Treat ACute Tcell mediated rejection in Kidney and SPK transpLant rEcIpienTs (TACKLE-IT)
Overview
Treat ACute T-cell mediated rejection in Kidney and SPK transplant rEcIpienTs (TACKLE-IT) is a large, international registry-embedded clinical trial testing the optimal steroid regimen for treating acute T-cell mediated rejection (TCMR) in kidney and simultaneous pancreas–kidney transplant recipients.
The trial uses a 2×2 factorial, triple-blind, randomised controlled design to compare high versus low doses of intravenous methylprednisolone and high versus low doses of oral prednisone taper. Participants include children (aged 2 years and older) and adults with biopsy-proven acute TCMR. Recruitment will take place over four years across multiple centres worldwide.
Led by an international, multidisciplinary team of transplant clinicians, trialists, biostatisticians, health economists, social scientists, and consumer representatives, TACKLE-IT seeks to answer a long-standing question in transplantation: what is the minimally effective, safe, and acceptable steroid dose to treat acute rejection?
| Principal Investigators: | Professor Germaine Wong and Professor Julie Ho |
| Trial Registration Number: | NCT06474273 |
| Objectives: | Primary: To test non-inferiority of low dose vs high dose corticosteroids to improve allograft function and achieve histological resolution of acute TCMR in kidney and simultaneous kidney-pancreas (SPK) transplant recipients. Secondary: To compare: i) risk of graft loss and death, ii) graft functional decline, iii) risk of ABMR, iv) risk of fibrosis, v) risk of infections and other adverse effects from steroids such as hospitalizations, hyperglycemia, cardiovascular events, vi) cancer Tertiary: i) To assess the impact, fidelity, preferences, and barriers of implementing a standardized first-line steroid treatment for acute TCMR in kidney and SPK transplant recipients, ii) To determine the incremental costs and benefits of low dose versus high dose steroids for the treatment of acute TCMR, iii) To create a multicentre transplant biobank for in-depth studies evaluating markers of treatment response vs non-response, iiia) To characterise and compare the T cell receptor (TCR) repertoire in transplant recipients who were responsive and not responsive to the various corticosteroid dosing strategies in acute TCMR (Australia), iiib) To determine the urine chemokine response, HLA eplet MM (immunological risk score), and biopsy transcriptomics (e.g. B-HOT panel) in those who were responsive and not responsive to various corticosteroid dosing strategies in acute TCMR (Canada). |
| Population: | 540 kidney and SPK transplant patients with biopsy-proven acute TCMR. |
| Comparator: | 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) vs higher dose (50mg daily x 7 days, or 30mg/m2 for those < 18 years) oral prednisone augmentation. |
| Follow-up: | 5 years |
| Primary composite outcome: | Composite of reduction in serum creatinine ≥20% between baseline and weeks 11-13 post-randomisation; or absence of any biopsy-proven acute rejection by the 2022 Banff criteria within 12 weeks; and avoidance of any forms of rescue therapies within 12 weeks post-randomisation. Rescue therapies may include additional doses of intravenous methylprednisolone, T cell depleting agents, plasma exchange, intravenous immunoglobulin, or anti-B cell therapies. |
| Status: | Recruitment not yet started |
| Target Recruitment: | Participants across Australia, New Zealand, and Canada |
Research Team
Prof Germaine Wong
Transplant Nephrologist and Director of Western Renal Service at Westmead Hospital
Prof Julie Ho
Transplant Nephrologist and Medical Director for the Transplant Manitoba Adult Kidney Program
Background
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.
Study Design and Population
| Aim: | The aim of the study is to determine whether lower doses of IV methylprednisolone and oral prednisone compared to higher doses improve outcomes following kidney or SPK transplantation. |
| Design: | International, multicentre, 2x2 factorial, triple-blind, non-inferiority, phase III, registry-embedded RCT of lower vs higher dose IV MP, and lower vs higher oral prednisone dose augmentation in kidney and SPK patients. The defining features are:
|
| Setting: | Australia, New Zealand, and Canada |
| Randomisation: | Randomisation will be stratified by countries; adult versus paediatric; and kidney alone versus SPK transplant. Allocation concealment will be preserved using a central computer-generated randomisation in a 4:1:1:4 manner across the 4 arms: (IV Low/Oral Low; IV Low/Oral High; IV High: Oral Low; IV High/Oral High). |
| Participants: | This clinical trial is designed to evaluate a “real-world” setting, requiring a broad study population. In order to be eligible, study participants must meet the following criteria:
|
| Outcomes: | Primary composite outcome: Composite of reduction in serum creatinine ≥20% between baseline and weeks 11-13 post-randomisation; or absence of any biopsy-proven acute rejection by the 2022 Banff criteria within 12 weeks; and avoidance of any forms of rescue therapies within 12 weeks post-randomisation. Rescue therapies may include additional doses of intravenous methylprednisolone, T cell depleting agents, plasma exchange, intravenous immunoglobulin, or anti-B cell therapies. Principal secondary outcome: Death and death-censored graft loss Secondary outcomes: (1) Absolute eGFR at 12, 24 and 48 weeks, and decline in eGFR from randomization to 48 weeks (slope); (2) Trajectories of serum creatinine changes from randomisation to 48 weeks; (3) Urine albumin: Cr at 12, 24 and 48 weeks; (4) Development of ABMR and mixed rejection; (5) Development of chronic fibrosis in the allograft at 12 weeks; (6) Infections (all types); (7) Cancer Safety outcomes: Hospitalisations, steroid-related adverse effects (adaption from the Steroid Patient Reported Outcome (Steroid-PRO)); bone fractures; major adverse cardiovascular events; development of dnDSA. Other outcomes: Life participation (total score in the PROMIS Ability to participate in social roles & activities (SF4a), preference-based QoL (Euro-Qol-5D for adults and EQ-5D-Y/proxy version of EQ-5D-Y for children and adolescents), costs, development of donor specific antibodies (dnDSA), iBOX score. Long-term outcomes: Graft loss & death at 1, 2, 5 yrs will be obtained through Canadian Organ Transplant Registry (CORR) & Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). |
| Study Duration: | The planned duration for recruitment is 4 years, with one year follow-up. The trial will complete in 2030. Results will be available for dissemination in 2031. |
Contact Us
Study Contact: Chandana Guha, chandana.guha@sydney.edu.au
Study Contact Backup: Angela Rejuso, angela.rejuso@sydney.edu.au
ANZDATA Coordinator: Lavern Greenham, trials@anzdata.org.au
Website Contact Link: https://tackleit.com.au/contact/