Impact of dairy fat manipulation on endothelial function and lipid regulation in human aortic endothelial cells exposed to human plasma samples: an in vitro investigation from the RESET study.

PURPOSE: Longer-term intake of fatty acid (FA)-modified dairy products (SFA-reduced, MUFA-enriched) was reported to attenuate postprandial endothelial function in humans, relative to conventional (control) dairy. Thus, we performed an in vitro study in human aortic endothelial cells (HAEC) to investigate mechanisms underlying the effects observed in vivo. METHODS: This sub-study was conducted within the framework of the RESET study, a 12-week randomised controlled crossover trial with FA-modified and control dairy diets. HAEC were incubated for 24 h with post-intervention plasma samples from eleven adults (age: 57.5 ± 6.0 years; BMI: 25.7 ± 2.7 kg/m2) at moderate cardiovascular disease risk following representative sequential mixed meals. Markers of endothelial function and lipid regulation were assessed. RESULTS: Relative to control, HAEC incubation with plasma following the FA-modified treatment increased postprandial NOx production (P-interaction = 0.019), yet up-regulated relative E-selectin mRNA gene expression (P-interaction = 0.011). There was no impact on other genes measured. CONCLUSION: Incubation of HAEC with human plasma collected after longer-term dairy fat manipulation had a beneficial impact on postprandial NOx production. Further ex vivo research is needed to understand the impact of partial replacement of SFA with unsaturated fatty acids in dairy foods on pathways involved in endothelial function.

Effect of fat-reformulated dairy food consumption on postprandial flow-mediated dilatation and cardiometabolic risk biomarkers compared with conventional dairy: a randomized controlled trial.

BACKGROUND: Longer-term consumption of SFA-reduced, MUFA-enriched dairy products has been reported to improve fasting flow-mediated dilatation (FMD). Yet, their impact on endothelial function in the postprandial state warrants investigation. OBJECTIVES: The aim was to compare the impact of a fatty acid (FA) modified with a conventional (control) dairy diet on the postprandial %FMD (primary outcome) and systemic cardiometabolic responses to representative meals, and retrospectively explore whether treatment effects differ by apolipoprotein E (APOE) or endothelial NO synthase (eNOS) Glu298Asp gene polymorphisms. METHODS: In a crossover-design randomized controlled study, 52 adults with moderate cardiovascular disease risk consumed dairy products [38% of total energy intake (%TE) from fat: FA-modified (target: 16%TE SFAs; 14%TE MUFAs) or control (19%TE SFAs; 11%TE MUFAs)] for 12 wk, separated by an 8-wk washout. Blood sampling and FMD measurements (0-480 min) were performed pre- and postintervention after sequential mixed meals that were representative of the assigned dairy diets (0 min, ∼50 g fat; 330 min, ∼30 g fat). RESULTS: Relative to preintervention (∆), the FA-modified dairy diet and meals (treatment) attenuated the increase in the incremental AUC (iAUC), but not AUC, for the %FMD response observed with the conventional treatment (-135 ± 69% vs. +199 ± 82% × min; P = 0.005). The ∆ iAUC, but not AUC, for the apoB response decreased after the FA-modified treatment yet increased after the conventional treatment (-4 ± 3 vs. +3 ± 3 mg/mL × min; P = 0.004). The ∆ iAUC decreased for plasma total SFAs (P = 0.003) and trans 18:1 (P < 0.0001) and increased for cis-MUFAs (P < 0.0001) following the conventional relative to the FA-modified treatment. No treatment × APOE or eNOS genotype interactions were evident for any outcome. CONCLUSIONS: This study provides novel insights into the longer-term effects of FA-modified dairy food consumption on postprandial cardiometabolic responses.

Expected Value of Sample Information to Guide the Design of Group Sequential Clinical Trials.

INTRODUCTION: Adaptive designs allow changes to an ongoing trial based on prespecified early examinations of accrued data. Opportunities are potentially being missed to incorporate health economic considerations into the design of these studies. METHODS: We describe how to estimate the expected value of sample information for group sequential design adaptive trials. We operationalize this approach in a hypothetical case study using data from a pilot trial. We report the expected value of sample information and expected net benefit of sampling results for 5 design options for the future full-scale trial including the fixed-sample-size design and the group sequential design using either the Pocock stopping rule or the O'Brien-Fleming stopping rule with 2 or 5 analyses. We considered 2 scenarios relating to 1) using the cost-effectiveness model with a traditional approach to the health economic analysis and 2) adjusting the cost-effectiveness analysis to incorporate the bias-adjusted maximum likelihood estimates of trial outcomes to account for the bias that can be generated in adaptive trials. RESULTS: The case study demonstrated that the methods developed could be successfully applied in practice. The results showed that the O'Brien-Fleming stopping rule with 2 analyses was the most efficient design with the highest expected net benefit of sampling in the case study. CONCLUSIONS: Cost-effectiveness considerations are unavoidable in budget-constrained, publicly funded health care systems, and adaptive designs can provide an alternative to costly fixed-sample-size designs. We recommend that when planning a clinical trial, expected value of sample information methods be used to compare possible adaptive and nonadaptive trial designs, with appropriate adjustment, to help justify the choice of design characteristics and ensure the cost-effective use of research funding. HIGHLIGHTS: Opportunities are potentially being missed to incorporate health economic considerations into the design of adaptive clinical trials.Existing expected value of sample information analysis methods can be extended to compare possible group sequential and nonadaptive trial designs when planning a clinical trial.We recommend that adjusted analyses be presented to control for the potential impact of the adaptive designs and to maintain the accuracy of the calculations.This approach can help to justify the choice of design characteristics and ensure the cost-effective use of limited research funding.

Recommendations for designing and analysing multi-arm non-inferiority trials: a review of methodology and current practice.

BACKGROUND AND PURPOSE: Multi-arm non-inferiority (MANI) trials, here defined as non-inferiority trials with multiple experimental treatment arms, can be useful in situations where several viable treatments exist for a disease area or for testing different dose schedules. To maintain the statistical integrity of such trials, issues regarding both design and analysis must be considered, from both the multi-arm and the non-inferiority perspectives. Little guidance currently exists on exactly how these aspects should be addressed and it is the aim of this paper to provide recommendations to aid the design of future MANI trials. METHODS: A comprehensive literature review covering four databases was conducted to identify publications associated with MANI trials. Literature was split into methodological and trial publications in order to investigate the required design and analysis considerations for MANI trials and whether they were being addressed in practice. RESULTS: A number of issues were identified that if not properly addressed, could lead to issues with the FWER, power or bias. These ranged from the structuring of trial hypotheses at the design stage to the consideration of potential heterogeneous treatment variances at the analysis stage. One key issue of interest was adjustment for multiple testing at the analysis stage. There was little consensus concerning whether more powerful p value adjustment methods were preferred to approximate adjusted CIs when presenting and interpreting the results of MANI trials. We found 65 examples of previous MANI trials, of which 31 adjusted for multiple testing out of the 39 that were adjudged to require it. Trials generally preferred to utilise simple, well-known methods for study design and analysis and while some awareness was shown concerning FWER inflation and choice of power, many trials seemed not to consider the issues and did not provide sufficient definition of their chosen design and analysis approaches. CONCLUSIONS: While MANI trials to date have shown some awareness of the issues raised within this paper, very few have satisfied the criteria of the outlined recommendations. Going forward, trials should consider the recommendations in this paper and ensure they clearly define and reason their choices of trial design and analysis techniques.

Postprandial Fatty Acid Profile, but Not Cardiometabolic Risk Markers, Is Modulated by Dairy Fat Manipulation in Adults with Moderate Cardiovascular Disease Risk: The Randomized Controlled REplacement of SaturatEd fat in dairy on Total cholesterol (RESET) Study.

