Kidney Transplant Failure and Rejection Clinical Trial
Official title:
AGe-adapted Benefits of Envarsus Versus Twice-daily Tacrolimus ImmunosuppressioN druGs After Kidney Transplantation (AGEING) - a Feasibility Study
The proportion of elderly patients with end-stage kidney disease undergoing renal replacement therapy (RRT) is steadily increasing. Although kidney transplantation remains the optimal RRT of choice, it is clear that older adults have a differential risk versus benefit profile after kidney transplantation compared to younger adults. No age-adapted immunosuppression for older adults has been shown to improve kidney allograft outcomes but recent sub-analyses of clinical trial data has hinted at improved outcomes for older kidney transplant patients receiving Envarsus versus standard twice-daily tacrolimus formulations. This feasibility study will investigate this effect to see whether a full scale randomised controlled trial is warranted and to provide information regarding study feasibility.
The proportion of elderly patients with end-stage kidney disease undergoing renal
replacement therapy (RRT) is steadily increasing. National registry data consistently shows
a trend towards increasing median ages for patients both starting dialysis and awaiting
kidney transplantation on deceased-donor waiting lists (www.renalreg.org). For example, in
the United Kingdom, national audit data from the UK Renal Registry demonstrates that the
median age for all incident patients commencing RRT was 64.5 years (www.renalreg.org). Among
the prevalent RRT population, the percentage of patients aged greater than 70 years has
increased from 19.2% (in 2000) to 25.0% (in 2013) in the last registry report
(www.renalreg.org). Focusing on data from the UK Transplant Registry, 28% of transplant
recipients receiving a deceased-donor kidney allograft in the last year were aged 60 and
over (7% were aged 70 and over), while 32% of the active kidney transplant waiting list is
aged 60 and over (9% aged 70 and over) (http://www.odt.nhs.uk/uk-transplant-registry/). With
chronic kidney disease increasingly recognized as a public health epidemic, the long-term
prospects are of an increasingly elderly component to our end-stage kidney disease
population.
Kidney transplantation is the gold standard method of RRT due to superior mortality, quality
of life and cost effectiveness versus dialysis. It is therefore concerning that
transplantation is an infrequent RRT choice for older adults and the number of older adults
aged 70 and over who are listed for a kidney transplant is <10%. The Renal Association
states; "age is not a contra-indication for transplantation but age related co-morbidity is
an important limiting factor", but clearly the risk versus benefit ratio remains unclear for
clinicians because mortality risk is higher for older versus younger kidney transplant
recipients. However, improved mortality is observed with kidney transplantation versus
wait-listed dialysis patients across all age groups, and specifically among older adults
aged 70 and above in US studies, and therefore Investigators should consider kidney
transplantation for this increasing large cohort. The risk of immunosuppression-related
complications increases with age and therefore age-adapted immunosuppression should be
considered to balance efficacy versus complications. However, no targeted age-adapted
immunosuppression clinical trials have been conducted in kidney transplantation and this
remains a major gap in the literature.
Sub-analyses of recently published work showed clinically relevant advantages of Envarsus
versus twice-daily tacrolimus for prevention of treatment failure after 2-years among
patients aged 65 and over (age ≥65 yrs; -25.89% (-45.11%, 0.36%), p=0.067) (Rostaing et al,
AJKD 2016; Budde et al, AJT 2014). However, small numbers render the effect of borderline
statistical significance
As one of the largest growing demographics, it is imperative to design a targeted clinical
trial to ascertain if Envarsus has clinical benefits above and beyond twice-daily tacrolimus
in older kidney transplant recipients. Before that is possible, investigators must
investigate two things in preparation for a definitive study; 1) investigators must confirm
reproducibility of this trend among older kidney transplant recipients in a separate cohort
to determine effect size and power calculations, and 2) identify possible mechanistic,
biological and/or pharmacogenomic rationale to understand any effect. This feasibility study
will be the first contemporary randomised controlled trial in kidney transplantation looking
at a modified age-adapted immunosuppression protocol specifically for older adults,
attempting to determine whether the above results can be recreated and probed in greater
detail. As one of the most topical questions in the field of transplantation, the results of
this feasibility study would advise on the merits of undertaking a more definitive study
which would almost certainly be one of the most eagerly awaited studies by global transplant
clinicians.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
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