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| Name | Class |
|---|---|
| Erasmus Medical Center | OTHER |
| Amsterdam UMC, location VUmc | OTHER |
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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.
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.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: LVRS is a routine procedure for treatment of emphysema and received a positive recommendation from the Cochrane Institute. The dose of MSC has been infused in over 200 patients in LUMC only causing mild side effects like fever and headache, mostly related to DMSO, which is present as a cryoprotectant in the verum. Placebo may also cause fever and headache (DMSO). For the study, additional physical exams will be performed 6 monthly for a period of 3 years after LVRS2 and additional blood sampling specific for the study protocol will be 50ml in total. A heparinized blood sample of 10 ml per sample will be taken: 1) just before the 1st LVRS while patient is under general anaesthesia, 2) just before the 1st MSC iv, 3) just before the 2nd MSC iv, 4) just before the 2nd LVRS while the patient is under general anaesthesia. Discomfort for the patient caused by the experimental treatment will be minimal while there is no reason to assume that hospital admission for the surgery will be prolonged by the cell therapy or placebo. The risks associated with the investigational treatment are low as the reported adverse events in Toetsing Online from previous MSC studies in LUMC show only mild to moderate severity. The risk-benefit analysis is low.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| MSC week 4 and 3 before LVRS2 | Experimental | 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 |
|
| Placebo week 4 and 3 before LVRS2 | Placebo Comparator | Placebo: consisting of a 5% DMSO-solution in isotonic solution |
|
| MSC week 12 and 11 before LVRS2 | Experimental | 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 |
|
| Placebo week 12 and 11 before LVRS2 | Placebo Comparator | Placebo: consisting of a 5% DMSO-solution in isotonic solution |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Allogeneic MSC | Genetic | These MSCs will originate from bone marrow that will be aspirated from healthy volunteer donors screened by a trained physician of the center for stem cell therapy of LUMC |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in expression of CD31 | 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 | Within one year after the last study patient had its second lung surgical procedure |
| The difference between MSC and placebo treatment in change in CO diffusion capacity | The difference between MSC and placebo treatment in change in CO diffusion capacity over a period of 3 years following LVRS2 | 1 year after the last CO diffusion measurement |
| Measure | Description | Time Frame |
|---|---|---|
| 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 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | Safety during and up to 2 hr after i.v. infusion of allogeneic bone marrow derived MSC or placebo will be evaluated according to the WHO toxicity criteria by grade. Furthermore, the difference in adverse events between placebo and MSC treated patients following a period of 3 years after the second LVRS | 3 years after last LVRS2 |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Jan Stolk, MD | Contact | +31715262950 | jstolk@lumc.nl |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Pulmonology, Leiden University Medical Center | Recruiting | Leiden | 2333 ZA | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22029986 | Background | Mitzner W. Emphysema--a disease of small airways or lung parenchyma? N Engl J Med. 2011 Oct 27;365(17):1637-9. doi: 10.1056/NEJMe1110635. No abstract available. | |
| 21907865 | Background | Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 2011 Sep 10;378(9795):1015-26. doi: 10.1016/S0140-6736(11)60988-4. |
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| ID | Term |
|---|---|
| D011656 | Pulmonary Emphysema |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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Randomisation (2:1) will allocate 30 patients to two treatment groups. The first group will receive either 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 or placebo (consisting of a 5% DMSO-solution in isotonic solution) at week 4 and 3 before the second LVRS. The second group will receive either the same dose of 2 x 10^6/kg body weight MSC iv or placebo at week 12 and 11 before the second LVRS.
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| Placebo | Drug | The placebo will be an equivalent volume NaCl 0,9% and DMSO 5% |
|
| 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 |
| 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 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 |
| Possible confounder smoking | Number of packyears of smoking habits before stopping smoking (packyears) | 4 years afters last LVRS2 |
| Possible confounder emphysema severity | Level of emphysema severity measured before LVRS 1 as expressed by PERC15 value of lung density value derived from Chest CT scan (g/L). | 4 years afters last LVRS 2 |
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| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |