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

Официальное название

A Multicenter Randomized Controlled Trial to Treat Acute t Cell Mediated Rejection in Kidney and Kidney-pancreas Transplant Recipients

Обзор

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.

Подробное описание

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?'

Вмешательства

• Препарат Methylprednisolone
  IV Methylprednisolone
• Препарат Prednisone
  Oral prednisone augmentation

Первичные конечные точки

• Histological resolution of biopsy-proven acute rejection [Срок оценки: 12 weeks post-randomization]
• Improvement in allograft function [Срок оценки: 12 weeks post-randomization]
• Avoidance of rescue therapies within 12 weeks post-randomization to achieve histological resolution and/or improvement in allograft function [Срок оценки: 12 weeks post-randomization]

Вторичные конечные точки (9)

• Estimated glomerular filtration rate (eGFR) [Срок оценки: At 12, 24 and 48 weeks post-randomization]
• All cause death and death-censored graft loss [Срок оценки: At 12 weeks post-randomization]
• Urine albumin: creatinine ratios [Срок оценки: At 12, 24 and 48 weeks post-randomization]
• Quality of life (QoL) [Срок оценки: Baseline (at randomization), 12 weeks , 24 weeks , and 48 weeks post-randomization]
• Cancer [Срок оценки: Anytime from randomization to 48 weeks]
• Trajectories of serum creatinine changes [Срок оценки: From randomization to 48 weeks post-randomization]
• Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR) [Срок оценки: 48 weeks post-randomization]
• Infections (including those requiring antimicrobials and hospitalisation) [Срок оценки: Anytime from randomization to 48 weeks post-randomization]
• Development of chronic fibrosis in the allograft [Срок оценки: Baseline to 12 weeks post-randomization]

Критерии участия

Критерии включения

• 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).

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Факторный дизайн

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Канада · 13 центров

• University of Calgary — Calgary
• University of Alberta — Edmonton
• Transplant Manitoba, adult — Winnipeg
• Transplant Manitoba, pediatric — Winnipeg
• Dalhousie University — Halifax
• Western University — London
• University of Toronto - St Michael Hospital — Toronto
• University of Toronto - Hospital for Sick Kids — Toronto
• … и ещё 5 центров

Австралия · 11 центров

• John Hunter Hospital — Lambton
• Prince of Wales Hospital — Randwick
• The Sydney Children's Hospital Network — Westmead
• Westmead Hospital — Westmead
• Queensland Children's Hospital — South Brisbane
• Princess Alexandra Hospital — Woolloongabba
• Royal Adelaide Hospital — Adelaide
• Monash Medical Centre — Clayton
• … и ещё 3 центра

Новая Зеландия · 1 центр

• Auckland City Hospital — Grafton

Публикации

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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 Transp PMID 27500269

Идентификаторы

NCT: NCT06474273 · GWCT051274

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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