Treatment of inflammation inside the eye caused by an overactive immune system (autoimmune uveitis) using adalimumab
| ISRCTN | ISRCTN31474800 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN31474800 |
| EudraCT/CTIS number | 2020-000754-97 |
| IRAS number | 271051 |
| Secondary identifying numbers | IRAS 271051, CPMS 45139 |
- Submission date
- 25/03/2020
- Registration date
- 14/04/2020
- Last edited
- 25/03/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Eye Diseases
Plain English Summary
Background and study aims
Autoimmune uveitis is a term for several rare eye diseases in which the body’s own immune system causes sight-threatening damage to the light sensitive retina at the back of the eye. Uveitis causes sight loss from inflammation inside the eye, damage to blood vessels in the retina or leakage of fluid into the central, most sensitive area of the retina. Two in 10,000 people are at risk of serious sight loss from uveitis. Usual treatment for autoimmune uveitis involves low dose steroids and one or two other drugs to reduce inflammation. Unfortunately, many patients do not respond to or tolerate usual treatment, or they need high dose steroids to control the uveitis. Long term high dose steroids increase the risk of heart attack, stroke, and infection and affect physical and mental health. Adalimumab is a drug that targets chemicals released by inflamed tissue, neutralising their damage to the body. This study aims, first, to identify patients who are most likely to benefit from adalimumab. Then, in patients who are successfully treated with adalimumab and low dose steroids, a randomised controlled trial will be conducted to compare adalimumab and placebo.
Who can participate?
Adults over 18 years, with sight-threatening autoimmune non-infectious uveitis and is prescribed corticosteroids greater than 5.0 mg/day.
What does the study involve?
All eligible patients who consent will be given adalimumab for a 16-week trial period, if necessary in combination with low dose of steroids; these patients will include those with impaired vision due to uveitis, requiring high dose steroids to bring the disease under control, and those with better vision but who require high dose steroids to keep the uveitis under control. Over the 16 weeks, doctors will aim to reduce the steroid dose to a low level that should not cause side effects.
Then, patients who are successfully treated with adalimumab and low dose steroids will enter the main study. They will be given adalimumab or a dummy treatment, in combination with their other medications (including low dose steroids). Chance will determine who receives which treatment and neither patients nor their eye doctors will know. Regular eye examinations, tests and questionnaires will be used to assess how well patients are doing. This part of the study, which will treat and follow up patients for 12 to 30 months, will find out whether adalimumab is better at preventing recurrence of uveitis than the dummy treatment and whether adalimumab is cost-effective compared to the dummy treatment.
What are the possible benefits and risks of participating?
The study cannot promise any benefits to participants but the information we get from this study will help improve the treatment of people with uveitis. Patients who are currently not eligible for adalimumab on the NHS could benefit from being prescribed it as part of this study. Participants might be able to reduce their dose of corticosteroids if taking adalimumab. It is possible, but cannot be guaranteed, that participants will eventually be able to stop taking at least one of their other immunosuppression medications.
There is a small risk of permanent eye damage from uveitis if participants are allocated to the placebo group, although the risk is the same as if they were receiving normal NHS care and not taking adalimumab. To minimise this risk, participants will be closely monitored with frequent enough hospital visits that if their condition relapses it should be picked up by their eye doctor before permanent uveitis damage occurs. In both group, injections under the skin can be mildly sore, and participants can get a reaction at the injection site. Adalimumab can cause side effects, although not everybody gets them. Most side effects are mild to moderate. However, some may be serious and require treatment. Side effects may occur up to four months or more after the last adalimumab injection.
Patient and public involvement
Patients with uveitis have contributed to the study from the start, helping to: design the protocol to ensure it applies to uveitis patients who may benefit; co-authoring the lay summary; helping to draft the application, providing feedback on the trial design and participating in a national survey to assess support for the study. They will continue to contribute in these ways and provide support to patients. The research team includes eye doctors and researchers with expertise in doing eye studies.
Where is the study run from?
