Treatment including surgery versus treatment without surgery for people with symptoms due to a cavernoma in the brain
| ISRCTN | ISRCTN41647111 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN41647111 |
| IRAS number | 289197 |
| Secondary identifying numbers | CPMS 49352, IRAS 289197 |
- Submission date
- 02/06/2021
- Registration date
- 18/06/2021
- Last edited
- 30/05/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Nervous System Diseases
Plain English Summary
Background and study aims
A cavernoma is a cluster of blood vessels that form blood-filled ‘caverns’ that look like a raspberry. Brain cavernomas can cause strokes or epileptic seizures. In the UK, most people with cavernomas have medical management (which may involve scans, drugs, or rehabilitation) to manage these symptoms. About one fifth also have ‘surgical management’ with either brain surgery to remove a cavernoma or stereotactic radiosurgery to stabilise it with radiation.
The pros and cons of medical management versus medical and surgical management are finely balanced. Finding out which is best was identified through work involving the charity Cavernoma Alliance UK as a top priority for cavernoma research. We first need to find out whether enough patients can be found for a randomised trial comparing ‘medical management' with ‘medical and surgical management’ of symptomatic cavernomas. We need to know this because cavernomas are rare and we do not know whether patients and doctors will take part. This will be the first randomised trial of its kind for brain cavernoma.
Who can participate?
We will recruit patients of all ages with brain cavernoma who meet the eligibility criteria, where there is uncertainty about the best treatment option.
What does the study involve?
Participants will be allocated at random to either medical management or medical and surgical treatment (neurosurgery or stereotactic radiosurgery). If patients do not have a preference for surgical treatment, type, they may be allocated randomly to neurosurgery or stereotactic radiosurgery. We aim to recruit ~60 participants.
An integrated qualitative research component (QuinteT), including analysis of screening log data and qualitative research (including interviews with patients and research staff), is included to understand recruitment processes and barriers as well as actions to address barriers.
What are the possible benefits and risks of participating?
There are some benefits from taking part in this research study:
Your participation in the Information Study will allow us to improve how cavernoma treatment research is discussed with patients.
• You may find it a relief to have the decision about whether to have surgery taken out of your hands.
• Your health in this study will be under review with the possibility of an additional brain MRI scan. You may feel supported by this.
• The results of this study will help us to improve the healthcare of patients in the future.
There are some risks from taking part in this research study:
Treatment without surgery and treatment including surgery in the CARE study involve health technologies that are available in standard clinical practice in the UK and Republic of Ireland.
• Treatment without surgery leaves patients at risk of a bleed/stroke and epileptic seizures.
• Neurosurgical excision is the most frequently-used form of surgical treatment for brain cavernoma in the UK. It involves an operation that creates an opening in the skull, called a craniotomy, which can result in infection, and the operation can cause a stroke or damage to the brain around the cavernoma.
• Stereotactic radiosurgery (using Gamma Knife) is non-invasive and may be used because neurosurgery is too risky or a patient wants a non-invasive treatment. This procedure uses ionising radiation to provide treatment. This can cause a stroke or damage to the brain around the cavernoma. Ionising radiation can cause cell damage that may, after many years or decades, turn cancerous. Taking part in this study will not significantly alter the chances of this happening to you. We are all at risk of developing cancer during our lifetime. The normal risk is that this will happen to about 50% of people at some point in their life. Taking part in this study will increase the chances of this happening to you from 50% to between 50 and 50.5%.
Where is the study run from?
The University of Edinburgh (UK)
When is the study starting and how long is it expected to run for?
September 2020 to October 2023
Who is funding the study?
National Institute for Health Research (NIHR) (UK)
Who is the main contact?
Prof Rustam Al-Shahi Salman, Rustam.Al-Shahi@ed.ac.uk
Contact information
Scientific
Centre for Clinical Brain Sciences
Chancellor’s Building
University of Edinburgh
49 Little France Crescent
Edinburgh
EH16 4SB
United Kingdom
 ORCID ID |
0000-0002-2108-9222 |
|---|---|
| Phone | +44 (0)131 242 7014 |
| Rustam.Al-Shahi@ed.ac.uk |
Study information
| Study design | Interventional randomized controlled trial with integrated qualitative sub-study |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | https://www.ed.ac.uk/usher/edinburgh-clinical-trials/our-studies/all-current-studies/care/care-study/get-involved |
| Scientific title | Cavernomas A Randomised Effectiveness (CARE) pilot study, to address the effectiveness of active treatment (with neurosurgery or stereotactic radiosurgery) versus conservative management in people with symptomatic brain cavernoma |
| Study acronym | CARE study |
| Study hypothesis | The shortage of high-quality evidence to inform the management of patients with brain cavernomas has prevented clinical guidelines in the UK and USA from making strong recommendations about whether to use treatment without surgery or treatment including surgery for brain cavernomas. We are working towards conducting a large-scale randomised controlled trial to find out which is best. This pilot phase randomised trial aims to assess the feasibility of conducting a definitive main phase randomised trial. |
| Ethics approval(s) |
1. Approved 31/03/2021, Yorkshire & the Humber - Leeds East Research Ethics Committee (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ, United Kingdom; +44 (0)207 104 8109; leedseast.rec@hra.nhs.uk), ref: 21/YH/0046 2. Approved 25/11/2022, Ethics (Medical Research) Committee - Beaumont Hospital (Beaumont, Dublin, Dublin 9, Ireland; +353-1-809 2680; beaumontethics@rcsi.com), ref: 21/84 3. Approved 23/08/2022, Clinical Research Ethics Committee of the Cork Teaching Hospitals (University College Cork Lancaster Hall 6 Little Hanover Street, Cork, T12 WV09, Ireland; +353-21-4901901; crec@ucc.ie), ref: ECM 4 (l) 10/8/2021 & ECM 5 (3) 26/10/2021 & ECM 3 (o) 20/09/2022 |
| Condition | Brain cavernoma |
| Intervention | Current interventions as of 28/10/2022: This prospective randomised open blinded end-point (PROBE) randomised controlled trial (RCT) aims to estimate the feasibility of performing a definitive main phase RCT comparing medical management to medical and surgical management (with neurosurgery or Gamma Knife stereotactic radiosurgery, according to their availability in clinical practice) for improving outcome for people with symptomatic brain cavernoma. Randomisation will allocate participants to groups in a 1:1 ratio, stratified by preferred type of surgical treatment, but if there is no clear preference for the type of surgical treatment, and both are available, the patient will be randomly allocated to either neurosurgery or stereotactic radiosurgery. The trial design includes an integrated QuinteT Recruitment Intervention (QRI) which aims to understand recruitment barriers (e.g. related to selection of patients during screening and recruitment processes, or equipoise), and optimise informed consent and recruitment processes in the trial. In one arm of the trial, participants will receive brain cavernoma treatment without surgery that is available in standard clinical practice. This may include anti-epileptic drugs to prevent epileptic seizures, rehabilitation of neurological deficits (e.g. physiotherapy, speech and language therapy), medical treatment of other neurological symptoms (e.g. headache, body pain, spasticity, dysaesthesia), and psychological support. In standard clinical practice, these treatments are usually provided for as long as they are required or likely to benefit patients. In the other arm of the trial, participants will receive brain cavernoma treatment including surgery that is available in standard clinical practice. This involves trying to remove the cavernoma using brain surgery (known as neurosurgery) or trying to stabilise the cavernoma using focussed radiation treatment (known as stereotactic radiosurgery) in addition to all of the treatments in the other arm of the trial. It is expected (but not mandated by the trial protocol) that surgical management will be delivered within 3 months of randomisation to the trial. Neurosurgery will be undertaken by a consultant neurosurgeon responsible for neurosurgical aspects of the clinical care of the cavernoma patient in CARE. The neurosurgical technique employed will be that used by the consultant neurosurgeon in clinical practice. Adjuncts such as image direction, microscopy, ultrasonic aspiration, awake/general anaesthesia surgery, cortical mapping/stimulation, and intra-operative MRI, will be used as considered appropriate by the consultant neurosurgeon. Stereotactic radiosurgery will be performed at the National Centre for Stereotactic Radiosurgery in Sheffield or the Queen Square Radiosurgery Centre, which are the two referral centres in the UK that are commissioned to provide Gamma Knife stereotactic radiosurgery for cavernoma. Standard clinical treatment protocols will be used which involve targeting the brain cavernoma, but not the surrounding haemosiderin ring. Treatment dosages will range from 12-16 Gy depending on size, shape, definition and site of the cavernoma. Around 6 months after the baseline visit that precedes randomisation, participants will be contacted by their local research team for a follow-up visit. This visit will involve a brain MRI scan and completion of questionnaires to check how the participant is doing. Every 6 months thereafter, participants will be contacted by a member of the central research team at the trial coordinating centre who will get in touch by phone or email to complete questionnaires and check how the participant is doing. Follow-up will end approximately 6 months after recruitment finishes. Participants are asked to consent to long-term follow up (i.e. beyond the planned follow-up in the CARE pilot trial), including the use of routinely collected data (such as hospital admissions, procedures, and death certificates), in case the CARE pilot trial is successful and runs seamlessly into a definitive main phase trial. Previous interventions: This prospective randomised open blinded end-point (PROBE) randomised controlled trial (RCT) aims to estimate the feasibility of performing a definitive main phase RCT comparing medical management to medical and surgical management (with neurosurgery or Gamma Knife stereotactic radiosurgery, according to their availability in clinical practice) for improving outcome for people with symptomatic brain cavernoma. Randomisation will allocate participants to groups in a 1:1 ratio, stratified by preferred type of surgical treatment, but if there is no clear preference for the type of surgical treatment, and both are available, the patient will be randomly allocated to either neurosurgery or stereotactic radiosurgery. The trial design includes an integrated QuinteT Recruitment Intervention (QRI) which aims to understand recruitment barriers (e.g. related to selection of patients during screening and recruitment processes, or equipoise etc), and optimise informed consent and recruitment processes in the trial. In one arm of the trial, participants will receive brain cavernoma treatment without surgery that is available in standard clinical practice. This may include anti-epileptic drugs to prevent epileptic seizures, rehabilitation of neurological deficits (e.g. physiotherapy, speech and language therapy), medical treatment of other neurological symptoms (e.g. headache, body pain, spasticity, dysaesthesia), and psychological support. In standard clinical practice, these treatments are usually provided for as long as they are required or likely to benefit patients. In the other arm of the trial, participants will receive brain cavernoma treatment including surgery that is available in standard clinical practice. This involves all of the treatments in the other arm of the trial that are available without surgery, as well as trying to remove the cavernoma using brain surgery (known as neurosurgery) or trying to stabilise the cavernoma using focussed radiation treatment (known as stereotactic radiosurgery). It is expected (but not mandated by the trial protocol) that surgical management will be delivered within 3 months of randomisation to the trial. Neurosurgery will be undertaken by a consultant neurosurgeon responsible for neurosurgical aspects of the clinical care of the cavernoma patient in CARE. The neurosurgical technique employed will be that used by the consultant neurosurgeon in clinical practice. Adjuncts such as image direction, microscopy, ultrasonic aspiration, awake/general anaesthesia surgery, cortical mapping/stimulation, and intra-operative MRI, will be used as considered appropriate by the consultant neurosurgeon. Stereotactic radiosurgery will be performed at the National Centre for Stereotactic Radiosurgery in Sheffield or the Queen Square Radiosurgery Centre, which are the two referral centres in the UK that are commissioned to provide Gamma Knife stereotactic radiosurgery for cavernoma. Standard clinical treatment protocols will be used which involve targeting the brain cavernoma, but not the surrounding haemosiderin ring. Treatment dosages will range from 12-16Gy depending on size, shape, definition and site of the cavernoma. Around 6 months after the baseline visit that precedes randomisation, participants will be contacted by their local research team to do a follow-up visit. This will involve completing some questionnaires to see how the participant is doing and having a brain MRI scan. Every 6 months thereafter, participants will be contacted by a member of the central research team at the trial coordinating centre who will get in touch by phone or email to complete some questionnaires and check how the patient is doing. Follow-up is scheduled to continue until February 2023. We will ask study participants to consent to long-term follow up (i.e. beyond the planned follow-up in the CARE pilot trial), including the use of routinely collected data (such as hospital admissions, procedures, and death certificates), in case the CARE pilot trial is successful and runs seamlessly into a definitive main phase trial. |
