AIR-NET- Testing anti-inflammatories for the treatment of bronchiectasis
| ISRCTN | ISRCTN17596258 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17596258 |
| IRAS number | 1010124 |
| Secondary identifying numbers | 1-027-24, CPMS 62256 |
- Submission date
- 02/08/2024
- Registration date
- 23/10/2024
- Last edited
- 06/11/2024
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Respiratory
Plain English Summary
Background and study aims
AIR-NET- Testing anti-inflammatories for the treatment of bronchiectasis
Who can participate?
Adults over 18 years, with bronchiectasis.
What does the study involve?
Not provided at time of registration
What are the possible benefits and risks of participating?
Benefits:
Not provided at time of registration
Risks:
This trial is categorised as: Type B, Somewhat higher than the risk of standard medical care. The trial treatments are all repurposed drugs already approved for use in conditions other than bronchiectasis.
Arm 1: Usual care
Arm 2: Disulfiram
Disulfiram is an alcohol deterrent compound licensed for use as an adjuvant in the treatment of drinking problems. The most common adverse reaction (AR) reported during treatment is alcohol reaction. Disulfiram–ethanol reactions often develop within 15 minutes after exposure to ethanol; symptoms usually peak within 30 minutes to 1 hour, and then gradually subside over the next few hours. Symptoms may be severe and life-threatening. Participants will be informed of the reaction risk and must agree to abstain from alcohol during treatment and for up to 14 days after discontinuation.
Arm 3: Dipyridamole
Dipyridamole is licensed for use in secondary prevention of ischaemic stroke and transient ischaemic attacks and as an adjunct to oral anti-coagulation for prophylaxis of thromboembolism associated with prosthetic heart valves. The most commonly reported adverse effects are headache, dizziness, diarrhoea, nausea (very common, ≥1/10) and angina pectoris, vomiting, rash, myalgia (common, ≥ 1/100 < 1/10).
Arm 4: Doxycycline
Doxycycline is licensed for use in the treatment of a variety of infections caused by susceptible strains of Gram-positive and Gram-negative bacteria and certain other micro-organisms. The most common adverse effects observed in patients receiving tetracyclines, including doxycycline, are hypersensitivity, headache, nausea/vomiting, photosensitivity reaction rash including maculopapular and erythematous rashes (common, ≥ 1/100 < 1/10).
Adverse events, medications, exacerbations and vital signs will be reviewed at each visit. Regular safety bloods will be performed to assess full blood count, urea and electrolytes and liver function tests.
The data monitoring committee will perform a safety review of each active treatment arm. Each safety review will take place after 10 participants have completed treatment in the active arm.
Where is the study run from?
University of Dundee (UK)
When is the study starting and how long is it expected to run for?
July 2024 to February 2027
Who is funding the study?
LifeArc (UK)
Who is the main contact?
