Allogeneic MSC Treatment for Pulmonary Emphysema

June 1, 2021 updated by: Jan Stolk, Leiden University Medical Center

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Anticipated)

30

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Jan Stolk, MD
  • Phone Number: +31715262950
  • Email: jstolk@lumc.nl

Study Locations

  • Netherlands
      • Leiden, Netherlands, 2333 ZA
        • Recruiting
        • Department of Pulmonology, Leiden University Medical Center
        • Contact:
          • Jan Stolk, MD
          • Phone Number: +31715262950 +31715262950
          • Email: jstolk@lumc.nl
        • Principal Investigator:
          • Jan Stolk, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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%

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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
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
1 year after the last CO diffusion measurement

Secondary Outcome Measures

Outcome Measure
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.
Time Frame: Within one year after the last study patient had its second lung surgical procedure
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
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
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
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
at 12 weeks, as well as after 6 and 12 months, after discharge of admission for LVRS2

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
3 years after last LVRS2
Possible confounder smoking
Time Frame: 4 years afters last LVRS2
Number of packyears of smoking habits before stopping smoking (packyears)
4 years afters last LVRS2
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).
4 years afters last LVRS 2

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Leiden University Medical Center

Collaborators

Erasmus Medical Center
Amsterdam UMC, location VUmc

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 25, 2019

Primary Completion (Anticipated)

September 1, 2021

Study Completion (Anticipated)

June 1, 2022

Study Registration Dates

First Submitted

November 3, 2020

First Submitted That Met QC Criteria

June 1, 2021

First Posted (Actual)

June 9, 2021

Study Record Updates

Last Update Posted (Actual)

June 9, 2021

Last Update Submitted That Met QC Criteria

June 1, 2021

Last Verified

June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HEP study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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