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.
A large-scale trial will test whether screening kidney transplant recipients for harmful antibodies and then adjusting their immunosuppressant drugs can prevent the organ from failing years later. Around 30 percent of patients who develop donor-specific antibodies (DSA) after a transplant lose their kidney within five years, compared to 16 percent whose treatment is optimised. Current practice does not routinely screen for these antibodies or escalate medication in response to them. The trial will recruit roughly 2,357 patients from 13 UK units, randomising those with DSA to either biomarker-led care—where doctors reveal the antibody status and optimise prednisone, tacrolimus, and mycophenolate mofetil—or to standard care, where existing therapy continues unchanged. Patients without antibodies will be randomised to blinded or unblinded screening to assess whether simply knowing their status affects outcomes. If the biomarker-led strategy reduces graft failure from 30 percent to 16 percent in DSA-positive patients, it would provide a clear, actionable protocol for extending transplant survival. This would reduce the need for dialysis and repeat transplantation, saving the NHS significant costs and improving quality of life for thousands of patients. The trial also addresses a psychological gap: whether informing antibody-negative patients of their low-risk status changes medication adherence or anxiety.
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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, 18-75yrs old, > 1yr post-transplant, with good renal function. Exclusion criteria: history of malignancy, acute rejection. 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. PROPOSED outcome measures: Primary endpoint (EP); Time to graft failure in HLA Ab+ recruits randomized to BLC vs. time to graft failure in HLA Ab+ recruits positive patients randomized to 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. 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 will be at 8 monthly intervals. PROPOSED sample size; Recruiting from 13 units (over 45 months), with recruits followed up intensively for 32 months (maximum 64 months). The primary endpoint will be assessed by remote evaluation when 43 months post-randomisation is achieved by all. WE WILL recruit approximately 2357 participants. Given observed proportions of DSA participants, predicted drop outs and HLA Ab conversion rates, this will allow the target of 165 (~83 per group) DSA participants to be recruited. It is expected that this will result in approximately 824 (412 per group) non-DSA participants being recruited and 1368 (684 per group) participants remaining HLA Ab negative at the primary endpoint, exceeding the target numbers required for these groups. For 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; for non-DSA+ groups, power calculations based on 16% failure in SC and 6% in BLC; numbers will provide 80% power to determine a statistically significant difference between SC and BLC, using a log-rank test, with a 2-sided type-I error rate. 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. We will use Cox proportional hazards regression models to estimate the graft failure hazard ratio between the BLC and SC groups and test at the 5% level of significance. Similar procedures using Cox proportional hazards regression will be used for the analysis of secondary time to event outcomes. Where numbers allow, secondary binary outcomes will be analysed using logistic regression with adjustment for stratification factors. Where numbers are too small for this, the z-test or Fisher’s exact will be used. Results will be given as estimates (odds ratios or differences in proportions) and 95% CIs. For continuous secondary outcomes we will use linear regression (or a linear mixed model if accounting for repeated measures) with adjustment for stratification factors, transforming data where they are skew. PROJECT timetables including recruitment rates; The trial will commence on 01/03
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