Treating people with idiopathic pulmonary fibrosis with the addition of lansoprazole (TIPAL)
| ISRCTN | ISRCTN13526307 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN13526307 |
| EudraCT/CTIS number | 2020-000041-14 |
| IRAS number | 269050 |
| ClinicalTrials.gov number | NCT04965298 |
| Secondary identifying numbers | CPMS 44455, IRAS 269050 |
- Submission date
- 10/02/2020
- Registration date
- 25/02/2020
- Last edited
- 07/02/2025
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Respiratory
Plain English Summary
Background and study aims
Idiopathic pulmonary fibrosis (IPF) is a progressive scarring lung condition causing coughing and breathlessness. IPF patients often have reflux disease meaning stomach acid may be breathed into the lungs, potentially damaging them. Medicines that stop stomach acid production, including proton pump inhibitors (PPIs), can be used to reduce reflux symptoms including heartburn. Some researchers suggest PPIs also reduce IPF progression.
This research aims to see if IPF progresses slower if treated with PPIs. Based on the results, the researchers will be able to recommend whether or not IPF patients should take PPIs.
Who can participate?
Patients aged 40 years or above with a diagnosis of idiopathic pulmonary fibrosis. People taking medicines that interact with PPIs or have other serious medical conditions won’t be able to participate. People receiving PPIs will only be able to participate if they can stop taking their medication without their heartburn returning.
What does the study involve?
At the beginning of the study, the researchers will ask patients to perform breathing tests, and ask those with a cough to use a device to count the number of times they cough in 24hours. The researchers will ask them to answer two questions rating their coughing and breathlessness, and complete questionnaires on their coughing, IPF, sleep habits and general condition. People will be given a PPI, called lansoprazole, or dummy tablets, twice per day for 12 months. They will be given a leaflet telling them what to do about reflux symptoms. At the end of the study, the researchers will repeat these tests and analyse the results. The researchers will record any side effects people may get. If people suffer side effects, they can reduce the dose.
What are the possible benefits and risks of participating?
Benefits: There is no guarantee that the study will help participants personally, but the information we get from this study will improve our ability to treat patients with pulmonary fibrosis in the future.
Risks: Participants may not get the active treatment, lansoprazole, and may receive the dummy treatment, placebo. However participants will still receive any approved treatment for pulmonary fibrosis from their doctor. Participants will need to attend the hospital for visits in addition to their routine clinic visits. Although participants will receive reimbursement for their travel expenses of up to £100 in total for trial participation. The blood tests may cause discomfort and bruising. Questionnaires will take time to complete. Breathing tests may cause slight breathlessness, difficulty breathing or chest discomfort for a few minutes at the most following the tests. Participants may experience side effects from the active treatment. However, participants are free to reduce their dose of trial treatment under the guidance of their doctor/research team. Participants are also free to withdraw from the study at any time without giving a reason and without any effect on the standard of care participants receive.
Where is the study run from?
Norfolk and Norwich University Hospitals NHS Foundation Trust (UK)
When is the study starting and how long is it expected to run for?
March 2020 to July 2025
Who is funding the study?
NIHR Evaluation, Trials and Studies Co-ordinating Centre (NETSCC) (UK)
Who is the main contact?
