compared with continued GP management alone (-3.01 difference in DI-SMFA [95%CI -5.25, -0.76], p = 0.01). CONCLUSIONS: A generic exercise and self-management intervention resulted in statistically significant changes in function after six-months compared with GP management alone, but clinical significance of these findings is less clear. This may be an effective way of managing group interventions for lower limb OA and chronic lower back pain.

How to design a dose-finding study using the continual reassessment method.

INTRODUCTION: The continual reassessment method (CRM) is a model-based design for phase I trials, which aims to find the maximum tolerated dose (MTD) of a new therapy. The CRM has been shown to be more accurate in targeting the MTD than traditional rule-based approaches such as the 3 + 3 design, which is used in most phase I trials. Furthermore, the CRM has been shown to assign more trial participants at or close to the MTD than the 3 + 3 design. However, the CRM's uptake in clinical research has been incredibly slow, putting trial participants, drug development and patients at risk. Barriers to increasing the use of the CRM have been identified, most notably a lack of knowledge amongst clinicians and statisticians on how to apply new designs in practice. No recent tutorial, guidelines, or recommendations for clinicians on conducting dose-finding studies using the CRM are available. Furthermore, practical resources to support clinicians considering the CRM for their trials are scarce. METHODS: To help overcome these barriers, we present a structured framework for designing a dose-finding study using the CRM. We give recommendations for key design parameters and advise on conducting pre-trial simulation work to tailor the design to a specific trial. We provide practical tools to support clinicians and statisticians, including software recommendations, and template text and tables that can be edited and inserted into a trial protocol. We also give guidance on how to conduct and report dose-finding studies using the CRM. RESULTS: An initial set of design recommendations are provided to kick-start the design process. To complement these and the additional resources, we describe two published dose-finding trials that used the CRM. We discuss their designs, how they were conducted and analysed, and compare them to what would have happened under a 3 + 3 design. CONCLUSIONS: The framework and resources we provide are aimed at clinicians and statisticians new to the CRM design. Provision of key resources in this contemporary guidance paper will hopefully improve the uptake of the CRM in phase I dose-finding trials.

Adaptive designs in clinical trials: why use them, and how to run and report them.

Adaptive designs can make clinical trials more flexible by utilising results accumulating in the trial to modify the trial's course in accordance with pre-specified rules. Trials with an adaptive design are often more efficient, informative and ethical than trials with a traditional fixed design since they often make better use of resources such as time and money, and might require fewer participants. Adaptive designs can be applied across all phases of clinical research, from early-phase dose escalation to confirmatory trials. The pace of the uptake of adaptive designs in clinical research, however, has remained well behind that of the statistical literature introducing new methods and highlighting their potential advantages. We speculate that one factor contributing to this is that the full range of adaptations available to trial designs, as well as their goals, advantages and limitations, remains unfamiliar to many parts of the clinical community. Additionally, the term adaptive design has been misleadingly used as an all-encompassing label to refer to certain methods that could be deemed controversial or that have been inadequately implemented.We believe that even if the planning and analysis of a trial is undertaken by an expert statistician, it is essential that the investigators understand the implications of using an adaptive design, for example, what the practical challenges are, what can (and cannot) be inferred from the results of such a trial, and how to report and communicate the results. This tutorial paper provides guidance on key aspects of adaptive designs that are relevant to clinical triallists. We explain the basic rationale behind adaptive designs, clarify ambiguous terminology and summarise the utility and pitfalls of adaptive designs. We discuss practical aspects around funding, ethical approval, treatment supply and communication with stakeholders and trial participants. Our focus, however, is on the interpretation and reporting of results from adaptive design trials, which we consider vital for anyone involved in medical research. We emphasise the general principles of transparency and reproducibility and suggest how best to put them into practice.

A phase-I trial of pre-operative, margin intensive, stereotactic body radiation therapy for pancreatic cancer: the 'SPARC' trial protocol.

