Dupilumab in Severe Asthma version 2.0
Research type
Research Study
Full title
A Pragmatic Proof of Concept Study to Evaluate the Effect of Dupilumab on Mannitol Challenge in Severe Asthma with Type 2 Inflammation
IRAS ID
305542
Contact name
Brian Lipworth
Contact email
Sponsor organisation
Tayside Medical Sciences Centre on behalf of University of Dundee & NHS Tayside
Eudract number
2021-005593-25
ISRCTN Number
ISRCTN70810039
Duration of Study in the UK
2 years, 0 months, 1 days
Research summary
Summary Of Research
The presence of airway twitchiness, also known as airway hyper-responsiveness, is one of the hallmark features of persistent asthma, reflecting increased sensitivity of the airway to a variety of external stimuli. Studies have found that asthmatic patients with airway twitchiness have significantly higher levels of particular white blood cells called eosinophils, and higher levels of a molecule found in exhaled breath called fractional exhaled nitric oxide (FeNO). Together, eosinophils and FeNO can indicate a specific form of airway inflammation also known as type 2 inflammation.Dupilumab, also known by the trade name of Dupixent, is a monoclonal antibody which is a type of protein that inhibits the signalling of target proteins called interleukin-4 and interleukin-13. By blocking the signalling of these proteins, dupilumab helps to reduce the airway inflammation caused by eosinophils in asthma. Dupilumab is currently being appraised by National Institute for Health and Care Excellence (NICE) as an add-on treatment option for severe asthma in adults. Eligible patients will be those with severe asthma who are already taking a medium to high dose of inhaled corticosteroid and long-acting beta agonist who exhibit a significant degree of airway twitchiness and a raised blood eosinophil level.
The primary objective is to assess the effect of dupilumab on airway hyper-responsiveness, after 12 weeks of treatment with dupilumab utilising mannitol challenge as the provocative dose causing a 10% fall in FEV1 (PD10 Mannitol).
Summary of Results
The presence of airway over-reactivity, also known as airway hyper-responsiveness, is one of the hallmark features of persistent asthma, reflecting increased sensitivity of the airway. Dupilumab, also known as Dupixent, is a monoclonal antibody which has been used to improve symptoms in people with severe asthma. In this study, we aimed to assess if dupilumab, after 12 weeks of treatment, reduced airway hyper-responsiveness in people with severe asthma which had not previously been investigated.The project’s short title is ‘Dupilumab in severe asthma’. The research project was sponsored by the University of Dundee and NHS Tayside, and was funded by Sanofi Genzyme. The study took place at the Scottish Centre for Respiratory Research at the University of Dundee.
People with severe asthma were recruited to the study. All participants received 12 weeks of dupilumab treatment which was given as a 2-weekly injection. 23 participants completed all the investigations in the study up to week 12. During the study, all participants took the same background inhaler (Fostair Nexthaler) which was a maintenance and reliever therapy that was used between 2 and 8 puffs per day. Participants had regular assessment of their asthma with questionnaires about their symptoms as well as several regular lung function tests and airway investigations. Spirometry is a test where people perform a forced exhale, and the volumes are measured. A test called mannitol challenge was used to assess airway hyper-responsiveness. Mannitol can cause symptoms of asthma when inhaled. The test is done by increasing the inhaled dose of mannitol to measure how much mannitol people can tolerate before a threshold is reached where the lung function has reduced.
The average (mean) dose of mannitol tolerated at the start of the study before any dupilumab was 125mg. By week 4 this significantly increased to 329mg, and by week 12 it significantly increased to 428mg, meaning that on average participants were able to tolerate higher doses of mannitol before their lung function was affected whilst taking dupilumab. When assessing spirometry, the forced expiratory volume of air in 1 second significantly improved from 2.51L prior to dupilumab to 2.90L at 12 weeks. Questionnaires about asthma symptoms and asthma quality of life also showed a significant improvement with dupilumab treatment. In addition, the number of puffs of the background inhaler that participants were using, reduced significantly from an average (mean) of 5.2 puffs per day, to 3.6 puffs per day after dupilumab.
Reactions noted during the trial, included injection site reaction (swelling or redness) in 5 participants, injection site pain in 2 participants, mouth ulcers in 1 participant, and blood eosinophilia (a raised white cell in the blood) in 1 participant. One participant required admission to hospital for a urinary tract infection which was unrelated to asthma and dupilumab. Two participants were withdrawn early from the study due to high eosinophils and were not included in the rest of the study.
The study investigators wish to thank all participants for their contribution to the study. The full results from this study can be found at the publication below:
Effects of dupilumab on mannitol airway hyperresponsiveness in uncontrolled severe asthma Stewart, Kirsten E. et al. Journal of Allergy and Clinical Immunology, Volume 155, Issue 3, 834 - 842.e6
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fpubmed.ncbi.nlm.nih.gov%252F39608583%252F%2FNBTI%2F4_S8AQ%2FAQ%2Ffbd165c1-83e4-4e1a-b4a9-598c625b21aa%2F2%2FRRzgEBZlXd&data=05%7C02%7Capprovals%40hra.nhs.uk%7C68d13086629943c4ffb308dd83407e8d%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638811035238021002%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=arqRtkIEMSEAgYMA2yssf5KmbMZg8YCb8%2FklRqRUWio%3D&reserved=0
https://eur03.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fwww.jacionline.org%252Farticle%252FS0091-6749&data=05%7C02%7Capprovals%40hra.nhs.uk%7C68d13086629943c4ffb308dd83407e8d%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638811035238040895%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=modGBZmqs38Xp%2F9QYRpDCvKIcvHjmkWF87UJ0jESvtw%3D&reserved=0(24)01275-2%2Ffulltext/NBTI/4_S8AQ/AQ/fbd165c1-83e4-4e1a-b4a9-598c625b21aa/3/ViH4pXnrgeREC name
West of Scotland REC 1
REC reference
21/WS/0151
Date of REC Opinion
7 Feb 2022
REC opinion
Further Information Favourable Opinion