Matthew Hammond, m.hammond@uea.ac.uk, tipal@uea.ac.uk
Contact information
Public
NCTU
Norwich Medical School
University of East Anglia
Norwich
NR4 7TJ
United Kingdom
| Phone | +44 (0)1603591224 |
|---|---|
| tipal@uea.ac.uk |
Scientific
Norwich Medical School
University of East Anglia
Floor 2 Bob Champion Research and Education Building
Norwich
NR4 7TJ
United Kingdom
| Phone | +44 (0)1603 591257 |
|---|---|
| a.m.wilson@uea.ac.uk |
Study information
| Study design | Interventional randomized controlled trial with a decentralised design |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Home, Hospital |
| Study type | Treatment |
| Participant information sheet | ISRCTN13526307_PIS_V2.6_11Aug22.pdf |
| Scientific title | The effectiveness and risks of Treating people with Idiopathic Pulmonary fibrosis with the Addition of Lansoprazole (TIPAL): a randomised placebo-controlled multi-centre clinical trial |
| Study acronym | TIPAL |
| Study hypothesis | Participants treated with lansoprazole will have a smaller absolute decline in percentage predicted (%) FVC at 12 months post-randomisation versus participants treated with placebo. |
| Ethics approval(s) | Approved 29/04/2020, East of England - Cambridgeshire and Hertfordshire Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 104 8106; cambsandherts.rec@hra.nhs.uk), ref: 20/EE/0043 |
| Condition | Idiopathic pulmonary fibrosis |
| Intervention | This project is a clinical trial of an investigational medicinal product (drug). The drug (lansoprazole) is well established and approved for use for another medical condition. The drug will be assessed against placebo (dummy) tablets, with patients allocated to either group by chance. Patients on the drug and dummy tablets will be assessed at the same time. Neither patients nor their doctors or the research team will know which treatment they have been allocated to (although the doctors will be able to find out in an emergency). The researchers will be running the study at approximately 37 hospitals across the UK. Potentially eligible patients will be approached in clinic or identified from local patient lists/databases. They will be given the relevant study literature to consider participation in the study and will be followed-up by a member of the local research team after they have had at least 24 h to consider participating. Interested patients will be invited to a screening appointment where they will be counselled on the study and what it entails in order to provide informed consent to participate. The patient will then be asked to complete baseline questionnaires, provide demographic, medical history and concomitant medication, and any other relevant study information, complete a lung function assessment (including spirometry and gas transfer assessments) and provide a blood sample for safety in order for the investigator to confirm their eligibility for the trial. Patients will also provide a blood sample for analysis in future research, a blood sample for genotype analysis and complete a 24-h period of cough frequency monitoring, and activity and sleep monitoring if applicable, if they have consented to do so. Patients in receipt of PPIs without a clear clinical indication for them at consent, will undergo a 2-week wash-out period (following agreement from the patient and their GP) to ascertain whether it is safe to stop this treatment and monitor whether their symptoms subside. Patients who remain asymptomatic at the end of this period will proceed to enter the study. For those whose symptoms return, PPI treatment will recommence and they will not enter the study. Once the results of all baseline assessments are known, patients will be randomised. Participants will receive an initial 6 month supply of trial medication and be instructed to take 2 tablets twice daily (approximately 12 hours apart), 30 min before meals, for 12 months. At 3 months post-randomisation, participants will attend the study site again to complete the relevant questionnaires, provide blood samples for safety checks, complete lung function assessments (including spirometry and gas transfer assessments) as before. Participants involved in the sub-study will again undergo cough frequency monitoring, and activity and sleep monitoring if applicable, for a final 24-h period. Patients will be asked to report any changes in their medical history, medication and any events which they have experienced since their last visit. Participants will attend the site again at 6 months post-randomisation where they will be required to complete questionnaires, provide a safety blood sample and complete lung function assessments (including spirometry and gas transfer assessments). Participants will again be asked to report any changes in their medical history, medication and any events which they have experienced since their last visit. Participant adherence to the trial medication will be checked via a pill count completed by local site staff. A final supply of trial medication will be dispensed to the patient with the appropriate dosing instructions. At 9 months post-randomisation, local site staff will contact patients by phone to record any changes in their medical history, medication and any events experienced since their last visit. Patients will be required to complete and return the required questionnaires (electronically or by post) and attend their GP surgery to provide a blood sample for safety checks. The final study visit occurs 12 months post-randomisation. Patients will be required to complete all necessary questionnaires, provide a blood sample for safety analysis and complete lung function assessments (including spirometry and gas transfer assessments). Participants will also have an additional blood sample taken for analysis in future research studies. Patients will be required to report any changes in their medical history, medication and any events they have experienced since their last report to site staff. If participants are suspected of or confirmed to have experienced any of the following they may reduce the dose of their trial treatment, at any point during the study, to 1 tablet, twice daily (approximately 12 hours apart), 30 min before meals: respiratory tract infection including pneumonia, Clostridium difficile infection and/or hypomagnesaemia. Participants may also reduce dose if the participant or clinician wishes them to do so. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Not Applicable |
| Phase | Phase III |
| Drug / device / biological / vaccine name(s) | Lansoprazole |
| Primary outcome measure | Predicted (%) forced vital capacity (FVC) at 12 months post-randomisation |
| Secondary outcome measures | 1. Cough frequency measured using a VitaloJAK cough monitor over a 24-h period at baseline and 3 months post-randomisation 2. Cough score measured using a 100-mm visual analogue scale (VAS) at baseline 3, 6, 9 and 12 months post-randomisation 3. Cough-related quality of life measured by the Leicester Cough Questionnaire at baseline, 3, 6, 9 and 12 months post-randomisation 4. Breathlessness measured by the Medical Research Council (MRC) Dyspnoea Scale at baseline, 3, 6, 9 and 12 months post-randomisation 5. Disease specific quality of life measured using the King’s Brief Interstitial Lung Disease (K-BILD) questionnaire at baseline, 3, 6, 9 and 12 months post-randomisation 6. Health related quality of life measured using the EQ-5D-5L questionnaire at baseline, 3, 6, 9 and 12 months post-randomisation (quality-adjusted life-years will be estimated) 7. Adverse events with particular relevance to respiratory tract infection including pneumonia, Clostridium difficile infection and hypomagnesaemia measured at 3, 6, 9 and 12 months post-randomisation 8. Total lung diffusing capacity of carbon monoxide (DLCO) measured at baseline, 3, 6 and 12 months post-randomisation 9. Sleep quality measured by the short Pittsburgh Sleep Quality Index at baseline, 3 and 12 months post-randomisation 10. Reflux characteristics measured by the DeMeester score at baseline, 3 and 12 months post-randomisation 11. Participant acceptability of trial treatment measured by a non-validated study-specific questionnaire at 12 months post-randomisation 12. Risk of sleep apnoea measured by the STOP-bang questionnaire at 12 months post-randomisation 13. Progression free survival (with progression defined as all-cause death, lung transplant, a 10% reduction in FVC % predicted from baseline, or 15% reduction in DLCO % predicted from baseline) at 12 months post-randomisation 14. Hospital-free survival defined as death (all causes) or first non-elective (all-cause) hospital admission at 12 months post-randomisation 15. Respiratory related hospital-free survival at 12 months post-randomisation |
| Overall study start date | 01/09/2019 |
| Overall study end date | 31/07/2025 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 40 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 298; UK Sample Size: 298 |
| Participant inclusion criteria | Current inclusion criteria as of 22/08/2023: 1. Male or female, aged greater than or equal to 40 years 2. A diagnosis of Idiopathic Pulmonary Fibrosis (IPF) based on local or regional multi-disciplinary consensus according to the latest international guidelines 3. Patients may be receiving licensed anti-fibrotic medication (for at least 4 weeks prior to randomisation with no planned amendments for at least 4 weeks post-randomisation) 4. Able to provide informed consent Additional inclusion criteria for cough count sub-study: 1. Pre-existing diagnosis of persistent cough (defined as troublesome for more than 8 weeks prior to study enrolment) Previous inclusion criteria: 1. Male or female, aged greater than or equal to 40 years 2. A diagnosis of Idiopathic Pulmonary Fibrosis (IPF) based on local or regional multi-disciplinary consensus according to the latest international guidelines (Am J Respir Crit Care Med. 2018;198:e44-e68) 3. Patients may be receiving licensed anti-fibrotic medication (for at least 4 weeks prior to randomisation with no planned amendments for at least 4 weeks post-randomisation) 4. Able to provide informed consent Additional inclusion criteria for cough count sub-study: 1. Pre-existing diagnosis of persistent cough (defined as troublesome for more than 8 weeks prior to study enrolment) |
| Participant exclusion criteria | Current exclusion criteria as of 22/08/2023: 1. Patients unable to complete reliable FVC measurements (i.e. the difference between the two largest values is NOT < = 0.150 L) 2. Concomitant use of a proton pump inhibitor (PPI) or prokinetic drugs (cisapride, domperidone, metoclopramide, erythromycin, pruclopride etc) within 2 weeks prior to randomisation 3. Patients with a self-reported significant respiratory tract infection, including COVID-19, within 4 weeks of screening. 4. Significant co-existing respiratory disease (defined as a respiratory condition that exhibits a clinically relevant effect on respiratory symptoms and disease progression as determined by the PI). The presence of bronchiectasis is permitted 5. Patients with FEV1/FVC< 0.7 6. Significant medical, surgical or psychiatric disease that in the opinion of the patient's attending physician would affect subject safety or influence the study outcomes including liver failure (e.g. serum transaminase > 2x upper limit of normal (ULN), bilirubin > 1.5x ULN (unless the patient has Gilbert's syndrome) and chronic kidney disease (CKD) no greater than stage 3 (stable for at least 3 months prior to enrolment), erosive oesophagitis, Barrett's oesophagus or any other condition requiring lifelong proton pump inhibitor use. 7. Known allergy to proton pump inhibitors or the contents of placebo 8. Concomitant use of atazanavir, ketoconazole, itraconazole, tacrolimus, methotrexate, fluvoxamine (see section 6.4.5 of protocol) 9. Females who are of childbearing potential or lactating. Non-childbearing potential is defined as follows: postmenopausal females who have had at least 12 months of spontaneous amenorrhoea or 6 months of spontaneous amenorrhoea with serum FSH> 40mlU/ml or females who have had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy at least 6 weeks prior to enrolment 10. Receipt of another investigational drug or biological agent associated with another clinical trial within the 4 weeks prior to TIPAL study enrolment or 5 times the drug half-life, whichever is the longer 11. Receiving long-term oxygen therapy 12. Patients with hypomagesmesmia (defined as magnesium < = 0.6mmol/L) Previous exclusion criteria: 1. Patients unable to complete reliable FVC measurements (i.e. the difference between the two largest values is NOT < = 0.150 L) 2. Concomitant use of a proton pump