A Multicenter Randomized Controlled Trial to Treat Acute t Cell Mediated Rejection in Kidney and Kidney-pancreas Transplant Recipients
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 540
- 试验地点
- 60
- 主要终点
- Improvement in allograft function
研究概览
简要总结
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.
详细描述
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?'
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Factorial
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
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.
入排标准
- 年龄范围
- 2 Years 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Higher dose IV methylprednisolone x lower dose oral prednisone
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 daily x 7 days, or to a max 25mg/dose for those < 18 years) oral prednisone augmentation then return to standard prednisone.
干预措施: Methylprednisolone (Drug)
Higher dose IV methylprednisolone x higher dose oral prednisone
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 daily x 7 days, or to a max 50mg/dose for those < 18 years) oral prednisone augmentation, then return to standard prednisone.
干预措施: Methylprednisolone (Drug)
Higher dose IV methylprednisolone x higher dose oral prednisone
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 daily x 7 days, or to a max 50mg/dose for those < 18 years) oral prednisone augmentation, then return to standard prednisone.
干预措施: Prednisone (Drug)
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 x 7 days, or to a max 25mg/dose for those < 18 years ) oral prednisone augmentation then return to standard prednisone.
干预措施: Methylprednisolone (Drug)
Higher dose IV methylprednisolone x lower dose oral prednisone
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 daily x 7 days, or to a max 25mg/dose for those < 18 years) oral prednisone augmentation then return to standard prednisone.
干预措施: Prednisone (Drug)
Lower dose IV methylprednisolone x Higher dose oral prednisone
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, or to a max 50mg/dose for those < 18 years) oral prednisone augmentation then return to standard prednisone.
干预措施: Methylprednisolone (Drug)
Lower dose IV methylprednisolone x Higher dose oral prednisone
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, or to a max 50mg/dose for those < 18 years) oral prednisone augmentation then return to standard prednisone.
干预措施: Prednisone (Drug)
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 x 7 days, or to a max 25mg/dose for those < 18 years ) oral prednisone augmentation then return to standard prednisone.
干预措施: Prednisone (Drug)
结局指标
主要结局
Improvement in allograft function
时间窗: 12 weeks post-randomization
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.
Histological resolution of biopsy-proven acute rejection
时间窗: 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.
Avoidance of rescue therapies within 12 weeks post-randomization to achieve histological resolution and/or improvement in allograft function
时间窗: 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.
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
时间窗: 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.
次要结局
- Development of acute antibody mediated rejection (ABMR) and mixed rejection (concomitant ABMR + TCMR)(48 weeks post-randomization)
- Infections (including those requiring antimicrobials and hospitalisation)(Anytime from randomization to 48 weeks post-randomization)
- Urine albumin: creatinine ratios(At 12, 24 and 48 weeks post-randomization)
- Cancer(Anytime from randomization to 48 weeks)
- 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)
- Quality of life (QoL)(Baseline (at randomization), 12 weeks , 24 weeks , and 48 weeks post-randomization)
- Trajectories of serum creatinine changes(From randomization to 48 weeks post-randomization)
- Development of chronic fibrosis in the allograft(Baseline to 12 weeks post-randomization)
- Infections (all types and sites)(Anytime from randomization to 48 weeks post-randomization)