Title: Dietary nitrate supplementation to enhance daily physical activity in hypoxic COPD: a randomised controlled trial
Funder: Medical Research Council

Abstract: Aims: We want to find out if taking a nutritional supplement, beetroot juice, is beneficial for people with the most severe form of chronic obstructive pulmonary disease (COPD). In this patient group, who have low oxygen levels, we will investigate whether the supplement can improve the amount of daily physical activity they can do and how hard they find it._x000D_ Background: COPD is a common lung condition, combining chronic bronchitis and emphysema which affects 1.3 million people in the UK. COPD causes breathlessness, cough and limits people’s ability to do daily activities like walking and housework. _x000D_ The reason for doing a trial of beetroot juice is that it is high in nitrate. The nitrate is absorbed and then broken down to nitric oxide (NO). Nitric oxide is an important molecule in the body. It influences how blood vessels work and how muscles use oxygen. There is evidence that beetroot juice improves athletic performance in healthy people, and we have shown that it makes training programmes more effective in people with COPD. _x000D_ We have previously found that giving people with COPD who need to use oxygen a single dose of beetroot juice, produces a substantial increase in how far they could walk. We now want to see if this benefit is sustained over a longer period and if it is enough to make a difference to day-to-day activities._x000D_ Design and methods: We will invite 96 people with COPD who use oxygen at home to take part in a three month long clinical trial. Half will take 70mls beetroot juice each morning, the other half will consume an otherwise identical placebo beetroot juice drink from which the nitrate has been removed. Participants will be allocated to one or other drink at random by a computer system. They and the trial team will not know which drink they are having so the study is “double-blind”. _x000D_ The main outcome measure for the study will be how difficult participants find physical activity. We will measure this using a measure developed specially for COPD called the “PROactive physical activity in COPD tool”. This combines results from an activity monitor which participants wear for 7 days with a questionnaire about the amount and difficulty of daily activity. We will also measure exercise capacity directly using a timed walking test (the endurance shuttle walk test) and ask about general respiratory symptoms and if any complications have occurred. _x000D_ We will use a device called an EndoPat that records the pulse pressure in people’s fingertips to measure blood vessel function, and also record blood pressure. Changes in all these measures will be compared between the active beetroot juice group and the placebo juice group. _x000D_ Patient and public involvement: the study has evolved through discussions with our British Lung Foundation BreatheEasy patient group and there will be patient involvement throughout the life cycle of the trial. A patient involvement lead will be recruited to sit on the trial management group committee to ensure study conduct is patient-centred. A patient advisory group will also be established to review patient facing documents and to help produce materials that are patient accessible for dissemination. _x000D_ Dissemination: If positive we will undertake a longer-term trial. We will publish the results in medical journals in the lay press with assistance from Communications Departments at Imperial College and Royal Brompton Hospital and our patient representatives.

Lay abstract: Research question_x000D_ In people with hypoxic COPD, does 3 months of treatment with 70mls beetroot juice containing 6.4mmol nitrate each morning, compared to an otherwise identical placebo beetroot juice drink from which the nitrate has been removed, improve daily physical activity._x000D_ Background_x000D_ People with severe COPD who are hypoxic and need to use home oxygen remain limited in their daily activities despite optimum medical care. Dietary nitrate supplementation can increase bioavailability of nitric oxide, a ubiquitous signalling molecule with roles in endothelial function and muscle metabolic efficiency. Reduction of dietary nitrate via nitrite to NO is favoured in hypoxic conditions. We have shown that dietary nitrate supplementation reduces the oxygen cost of exercise and consistently improves exercise capacity in people with COPD who require supplemental oxygen._x000D_ Aims and objectives_x000D_ Primary: To establish if dietary nitrate supplementation reduces the difficulty that patients with hypoxic COPD experience with day to day physical activity. _x000D_ Secondary outcomes are whether there are associated improvements in exercise capacity - endurance shuttle walk time (ESWT), Mean arterial pressure, step count/day, Quality of life (CAT score), BNP levels, Endothelial function assessed using the Endopat device, Blood nitrite/nitrate levels, Oxygenation and lower heart rate during exercise._x000D_ Methods_x000D_ We will conduct a double-blind, parallel group, randomised controlled trial powered to demonstrate the superiority of three months dietary nitrate supplementation with beetroot juice (70mL Beet-It® SPORT shot; 6.4mmol nitrate) to otherwise identical placebo juice from which the nitrate has been removed in 96 stable, adult patients with COPD who are hypoxic and under the care of home oxygen services._x000D_ Patient experience of physical activity, which is the primary endpoint of the study, will be assessed using the clinic visit PROactive consortium Physical Activity in COPD (c-PPAC) tool. This is a rigorously developed hybrid patient reported outcome measure which combines one week of physical activity monitoring (McRoberts MoveMonitor) with questionnaire items, to evaluate two domains; Amount and Difficulty. We will also measure exercise capacity, endothelial function using flow mediated dilatation, blood pressure and health status at the beginning and end of the study. _x000D_ Timelines for delivery_x000D_ Study commences research fellow in post, learns techniques, and undergoes research induction. eCRF developed, tested and finalised. Trial steering committee established._x000D_ 5 months Recruitment begins_x000D_ 12 months Recruitment milestone: 35 patients recruited _x000D_ 16 months Recruitment milestone: 65 patients recruited_x000D_ 21 months Recruitment milestone: 102 patients recruited_x000D_ 24 months Last patient last visit_x000D_ 30 Months Data cleaned, analysed and submitted for publication as research paper and reports._x000D_ _x000D_ Anticipated impact and dissemination_x000D_ Beetroot juice is a relatively cheap and readily available intervention which is well tolerated, so it could be added to care strategies for people with hypoxic COPD, improving daily experience of physical activity and quality of life. If positive, we plan to undertake a longer-term trial including economic evaluation. We will publish the results in medical journals and the lay press with assistance from Communications Departments at Imperial College and Royal Brompton Hospital and our patient representatives.

Research activity codes: 6.8 COMPLEMENTARY
Health categories: RESPIRATORY