A Multicenter Randomized Controlled Trial to Treat Acute T Cell Mediated Rejection in Kidney and Kidney-Pancreas Transplant Recipients

Phase 3RecruitingNCT06474273

University of Sydney540 enrolled

Overview

After a kidney or a 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, PROBE-style, 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?'

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Eligibility

Sex: ALLMin age: 2 Years

Medical Language ↔ Plain English

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). * Individuals with the following are eligible for inclusion: i. Concurrent acute TCMR and microvascular inflammation (MVI) defined as g+ptc, but without ABMR diagnosis. ii. Concurrent acute TCMR and chronic active TCMR. Exclusion Criteria: Individuals meeting any of the following criteria will be excluded from participation: * Mixed rejection. * Active or chronic active ABMR. * Chronic active TCMR. * 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.

Locations (30)

John Hunter Hospital

Lambton, New South Wales, Australia

NOT_YET_RECRUITING

Prince of Wales Hospital

Randwick, New South Wales, Australia

NOT_YET_RECRUITING

The Sydney Children's Hospital Network

Westmead, New South Wales, Australia

NOT_YET_RECRUITING

Westmead Hospital

Westmead, New South Wales, Australia

RECRUITING

Outcomes

Primary Outcomes

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.

Time frame: 12 weeks post-randomization

Improvement in allograft function for clinical rejection; and defined by an average of at least 2 serum creatinine at baseline and at least 2 serum creatinine from 11-13 weeks

Reduction in serum creatinine ≥20% is defined as the relative reduction in serum creatinine from baseline and at 11-13 weeks after randomisation, in the absence of dialysis or achieving freedom from dialysis. Staff are required to record the serum creatinine at each visit; or dates and modality of dialysis initiation and / or discontinuation.

Time frame: 11 to 13 weeks post-randomization

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 randomisation.

Time frame: 12 weeks post-randomization

Secondary Outcomes

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. All-cause death also includes cause-specific death (infections, cancers, cardiovascular-related, and other causes of death) at 12 weeks after randomisation.

Time frame: At 12 weeks post-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 \<18 years) 12, 24 and 48 weeks. * Decline in eGFR (slope) from randomization to 48 weeks.

Time frame: At 12, 24 and 48 weeks post-randomization

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

Time frame: At 12, 24 and 48 weeks post-randomization

Trajectories of serum creatinine changes

Time frame: From randomization to 48 weeks post-randomization

Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR)

Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR) within 48 weeks after randomisation. ABMR and mixed rejection are defined according to the Banff 2022 criteria

Time frame: 48 weeks post-randomization

Development of chronic fibrosis in the allograft

Development of chronic fibrosis in the allograft. This is defined as the absolute (Banff ci+ctscores) at 12 weeks

Time frame: Baseline to 12 weeks post-randomization

Infections (all types and sites)

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

Time frame: Anytime from randomization to 48 weeks post-randomization

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 2-7: EQ-5D-Y proxy version * Ages 8-17: EQ-5D-Y self-report 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.

Time frame: Baseline (at randomization), 12 weeks , 24 weeks , and 48 weeks post-randomization

Cancer

All types and sites

Time frame: Anytime from randomization to 48 weeks

A Multicenter Randomized Controlled Trial to Treat Acute T Cell Mediated Rejection in Kidney and Kidney-Pancreas Transplant Recipients

Overview

Conditions

Interventions

Eligibility

Locations (30)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts