The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. [ISRCTN64783481]

Barter, Philip J.; Best, James D.; Colman, Peter G; d’Emden, Michael C; Davis, Timothy; Drury, Paul; Ehnholm, Christian; Glasziou, Paul; Hunt, David; Keech, Anthony; Kesäniemi, Y. Antero; Lakso, M.; Scott, Russell S.; Simes, R. John; Sullivan, David; Taskinen, Marja‐Riitta; Whiting, Malcolm J.; Ansquer, Jean-Claude; Fraitag, B

doi:10.1186/1475-2840-3-9

Cited by 75 publications

(24 citation statements)

References 47 publications

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“…The study design was pragmatic in evaluating the effect of fenofibrate on a background of usual medical care [6], [7]. This meant that in the light of new clinical circumstances or the emergence of new evidence, additional cardiovascular medicines, including statins and other lipid modifying treatments, could be commenced during the course of the trial.…”

Section: Introductionmentioning

confidence: 99%

A Novel Method to Adjust Efficacy Estimates for Uptake of Other Active Treatments in Long-Term Clinical Trials

et al. 2010

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BackgroundWhen rates of uptake of other drugs differ between treatment arms in long-term trials, the true benefit or harm of the treatment may be underestimated. Methods to allow for such contamination have often been limited by failing to preserve the randomization comparisons. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, patients were randomized to fenofibrate or placebo, but during the trial many started additional drugs, particularly statins, more so in the placebo group. The effects of fenofibrate estimated by intention-to-treat were likely to have been attenuated. We aimed to quantify this effect and to develop a method for use in other long-term trials.Methodology/Principal FindingsWe applied efficacies of statins and other cardiovascular drugs from meta-analyses of randomized trials to adjust the effect of fenofibrate in a penalized Cox model. We assumed that future cardiovascular disease events were reduced by an average of 24% by statins, and 20% by a first other major cardiovascular drug. We applied these estimates to each patient who took these drugs for the period they were on them. We also adjusted the analysis by the rate of discontinuing fenofibrate. Among 4,900 placebo patients, average statin use was 16% over five years. Among 4,895 assigned fenofibrate, statin use was 8% and nonuse of fenofibrate was 10%. In placebo patients, use of cardiovascular drugs was 1% to 3% higher. Before adjustment, fenofibrate was associated with an 11% reduction in coronary events (coronary heart disease death or myocardial infarction) (P = 0.16) and an 11% reduction in cardiovascular disease events (P = 0.04). After adjustment, the effects of fenofibrate on coronary events and cardiovascular disease events were 16% (P = 0.06) and 15% (P = 0.008), respectively.Conclusions/SignificanceThis novel application of a penalized Cox model for adjustment of a trial estimate of treatment efficacy incorporates evidence-based estimates for other therapies, preserves comparisons between the randomized groups, and is applicable to other long-term trials. In the FIELD study example, the effects of fenofibrate on the risks of coronary heart disease and cardiovascular disease events were underestimated by up to one-third in the original analysis.Trial RegistrationControlled-Trials.com ISRCTN64783481

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Section: Introductionmentioning

confidence: 99%

A Novel Method to Adjust Efficacy Estimates for Uptake of Other Active Treatments in Long-Term Clinical Trials

et al. 2010

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“…Recently, data regarding the actual clinical significance of HRQOL have been brought to light. In a large quality of life sub-study by Hayes et al [42], based on the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study [43] population, better HRQOL was associated with significantly less risk for vascular events and other diabetic complications such as heart failure, end-stage renal disease and leg ulcers. Further-on, a recent prospective cohort study [44] highlighted the association between poor self-reported HRQOL and mortality in patients with diabetes.…”

Section: Discussionmentioning

confidence: 99%

The effectiveness of a community-based, type 2 diabetes prevention programme on health-related quality of life. The DE-PLAN study

