An Explorative Study for Halting Inflammation in Patients With Emphysema by Administration of Allogeneic Bone Marrow Derived Mesenchymal Stromal Cells.
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- Difference in expression of CD31
研究概览
简要总结
Rationale: Pulmonary emphysema is a component of Chronic Obstructive Pulmonary Disease (COPD) characterized by chronic inflammation with neutrophils and monocytes mediating the tissue destruction under the regulation of various types of lymphocytes. Bone marrow-derived mesenchymal stromal cells have potential to halt the progressive inflammatory response as indicated by the investigator's pilot study (CCMO NL28562.000.09) .
Objective: To determine whether patients with emphysema develop anti-inflammatory and tissue repair responses by treatment with allogeneic bone marrow-derived mesenchymal stromal cells (MSC) from healthy donors.
Study design: an explorative double-blind, placebo-controlled randomized (2:1) trial in 30 patients with moderate to severe emphysema who are scheduled for two separate sessions for surgical lung volume reduction (LVRS). The study treatment is intravenous allogeneic MSC or placebo treatment in between the first and second surgical session. Randomisation will allocate 10 patients to receive 2 x 106 /kg body weight MSC in a range of 1.5 x 106 MSC/ kg to 2.5 x 106 MSC/ kg (at a maximum of 200 x106 MSC per study participant) iv (or 5 patients to receive placebo) at week 4 and 3 before the second LVRS, and will allocate 10 patients to receive 2 x 106 /kg body weight MSC in a range of 1.5 x 106 MSC/ kg to 2.5 x 106 MSC/ kg (at a maximum of 200 x106 MSC per study participant) iv (or 5 patients to placebo) at week 12 and 11 before the second LVRS.
Main study parameters/endpoints: the study has a co-primary endpoint. First, the difference in expression of CD31 on cells per micrometer alveolar septae present in lung tissue harvested at the second LVRS from patients who received MSC at 3 and 4 weeks prior to LVRS2 or placebo. Second, the difference between MSC and placebo treatment in change in CO diffusion capacity over a period of 3 years following LVRS2.
详细描述
Rationale: Pulmonary emphysema is a component of Chronic Obstructive Pulmonary Disease (COPD) characterized by chronic inflammation with neutrophils and monocytes mediating the tissue destruction under the regulation of various types of lymphocytes. Since 25 years, patients with moderate to severe emphysema are treated with inhaled or oral corticosteroids. Currently, consensus is developing that this anti-inflammatory treatment is not effective to halt progression of emphysema. Therefore, emphysema may be classified as steroid-resistant and requires new anti-inflammatory treatment approaches, including cellbased therapies. Bone marrow-derived mesenchymal stromal cells have potential to halt the progressive inflammatory response in various diseases, including steroid-resistant transplant rejection, Crohn's disease and possibly emphysema as indicated by our pilot study (CCMO NL28562.000.09) .
Objective: To determine whether patients with emphysema develop anti-inflammatory and tissue repair responses by treatment with allogeneic bone marrow-derived mesenchymal stromal cells (MSC) from healthy donors.
Study design: an explorative double-blind, placebo-controlled randomized (2:1) trial in 30 patients with moderate to severe emphysema who are scheduled for two separate sessions for surgical lung volume reduction (LVRS). The study treatment is intravenous allogeneic MSC or placebo treatment in between the first and second surgical session. Randomisation will allocate 10 patients to receive 2 x 106 /kg body weight MSC in a range of 1.5 x 106 MSC/ kg to 2.5 x 106 MSC/ kg (at a maximum of 200 x106 MSC per study participant) iv (or 5 patients to receive placebo) at week 4 and 3 before the second LVRS, and will allocate 10 patients to receive 2 x 106 /kg body weight MSC in a range of 1.5 x 106 MSC/ kg to 2.5 x 106 MSC/ kg (at a maximum of 200 x106 MSC per study participant) iv (or 5 patients to placebo) at week 12 and 11 before the second LVRS.
