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

NCT06474273 | Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: GWCT051274
• Study Type: interventional
• Target: 540
• Locations: 3 countries
• Sites: 25

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.

Conditions

Rejection; Transplant, Kidney; Rejection; Transplant, Pancreas

Keywords

Acute T cell mediated rejection

Outcome Measures

Primary Outcomes (3)

• Histological resolution of biopsy-proven acute rejection

  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.

  12 weeks post-randomization

• Improvement in allograft function

  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.

  12 weeks post-randomization

• Avoidance of rescue therapies within 12 weeks post-randomization to achieve histological resolution and/or improvement in allograft function

  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.

  12 weeks post-randomization

Secondary Outcomes (9)

• Estimated glomerular filtration rate (eGFR)

  At 12, 24 and 48 weeks post-randomization

• All cause death and death-censored graft loss

  At 12 weeks post-randomization

• Urine albumin: creatinine ratios

  At 12, 24 and 48 weeks post-randomization

• Quality of life (QoL)

  Baseline (at randomization), 12 weeks , 24 weeks , and 48 weeks post-randomization

• Cancer

  Anytime from randomization to 48 weeks

Other Outcomes (6)

• Steroid-related adverse effects

  3 days post randomisation, 7 days post randomisation, week 12 post-randomisation, week 24 post-randomisation and week 48 post-randomisation

• Integrative Box Risk Prediction Score (iBOX)

  Week 13 to week 48 post-randomisation

• Economic evaluation: Incremental costs and benefits

  During the 52-week follow up period

Study Arms (4)

Lower dose IV methylprednisolone x Lower dose oral prednisone

EXPERIMENTAL

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.

Drug: Methylprednisolone; Drug: Prednisone

Lower dose IV methylprednisolone x Higher dose oral prednisone

EXPERIMENTAL

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.

Drug: Methylprednisolone; Drug: Prednisone

Higher dose IV methylprednisolone x lower dose oral prednisone

ACTIVE COMPARATOR

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.

Drug: Methylprednisolone; Drug: Prednisone

Higher dose IV methylprednisolone x higher dose oral prednisone

ACTIVE COMPARATOR

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.

Drug: Methylprednisolone; Drug: Prednisone

Interventions

Methylprednisolone DRUG

IV Methylprednisolone

Also known as: IV MP

Higher dose IV methylprednisolone x higher dose oral prednisone; Higher dose IV methylprednisolone x lower dose oral prednisone; Lower dose IV methylprednisolone x Higher dose oral prednisone; Lower dose IV methylprednisolone x Lower dose oral prednisone

Prednisone DRUG

Oral prednisone augmentation

Higher dose IV methylprednisolone x higher dose oral prednisone; Higher dose IV methylprednisolone x lower dose oral prednisone; Lower dose IV methylprednisolone x Higher dose oral prednisone; Lower dose IV methylprednisolone x Lower dose oral prednisone

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Sydney: lead
• University of Manitoba: collaborator

Study Sites (25)

John Hunter Hospital

Lambton, New South Wales, 2305, Australia

NOT YET RECRUITING

Prince of Wales Hospital

Randwick, New South Wales, 2031, Australia

NOT YET RECRUITING

The Sydney Children's Hospital Network

Westmead, New South Wales, 2145, Australia

NOT YET RECRUITING

Westmead Hospital

Westmead, New South Wales, 2145, Australia

RECRUITING

Queensland Children's Hospital

South Brisbane, Queensland, 2014, Australia

RECRUITING

Princess Alexandra Hospital

Woolloongabba, Queensland, 4102, Australia

NOT YET RECRUITING

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

NOT YET RECRUITING

Monash Medical Centre

Clayton, Victoria, 3168, Australia

NOT YET RECRUITING

Royal Perth Children's hospital

Nedlands, Western Australia, 6009, Australia

NOT YET RECRUITING

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

NOT YET RECRUITING

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

NOT YET RECRUITING

University of Calgary

Calgary, Alberta, T2N 1N4, Canada

NOT YET RECRUITING

University of Alberta

Edmonton, Alberta, T6G 2R3, Canada

NOT YET RECRUITING

Transplant Manitoba, adult

Winnipeg, Manitoba, R3A 1R9, Canada

NOT YET RECRUITING

Transplant Manitoba, pediatric

Winnipeg, Manitoba, R3A 1R9, Canada

NOT YET RECRUITING

Dalhousie University

Halifax, Nova Scotia, B3H 4R2, Canada

NOT YET RECRUITING

Western University

London, Ontario, N6A 3K7, Canada

NOT YET RECRUITING

University of Toronto - St Michael Hospital

Toronto, Ontario, M5B 1W8, Canada

NOT YET RECRUITING

University of Toronto - Hospital for Sick Kids

Toronto, Ontario, M5G 1E8, Canada

NOT YET RECRUITING

University of Toronto

Toronto, Ontario, M5S 1A1, Canada

NOT YET RECRUITING

McGill University

Montreal, Quebec, H3A 0G4, Canada

NOT YET RECRUITING

University of Montreal

Montreal, Quebec, H3T 1J4, Canada

NOT YET RECRUITING

University of Laval

Québec, Quebec, G1V 0B4, Canada

NOT YET RECRUITING

University of Saskatchewan

Saskatoon, Saskatchewan, S7N 5A2, Canada

NOT YET RECRUITING

Auckland City Hospital

Grafton, Auckland, 1023, New Zealand

NOT YET RECRUITING

Related Publications (14)

• Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ, Goldberg A, Birk PE, Rush DN, Nickerson PW. Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant. Am J Transplant. 2012 May;12(5):1157-67. doi: 10.1111/j.1600-6143.2012.04013.x. Epub 2012 Mar 19.

  PMID: 22429309 BACKGROUND

• Wiebe C, Kosmoliaptsis V, Pochinco D, Gibson IW, Ho J, Birk PE, Goldberg A, Karpinski M, Shaw J, Rush DN, Nickerson PW. HLA-DR/DQ molecular mismatch: A prognostic biomarker for primary alloimmunity. Am J Transplant. 2019 Jun;19(6):1708-1719. doi: 10.1111/ajt.15177. Epub 2018 Dec 15.

  PMID: 30414349 BACKGROUND

• Wiebe C, Rush DN, Gibson IW, Pochinco D, Birk PE, Goldberg A, Blydt-Hansen T, Karpinski M, Shaw J, Ho J, Nickerson PW. Evidence for the alloimmune basis and prognostic significance of Borderline T cell-mediated rejection. Am J Transplant. 2020 Sep;20(9):2499-2508. doi: 10.1111/ajt.15860. Epub 2020 Apr 9.

  PMID: 32185878 BACKGROUND

• Nickerson PW, Balshaw R, Wiebe C, Ho J, Gibson IW, Bridges ND, Rush DN, Heeger PS. A noninferiority design for a delayed calcineurin inhibitor substitution trial in kidney transplantation. Am J Transplant. 2021 Apr;21(4):1503-1512. doi: 10.1111/ajt.16311. Epub 2020 Oct 6.

  PMID: 32956576 BACKGROUND

• Rampersad C, Balshaw R, Gibson IW, Ho J, Shaw J, Karpinski M, Goldberg A, Birk P, Rush DN, Nickerson PW, Wiebe C. The negative impact of T cell-mediated rejection on renal allograft survival in the modern era. Am J Transplant. 2022 Mar;22(3):761-771. doi: 10.1111/ajt.16883. Epub 2021 Nov 24.

  PMID: 34717048 BACKGROUND

• Ho J, Okoli GN, Rabbani R, Lam OLT, Reddy VK, Askin N, Rampersad C, Trachtenberg A, Wiebe C, Nickerson P, Abou-Setta AM. Effectiveness of T cell-mediated rejection therapy: A systematic review and meta-analysis. Am J Transplant. 2022 Mar;22(3):772-785. doi: 10.1111/ajt.16907. Epub 2021 Dec 10.

