TACKLE-IT Trial - Treat Acute T Cell Rejection With Evidence and Confidence in Kidney Transplant Recipients
- Conditions
- Rejection; Transplant, PancreasRejection; Transplant, Kidney
- Interventions
- Registration Number
- NCT06474273
- Lead Sponsor
- University of Sydney
- Brief Summary
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's 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.
- Detailed Description
TACKLE-IT is an international, multi-centre, 2x2 factorial, registry-based, single-blind, 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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 540
- 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).
- 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.
- Higher grade acute TCMR, ≥Banff 2A.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- FACTORIAL
- Arm && Interventions
Group Intervention Description Lower dose IV methylprednisolone x Higher dose oral prednisone Prednisone Lower dose IV MP (250 mg daily x 3 days in adults or 150 mg/m² daily x 3, or to a max 250 mg/dose in children (\<18 years), with higher dose (50mg daily x 7 days, or or 30mg/m2 for those \< 18 years) oral prednisone augmentation. Lower dose IV methylprednisolone x Lower dose oral prednisone Prednisone Lower dose IV MP (250 mg daily x 3 days in adults or 150 mg/m² daily x 3, or to a max 250 mg/dose in children (\<18 years), with lower dose (25mg daily x 7 days, or 15mg/m2 for those \< 18 years ) vs higher dose (50mg daily x 7 days, or or 30mg/m2 for those \< 18 years) oral prednisone augmentation. Higher dose IV methylprednisolone x lower dose oral prednisone Methylprednisolone Higher dose IV MP (500 mg daily x 3 days in adults or 300 mg/m² daily x 3 or to a max 500 mg/dose in children (\<18 years), with lower dose (25mg daily x 7 days, or 15mg/m2 for those \< 18 years) oral prednisone augmentation. Higher dose IV methylprednisolone x lower dose oral prednisone Prednisone Higher dose IV MP (500 mg daily x 3 days in adults or 300 mg/m² daily x 3 or to a max 500 mg/dose in children (\<18 years), with lower dose (25mg daily x 7 days, or 15mg/m2 for those \< 18 years) oral prednisone augmentation. Higher dose IV methylprednisolone x higher dose oral prednisone Prednisone Higher dose IV MP (500 mg daily x 3 days in adults or 300 mg/m² daily x 3 or to a max 500 mg/dose in children (\<18 years), with higher dose (50mg daily x 7 days, or 30mg/m2 for those \< 18 years) oral prednisone augmentation. Lower dose IV methylprednisolone x Lower dose oral prednisone Methylprednisolone Lower dose IV MP (250 mg daily x 3 days in adults or 150 mg/m² daily x 3, or to a max 250 mg/dose in children (\<18 years), with lower dose (25mg daily x 7 days, or 15mg/m2 for those \< 18 years ) vs higher dose (50mg daily x 7 days, or or 30mg/m2 for those \< 18 years) oral prednisone augmentation. Lower dose IV methylprednisolone x Higher dose oral prednisone Methylprednisolone Lower dose IV MP (250 mg daily x 3 days in adults or 150 mg/m² daily x 3, or to a max 250 mg/dose in children (\<18 years), with higher dose (50mg daily x 7 days, or or 30mg/m2 for those \< 18 years) oral prednisone augmentation. Higher dose IV methylprednisolone x higher dose oral prednisone Methylprednisolone Higher dose IV MP (500 mg daily x 3 days in adults or 300 mg/m² daily x 3 or to a max 500 mg/dose in children (\<18 years), with higher dose (50mg daily x 7 days, or 30mg/m2 for those \< 18 years) oral prednisone augmentation.
- Primary Outcome Measures
Name Time Method Avoidance of rescue therapies within 12 weeks post-randomisation to achieve histological resolution and/or improvement in allograft function 12 weeks post-randomization 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.
Histological resolution of biopsy-proven acute rejection 12 weeks post-randomization 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 12 weeks post-randomization Baseline serum creatinine is defined by an average of three 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. If randomisation and treatment with the first IV MP occur on the same day, then only a single serum creatinine will be required.
Reduction in serum creatinine ≥20% is defined as the relative reduction in serum creatinine from baseline and at 12 weeks after randomisation. Staff are required to record all available serum creatinine from randomization to 12 weeks, and then at each study visit.
- Secondary Outcome Measures
Name Time Method Estimated glomerular filtration rate (eGFR) At 12, 24 and 48 weeks post-randomization * 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.Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR) 48 weeks post randomization ABMR and mixed rejection are defined according to the Banff 2022 criteria
Infections (requiring antimicrobials and hospitalisation) Anytime from randomization to 48 weeks The types and number of events related to infections that required antimicrobials and hospitalisation for infections will be recorded.
Cancer Anytime from randomization to 48 weeks All types and sites
Quality of life (QoL) At randomization, 12 weeks post-randomization, 24 weeks post-randomization, and 48 weeks post-randomization QoL will be assessed using the EuroQol-5 Dimension-5 Level (EQ-5D-5L) for adults (participants ≥18 years), and ED-5D-Y for paediatric participants (aged between 2- 18 years)
Infections (all types) Anytime from randomization to 48 weeks All types
All cause death and death-censored graft loss At 12 weeks post-randomization 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 At 12, 24 and 48 weeks post-randomization Urine ACR is measured as standard of care. Rationale: ACR screens for graft dysfunction and is a marker for graft outcomes
Trajectories of serum creatinine changes From randomization to 48 weeks \*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. If randomisation and treatment with the first IV MP occur on the same day, then only a single serum creatinine will be required.)
Development of chronic fibrosis in the allograft Baseline to 12 weeks post-randomisation 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)
Trial Locations
- Locations (22)
Transplant Manitoba, adult
🇨🇦Winnipeg, Manitoba, Canada
Royal Adelaide Hospital
🇦🇺Adelaide, South Australia, Australia
Queensland Children's Hospital
🇦🇺South Brisbane, Queensland, Australia
Royal Children's Hospital Melbourne
🇦🇺Parkville, Victoria, Australia
University of Calgary
🇨🇦Calgary, Alberta, Canada
University of Saskatchewan
🇨🇦Saskatoon, Saskatchewan, Canada
Monash Medical Centre
🇦🇺Clayton, Victoria, Australia
University of Toronto
🇨🇦Toronto, Ontario, Canada
The Sydney Children's Hospital Network
🇦🇺Westmead, New South Wales, Australia
John Hunter Hospital
🇦🇺Lambton, New South Wales, Australia
Prince of Wales Hospital
🇦🇺Randwick, New South Wales, Australia
Westmead Hospital
🇦🇺Westmead, New South Wales, Australia
Princess Alexandra Hospital
🇦🇺Woolloongabba, Queensland, Australia
Royal Perth Children's hospital
🇦🇺Nedlands, Western Australia, Australia
Sir Charles Gairdner Hospital
🇦🇺Nedlands, Western Australia, Australia
Royal Perth Hospital
🇦🇺Perth, Western Australia, Australia
Transplant Manitoba, pediatric
🇨🇦Winnipeg, Manitoba, Canada
Western University
🇨🇦London, Ontario, Canada
McGill University
🇨🇦Montréal, Quebec, Canada
University of Montreal
🇨🇦Montréal, Quebec, Canada
University of Laval
🇨🇦Québec, Quebec, Canada
Auckland City Hospital
🇳🇿Grafton, Auckland, New Zealand