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

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.

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.

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.

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

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.

All types and sites

An average of three serum creatinine measures will be considered as baseline serum creatinine measures: i) first serum creatinine preceding randomization, ii) serum creatinine at the time of randomisation, iii) serum creatinine at the time of the first IV MP.

ABMR and mixed rejection are defined according to the Banff 2022 criteria

All types and number of events related to infections that required antimicrobials and hospitalisation for infections will be recorded.

This is defined as a change in ci and ct scores (a marker of interstitial fibrosis and tubular atrophy, measurement of fibrosis, defined by the Banff 2022 criteria)

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

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

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.

To characterise and compare the T cell receptor (TCR) repertoire in transplant recipients who were responsive and not responsive to the various corticosteroid dosing strategies in acute TCMR.

Life participation will be assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS®) Ability to Participate in Social Roles and Activities - Short Form 4a (SF4a). This instrument measures perceived ability to perform usual social roles and activities.

Scores are reported as T-scores standardized to the general U.S. population (mean = 50, SD = 10).

• Minimum score: 20
• Maximum score: 80

Higher scores indicate better ability to participate in social roles and activities (i.e., a more favorable outcome).