Title: Feasibility of the safe withdrawal of inhaled corticosteroids in patients with mild to moderate COPD prescribed outside guidelines
Funder: Department of Health and Social Care

Abstract: There is growing international evidence of widespread prescribing of high dose inhaled corticosteroids (ICS) to patients with chronic obstructive pulmonary disease (COPD) outside guidelines, the majority of prescribing occurring in primary care. High dose ICS are associated with an increased risk of serious pneumonia, 1.5 times the risk of someone with COPD who is not on high dose ICS. This accounts for an estimated excess of 3000 cases per year in England. They are also associated with higher risk of fractures and cataract. Inappropriately prescribed ICS are also a major drain on health services costing an estimated &pound;122 million in England annually. Seretide, a combined inhaled long-acting beta-agonist and corticosteroid, was the single most costly drug prescribed by general practitioners (GPs) in England in 2012. The risk of harm from these drugs among patients in whom the evidence of benefit is lacking raises the question as to whether this trend in over-prescribing of high dose ICS in COPD can be reversed. We propose to investigate whether high dose ICS can be withdrawn safely from COPD patients for whom they have been prescribed outside guidelines. We also aim to identify those patients with mild or moderate COPD in whom high dose ICS appear to be effective. Little is known about patients perceptions of the withdrawal of medication for chronic diseases prescribed outside guidelines or of the effect of stopping ICS in mild or moderate COPD. This research is a feasibility study for a cluster randomised controlled trial in primary care in which patients will be randomised to withdrawal or continuation of high dose ICS. In this feasibility study there will be two phases. In the first phase a qualitative study of the perceptions of high dose ICS withdrawal among patients with mild or moderate COPD will be carried out. In the second phase, the feasibility phase, the acceptability to patients and to general practices of random selection to withdrawal or continuation of high dose ICS will be assessed. The feasibility of assessing the effects on symptoms, quality of life, exacerbations, cellular and molecular biomarkers, and neural respiratory drive of the withdrawal of high dose ICS will be determined. We will define the distribution of these outcomes so that accurate estimates of required sample size can be made for the trial. Finally we will assess the frequency of severe exacerbations after withdrawal of high dose ICS, so that safety parameters for the main trial can be determined. We will conduct this research with patients with mild or moderate COPD in London. We expect to recruit at least 3 eligible patients in a practice of 10000. We will require the participation of about 26 such practices to demonstrate the feasibility of the main trial. This novel research offers considerable opportunity for patient benefit. The assessment from the perspective of the patient of the acceptability and impact of treatment withdrawal has not been done before in this group of patients. Patients with mild or moderate COPD are infrequently the subjects of therapeutic research. The withdrawal of high dose ICS provides an exceptional opportunity to improve their safe treatment in a controlled setting.

Lay abstract: Patients with severe or very severe chronic obstructive pulmonary disease (COPD) may benefit from using high dose inhaled corticosteroid drugs. There is evidence of widespread overprescribing of these drugs to patients with mild or moderate COPD in many countries. These drugs can increase the risk to patients of developing pneumonia (an estimated extra 3000 cases per year in England), fractures and cataracts. In most patients with mild or moderate COPD there is no evidence of any benefit from high dose inhaled corticosteroids. The drugs prescribed to patients with mild or moderate COPD are costly. In the NHS in England an estimated &pound;122 million is spent each year in prescribing high dose inhaled corticosteroids in mild and moderate COPD, approximately 20% of the total spend on these drugs. Little is known of patients perceptions of the proposed withdrawal of these drugs when prescribed outside guidelines. This research will examine the feasibility of carrying out a trial of withdrawing these high dose inhaled corticosteroids in patients with mild or moderate COPD. In the trial for which this is a feasibility study we will assess whether withdrawal of high dose inhaled corticosteroids has any impact on patients' quality of life, lung function, exacerbation frequency, markers of inflammation in the blood, or evidence of interference with breathlessness. We will assess whether patients and practices find this research acceptable and safe. We will also assess the distribution of the outcome measures we intend to assess in the main trial. Finally we will determine our ability to test the safety of withdrawing high dose inhaled corticosteroids by assessing the frequency of exacerbations of the disease. Success in these aims will enable us to proceed later with a definitive cluster randomised controlled trial of the withdrawal of high dose inhaled corticosteroids.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: RESPIRATORY