A product of independent beta probabilities dose escalation design for dual-agent phase I trials.

Dual-agent trials are now increasingly common in oncology research, and many proposed dose-escalation designs are available in the statistical literature. Despite this, the translation from statistical design to practical application is slow, as has been highlighted in single-agent phase I trials, where a 3 + 3 rule-based design is often still used. To expedite this process, new dose-escalation designs need to be not only scientifically beneficial but also easy to understand and implement by clinicians. In this paper, we propose a curve-free (nonparametric) design for a dual-agent trial in which the model parameters are the probabilities of toxicity at each of the dose combinations. We show that it is relatively trivial for a clinician's prior beliefs or historical information to be incorporated in the model and updating is fast and computationally simple through the use of conjugate Bayesian inference. Monotonicity is ensured by considering only a set of monotonic contours for the distribution of the maximum tolerated contour, which defines the dose-escalation decision process. Varied experimentation around the contour is achievable, and multiple dose combinations can be recommended to take forward to phase II. Code for R, Stata and Excel are available for implementation.We would like to acknowledge funding from the UK Medical Research Council (grant code U1052.00.014) for this work. We would also like to thank the reviewers for providing some excellent suggestions to help improve the manuscript.This is the final published version. It first appeared at http://onlinelibrary.wiley.com/doi/10.1002/sim.6434/abstract

Designs for adding a treatment arm to an ongoing clinical trial.

BACKGROUND:For many disease areas, there are often treatments in different stages of the development process. We consider the design of a two-arm parallel group trial where it is planned to add a new experimental treatment arm during the trial. This could potentially save money, patients, time and resources; however, the addition of a treatment arm creates a multiple comparison problem. Current practice in trials when a new treatment arm has been added is to compare the new treatment only to controls randomised concurrently, and this is the setting we consider here. Furthermore, for standard multi-arm trials, optimal allocation randomises a larger number of patients to the control arm than to each experimental treatment arm. METHODS:In this paper we propose an adaptive design, the aim of which is to adapt the sample size of the trial when the new treatment arm is added to control the family-wise error rate (FWER) in the strong sense, whilst maintaining the marginal power of each treatment-to-control comparison at the level of the original study. We explore optimal allocation for designs where a treatment arm is added with the aim of increasing the overall power of the study, where we define the overall power to be the probability of detecting all treatments that are better than the control. RESULTS AND CONCLUSIONS:An increase in sample size is required to maintain the marginal power for each pairwise comparison when adding a treatment arm if control of the FWER is required at the level of the type I error in the original study. When control of the FWER is required in a single trial which adds an additional experimental treatment arm, but control of the FWER is not required in separate trials, depending on the design characteristics, it may be better to run a separate trial for each experimental treatment, in terms of the number of patients required. An increase in overall power can be achieved when optimal allocation is used once a treatment arm has been added to the trial, rather than continuing with equal allocation to all treatment arms

Do single-arm trials have a role in drug development plans incorporating randomised trials?

Often, single-arm trials are used in phase II to gather the first evidence of an oncological drug's efficacy, with drug activity determined through tumour response using the RECIST criterion. Provided the null hypothesis of 'insufficient drug activity' is rejected, the next step could be a randomised two-arm trial. However, single-arm trials may provide a biased treatment effect because of patient selection, and thus, this development plan may not be an efficient use of resources. Therefore, we compare the performance of development plans consisting of single-arm trials followed by randomised two-arm trials with stand-alone single-stage or group sequential randomised two-arm trials. Through this, we are able to investigate the utility of single-arm trials and determine the most efficient drug development plans, setting our work in the context of a published single-arm non-small-cell lung cancer trial. Reference priors, reflecting the opinions of 'sceptical' and 'enthusiastic' investigators, are used to quantify and guide the suitability of single-arm trials in this setting. We observe that the explored development plans incorporating single-arm trials are often non-optimal. Moreover, even the most pessimistic reference priors have a considerable probability in favour of alternative plans. Analysis suggests expected sample size savings of up to 25% could have been made, and the issues associated with single-arm trials avoided, for the non-small-cell lung cancer treatment through direct progression to a group sequential randomised two-arm trial. Careful consideration should thus be given to the use of single-arm trials in oncological drug development when a randomised trial will follow.Michael J. Grayling is supported by the Wellcome Trust [grant number 099770/Z/12/Z]. Adrian P. Mander is supported by the Medical Research Council [grant number G0800860].This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/pst.172

