OuTSMART
Research type
Research Study
Full 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. Short Title – ‘Optimized TacrolimuS and MMF for HLA Antibodies after Renal Transplantation:’ – “OuTSMART”
IRAS ID
112232
Contact name
Anthony Dorling
Sponsor organisation
Kings College London
Eudract number
2012-004308-36
ISRCTN Number
n/a
Research summary
Summary of Research
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.
Summary of Results
Optimized TacrolimuS and MMF for HLA Antibodies after Renal Transplantation: 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.
This clinical trial was funded by the NIHR EME programme and was sponsored jointly by King’s College London and Guy’s & St Thomas’ NHS Foundation Trust.
Thank you to all the patients who took part, from all 13 different kidney units around the UK
The trial addressed an important topic in kidney transplantation: kidney transplants do not last for the natural lifespan of most recipients and many patients end up having to go back onto dialysis. This problem has been identified by patient surveys as being an important problem requiring solution. The single biggest cause is ‘chronic’ or smouldering rejection by the immune system, which recognises the transplant as being from another individual and then sets about damaging the transplant, often insidiously, or ‘bit by bit’.
When the immune system first recognises the transplant as ‘foreign’, it often makes antibodies against the transplant that we can detect in the blood stream. These antibodies can be directly damaging to the transplant, but for the purpose of this trial, we used their appearance simply as a ‘flag’ or a biomarker, to let us know that the damaging immune process had begun. Thus, an integral part of what we did was to screen the blood from all patients on the trial, every 8 months, for the presence of these antibodies.We know that these antibodies tend to appear when patients are on doses of immunosuppression medications that are too small to adequately suppress their immune system. This can happen for a variety of reasons, including doctors advising reduction in tablets after an infection, or in response to a serious illness. Sometimes, the patients forget to take medicines, and sometimes patients make a decision independently of their doctors to reduce pills because they are worried about side effects.
Patients were involved in the design of the trial we performed through the Renal Research Governance Committee off Guy’s Hospital. The main purpose was to ask whether routine screening for antibodies, followed by increasing the amount of immunosuppression in those with antibodies, could halt the ongoing damage to the transplant and prevent the transplant from failing. For the purpose of the trial, ‘increase’ meant two things. First, giving the patients information to inform their decisions about the importance of taking their existing immunosuppression (i.e. to encourage compliance with their current pills) and second, advising change to optimised doses of the best three types of immunosuppression available (Tacrolimus, Mycophenolate mofetil and Prednisolone).
Because we wanted to avoid biasing the results, we informed only half the patients of their antibody screening results (i.e they were ‘unblinded’ to the results, and only patients in this group got treated). In the other half, the screening for antibodies took place in the background, and neither patients nor their doctors were aware of the results. In these patients, which we call ‘blinded controls’, no information was given to alter tablet taking habits, and no changes to the immunosuppression medications were made. Patients were randomly allocated to the groups. At the end of the trial, as the primary measure to assess whether our strategy had worked, we compared the number of patients who had suffered transplant failure after our interventions, to the number of control patients who had suffered transplant failure. Additionally, we asked whether these two groups had different rates of death, transplant function, diabetes mellitus, acute rejection, serious infections, cancers, and different side effect profiles. Finally, we asked whether our intervention was cost effective, and whether we could detect any change in patients’ attitudes to their transplant or immunosuppression tablets.
Recruitment started in September 2013 initially from 5 expanding to 13 UK kidney transplant centres. Patients were between the ages of 18-75, more than 1 year post-kidney only transplantation with good transplant function (defined by estimated GFR>30mls/min). Specific exclusion criteria were checked at the point of recruitment. The last patient was recruited on 27/10/2016 and randomised on 4/11/2016, bringing the total randomised to 2037. The primary endpoint data collection was delayed by the COVID-19 pandemic and finished on 30/11/20.
The two groups were well matched in terms of baseline characteristics. Approximately 60% were taking Tacrolimus and MMF at the point of recruitment. In the group who developed antibodies and received the intervention, there were 42 transplant failures, compared to 34 in the blinded controls. Our statistical analysis revealed no evidence that our screening and intervention had prevented transplant failure. There were also no differences in rates of patient death, transplant function, rates of rejection, diabetes mellitus, serious infections, or cancer. The health economic analysis revealed no benefit for screening or intervention. The analysis of health beliefs and compliance indicated that this population was highly motivated to take their pills, and the intervention had no discernible impact on that.
Therefore we found no evidence to justify routine screening and optimisation of immunosuppression in patients at risk of transplant failure.
This is the largest study of its kind in transplant medicine to test a biomarker led, stratified medicine approach to post-transplant care, and the largest to use the measure of transplant failure as the endpoint for assessing the success of an intervention. The implication of our findings is that, in the absence of a successful treatment, there is currently no justification for routine screening for antibodies in patients beyond the first year of transplantation.
The full details of the results will be available in the NIHR website in 2022.
REC name
London - Hampstead Research Ethics Committee
REC reference
12/LO/1759
Date of REC Opinion
14 Jan 2013
REC opinion
Further Information Favourable Opinion