Testing for bile duct stones before gallbladder surgery
| ISRCTN | ISRCTN10378861 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN10378861 |
| Secondary identifying numbers | 16/142/04 |
- Submission date
- 24/09/2018
- Registration date
- 02/10/2018
- Last edited
- 13/12/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Surgery
Plain English Summary
Background and study aims
Surgery to remove the gallbladder is required if it contains gallstones that cause problems. About 70,000 operations are performed annually in England. Sometimes, gallstones cause other problems if they pass from the gallbladder into the nearby bile duct (e.g. jaundice/inflammation of the pancreas). If this happens, it is necessary to remove the bile duct stones before or during the gallbladder operation. Because of this, patients requiring gallbladder surgery are assessed for any risk of bile duct stones. If the risk is high, further tests are done to identify if bile duct stones are present. If the risk is moderate or low (although it can be difficult to distinguish between the two), then it is uncertain whether further tests to look for bile duct stones are necessary. As a result, some surgeons choose to perform tests and others don’t. A UK-wide research study found that a third of patients undergoing gallbladder surgery were tested, usually before surgery using an MRI scanner. This test, called a Magnetic Resonance Cholangiopancreatography (MRCP), involves a 1-hour visit to hospital and costs the NHS about £365. The MRCP identifies bile duct stones but may delay gallbladder surgery which can lead to increased problems with gallstones whilst waiting. There are other uncertainties about the need for testing using MRCP. Even if the MRCP shows bile duct stones, the stones can pass into the bowel spontaneously; and removing the stones can cause complications. Not having the MRCP avoids these risks, but can lead to bile duct stones being left behind after surgery, which may also cause complications. Research to establish if going straight to gallbladder surgery without testing the bile duct beforehand is needed.
The Sunflower Study will find out whether testing for bile duct stones with MRCP before gallbladder surgery is worthwhile or not in patients with a low or moderate risk of having stones.
Who can participate?
Adults with symptomatic gallstone disease who are scheduled and fit to receive gallbladder surgery, with a low to moderate risk of common bile duct stones
What does the study involve?
Participants in the Sunflower study will be divided into two groups. One group will go straight to surgery (i.e. no additional testing) and the other will receive an MRCP before surgery. The groups will be selected by a process called randomisation to ensure that groups have similar patients in terms of factors such as general health, age and gender. The ‘straight to surgery’ group will have twice as many people in as the ‘tested’ group to reduce the number of extra MRCPs performed. Both groups will be followed for 18 months and information about the need for treatment of bile duct stones, complications of surgery and costs collected.
What are the possible benefits and risks of participating?
For participants who receive MRCP, the possible benefit of participating is that this procedure may detect and, if needed, treat problematic bile duct stones. However for participants who do not receive MRCP, the possible benefit is that this allows their gallbladder surgery to go ahead immediately, without the possible disadvantages of testing for bile duct stones.
For participants who receive MRCP, the possible risks of participating is that the procedure may be unnecessary, as bile duct stones often pass safely and spontaneously into the bowel. Additionally, in 10-20% of cases, MRCP may not detec bile duct stones. Additionally, some patients may experience claustrophobia during the scan. For some patients, the scan and endoscope procedure (if required) may lead to a longer wait time for gallbladder surgery, which can lead to problems with gallstones whilst waiting (however, the surgery may not always be delayed by this).
For participants who do not receive MRCP, the possible risk is that any bile duct stones present will not be detected, which could lead to problems after gallbladder surgery (i.e. jaundice, infection, pancreatitis) and therefore require further treatment or readmission to hospital. If bile duct stones are suspected later, a scan and potentially endoscope procedure will be likely needed to remove them.
Where is the study run from?
Leeds Teaching Hospitals NHS Trust and at least 50 hospitals throughout the UK.
When is the study starting and how long is it expected to run for?
January 2018 to November 2025
Who is funding the study?
National Institute for Health Research (NIHR) Health Technology Assessment Programme (UK)
Who is the main contact?
Stephen Palmer
sunflower-study@bristol.ac.uk
Contact information
Public
SUNFLOWER Study
Bristol Trials Centre
1-5 Whiteladies Road
Bristol
BS8 1NU
United Kingdom
| Phone | +44 (0)7929 771395 |
|---|---|
| sunflower-study@bristol.ac.uk |
Study information
| Study design | Interventional multi-centre pragmatic randomized controlled trial with an internal pilot phase (Phase I) and a quintet recruitment intervention (QRI) |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Diagnostic |
| Participant information sheet | 35777 Sunflower Participant Information Leaflet v7.0.pdf |
| Scientific title | The Sunflower Study: A randomised controlled trial to establish the clinical and cost effectiveness of expectant management versus pre-operative imaging with MRCP in patients with symptomatic gallstones undergoing laparoscopic cholecystectomy at low or moderate risk of common bile duct stones |
| Study acronym | The Sunflower Study |
| Study hypothesis | We will test the hypothesis that expectant management is non-inferior to magnetic resonance pancreaticogram (MRCP) with respect to hospitalisation for treatment for a complication of gallstones up to 18 months after randomisation. |
| Ethics approval(s) | Approved 10/12/2018, Yorkshire & The Humber – South Yorkshire Ethics Committee (NHSBT Newcastle Blood Donor Centre, Holland Drive, Newcastle upon Tyne, NE2 4NQ; Tel: +44 (0)207 1048091; Email: nrescommittee.yorkandhumber-southyorks@nhs.net), ref: 18/YH/0358 |
| Condition | Symptomatic gallbladder disease, requiring gallbladder surgery |
| Intervention | Participants will be randomly allocated in a 1:2 ratio to receive either a reoperative magnetic resonance pancreaticogram (magentic resonance cholangiopancreatography - MRCP) or no MRCP (expectant management) using an online system. In the MRCP arm, participants will undergo an MRCP prior to their gallbladder surgery. An MRCP takes on average 20-30 minutes. In the expectant management arm, participants will proceed directly to surgery without undergoing an MRCP. The follow up will be the same in both groups – a 20% sample will be asked to complete questionnaires at 3, 6, 12 and 18 months post randomisation. |
| Intervention type | Other |
| Primary outcome measure | Current primary outcome measure: Any of the following: 1. Any hospital admission within 18 months of randomisation for treatment of complications of gallstones whether in the CBD or gallbladder 2. Complications during the admission for LC for the treatment for gallstones or any readmission for complications of the LC leading to a hospital stay of >2 days. Complications will include, but not be limited to: 2.1. Return to theatre post LC for any cause 2.2. Percutaneous radiological drainage 2.3. ERCP for non-diagnostic reasons (e.g. for a bile leak). It does not include a diagnostic ERCP performed following an MRCP where CBD stones were identified. 3. Complications during any ERCP for the treatment for gallstones. Complications will include: 3.1. Blood transfusion post ERCP 3.2. Percutaneous radiological drainage 3.3. Treatment of a perforation occurring during ERCP 3.4. Acute pancreatitis 3.5. Other complications leading to a hospital stay of >2 days This will be acquired from routine data sources, such as HES data from NHS Digital in England. The HES data will be reviewed and specific OPCS-4 and ICD-10 codes will be searched for. These codes identify specific diagnoses, procedures, etc which will form the primary outcome measure. This will be measured in the 18 months following randomisation. Previous primary outcome measure: Any of the following: 1. Any hospital admission within 18 months of randomisation for treatment of complications of gallstones whether in the CBD or gallbladder 2. Complications during the admission for LC for the treatment for gallstones or readmission for complications of the LC. Complications comprise: 2.1. Return to theatre post LC for any cause 2.2. Percutaneous radiological drainage 2.3. ERC 3. Complications during the index admission for ERCP for the treatment for gallstones (i.e. an ERCP performed following an MRCP where CBD stones were identified). Complications