A comparison of methods for treatment selection in seamless phase II/III clinical trials incorporating information on short-term endpoints

In an adaptive seamless phase II/III clinical trial interim analysis data are used for treatment selection, enabling resources to be focussed on comparison of more effective treatment(s) with a control. In this paper we compare two methods recently proposed to enable use of short-term endpoint data for decision-making at the interim analysis. The comparison focusses on the power and the probability of correctly identifying the most promising treatment. We show that the choice of method depends on how well short-term data predict the best treatment, which may be measured by the correlation between treatment effects on short-term and long-term endpoints

Operational loads on a tidal turbine due to environmental conditions

Accurate assessment of the fatigue life of tidal stream turbines and components requires prediction of the unsteady loading of turbine components over a wide range of frequencies. This study focuses on the influence of ambient turbulence, velocity shear and the approach taken to model wave kinematics, on the variation of thrust load imposed on the rotor shaft and supporting tower. Load cycles are assessed based on sea-state occurrence data taken over a five month period for a case study site. The influence of each environmental parameter on component loading is evaluated and the impact on material design parameters assessed. Alternative approaches are considered for modelling turbulent loading and wave loading. The frequency variation of loads due to turbulence are scaled from experimental data from trials of a three-bladed horizontal axis turbine of 1.2 m diameter on a bed-mounted supporting structure. Frequency dependent wave loading is estimated by a relative form of the drag term of the widely used equation of Morison et al. (1950), with the depth decay of kinematics modelled by linear wave theory. Over the five month interval considered a ten year design life can be obtained with a lower design load by accounting for variation of turbulence intensity that occurs during each tidal cycle. This is expected to vary further with the approach taken to model the onset turbulence. A component can also be designed for lower loads over the same time period if irregular waves are modelled instead of regular

Assessment of Dependency of Unsteady Onset Flow and Resultant Tidal Turbine Fatigue Loads on Measurement Position at a Tidal Site

From MDPI via Jisc Publications RouterHistory: accepted 2021-08-25, pub-electronic 2021-09-02Publication status: PublishedFunder: Interreg; Grant(s): TIGERThis work determines the variation in the fatigue loading on a tidal turbine at two depth positions and two different locations within a site. Site data were obtained at the European Marine Energy Centre, EMEC, test facility in Scotland, which has been compiled at the University of Edinburgh. The turbine modelled is the 18m Diameter DEEP-gen 1MW horizontal axis turbine. A blade element method is combined with a synthetic turbulence inflow to determine forces along the blade over a period of five tidal cycles. The focus is on establishing the difference between the loads at one tidal site, with an emphasis on the variety of turbulent conditions, with the onset flow fluctuations as great as 17% and the average integral lengthscales varying from 11 to 14 m at hub height. Fatigue loading is assessed using damage equivalent loads, with a 30% variation between turbine positions and 32% between turbine locations within a site, for one design case. When long term loading is assessed, a 41% difference is found for aggregated loads for a near surface turbine and a 28% difference for a near bed turbine

Adaptive clinical trials incorporating treatment selection and evaluation: methodology and application in progressive multiple sclerosis

In progressive multiple sclerosis (MS) irreversible disability often takes many years to accumulate as a result prolonged trials are required to assess the benefits of therapies. There is a need to understand the relationship between short-term outcome measures such as MRI endpoints and long-term clinical outcomes in progression to determine the evolution of the disease early on. Thus, the common phase I-II-III paradigm for clinical trial design with separate trials for each phase may not be appropriate

Analysis of the kinetic energy recovery behind a tidal stream turbine for various submergence levels

Tidal turbines are commonly deployed at sea sites with water depths of up to 50 m to ease their deployment and quick maintenance operations. In these relatively shallow water depth conditions, the vertical expansion of tidal stream turbine wakes is restricted by the proximity of the rotor blades to the bottom bed and free-surface layer. These physical constrains can lead to changes in the flow mechanisms that drive momentum recovery behind the turbines, e.g. limiting the vertical fluxes of velocity. Understanding how the wake recovers depending on the submergence ratio is of utmost importance to designing the future multi-row tidal turbine arrays. Here, we adopt high-fidelity Large-Eddy Simulations (LES) with an Actuator Line Method (ALM) to represent the turbine's rotor to analyse the mean flow and transport equation for mean kinetic energy (MKE) behind a single bottom-fixed tidal turbine for four water depth values. Our results show that the close proximity of the turbine blade tip to the free-surface can notably constrain the wake expansion, with very shallow conditions leading to a limited contribution to the MKE replenishment of the turbulent momentum exchange over the vertical direction. Conversely, under such shallow conditions, the horizontal flux of MKE is enhanced over the lateral boundaries of the downstream wake. Our study evidences that the ratio of water depth to turbine diameter plays a relevant role in future tidal arrays and needs to be correctly accounted for in numerical models to provide reliable results

Adaptive seamless clinical trials using early outcomes for treatment or subgroup selection : methods, simulation model and their implementation in R

Adaptive seamless designs combine confirmatory testing, a domain of phase III trials, with features such as treatment or subgroup selection, typically associated with phase II trials. They promise to increase the efficiency of development programmes of new drugs, for example, in terms of sample size and/or development time. It is well acknowledged that adaptive designs are more involved from a logistical perspective and require more upfront planning, often in the form of extensive simulation studies, than conventional approaches. Here, we present a framework for adaptive treatment and subgroup selection using the same notation, which links the somewhat disparate literature on treatment selection on one side and on subgroup selection on the other. Furthermore, we introduce a flexible and efficient simulation model that serves both designs. As primary endpoints often take a long time to observe, interim analyses are frequently informed by early outcomes. Therefore, all methods presented accommodate interim analyses informed by either the primary outcome or an early outcome. The R package asd, previously developed to simulate designs with treatment selection, was extended to include subgroup selection (so‐called adaptive enrichment designs). Here, we describe the functionality of the R package asd and use it to present some worked‐up examples motivated by clinical trials in chronic obstructive pulmonary disease and oncology. The examples both illustrate various features of the R package and provide insights into the operating characteristics of adaptive seamless studies