BACKGROUND: Chronic consumption of dairy products with an SFA-reduced, MUFA-enriched content was shown to impact favorably on brachial artery flow-mediated dilatation (FMD). However, their acute effect on postprandial cardiometabolic risk biomarkers requires investigation. OBJECTIVE: The effects of sequential high-fat mixed meals rich in fatty acid (FA)-modified or conventional (control) dairy products on postprandial FMD (primary outcome) and systemic cardiometabolic biomarkers in adults with moderate cardiovascular risk (≥50% above the population mean) were compared. METHODS: In a randomized crossover trial, 52 participants [mean ± SEM age: 53 ± 2 y; BMI (kg/m2) 25.9 ± 0.5] consumed a high-dairy-fat breakfast (0 min; ∼50 g total fat: modified: 25 g SFAs, 20 g MUFAs; control: 32 g SFAs, 12 g MUFAs) and lunch (330 min; ∼30 g total fat; modified: 15 g SFAs, 12 g MUFAs; control: 19 g SFAs, 7 g MUFAs). Blood samples were obtained before and until 480 min after breakfast, with FMD assessed at 0, 180, 300, and 420 min. Data were analyzed by linear mixed models. RESULTS: Postprandial changes in cardiometabolic biomarkers were comparable between the different dairy meals, with the exception of a tendency for a 4% higher AUC for the %FMD response following the modified-dairy-fat meals (P = 0.075). Plasma total lipid FA analysis revealed that incremental AUC responses were 53% lower for total SFAs, 214% and 258% higher for total cis-MUFAs (predominantly cis-9 18:1), and trans-18:1, respectively, following the modified relative to the control dairy meals (all P < 0.0001). CONCLUSIONS: In adults at moderate cardiovascular risk, acute consumption of sequential high-fat meals containing FA-modified dairy products had little impact on postprandial endothelial function or systemic cardiometabolic biomarkers, but a differential effect on the plasma total lipid FA profile, relative to conventional dairy fat meals.This trial was registered at clinicaltrials.gov as NCT02089035.

A platform trial in practice: adding a new experimental research arm to the ongoing confirmatory FLAIR trial in chronic lymphocytic leukaemia.

BACKGROUND: The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success. METHODS: FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial. RESULTS: The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres. CONCLUSIONS: FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community. TRIAL REGISTRATION: ISRCTN Registry ISRCTN01844152 . Registered on August 08, 2014.

Assessment of the information theory approach to evaluating time-to-event surrogate and true endpoints in a meta-analytic setting.

In many disease areas, commonly used long-term clinical endpoints are becoming increasingly difficult to implement due to long follow-up times and/or increased costs. Shorter-term surrogate endpoints are urgently needed to expedite drug development, the evaluation of which requires robust and reliable statistical methodology to drive meaningful clinical conclusions about the strength of relationship with the true long-term endpoint. This paper uses a simulation study to explore one such previously proposed method, based on information theory, for evaluation of time to event surrogate and long-term endpoints, including the first examination within a meta-analytic setting of multiple clinical trials with such endpoints. The performance of the information theory method is examined for various scenarios including different dependence structures, surrogate endpoints, censoring mechanisms, treatment effects, trial and sample sizes, and for surrogate and true endpoints with a natural time-ordering. Results allow us to conclude that, contrary to some findings in the literature, the approach provides estimates of surrogacy that may be substantially lower than the true relationship between surrogate and true endpoints, and rarely reach a level that would enable confidence in the strength of a given surrogate endpoint. As a result, care is needed in the assessment of time to event surrogate and true endpoints based only on this methodology.

The adaptive designs CONSORT extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites."To maximise the benefit to society, you need to not just do research but do it well" Douglas G Altman.

The Adaptive designs CONSORT Extension (ACE) statement: a checklist with explanation and elaboration guideline for reporting randomised trials that use an adaptive design.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits.

Point and interval estimation in two-stage adaptive designs with time to event data and biomarker-driven subpopulation selection.

In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two-stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous.

How can health economics be used in the design and analysis of adaptive clinical trials? A qualitative analysis.