BACKGROUND: Standard therapy for borderline-resectable pancreatic cancer in the UK is surgery with adjuvant chemotherapy, but rates of resection with clear margins are unsatisfactory and overall survival remains poor. Meta-analysis of single-arm studies shows the potential of neo-adjuvant chemo-radiotherapy but the relative radio-resistance of pancreatic cancer means the efficacy of conventional dose schedules is limited. Stereotactic radiotherapy achieves sufficient accuracy and precision to enable pre-operative margin-intensive dose escalation with the goal of increasing rates of clear resection margins and local disease control. METHODS/DESIGN: SPARC is a "rolling-six" design single-arm study to establish the maximum tolerated dose for margin-intensive stereotactic radiotherapy before resection of pancreatic cancer at high risk of positive resection margins. Eligible patients will have histologically or cytologically proven pancreatic cancer defined as borderline-resectable per National Comprehensive Cancer Network criteria or operable tumour in contact with vessels increasing the risk of positive margin. Up to 24 patients will be recruited from up to 5 treating centres and a 'rolling-six' design is utilised to minimise delays and facilitate ongoing recruitment during dose-escalation. Radiotherapy will be delivered in 5 daily fractions and surgery, if appropriate, will take place 5-6 weeks after radiotherapy. The margin-intense radiotherapy concept includes a systematic method to define the target volume for a simultaneous integrated boost in the region of tumour-vessel infiltration, and up to 4 radiotherapy dose levels will be investigated. Maximum tolerated dose is defined as the highest dose at which no more than 1 of 6 patients or 0 of 3 patients experience a dose limiting toxicity. Secondary endpoints include resection rate, resection margin status, response rate, overall survival and progression free survival at 12 and 24 months. Translational work will involve exploratory analyses of the cytological and humoral immunological responses to stereotactic radiotherapy in pancreatic cancer. Radiotherapy quality assurance of target definition and radiotherapy planning is enforced with pre-trial test cases and on-trial review. Recruitment began in April 2015. DISCUSSION: This prospective multi-centre study aims to establish the maximum tolerated dose of pre-operative margin-intensified stereotactic radiotherapy in pancreatic cancer at high risk of positive resection margins with a view to subsequent definitive comparison with other neoadjuvant treatment options. TRIAL REGISTRATION: ISRCTN14138956 . Funded by CRUK.

The Prognostic Value of Patient-Reported Outcome Data in Patients With Colorectal Hepatic Metastases Who Underwent Surgery.

INTRODUCTION: Patient-reported outcomes (PROs) are critical to evaluate clinically effective treatments and evidence suggests that PROs might predict survival. The prognostic value of PROs in patients with isolated liver metastases from colorectal cancer (CRC) who undergo surgery is unclear. In this study we investigated whether baseline PROs are prognostic in this patient group. PATIENTS AND METHODS: From April 2004 to May 2007, consecutive patients who underwent curative resection of CRC liver metastases completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ)-C30 and QLQ-LMC21 questionnaires before surgery. Patients were followed until death or data were censored on April 9, 2012. Cox proportional hazards models were used to assess the effect of PROs on survival controlling for predefined clinical covariates. Models were simplified using a backwards stepwise approach and model utility appraised using the Harrell C and Somers D statistics and bootstrap methods. RESULTS: Two hundred thirty-two patients underwent liver resection and 101 (43.5%) survived 5 years. Multivariate analysis controlling for relevant clinical covariates showed that a 10-point improvement in baseline global quality of life scores was associated with a 54% improvement in survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.33-0.63; P < .001), and a clinically significant weight loss was associated with 75% worse survival (HR, 1.75; 95% CI, 1.20-2.55; P = .004). Smaller effects were noted for worsening abdominal pain, taste problems, and fatigue (30%-38% poorer survival). Results of bootstrap resampling suggested that global health and weight loss most reliably predicted survival. CONCLUSION: Results of this study demonstrated that patients who reported worse baseline global quality of life and increased weight loss before liver resection for CRC liver metastases had significantly poorer survival. These findings if externally validated might be used to inform patients, and could also influence treatment planning and advise follow-up strategies and supportive care.

Clinical effectiveness and cost-effectiveness of cognitive behavioural therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: the CoBalT randomised controlled trial.

BACKGROUND: Only one-third of patients with depression respond fully to treatment with antidepressant medication. However, there is little robust evidence to guide the management of those whose symptoms are 'treatment resistant'. OBJECTIVE: The CoBalT trial examined the clinical effectiveness and cost-effectiveness of cognitive behavioural therapy (CBT) as an adjunct to usual care (including pharmacotherapy) for primary care patients with treatment-resistant depression (TRD) compared with usual care alone. DESIGN: Pragmatic, multicentre individually randomised controlled trial with follow-up at 3, 6, 9 and 12 months. A subset took part in a qualitative study investigating views and experiences of CBT, reasons for completing/not completing therapy, and usual care for TRD. SETTING: General practices in Bristol, Exeter and Glasgow, and surrounding areas. PARTICIPANTS: Patients aged 18-75 years who had TRD [on antidepressants for ≥ 6 weeks, had adhered to medication, Beck Depression Inventory, 2nd version (BDI-II) score of ≥ 14 and fulfilled the International Classification of Diseases and Related Health Problems, Tenth edition criteria for depression]. Individuals were excluded who (1) had bipolar disorder/psychosis or major alcohol/substance abuse problems; (2) were unable to complete the questionnaires; or (3) were pregnant, as were those currently receiving CBT/other psychotherapy/secondary care for depression, or who had received CBT in the past 3 years. INTERVENTIONS: Participants were randomised, using a computer-generated code, to usual care or CBT (12-18 sessions) in addition to usual care. MAIN OUTCOME MEASURES: The primary outcome was 'response', defined as ≥ 50% reduction in depressive symptoms (BDI-II score) at 6 months compared with baseline. Secondary outcomes included BDI-II score as a continuous variable, remission of symptoms (BDI-II score of < 10), quality of life, anxiety and antidepressant use at 6 and 12 months. Data on health and social care use, personal costs, and time off work were collected at 6 and 12 months. Costs from these three perspectives were reported using a cost-consequence analysis. A cost-utility analysis compared health and social care costs with quality adjusted life-years. RESULTS: A total of 469 patients were randomised (intervention: n = 234; usual care: n = 235), with 422 participants (90%) and 396 (84%) followed up at 6 and 12 months. Ninety-five participants (46.1%) in the intervention group met criteria for 'response' at 6 months compared with 46 (21.6%) in the usual-care group {odds ratio [OR] 3.26 [95% confidence interval (CI) 2.10 to 5.06], p < 0.001}. In repeated measures analyses using data from 6 and 12 months, the OR for 'response' was 2.89 (95% CI 2.03 to 4.10, p < 0.001) and for a secondary 'remission' outcome (BDI-II score of < 10) 2.74 (95% CI 1.82 to 4.13, p < 0.001). The mean cost of CBT per participant was £ 910, the incremental health and social care cost £ 850, the incremental QALY gain 0.057 and incremental cost-effectiveness ratio £ 14,911. Forty participants were interviewed. Patients described CBT as challenging but helping them to manage their depression; listed social, emotional and practical reasons for not completing treatment; and described usual care as mainly taking medication. CONCLUSIONS: Among patients who have not responded to antidepressants, augmenting usual care with CBT is effective in reducing depressive symptoms, and these effects, including outcomes reflecting remission, are maintained over 12 months. The intervention was cost-effective based on the National Institute for Health and Care Excellence threshold. Patients may experience CBT as difficult but effective. Further research should evaluate long-term effectiveness, as this would have major implications for the recommended treatment of depression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38231611.

Applying optimal model selection in principal stratification for causal inference.

