Controlled backfill in oncology dose-finding trials

The use of backfill in early phase dose-finding trials is a relatively recent practice. It consists of assigning patients to dose levels below the level where the study is at. The main reason for backfilling is to collect additional pharmacokinetic, pharmacodynamic and response data, in order to assess whether a plateau may exist on the dose-efficacy curve. This is a possibility in oncology with molecularly targeted agents or immunotherapy. Recommending for further study a dose level lower than the maximum tolerated dose could be supported in such situations. How to best allocate backfill patients to dose levels is not yet established. In this paper we propose to randomise backfill patients below the dose level where the study is at. A refinement of this would be to stop backfilling to lower dose levels when these show insufficient efficacy compared to higher levels, starting at dose level 1 and repeating this process sequentially. At study completion, data from all patients (both backfill patients and dose-finding patients) is used to estimate the dose-response curve. The fit from a change point model is compared to the fit of a monotonic model to identify a potential plateau. Using simulations, we show that this approach can identify the plateau on the dose-response curve when such a plateau exists, allowing the recommendation of a dose level lower than the maximum tolerated dose for future studies. This contribution provides a methodological framework for backfilling, from the perspective of both design and analysis in early phase oncology trials

Life expectancy difference and life expectancy ratio: two measures of treatment effects in randomised trials with non-proportional hazards

The hazard ratio (HR) is the most common measure of treatment effect in clinical trials that use time-to-event outcomes such as survival. When survival curves cross over or separate only after a considerable time, the proportional hazards assumption of the Cox model is violated, and HR can be misleading. We present two measures of treatment effects for situations where the HR changes over time: the life expectancy difference (LED) and life expectancy ratio (LER). LED is the difference between mean survival times in the intervention and control arms. LER is the ratio of these two times. LED and LER can be calculated for at least two time intervals during the trial, allowing for curves where the treatment effect changes over time. The two measures are readily interpretable as absolute and relative gains or losses in life expectancy

Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes.

OBJECTIVES: The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND: Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS: The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS: Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS: Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year.info:eu-repo/semantics/publishedVersio

A Protocol for an economic evaluation of a polypill in patients with established or at high risk of cardiovascular disease in a UK NHS setting: RUPEE (NHS) study

Copyright © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. Introduction: The ‘Use of a Multi-drug Pill in Reducing cardiovascular Events’ (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data. This paper describes the design of a modelled economic evaluation of the impact of increased adherence to the polypill versus usual care among the UK UMPIRE participants. Methods and analysis: As recommended by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modelling guidelines, a review of published CVD models was undertaken to identify the most appropriate modelling approach and structure. The review was carried out in the electronic databases, MEDLINE and EMBASE. 40 CVD models were identified from 57 studies, the majority of economic models were health state transition cohort models and individual-level simulation models. The findings were discussed with clinical experts to confirm the approach and structure. An individual simulation approach was identified as the most suitable method to capture the heterogeneity in the population at CVD risk. RUPEE-NHS will use UMPIRE trial data on adherence to estimate the long-term cost-effectiveness of the polypill strategy. Dissemination: The evaluation findings will be presented in open-access scientific and healthcare policy journals and at national and international conferences. We will also present findings to NHS policy makers and pharmaceutical companies

A protocol for an economic evaluation of a polypill in patients with established or at high risk of cardiovascular disease in a UK NHS setting: RUPEE (NHS) study.

INTRODUCTION: The 'Use of a Multi-drug Pill in Reducing cardiovascular Events' (UMPIRE) trial was a randomised controlled clinical trial evaluating the impact of a polypill strategy on adherence to indicated medication in a population with established cardiovascular disease (CVD) of or at high risk thereof. The aim of Researching the UMPIRE Processes for Economic Evaluation in the National Health Service (RUPEE NHS) is to estimate the potential health economic impact of a polypill strategy for CVD prevention within the NHS using UMPIRE trial and other relevant data. This paper describes the design of a modelled economic evaluation of the impact of increased adherence to the polypill versus usual care among the UK UMPIRE participants. METHODS AND ANALYSIS: As recommended by the International Society for Pharmacoeconomics and Outcomes Research and the Society for Medical Decision Making modelling guidelines, a review of published CVD models was undertaken to identify the most appropriate modelling approach and structure. The review was carried out in the electronic databases, MEDLINE and EMBASE. 40 CVD models were identified from 57 studies, the majority of economic models were health state transition cohort models and individual-level simulation models. The findings were discussed with clinical experts to confirm the approach and structure. An individual simulation approach was identified as the most suitable method to capture the heterogeneity in the population at CVD risk. RUPEE-NHS will use UMPIRE trial data on adherence to estimate the long-term cost-effectiveness of the polypill strategy. DISSEMINATION: The evaluation findings will be presented in open-access scientific and healthcare policy journals and at national and international conferences. We will also present findings to NHS policy makers and pharmaceutical companies

Experiments performed with bubbly flow in vertical pipes at different flow conditions covering the transition region: Simulation by coupling Eulerian, Lagrangian and 3D random walks models

[EN] Two phase flow experiments with different superficial velocities of gas and water were performed in a vertical upward isothermal cocurrent air-water flow column with conditions ranging from bubbly flow, with very low void fraction, to transition flow with some cap and slug bubbles and void fractions around 25%. The superficial velocities of the liquid and the gas phases were varied from 0.5 to 3 m/s and from 0 to 0.6 m/s, respectively. Also to check the effect of changing the surface tension on the previous experiments small amounts of 1-butanol were added to the water. These amounts range from 9 to 75 ppm and change the surface tension. This study is interesting because in real cases the surface tension of the water diminishes with temperature, and with this kind of experiments we can study indirectly the effect of changing the temperature on the void fraction distribution. The following axial and radial distributions were measured in all these experiments: void fraction, interfacial area concentration, interfacial velocity, Sauter mean diameter and turbulence intensity. The range of values of the gas superficial velocities in these experiments covered the range from bubbly flow to the transition to cap/slug flow. Also with transition flow conditions we distinguish two groups of bubbles in the experiments, the small spherical bubbles and the cap/slug bubbles. Special interest was devoted to the transition region from bubbly to cap/slug flow; the goal was to understand the physical phenomena that take place during this transition A set of numerical simulations of some of these experiments for bubbly flow conditions has been performed by coupling a Lagrangian code, that tracks the three dimensional motion of the individual bubbles in cylindrical coordinates inside the field of the carrier liquid, to an Eulerian model that computes the magnitudes of continuous phase and to a 3D random walk model that takes on account the fluctuation in the velocity field of the carrier fluid that are seen by the bubbles due to turbulence fluctuations. Also we have included in the model the deformation that suffers the bubble when it touches the wall and it is compressed by the forces that pushes it toward the wall, provoking that the bubble rebound like a ball.The authors of this paper are indebted to the National Plan of I+D by the support of the coordinated projects REMOD-ERN ENE2010-21368-C02-01/CON and ENE2010-21368-C02-02/CON to perform the experiments.Muñoz-Cobo, JL.; Chiva, S.; Ali Abdelaziz Essa, M.; Mendez, S. (2012). Experiments performed with bubbly flow in vertical pipes at different flow conditions covering the transition region: Simulation by coupling Eulerian, Lagrangian and 3D random walks models. Archives of Thermodynamics. 33(1):3-39. https://doi.org/10.2478/v10173-012-0001-4S33933