INTRODUCTION: Adaptive designs offer a flexible approach, allowing changes to a trial based on examinations of the data as it progresses. Adaptive clinical trials are becoming a popular choice, as the prudent use of finite research budgets and accurate decision-making are priorities for healthcare providers around the world. The methods of health economics, which aim to maximise the health gained for money spent, could be incorporated into the design and analysis of adaptive clinical trials to make them more efficient. We aimed to understand the perspectives of stakeholders in health technology assessments to inform recommendations for the use of health economics in adaptive clinical trials. METHODS: A qualitative study explored the attitudes of key stakeholders-including researchers, decision-makers and members of the public-towards the use of health economics in the design and analysis of adaptive clinical trials. Data were collected using interviews and focus groups (29 participants). A framework analysis was used to identify themes in the transcripts. RESULTS: It was considered that answering the clinical research question should be the priority in a clinical trial, notwithstanding the importance of cost-effectiveness for decision-making. Concerns raised by participants included handling the volatile nature of cost data at interim analyses; implementing this approach in global trials; resourcing adaptive trials which are designed and adapted based on health economic outcomes; and training stakeholders in these methods so that they can be implemented and appropriately interpreted. CONCLUSION: The use of health economics in the design and analysis of adaptive clinical trials has the potential to increase the efficiency of health technology assessments worldwide. Recommendations are made concerning the development of methods allowing the use of health economics in adaptive clinical trials, and suggestions are given to facilitate their implementation in practice.

Reformulation initiative for partial replacement of saturated with unsaturated fats in dairy foods attenuates the increase in LDL cholesterol and improves flow-mediated dilatation compared with conventional dairy: the randomized, controlled REplacement of SaturatEd fat in dairy on Total cholesterol (RESET) study.

BACKGROUND: Modifying dairy fat composition by increasing the MUFA content is a potential strategy to reduce dietary SFA intake for cardiovascular disease (CVD) prevention in the population. OBJECTIVES: To determine the effects of consuming SFA-reduced, MUFA-enriched (modified) dairy products, compared with conventional dairy products (control), on the fasting cholesterol profile (primary outcome), endothelial function assessed by flow-mediated dilatation (FMD; key secondary outcome), and other cardiometabolic risk markers. METHODS: A double-blind, randomized, controlled crossover 12-wk intervention was conducted. Participants with a 1.5-fold higher (moderate) CVD risk than the population mean replaced habitual dairy products with study products (milk, cheese, and butter) to achieve a high-fat, high-dairy isoenergetic daily dietary exchange [38% of total energy intake (%TE) from fat: control (dietary target: 19%TE SFA; 11%TE MUFA) and modified (16%TE SFA; 14%TE MUFA) diet]. RESULTS: Fifty-four participants (57.4% men; mean ± SEM age: 52 ± 3 y; BMI: 25.8 ± 0.5 kg/m2) completed the study. The modified diet attenuated the rise in fasting LDL cholesterol observed with the control diet (0.03 ± 0.06 mmol/L and 0.19 ± 0.05 mmol/L, respectively; P = 0.03). Relative to baseline, the %FMD response increased after the modified diet (0.35% ± 0.15%), whereas a decrease was observed after the control diet (-0.51% ± 0.15%; P< 0.0001). In addition, fasting plasma nitrite concentrations increased after the modified diet, yet decreased after the control diet (0.02 ± 0.01 µmol/L and -0.03 ± 0.02 µmol/L, respectively; P = 0.01). CONCLUSIONS: In adults at moderate CVD risk, consumption of a high-fat diet containing SFA-reduced, MUFA-enriched dairy products for 12 wk showed beneficial effects on fasting LDL cholesterol and endothelial function compared with conventional dairy products. Our findings indicate that fatty acid modification of dairy products may have potential as a public health strategy aimed at CVD risk reduction. This trial was registered at clinicaltrials.gov as NCT02089035.

Comparison of Bayesian and frequentist group-sequential clinical trial designs.

