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 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.
- Detailed Description
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?'
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.
- 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 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 ) oral prednisone augmentation then return to standard prednisone. 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 ) oral prednisone augmentation then return to standard prednisone. Lower dose IV methylprednisolone x Higher dose oral prednisone Methylprednisolone Lower dose IV MP (250 mg daily x 3 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 , or 30mg/m² daily x 7 for those \< 18 years) oral prednisone augmentation then return to standard prednisone. Lower dose IV methylprednisolone x Higher dose oral prednisone Prednisone Lower dose IV MP (250 mg daily x 3 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 , or 30mg/m² daily x 7 for those \< 18 years) oral prednisone augmentation then return to standard prednisone. Higher dose IV methylprednisolone x lower dose oral prednisone Methylprednisolone Higher dose IV MP (500mg daily x 3 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 then return to standard prednisone. Higher dose IV methylprednisolone x lower dose oral prednisone Prednisone Higher dose IV MP (500mg daily x 3 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 then return to standard prednisone. Higher dose IV methylprednisolone x higher dose oral prednisone Methylprednisolone Higher dose IV MP (500 mg daily x 3 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, then return to standard prednisone. Higher dose IV methylprednisolone x higher dose oral prednisone Prednisone Higher dose IV MP (500 mg daily x 3 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, then return to standard prednisone.
- Primary Outcome Measures
Name Time Method 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 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.Avoidance of rescue therapies within 12 weeks post-randomization 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 randomization.
- Secondary Outcome Measures
Name Time Method 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 (including those requiring antimicrobials and hospitalisation) Anytime from randomization to 48 weeks post-randomization All types and number of events related to infections that required antimicrobials and hospitalisation for infections will be recorded.
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 \&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 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
Quality of life (QoL) Baseline (at randomization), 12 weeks , 24 weeks , and 48 weeks post-randomization 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.Cancer Anytime from randomization to 48 weeks All types and sites
Trajectories of serum creatinine changes From randomization to 48 weeks post-randomization 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.
Development of chronic fibrosis in the allograft Baseline to 12 weeks post-randomization 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 (25)
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Dalhousie University
🇨🇦Halifax, Nova Scotia, Canada
University of Toronto - St Michael Hospital
🇨🇦Toronto, Ontario, Canada
University of Toronto - Hospital for Sick Kids
🇨🇦Toronto, Ontario, Canada
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
Scroll for more (15 remaining)University of Alberta🇨🇦Edmonton, Alberta, Canada