Plain English Summary
Background and study aims
Treatment of kidney disease accounts for a significant proportion of NHS spending. Transplantation is the best treatment for kidney failure, in terms of length and quality of life. It is also more cost-effective than dialysis. However, most transplants fail after 10-12 years and patients have to go back onto dialysis, placing a considerable burden on the NHS. Damage by the immune system, called 'chronic rejection' accounts for 50% of failing transplants and it is now possible to identify patients at risk by screening for a biomarker of chronic rejection called HLA antibodies (found in the blood). All transplant units in the UK can do this, but routine screening of patients has not been adopted because it is not clear how best to treat patients with antibodies. This study will test a screening and treatment protocol for HLA antibodies. The aim is to reduce transplant failure rates over 3 years.
Who can participate?
The trial is open to all kidney transplant recipients aged 18-70 years who have had their transplant for 12 months or more and currently have good kidney function.
What does the study involve?
Participants with antibodies will be randomly allocated to one of two groups: the biomarker-led (BLC) group or the standard care (SC) group. In the BLC group, test results are revealed and recruits will have their anti-rejection drugs changed to a regime of three drugs, prednisone, tacrolimus and MMF, each already licensed for use in transplant recipients. We have evidence that this treatment will be effective at preventing dysfunction and expect this to feed through to improvements in graft survival. In the SC group, screening results are not made available and participants will remain on their current treatments. Participants without antibodies will be randomly allocated to one of two groups: a group called blinded screening where results will not be given or a group called unblinded screening where results will be given. They will remain on standard treatment. Testing will continue every 8 months. Recruits in the SC group will move into the BLC group if they become antibody positive.
What are the possible benefits and risks of participating?
As well as the potential impact on transplant failure, the drugs used here are associated with better cholesterol profiles and lower blood pressures than others in common usage. There are potential risks. Tacrolimus is associated with an increased risk of diabetes mellitus and enhanced immunosuppression in general is associated with an increased incidence of infection, especially viral and with an increased risk of malignancy. It is difficult to predict such risks in this study. The incidence of diabetes, infection and malignancy will be monitored carefully on this trial.
Where is the study run from?
The study is run and coordinated by a team from King's College London, based at Guy's Hospital (UK).
When is the study starting and how long is it expected to run for?
June 2013 to September 2020 (updated 12/05/2020, previously: Recruitment will begin in June 2013 and finish by May 2016. The study is scheduled to finish in May 2019.)
Who is funding the study?
National Institute for Health Research through an EME programme grant (UK)
Who is the main contact?
Professor Anthony Dorling
anthony.dorling@kcl.ac.uk
added 12/05/2020: Senior Trial Manager
Dr Leanne Gardner
leanne.gardner@kcl.ac.uk
Trial website
Contact information
Type
Scientific
Primary contact
Prof Anthony Dorling
ORCID ID
Contact details
MRC Centre for Transplantation
Dept. of Nephrology and Transplantation
Guy's Hospital Great Maze Pond
London
SE1 9RT
United Kingdom
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anthony.dorling@kcl.ac.uk
Additional identifiers
EudraCT number
2012-004308-36
ClinicalTrials.gov number
Protocol/serial number
13990
Study information
Scientific title
A randomized controlled clinical trial to determine if a combined screening /treatment programme can prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies
Acronym
OuTSMART
Study hypothesis
Current study hypothesis as of 12/05/2020:
Treatment of kidney disease accounts for a significant proportion of NHS spending. Although transplantation is the best treatment for kidney failure, most transplants do not survive for the recipient's natural lifespan, but instead fail after 10-12 years. Damage by the immune system, called 'chronic rejection' accounts for 50% of failing transplants and it is now possible to identify patients at risk by screening for 'HLA antibodies' in the blood. This application is to test a screening and treatment protocol for antibodies in a randomised controlled trial. Those with antibodies will be randomised into biomarker-led (BLC) or standard care (SC) groups. In the former, test results are revealed and recruits will have their anti-rejection drugs changed to a regime of prednisone, tacrolimus and MMF, each already licensed for use in transplant recipients. We have evidence that this regime is effective at preventing graft dysfunction and expect this to double blinded and recruits will remain on their current therapies. In those without antibodies, recruits will be randomised to either blinded or unblinded screening and remain on standard treatment. Testing will continue every 8 months; recruits in the unblinded screening group will move into the BLC group if they become antibody positive. The primary outcome is to determine the time to graft
failure in patients testing positive for HLA Ab at baseline or within 32 months of randomization who receive an optimized anti-rejection medication intervention with prednisone, Tac and MMF (‘treatment’), compared to a control group who test positive for HLA Ab at baseline or within 32 months post-randomization who remain on their established immunotherapy and whose clinicians are not aware of their Ab status. The primary endpoint will be assessed remotely when a minimum of 43 months post-randomisation has been achieved by all. Secondary outcomes include rates of deterioration, the incidence of infections, cancers and diabetes, an analysis of the role of non-adherence with medication, and a scientific study to identify new biomarkers associated with outcomes. A cost analysis will confirm whether the screening programme and treatment protocol can save money by keeping kidney transplants functioning for longer.
The recruitment target is to enroll 1900 HLA antibody-negative patients. This should allow recruitment of sufficient numbers of HLA antibody-positive patients.
More details can be found at: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=13990
Previous study hypothesis:
Treatment of kidney disease accounts for a significant proportion of NHS spending. Although transplantation is the best treatment for kidney failure, most transplants do not survive for the recipient's natural lifespan, but instead fail after 10-12 years. Damage by the immune system, called 'chronic rejection' accounts for 50% of failing transplants and it is now possible to identify patients at risk by screening for 'HLA antibodies' in the blood. This application is to test a screening and treatment protocol for antibodies in a randomised controlled trial. Those with antibodies will be randomised into biomarker-led (BLC) or standard care (SC) groups. In the former, test results are revealed and recruits will have their anti-rejection drugs changed to a regime of prednisone, tacrolimus and MMF, each already licensed for use in transplant recipients. We have evidence that this regime is effective at preventing graft dysfunction and expect this to feed through to improvements in survival. In the SC group, screening results are double blinded and recruits will remain on their current therapies. In those without antibodies, recruits will be randomised to either blinded or unblinded screening and remain on standard treatment. Testing will continue every 8 months; recruits in the unblinded screening group will move into the BLC group if they become antibody positive. The primary outcome is kidney failure rates within 3 years of randomisation in HLA antibody+ recruits, predicted to be approximately 20% in the SC but <10% in the BLC groups. Secondary outcomes include rates of deterioration, the incidence of infections, cancers and diabetes, an analysis of the role of non-adherence with medication, and a scientific study to identify new biomarkers associated with outcomes. A cost analysis will confirm whether the screening programme and treatment protocol can save money by keeping kidney transplants functioning for longer.
The recruitment target is to enroll 1900 HLA antibody-negative patients. This should allow recruitment of sufficient numbers of HLA antibody-positive patients.
More details can be found at: http://public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=13990
Ethics approval
NRES Committee London - Hampstead, 14/01/2013, ref: 12/LO/1759
Study design
Randomised; Interventional; Design type: Screening, Treatment
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Not available in web format, please use the contact details below to request a patient information sheet
Condition
Topic: Renal and Urogenital; Subtopic: Renal and Urogenital (all Subtopics); Disease: Renal
Intervention
Optimized Treatment protocol, The 'optimized treatment' protocol in the recruits with HLA Ab in unblinded group will be:
1. Mycophenolate mofetil bd, tds or qds, or enteric coated mycophenolic acid bd, with daily dose determined according to local unit guidelines. The patient will be stabilized on the maximum tolerated dose.
2. Tacrolimus od or bd, according to local unit preference, with dose titrated to achieve 12-hour post-dose levels of 4g/L to 8g/L (4-8 ng/ml). The patient will be stabilized on the maximumtolerated dose that achieves these levels.
3. Prednisolone od. Starting at 20mg for two weeks, then reducing by 5 mg od every two weeks down to a maintenance dose of 5mg od.
Screening for HLA antibodies, Serum prepared from 10mls of blood will be used in the commercially available 'LABScreen' tests, containing fluorescently tagged beads coated with purified HLA antigens. All participating centres have 'Luminex' equipment for analysis of these tests and the skills to process samples and interpret results. Therefore, the tests will be performed in each of the centres.
Follow-Up Length: 36 month(s)
Intervention type
Drug
Phase
Not Applicable
Drug names
Mycophenolate mofetil, tacrolimus, prednisolone
Primary outcome measure
Current primary outcome measure as of 12/05/2020:
Determine the time to graft failure in patients testing positive for HLA Ab at baseline or within 32 months of randomization who receive an optimized anti-rejection medication intervention with prednisone, Tac and MMF (‘treatment’), compared to a control group who test positive for HLA Ab at baseline or within 32 months post-randomization who remain on their established immunotherapy and whose clinicians are not aware of their Ab status. The primary endpoint will be assessed remotely when a minimum of 43 months post-randomisation has been achieved by all.
Previous primary outcome measure:
Renal Transplant Failure Rates; Timepoint(s): 3 Years post-recruitment
Secondary outcome measures
Current secondary outcome measures as of 12/05/2020:
1. Analysis of adherence and perceptions of risk; Timepoint(s): 32 months
2. Change in estimated Glomerular Filtration Rate; Timepoint(s): 32 months
3. Patient Survival; Timepoint(s): 32 months
4. Proteinuria; Timepoint(s): 32 months
5. Rate of acute rejection; Timepoint(s): 32 months
6. Rates of biopsy proven malignancy; Timepoint(s): 32 months
7. Rates of Culture-positive infection; Timepoint(s): 32 months
8. Rates of Diabetes Mellitus; Timepoint(s): 32 months
9. Scientific analyses of humoral & cellular immunity and CD34+ cells; Timepoint(s): 32 months
Previous secondary outcome measures:
1. Analysis of adherence and perceptions of risk; Timepoint(s): 3 years
2. Change in estimated Glomerular Filtration Rate; Timepoint(s): 3 years
3. Patient Survival; Timepoint(s): 3 years
4. Proteinuria; Timepoint(s): 3 years
5. Rate of acute rejection; Timepoint(s): 3 years
6. Rates of biopsy proven malignancy; Timepoint(s): 3 years
7. Rates of Culture-positive infection; Timepoint(s): 3 years
8. Rates of Diabetes Mellitus; Timepoint(s): 3 years
9. Scientific analyses of humoral & cellular immunity and CD34+ cells; Timepoint(s): 3 year
Overall trial start date
01/06/2013
Overall trial end date
30/09/2020
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
1. Renal transplant recipients >1 year post transplantation
2. Aged 18-70 years, male and female
3. Estimated glomerular filtration rate (eGFR) of >=30
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
Planned Sample Size: 3,000; UK Sample Size: 3,000; Description: 3,000 is approximate
Total final enrolment
2037
Participant exclusion criteria
1. Recipient requiring HLA desensitisation to remove antibody for a positive XM transplant
2. Recipient known already to have HLA antibody who has received specific intervention for that antibody or for CAMR / chronic rejection
3. Recipient of additional solid organ transplants (e.g. pancreas, heart, etc).
4. History of malignancy in previous 5 years (excluding non-melanomatous tumours limited to skin)
5. HBsAg+,HBcAb+, HepC+ or HIV+ recipient (on test performed within previous 5 years)
6. History of acute rejection requiring escalation of immunosuppression in the 6 months prior to screening.
7. History of an ongoing or previous infection (no time limit) that would prevent optimization of immunosuppression, including ocular Herpes simplex.
8. Known hypersensitivity to any of the IMPs
9. Known hereditary disorders of carbohydrate metabolism
10. Patient enrolled in any other studies involving administration of another IMP at time of recruitment
11. Pregnancy or breastfeeding females (based on verbal history of recipient)
12. Pre-menopausal females who refuse to consent to using suitable methods of contraception throughout the trial.
Recruitment start date
01/09/2013
Recruitment end date
30/09/2016
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Guy's and St Thomas' Hospital
Great Maze Pond
London
SE1 9RT
United Kingdom
Trial participating centre
Royal Free Hospital
Pond Street
London
NW3 2QG
United Kingdom
Trial participating centre
The Royal London Hospital
Whitechapel Road
London
E1 1FR
United Kingdom
Trial participating centre
St Helier Hospital
Epson
KT18 7EG
United Kingdom
Trial participating centre
Bradford Royal Infirmary
Duckworth Lane
Bradford
BD9 6RJ
United Kingdom
Trial participating centre
Manchester Royal Infirmary
North Road
Manchester
M13 9WL
United Kingdom
Trial participating centre
St James Hospital
Beckett St.
Leeds
LS9 7TF
United Kingdom
Trial participating centre
Salford Royal Hospital
Stott Lane
Salford
M6 8HD
United Kingdom
Trial participating centre
York Hospital
Wigginton Road
York
YO31 8HE
United Kingdom
Trial participating centre
University Hospitals Birmingham
Mindelsohn Way
Edgbaston
Birmingham
B15 2GW
United Kingdom
Trial participating centre
Royal Preston Hospital
Sharoe Green Lane North
Fulwood
Preston
PR2 9HT
United Kingdom
Trial participating centre
University Hospitals Coventry and Warwickshire
Clifford Bridge Road
Coventry
CV2 2DX
United Kingdom
Sponsor information
Organisation
King's College London (UK)
Sponsor details
MRC Centre for Transplantation
Dept. of Nephrology and Transplantation
Guy's Hospital Great Maze Pond
London
SE1 9RT
United Kingdom
Sponsor type
University/education
Website
Funders
Funder type
Government
Funder name
NIHR (UK) - Efficacy and Mechanism Evaluation; Grant Codes: 11/100/34
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer-reviewed journal.
IPD sharing statement
The datasets generated during and/or analysed during the current study are/will be available upon request from Prof. Anthony Dorling (Anthony.dorling@kcl.ac.uk).
Intention to publish date
01/11/2021
Participant level data
Available on request
Basic results (scientific)
Publication list
2014 protocol in: https://www.ncbi.nlm.nih.gov/pubmed/24447519
2019 updated protocol and statistical analysis plan in: https://www.ncbi.nlm.nih.gov/pubmed/31383029 (added 07/08/2019)
Publication citations
-
Protocol
Dorling A, Rebollo-Mesa I, Hilton R, Peacock JL, Vaughan R, Gardner L, Danzi G, Baker R, Clark B, Thuraisingham RC, Buckland M, Picton M, Martin S, Borrows R, Briggs D, Horne R, McCrone P, Kelly J, Murphy C, Can a combined screening/treatment programme prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies: study protocol for the multicentre randomised controlled OuTSMART trial., Trials, 2014, 15, 30, doi: 10.1186/1745-6215-15-30.