Bristol Trials Centre (UK)
When is the study starting and how long is it expected to run for?
November 2020 to June 2026
Who is funding the study?
National Institute for Health Research (UK)
Who is the main contact?
Kirsty Lanyon, astute-trial@bristol.ac.uk
Contact information
Public
Bristol Trials Centre
University of Bristol
Level 7 Queens Building
Bristol Royal Infirmary
Bristol
BS2 8HW
United Kingdom
| Phone | +44 (0)117 455 1343 |
|---|---|
| astute-trial@bristol.ac.uk |
Study information
| Study design | Double-blind parallel multi-centre randomized placebo-controlled trial with open-label treatment run-in period |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | The ASTUTE trial: Adalimumab vs placebo as add-on to Standard Therapy for autoimmune Uveitis: Tolerability, Effectiveness and cost-effectiveness: a randomized controlled trial |
| Study acronym | ASTUTE |
| Study hypothesis | The trial hypothesises that adalimumab reduces the hazard of treatment failure in patients with autoimmune non-infectious uveitis (ANIU), after weaning of corticosteroids (CS) to less than or equal to 5 mg/day in a treatment run-in period. |
| Ethics approval(s) |
Approved 03/06/2020, South Central - Oxford B Research Ethics Committee (Level 3, Block B, Whitefriars, Lewins Mead, Bristol, BS1 2NT, United Kingdom; +44 (0)2071048046; oxfordb.rec@hra.nhs.uk), ref: 20/SC/0153 |
| Condition | Autoimmune non-infectious uveitis |
| Intervention | Current interventions as of 25/03/2025: All participants start on open-label adalimumab for 16 weeks. Participants who respond to adalimumab are randomised to adalimumab or placebo for up to 128 weeks. Randomisation is concealed and done by an online computer program after data to confirm eligibility is recorded. Adalimumab (Imraldi) and placebo Dose: 80mg followed by 40mg every 2 weeks, starting 1 week after the initial dose. During the treatment run-in phase, data are collected at week 4, week 8, and week 16. During the RCT phase, data is collected at 12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, 128 weeks, 144 weeks and 160 weeks. Open-Label Extension: active patients were approached to consent to being unmasked to their current allocation. Patients allocated to placebo no longer receive the study drug, and patients allocated to adalimumab will continue to receive the study drug until the end of the follow-up period. Patients who did not consent to transition to the Open-Label Extension were withdrawn from the study. Previous interventions: All participants start on open-label adalimumab for 16 weeks. Participants who respond to adalimumab are randomised to adalimumab or placebo for up to 128 weeks. Randomisation is concealed and done by an online computer program after data to confirm eligibility is recorded. Adalimumab (Imraldi) and placebo Dose: 80mg followed by 40mg every 2 weeks, starting 1 week after the initial dose. During the treatment run-in phase, data are collected at week 4, week 8, and week 16. During the RCT phase, data is collected at 12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, and 128 weeks. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase IV |
| Drug / device / biological / vaccine name(s) | Adalimumab |
| Primary outcome measure | Current primary outcome measure as of 25/03/2025: Time to the first treatment failure (TF) assessed at each visit after randomisation (12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, 128 weeks, 144 weeks and 160 weeks) i.e. TF may occur in either eye and may be triggered by incident ANIU in an eye that did not previously have ANIU. TF is defined as a composite of standard criteria reflecting clinical decision-making, including visual acuity and clinical signs of active inflammation, which have been used successfully in other ANIU trials. Participants will be assessed for TF at each visit after randomisation. Any of the following criteria in one or both eyes, where applicable, will constitute TF: 1. greater than or equal to 15 letter decrease in best-corrected visual acuity (BCVA), compared to BCVA measured by an optometrist masked to treatment allocation at the 16-week treatment run-in (TRI) visit 2. new active inflammatory chorioretinal lesions 3. greater than 20% increase in central macular thickness (CMT), compared to CMT at the 16-week TRI timepoint 4. onset or worsening of retinal vasculitis 5. 2-step worsening of vitreous haze cf. compared to best score at either the 8- or 16-week TRI visit vi. prescription by a masked clinician of greater than 5mg/day corticosteroids to maintain disease remission (i.e. to avert relapse before any of the above criteria for manifest active disease (i-v)) Previous primary outcome measures: Time to the first treatment failure (TF) assessed at each visit after randomisation (12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, and 128 weeks) i.e. TF may occur in either eye and may be triggered by incident ANIU in an eye that did not previously have ANIU. TF is defined as a composite of standard criteria reflecting clinical decision-making, including visual acuity and clinical signs of active inflammation, which have been used successfully in other ANIU trials. Participants will be assessed for TF at each visit after randomisation. Any of the following criteria in one or both eyes, where applicable, will constitute TF: 1. greater than or equal to 15 letter decrease in best-corrected visual acuity (BCVA), compared to BCVA measured by an optometrist masked to treatment allocation at the 16-week treatment run-in (TRI) visit 2. new active inflammatory chorioretinal lesions 3. greater than 20% increase in central macular thickness (CMT), compared to CMT at the 16-week TRI timepoint 4. onset or worsening of retinal vasculitis 5. 2-step worsening of vitreous haze cf. compared to best score at either the 8- or 16-week TRI visit vi. prescription by a masked clinician of greater than 5mg/day corticosteroids to maintain disease remission (i.e. to avert relapse before any of the above criteria for manifest active disease (i-v)) |
| Secondary outcome measures | Current primary outcome measure as of 25/03/2025: At 12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, 128 weeks, 144 weeks and 160 weeks, unless otherwise noted. 1. Individual treatment failure (TF) components, assessed at each trial visit 2. Retinal morphology (OCT; macular and retinal nerve fibre layer), assessed at each trial visit 3. Adverse events, assessed at each trial visit 4. Health-related quality of life measured using the EQ-5D-5L questionnaire at the start of treatment run-in (TRI), at 16 weeks immediately before randomisation, then 12-weekly after randomisation up to week 48 and 16-weekly thereafter 5. Patient-reported symptoms of side-effects at each trial visit after starting the TRI and at any interim attendance prompted by an adverse event 6. Patient-reported visual function at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter 7. Best corrected visual acuity (BCVA) assessed at each trial visit 8. Employment status at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter 9. Resource use during follow-up after randomisation, at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter Previous secondary outcome measures as of 13/12/2023 to 25/03/2025: At 12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, and 128 weeks unless otherwise noted. 1. Individual treatment failure (TF) components, assessed at each trial visit 2. Retinal morphology (OCT; macular and retinal nerve fibre layer), assessed at each trial visit 3. Adverse events, assessed at each trial visit 4. Health-related quality of life measured using the EQ-5D-5L questionnaire at the start of treatment run-in (TRI), at 16 weeks immediately before randomisation, then 12-weekly after randomisation up to week 48 and 16-weekly thereafter 5. Patient-reported symptoms of side-effects at each trial visit after starting the TRI and at any interim attendance prompted by an adverse event 6. Patient-reported visual function at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter 7. Best corrected visual acuity (BCVA) assessed at each trial visit 8. Employment status at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter 9. Resource use during follow-up after randomisation, at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter Previous secondary outcome measures: At 12 weeks, 24 weeks, 36 weeks, 48 weeks, 64 weeks, 80 weeks, 96 weeks, 112 weeks, and 128 weeks unless otherwise noted. 1. Individual treatment failure (TF) components, assessed at each trial visit 2. Retinal morphology (OCT; macular and retinal nerve fibre layer), assessed at each trial visit 3. Adverse events, assessed at each trial visit 4. Health-related quality of life measured using the EQ-5D-5L questionnaire at the start of treatment run-in (TRI), at 16 weeks immediately before randomisation, then 12-weekly after randomisation up to week 48 and 16-weekly thereafter 5. Patient-reported symptoms of side-effects at each trial visit after starting the TRI and at any interim attendance prompted by an adverse event 6. Patient-reported visual function at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter 7. Employment status at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter 8. Resource use during follow-up after randomisation, at the start of TRI, at 16 weeks immediately before randomisation, 12-weekly up to week 48 and 16 weekly thereafter |
| Overall study start date | 01/04/2020 |
| Overall study end date | 30/06/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 174 |
| Total final enrolment | 115 |
| Participant inclusion criteria | Current inclusion criteria as of 21/11/2023: 1. Aged 18 years or over 2. Participant has: 2.1. Active sight-threatening ANIU (active inflammatory chorioretinal lesions OR abnormal central macular thickness (CMT) OR evidence of retinal vasculitis OR vitreous haze >0.5) and is being prescribed (already taking or being started on, if newly presenting with ANIU) oral prednisolone >5.0 mg/day; OR 2.2. Has controlled ANIU and is being prescribed oral prednisolone >5.0 mg/day. 3. Women must have a negative pregnancy test and be willing to use effective contraception for the duration of the participation in the trial and for 5 months after, or be surgically sterile or post-menopausal for >12 months 4. Able to provide informed consent Previous inclusion criteria: 1. Aged 18 years or over 2. Sight-threatening ANIU and is prescribed CS greater than 5.0 mg/day 3. Women must have a negative pregnancy test and be willing to use effective contraception for the duration of the participation in the trial and for 5 months after, or be surgically sterile or post-menopausal for >12 months 4. Able to provide informed consent |
| Participant exclusion criteria | Current participant exclusion criteria as of 06/07/2022: 1. Participant has controlled ANIU and is maintained on oral prednisolone ≤5.0mg/day at the time of screening 2. Participant has systemic disease (whether associated with ANIU or not) that is being treated with steroids and requires >5mg/day oral prednisolone 3. Participant has untreated or active tuberculosis 4. Participant has severe infection, sepsis, or opportunistic infection 5. Participant has uncontrolled glaucoma 6. Participant has multiple sclerosis 7. Participant is HIV positive 8. Participant has hepatitis B or hepatitis C 9. Participant has syphilis 10. Participant has Lyme disease 11. Participant has Behcet’s disease 12. Participant has toxoplasmosis chorioretinitis 13. Participant has heart failure (NYHA III/IV) 14. Participant has been diagnosed with cancer <5 years ago 15. Participant is undergoing monitoring for recurrence of cancer/tumour growth where their oncologist has concern that a TNFalpha inhibitor would be contraindicated 16. Participant is taking another biologic drug 17. Participant has taken an anti-TNF drug within the previous 90 days (anakinra and abatacept are contraindicated); 18. Participant has had an Iluvien® implant within the previous 18 months and has controlled ANIU, or has had an Iluvien® implant within the previous 12 weeks regardless of whether ANIU is active or controlled 19. Participant has had an Ozurdex® implant, or an intravitreal steroid injection, or periocular steroid within the previous 12 weeks regardless of whether ANIU is active or controlled 20. Participant is pregnant 21. Participant has a known allergy or hypersensitivity to adalimumab or any of its excipients 22. Participant is taking part in another interventional study 23. Participant has an epiretinal membrane likely to prevent an eye meeting response criterion at 16 weeks of central macular thickness <320um Previous exclusion criteria as of 08/06/2020: 1. Participant has controlled ANIU and is maintained on CS ≤5.0mg/day at the time of screening 2. Participant has untreated or active tuberculosis 3. Participant has severe infection, sepsis or opportunistic infection 4. Participant has uncontrolled glaucoma 5. Participant has multiple sclerosis 6. Participant is HIV positive 7. Participant has hepatitis B or hepatitis C 8. Participant has syphilis 9. Participant has Lyme disease 10. Participant has Behcet's disease 11. Participant has heart failure (NYHA III/IV; 12. Participant has been diagnosed with cancer <5 years ago 13. Participant is undergoing monitoring for recurrence of cancer/tumour growth where their oncologist has concern that a TNFalpha inhibitor would be contraindicated 14. Participant is taking another biologic drug 15. Participant has taken an anti-TNF drug within the previous 90 days (anakinra and abatacept are contraindicated) 16. Participant has an ocular CS implant within the previous 12 months or an intravitreal