Design of Major Randomized Trials: Part 3 of a 4-Part Series on Statistics for Clinical Trials.

This paper provides practical guidance on the fundamentals of design for major randomized controlled trials. Topics covered include the choice of patients, choice of treatment and control groups, choice of primary and secondary endpoints, methods of randomization, appropriate use of blinding, and determination of trial size. Insights are made with reference to contemporary major trials in cardiology

A multicentre, patient- and assessor-blinded, non-inferiority, randomised and controlled phase II trial to compare standard and torque teno virus-guided immunosuppression in kidney transplant recipients in the first year after transplantation:TTVguideIT

Background: Immunosuppression after kidney transplantation is mainly guided via plasma tacrolimus trough level, which cannot sufficiently predict allograft rejection and infection. The plasma load of the non-pathogenic and highly prevalent torque teno virus (TTV) is associated with the immunosuppression of its host. Non-interventional studies suggest the use of TTV load to predict allograft rejection and infection. The primary objective of the current trial is to demonstrate the safety, tolerability and preliminary efficacy of TTV-guided immunosuppression. Methods: For this purpose, a randomised, controlled, interventional, two-arm, non-inferiority, patient- and assessor-blinded, investigator-driven phase II trial was designed. A total of 260 stable, low-immunological-risk adult recipients of a kidney graft with tacrolimus-based immunosuppression and TTV infection after month 3 post-transplantation will be recruited in 13 academic centres in six European countries. Subjects will be randomised in a 1:1 ratio (allocation concealment) to receive tacrolimus either guided by TTV load or according to the local centre standard for 9 months. The primary composite endpoint includes the occurrence of infections, biopsy-proven allograft rejection, graft loss, or death. The main secondary endpoints include estimated glomerular filtration rate, graft rejection detected by protocol biopsy at month 12 post-transplantation (including molecular microscopy), development of de novo donor-specific antibodies, health-related quality of life, and drug adherence. In parallel, a comprehensive biobank will be established including plasma, serum, urine and whole blood. The date of the first enrolment was August 2022 and the planned end is April 2025. Discussion: The assessment of individual kidney transplant recipient immune function might enable clinicians to personalise immunosuppression, thereby reducing infection and rejection. Moreover, the trial might act as a proof of principle for TTV-guided immunosuppression and thus pave the way for broader clinical applications, including as guidance for immune modulators or disease-modifying agents.</p

Wind Damage in Maine Forests: Trends and Vulnerability Assessment

The likelihood of windthrow or windsnap occurring in a forest stand includes numerous factors; however, past research suggests that these factors can be grouped into four broad categories: regional climate, topographic exposure, soil properties and stand characteristics (Mitchell, 1995). Of the three categories, stand characteristics are most commonly and easily modified through forest management. Vulnerability to wind damage in Maine may increase in the future because of three trends influencing stand conditions. One, Maine forests contain a considerable amount of balsam fir and red spruce, tree species that are considered particularly susceptible to wind damage. Two, extensive areas regenerated after the 1970\u27s and 1980\u27s era spruce budworm outbreak are maturing. Three, partial removals currently account for over 74 percent of the area harvested annually in the state (McWilliams et al. 2005). Two approaches to augment our understanding of the interaction between forest management and wind damage vulnerability in Maine forests were developed The first approach combined information from the base of scientific wind disturbance literature with more localized information from Maine\u27s forest resource managers. Forest resource professionals were surveyed through phone calls and professional meetings to gather information about wind damage over their careers. The second approach developed a general vulnerability to wind damage model that reflects topographic exposure (distance limited TOPEX (Ruel et al. 1997), restricted rooting depth, elevation, and stand characteristics (height, density, edge, treatment history, and species composition). Results of the first approach reveal serious limitations in information about wind damage statewide. However, numerous patterns and trends were identified. Damage differs by storm type and storms impact the state on a continuum of storm intensity, frequency, and scale. Numerous factors influence the damage potential of these wind events on forests. These factors include topographic exposure, soil conditions and stand characteristics. Damaging storms appear to originate from the southwest most frequently and impact softwoods more severely than hardwoods. Frequent low-intensity winds tend to eliminate softwoods from hardwood dominated stands. The general vulnerability to wind damage model is based on Mitchell\u27s (1998) conceptual windthrow triangle and is built from eight component variables describing stand, soil, and topographic characteristics. The model is built and calibrated from composite variables which combine the component variables into distinct site and stand components. The model was tested on a 40,800 hectare forest area in northern Maine with spatially explicit wind damage records. To avoid problems with spatial autocorrelation ten random samples were drawn from the study area and evaluated individually with a Mann-Whitney non-parametric comparison of means test (alpha 0.05). Results from the ten samples were pooled, and a one sample comparison of means t-test was used to analyze the consistency of the results from the ten individual samples (alpha 0.05). The final model identifies significant and consistent differences between damaged and undamaged areas (p-value 0.000). When evaluated individually, not all model components were significantly different (e.g., density, edge, exposure and species composition). Variables describing thinning, stand height, and elevation had the greatest differences between means of the populations of damaged and undamaged stands in the study area. The general model developed proved useful on the study area and by design should be transferable to diverse regions throughout the state

