After a kidney or a simultaneous kidney-pancreas transplant, some patients may face problems with their new organs. This happens because the body sometimes makes a mistake and tries to get rid of the organ. This problem is called rejection. One type of rejection is known as Acute T cell mediated rejection (TCMR). This can lead to many problems or even stop the transplant from working.

Doctors give strong steroids to treat this problem, but there are no rules for how much steroid to give. Too much steroids can cause problems like heart and bone problems, bad infections, and weight gain. That is why we need to find the right dose of steroids for each person to treat this.

TACKLE-IT is a study that will try to find the right steroid dose for treating rejection.

TACKLE-IT is an international, multi-centre, 2x2 factorial, triple-blind, non-inferiority registry-embedded, randomised controlled trial (RCT) that compares the effectiveness and safety of high vs low dose IV MP, and high vs low dose oral prednisone taper as the first-line therapy for acute TCMR in kidney and SPK transplant recipients. This RCT was conceived and developed through extensive consultation and collaboration with our key stakeholders, including transplant recipients with lived experience and the International TCMR Working Group with sponsorship by 4 international transplant societies (The Transplantation Society (TTS), American Society of Transplantation (AST), European Society of Transplantation (ESOT) and Transplant Society of Australia and New Zealand (TSANZ). TACKLE-IT is led by an international multi-disciplinary team of transplant health professionals, clinical trialists, biostatisticians, health economist, social scientist, consumers.

TACKLE-IT will address the critical unmet need and resolve a decades-long unanswered question, 'What is the minimally acceptable, safe and effective steroid dose for the treatment of acute TCMR in kidney and SPK transplant recipients?'

Inclusion Criteria:

• Participants or their legal guardian must be able to understand and provide written informed consent;
• Stated willingness to comply with all study procedures and availability for the duration of the study;
• All ethnic and gender groups will have equal access to the study;
• All children (aged 2+ years) and adults who have received a kidney or SPK transplant with biopsy proven acute TCMR (≥ Banff borderline (minimum i1 score) whether clinical or subclinical).

Exclusion Criteria:

• Mixed rejection.
• Active or chronic active ABMR.
• Chronic active TCMR. *Patients with concomitant acute TCMR and chronic active TCMR will not be excluded from the trial.
• Isolated v1 without inflammation.
• Concurrent renal disease, such as recurrent glomerulonephritis or polyomavirus nephropathy.
• Active malignancies or active infection that preclude immunosuppression augmentation.
• Use of other immunomodulatory agents, including, but not limited to, Rituximab, Anti-TNF monoclonal antibody, Belatacept, Abatacept, Janus kinase inhibitors, Eculizumab, Pegcetacoplan.
• Enrolment in other interventional drug trials.
• Use of other investigational agents.
• Unable to adhere to the study protocol.

The data collected for the study, including individual patient data and a data dictionary that defines each field in the data set, will be made available as deidentified participant data to researchers who propose to use the data for individual patient data meta-analysis. Data will be shared following approval of the proposal by the corresponding author and a signed data access agreement, beginning 2 years following main publication.

Study protocol, SAP, ICF will be provided 3 months after registration. The Clinical study report and code will be provided after completion of the trial.

All IPD data arising from the trial will be shared 2 years after publication of the main results.

As a triple-blind study, all investigators, research staff, clinicians, outcome assessors, data analysts and participants will be blinded to the allocation of the IV MP treatment comparisons.

All key stakeholders including the global steering committee, the site investigators, and the trial management committee (TMC) will remain blinded to the individual patient randomization and the aggregate data that may reveal the unblinded outcomes. All researchers responsible for the analysis will remain blinded for the duration of the trial. Only the members of the Data Safety Monitoring Board (DSMB) and the independent statistician supporting their work will be unblinded prior to study completion.