Allogeneic MSC Treatment for Pulmonary Emphysema

Pulmonary Emphysema Clinical Trial

Official title:

An Explorative Study for Halting Inflammation in Patients With Emphysema by Administration of Allogeneic Bone Marrow Derived Mesenchymal Stromal Cells.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04918706
• Other study ID #: HEP study
• Status: Recruiting
• Phase: Phase 2
• Start date: June 25, 2019
• Est. completion date: June 1, 2022

Study information

• Verified date: June 2021
• Source: Leiden University Medical Center
• Contact: Jan Stolk, MD
• Phone: +31715262950
• Email: jstolk[@]lumc.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: June 1, 2022
• Est. primary completion date: September 1, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years to 65 Years

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Emphysema
• Mesenchymal Stromal Cells
• Pulmonary Emphysema

Intervention

Genetic:
• Allogeneic MSC
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

Drug:
• Placebo
The placebo will be an equivalent volume NaCl 0,9% and DMSO 5%

Locations

Country	Name	City	State
Netherlands	Department of Pulmonology, Leiden University Medical Center	Leiden

Sponsors (3)

Lead Sponsor	Collaborator
Leiden University Medical Center	Erasmus Medical Center, VU University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (38)

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* Note: There are 38 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	Possible confounder smoking	Number of packyears of smoking habits before stopping smoking (packyears)	4 years afters last LVRS2
Other	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
Primary	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
Primary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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