Challenging Issues in Clinical Trial Design: Part 4 of a 4-Part Series on Statistics for Clinical Trials.

As a sequel to last week's paper on the fundamentals of clinical trial design, this paper tackles related controversial issues: noninferiority trials, the value of factorial designs, the importance and challenges of strategy trials, Data Monitoring Committees (including when to stop a trial early), and the role of adaptive designs. All topics are illustrated by relevant examples from cardiology trials

A trial to evaluate the effect of the sodium–glucose co‐transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA‐HF)

Background: Sodium–glucose co‐transporter 2 (SGLT2) inhibitors have been shown to reduce the risk of incident heart failure hospitalization in individuals with type 2 diabetes who have, or are at high risk of, cardiovascular disease. Most patients in these trials did not have heart failure at baseline and the effect of SGLT2 inhibitors on outcomes in individuals with established heart failure (with or without diabetes) is unknown. Design and methods: The Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure trial (DAPA‐HF) is an international, multicentre, parallel group, randomized, double‐blind, study in patients with chronic heart failure, evaluating the effect of dapagliflozin 10 mg, compared with placebo, given once daily, in addition to standard care, on the primary composite outcome of a worsening heart failure event (hospitalization or equivalent event, i.e. an urgent heart failure visit) or cardiovascular death. Patients with and without diabetes are eligible and must have a left ventricular ejection fraction ≤ 40%, a moderately elevated N‐terminal pro B‐type natriuretic peptide level, and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2. The trial is event‐driven, with a target of 844 primary outcomes. Secondary outcomes include the composite of total heart failure hospitalizations (including repeat episodes), and cardiovascular death and patient‐reported outcomes. A total of 4744 patients have been randomized. Conclusions: DAPA‐HF will determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in a broad spectrum of patients with heart failure and reduced ejection fraction

Quantitative Methods for Improving Medical Decision-Making

Innovation in causal inference and implementation of electronic health record systems are rapidly transforming medical care. In this dissertation, we present three examples in which use of methods in causal inference and large electronic health record data address existign challenges in medical decision-making. First, we use principles of causal inference to examine the structure of randomized trials of biomarker targets, which have produced divergent results and controversial clinical guidelines for management of hypertension and other chronic diseases. We discuss four key threats to the validity of trials of this design. Second, we use methods in causal inference for adjustment of time-varying confounding to estimate the effect of time-varying treatment strategies for hypertension. We report the results of a study which used longitudinal electronic health record data from a prospective virtual cohort of veterans. Third, we use individual-level electronic health record data to predict the need for critical care resources during surges in COVID-19 cases, to aid hospital administrators with resource allocation in periods of crisis

The interplay between glycaemia and cardiovascular disease

Numerous large clinical trials of cardiovascular risk lowering agents have been conducted in the hope of reducing the excess cardiovascular risk found in patients with diabetes mellitus. However, the relationship between glucose and cardiovascular disease remains complex and various areas require further study. Even in patients with diabetes, an individual’s cardiovascular risk is highly variable depending on other clinical characteristics, the assumption that glucose is a continuous risk factor has often been based on weak evidence from relatively short studies, the effect of commonly used cardiovascular risk lowering agents often has unexpected effects on new-onset diabetes and statins have not yet been studied in detail, and whether glucose-lowering therapies actually reduce cardiovascular risk has remained a contentious issue despite the conduct of large clinical trials. Furthermore, the realisation that the combination of diabetes and chronic heart failure, a common complication of coronary disease, carries a particularly poor prognosis suggests that prediction of diabetes in this population may be clinically valuable. Aims: I aimed to address the following different, though related, questions regarding glucose and cardiovascular disease: 1. Are anticipated cardiovascular event rates in diabetes endpoint trials actually achieved? Is it possible to easily identify patients with diabetes that are at particular risk of events (information that is crucial to investigators who wish to design clinical trials)? 2. Is fasting glucose concentration independently and convincingly associated with increased risk of cardiovascular events in those without diabetes? 3. Do statins, the most commonly prescribed medications worldwide, have any influence on the risk of developing diabetes? 4. If statins do indeed affect new-onset diabetes, is there any evidence of a dose-dependent effect? 5. How effectively can clinicians predict the development of diabetes in chronic heart failure using commonly recorded clinical information? 6. Does intensive glucose-lowering therapy reduce the risk of cardiovascular events in patients with diabetes? Methods: To address these questions three approaches were used, namely (i) systematic review of previously published data from large cardiovascular endpoint trials conducted in patients with diabetes; (ii) analyses of existing datasets from two large clinical trials; (iii) meta-analyses of published and unpublished data from large clinical trials. Results and interpretation: 1. In a systematic review of 29 trials with 116,790 patients with diabetes, it was apparent that the majority of large cardiovascular endpoint trials conducted in patients with diabetes vastly overestimated the likely cardiovascular event rates in initial power calculations. Introduction of (i) previous history of cardiovascular disease and/or (ii) presence of proteinuria, as binary trial inclusion criteria, provides a simple and effective way to identify patients at high risk, something that is sought after for appropriate clinical trial power calculations. 2. In a population of 6,447 men without diabetes at baseline, impaired fasting glycaemia was not associated with increased risk of cardiovascular events over 15 years. Similarly, when baseline fasting glucose values <7.0mmol/L were split into quintiles, patients in the highest quintile were at similar risk of all vascular endpoints to those in the lowest. By contrast, impaired fasting glycaemia was a powerful risk factor for developing diabetes. 3. A meta-analysis of published and unpublished data from most large placebo- and standard care-controlled statin trials, which included data for 91,140 trial participants without diabetes at baseline, revealed that statin therapy is associated with a 9% higher risk for developing diabetes. 4. A subsequent meta-analysis of unpublished data from five large trials comparing intensive statin therapy with moderate dose therapy found that intensive statin therapy increases the risk of developing diabetes by 12% compared to moderate dosing, in keeping with a dose-dependent effect. While statin therapy remains effective at reducing cardiovascular risk it appears that patients on statin therapy, especially those on intensive regimens, should be considered for diabetes screening. 5. In an analysis of data for 1,620 patients with chronic heart failure and no diabetes at baseline studied for 2.8 years, the strongest predictors of new-onset diabetes were similar to those in the general population. In particular, the combination of HbA1c and body mass index provided a c-statistic of 0.79. 6. In a meta-analysis of published data for 33,040 patients with diabetes who participated in clinical trials comparing intensive glucose-lowering therapy with standard therapy, non-fatal myocardial infarctions were reduced by 17% on intensive therapy but no other cardiovascular endpoints were reduced. Death rates were similar in both groups. Conclusion: While diabetes is associated with excess cardiovascular risk, risk varies considerably depending on other risk factors. Glucose is, at best, a weak risk factor in those without diabetes, and glucose-lowering in patients with diabetes has only yielded a modest reduction in non-fatal myocardial infarctions but not other events; by contrast, measures of glycaemia are powerful predictors of new-onset diabetes in patients with and without chronic heart failure. Finally, the relationship between glucose and vascular disease is further complicated by the fact that numerous medications designed to reduce cardiovascular risk appear to have surprising effects on the risk of developing diabetes