Model studies toward the synthesis of the bioactive diterpenoid, harringtonolide

In model studies towards the synthesis of harringtonolide, the construction of the tropone moiety via arene cyclopropanation was investigated. The installation of the lactone ring was accomplished by way of a Diels-Alder cycloaddition of various indenones and \u1d6fc-pyones. The incorporation of the key bridge methyl group and subsequent control of its stereochemistry is also outlined

Damage avoidance design steel beam-column moment connection using high-force-to-volume dissipators

Existing welded steel moment frames are designed to tolerate substantial yielding and plastic rotation under earthquake loads. This sacrificial design approach can lead to permanent, and often irreparable damage when interstory drifts exceed 2%. The experimental seismic performance of a 50% full-scale damage avoidance designed structural steel beam-column connection is presented. The beam-column joint region consists of a top flange-hung beam connected to the column by an angle bracket. High-force-to-volume (HF2V) devices are attached from the column to the beam to provide joint rigidity and energy dissipation as the joint opens and closes. The HF2V devices are connected either below the beam flange or concealed above the beam's lower flange. Reversed cyclic lateral load tests are conducted with drift amplitudes up to 4%. No damage is observed in the principal beam and column structural elements. The need for stiff device connections to achieve optimal device performance is demonstrated, and potential design solutions presented. Stable hysteresis and repeatable energy dissipation for a large number of cycles up to the 4% drift level is observed. It is concluded that superior and repeatable energy dissipation without damage can be achieved for every dynamic motion cycle, in contrast to conventional sacrificially designed welded moment frame connections

Group sequential designs for stepped-wedge cluster randomised trials.

BACKGROUND/AIMS: The stepped-wedge cluster randomised trial design has received substantial attention in recent years. Although various extensions to the original design have been proposed, no guidance is available on the design of stepped-wedge cluster randomised trials with interim analyses. In an individually randomised trial setting, group sequential methods can provide notable efficiency gains and ethical benefits. We address this by discussing how established group sequential methodology can be adapted for stepped-wedge designs. METHODS: Utilising the error spending approach to group sequential trial design, we detail the assumptions required for the determination of stepped-wedge cluster randomised trials with interim analyses. We consider early stopping for efficacy, futility, or efficacy and futility. We describe first how this can be done for any specified linear mixed model for data analysis. We then focus on one particular commonly utilised model and, using a recently completed stepped-wedge cluster randomised trial, compare the performance of several designs with interim analyses to the classical stepped-wedge design. Finally, the performance of a quantile substitution procedure for dealing with the case of unknown variance is explored. RESULTS: We demonstrate that the incorporation of early stopping in stepped-wedge cluster randomised trial designs could reduce the expected sample size under the null and alternative hypotheses by up to 31% and 22%, respectively, with no cost to the trial's type-I and type-II error rates. The use of restricted error maximum likelihood estimation was found to be more important than quantile substitution for controlling the type-I error rate. CONCLUSION: The addition of interim analyses into stepped-wedge cluster randomised trials could help guard against time-consuming trials conducted on poor performing treatments and also help expedite the implementation of efficacious treatments. In future, trialists should consider incorporating early stopping of some kind into stepped-wedge cluster randomised trials according to the needs of the particular trial

AplusB: A Web Application for Investigating A + B Designs for Phase I Cancer Clinical Trials.

In phase I cancer clinical trials, the maximum tolerated dose of a new drug is often found by a dose-escalation method known as the A + B design. We have developed an interactive web application, AplusB, which computes and returns exact operating characteristics of A + B trial designs. The application has a graphical user interface (GUI), requires no programming knowledge and is free to access and use on any device that can open an internet browser. A customised report is available for download for each design that contains tabulated operating characteristics and informative plots, which can then be compared with other dose-escalation methods. We present a step-by-step guide on how to use this application and provide several illustrative examples of its capabilities.GMW and APM are supported by the UK Medical Research Council (www.mrc.ac.uk; grant number G0800860). MJS is supported by a European Research Council Advanced Investigator Award: EPIC-Heart (https://erc.europa.eu; grant number 268834), the UK Medical Research Council (grant number MR/L003120/1), the British Heart Foundation (www.bhf.org.uk), and the Cambridge National Institute for Health Research Biomedical Research Centre (http://www.cambridge-brc.org.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.This is the final version of the article. It first appeared from PLOS at http://dx.doi.org/10.1371/journal.pone.0159026