Noncompliance to treatment allocation is a key source of complication for causal inference. Efficacy estimation is likely to be compounded by the presence of noncompliance in both treatment arms of clinical trials where the intention-to-treat estimate provides a biased estimator for the true causal estimate even under homogeneous treatment effects assumption. Principal stratification method has been developed to address such posttreatment complications. The present work extends a principal stratification method that adjusts for noncompliance in two-treatment arms trials by developing model selection for covariates predicting compliance to treatment in each arm. We apply the method to analyse data from the Esprit study, which was conducted to ascertain whether unopposed oestrogen (hormone replacement therapy) reduced the risk of further cardiac events in postmenopausal women who survive a first myocardial infarction. We adjust for noncompliance in both treatment arms under a Bayesian framework to produce causal risk ratio estimates for each principal stratum. For mild values of a sensitivity parameter and using separate predictors of compliance in each arm, principal stratification results suggested that compliance with hormone replacement therapy only would reduce the risk for death and myocardial reinfarction by about 47% and 25%, respectively, whereas compliance with either treatment would reduce the risk for death by 13% and reinfarction by 60% among the most compliant. However, the results were sensitive to the user-defined sensitivity parameter.

Performance of statistical methods for analysing survival data in the presence of non-random compliance.

Noncompliance often complicates estimation of treatment efficacy from randomized trials. Under random noncompliance, per protocol analyses or even simple regression adjustments for noncompliance, could be adequate for causal inference, but special methods are needed when noncompliance is related to risk. For survival data, Robins and Tsiatis introduced the semi-parametric structural Causal Accelerated Life Model (CALM) which allows time-dependent departures from randomized treatment in either arm and relates each observed event time to a potential event time that would have been observed if the control treatment had been given throughout the trial. Alternatively, Loeys and Goetghebeur developed a structural Proportional Hazards (C-Prophet) model for when there is all-or-nothing noncompliance in the treatment arm only. Whitebiet al. proposed a 'complier average causal effect' method for Proportional Hazards estimation which allows time-dependent departures from randomized treatment in the active arm. A time-invariant version of this estimator (CHARM) consists of a simple adjustment to the Intention-to-Treat hazard ratio estimate. We used simulation studies mimicking a randomized controlled trial of active treatment versus control with censored time-to-event data, and under both random and non-random time-dependent noncompliance, to evaluate performance of these methods in terms of 95 per cent confidence interval coverage, bias and root mean square errors (RMSE). All methods performed well in terms of bias, even the C-Prophet used after treating time-varying compliance as all-or-nothing. Coverage of the latter method, as implemented in Stata, was too low. The CALM method performed best in terms of bias and coverage but had the largest RMSE.

The use of fixed appliances in the UK: a survey of specialist orthodontists.

OBJECTIVE: To investigate the use of fixed appliances in the UK. DESIGN: Prospective postal questionnaire. SETTING: UK. PARTICIPANTS: All members of the General Dental Council Specialist List in Orthodontics still in active practice and not in training posts. METHOD: A preemptive letter of explanation was sent inviting orthodontists to participate in the survey. The questionnaire was subsequently posted to 935 specialists. Data analysis investigated differences in clinical practice related to varying provider groups, level of operator experience and geographical region. RESULTS: The response rate achieved was 66.3%. A majority of orthodontists routinely used the 0.022 inch pre-adjusted edgewise system, standard size Siamese pattern stainless steel brackets, conventionally ligated and bonded using standard etch and light cured composite. Nickel titanium and stainless steel were the most popular archwire materials. Anchorage was supported routinely by palatal and lingual arches in up to 25% and by headgear in over a third of respondents. Newer innovations showed variable popularity. Self-etching primer was used routinely by one-third of respondents with 11% use of self-ligating brackets. Banding of first molars was preferred by over 60% of clinicians. Bone screw implants were used by only 0.2% of respondents. Clinicians with less than 10 years experience used more headgear, light curing, MBT prescription and molar bonding. Operators with over 20 years experience used more chemically cured bonding, Roth prescription, banded first molars, 0.018 inch slot size and Tip-Edge(TM), with less use of headgear. Fixed appliance use differed from that reported in the US with lower use in the UK of standard edgewise and Roth systems, aesthetic, miniaturised and 0.018 inch slot brackets and rapid maxillary expansion. CONCLUSION: Most UK orthodontic specialists routinely used the 0.022 inch pre-adjusted edgewise system with standard size Siamese steel brackets bonded using standard etch and light cured composite with conventional ligation. Variations were seen between different provider groups, types of treatment funding, levels of operator seniority and geographical regions. Differences were noted particularly in the use of bracket prescription and design, types of molar attachment and anchorage control.