Nutrition and dietary intake and their association with mortality and hospitalization in adults with chronic kidney disease treated with hemodialysis

Adults receiving hemodialysis still experience high mortality rates. Several interventions that address the typical cardiovascular risk factors which are almost universally present in people with ESKD have been introduced. These interventions unfortunately do not significantly improve health outcomes in such populations. Nutrition and dietary patterns are potential factors influencing health in other health settings but poorly explored in the setting of ESKD. The aim of this body of work was to evaluate the association between exposure to different nutrients and dietary patterns and the risk of mortality (all-cause and cause-specific) and hospital admissions (any, and cause-specific) in adults with chronic kidney disease and specifically those with or end stage kidney disease receiving hemodialysis for renal replacement therapy. This project focused on understanding the impact of diet and nutrient intake, on CKD and ESKD through a comprehensive and systematic series of literature reviews and the design and conduct of the first large scale multinational primary cohort study to explore the association between nutrition (dietary intake) and clinical adverse events in the setting of hemodialysis

Preconditioning Shields Against Vascular Events in Surgery (SAVES), a multicentre feasibility trial of preconditioning against adverse events in major vascular surgery: study protocol for a randomised control trial.

Patients undergoing vascular surgery procedures constitute a 'high-risk' group. Fatal and disabling perioperative complications are common. Complications arise via multiple aetiological pathways. This mechanistic redundancy limits techniques to reduce complications that target individual mechanisms, for example, anti-platelet agents. Remote ischaemic preconditioning (RIPC) induces a protective phenotype in at-risk tissue, conferring protection against ischaemia-reperfusion injury regardless of the trigger. RIPC is induced by repeated periods of upper limb ischaemia-reperfusion produced using a blood pressure cuff. RIPC confers some protection against cardiac and renal injury during major vascular surgery in proof-of-concept trials. Similar trials suggest benefit during cardiac surgery. Several uncertainties remain in advance of a full-scale trial to evaluate clinical efficacy. We propose a feasibility trial to fully evaluate arm-induced RIPC's ability to confer protection in major vascular surgery, assess the incidence of a proposed composite primary efficacy endpoint and evaluate the intervention's acceptability to patients and staff

Options for basing Dietary Reference Intakes (DRIs) on chronic disease endpoints: report from a joint US-/Canadian-sponsored working group.

Dietary Reference Intakes (DRIs) are used in Canada and the United States in planning and assessing diets of apparently healthy individuals and population groups. The approaches used to establish DRIs on the basis of classical nutrient deficiencies and/or toxicities have worked well. However, it has proved to be more challenging to base DRI values on chronic disease endpoints; deviations from the traditional framework were often required, and in some cases, DRI values were not established for intakes that affected chronic disease outcomes despite evidence that supported a relation. The increasing proportions of elderly citizens, the growing prevalence of chronic diseases, and the persistently high prevalence of overweight and obesity, which predispose to chronic disease, highlight the importance of understanding the impact of nutrition on chronic disease prevention and control. A multidisciplinary working group sponsored by the Canadian and US government DRI steering committees met from November 2014 to April 2016 to identify options for addressing key scientific challenges encountered in the use of chronic disease endpoints to establish reference values. The working group focused on 3 key questions: 1) What are the important evidentiary challenges for selecting and using chronic disease endpoints in future DRI reviews, 2) what intake-response models can future DRI committees consider when using chronic disease endpoints, and 3) what are the arguments for and against continuing to include chronic disease endpoints in future DRI reviews? This report outlines the range of options identified by the working group for answering these key questions, as well as the strengths and weaknesses of each option