inhibitor (PPI) or prokinetic drugs (cisapride, domperidone, metoclopramide, erythromycin, pruclopride etc) within 2 weeks prior to randomisation 3. Patients with a self-reported respiratory tract infection within 4 weeks of screening (defined as two or more of: increased cough, sputum or breathlessness and requiring antimicrobial therapy) 4. Significant co-existing respiratory disease (defined as a respiratory condition that exhibits a clinically relevant effect on respiratory symptoms and disease progression as determined by the PI). The presence of bronchiectasis is permitted 5. Patients with FEV1/FVC< 0.7 6. Significant medical, surgical or psychiatric disease that in the opinion of the patient's attending physician would affect subject safety or influence the study outcomes including liver failure (e.g. serum transaminase > 2x upper limit of normal (ULN), bilirubin > 1.5x ULN (unless the patient has Gilbert's syndrome) and chronic kidney disease (CKD) no greater than stage 3 (stable for at least 3 months prior to enrolment), erosive oesophagitis, Barrett's oesophagus or any other condition requiring lifelong proton pump inhibitor use. 7. Known allergy to proton pump inhibitors or the contents of placebo 8. Concomitant use of atazanavir, ketoconazole, itraconazole, tacrolimus, methotrexate, fluvoxamine (see section 6.4.5 of protocol) 9. Females who are of childbearing potential or lactating. Non-childbearing potential is defined as follows: postmenopausal females who have had at least 12 months of spontaneous amenorrhoea or 6 months of spontaneous amenorrhoea with serum FSH> 40mlU/ml or females who have had a hysterectomy, bilateral salpingectomy or bilateral oophorectomy at least 6 weeks prior to enrolment 10. Receipt of another investigational drug or biological agent associated with another clinical trial within the 4 weeks prior to TIPAL study enrolment or 5 times the drug half-life, whichever is the longer 11. Receiving long-term oxygen therapy 12. Patients with hypomagesmesmia (defined as magnesium < = 0.6mmol/L) |
| Recruitment start date | 16/06/2021 |
| Recruitment end date | 31/08/2024 |
Locations
Countries of recruitment
- England
- Northern Ireland
- Scotland
- United Kingdom
- Wales
Study participating centres
Norwich
NR4 7UY
United Kingdom
Mindelsohn Way
Birmingham
B15 2TH
United Kingdom
Oxford Road
Manchester
M13 9WL
United Kingdom
Fazakerley Hospital
Lower Lane Liverpool
Merseyside
Liverpool
L9 7AL
United Kingdom
Cambridge
CB23 3RE
United Kingdom
Sydney Street
London
SW3 6NP
United Kingdom
High Heaton
Newcastle upon Tyne
NE7 7DN
United Kingdom
Glenshane Road
Derry
BT47 6SB
United Kingdom
Leicester
LE1 5WW
United Kingdom
Burton Road
Kendal
LA9 7RG
United Kingdom
Southmead Road
Westbury-on-trym
Bristol
BS10 5NB
United Kingdom
Wolverhampton Road
Heath Town
Wolverhampton
WV10 0QP
United Kingdom
Herries Road
Sheffield
S5 7AU
United Kingdom
Harton Lane
South Shields
NE34 0PL
United Kingdom
Charles Hastings Way
Worcester
WR5 1DD
United Kingdom
Sutton-in-Ashfield
NG17 4JL
United Kingdom
Whinney Heys Road
Blackpool
FY3 8NR
United Kingdom
Praed Street
London
W2 1NY
United Kingdom
2 Eday Road
Aberdeen
AB15 6RE
United Kingdom
Tremona Road
Southampton
SO16 6YD
United Kingdom
Leighton
Crewe
CW1 4QJ
United Kingdom
Sharoe Green Lane
Fulwood
Preston
PR2 9HT
United Kingdom
Anlaby Road
Hull
HU3 2JZ
United Kingdom
Shrewsbury
SY3 8XQ
United Kingdom
Cardiff
CF14 4XW
United Kingdom
Headley Way
Headington
Oxford
OX3 9DU
United Kingdom
Acre Street
Huddersfield
HD3 3EA
United Kingdom
London
NW1 2PG
United Kingdom
Derby Road
Nottingham
NG7 2UH
United Kingdom
Stoke-on-Trent
ST4 6QG
United Kingdom
Whitechapel
London
E1 1BB
United Kingdom
Bordesley Green
Birmingham
B9 5SS
United Kingdom
Wigan
WN1 2NN
United Kingdom
Rake Lane
North Shields
NE29 8NH
United Kingdom
Craigavon
BT63 5QQ
United Kingdom
Antrim
BT41 2RL
United Kingdom
Perth
PH1 1NX
United Kingdom
Dundee
DD1 9SY
United Kingdom
Taunton
TA1 5DA
United Kingdom
Gledow Wing
Beckett Street
Leeds
LS9 7TF
United Kingdom
Victoria Road
Macclesfield
SK10 3BL
United Kingdom
Hardwick
Stockton-on-tees
TS19 8PE
United Kingdom
Lewisham High Street
London
SE13 6LH
United Kingdom
Luton
LU4 0DZ
United Kingdom
St Davids Parc
Job's Well Road
Carmarthen
SA31 3BB
United Kingdom