| Intervention type | Procedure/Surgery |
| Primary outcome measure | Feasibility measured using the following questions answered from the assessments performed and data collected at the baseline, 6-month local in-person follow-up and 6-monthly central follow-up: 1. What proportion of the collaborating centres take part and recruit participants to the CARE pilot trial? 2. Can the investigators implement trial procedures correctly? 3. What proportion of screened patients is eligible? 4. What proportions of eligible patients are approached and randomised (and why are eligible patients not approached or not randomised)? 5. What is the distribution of participants between neurosurgery and stereotactic radiosurgery? 6. Do participants adhere to the allocated intervention and follow-up? 7. How complete are baseline, imaging and outcome data? 8. What are the outcome event rates? 9. How do the baseline characteristics, outcome event rates and differences between treatment groups compare to observational data about outcomes during medical management or after medical and surgical management? 10. What estimates of effect size/variability should be used in the design of the CARE definitive main phase trial? 11. What is the sample size required for a definitive trial to address the overall question over a 10-year follow-up? 12. Can the CARE pilot trial data describe care pathways, linked to health states and outcomes, to develop a robust economic model to evaluate cost-effectiveness in a CARE definitive main phase trial? 13. Which international research partners in other countries could contribute to the CARE definitive main phase trial? Primary clinical outcome: Intracranial haemorrhage or new persistent/progressive focal neurological deficit due to brain cavernoma or surgical management (neurosurgery or stereotactic radiosurgery), whether fatal (leading to death within 30 days of the outcome event) or non-fatal measured using patient records at 6-monthly follow-up until the end of the trial |
| Secondary outcome measures | Measured at 6-monthly follow-up until the end of the trial: 1. Death not due to a primary clinical outcome measured using patient records 2. Seizure severity and frequency measured using the Liverpool Seizure Severity Scale plus epileptic seizure frequency (number of seizures in the preceding four weeks, and attainment of one-year seizure freedom) 3. Degree of disability or dependence in the daily activities measured using the Modified Rankin Scale (mRS) score 4. Impairment caused by stroke measured using the National Institute of Health Stroke Scale Score (adult or paediatric) 5. Quality of life measured using the EQ-5D-5L in adults and EQ-5D-Y in children 6. Functional status measured using the Karnofsky Performance Status (KPS) scale in adults and Lanksy Play-Performance Scale (LPPS) in children 7. Health service use and healthcare and socioeconomic costs measured from patient records |
| Overall study start date | 01/09/2020 |
| Overall study end date | 31/10/2023 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | All |
| Sex | Both |
| Target number of participants | Planned Sample Size: 60; UK Sample Size: 60 |
| Total final enrolment | 72 |
| Participant inclusion criteria | 1. People of any age 2. At least one brain cavernoma diagnosed by brain MRI that included a gradient echo or susceptibility-weighted sequence, according to standard diagnostic criteria 3. Clinical history attributable to a brain cavernoma of: 3.1. Symptomatic stroke due to intracranial haemorrhage, or 3.2. Symptomatic stroke due to a persistent or progressive non-haemorrhagic, or not otherwise specified, focal neurological deficit, or 3.3. Epileptic seizure(s) meeting the definition of definite or probable cavernoma-related epilepsy 4. Patient and doctor are uncertain about medical management or medical and surgical management of the symptomatic brain cavernoma, following consultation with a neurosurgeon 5. Patient has mental capacity to consent for themselves (adult participants or paediatric participants with capacity) or parent/legal guardian provides consent (paediatric participants) |
| Participant exclusion criteria | Current exclusion criteria as of 28/10/2022: 1. Surgical management of a solitary symptomatic brain cavernoma with MRI evidence of cavernoma removal/obliteration 2. Spinal cavernoma alone, without symptomatic brain cavernoma 3. Asymptomatic brain cavernoma. Patients with radiographic cavernoma enlargement (with or without intralesional haemorrhage) but without new symptoms are still regarded as asymptomatic 4. Previously randomised in the CARE pilot trial Previous exclusion criteria: 1. Surgical management of a solitary symptomatic brain cavernoma with MRI evidence of cavernoma removal/obliteration 2. Spinal cavernoma 3. Asymptomatic brain cavernoma. Patients with radiographic cavernoma enlargement (with or without intralesional haemorrhage) but without new symptoms are still regarded as asymptomatic 4. Previously randomised in the CARE pilot trial |
| Recruitment start date | 30/06/2021 |
| Recruitment end date | 30/04/2023 |
Locations
Countries of recruitment
- England
- Ireland
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Old Dalkeith Road
Edinburgh
Lothian
EH16 4SA
United Kingdom
Aberdeen
AB25 2ZN
United Kingdom
Birmingham
B4 6NH
United Kingdom
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom
Hills Road
Cambridge
CB2 0QQ
United Kingdom
Hull
HU3 2JZ
United Kingdom
Liverpool
L9 7LJ
United Kingdom
Eaton Road
Liverpool
L12 2AP
United Kingdom
London
W6 8RF
United Kingdom
London
SE5 9RS
United Kingdom
London
WC1N 3JH
United Kingdom
Blackshaw Road
Tooting
London
SW17 0QT
United Kingdom
University College London Hospitals NHS Foundation Trust
250 Euston Road
London
NW1 2PG
United Kingdom
80 Newark Street
London
E1 2ES
United Kingdom
Manchester
M13 9WL
United Kingdom
Eccles
Salford
M6 8HD
United Kingdom
Middlesbrough
TS4 3BW
United Kingdom
Newcastle upon Tyne
NE1 4LP
United Kingdom
Sharoe Green Lane
Fulwood
Preston
PR2 9HT
United Kingdom
Sheffield
S10 2JF
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Stoke-on-trent
ST4 6QG
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Upper Maudlin Street
St Michael's Hill
Bristol
BS2 8BJ
United Kingdom
Sheffield
S10 2TH
United Kingdom
Edgbaston
Birmingham
B15 2GW
United Kingdom
Romford
RM7 0AG
United Kingdom
Leeds
LS1 3EX
United Kingdom
Sponsor information
University/education
The Queen's Medical Research Institute
47 Little France Crescent
Edinburgh
EH1 1HT
Scotland
United Kingdom
| Phone | +44 (0)1312423326 |
|---|---|
| resgov@accord.scot | |
| Website | https://www.accord.scot/ |
"ROR" |
https://ror.org/01nrxwf90 |
Hospital/treatment centre
The Queen's Medical Research Institute
47 Little France Crescent
Edinburgh
EH16 4TJ
Scotland
United Kingdom
| accord@nhslothian.scot.nhs.uk | |
| Website | http://www.nhslothian.scot.nhs.uk/Pages/default.aspx |
|
"ROR" |
https://ror.org/03q82t418 |
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 | 18/04/2024 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | • Trial results may be published in peer-reviewed journals and presented at conferences. • Our collaborator, Cavernoma Alliance UK are likely to share the findings through their website, social media channels or other platforms. • We will provide a results summary to participants interested in receiving this. The most appropriate method for distribution will be considered at the time but may include posting/emailing a summary to participants, distributing via recruitment centre research teams or presentation in a PPI setting in order to get patient feedback for a subsequent grant application. |
| IPD sharing plan | Current Individual participant data (IPD) sharing plan as of 22/04/2024: A de-identified version of the dataset used for analysis with individual participant data and a data dictionary will be available for other researchers to apply for use 1 year after publication, via ECTUdatashare@ed.ac.uk. Written proposals will be assessed by members of the Edinburgh Clinical Trials Unit Portfolio Management committee, and a decision made about the appropriateness of the use of data will be made. A data sharing agreement might need to be put in place before any data are shared. _____ Previous Individual participant data (IPD) sharing plan: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Data access requests will be reviewed by the Chief Investigator and the Edinburgh Clinical Trials Unit (Rustam.Al-Shahi@ed.ac.uk). Researchers will be asked to outline in their request to use the data the purpose for which it is being requested. Study participants will be invited to consent to the use of their de-identified data, brain imaging and blood sample in future research. It has not been decided at this point what data will be available and for how long. Researchers using the data will be responsible for seeking the relevant approvals for the research. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol article | 09/08/2023 | 11/08/2023 | Yes | No | |
| Results article | 18/04/2024 | 22/04/2024 | Yes | No | |
| Statistical Analysis Plan | version 1.0 | 08/12/2022 | 22/04/2024 | No | No |
| Other publications | 18/04/2024 | 30/05/2024 | Yes | No |
Additional files
Editorial Notes
30/05/2024: Publication reference added.
22/04/2024: The following changes were made to the trial record:
1. Publication reference added.
2. The statistical analysis plan was uploaded as an additional file.
3. The scientific title was changed from "Cavernomas A Randomised Effectiveness (CARE) pilot trial, to address the effectiveness of active treatment (with neurosurgery or stereotactic radiosurgery) versus conservative management in people with symptomatic brain cavernoma" to "Cavernomas A Randomised Effectiveness (CARE) pilot study, to address the effectiveness of active treatment (with neurosurgery or stereotactic radiosurgery) versus conservative management in people with symptomatic brain cavernoma".
4. The participant level data sharing statement was changed.
5. The intention to publish date was changed from 16/04/2024 to 18/04/2024.
16/01/2024: The ethics approval (2, 3) was added.
10/10/2023: The intention to publish date was changed from 29/02/2024 to 16/04/2024.
11/08/2023: Publication reference added.
02/05/2023: The following changes have been made:
1. The final enrolment number has been added.
2. Royal Infirmary of Edinburgh at Little France, Aberdeen Royal Infirmary, Birmingham Children's Hospital, Southmead Hospital, Charing Cross Hospital, Manchester Childrens Hospital, Royal Victoria Infirmary, University Hospital of Wales, Bristol Royal Hospital for Children, Sheffield Childrens Hospital, Queen Elizabeth Hospital, Queen's Hospital and Leeds General Infirmary have been added to the trial participating centres and NHS Lothian, NHS Grampian, Birmingham Women's and Children's NHS Foundation Trust, Bristol Royal Infirmary, St Mary's Hospital, Manchester University NHS Foundation Trust, Freeman Hospital, Northern General Hospital, University Hospitals of North Midlands NHS Trust and Cardiff & Vale University Lhb removed.
24/02/2023: The following changes were made to the trial record:
1. The recruitment end date was changed from 28/02/2023 to 30/04/2023.
2. The overall trial end date was changed from 31/08/2023 to 31/10/2023 and the plain English summary was updated accordingly.
3. The Intention to publish date was changed from 31/12/2024 to 29/02/2024.
08/11/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/11/2022 to 28/02/2023.
2. The overall trial end date was changed from 31/05/2023 to 31/08/2023.
28/10/2022: The following changes were made to the trial record:
1. The scientific title was changed from 'Cavernomas A Randomised Effectiveness (CARE) pilot trial, to address the effectiveness of medical management versus medical and surgical management (with neurosurgery or stereotactic radiosurgery) in people with symptomatic brain cavernoma' to 'Cavernomas A Randomised Effectiveness (CARE) pilot trial, to address the effectiveness of active treatment (with neurosurgery or stereotactic radiosurgery) versus conservative management in people with symptomatic brain cavernoma'.
2. The interventions and exclusion criteria were updated.
3. NHS Tayside, NHS Greater Glasgow and Clyde, University Hospitals Birmingham NHS Foundation Trust, Royal Sussex County Hospital, Walsgrave General Hospital, St James's University Hospital, Nottingham University Hospitals NHS Trust, John Radcliffe Hospital, Derriford Hospital, Queens Hospital, Sheffield Children's NHS Foundation Trust, Belfast City Hospital, Cork University Hospital, Beaumont Hospital and Children's University Hospital were removed from the trial participating centres.
20/09/2021: Internal review.
02/06/2021: Trial's existence confirmed by the National Institute for Health Research (NIHR) (UK).
