Clinical trial NCT06474273: TACKLE-IT Trial - Treat Acute T Cell Rejection With Evidence and Confidence in Kidney Transplant Recipients
Official title: A Multicenter Randomized Controlled Trial to Treat Acute t Cell Mediated Rejection in Kidney and Kidney-pancreas Transplant Recipients
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Rejection; Transplant, Kidney
Rejection; Transplant, Pancreas
Keywords: Acute T cell mediated rejection
Lead sponsor: University of Sydney
Sponsor class: OTHER
Collaborators: name: University of Manitoba
First posted: 2024-06-25
Enrollment: 540
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: 2x2 factorial, triple-blind, non-inferiority, RCT of lower vs higher dose IV MP (methylprednisolone), and lower vs higher oral prednisone dose augmentation.
Primary purpose: TREATMENT

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?'

Eligibility criteria: 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.
* 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.

Primary outcomes:
measure: Histological resolution of biopsy-proven acute rejection
timeFrame: 12 weeks post-randomization
measure: Improvement in allograft function
timeFrame: 12 weeks post-randomization
measure: Avoidance of rescue therapies within 12 weeks post-randomization to achieve histological resolution and/or improvement in allograft function
timeFrame: 12 weeks post-randomization
Secondary outcomes:
measure: Estimated glomerular filtration rate (eGFR)
timeFrame: At 12, 24 and 48 weeks post-randomization
measure: All cause death and death-censored graft loss
timeFrame: At 12 weeks post-randomization
measure: Urine albumin: creatinine ratios
timeFrame: At 12, 24 and 48 weeks post-randomization
measure: Quality of life (QoL)
timeFrame: Baseline (at randomization), 12 weeks , 24 weeks , and 48 weeks post-randomization
measure: Cancer
timeFrame: Anytime from randomization to 48 weeks
measure: Trajectories of serum creatinine changes
timeFrame: From randomization to 48 weeks post-randomization
measure: Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR)
timeFrame: 48 weeks post-randomization
measure: Infections (including those requiring antimicrobials and hospitalisation)
timeFrame: Anytime from randomization to 48 weeks post-randomization
measure: Development of chronic fibrosis in the allograft
timeFrame: Baseline to 12 weeks post-randomization
Other outcomes:
measure: Steroid-related adverse effects
timeFrame: 3 days post randomisation, 7 days post randomisation, week 12 post-randomisation, week 24 post-randomisation and week 48 post-randomisation
measure: Integrative Box Risk Prediction Score (iBOX)
timeFrame: Week 13 to week 48 post-randomisation
measure: Economic evaluation: Incremental costs and benefits
timeFrame: During the 52-week follow up period
measure: Process evaluation: patients' and clinicians' perspectives on the treatment of acute TCMR
timeFrame: Anytime between week 12 and 48 of the trial
measure: T cell receptor repertoire
timeFrame: Week 13 to week 48 post-randomization
measure: Life participation
timeFrame: Randomisation, week 12 post-randomization, week 24 post-randomization and week 48 post-randomization
Locations:
city: Lambton
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Westmead
country: Australia
facility: The Sydney Children's Hospital Network
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Woolloongabba
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Nedlands
country: Australia
facility: Royal Perth Children's hospital
state: Western Australia
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Calgary
country: Canada
facility: University of Calgary
state: Alberta
city: Edmonton
country: Canada
facility: University of Alberta
state: Alberta
city: Winnipeg
country: Canada
facility: Transplant Manitoba, adult
state: Manitoba
city: Winnipeg
country: Canada
facility: Transplant Manitoba, pediatric
state: Manitoba
city: Halifax
country: Canada
facility: Dalhousie University
state: Nova Scotia
city: London
country: Canada
facility: Western University
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto - St Michael Hospital
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto - Hospital for Sick Kids
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto
state: Ontario
city: Montréal
country: Canada
facility: McGill University
state: Quebec
city: Montréal
country: Canada
facility: University of Montreal
state: Quebec
city: Québec
country: Canada
facility: University of Laval
state: Quebec
city: Saskatoon
country: Canada
facility: University of Saskatchewan
state: Saskatchewan
city: Grafton
country: New Zealand
facility: Auckland City Hospital
state: Auckland
Study officials:
affiliation: University of Sydney
name: Germaine Wong, PhD, FRACP
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba
name: Julie Ho, FRCPC
role: PRINCIPAL_INVESTIGATOR
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