Basingstoke
RG24 9NA
United Kingdom
Winchester
SO22 5DG
United Kingdom
Newton Road
Torquay
TQ2 7AA
United Kingdom
St Thomas Street
London
SE1 9RT
United Kingdom
Bath
BA1 3NG
United Kingdom
Hermitage Lane
Maidstone
ME16 9QQ
United Kingdom
Southwick Hill Road
Cosham
Portsmouth
PO6 3LY
United Kingdom
Coreys Mill Lane
Stevenage
SG1 4AB
United Kingdom
Blackburn
BB2 3HH
United Kingdom
Burnley
BB10 2PQ
United Kingdom
Portsmouth Road
Frimley
Camberley
GU16 7UJ
United Kingdom
Kingston upon Thames
KT2 7QB
United Kingdom
Armthorpe Road
Doncaster
DN2 5LT
United Kingdom
Sterling Way
London
N18 1QX
United Kingdom
Harlow
CM20 1QX
United Kingdom
Watford
WD18 0HB
United Kingdom
Sponsor information
Hospital/treatment centre
Colney Lane
Colney
Norwich
NR4 7UY
England
United Kingdom
| Phone | +44 (0)1603 647882 |
|---|---|
| julie.dawson@nnuh.nhs.uk | |
| Website | http://www.nnuh.nhs.uk/ |
"ROR" |
https://ror.org/01wspv808 |
Funders
Funder type
Government
No information available
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 | 31/08/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version v2.1 | 23/03/2021 | 12/04/2021 | No | No |
| HRA research summary | 28/06/2023 | No | No | ||
| Participant information sheet | version 2.6 | 11/08/2022 | 22/08/2023 | No | Yes |
| Protocol article | 05/02/2025 | 07/02/2025 | Yes | No |
Additional files
- ISRCTN13526307_PROTOCOL_v2.1_23Mar2021.pdf
- Uploaded 12/04/2021
- ISRCTN13526307_PIS_V2.6_11Aug22.pdf
Editorial Notes
07/02/2025: Publication reference added.
12/11/2024: The public contact was changed.
13/08/2024: Internal review.
22/08/2023: The following changes were made to the study record:
1. Ethics approval details and study website added.
2. The study design was changed from 'Interventional randomized controlled trial' to 'Interventional randomized controlled trial with a decentralised design'.
3. The recruitment end date was changed from 31/08/2023 to 31/08/2024.
4. The overall study end date was changed from 31/08/2024 to 31/07/2025.
5. The study participating centres were updated to remove Walsgrave General Hospital, NHS Forth Valley, Queen Elizabeth Hospital, and St George's Hospital, and to add Heartlands Hospital, Royal Albert Edward Infirmary, Northumbria Healthcare NHS Foundation Trust, Craigavon Area Hospital, Antrim Area Hospital, Perth Royal Infirmary, Ninewells Hospital, Musgrove Park Hospital, St James's University Hospital NHS Trust, Macclesfield District General Hospital, North Tees Health NHS Trust, Lewisham and Greenwich NHS Trust, Luton and Dunstable University Hospital, Hywel Dda Health Board, Basingstoke and North Hampshire Hospital, Royal Hampshire County Hospital, Torbay and South Devon NHS Foundation Trust, The Guys and Lewisham NHS Trust, Royal United Hospital, Maidstone & Tunbridge Wells NHS Trust, Portsmouth Hospitals University National Health Service Trust, East and North Hertfordshire NHS Trust, Royal Blackburn Hospital, Burnley General Hospital, Frimley Park Hospital, Kingston Hospital, Doncaster and Bassetlaw Teaching Hospitals NHS Foundation Trust, North Middlesex University Hospital NHS Trust, Princess Alexandra Hospital, and Watford General Hospital.
6. Participant information sheet uploaded.
10/05/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/05/2022 to 31/08/2023.
2. The overall end date was changed from 31/08/2023 to 31/08/2024.
3. The intention to publish date was changed from 31/08/2024 to 31/08/2025.
4. The plain English summary was updated to reflect these changes.
5. The clinicaltrials.gov number was added
17/06/2021: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/05/2021 to 16/06/2021.
2. The trial website has been added.
12/04/2021: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/04/2021 to 01/05/2021.
2. Uploaded protocol version 2.1, 23 March 2021 (not peer reviewed).
18/01/2021: The recruitment start date was changed from 01/01/2021 to 01/04/2021.
15/10/2020: The recruitment start date was changed from 01/10/2020 to 01/01/2021.
29/07/2020: The following changes were made to the trial record:
1. The ethics approval was added.
2. The recruitment start date was changed from 31/03/2020 to 01/10/2020.
13/02/2020: Trial’s existence confirmed by National Institute for Health Research (NIHR).