BACKGROUND: There is a growing interest in the use of Bayesian adaptive designs in late-phase clinical trials. This includes the use of stopping rules based on Bayesian analyses in which the frequentist type I error rate is controlled as in frequentist group-sequential designs. METHODS: This paper presents a practical comparison of Bayesian and frequentist group-sequential tests. Focussing on the setting in which data can be summarised by normally distributed test statistics, we evaluate and compare boundary values and operating characteristics. RESULTS: Although Bayesian and frequentist group-sequential approaches are based on fundamentally different paradigms, in a single arm trial or two-arm comparative trial with a prior distribution specified for the treatment difference, Bayesian and frequentist group-sequential tests can have identical stopping rules if particular critical values with which the posterior probability is compared or particular spending function values are chosen. If the Bayesian critical values at different looks are restricted to be equal, O'Brien and Fleming's design corresponds to a Bayesian design with an exceptionally informative negative prior, Pocock's design to a Bayesian design with a non-informative prior and frequentist designs with a linear alpha spending function are very similar to Bayesian designs with slightly informative priors.This contrasts with the setting of a comparative trial with independent prior distributions specified for treatment effects in different groups. In this case Bayesian and frequentist group-sequential tests cannot have the same stopping rule as the Bayesian stopping rule depends on the observed means in the two groups and not just on their difference. In this setting the Bayesian test can only be guaranteed to control the type I error for a specified range of values of the control group treatment effect. CONCLUSIONS: Comparison of frequentist and Bayesian designs can encourage careful thought about design parameters and help to ensure appropriate design choices are made.

A Review of Clinical Trials With an Adaptive Design and Health Economic Analysis.

OBJECTIVE: An adaptive design uses data collected as a clinical trial progresses to inform modifications to the trial. Hence, adaptive designs and health economics aim to facilitate efficient and accurate decision making. Nevertheless, it is unclear whether the methods are considered together in the design, analysis, and reporting of trials. This review aims to establish how health economic outcomes are used in the design, analysis, and reporting of adaptive designs. METHODS: Registered and published trials up to August 2016 with an adaptive design and health economic analysis were identified. The use of health economics in the design, analysis, and reporting was assessed. Summary statistics are presented and recommendations formed based on the research team's experiences and a practical interpretation of the results. RESULTS: Thirty-seven trials with an adaptive design and health economic analysis were identified. It was not clear whether the health economic analysis accounted for the adaptive design in 17/37 trials where this was thought necessary, nor whether health economic outcomes were used at the interim analysis for 18/19 of trials with results. The reporting of health economic results was suboptimal for the (17/19) trials with published results. CONCLUSIONS: Appropriate consideration is rarely given to the health economic analysis of adaptive designs. Opportunities to use health economic outcomes in the design and analysis of adaptive trials are being missed. Further work is needed to establish whether adaptive designs and health economic analyses can be used together to increase the efficiency of health technology assessments without compromising accuracy.

Kidney Safety Assessment: Current Practices in Drug Development.

The kidney's role as a major route of metabolism and clearance of xenobiotics and its ability to concentrate the glomerular filtrate make it particularly vulnerable to drug-induced toxicity. Improving kidney safety is an active area of research and there is a need in early stages of drug development for strategies and model systems to reliably identify nephrotoxic compounds and sufficiently characterize mechanisms to support drug pipeline decision making. In later stages of drug development the value of sensitive translational biomarkers to monitor kidney toxicity across species in nonclinical and clinical settings is gaining realization. Various tools and strategies for kidney safety assessment have emerged over the past decade; however, there is currently no clear consensus on best practices for their use across different phases of drug development. Here, we provide perspective on the scope of this problem in drug development, and an overview of progress in the field of kidney safety including several informative case examples of kidney toxicity de-risking scenarios encountered in the pharmaceutical industry. The results of a survey of pharmaceutical companies conducted through the Innovation and Quality Drug Safety consortium provides additional insight into recent experiences with compound attrition and different de-risking approaches across the industry.

Comparing the MAMS framework with the combination method in multi-arm adaptive trials with binary outcomes.

In multi-arm adaptive trials, several treatments are assessed simultaneously and accumulating data are used to inform decisions about the trial, such as whether treatments are dropped or continued. Different methodological approaches have been developed for such trials and research has compared the performance of different subsets of these. One particular approach, for which we use the acronym MAMS(R), has generally not been included in these comparisons because control of the family-wise error rate (FWER) could not be guaranteed. Recently, the MAMS(R) approach has been extended to facilitate the generation of efficient designs which strongly control the FWER. We consider multi-arm two-stage trials with binary outcomes and propose parameterising treatment effects using the log odds ratio. We conduct a simulation study comparing the extended MAMS(R) framework with the well-established combination method both for trials where a different outcome is used for mid-trial analysis and for trials where the same outcome is used throughout. We show how the MAMS(R) framework compares favourably only in scenarios where the same outcome is used. We propose a hybrid selection rule within MAMS(R) methodology and demonstrate that this makes it possible to use the MAMS(R) framework in trials incorporating comparative treatment selection.

Development process of a consensus-driven CONSORT extension for randomised trials using an adaptive design.

BACKGROUND: Adequate reporting of adaptive designs (ADs) maximises their potential benefits in the conduct of clinical trials. Transparent reporting can help address some obstacles and concerns relating to the use of ADs. Currently, there are deficiencies in the reporting of AD trials. To overcome this, we have developed a consensus-driven extension to the CONSORT statement for randomised trials using an AD. This paper describes the processes and methods used to develop this extension rather than detailed explanation of the guideline. METHODS: We developed the guideline in seven overlapping stages: 1) Building on prior research to inform the need for a guideline; 2) A scoping literature review to inform future stages; 3) Drafting the first checklist version involving an External Expert Panel; 4) A two-round Delphi process involving international, multidisciplinary, and cross-sector key stakeholders; 5) A consensus meeting to advise which reporting items to retain through voting, and to discuss the structure of what to include in the supporting explanation and elaboration (E&E) document; 6) Refining and finalising the checklist; and 7) Writing-up and dissemination of the E&E document. The CONSORT Executive Group oversaw the entire development process. RESULTS: Delphi survey response rates were 94/143 (66%), 114/156 (73%), and 79/143 (55%) in rounds 1, 2, and across both rounds, respectively. Twenty-seven delegates from Europe, the USA, and Asia attended the consensus meeting. The main checklist has seven new and nine modified items and six unchanged items with expanded E&E text to clarify further considerations for ADs. The abstract checklist has one new and one modified item together with an unchanged item with expanded E&E text. The E&E document will describe the scope of the guideline, the definition of an AD, and some types of ADs and trial adaptations and explain each reporting item in detail including case studies. CONCLUSIONS: We hope that making the development processes, methods, and all supporting information that aided decision-making transparent will enhance the acceptability and quick uptake of the guideline. This will also help other groups when developing similar CONSORT extensions. The guideline is applicable to all randomised trials with an AD and contains minimum reporting requirements.

Point estimation following two-stage adaptive threshold enrichment clinical trials.

Recently, several study designs incorporating treatment effect assessment in biomarker-based subpopulations have been proposed. Most statistical methodologies for such designs focus on the control of type I error rate and power. In this paper, we have developed point estimators for clinical trials that use the two-stage adaptive enrichment threshold design. The design consists of two stages, where in stage 1, patients are recruited in the full population. Stage 1 outcome data are then used to perform interim analysis to decide whether the trial continues to stage 2 with the full population or a subpopulation. The subpopulation is defined based on one of the candidate threshold values of a numerical predictive biomarker. To estimate treatment effect in the selected subpopulation, we have derived unbiased estimators, shrinkage estimators, and estimators that estimate bias and subtract it from the naive estimate. We have recommended one of the unbiased estimators. However, since none of the estimators dominated in all simulation scenarios based on both bias and mean squared error, an alternative strategy would be to use a hybrid estimator where the estimator used depends on the subpopulation selected. This would require a simulation study of plausible scenarios before the trial.

Replacement of dietary saturated fat with unsaturated fats increases numbers of circulating endothelial progenitor cells and decreases numbers of microparticles: findings from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study.

Background: Endothelial progenitor cells (EPCs) and microparticles are emerging as novel markers of cardiovascular disease (CVD) risk, which could potentially be modified by dietary fat. We have previously shown that replacing dietary saturated fatty acids (SFAs) with monounsaturated or n-6 (ω-6) polyunsaturated fatty acids (MUFAs or PUFAs, respectively) improved lipid biomarkers, blood pressure, and markers of endothelial activation, but their effects on circulating EPCs and microparticles are unclear. Objective: The Dietary Intervention and VAScular function (DIVAS) Study investigated the replacement of 9.5-9.6% of total energy (%TE) contributed by SFAs with MUFAs or n-6 PUFAs for 16 wk on EPC and microparticle numbers in United Kingdom adults with moderate CVD risk. Design: In this randomized, controlled, single-blind, parallel-group dietary intervention, men and women aged 21-60 y (n = 190) with moderate CVD risk (≥50% above the population mean) consumed 1 of three 16-wk isoenergetic diets. Target compositions for total fat, SFAs, MUFAs, and n-6 PUFAs (%TE) were as follows: SFA-rich diet (36:17:11:4; n = 64), MUFA-rich diet (36:9:19:4; n = 62), and n-6 PUFA-rich diet (36:9:13:10; n = 66). Circulating EPC, endothelial microparticle (EMP), and platelet microparticle (PMP) numbers were analyzed by flow cytometry. Dietary intake, vascular function, and other cardiometabolic risk factors were determined at baseline. Results: Relative to the SFA-rich diet, MUFA- and n-6 PUFA-rich diets decreased EMP (-47.3%, -44.9%) respectively and PMP (-36.8%, -39.1%) numbers (overall diet effects, P < 0.01). The MUFA-rich diet increased EPC numbers (+28.4%; P = 0.023). Additional analyses that used stepwise regression models identified the augmentation index (measuring arterial stiffness determined by pulse-wave analysis) as an independent predictor of baseline EPC and microparticle numbers. Conclusions: Replacement of 9.5-9.6%TE dietary SFAs with MUFAs increased EPC numbers, and replacement with either MUFAs or n-6 PUFAs decreased microparticle numbers, suggesting beneficial effects on endothelial repair and maintenance. Further studies are warranted to determine the mechanisms underlying the favorable effects on EPC and microparticle numbers after SFA replacement. This trial was registered at www.clinicaltrials.gov as NCT01478958.

Age-Related Changes in the Natural Killer Cell Response to Seasonal Influenza Vaccination Are Not Influenced by a Synbiotic: a Randomised Controlled Trial.

Natural killer (NK) cells are an important component of the immune response to influenza infection, but are subject to alteration during aging, which may play a role in impaired response to infection and vaccination in older people. Enhancement of NK cell activity could, therefore, present a means to improve the immune response to vaccination in older subjects, and pre- and probiotics offer an opportunity to modulate antiviral defenses via alteration of the gut microbiota. This study investigated the effect of a novel probiotic, Bifidobacterium longum bv. infantis CCUG 52486, combined with a prebiotic, gluco-oligosaccharide (B. longum + Gl-OS), on the NK cell response to seasonal influenza vaccination in young and older subjects in a double-blind, randomized controlled trial. There were significant effects of aging on NK cell phenotype, the most notable of which were an increase in CD56dim cells, mainly reflected in the CD16+ subset, a decrease in CD56bright cells, mainly reflected in the CD16- subset, and greater expression of the immunosenescence marker, CD57, on NK cell subsets. However, these changes only partially translated to differences in NK cell activity, observed as trends toward reduced NK cell activity in older subjects when analyzed on a per cell basis. Influenza vaccination increased the proportion of CD56bright cells and decreased the proportion of CD56dim cells, in young, but not older subjects. Although NK cell activity in response to vaccination was not significantly different between the young and older subjects, low post-vaccination NK cell activity was associated with poor seroconversion in only the older subjects. There was no influence of the synbiotic on NK cell phenotype or activity, either before or after influenza vaccination. In conclusion, aging is associated with marked alteration of the phenotype of the NK cell population and there was evidence of an impaired NK cell response to influenza vaccination in older subjects. The effects of aging on NK cell phenotype and activity could not be offset by B. longum + Gl-OS. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01066377.