An Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of Tafamidis in Patients With Transthyretin-mediated Amyloidosis Post Orthotopic Heart Transplantation
试验速览
- 阶段
- 4 期
- 状态
- 进行中（未招募）
- 入组人数
- 25
- 试验地点
- 8
- 主要终点
- Serial change from baseline in plasma TTR levels at 12 months
研究概览
简要总结
Transthyretin cardiac amyloidosis (ATTR-CA) is a relentlessly progressive disease that can progress to end stage heart failure, at which point recently approved transthyretin production silencing or structure stabilizing therapies provide no clinical benefit. For well-selected individuals, heart transplantation is an excellent therapeutic option to improve survival. Historically, concomitant liver transplantation has been used to halt the progression of non-cardiac transthyretin amyloidosis (ATTR) manifestations, especially for individuals with TTR genotypes associated with significant neuropathy. However, despite this, patients continue to experience progressive non-cardiac manifestations, particularly gastrointestinal and neuropathic, which can have a substantial influence on post-heart transplantation morbidity. Concomitant liver transplantation is also associated with substantial morbidity and its future therapeutic role is questionable with recently established therapies for ATTR. Therefore, there is a clear unmet need to determine the utility and safety of ATTR targeted therapies for patients with recent heart transplantation for end-stage ATTR-CA. The central hypothesis of this proposal is that in patients who have received a heart transplantation for end-stage ATTR-CA, tafamidis therapy will be efficacious and well-tolerated. We aim to determine the safety and efficacy of tafamidis in stable patients who have undergone heart or combined heart/liver transplantation for ATTR (wild-type or variant) cardiac amyloidosis. The proposed study will be a single-arm intervention clinical trial with tafamidis. Because of the efficacy of tafamidis for both variant ATTR-CA and wild-type ATTR-CA, there is no clinical equipoise for an inactive-comparator placebo arm. The primary endpoint of this study will be serial change in plasma transthyretin (TTR) levels from baseline to 12 months at 3-month intervals. The secondary endpoints of this study will include serial changes in neuropathy assessments, modified body mass indices, incident transplant-specific adverse events, and pharmacokinetics of tafamidis. Observations from this study will establish the role of tafamidis use for the management of ATTR in patients after transplantation for end-stage ATTR-CA.
详细描述
A. Primary Aim
To determine the safety and efficacy of tafamidis in patients who have undergone heart or combined heart/liver transplantation for ATTR (wild-type or variant) cardiac amyloidosis.
Primary Hypothesis. Initiation of the TTR stabilizer, tafamidis, post heart or heart/liver transplant for ATTR cardiac amyloidosis, (wild-type or variant disease) will be associated with an increase in plasma transthyretin levels during 12 months of therapy.
B. Secondary Aims
- To determine the impact of tafamidis on serial questionnaire assessments that quantitate and determine the severity and clinical implications of motor, sensory, and autonomic neurologic impairment in participants over 12 months with cardiac transplantation.
- To determine the impact of tafamidis on serial questionnaire assessment of activity and social participation limitation, dysautonomia and nutritional status in participants over 12 months with cardiac transplantation.
- To determine the impact of tafamidis on transplantation-related adverse events in participants over 12 months with cardiac transplantation.
- To establish the pharmacokinetics of tafamidis in participants with cardiac transplantation over 12 months.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has received orthotopic heart transplantation for end-stage ATTRv or ATTRwt ≥12 months prior to screening. Concomitant hepatic and renal transplantation with adequate allograft function are included.
- •Has a stable immunosuppressive regimen and ≤ 10 mg of prednisone (or equivalent) at time of enrollment.
- •Has a Karnofsky performance status ≥ 70%
排除标准
- •Has previously received inotersen within the past 180 days, patisiran within the past 90 days, tafamidis within the past 14 days, or diflunisal in the past 14 days.
- •Participating in a clinical trial for ATTR targeted therapies.
- •Has an estimated glomerular filtration rate (eGFR) ≤ 15 ml/min/1.73 m2
- •Has known leptomeningeal or AL amyloidosis
- •Has active post-transplant lymphoproliferative disease
- •Excluding non-melanomatous skin cancers, has an active malignancy.
- •Has active infection with hepatitis B, hepatitis C, human immunodeficiency virus, or cytomegalovirus (CMV). For CMV, donor/ recipient exposure status and prior treated CMV disease on stable doses of antiviral therapies are not excluded.
- •Has cardiac allograft dysfunction defined by left ventricular ejection fraction (LVEF) <50% by echocardiogram within the past 3 months
- •Has been treated for acute cellular or antibody mediated rejection in the past 3 months
- •Has criteria to meet International Society for Heart and Lung Transplantation standardized nomenclature for severe coronary allograft vasculopathy ("ISHLT CAV3")
研究组 & 干预措施
Treatment Arm
Tafamidis 61 mg
干预措施: Tafamidis 61 MG (Drug)
结局指标
主要结局
Serial change from baseline in plasma TTR levels at 12 months
时间窗: Baseline, 3, 6, 9, and 12 months
Serial change from baseline in plasma Time in Therapeutic Range (TTR) levels at 12 months is measured at 3 month intervals. TTR tetramer stability is measured using an immunoturbidimetric assay. Increase in plasma TTR levels indicate TTR tetramer stability.
次要结局
- Serial change from baseline in Composite Autonomic Symptom Score (COMPASS-31) at12 months(Baseline, 3, 6, 9, and 12 months)
- Number of hepatic or renal transplant-specific adverse events(12 months)
- Steady-state plasma concentration of tafamidis in patients undergone HT for end stage ATTR-CA(Baseline, 3, 6, 9, and 12 months)
- Serial change from baseline in Norfolk QoL-DN at 12 months(Baseline, 3, 6, 9, and 12 months)
- Number of transplant-specific adverse events(12 months)
研究者
Justin Grodin
Associate Professor of Medicine
University of Texas Southwestern Medical Center