comprise: 3.1. Blood transfusion post ERCP 3.2. Percutaneous radiological drainage 3.3. Further ERCP 3.4. Treatment of a perforation occurring during ERCP 3.5. Acute pancreatitis 3.6. Respiratory complications leading to extended hospital stay of > 2 days 3.7. Cardiac complications leading to extended hospital stay of > 2 days 3.8. Infective complications leading to extended hospital stay of > 2 days 3.9. Other complications leading to extended hospital stay of > 2 days (detail to be recorded). This will be acquired from routine data sources, such as HES data from NHS Digital in England. The HES data will be reviewed and specific OPCS-4 and ICD-10 codes will be searched for. These codes identify specific diagnoses, procedures, etc which will form the primary outcome measure. This will be measured in the 18 months following randomisation. |
| Secondary outcome measures | 1. Health-related quality of life, assessed using the EQ-5D-5L questionnaire at time of randomisation, admission for LC and 3, 6, 12 and 18 months after randomisation (participants will not be asked to complete the admission for LC questionnaire if they have completed their baseline questionnaire within the previous two days) 2. Items in the LC core outcome set, which is due to be published at the end of 2018 3. NHS resource use to 18 months post randomisation, taken from routine data sources such as HES data from NHS Digital in England |
| Overall study start date | 01/01/2018 |
| Overall study end date | 30/11/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 7,457 |
| Total final enrolment | 7471 |
| Participant inclusion criteria | Current inclusion criteria as of 15/01/2020: 1. Aged 18 years or older 2. Symptomatic gallbladder disease, confirmed by trans-abdominal ultrasound scan (USS) or computed tomography (CT) scan, including, for example: 2.1. Biliary colic 2.2. Cholecystitis 2.3. Mild and severe gallstone pancreatitis 2.4. Gallbladder polyps 2.5. Gallbladder dyskinesia, etc 3. Scheduled and fit for laparoscopic cholecystectomy (LC) as an elective or urgent procedure 4. Low or moderate risk of common bile duct (CBD) stones, including all of the following: 4.1. CBD diameter ≤8 mm on USS 4.2. Bilirubin ≤ 50umol/l 4.3. Alanine transferase less than three times the upper limit of normal (≤3 x ULN) and/or alkaline phosphatase ≤3 x ULN If a patient does not meet the definition of low or moderate risk of CBD stones solely because both alanine transferase and alkaline phosphatase are > 3 x ULN, if repeat blood tests are carried out and at least one of the second or subsequent test results is within range (i.e. ≤ 3 x ULN) the patient may be recruited at that time. If a patient does not meet the definition of low or moderate risk of CBD stones solely because bilirubin > 50umol/l, if repeat blood tests are carried out and at least one of the second or subsequent test results is within range the patient may be recruited at that time. If CBD cannot be seen on USS or CT scan, the patient may be recruited as long as all the other inclusion criteria are met and there is no intrahepatic duct dilatation reported. Previous inclusion criteria: 1. Aged 18 years or older 2. Symptomatic gallstone disease, confirmed by trans-abdominal ultrasound scan (USS) or computed tomography (CT) scan, including: 2.1. Biliary colic 2.2. Cholecystitis 2.3. Mild and severe pancreatitis 2.4. Gallbladder polyps 2.5. Gallbladder dyskinesia 3. Scheduled and fit for laparascopic cholecystectomy (LC) as an elective or urgent procedure 4. Low or moderate risk of common bile duct (CBD) stones, including all of the following: 4.1. CBD diameter ≤8 mm on USS 4.2. Bilirubin ≤ 50umol/l 4.3. Alanine transferase less than twice the upper limit of normal (≤2 x ULN) and/or alkaline phosphatase ≤2 x ULN. If a patient does not meet the definition of low or moderate risk of CBD stones solely because both alanine transferase and alkaline phosphatase are > 2 x ULN, if repeat blood tests are carried out and at least one of the second or subsequent test results is within range (i.e. ≤ 2 x ULN) the patient may be recruited at that time. If a patient does not meet the definition of low or moderate risk of CBD stones solely because bilirubin > 50umol/l, if repeat blood tests are carried out and at least one of the second or subsequent test results is within range the patient may be recruited at that time. If CBD cannot be seen on USS or CT scan, the patient may be recruited as long as all the other inclusion criteria are met and there is no intrahepatic duct dilatation reported. |
| Participant exclusion criteria | Current exclusion criteria as of 15/01/2020: 1. Unable to undergo MRCP 2. Evidence of empyema or perforated gallbladder requiring urgent intervention 3. Previous gastric bypass 4. Previous MRCP or endoscopic ultrasound (EUS) within last 3 months 5. Any previous ERCP 6. Haemolytic disease 7. Pregnancy 8. Unwilling to participate in follow up 9. Unable to provide written informed consent 10. Prisoner Previous exclusion criteria: 1. Unable to undergo MRCP 2. Evidence of empyema or perforated gallbladder requiring urgent intervention 3. Previous duodenal bypass 4. Previous MRCP within last 3 months 5. Haemolytic disease 6. Pregnancy 7. Unwilling to participate in follow up 8. Unable to provide written informed consent 9. Prisoner |
| Recruitment start date | 01/12/2018 |
| Recruitment end date | 30/08/2024 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
United Kingdom
Acre Street
Lindley
Huddersfield
HD3 3EA
United Kingdom
Derby Road
Nottingham
NG7 2UH
United Kingdom
Worcester
WR5 1DD
United Kingdom
Bristol
BS10 5NB
United Kingdom
Bristol
BS2 8HW
United Kingdom
Canada Avenue
Redhill
RH1 5RH
United Kingdom
Liverpool Road
Chester
CH2 1UL
United Kingdom
Mandeville Road
Aylesbury
HP21 8AL
United Kingdom
Rake Lane
North Shields
NE29 8NH
United Kingdom
Plymouth
PL6 8DH
United Kingdom
Raleigh Park
Barnstaple
EX31 4JB
United Kingdom
Westminster Bridge Road
London
SE1 7EH
United Kingdom
Mansfield Road
Sutton In Ashfield
NG17 4JL
United Kingdom
Marlborough Road
Swindon
SN3 6BB
United Kingdom
Sheffield
S5 7AU
United Kingdom
Nethermayne
Basildon
SS16 5NL
United Kingdom
Belvedere Road
Burton-on-Trent
DE13 0RB
United Kingdom
Great Western Road
Gloucester
GL1 3NN
United Kingdom
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom
North Road
Durham
DH1 5TW
United Kingdom
Castle Lane East
Bournemouth
BH7 7DW
United Kingdom
London
NW3 2QG
United Kingdom
Exeter
EX2 5DW
United Kingdom
HR1 2ER
United Kingdom
Bolton
BL4 0JR
United Kingdom
Blackburn
BB2 3HH
United Kingdom
Ashton Under Lyne
OL6 9RW
United Kingdom
London
N19 5NF
United Kingdom
Derby
DE22 3NE
United Kingdom
TA1 5DA
United Kingdom
Worthing
BN11 2DH
United Kingdom
Wigan
WN1 2NN
United Kingdom
Uphill
Weston-Super-Mare
BS22 4TQ
United Kingdom
Lancaster
LA1 4RP
United Kingdom
Newport
PO30 5TG
United Kingdom
Coventry
CV2 2DX
United Kingdom
Larbert
FK5 4WR
United Kingdom
TS19 8PE
United Kingdom
SS0 0RY
United Kingdom
Sunderland
SR4 7TP
United Kingdom
Bath
BA1 3NG
United Kingdom
Cardiff Road
Newport
NP20 2UB
United Kingdom
Jenner Wing
Cranmer Terrace
London
SW17 0RE
United Kingdom
Eaglestone
Milton Keynes
MK6 5LD
United Kingdom
B15 2TH
United Kingdom
Southampton
SO16 6YD
United Kingdom
Doncaster
DN2 5LT
United Kingdom
NE7 7DN
United Kingdom
Northampton
NN5 1BD
United Kingdom
Belfast City Hospital
51 Lisburn Road
Belfast
BT9 7AB
United Kingdom
York
YO31 8HE
United Kingdom
Gateshead
NE9 6SX
United Kingdom
W2 1NY
United Kingdom
Bridgend
Bridgend County Borough
CF31 1RQ
United Kingdom
Castle Road
Cottingham
HU16 5JQ
United Kingdom
Ipswich
IP4 5PD
United Kingdom
Shrewsbury
SY3 8XQ
United Kingdom
Sponsor information
Hospital/treatment centre
Leeds General Infirmary
Great George Street
Leeds
LS1 3EX
England
United Kingdom
"ROR" |
https://ror.org/00v4dac24 |
|---|
Funders
Funder type
Not defined
Government organisation / National government
- Alternative name(s)
- NIHR Health Technology Assessment Programme, HTA
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 30/11/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | The data from this study will be used to produce outputs including publications in peer-reviewed academic journals, and presentations at national and international conferences. A simplified version of the findings will also be disseminated as newsletters to patients, in accordance with advice from the PPI group about how best to do this effectively. A report to the funding body (HTA) will be sent to the NIHR in May 2024, and will provide a summary of the work undertaken during the life of the study. The target journals for the main study paper and other related publications (e.g. health economics, qualitative) have not been identified, but these will be Open Access and should be completed by early 2025. These will communicate the results of the primary and secondary outcomes of the study. The main study paper should be published in Summer 2024. A summary for stakeholders will be provided in late 2024, and will be aimed both externally (e.g. general public/patients, media, commissioners) and internally (e.g. participating Trust stuff, operational staff). All outputs will be reviewed by the Chief Investigator and other collaborators, as necessary. Findings will be shared with the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS) and the Great Britain and Ireland Hepato Pancreato Biliary Association (GBIHPBA). The Chief Investigator and co-applicants have close links with these groups who are already aware and supportive of the study and awaiting its results. The study team intend to make presentations to both of them. Presentations will be given at national and international conferences relevant to gallbladder surgery e.g. The International Hepatopancreatobiliary Association and other sister Societies (e.g. European and African Hepatopancreatobiliary Association and the American Hepatopancreatobiliary Association). We expect that the results of the study will be used by NHS England to formulate a commissioning policy and will inform national and international guidelines. |
| IPD sharing plan | Data requests would be sent to the study manager via sunflower-study@bristol.ac.uk. The full de-identified dataset would be available and will be held indefinitely. Access would be dependent on provision of an ethically approval study protocol and could cover numerous analysis types. The mechanism of data sharing would be determined at the time. Consent from participants will be obtained for data sharing. Data will be de-identified. Ethical approval for a new project would need to be in place. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version v4.0 | 18/08/2020 | 23/09/2020 | No | No |
| Protocol article | 29/06/2021 | 13/08/2021 | Yes | No | |
| Protocol file | version 5.0 | 08/09/2021 | 27/10/2021 | No | No |
| Participant information sheet | version 7.0 | 11/07/2022 | 29/07/2022 | No | Yes |
| HRA research summary | 28/06/2023 | No | No | ||
| Protocol file | version 7.0 | 07/09/2023 | 17/10/2023 | No | No |
| Protocol file | 13/12/2024: The sunflower-study contact stated that based on funder recommendations protocol v8.0 had been withdrawn and the withdrawal has been confirmed by the HRA/REC, which fully withdrew the amendment to introduce version 8.0. Protocol v7.0, dated 07/09/2023 is in use. version 8.0 |
10/10/2024 | 20/11/2024 | No | No |
Additional files
- ISRCTN10378861_PROTOCOL_v4.0_18Aug20.pdf
- Uploaded 23/09/2020
- ISRCTN10378861_Protocol_v5.0_08Sep21.pdf
- 35777 Sunflower Participant Information Leaflet v7.0.pdf
- ISRCTN10378861 Protocol v7.0 07Sep2023.pdf
- ISRCTN10378861_Protocol_v8.0_10Oct2024.pdf
- 13/12/2024: The sunflower-study contact stated that based on funder recommendations protocol v8.0 had been withdrawn and the withdrawal has been confirmed by the HRA/REC, which fully withdrew the amendment to introduce version 8.0. Protocol v7.0, dated 07/09/2023 is in use.
Editorial Notes
13/12/2024: The sunflower-study contact stated that based on funder recommendations protocol v8.0 had been withdrawn and the withdrawal has been confirmed by the HRA/REC, which fully withdrew the amendment to introduce version 8.0. Protocol v7.0, dated 07/09/2023 is in use.
20/11/2024: Uploaded protocol v8.0 (not peer-reviewed) as an additional file.
09/09/2024: Total final enrolment added. Contact details updated.
30/08/2024: The recruitment end date was changed from 31/05/2024 to 30/08/2024.
