Award Title: The efficacy and mechanisms of action of n-3 poly-unsaturated fatty acid supplementation in people with non-steroidal exacerbated airways disease and uncontrolled asthma
Funder: Medical Research Council

Abstract: Some people with asthma are allergic to aspirin and other similar painkillers, like ibuprofen. These make their asthma worse. This type of asthma, known as aspirin sensitive asthma, can be difficult to treat and sometimes requires specialist injections of anti-body type drugs. We know that being allergic to aspirin causes in high levels of inflammatory chemicals (called leukotrienes). Taking fish oil supplements has been shown to change leukotrienes. This may reduce the inflammation in the lungs and improve asthma symptoms. People find it easy to take fish oils and they do not cause side effects. _x000D_
The aim of this research is to test, if fish oil supplements improve asthma symptoms. This will be done by using questionnaires. We will also measure breathing and chemicals in breath, sputum (spit), blood and urine to find out how fish oils may be working. Based on the results of the study, we will be able to recommend whether people who are allergic to aspirin should take fish oils or not._x000D_
We plan to do a small clinical trial involving people from hospitals throughout the UK. We will identify 98 people who have troublesome aspirin sensitive asthma. At the beginning of the study, we will ask patients to complete questionnaires about their asthma symptoms and general well-being, perform routine forced (spirometry) and gentle (exhaled nitric oxide) breathing tests, if possible, and to give blood and urine samples to measure inflammation. Some patients will be asked to produce a sputum sample either spontaneously or after inhaling salty mist to measure standard and new tests of inflammation. We plan to give people either six fish oil capsules, or dummy capsules (placebo), every day for six months, as we think this dose will be effective. We will repeat these tests after 3 months and 6 months (end of the study). We will measure the amount of the fats from fish oils in patients’ blood cells to work out if they have been taking the capsules. The results will tell us if fish oils improve peoples’ asthma symptoms or not and whether they change the inflammatory chemicals. _x000D_
We have consulted people living with asthma in planning this study. Based on this, we have checked that:_x000D_
•	measuring the burden of asthma symptoms is important for people with asthma_x000D_
•	the questionnaires we will use will be easy to complete._x000D_
•	people are happy to provide blood, sputum and urine samples _x000D_
•	taking capsules every day is acceptable. _x000D_
_x000D_
Asthma UK Centre for Applied Research (AUKCAR), a national research group which includes people with asthma, will support our study by working with us to make sure it is helpful for people with asthma. Someone living with asthma who cannot take aspirin medication (Olivia Fulton) is an applicant on this grant and will be joined by other people from AUKCAR to provide advice during our study. There will be someone with asthma at all of our decision-making group meetings. _x000D_
The study will be undertaken by doctors and researchers with experience of asthma, aspirin sensitivity, fish oils and inflammatory chemicals. We are confident that we will be able to find out whether fish oils help people who are allergic to aspirin and how they may be working. We will widely publicise our results with the help of AUKCAR. We will write reports for medical publications, media articles and use social media. Hopefully, as a result of the study, asthma treatment guidelines will be changed.

Lay Abstract: Research question_x000D_
Is omega-3 poly-unsaturated fatty acid (n-3 PUFA) supplementation efficacious in people with non-steroidal exacerbated respiratory disease (N-ERD), and what is its mechanism of action?_x000D_
Background_x000D_
Asthma is a syndrome compromising many phenotypes including N-ERD (caused by increased 4-series leukotriene (LT) production). n-3 PUFA supplementation modulates 4-series LT and has anti-inflammatory effects. However, other than in a pilot study with dietary manipulation, the effects of N-ERD are unknown._x000D_
Aims and Objectives_x000D_
The primary objective is to determine whether n-3 PUFA supplementation in people with N-ERD can improve asthma control using the asthma control questionnaire (ACQ-6). Secondary objectives are to determine whether n-3 PUFA improves asthma and rhinitis symptoms and quality of life and airway calibre. Mechanistic objectives are to assess effects on red blood cell fatty acid composition, cyclooxygenase pathways and airway inflammation._x000D_
Methods_x000D_
This is a placebo controlled randomised controlled parallel multicentre study with of 6g per day of PUFA for 6 months in people with N-ERD and poor asthma control. Ninety-eight people will be included in the study if they have a reliable history of N-ERD or a positive nasal aspirin challenge, an ACQ-6 > 1.5 and are on stable treatment. People with other significant disease, recent respiratory tract infection, receiving aspirin desensitisation, biological asthma therapies will be excluded, as will those with a significant smoking history or alcohol consumption. _x000D_
The intervention will be 6g of n-3 PUFA (EPA and DHA as six (5.04g EPA+DHA) taken once daily, or in divided doses, with food for 6 months. The control will be matched placebo._x000D_
Measurements will be at be made every 6 weeks for ACQ-6. At baseline, 3 months and 6 months exhaled nitric oxide (FeNO), spirometry (where possible), blood for red blood cell fatty acid concentration, blood eosinophil count and safety markers. The following questionnaires will also be undertaken at these time-points: Mini Asthma Quality of Life Questionnaire (mini-AQLQ), and Euroqol 5 dimension 5 level (EQ5D-5L). The food frequency questionnaire will be measured at baseline and 6 months. Urine will be analysed for uLTE4 and prostaglandin D2 at baseline and 6 months. Induced or spontaneous sputum (where possible) will be obtained at baseline and 6 months in a subgroup for differential cell count and specialised pro-resolving mediators._x000D_
Timelines for delivery_x000D_
We will require 9 months to set up the sites. We will require 15 months to recruit the participants. We require four patients per site at the initial phase, and between 0.5 and 1 patient per month for the study as a whole, depending on site involvement. The intervention is for 6 months’ duration. We will require 6 months at the end of the study for analysis, report writing and dissemination._x000D_
Anticipated impact and dissemination_x000D_
We will determine the efficacy of this cheap, novel treatment option and understand its mechanism of action. We will share the findings through the scientific and social media supported by Asthma UK Centre for Applied Research.

Research Activity Codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health Categories: RESPIRATORY