Title: A randomised, double-blind placebo controlled trial of the effectiveness of low dose oral theophylline as an adjunct to inhaled corticosteroids in preventing exacerbations of chronic obstructive pulmonary disease.
Funder: Chief Scientist Office, Scotland

Abstract: Rationale: Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterised by progressive airflow limitation. It affects approximately 3 million people in the UK, is the fifth leading cause of death in the UK and costs the NHS approximately £1 billion annually. Exacerbations of COPD account for 60% of NHS COPD costs and are associated with accelerated rate of lung function decline, reduced physical activity, reduced quality of life, increased mortality and increased risk of comorbidities such as acute myocardial infarction and stroke. The majority of COPD treatment guidelines recommend inhaled corticosteroids (ICS), usually in combination with inhaled LABA to reduce exacerbation rates and improve lung function. However, compared to the marked response observed in asthma, COPD airway inflammation is relatively insensitive to the anti-inflammatory effects of ICS and even high doses fail to prevent exacerbations. In COPD, airway inflammation is driven by expression of multiple inflammatory genes, regulated by acetylation of core histones which open up the chromatin structure. Corticosteroids appear to work by reversing histone acetylation through the recruitment of histone deacetylase-2 (HDAC2) thereby switching off activated inflammatory genes. In COPD there is increased histone acetylation consequent upon markedly reduced HDAC2 activity/expression in airways, lung tissue and alveolar macrophages. It has been observed that the reduced HDAC2 activity of COPD can be reversed in a dose-dependent manner by theophylline at ‘low’ concentrations of 1-5mg/l. This basic research is supported by two small RCTs and a population based health administration database study. Objectives & Outcomes: To determine the clinical effectiveness and cost-effectiveness of adding low dose theophylline (Uniphyllin MR 200mg od or bd [depending on smoking status and ideal body weight]) to ICS therapy in patients with COPD and a history of exacerbations treated with antibiotic and/or ICS. The primary clinical outcome is the number of participant reported COPD exacerbations necessitating a change in management (minimum change treatment with antibiotics and/or oral corticosteroids) during the one year treatment period. The primary economic outcome is the cost-per-QALY gained during the one year treatment period. Secondary outcomes include: • Total number of COPD exacerbations requiring hospital admission. • Total number of emergency hospital admissions (all causes). • Disease specific health status (CATest; HARQ at some sites). • Generic health related quality of life (EQ-5D). • Lung function, post bronchodilator FEV1, FVC. • Total inhaled corticosteroid dose/usage. • Health care utilisation. • Incremental cost-per-exacerbation avoided. • Other adverse events. • All cause and respiratory mortality. • Modelled lifetime incremental cost per QALY. Method: A pragmatic randomised, double-blind, placebo-controlled, multicentre clinical trial. Setting: Primary and Secondary care; General Practice and NHS hospitals. Target population: 1424 patients with diagnosed COPD (post bronchodilator FEV1/FVC<0.7), currently receiving ICS as part of COPD treatment and with a history of =2 COPD exacerbations in the previous year requiring treatment with oral corticosteroids and/or antibiotics. Inclusion criteria: • Aged = 40 years. • A smoking history of at least 10 pack years ([average number of cigarettes/day x years smoked]/20). • An established predominant respiratory diagnosis of COPD (GOLD/NICE Guideline definition: post bronchodilator FEV1/FVC<0.7). • Current use of ICS therapy (irrespective of LABA and/or LAMA use). • A history of at least two exacerbations requiring treatment with antibiotics and/or oral corticosteroid use in the previous year, based on patient report. • Clinically stable with no COPD exacerbation for at least 4 weeks. • Able to swallow study medication. • Able and willing to give informed consent to participate. • Able and willing to participate in the study procedures; undergo spirometric assessment, complete study questionnaire. Exclusion Criteria: • Severe or unstable ischaemic heart disease. • A predominant respiratory disease other than COPD. • Any other significant disease/disorder which, in the investigator’s opinion, either puts the patient at risk because of study participation or may influence the results of the study or the patient's ability to participate in the study. • Previous allocation of a randomisation code in the study or current participation in another interventional