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?'
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
540
IV Methylprednisolone
Oral prednisone augmentation
John Hunter Hospital
Lambton, New South Wales, Australia
Prince of Wales Hospital
Randwick, New South Wales, Australia
The Sydney Children's Hospital Network
Westmead, New South Wales, Australia
Westmead Hospital
Westmead, New South Wales, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Princess Alexandra Hospital
Woolloongabba, Queensland, Australia
Royal Adelaide Hospital
Adelaide, South Australia, Australia
Monash Medical Centre
Clayton, Victoria, Australia
Royal Perth Children's hospital
Nedlands, Western Australia, Australia
Sir Charles Gairdner Hospital
Nedlands, Western Australia, Australia
...and 15 more locations
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
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.
Time frame: 12 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 randomization.
Time frame: 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 \&amp;amp;amp;amp;amp;amp;amp;lt; 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
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.
Time frame: At 12 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
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.
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
Trajectories of serum creatinine changes
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.
Time frame: From randomization to 48 weeks post-randomization
Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR)
ABMR and mixed rejection are defined according to the Banff 2022 criteria
Time frame: 48 weeks post-randomization
Infections (including those requiring antimicrobials and hospitalisation)
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
Development of chronic fibrosis in the allograft
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)
Time frame: Baseline to 12 weeks post-randomization
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