Rejection; Transplant, Kidney, Rejection; Transplant, Pancreas
Conditions
Keywords
Acute T cell mediated rejection
Brief summary
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.
Detailed description
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?'
Interventions
DRUGMethylprednisolone
IV Methylprednisolone
DRUGPrednisone
Oral prednisone augmentation
Sponsors
University of Sydney
University of Manitoba
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
All researchers responsible for the trial analysis and interpretation, including members of the Trial Management Committee (TMC) and Global Steering Committee, will remain blinded to aggregate treatment outcomes for the duration of the trial. Due to the open-label IV component of the study, site investigators and study staff involved in participant management will be aware of the allocated IV treatment dose for participants at their site. However, oral treatment allocation and aggregate study outcomes will remain blinded. Only the members of the Data Safety Monitoring Board (DSMB) and the independent statistician supporting DSMB activities will have access to unblinded aggregate data prior to study completion.
Intervention model description
International, multicentre, 2x2 factorial, PROBE-style, non-inferiority, registry-embedded RCT of lower vs higher dose IV MP (methylprednisolone), and lower vs higher oral prednisone dose augmentation. The IV methylprednisolone component is open-label. The oral prednisone component remains triple-blinded, and all primary and key secondary endpoints will be assessed using blinded central adjudication.
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 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 | 11 to 13 weeks post-randomization | 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. |
| 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 randomisation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. All-cause death also includes cause-specific death (infections, cancers, cardiovascular-related, and other causes of death) at 12 weeks after randomisation. |
| 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. |
| 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 post-randomization | — |
| Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR) | 48 weeks post-randomization | 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 |
| Development of chronic fibrosis in the allograft | Baseline to 12 weeks post-randomization | Development of chronic fibrosis in the allograft. This is defined as the absolute (Banff ci+ctscores) at 12 weeks |
| Infections (all types and sites) | 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. |
| 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 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. |
| Cancer | Anytime from randomization to 48 weeks | All types and sites |
Countries
Australia, Canada, New Zealand
Contacts
CONTACTNHMRC Clinical Trials Centre THE UNIVERSITY OF SYDNEY
PRINCIPAL_INVESTIGATORGermaine Wong, PhD, FRACP
University of Sydney
PRINCIPAL_INVESTIGATORJulie Ho, FRCPC
University of Manitoba
Outcome results
None listed