BEAT Severe Asthma
Research type
Research Study
Full title
Beyond Allergic Th2 Severe Asthma
IRAS ID
247350
Contact name
Salman Siddiqui
Contact email
Eudract number
2019-003013-34
Duration of Study in the UK
2 years, 8 months, 29 days
Research summary
Research Summary
This is a platform trial with two parallel group, randomised double blind, placebo controlled, cohorts in participants with severe asthma.
We will work with severe asthma specialist centres in the UK to identify patients who experience frequent severe asthma attacks (2 or more per year). We will take a blood test that measures blood eosinophil levels (a type of blood cell associated with inflammation) to identify two important sub-types of severe asthma. The first of interest to us is called “T2-HIGH” severe asthma and might be driven by high numbers of eosinophils in the blood that then move to the airways in the lungs and may cause asthma attacks. The second is called “T2-LOW” severe asthma and might be caused by bacteria living in the lungs and how they work with the immune cells. Once we have identified patients in the T2-LOW sub-type group we will test whether a simple, antibiotic (doxycycline) can reduce asthma attacks by changing the bacteria present in the lungs. This will help to identify the right patients to give “long-term” antibiotics to, and to see whether the bacteria that live in the lungs might be responsible for causing asthma attacks. If we find out that targeting certain bacteria that live in the lung reduces asthma attacks, this could pave the way for a future trial evaluating other types of interventions such as probiotics. The patients in the T2-HIGH sub-type will test a new oral tablet called dexpramipexole, which lowers the number of eosinophils in the blood by stopping them growing in the person’s bone marrow (the part of the body that produces new blood cells). We want to see if this treatment will be effective in reducing asthma attacks in this sub-type.Summary of Results
Background It is estimated that around 5% of people with asthma have severe asthma. This typically presents as a high number of symptoms and poor lung function, despite regular medications, and repeated asthma attacks frequently requiring time off work and hospital admission. Severe asthma is an umbrella term for several different disease types, which can be identified using blood tests (biomarkers). Many patients with severe asthma find that regular oral steroids have multiple intolerable side effects, including difficulty sleeping, weight gain, changes in mood, diabetes, weakening of the bones, high blood pressure and eye conditions such as glaucoma and cataracts, and wish to stop taking oral steroids as early as possible. In this study we will work with severe asthma specialist centres in the UK to identify patients who experience frequent asthma attacks (2 or more per year). There are currently 2 recognised subtypes of severe asthma which can be characterised by their level of eosinophils (a type of white blood cells). We will test whether a simple, once daily oral antibiotic (doxycycline) can reduce asthma attacks in individuals with low levels of eosinophils. We will also test whether a simple twice daily oral drug (dexpramipexole) can reduce asthma attacks in individuals with high levels of eosinophils. This work will help to identify the right patients to give which drugs to. If we find out that this targeted approach reduces asthma attacks, this could pave the way for future trial evaluating other types of intervention.
Objectives
Stage 1 (Screening) Primary Objectives:
I. Identify patients with severe, exacerbation prone asthma in UK specialist severe asthma centres.
II. Stratify patients using blood eosinophil levels into T2-HIGH/T2-LOW phenotypes.
III. Conduct two, 58-week, phase 2, randomised double blind placebo-controlled exacerbation trials
(RDBPCT) of oral dexpramipexole (T2-HIGH) and oral doxycycline (T2-LOW).Stage 1 (Screening) Secondary Objectives:
I. Efficient Trial Setup
Establish and implement the clinical trial protocol (with appropriate approvals) across the core trial sites in conjunction with the Sponsor (the University of Leicester and its clinical trials unit (Leicester Clinical Trials Unit, LCTU)).II. Efficient Trial Delivery
Undertake RDBPCTs of IMPs in T2-HIGH and T2-LOW severe asthma and evaluate the impact upon severe exacerbations (primary endpoint), lung function, asthma control, and quality of life.III. Mechanisms of Action
To understand the mechanisms of therapeutic response in the trials. Specifically, modification of blood eosinophils (T2-HIGH), airways dysbiosis (T2-HIGH and T2-LOW) and neutrophilic inflammation (T2-LOW trial) will be evaluated as a potential mechanism of exacerbation reduction and broader therapeutic response. The impact of T2-HIGH/T2-LOW interventions on subclinical exacerbations will be evaluated using a statistical algorithm (CompEx) applied to daily symptom, reliever use and peak flow micro diary data, where available, in consenting participants.Study Design
Platform trial currently two embedded (parallel group), randomised, double blind, placebo controlled, treatment approaches in patients stratified into T2-HIGH/T2-LOW severe asthma phenotypes (using blood eosinophil levels). (Additional trial arms may be added subject to funding and sponsorship).Hypothesis
The BEyond Allergic Th2 Severe asthma consortium hypothesise that:
(i) The development of a severe asthma multi-disciplinary team (MDT) (or non-English equivalent see protocol section 3.2), centred clinical trial platform will facilitate the delivery of severe asthma trials in the UK.
(ii) Stratified approaches utilising blood eosinophils to target exacerbation prone T2-HIGH/T2-LOW subtypes of severe asthma, will provide a step change in asthma care by reducing asthma exacerbations and improving asthma control and quality of life.Results
The T2-LOW treatment cohort of the BEyond Allergic Th2 Severe Asthma (BEAT-SA) study was made-up of 26 participants, with 13 participants allocated to the Doxycycline group and another 13 being allocated to the Placebo group. The trial was closed to recruitment following review by the funder at the end of the funded grant period having failed to reach the recruitment target in the post covid era. A total of 2 (7.7%) participants attended the last dispensing visit at 365 days follow-up while 24 (92.3%) participants attended the Safety Follow-up visit.
The T2-HIGH treatment cohort of the BEyond Allergic Th2 Severe Asthma (BEAT-SA) study was made-up of 5 participants, with 3 participants allocated to the Dexpramipexole group and another 2 being allocated to the Placebo group. The trial was closed to recruitment following agreement with the trial management group, oversight committees and sponsor, a factor being the parallel completion of a successful early phase clinical trial of dexpramipexole allowing the drug to progress to definitive clinical trials. No participants attended the last dispensing visit at 365 days follow-up; however, 4 (80%) participants attended the Safety Follow-up visit.
It is important to note that it was not possible to conduct any powered statistical hypothesis testing/modelling for any of the outcomes of the T2-LOW and T2-HIGH treatment cohorts as originally planned in the Protocol due to lack of data.
Conclusion
An ongoing Phase 3 clinical trial is evaluating dexpramipexole in asthma and further research is required to determine the role of doxycycline in T2-Low asthma. There are barriers to completing the T2-Low trial which can provide lessons to help deliver other asthma trials in the future.
Dissemination
It is planned that the learning from this trial will be published in peer-reviewed journals as well as disseminated to patients and the wider public (e.g. using Asthma UK websites or social media channels).REC name
East Midlands - Leicester South Research Ethics Committee
REC reference
20/EM/0015
Date of REC Opinion
2 Mar 2020
REC opinion
Further Information Favourable Opinion