09/01/2024: Shrewsbury & Telford Hospital NHS Trust added as a study participating centre.
22/11/2023: The study participating centre Ipswich Hospital was added.
20/10/2023: The study participating centre Hull University Teaching Hospitals NHS Trust was added.
17/10/2023: The following changes were made to the trial record:
1. Uploaded protocol v7.0 (not peer-reviewed) as an additional file.
2. The target number of participants was changed from 7,500 to 7,457.
3. The recruitment end date was changed from 30/11/2024 to 31/05/2024.
4. The overall end date was changed from 31/05/2025 to 30/11/2025.
5. The intention to publish date was changed from 31/05/2025 to 30/11/2026.
6. The plain English summary was updated to reflect these changes.
LH 31/05/2023: The following updates have been made to the study record and the plain English summary updated accordingly:
1. The recruitment end date has been changed from 31/05/2023 to 30/11/2024.
2. The overall study end date has been changed from 31/05/2024 to 31/05/2025.
3. The intention to publish date has been changed from 31/05/2024 to 31/05/2025.
4. The target number of participants has been changed from 13,680 to 7,500.
02/11/2022: The recruitment end date has been changed from 30/11/2022 to 31/05/2023.
29/07/2022: The participant information sheet was uploaded as an additional file.
03/03/2022: Contact details updated, Princess of Wales Hospital added as a trial participating centre.
19/01/2022: St Mary's Hospital was added as a trial participating centre.
15/11/2021: Queen Elizabeth Hospital Gateshead was added as a trial participating centre.
27/10/2021: The protocol (not peer reviewed) has been uploaded as an additional file.
20/08/2021: York and Scarborough Teaching Hospitals NHS Foundation Trust was added as a trial participating centre.
13/08/2021: Internal review.
27/07/2021: Belfast Health and Social Care Trust was added as a trial participating centre.
01/07/2021: Publication reference added.
16/12/2020: The trial website has been updated.
14/12/2020: Northampton General Hospital was added as a trial participating centre.
13/10/2020: Freeman Hospital was added as a trial participating centre.
23/09/2020: Uploaded protocol Version 4.0, 18 August 2020 (not peer reviewed)
17/07/2020: Recruitment has resumed.
19/06/2020: The public contact details have been changed.
12/06/2020: The public contact details have been made publicly visible.
24/04/2020: Due to current public health guidance, recruitment for this study has been paused.
27/02/2020: Doncaster Royal Infirmary added as a trial participating centre.
19/02/2020: University Hospitals Birmingham NHS Foundation Trust and University Hospital Southampton NHS Foundation Trust added as trial participating centres.
14/02/2020: Milton Keynes University Hospital added as a trial participating centre.
05/02/2020: St George’s Hospital NHS Foundation Trust added as a trial participating centre.
04/02/2020: Aneurin Bevan University Health Board added as a trial participating centre.
30/01/2020: Royal United Hospitals Bath NHS Foundation Trust was added as a trial participating centre.
15/01/2020: The primary outcome measure and the inclusion and exclusion criteria were updated.
03/01/2020: Sunderland Royal Hospital has been added as a trial participating centre.
17/12/2019: The trial website has been added.
08/11/2019: The trial participating centre "Southend University Hospital NHS Foundation Trust" was added.
06/11/2019: The trial participating centre "University Hospital of North Tees" was added.
16/10/2019: The trial participating centre "Forth Valley Royal Hospital" was added.
04/10/2019: The trial participating centre "University Hospitals Coventry and Warwickshire" was added.
20/09/2019: Trial participating centre added.
12/09/2019: Trial participating centre added.
10/09/2019: Trial participating centre added.
02/09/2019: Trial participating centre added.
23/08/2019: Trial participating centre added.
08/08/2019: Trial participating centre added.
02/08/2019: Trial participating centre added.
31/07/2019: Trial participating centre added.
30/07/2019: Trial participating centre added.
22/07/2019: Trial participating centre added.
18/07/2019: Trial participating centre added.
17/07/2019: Trial participating centre added.
03/07/2019: Trial participating centre added.
02/07/2019: Trial participating centre added.
13/06/2019: Trial participating centre added.
12/06/2019: Trial participating centres and ethics approval details added.