Study population: patients between age 45 and 65; a gradient of emphysema severity towards the lung apex as assessed by CT-derived lung densitometry and equally distributed between left and right lung; FEV1 between 20% and 45% pred; Gas diffusion capacity between 30% and 45% pred. Intervention (if applicable): MSC infusions with cryo-preserved MSC in a dose of 2 x 106 /kg body weight in a range of 1.5 x 106 MSC/ kg to 2.5 x 106 MSC/ kg ( at a maximum of 200 x106 MSC per study participant) in a covered bag or NaCl 0.9% with 5% DMSO in a covered bag, both produced in the GMP facility of LUMC.
Main study parameters/endpoints: the study has a co-primary endpoint. First, the difference in expression of CD31 on cells per micrometer alveolar septae present in lung tissue harvested at the second LVRS from patients who received MSC at 3 and 4 weeks prior to LVRS2 or placebo. Second, the difference between MSC and placebo treatment in change in CO diffusion capacity over a period of 3 years following LVRS2.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 45 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Signed informed consent consistent with ICH-GCP guidelines and local legislation prior to participation in the trial;
- •Scheduled for lung volume reduction surgery for emphysema as determined by a referring chest physician;
- •Pre-bronchodilator measured FEV1 between 20% and 45% predicted; TLCO between 30% and 45% pred.; RV/TLC ≥ 50%;
- •Patients in a stable clinical condition.
排除标准
- •Significant cardiac failure;
- •Active smoking, or < 6 months smoking cessation;
- •Failure to complete pulmonary rehab program before randomization
- •Women of child bearing potential;
- •Any cancer treated in the previous 5 years;
- •Women of child-bearing potential not using adequate contraception;
- •Any other condition of the patient that the clinical investigator deemed harmful for study participation.
研究组 & 干预措施
Placebo week 4 and 3 before LVRS2
Placebo: consisting of a 5% DMSO-solution in isotonic solution
干预措施: Placebo (Drug)
MSC week 4 and 3 before LVRS2
Allogeneic mesenchymal Stromal cells: 2 x 10^6/kg body weight MSC in a range of 1.5 x 10^6 MSC/ kg to 2.5 x 10^6 MSC/kg (at a maximum of 200 x10^6 MSC per study participant) with 5% DMSO iv
干预措施: Allogeneic MSC (Genetic)
MSC week 12 and 11 before LVRS2
Allogeneic mesenchymal Stromal cells: 2 x 10^6/kg body weight MSC in a range of 1.5 x 10^6 MSC/ kg to 2.5 x 10^6 MSC/kg (at a maximum of 200 x10^6 MSC per study participant) with 5% DMSO iv
干预措施: Allogeneic MSC (Genetic)
Placebo week 12 and 11 before LVRS2
Placebo: consisting of a 5% DMSO-solution in isotonic solution
干预措施: Placebo (Drug)
结局指标
主要结局
Difference in expression of CD31
时间窗: Within one year after the last study patient had its second lung surgical procedure
The difference in expression of CD31 on cells per micrometer alveolar septae present in lung tissue harvested at the second LVRS from patients who received MSC at 3 and 4 weeks prior to LVRS2 or placebo
The difference between MSC and placebo treatment in change in CO diffusion capacity
时间窗: 1 year after the last CO diffusion measurement
The difference between MSC and placebo treatment in change in CO diffusion capacity over a period of 3 years following LVRS2
次要结局
- The correlation between arterial pO2 or gas transfer value TLCO (measured as standard of care) and the outcome of the primary objective of the study for patients treated with MSC or placebo.(at 12 weeks, as well as after 6 and 12 months, after discharge of admission for LVRS2)
- The differences in expression of Surfactant Protein-C expression by alveolar type II cells in lung tissue obtained from study patients treated with placebo or MSC.(Within one year after the last study patient had its second lung surgical procedure)
- The difference in endothelial microparticles concentration and concentration of immunological markers in blood samples from study patients treated with placebo or MSC.(Within one year after the last study patient had its second lung surgical procedure)
- The difference in immunostaining of various leukocytes in resected lung tissue, including T lymphocytes, B lymphocytes, macrophages and neutrophils obtained from study patients treated with placebo or MSC.(Within one year after the last study patient had its second lung surgical procedure)
- The difference in shear stress responses, expressed as % elongation of 100 cells, of isolated pMVECs ex vivo obtained from study patients treated with placebo or MSC.(Within one year after the last study patient had its second lung surgical procedure)
研究者
Jan Stolk
PI
Leiden University Medical Center