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

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

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

Achieving optimal adherence to medical therapy by telehealth: Findings from the ORBITA medication adherence sub-study

INTRODUCTION: The ORBITA trial of percutaneous coronary intervention (PCI) versus a placebo procedure for patients with stable angina was conducted across six sites in the United Kingdom via home monitoring and telephone consultations. Patients underwent detailed assessment of medication adherence which allowed us to measure the efficacy of the implementation of the optimization protocol and interpretation of the main trial endpoints. METHODS: Prescribing data were collected throughout the trial. Self-reported adherence was assessed, and urine samples collected at pre-randomization and at follow-up for direct assessment of adherence using high-performance liquid chromatography with tandem mass spectrometry (HPLC MS/MS). RESULTS: Self-reported adherence was >96% for all drugs in both treatment groups at both stages. The percentage of samples in which drug was detected at pre-randomization and at follow-up in the PCI versus placebo groups respectively was: clopidogrel, 96% versus 90% and 98% versus 94%; atorvastatin, 95% versus 92% and 92% versus 91%; perindopril, 95% versus 97% and 85% versus 100%; bisoprolol, 98% versus 99% and 96% versus 97%; amlodipine, 99% versus 99% and 94% versus 96%; nicorandil, 98% versus 96% and 94% versus 92%; ivabradine, 100% versus 100% and 100% versus 100%; and ranolazine, 100% versus 100% and 100% versus 100%. CONCLUSIONS: Adherence levels were high throughout the study when quantified by self-reporting methods and similarly high proportions of drug were detected by urinary assay. The results indicate successful implementation of the optimization protocol delivered by telephone, an approach that could serve as a model for treatment of chronic conditions, particularly as consultations are increasingly conducted online

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

Finger-Prick Autologous Blood (FAB) Eye Drops for Dry Eye Disease: Single Masked Multi-Centre Randomised Controlled Trial

PURPOSE: To investigate the quantitative and qualitative efficacy of finger-prick autologous blood (FAB) eye drops versus conventional medical therapy for the treatment of severe dry eye disease (DED). METHODS: Two centre, single masked, randomised controlled trial. Sixty patients in total were recruited with thirty patients (sixty eyes) treated with FAB eye drops four times per day in addition to their conventional DED treatment, and thirty patients (fifty-eight eyes) served as control subjects on conventional treatment alone. Ocular surface disease index (OSDI), Schirmer’s test, fluorescein ocular staining grade (OCSG) Oxford schema and fluorescein tear film break-up time (TBUT), were performed at baseline, at 4 and 8 weeks. RESULTS: OSDI scores significantly decreased in the FAB arm by greater than − 17.68 (− 37.67 to − 2.96, p=0.02) compared to the control arm. There were greater improvements in OCSG and TBUT in the FAB arm but these were non-significant (p> 0.05). CONCLUSION: This feasibility study demonstrates adding FAB eye drops to conventional medical therapy for DED improves mean OSDI symptom score compared to conventional medical therapy alone. It may have particular use in settings where serum is unobtainable. An adequately powered and well-designed randomised trial is needed to further evaluate the long-term clinical benefit of FAB

Ethnic Differences in Associations Between Fat Deposition and Incident Diabetes and Underlying Mechanisms: The SABRE Study

OBJECTIVE: To examine ethnic differences in ectopic fat and associations with incident diabetes. METHODS: In a UK cohort study, 1338 Europeans, 838 South Asians, and 330 African Caribbeans living in London were aged 40-69 years at baseline. Baseline assessment included blood tests, anthropometry, and questionnaires. Anthropometry-based prediction equations estimated baseline visceral adipose tissue (VAT). Incident diabetes was ascertained from record review, self-report, or oral glucose tolerance testing. RESULTS: South Asians had more and African Caribbeans less estimated VAT than Europeans. Both ethnic minorities had larger truncal skinfolds than Europeans. In men, adjustment for risk factors (BMI, smoking, systolic blood pressure, and HDL-cholesterol) markedly attenuated the association between estimated VAT and diabetes in Europeans (standardized subhazard ratios [95% CI]: from 1.74 [1.49, 2.03] to 1.16 [0.77, 1.76]) and African Caribbeans (1.72 [1.26, 2.35] to 1.44 [0.69, 3.02]) but not South Asians (1.60 [1.38, 1.86] to 1.90 [1.37, 2.64]). In women, attenuation was observed only for South Asians (1.80 [1.01, 3.23] to 1.07 [0.49, 2.31]). Associations between truncal skinfolds and diabetes appeared less affected by multivariable adjustment in South Asians and African Caribbeans than Europeans (1.24 [0.97, 1.57] and 1.28 [0.89, 1.82] versus 1.02 [0.77, 1.36] in men; 1.91 [1.03, 3.56] and 1.42 [0.86, 2.34] versus 1.23 [0.74, 2.05] in women). CONCLUSIONS: Differences in overall truncal fat, as well as VAT, may contribute to the excess of diabetes in South Asian and African Caribbean groups, particularly for women