TACKLE-IT Trial - Treat Acute T Cell Rejection With Evidence and Confidence in Kidney Transplant Recipients

Histological resolution of biopsy-proven acute rejection

Histological resolution of biopsy-proven acute rejection is defined by the absence of any biopsy-proven acute rejection (BPAR) on follow-up biopsy, including \<Banff Borderline (i1 t1), mixed rejection, ABMR and chronic active TCMR using Banff 2022 criteria.

Improvement in allograft function

Baseline serum creatinine is defined by an average of three serum creatinine measures: i) first serum creatinine preceding randomisation , ii) serum creatinine at the time of randomisation, iii) serum creatinine at the time of the first IV MP. Reduction in serum creatinine ≥20% is defined as the relative reduction in serum creatinine from baseline and at 12 weeks after randomisation.

Avoidance of rescue therapies within 12 weeks post-randomization to achieve histological resolution and/or improvement in allograft function

Use of rescue therapy is defined as: the use of any adjunctive T and B cell depleting therapies such as intravenous thymoglobulin, alemtuzumab, bortezomib, or rituximab, or additional doses of IV MP within the first 12 weeks after randomization.

Estimated glomerular filtration rate (eGFR)

* Absolute eGFR (2021 CKD-EPI eGFR without race modifier for adults, and the CKiD U25 equation to estimate GFR in children \&amp;amp;amp;amp;amp;amp;amp;amp;lt; 18 years) 12, 24 and 48 weeks. * Decline in eGFR (slope) from randomization to 48 weeks.

All cause death and death-censored graft loss

All cause death and death-censored graft loss have been identified as the core outcomes for kidney transplant recipients. However, death and death-censored graft loss are anticipated to have a very low incidence at the 12 weeks post-randomization primary outcome ascertainment and were therefore not included in the primary composite outcome. They will be reported as principal secondary endpoints.

Urine albumin: creatinine ratios

Urine ACR is measured as standard of care. Rationale: ACR screens for graft dysfunction and is a marker for graft outcomes

Quality of life (QoL)

QoL will be assessed using the EuroQol-5 Dimension-5 Level (EQ-5D-5L) for adult participants (aged ≥18 years). For paediatric participants (aged 2-17 years), age-appropriate versions of the EuroQol Youth version (EQ-5D-Y) will be used as follows: * Ages 4-7: EQ-5D-Y proxy version * Ages 8-11: EQ-5D-Y self-report version * Ages 12-15: EQ-5D-Y self-report version * Age ≥16: EQ-5D-5L adult version Both the EQ-5D-5L and EQ-5D-Y report utility scores ranging from -0.281 to 1 (EQ-5D-5L UK value set) and -0.109 to 1 (EQ-5D-Y, proxy or self-report), where 1 represents perfect health, 0 represents a health state equivalent to death, and negative scores represent health states worse than death. Higher scores indicate better health-related quality of life.

Steroid-related adverse effects

Adaption from the Steroid Patient Reported Outcome (Steroid PRO).

Integrative Box Risk Prediction Score (iBOX)

Graft survival prediction will be assessed using the Integrative Box Risk Prediction Score (iBOX), a validated composite risk prediction tool for kidney transplant outcomes. The iBOX score integrates clinical, functional, and immunological parameters including serum creatinine, proteinuria, biopsy findings, and presence of donor-specific antibodies to estimate the risk of allograft failure. The iBox score essentially assigns a numerical value based on these parameters, indicating the risk of allograft loss (kidney transplant failure).

Economic evaluation: Incremental costs and benefits

Economic evaluation to compare the incremental benefits (in QALYs) and costs between the treatment arms.

Process evaluation: patients' and clinicians' perspectives on the treatment of acute TCMR

Semi-structured interviews will be conducted to elicit patients' perspectives and experiences of having acute TCMR, the adverse effects of the treatments. Health professionals' will also be interviewed to elicit their perspectives and experiences regarding the barriers, challenges, and enablers for implementing the intervention, the perceived benefits, and harms of the intervention and how the intervention should be delivered such that maximal interactions of the intervention are reached for the intended participants.