study (CTIMP or non-CTIMP). • Theophylline use currently. • Known or suspected hypersensitivity to theophylline. • Current use of drugs known to interact with theophylline and/or increase serum theophylline: antimicrobials: aciclovir, clarithromycin, ciprofloxacin, erythromycin, fluconazole, ketoconazole, levofloxacin, norfloxacin; cardiovascular: diltiazem, mexiletine, pentoxifylline, verapamil; neurological: bupropion, disulfiram, fluvoxamine, lithium; hormonal: medroxyprogesterone, oestrogens; immunological: methotrexate, peginterferon alpha, tacrolimus; miscellaneous: cimetidine, deferasirox, febuxostat, roflumilast, thiabendazole.29 • For women, current pregnancy or breast-feeding, or planned pregnancy during the study. Randomisation: When clinically stable subjects will be assessed, recruited and randomised with equal probability to intervention or control group. Intervention: Intervention and control groups will receive usual guideline compliant NHS care: intervention group will also receive oral Uniphyllin MR at a dose predicted by pharmacokinetic modelling to achieve steady state serum concentration of 1-5mg/l for one year. Participants who do not smoke will receive 200mg od, participants who smoke will receive 200mg od if ideal body weight=60kg and 200mg bd if ideal body weight>60kg. Control group will receive an identical oral placebo tablet od/bd (based on same weight and smoking criteria) for one year. Assessment: Face to face health outcome assessments will be carried out for all participants at recruitment/baseline, 6, and 12 months, telephone contact will be made at approximately two weeks to ensure no adverse events and tolerating study medication. Participants will also be asked to record exacerbations and associated treatment and health service contact – space will be provided for this on the carton that study medication is shipped in. At 6 and 12 month follow-up, the following will be collected: history of exacerbations, health care utilisation, disease-related quality of life status (COPD assessment test [CATest]), MRC dyspnoea score, health related quality of life (EQ-5D), lung function (FEV1, FVC), adverse reactions and serious adverse events. The Hull Airways Reflux Questionnaire (HARQ) will be used at some sites to collect data on respiratory and GI symptoms. Clinical relevance: Low dose theophylline is cheap (10p/day) and, if shown to make current ICS therapy more effective in a cost effective manner, it will improve the quality of life of COPD patients and reduce the burden of COPD on the NHS.

Lay abstract: Chronic Obstructive Pulmonary Disease (COPD) is a progressive lung disease characterised by progressive airflow limitation. In the UK, it affects around 3 million people, is the fifth leading cause of death and costs the NHS approximately £1 billion annually. Exacerbations of COPD account for 60% of NHS COPD costs and are associated with accelerated rate of lung function decline, reduced physical activity, reduced quality of life, increased mortality and increased risk of comorbidities. COPD treatment guidelines recommend inhaled corticosteroids (ICS) to reduce exacerbations and improve lung function. However, in COPD, airway inflammation is relatively insensitive to the anti-inflammatory effects of ICS and even high doses fail to prevent exacerbations. Preclinical and pilot studies demonstrate that low dose theophylline may increase the sensitivity of the airway inflammation to ICS, and thus when used with ICS will reduce the rate of COPD exacerbation. In this study we will we will investigate whether adding low dose theophylline to current ICS treatment reduces the rate of hospitalisation with exacerbations of COPD and makes patients feel better. We will determine the clinical effectiveness and cost effectiveness of adding low dose theophylline to ICS therapy in patients with COPD. The primary outcome is the number of exacerbations. The primary economic outcome is the cost per QALY gained during the one year treatment period. We will recruit 1424 participants from primary and secondary care across seven areas of the UK. Participants will be randomised to theophylline (200 mg once or twice daily depending on smoking status and weight) or inactive placebo “dummy” tablet for 12 months. We will follow participants up at six and twelve months to assess the number of exacerbations. We will also collect data on adverse events, health care utilisation, quality of life and breathlessness, and lung function. Low dose theophylline is cheap (10p/day) and, if shown to make current ICS therapy more effective in a cost effective manner, it will improve the quality of life of COPD patients and reduce the burden of COPD on the NHS.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: RESPIRATORY