使用从胸腺组织获得的 Treg 细胞 (thyTreg) 进行细胞疗法来控制与 COVID-19 相关的免疫过度激活 (THYTECH2) (THYTECH2)
开放 I/IIa 期临床试验，评估从胸腺组织获得的 Treg 细胞 (thyTreg) 的同种异体给药控制与 COVID-19 相关的免疫过度激活的安全性和有效性
The investigators developed a GMP protocol to isolate Treg cells from thymic tissue (thyTreg). The thyTreg cells are being evaluated in a Phase I/II clinical trial to evaluate the safety and efficacy of the adoptive transfer of autologous thyTreg to prevent rejection in heart transplant children (NCT04924491), with preliminary results indicating the feasibility and safety of the therapy.
In addition, thyTreg cells have shown low immunogenicity in the pre-clinical setting, indicating that allogeneic use of these thyTreg cells (allo-thyTreg) would have a low risk of adverse effects. These thyTreg cells could inhibit an excessive inflammation in SARS-CoV-2 infection, or ameliorate the immunological affection underlying Acute respiratory distress syndrome, improving life-threatening manifestations, restoring immune balance, and protecting affected tissues.
This clinical trial is an open-label Sequential Parallel Group Phase I/II study to evaluate the safety and efficacy of allogeneic thymus derived Tregs (thyTreg) (thyTreg) in controlling the immune dysregulation associated with SARS-CoV-2 infection and/or Acute Respiratory Distress Syndrome.
研究概览
详细说明
The immune system is the body's defense system against pathogens and other harmful agents, but it is also responsible for transplant rejection or autoimmune diseases. Another scenario of disproportionate immune response is the Immune Hyperactivation, an exaggerated systemic inflammatory response such as that caused by respiratory infections like COVID-19, a major cause of acute respiratory distress syndrome (ARDS) in critically ill patients.
The standard treatment to prevent these immune responses is the use of immunosuppressive and immunomodulatory therapy, which produces a pleotropic inhibition on the immune system and have a high cost. However, a widespread feeling among the scientific community is that only re-educating immune system to promote immune tolerance will decline the harmful immune responses without prejudice to the functional integrity of the immune system.
In the context of severe COVID-19 and ARDS, it has been shown that an alteration in the frequency and functionality of Tregs. In addition, it has been described that the increased oxygen therapy requirements is not due to the viral effect, but to the triggered immune hyperinflammation that can lead to multi-organ failure and death. Therefore, although the adoptive transfer of Treg is a promising cell therapy for the treatment of this type of disease, the characteristics of the patients make it unfeasible to obtain enough Treg from the patient to produce a therapeutic dose and, if achieved, the quality of these cells does not allow a prolonged therapeutic effect to be obtained over time.
Tregs are a subset of CD4+ T cells with suppressive function that maintain the immune system balance. Adoptive Treg cell therapy has shown efficacy in a variety of immune-mediated diseases in preclinical and clinical studies. To date, most of the clinical trials employing Treg cell therapy have been limited due to a small Treg numbers obtained (Treg cells represent less than 10% of CD4+ T cells) and the low quality of infused Treg (in terms of purity, survival, and suppressor capacity).
The investigators have developed an innovative Treg manufacturing protocol, that overcome the existing difficulties by employing a new source of cells, which is the thymic tissue routinely removed and discarded in paediatric cardiac surgeries. The protocol allows to produce massive amounts of thymus derived Treg cells (thyTreg), with improved survival, high suppressive capacity and suitable for therapeutic use.
The study will evaluate escalating doses of thyTreg administrated as a single IV dose. The study will include up to 2 cohorts of 4 to 8 subjects per each arm (control group and thyTreg group) followed for a total of 24 months. All subjects will receive standard of care treatment for COVID-19 or ARDS, including dexamethasone and other approved therapies from institutional guidelines.
研究类型
注册 (估计的)
阶段
- 阶段2
- 阶段1
联系人和位置
学习联系方式
- 姓名：Marta Martínez-Bonet, PhD
- 电话号码：34 915866455
- 邮箱：marta.mbonet@iisgm.com
研究联系人备份
- 姓名：Diana Hernández Flórez, PhD
- 电话号码：34 915866455
- 邮箱：diana.hernandez@iisgm.com
学习地点
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Madrid
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Madrid、Madrid、西班牙、28007
- 招聘中
- Hospital General Universitario Gregorio Marañon
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接触：
- Rafael Correa-Rocha, PhD
- 电话号码：+34 915866455
- 邮箱：rafael.correa@iisgm.com
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副研究员：
- Marjorie Pion, PhD
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副研究员：
- Diana Hernández-Flórez, PhD
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副研究员：
- Marta Martínez-Bonet, PhD
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副研究员：
- Juan Miguel Gil-Jaurena, MD
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副研究员：
- Carlos Pardo, MD PhD
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副研究员：
- Mª Eugenia Fernández-Santos, PhD
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副研究员：
- Ramón Pérez-Caballero, MD PhD
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副研究员：
- Ana Pita, MD
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副研究员：
- Esther Bernaldo-de-Quirós, PhD
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副研究员：
- María Abad Ferry, MsC
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副研究员：
- Beatriz Cózar Fernández, MsC
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副研究员：
- Sergio Gil Manso, PhD
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副研究员：
- Rocio López Esteban
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副研究员：
- José Eugenio Guerrero Sanz, MD PhD
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副研究员：
- Carmen Martínez Mata, MD
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副研究员：
- José Luis Vicario Moreno, PhD
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参与标准
资格标准
适合学习的年龄
接受健康志愿者
有资格学习的性别
描述
Inclusion Criteria:
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Patient over 18 to 65 years of age
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Patient Informed and non-opposed to the research by his medical doctor during hospitalization
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Patient with clinical, radiological, gasometric and immunological criteria defined as:
- Acute respiratory failure secondary to acute lung injury of noncardiogenic cause
- Pulmonary abnormalities compatible with bilateral alveoloinsterstitial infiltrates by chest imaging (radiograph or scan)
- PaO2/FiO2≤ 300 Presence of at least one of the following markers of inflammation: IL6 > 40 pg/ml or ferritin >300 ng/ml or CRP >3 mg/dl or increasing over the last 24 hours
Exclusion Criteria:
- Pregnancy or breast feeding
- Body mass index >35
- Patients not expected to survive 48 hours after enrolment based on clinical assessment
- Patients with an extracorporeal respiratory support
- Neutropenia (absolute neutrophil count <1000/uL)
- Thrombocytopenia (absolute neutrophil count <50000/uL)
- Positive serology for HBV, HCV, or HIV at Screening
- Life expectancy of less than 6 months due to other pathologies
- History of significant underlying pulmonary disease requiring oxygen therapy prior to inclusion.