airnet-tm@dundee.ac.uk
Professor James Chalmers, j.chalmers@dundee.ac.uk
Contact information
Principal Investigator
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
| Phone | +44 1382 386131 |
|---|---|
| j.chalmers@dundee.ac.uk |
Public, Scientific
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
| airnet-tm@dundee.ac.uk |
Study information
| Study design | Interventional double blind randomized parallel group controlled trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised parallel trial |
| Study setting(s) | Hospital |
| Study type | Safety, Efficacy |
| Scientific title | A randomised, open-label, multifactorial, multicentre, platform trial using a range of repurposed anti-inflammatory treatments to improve outcomes in patients with bronchiectasis not due to cystic fibrosis, within the EMBARC international clinical research network. |
| Study acronym | AIR-NET |
| Study hypothesis | Primary objective: To evaluate the effect of a range of interventions compared to usual care on the activity of NE in sputum Secondary objectives: 1. To evaluate the effect of a range of interventions compared to usual care on the activity of NE in sputum 2. To evaluate the effect of a range of interventions compared to usual care on time to onset of first bronchiectasis exacerbation 3. To evaluate the effect of a range of interventions compared to usual care on quality of life 4. To evaluate the effect of a range of interventions compared to usual care on clinical benefits 5. To evaluate the effect of a range of interventions compared to usual care on walking distance 6. To evaluate the safety of a range of interventions compared with usual care 7. To evaluate the effect of a range of interventions on peripheral blood neutrophil function |
| Ethics approval(s) |
Approved 21/10/2024, London-Central Research Ethics Committee (3rd Floor 3 picadilly Place, London Road, Manchester, M1 3BN, United Kingdom; +44 (0)207 104 8061; londoncentral.rec@hra.nhs.uk), ref: 24/LO/0679 |
| Condition | Bronchiectasis |
| Intervention | Participants will be randomised using the online Tayside Randomisation System (TRuST) to one of the trial arms: Arm 1: Usual care Arm 2: Disulfiram 200 mg, two tablets taken orally, once daily Arm 3: Dipyridamole 200 mg, one capsule taken orally, twice daily Arm 4: Doxycycline 100 mg, one capsule taken orally, once daily Trial treatment will be for 28 days, with a 28 day follow up period. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Therapy |
| Phase | Phase II |
| Drug / device / biological / vaccine name(s) | Disulfiram, dipyridamole, doxycycline |
| Primary outcome measure | Activity of sputum Neutrophil elastase. Day 0 and 28 |
| Secondary outcome measures | Current secondary outcome measures as of 06/11/2024: 1. Activity of sputum Neutrophil elastase. Days 0, 7, 14 and 56 2. Time to first pulmonary exacerbation (EMBARC definition). Days 0 to 28 3. Quality of life-bronchiectasis (QOL-B) respiratory symptom scale, Bronchiectasis Impact Measure (BIM) questionnaire. Days 0, 7, 14, 28 and 56 4. Distance covered during a 6-minute walk. Days 0 to 28 5. Frequency of adverse events (AEs) and serious adverse events (SAEs). Day 0, 28 6. Phagocytosis of bacteria; Reactive oxygen species generation; Degranulation; Ex-vivo formation of neutrophil extracellular traps; Mass cytometry (endpoints may vary depending on the experimental arm). Days 0 to 56 Tertiary outcome measures: 1. Frequency of pulmonary exacerbations (EMBARC definition). Days 0 to 28; Days 0 to 56 2. Measure the concentration of MMPs and NETs in sputum, as well as other biomarkers e.g. proteomics, bacterial load, microbiome. Days 0, 7, 14, 28 and 56 3. Measure serum biomarkers of inflammation and redox status. Days 0, 7, 14, 28 and 56 4. Peripheral blood neutrophil proteomics performed on isolated cells. Days 0 and 28 Previous secondary outcome measures: 1. Activity of sputum Neutrophil elastase. Days 0, 7, 14 and 56 2. Time to first pulmonary exacerbation (EMBARC definition). Days 0 to 28 3. Quality of life-bronchiectasis (QOL-B) respiratory symptom scale, Bronchiectasis Impact Measure (BIM) questionnaire. Days 0, 7, 14, 28 and 56 4. Distance covered during a 6-minute walk. Days 0 to 28 5. Frequency of adverse events (AEs) and serious adverse events (SAEs). Day 0, 28 6. Phagocytosis of bacteria; Reactive oxygen species generation; Degranulation; Ex-vivo formation of neutrophil extracellular traps; Mass cytometry (endpoints may vary depending on the experimental arm). Days 0 to 56 Tertiary outcome measures: 1. Frequency of pulmonary exacerbations (EMBARC definition). Days 0 to 28; Days 0 to 56 2. Measure the concentration of MMPs and NETs in sputum, as well as other biomarkers e.g. proteomics, bacterial load, microbiome. Days 0, 7, 14, 28 and 56 3. Measure serum biomarkers of inflammation and redox status. Days 0, 7, 14, 28 and 56 4. Peripheral blood neutrophil proteomics performed on isolated cells. Days 0 and 28 5. Label-free liquid chromatography/mass spectrometry sputum identification and relative quantification of proteins. Day 0 and 28 6. Peripheral blood transcriptomics. Day 0 and 28 7. Nasal brushing transcriptomics. Day 0 and 28 Sub-study outcome measures: 1. Change in skin perfusion with iontophoresis of acetylcholine and sodium nitroprusside using laser Doppler perfusion imaging. Days 0, 28 and 56 2. Change in arterial stiffness index. Days 0, 28 and 56 3. Change in pulse wave velocity. Days 0, 28 and 56 |
| Overall study start date | 31/07/2024 |
| Overall study end date | 28/02/2027 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 168 |
| Participant inclusion criteria | 1. ≥18 years 2. Able to provide informed consent. 3. Capable of complying with all trial procedures and of completing the trial, in the opinion of the investigator. 4. Bronchiectasis, confirmed by computed tomography (CT), showing bronchiectasis in 1 or more lobes. 5. Normally produces sputum daily. 6. Able to provide a sputum sample at the screening visit or between screening and randomisation. 7. Active neutrophilic inflammation at screening/baseline indicated by a positive NEATstik (Neutrophil Elastase Airways Test) result. |
| Participant exclusion criteria | 1. Enrolled previously in the trial 3 times. 2. Respiratory infection or bronchiectasis exacerbation 4 weeks prior to screening and/or between screening and randomisation 3. Antibiotic or corticosteroid 4 weeks prior to screening and/or between screening and randomisation 4. Active allergic bronchopulmonary aspergillosis (defined by International Society for Human and Animal Mycology criteria) on steroids and/or anti-fungals, 5. Nontuberculous mycobacterial infection on antibiotic therapy 6. Immunodeficiency on immunoglobulin replacement 7. A primary diagnosis of COPD or asthma (a secondary diagnosis of COPD or asthma is permitted) 8. Cystic fibrosis 9. Active malignancy except non-melanoma skin cancer 10. Currently taking brensocatib 11. Use of any investigational drugs within five times of the elimination half-life after the last dose or within 30 days, whichever is longer. Current enrolment in non-interventional, observational studies will be allowed 12. Currently pregnant or breast-feeding 13. Women of childbearing age and not practicing an acceptable method of birth control 14. Additional exclusion criteria for individual treatment arms are described in the protocol |
| Recruitment start date | 18/11/2024 |
| Recruitment end date | 01/03/2026 |
Locations
Countries of recruitment
- United Kingdom
Study participating centre
United Kingdom
Sponsor information
University/education
Ninewells Hospital and Medical School
Dundee
DD1 9SY
United Kingdom
| Phone | +44 1382 383297 |
|---|---|
| TASCgovernance@dundee.ac.uk | |
| Website | http://www.dundee.ac.uk/ |
"ROR" |
https://ror.org/03h2bxq36 |
Funders
Funder type
Research organisation
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 28/02/2028 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Peer reviewed scientific journals Conference presentation Submission to regulatory authorities Other Consent will be sought for data to be shared for the purposes of research. Any information which identifies the participant will be removed prior to sharing. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are/will be available upon request from the Chief Investigator (Professor James Chalmers, j.chalmers@dundee.ac.uk). Approval of requests will be at the discretion of the Chief Investigator. Data will be available after the primary publication of the relevant experimental arm; there is no end date for requests. Data will be transferred using an appropriate secure method (e.g. encrypted email, file transfer system, or similar), and will be limited to only data required to perform the proposed analysis. Data will be anonymised or pseudonymised as appropriate. Patient consent for data sharing will be obtained at trial entry. The full details and terms of the transfer will be set out in a data sharing agreement. |
Editorial Notes
06/11/2024: The following changes were made:
1. Ethics approval was added.
2. The recruitment start date was changed from 31/08/2024 to 18/11/2024.
3. The secondary outcome measures were updated.
06/11/2024: Internal review.
02/08/2024: Trial's existence confirmed by NHS HRA.
