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Placebo Effects in Asthma Randomized Clinical Trials: Their Magnitudes, Causes and Potential for Improving Care

Placebo Effects in Asthma Randomized Clinical Trials: Their Magnitudes, Causes and Potential for Improving Care

Shawn D. Aaron

The Ottawa Hospital Research Institute, University of Ottawa

Internal funding will be provided for this study through Dr. Aaron's accumulated research funds. Neither Drs. Aaron nor Whitmore will be receiving salary or direct funding from this project.

No potential conflicts of interest exist with respect to this study.

08 June 2018

An estimated 300 million people worldwide suffer from asthma and 250,000 annual deaths are attributed to it. The disease involves huge costs for treatment, substantial productivity losses, and severe impacts on quality of life. Acute exacerbations of asthma are an index of disease severity and are among the most adverse and consequential manifestations of the disease.

A randomized clinical trial (RCT) for asthma often uses the occurrence rate of acute exacerbations as a primary study outcome. It is common in such studies that exacerbation rates for study subjects prior to enrolment in the trial differ substantially from exacerbation rates observed for the same subjects assigned to the placebo arm in the trial. These differences generally favour the placebo arm, revealing a so-called placebo effect. It is this placebo effect or response that is of interest in our study.

We are seeking access to de-identified data for three related asthma RCTs conducted by GlaxoSmithKline (GSK). These studies test the benefit of mepolizumab, an anti-interleukin-5 monoclonal antibody, for treatment of eosinophilic asthmatics. The data sets will allow us to investigate the following research questions:

A.   What are the causes of differences in asthma exacerbation rates between pre-study and placebo-arm conditions?
B.   What are the magnitudes of placebo effects for asthma exacerbations? How do the effects vary by characteristics of the study population? How can statistical methods be used to isolate significant explanatory factors for these effects?
C.   What beneficial lessons for primary care management of asthma can be extracted from a deeper understanding of these placebo effects?

Anticipated causes of measured placebo effects include: (1) statistical artifacts such as regression to the mean, (2) psychological factors arising from perceptions, (3) neurobiological responses, (4) better-than-usual clinical monitoring and patient care by the study team, (5) better compliance by subjects to medications and therapies while on the study, (6) beneficial self-prompted changes in life style by subjects not explicitly prescribed in the study protocol, and (7) reduced exposures to aggravating environmental substances because of increased awareness on the part of subjects.

Potential lessons for primary care management that might come from this research include better clinical work-up and monitoring of patients by primary care givers and better patient education that promotes self-awareness, improved compliance, and positive life-style changes, to name a few. Potential net savings to the health care system could be substantial if some elements of the placebo response can be captured in actual practice. The health care savings would come from fewer exacerbations and the elimination of hospitalizations and emergency room visits that they entail. The savings would be offset, however, by any consequent costs of deploying health-care resources in an attempt to imitate RCT placebo-arm conditions for patients.

Although our focus in this research is on asthma and asthma exacerbations, we recognize that asthma is but one of many chronic diseases that might benefit from capturing placebo effects in chronic care management.

[{ "PostingID": 3793, "Title": "GSK-MEA115588", "Description": "MEA115588 A randomised, double-blind, double-dummy, placebo-controlled, parallel-group, multi-centre study of the efficacy and safety of mepolizumab adjunctive therapy in subjects with severe uncontrolled refractory asthma" },{ "PostingID": 3794, "Title": "GSK-MEA115575", "Description": "MEA115575: A Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study of Mepolizumab Adjunctive Therapy to Reduce Steroid Use in Subjects with Severe Refractory Asthma" },{ "PostingID": 4878, "Title": "GSK-200862", "Description": "A Randomised, Double-blind, Placebo-controlled, Parallel-group, Multi-centre 24-week Study to Evaluate the Efficacy and Safety of Mepolizumab Adjunctive Therapy in Subjects with Severe Eosinophilic Asthma on Markers of Asthma Control" }]

Statistical Analysis Plan