Karamanakos

Costa²,

Gilis‐Januszewska

et al. 2019

PLoS ONE

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Background and aimsThe DE-PLAN was a European multicenter study, with the primary objective of testing whether a community-based lifestyle modification programme could serve as a means of primary prevention for type 2 diabetes (T2D) in high-risk individuals (based on the FINDRISC questionnaire). The aim of this study was to examine the impact of a 1-year community-based lifestyle intervention on health-related quality of life (HRQOL) in individuals from four participating European centers (Athens, Barcelona, Krakow, Kaunas), through a post-hoc analysis.Materials and methodsEach center was allowed to implement different intervention strategies specifically tailored to the needs of their corresponding population sample. Before and after the intervention, participants underwent clinical evaluation, anthropometric measurements, an oral glucose tolerance test and lipid profile measurements. Health-related quality of life was assessed using the validated HRQOL-15D questionnaire. A difference of ±0.015 in the 15D questionnaire score was set as the threshold of clinically meaningful change.ResultsData from 786 participants (67% females, mean age 59.7±9.4 years, BMI 31.5±4.5 kg/m2) with complete data regarding the HRQOL were analyzed (Athens: 104, Barcelona: 434, Krakow: 175, Kaunas: 70). After 1 year, a significant overall improvement in HRQOL was shown, as depicted by a change of 15D score from baseline value (0.88±0.9) to post-intervention (0.90±0.87, P<0.001), achieving the threshold of clinically meaningful change. A significant weight reduction was also observed (-0.8±4.0 kg, P<0.001). In multivariate analysis, improvement in HRQOL was independently associated with lower 15D score at baseline (P<0.001) and self-reported increase in overall exercise time (P<0.001) as assessed through specifically designed trial questionnaires.ConclusionA community-based lifestyle intervention programme aiming at T2D prevention, applied on a heterogeneous population and with varied methods, was shown to improve overall health-related quality of life to a clinically meaningful degree.

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“…The study offered 80% power to detect an observed 22% reduction in cardiovascular events 4 . All analyses were done on an intention-to-treat basis.…”

Section: Methodsmentioning

confidence: 99%

“…The aim of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was to assess whether long-term lipid-lowering treatment with fenofibrate could reduce adverse macrovascular and microvascular outcomes in patients with type 2 diabetes, including amputations 4 . Previously, we found that fenofibrate had a favourable effect on microvascular disease in terms of the need for laser therapy for diabetic retinopathy, 5 beyond what could be expected from a moderate observed reduction in blood pressure.…”

Section: Introductionmentioning

confidence: 99%

Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial

et al. 2009

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SummaryBackgroundAmputations in people with type 2 diabetes mellitus substantially impair their quality of life and impose high costs on health-care systems. Our aim was to assess the effect of fenofibrate on amputation events in a large cohort of patients with type 2 diabetes.MethodsIn the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, 9795 patients aged 50–75 years with type 2 diabetes were randomly assigned by computer-generated randomisation sequence to receive fenofibrate 200 mg per day (n=4895) or matching placebo (n=4900) for 5 years' duration. Information about non-traumatic amputation—a prespecified tertiary endpoint of the study—was routinely gathered. Clinicians who were masked to treatment allocation adjudicated amputations as minor or major (below or above the ankle, respectively). Amputations were also classified on the basis of whether or not large-vessel disease was present in the limb, to distinguish those related to large-artery atherosclerosis from those predominantly related to microvascular disease. Analysis was by intention to treat (ITT). The FIELD study is registered as an International Standard Randomised Controlled Trial, number ISRCTN64783481.FindingsAll 9795 patients were included in the ITT population. 115 patients had one or more non-traumatic lower-limb amputations due to diabetes. Previous cardiovascular disease, microvascular disease, previous non-traumatic amputation or skin ulcer, smoking, and longer duration of diabetes were more frequent in patients who had amputations during the trial than in those who had other cardiovascular events or in those who had neither event (all p<0·001 for three-way comparison). Mean lipid concentrations differed between patients who had on-study amputations and those who had other cardiovascular events or neither event, but by no more than 0·2 mmol/L. The risks of first amputation (45 vs 70 events; hazard ratio [HR] 0·64, 95% CI 0·44–0·94; p=0·02) and minor amputation events without known large-vessel disease (18 vs 34 events; 0·53, 0·30–0·94; p=0·027) were lower for patients assigned to fenofibrate than for patients assigned to placebo, with no difference between groups in risk of major amputations (24 vs 26 events; 0·93, 0·53–1·62; p=0·79).InterpretationClassic markers of macrovascular and microvascular risk were associated with lower extremity amputations in patients with type 2 diabetes. Treatment with fenofibrate was associated with a lower risk of amputations, particularly minor amputations without known large-vessel disease, probably through non-lipid mechanisms. These findings could lead to a change in standard treatment for the prevention of diabetes-related lower-limb amputations.FundingLaboratoires Fournier SA (now part of Solvay Pharmaceuticals) and National Health and Medical Research Council of Australia.

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The need for a large-scale trial of fibrate therapy in diabetes: the rationale and design of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. [ISRCTN64783481]

Cited by 75 publications

References 47 publications

A Novel Method to Adjust Efficacy Estimates for Uptake of Other Active Treatments in Long-Term Clinical Trials

A Novel Method to Adjust Efficacy Estimates for Uptake of Other Active Treatments in Long-Term Clinical Trials

The effectiveness of a community-based, type 2 diabetes prevention programme on health-related quality of life. The DE-PLAN study

Effect of fenofibrate on amputation events in people with type 2 diabetes mellitus (FIELD study): a prespecified analysis of a randomised controlled trial

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