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Proposal 977

Title of the Proposed Research

The implication of central adjudication of COPD exacerbations by experts for treatment effect estimates and sample size calculation

Lead Researcher

Milo Puhan

Affiliation

University of Zurich
Zurich, CH

Funding Source

The cohort study which we used to evaluate the accuracy of COPD exacerbation ascertainment was the prospective ICE COLD ERIC cohort study. This study was supported by the Swiss National Science Foundation (grant # 3233B0/115216/1), Dutch Asthma Foundation (grant # 3.4.07.045), Stichting Astmabestrijding (grant # SAB 2012/043 and Zurich Lung League (unrestricted grant).

Potential Conflicts of Interest

None

Data Sharing Agreement Date

12 May 2014

Lay Summary

Background to the research:
Accurate ascertainment of clinical endpoints is crucial to minimise endpoint misclassification when estimating effects in observational studies and randomised controlled trials (RCTs). Non-differential misclassification of endpoints, i.e. misclassification that is independent of treatment assignment or some other exposure generally leads to underestimation of treatment effects and loss of precision.

Exacerbations of chronic obstructive pulmonary disease (COPD) are an increasingly important outcome measure in COPD trials. Usually, exacerbations are assessed by patient self-reports or single physicians’ judgements. In contrast to large cardiovascular RCTs where endpoint adjudication committees have become common, COPD exacerbations have rarely been adjudicated centrally by blinded experts.

In a recent study nested within a cohort of Dutch and Swiss COPD patients, we evaluated the accuracy of COPD exacerbation ascertainment through patient self-reports and single expert adjudication against a reference standard of central event adjudication by a committee. The study showed that COPD exacerbations as measured by patient self-reports are only moderately accurate and that accuracy between different single experts differed. We have not published these results yet as they will be incorporated into the paper proposed here.

Our hypothesis is that the use of an expert adjudication committee may reduce sample size requirements and cost. To investigate this hypothesis we need a data set from a large COPD trial such as the Towards a Revolution in COPD Health (TORCH) Trial that contains individual patient data on the number of exacerbations and exposure time for each treatment arm (i.e. exacerbation rates). Thereby, we will be able to quantify the impact of misclassification on treatment effect estimates and precision of these estimates.

How the research will add to medical science or improve patient care: This research will add knowledge regarding the impact of event adjudication by experts in randomised controlled trials and observational studies using COPD exacerbations as outcomes. This will be the first study to quantify the effects of misclassification of exacerbations and the implication for sample size and cost of running trials where the primary outcome of COPD exacerbations is determined with and without an adjudication committee.

The aims and objectives of the research:
The aim of this study is to demonstrate the implications of centrally adjudicated COPD exacerbations by experts on treatment effect estimates and sample size requirements, exemplified by the data of the TORCH study.

How the research will be conducted:
We will adjust the annual exacerbation rates reported in the TORCH trial for outcome misclassification using sensitivities and specificities detected in our exacerbation adjudication study.

The results of this study will be published in a general medical or a specialised medical journals.

Study Data Provided

Study SCO30003: A multicentre, randomised, double-blind, parallel group, placebo-controlled study to investigate the long-term effects of salmeterol/fluticasone propionate (Seretide®) 50/500mcg BD, salmeterol 50mcg BD and fluticasone propionate 500mcg BD, all delivered via the Diskus®/Accuhaler® inhaler, on mortality and morbidity of subjects with chronic obstructive pulmonary disease (COPD) over 3 years of treatment

Statistical Analysis Plan

Publication Citation

Bias away from the null due to miscounted outcomes? A case study on the TORCH trial
Stefanie Muff, Milo A Puhan, Leonhard Held
January 1, 2017
DOI: https://doi.org/10.1177/0962280217694403

Summary Results

Results summary or link will be posted when available.