TACKLE-IT Trial - Treat Acute T Cell Rejection With Evidence and Confidence in Kidney Transplant Recipients

PHASE4NOT_YET_RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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).
  • Exclusion criteria

  • 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.
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    Eligibility

    Age eligible for study : 2 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2024-12-01

    Primary completion: 2029-12-01

    Study completion finish: 2029-12-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE4

    trial

    Trial ID

    NCT06474273

    Intervention or treatment

    DRUG: Methylprednisolone

    DRUG: Prednisone

    Conditions

    • Rejection; Transplant, Kidney
    • Rejection; Transplant, Pancreas
    Image related to Rejection; Transplant, Kidney
    • Condition: Rejection; Transplant, Kidney, Rejection; Transplant, Pancreas

    • DRUG: Methylprednisolone and other drugs

    • Adelaide, South Australia, Australia and more

    • Sponsor: University of Sydney

    Find a site

    Closest Location:

    Royal Adelaide Hospital

    Research sites nearby

    Select from list below to view details:

    • Royal Adelaide Hospital

      Adelaide, South Australia, Australia

    • Monash Medical Centre

      Clayton, Victoria, Australia

    • John Hunter Hospital

      Lambton, New South Wales, Australia

    • Prince of Wales Hospital

      Randwick, New South Wales, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    EXPERIMENTAL: Lower dose IV methylprednisolone x Lower dose oral 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.
    DRUG: Methylprednisolone
    • IV Methylprednisolone
    EXPERIMENTAL: Lower dose IV methylprednisolone x Higher dose oral 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.
    DRUG: Methylprednisolone
    • IV Methylprednisolone
    ACTIVE_COMPARATOR: Higher dose IV methylprednisolone x lower dose oral 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.
    DRUG: Methylprednisolone
    • IV Methylprednisolone
    ACTIVE_COMPARATOR: Higher dose IV methylprednisolone x higher dose oral 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.
    DRUG: Methylprednisolone
    • IV Methylprednisolone

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Histological resolution of biopsy-proven acute rejectionHistological 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.12 weeks post-randomization
    Improvement in allograft functionBaseline 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.12 weeks post-randomization
    Avoidance of rescue therapies within 12 weeks post-randomisation to achieve histological resolution and/or improvement in allograft functionUse 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.12 weeks post-randomization

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    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 \< 18 years) 12, 24 and 48 weeks. * Decline in eGFR (slope) from randomization to 48 weeks.At 12, 24 and 48 weeks post-randomization
    All cause death and death-censored graft lossAll 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.At 12 weeks post-randomization
    Urine albumin: creatinine ratiosUrine ACR is measured as standard of care. Rationale: ACR screens for graft dysfunction and is a marker for graft outcomesAt 12, 24 and 48 weeks post-randomization
    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. If randomisation and treatment with the first IV MP occur on the same day, then only a single serum creatinine will be required.)From randomization to 48 weeks
    Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR)ABMR and mixed rejection are defined according to the Banff 2022 criteria48 weeks post randomization
    Development of chronic fibrosis in the allograftThis 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)Baseline to 12 weeks post-randomisation
    Infections (requiring antimicrobials and hospitalisation)The types and number of events related to infections that required antimicrobials and hospitalisation for infections will be recorded.Anytime from randomization to 48 weeks
    Quality of life (QoL)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)At randomization, 12 weeks post-randomization, 24 weeks post-randomization, and 48 weeks post-randomization
    Infections (all types)All typesAnytime from randomization to 48 weeks
    CancerAll types and sitesAnytime from randomization to 48 weeks

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    References

    Clinical Trials Gov: TACKLE-IT Trial - Treat Acute T Cell Rejection With Evidence and Confidence in Kidney Transplant Recipients

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