steroid injection within the previous 3 months 17. Participant is pregnant 18. Participant has a known allergy or hypersensitivity to adalimumab or any of its excipients 19. Participant is taking part in another interventional study _____ Previous exclusion criteria: 1. Controlled ANIU and is maintained on CS less than or equal to 5.0 mg/day at the time of screening 2. Untreated or active tuberculosis 3. Severe infection, sepsis or opportunistic infection 4. Uncontrolled glaucoma 5. Multiple sclerosis 6. HIV positive 7. Hepatitis B or hepatitis C 8. Behcet’s disease 9. Heart failure (NYHA III/IV) 10. No history of varicella or does not have varicella antibodies 11. Taking another biologic drug 12. Taken an anti-TNF drug within the previous 90 days (anakinra and abatacept are contraindicated) 13. Ocular CS implant within the previous 12 months or an intravitreal steroid injection within the previous 3 months 14. Pregnant 15. Known allergy or hypersensitivity to adalimumab or any of its excipients 16. Taking part in another interventional study |
| Recruitment start date | 01/12/2020 |
| Recruitment end date | 07/06/2024 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Marlborough Street
Bristol
BS1 3NU
United Kingdom
Headley Way
Oxford
OX3 9DU
United Kingdom
Prescot Street
Liverpool
L7 8XP
United Kingdom
Colney Lane
Norwich
NR4 7UY
United Kingdom
Wigginton Road
York
YO31 8HE
United Kingdom
Infirmary Square
Leicester
LE1 5WW
United Kingdom
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Derby Road
Nottingham
NG7 2UH
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Beckett Street
Leeds
LS9 7TF
United Kingdom
162 City Rd
London
EC1V 2PD
United Kingdom
Bradford
BD9 6RJ
United Kingdom
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Glossop Road
Sheffield
S10 2JF
United Kingdom
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
University Hospitals Sussex NHS Foundation Trust
Eastern Road
Brighton
BN2 5BF
United Kingdom
Sponsor information
Hospital/treatment centre
Marlborough Street
Bristol
BS1 3NU
England
United Kingdom
| Phone | +44 (0)1173420233 |
|---|---|
| research@uhbw.nhs.uk | |
| Website | https://www.uhbw.nhs.uk/ |
Funders
Funder type
Government
Government organisation / National government
- Alternative name(s)
- National Institute for Health Research, NIHR Research, NIHRresearch, NIHR - National Institute for Health Research, NIHR (The National Institute for Health and Care Research), NIHR
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/07/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Results will be published in peer-reviewed medical journals and presented at professional conferences. Results will be disseminated via patient groups, on the trial web-page and publicised on social media. A summary of the results will be sent to participants who specify that they would like to receive them. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. (Contact the chief investigator Prof Andrew Dick; Email: a.dick@bristol.ac.uk. Data will be made available after the trial outcomes paper is published in a peer-reviewed journal; applicants must provide an as a minimum a publicly available pre-specified protocol describing the purpose, methods and analysis of the secondary research; de-identified data will be available indefinitely; consent from participants for secondary use of data will be obtained; patient identifiable data will never be shared with third parties. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version v3.0 | 20/05/2020 | 06/11/2020 | No | No |
| Protocol file | version V4.0 | 15/10/2020 | 19/11/2020 | No | No |
| Protocol file | version 6.0 | 11/11/2021 | 21/03/2022 | No | No |
| Protocol file | version 7.0 | 25/04/2022 | 06/07/2022 | No | No |
| Protocol file | version 8.0 | 29/07/2022 | 23/01/2023 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 24/01/2024 | 25/01/2024 | Yes | No | |
| Protocol file | version 9.0 | 31/10/2023 | 25/03/2025 | No | No |
| Protocol file | version 10.0 | 12/07/2024 | 25/03/2025 | No | No |
| Protocol file | version 11.0 | 10/09/2024 | 25/03/2025 | No | No |
Additional files
- ISRCTN31474800_Protocol_v3.0_20May2020.pdf
- Uploaded 06/11/2020
- ISRCTN31474800_PROTOCOL_V4.0_15Oct20.pdf
- Uploaded 19/11/2020
- ISRCTN31474800_Protocol_v6.0_11Nov2021.pdf
- ISRCTN31474800_Protocol_v7.0_25Apr22.pdf
- ISRCTN31474800_PROTOCOL_V8.0_29Jul22.pdf
- ISRCTN31474800_protocol_v9.0_31Oct2023.pdf
- ISRCTN31474800_protocol_v10.0_12July2024.pdf
- ISRCTN31474800_protocol_v11.0_10Sept2024.pdf
Editorial Notes
25/03/2025: The following changes were made:
1. Protocol versions 9.0, 10.0 and 11.0 were uploaded (not peer-reviewed).
2. Contact information was updated.
3. The interventions, primary and secondary outcome measures were amended to include a study amendment that was approved in September 2024.
4. The study website link was amended.
5. The recruitment end date was changed from 16/10/2024 to 07/06/2024.
6. The study participating centres, University Hospital Coventry and Manchester Royal Infirmary, were removed.
11/11/2024: The following changes were made to the study record:
1. The recruitment end date was changed from 30/11/2024 to 16/10/2024.
2. Total final enrolment added.
25/01/2024: Publication reference added.
13/12/2023: The secondary outcome measures were amended.
21/11/2023: The following changes were made to the study record:
1. The recruitment end date was changed from 30/04/2023 to 30/11/2024.
2. The overall study end date was changed from 31/03/2024 to 30/06/2026.
3. The intention to publish date was changed from 01/04/2024 to 01/07/2026.
4. The target number of participants was changed from 400 to 174.
5. Contact details and inclusion criteria updated.
10/02/2023: The recruitment end date was changed from 28/02/2023 to 30/04/2023.
23/01/2023: A protocol (not peer reviewed) has been uploaded as an additional file.
07/12/2022: The recruitment end date was changed from 31/12/2022 to 28/02/2023.
24/11/2022: Sussex Eye Hospital was added as a trial participating centre.
09/09/2022: James Cook University Hospital was added as a trial participating centre.
11/08/2022: The trial participating centre Maidstone Hospital was added.
06/07/2022: The following changes have been made:
1. The participant exclusion criteria have been updated.
2. Royal Hallamshire Hospital was added as a trial participating centre.
3. Royal Surrey County Hospital was removed as a trial participating centre.
4. A protocol (not peer reviewed) has been uploaded as an additional file.
25/04/2022: St Thomas’ Hospital was added as a trial participating centre.
01/04/2022: The recruitment end date was changed from 30/04/2022 to 31/12/2022.
21/03/2022: The following changes have been made:
1. The public contact has changed.
2. Bradford Royal Infirmary has been added to the trial participating centres.
3. The sponsor name and website have been updated.
4. The trial website has been updated.
5. An updated protocol has been uploaded.
19/11/2020: The following changes have been made:
1. Contact details updated.
2. Uploaded protocol Version 4.0, 15 October 2020 (not peer reviewed).
06/11/2020: The following changes have been made:
1. The recruitment end date has been changed from 01/11/2020 to 01/12/2020.
2. Uploaded protocol Version 3.0, 20 May 2020 (not peer reviewed).
06/07/2020: The recruitment end date was changed from 30/04/2021 to 30/04/2022.
08/06/2020: The following changes have been made:
1. The ethics approval has been updated.
2. The participant exclusion criteria have been changed.
25/03/2020: Trial’s existence confirmed by National Institute for Health Research (NIHR).