- Patients with a history of autoimmune diseases
- Patients with a history of hematopoietic neoplasia or oncology disease
- Patients with a history of hematopoietic or solid organ transplant
- Patients with a congenital or induced immunodeficiency
- Patients received thymoglobulin, basiliximab or any anti-T-cell therapies within 6 moths prior to the screening visit
- Patients received other cell therapy in the last 12 months
- Patients received intravenous immunoglobulin (IVIg) within 5 moths prior to the screening visit
- Patients who have participated or is participating in a clinical research study evaluating COVID-19 or ARDS within 30 days prior to the screening visit
学习计划
研究是如何设计的？
设计细节
- 主要用途：治疗
- 分配：非随机化
- 介入模型：阶乘赋值
- 屏蔽：无（打开标签）
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
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实验性的：Phase A: 5.000.000 thyTreg /kg
Allogeneic thyTreg 5.000.000 |
Treg lymphocytic cells, differentiated, allogeneic, of thymic tissue, expanded and stimulated with Interleukin (IL-) 2 (thyTreg)
其他名称：
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无干预：Phase A: standard of care
Standard of care |
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实验性的：Phase B: 10.000.000 thyTreg /kg
Allogeneic thyTreg 10.000.000 |
Treg lymphocytic cells, differentiated, allogeneic, of thymic tissue, expanded and stimulated with Interleukin (IL-) 2 (thyTreg)
其他名称：
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无干预：Phase B: standard of care
Standard of care |
研究衡量的是什么？
主要结果指标
结果测量 |
大体时间 |
|---|---|
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1. 输注相关不良事件（安全性）的发生率（按类型、频率、严重程度和因果关系划分）
大体时间：24个月
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24个月
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次要结果测量
结果测量 |
大体时间 |
|---|---|
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重症监护室住院时间
大体时间：24个月
|
24个月
|
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使用序贯器官衰竭评估评分评估临床状态的变化
大体时间：24个月
|
24个月
|
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使用急性生理学和慢性健康疾病分类系统 (APACHE) III 评估的临床状态变化
大体时间：24个月
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24个月
|
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使用 Barthel 评分评估临床状态的变化
大体时间：24个月
|
24个月
|
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使用多普勒超声心动图通过二尖瓣和三尖瓣反流测量心肌功能的变化
大体时间：24个月
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24个月
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使用多普勒超声心动图通过二尖瓣和组织二尖瓣多普勒测量心肌功能的变化
大体时间：24个月
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24个月
|
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使用多普勒超声心动图通过三尖瓣和组织三尖瓣测量心肌功能的变化
大体时间：24个月
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24个月
|
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白细胞介素 6 (IL-6) 相对于基线的变化
大体时间：24个月
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24个月
|
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C 反应蛋白 (PCR) 相对于基线的变化
大体时间：24个月
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24个月
|
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外周血中 Treg 细胞数量较基线的变化
大体时间：24个月
|
24个月
|
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外周血中T细胞、B细胞、NK细胞、单核细胞、树突状细胞、粒细胞的数量
大体时间：24个月
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24个月
|
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干扰素 γ、肿瘤坏死因子 α 和白细胞介素（IL-6 和 IL-10）细胞因子水平相对于基线的变化。
大体时间：24个月
|
24个月
|
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24 个月患者总体生存率
大体时间：24个月
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24个月
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使用 PaO2/FiO2 和/或 SaO2/FiO2 评估氧合改善
大体时间：24个月
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24个月
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使用诊断测试评估 SARS-CoV-2 阳性或 ARDS 病因的变化
大体时间：24个月
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24个月
|
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铁蛋白参数相对于基线的变化
大体时间：24个月
|
24个月
|
合作者和调查者
调查人员
- 首席研究员：Rafael Correa-Rocha, PhD、Hospital General Universitario Gregorio Marañon
研究记录日期
研究主要日期
学习开始 (实际的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
与本研究相关的术语
其他相关的 MeSH 术语
其他研究编号
- FIBHGM-ECNC003-2021
- 2021-003240-25 (其他标识符：AEMPS)
- 2024-519799-25 (EudraCT编号)
药物和器械信息、研究文件
研究美国 FDA 监管的药品
研究美国 FDA 监管的设备产品
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