  PMID: 34860468 BACKGROUND

• Nankivell BJ, Shingde M, Keung KL, Fung CL, Borrows RJ, O'Connell PJ, Chapman JR. The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion. Am J Transplant. 2018 Feb;18(2):364-376. doi: 10.1111/ajt.14609. Epub 2018 Jan 3.

  PMID: 29194971 BACKGROUND

• Tong A, Budde K, Gill J, Josephson MA, Marson L, Pruett TL, Reese PP, Rosenbloom D, Rostaing L, Warrens AN, Wong G, Craig JC, Crowe S, Harris T, Hemmelgarn B, Manns B, Tugwell P, Van Biesen W, Wheeler DC, Winkelmayer WC, Evangelidis N, Sautenet B, Howell M, Chapman JR. Standardized Outcomes in Nephrology-Transplantation: A Global Initiative to Develop a Core Outcome Set for Trials in Kidney Transplantation. Transplant Direct. 2016 May 19;2(6):e79. doi: 10.1097/TXD.0000000000000593. eCollection 2016 Jun.

  PMID: 27500269 BACKGROUND

• Sautenet B, Tong A, Chapman JR, Warrens AN, Rosenbloom D, Wong G, Gill J, Budde K, Rostaing L, Marson L, Josephson MA, Reese PP, Pruett TL, Evangelidis N, Craig JC. Range and Consistency of Outcomes Reported in Randomized Trials Conducted in Kidney Transplant Recipients: A Systematic Review. Transplantation. 2018 Dec;102(12):2065-2071. doi: 10.1097/TP.0000000000002278.

  PMID: 29781954 BACKGROUND

• Sautenet B, Tong A, Manera KE, Chapman JR, Warrens AN, Rosenbloom D, Wong G, Gill J, Budde K, Rostaing L, Marson L, Josephson MA, Reese PP, Pruett TL, Hanson CS, O'Donoghue D, Tam-Tham H, Halimi JM, Shen JI, Kanellis J, Scandling JD, Howard K, Howell M, Cross N, Evangelidis N, Masson P, Oberbauer R, Fung S, Jesudason S, Knight S, Mandayam S, McDonald SP, Chadban S, Rajan T, Craig JC. Developing Consensus-Based Priority Outcome Domains for Trials in Kidney Transplantation: A Multinational Delphi Survey With Patients, Caregivers, and Health Professionals. Transplantation. 2017 Aug;101(8):1875-1886. doi: 10.1097/TP.0000000000001776.

  PMID: 28738403 BACKGROUND

• Tong A, Gill J, Budde K, Marson L, Reese PP, Rosenbloom D, Rostaing L, Wong G, Josephson MA, Pruett TL, Warrens AN, Craig JC, Sautenet B, Evangelidis N, Ralph AF, Hanson CS, Shen JI, Howard K, Meyer K, Perrone RD, Weiner DE, Fung S, Ma MKM, Rose C, Ryan J, Chen LX, Howell M, Larkins N, Kim S, Thangaraju S, Ju A, Chapman JR; SONG-Tx Investigators. Toward Establishing Core Outcome Domains For Trials in Kidney Transplantation: Report of the Standardized Outcomes in Nephrology-Kidney Transplantation Consensus Workshops. Transplantation. 2017 Aug;101(8):1887-1896. doi: 10.1097/TP.0000000000001774.

  PMID: 28737661 BACKGROUND

• Tong A, Sautenet B, Poggio ED, Lentine KL, Oberbauer R, Mannon R, Murphy B, Padilla B, Chow KM, Marson L, Chadban S, Craig JC, Ju A, Manera KE, Hanson CS, Josephson MA, Knoll G; SONG-Tx Graft Health Workshop Investigators. Establishing a Core Outcome Measure for Graft Health: A Standardized Outcomes in Nephrology-Kidney Transplantation (SONG-Tx) Consensus Workshop Report. Transplantation. 2018 Aug;102(8):1358-1366. doi: 10.1097/TP.0000000000002125.

  PMID: 29470347 BACKGROUND

• Ju A, Josephson MA, Butt Z, Jowsey-Gregoire S, Tan J, Taylor Q, Fowler K, Dobbels F, Caskey F, Jha V, Locke J, Knoll G, Ahn C, Hanson CS, Sautenet B, Manera K, Craig JC, Howell M, Rutherford C, Tong A, Harden P, Hawley C, Holdaas H, Israni A, Jesse M, Kane B, Kanellis J, Kiberd B, Kim J, Larsen C, Leichtman A, Lentine K, Malone A, Mannon R, Oberbauer R, Patzer R, Peipert JD, Phan HA, Poggio E, Reed R, Scandling J, Tang I, Watson C, Contrares D, Contreras P, Cross D, Juodvalkis E, Koide D, Koide J, Kozarewicz A, Kozarewicz L, Kozarewicz R, Koritala A, Lisiecki E, Lipuma C, Lyman M, Mueller R, Mueller G, Noble L, Nolan N, Nolan S, Thomas J, Urbancyzk L, Zerante J, Zerante S; SONG-Tx Life Participation Workshop Investigators; Health professionals (*includes 2 patients from the SONG-Tx Graft Health Expert Working Group); Patients and family members. Establishing a Core Outcome Measure for Life Participation: A Standardized Outcomes in Nephrology-kidney Transplantation Consensus Workshop Report. Transplantation. 2019 Jun;103(6):1199-1205. doi: 10.1097/TP.0000000000002476.

  PMID: 30300284 BACKGROUND

• Ju A, Chow BY, Ralph AF, Howell M, Josephson MA, Ahn C, Butt Z, Dobbels F, Fowler K, Jowsey-Gregoire S, Jha V, Locke JE, Tan JC, Taylor Q, Rutherford C, Craig JC, Tong A. Patient-reported outcome measures for life participation in kidney transplantation: A systematic review. Am J Transplant. 2019 Aug;19(8):2306-2317. doi: 10.1111/ajt.15267. Epub 2019 Feb 28.

  PMID: 30664327 BACKGROUND

MeSH Terms

Conditions

Rejection, Psychology

Interventions

Methylprednisolone; Prednisone

Condition Hierarchy (Ancestors)

Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Pregnadienediols

Study Officials

• Germaine Wong, PhD, FRACP

  University of Sydney

  PRINCIPAL INVESTIGATOR

• Julie Ho, FRCPC

  University of Manitoba

  PRINCIPAL INVESTIGATOR

Central Study Contacts

NHMRC Clinical Trials Centre THE UNIVERSITY OF SYDNEY

CONTACT

+61 2 9562 5000; tackle-it.study@sydney.edu.au

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: As a triple-blind study, all investigators, research staff, clinicians, outcome assessors, data analysts and participants will be blinded to the allocation of the IV MP treatment comparisons. All key stakeholders including the global steering committee, the site investigators, and the trial management committee (TMC) will remain blinded to the individual patient randomization and the aggregate data that may reveal the unblinded outcomes. All researchers responsible for the analysis will remain blinded for the duration of the trial. Only the members of the Data Safety Monitoring Board (DSMB) and the independent statistician supporting their work will be unblinded prior to study completion.
• Purpose: TREATMENT
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 2x2 factorial, triple-blind, non-inferiority, RCT of lower vs higher dose IV MP (methylprednisolone), and lower vs higher oral prednisone dose augmentation.

Study Record Dates

• First Submitted: June 19, 2024
• First Posted: June 25, 2024
• Study Start: March 13, 2026
• Primary Completion (Estimated): June 1, 2030
• Study Completion (Estimated): June 1, 2030
• Last Updated: May 6, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Study protocol, SAP, ICF will be provided 3 months after registration. The Clinical study report and code will be provided after completion of the trial.
• Access Criteria: All IPD data arising from the trial will be shared 2 years after publication of the main results.

Locations

NZ (1); AU (11); CA (13)