Title: Optimized TacrolimuS and MMF for HLA Antibodies after Renal Transplantation. An RCT to determine if a combined screening/treatment programme can prevent premature failure of renal transplants due to chronic rejection in patients with HLA antibodies.
Funder: Department of Health and Social Care

Abstract: RESEARCH Design: Prospective randomized open-labelled MARKER-BASED STRATEGY (HYBRID) DESIGN, with two arms stratified by HLA antibody (Ab) status. STUDY Population: Inclusion criteria: Cross-match-NEG recipients, 18-70yrs old, > 1yr post-transplant, with good renal function. Exclusion criteria: history of malignancy, acute rejection, ongoing infection. PLANNED Interventions: Recruits will consent to a combined screening/treatment process. Screening will determine presence and specificity of HLA Ab. HLA-Ab+ RECRUITS WILL BE SUBDEFINED AS DONOR SPECIFIC Ab (DSA), OR NON-DONOR SPECIFIC Ab (NON-DSA) AND RANDOMIZED 1:1 INTO BIOMARKER-LED CARE (BLC) OR STANDARD CARE (SC) GROUPS. IN BLC, HLA Ab STATUS WILL BE REVEALED AND RECRUITS OPTIMIZED ON PREDNISONE, TACROLIMUS AND MMF. IN SC, RECRUITS WILL MAINTAIN EXISTING THERAPY. HLA Ab-NEG RECRUITS WILL BE RANDOMISED 1:1 TO UNBLINDED OR BLINDED SCREENING; ONLY THE FORMER WILL LEARN THE RESULTS OF SCREENING. BOTH WILL MAINTAIN EXISTING TREATMENT AND UNDERGO REGULAR RE-TESTING TO END OF YEAR 3 OF THE TRIAL. PROPOSED outcome measures: Primary endpoint (EP); 3-year graft failure rates in HLA Ab+ recruits randomized to BLC vs. SC (defined as restarting dialysis or requiring a new transplant). Secondary EPs; Patient survival; graft dysfunction; acute rejection; rates of infection, malignancy & diabetes; health economic analysis; analysis of adherence to medication & perception of risk, especially in HLA Ab-neg patients. Samples will be used to define new biomarkers of progression/response to treatment (funded separately).ASSESSMENT & follow-up; Data collected during routine visits. HLA Ab+ patients in BLC will require extra follow-up during optimized treatment. All other clinic visits at least 4 monthly. PROPOSED sample size; Recruiting from 5 units (3 yrs), with recruits followed for 3 yrs. WE WILL screen 2790 TO ensure 879 in each of the two HLA Ab-neg. groups (627 estimated to stay Ab-neg to 1o EP). This will enable recruitment of; a) 174 to DSA+ groups. Power calculations based on 30% failure in SC vs. 16% in BLC; numbers will provide 86% power and 5% type I error for a two-sided Z test; b) 347 to non-DSA+ groups; Power calculation based on 16% failure in SC and 6% in BLC; numbers will provide 98% power and 5% type I error for a two-sided Z test. Total numbers will enable a test for non-inferior (5% difference) outcomes IN BLINDED VS. UNBLINDED SCREENING with 90% power and 2.5% type 1 error for a one-sided Z test. STATISTICAL analysis will be on intention to treat and treatment-received basis. Z-tests used for analysis of primary and secondary binary outcomes. Cox proportional hazards regression used for the analysis of survival outcomes. Two-sample t-tests used for continuous secondary outcomes, transforming data if skewed. Multivariable analyses, using generalized linear models will be used to study possible effects of covariates on outcomes of univariate analysis. PROJECT timetables including recruitment rates; An audit indicates screening 2100 in round 1, identifying approx. 520 HLA Ab+. In each successive round, we expect 200 new recruits. Our target is 1758 to the HLA Ab-neg groups. Audits will trigger involvement of new sites if recruitment targets not met. Trial will start on 1/03/13, recruitment/follow-up stops at end of years 3/6 respectively.

Lay abstract: Treatment of kidney disease accounts for a significant proportion of NHS spending. Transplantation is the best treatment forkidney failure, in terms of length and quality of life and is also more cost-effective than dialysis. However, most transplants do not survive for the recipient“s natural lifespan, but instead fail after 10-12 years, consigning many patients back onto dialysis and 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 of this problem by screening for the presence of 'HLA antibodies' 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 application is to test a screening and treatment protocol for antibodies in a randomized controlled trial. THOSE WITH ANTIBODIES WILL BE RANDOMIZED 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 THREE DRUGS, PREDNISONE, TACROLIMUS AND MMF, EACH ALREADY LICENSED FOR USE IN TRANSPLANT RECIPIENTS. WE HAVE EVIDENCE THAT THIS REGIME WILL BE EFFECTIVE AT PREVENTING GRAFT DYSFUNCTION AND EXPECT THIS TO FEED THROUGH TO IMPROVEMENTS IN GRAFT SURVIVAL. IN THE STANDARD CARE ARM, 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 IN THESE GROUPS; 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 randomization IN THE HLA ANTIBODY+ RECRUITS, predicted to be approximately 20% in the SC arm but <10% in the BLC arm. The secondary outcomes will include whether rates of deterioration are altered, as well as the incidence of infections, cancers and diabetes and an analysis of the role of non-adherence with medication. A cost analysis will confirm whether the screening programme and treatment protocol can save money by keeping kidney transplants functioning for longer. The trial includes collection and storage of blood samples every four months; these will form the basis of later, separately funded studies to identify new biomarkers associated with outcomes in this group. The team assembled to perform this study come from the UK“s largest renal transplant centres, to enable screening of 3,000 patients in three years and include nephrologists experienced in clinical trial management, along with some of UK“s most eminent antibody experts. We are requesting direct costs to cover the staff required to run the trial and receive and process trial blood samples. We are asking the NHS to cover the costs OF analysing the antibody samples and treatment.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL