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出境医 / 临床实验 / Allogeneic MSC Treatment for Pulmonary Emphysema

Allogeneic MSC Treatment for Pulmonary Emphysema

Study Description
Brief 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.


Condition or disease Intervention/treatment Phase
Pulmonary Emphysema Mesenchymal Stromal Cells Genetic: Allogeneic MSC Drug: Placebo Phase 2

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Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: 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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: An Explorative Study for Halting Inflammation in Patients With Emphysema by Administration of Allogeneic Bone Marrow Derived Mesenchymal Stromal Cells.
Actual Study Start Date : June 25, 2019
Estimated Primary Completion Date : September 1, 2021
Estimated Study Completion Date : June 1, 2022
Arms and Interventions
Arm Intervention/treatment
Experimental: 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
 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
Placebo Comparator: Placebo week 4 and 3 before LVRS2
Placebo: consisting of a 5% DMSO-solution in isotonic solution
 Drug: Placebo
The placebo will be an equivalent volume NaCl 0,9% and DMSO 5%
Experimental: 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
 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
Placebo Comparator: Placebo week 12 and 11 before LVRS2
Placebo: consisting of a 5% DMSO-solution in isotonic solution
 Drug: Placebo
The placebo will be an equivalent volume NaCl 0,9% and DMSO 5%
Outcome Measures
Primary Outcome Measures :
  1. Difference in expression of CD31 [ Time Frame: 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

  2. The difference between MSC and placebo treatment in change in CO diffusion capacity [ Time Frame: 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


Secondary Outcome Measures :
  1. 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. [ Time Frame: Within one year after the last study patient had its second lung surgical procedure ]
  2. 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. [ Time Frame: Within one year after the last study patient had its second lung surgical procedure ]
  3. 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. [ Time Frame: Within one year after the last study patient had its second lung surgical procedure ]
  4. The difference in endothelial microparticles concentration and concentration of immunological markers in blood samples from study patients treated with placebo or MSC. [ Time Frame: Within one year after the last study patient had its second lung surgical procedure ]
  5. 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. [ Time Frame: at 12 weeks, as well as after 6 and 12 months, after discharge of admission for LVRS2 ]

Other Outcome Measures:
  1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: 3 years after last LVRS2 ]
    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

  2. Possible confounder smoking [ Time Frame: 4 years afters last LVRS2 ]
    Number of packyears of smoking habits before stopping smoking (packyears)

  3. Possible confounder emphysema severity [ Time Frame: 4 years afters last LVRS 2 ]
    Level of emphysema severity measured before LVRS 1 as expressed by PERC15 value of lung density value derived from Chest CT scan (g/L).


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   45 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Jan Stolk, MD +31715262950 jstolk@lumc.nl

Locations
Layout table for location information
Netherlands
Department of Pulmonology, Leiden University Medical Center Recruiting
Leiden, Netherlands, 2333 ZA
Contact: Jan Stolk, MD    +31715262950 ext +31715262950    jstolk@lumc.nl   
Principal Investigator: Jan Stolk, MD         
Sponsors and Collaborators
Leiden University Medical Center
Erasmus Medical Center
VU University Medical Center
Tracking Information
First Submitted Date  ICMJE November 3, 2020
First Posted Date  ICMJE June 9, 2021
Last Update Posted Date June 9, 2021
Actual Study Start Date  ICMJE June 25, 2019
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 1, 2021)
  • Difference in expression of CD31 [ Time Frame: 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 [ Time Frame: 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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: June 1, 2021)
  • 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: 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. [ Time Frame: at 12 weeks, as well as after 6 and 12 months, after discharge of admission for LVRS2 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: June 1, 2021)
  • Incidence of Treatment-Emergent Adverse Events [ Time Frame: 3 years after last LVRS2 ]
    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
  • Possible confounder smoking [ Time Frame: 4 years afters last LVRS2 ]
    Number of packyears of smoking habits before stopping smoking (packyears)
  • Possible confounder emphysema severity [ Time Frame: 4 years afters last LVRS 2 ]
    Level of emphysema severity measured before LVRS 1 as expressed by PERC15 value of lung density value derived from Chest CT scan (g/L).
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Allogeneic MSC Treatment for Pulmonary Emphysema
Official Title  ICMJE An Explorative Study for Halting Inflammation in Patients With Emphysema by Administration of Allogeneic Bone Marrow Derived Mesenchymal Stromal Cells.
Brief 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.
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
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.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Pulmonary Emphysema
  • Mesenchymal Stromal Cells
Intervention  ICMJE
  • 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%
Study Arms  ICMJE
  • Experimental: 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
    Intervention: Genetic: Allogeneic MSC
  • Placebo Comparator: Placebo week 4 and 3 before LVRS2
    Placebo: consisting of a 5% DMSO-solution in isotonic solution
    Intervention: Drug: Placebo
  • Experimental: 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
    Intervention: Genetic: Allogeneic MSC
  • Placebo Comparator: Placebo week 12 and 11 before LVRS2
    Placebo: consisting of a 5% DMSO-solution in isotonic solution
    Intervention: Drug: Placebo
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  • Røsland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lønning PE, Bjerkvig R, Schichor C. Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res. 2009 Jul 1;69(13):5331-9. doi: 10.1158/0008-5472.CAN-08-4630. Epub 2009 Jun 9.
  • Schrepfer S, Deuse T, Reichenspurner H, Fischbein MP, Robbins RC, Pelletier MP. Stem cell transplantation: the lung barrier. Transplant Proc. 2007 Mar;39(2):573-6.
  • Bandura DR, Baranov VI, Ornatsky OI, Antonov A, Kinach R, Lou X, Pavlov S, Vorobiev S, Dick JE, Tanner SD. Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. Anal Chem. 2009 Aug 15;81(16):6813-22. doi: 10.1021/ac901049w.
  • van Unen V, Höllt T, Pezzotti N, Li N, Reinders MJT, Eisemann E, Koning F, Vilanova A, Lelieveldt BPF. Visual analysis of mass cytometry data by hierarchical stochastic neighbour embedding reveals rare cell types. Nat Commun. 2017 Nov 23;8(1):1740. doi: 10.1038/s41467-017-01689-9.
  • van Unen V, Li N, Molendijk I, Temurhan M, Höllt T, van der Meulen-de Jong AE, Verspaget HW, Mearin ML, Mulder CJ, van Bergen J, Lelieveldt BP, Koning F. Mass Cytometry of the Human Mucosal Immune System Identifies Tissue- and Disease-Associated Immune Subsets. Immunity. 2016 May 17;44(5):1227-39. doi: 10.1016/j.immuni.2016.04.014. Epub 2016 May 10.
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 1, 2021) 		30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 1, 2022
Estimated Primary Completion Date September 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 45 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jan Stolk, MD +31715262950 jstolk@lumc.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04918706
Other Study ID Numbers  ICMJE HEP study
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jan Stolk, Leiden University Medical Center
Study Sponsor  ICMJE Leiden University Medical Center
Collaborators  ICMJE
  • Erasmus Medical Center
  • VU University Medical Center
Investigators  ICMJE Not Provided
PRS Account Leiden University Medical Center
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP