Clinical Study of the Efficacy and Safety of the Application of Allogeneic Mesenchymal (Stromal) Cells of Bone Marrow, Cultured Under the Hypoxia in the Treatment of Patients With Severe Pulmonary Emphysema

Study Overview
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Brief Summary
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Actively developing stem cells (SCs) transplantation techniques cause natural interest to the problem of regeneration in the lungs. Numerous experimental studies proved the benefits of different types of SCs in experimental models of pulmonary emphysema (PE). G. Zhen et al. have shown that the transplantation of mesenchymal stem cells (MSCs) to rats with papain-induced emphysema leads to their migration into the lungs, differentiation into type 2 alveolocytes, and inhibition of apoptosis and prevention PE. K. Schweitzer et al. have proved the activity of inflammation in the airways, alveolocytes and endothelial cells apoptosis decreased after adipose SCs intravenous administration to mice with emphysema caused by chronic exposure to tobacco smoke or VEGF receptors blockade. The study of E.P. Ingenito et al. found that endobronchial installed MSCs engraft into the alveolar wall and peribronchial interstitium and release integrins, extracellular matrix components (collagen IV, laminin and fibrillin), platelet-derived growth factor receptor and transforming growth factor β2. Our study also found reliable deterrent effect of allogeneic bone marrow MSCs on the development of elastase-induced emphysema in rats at different terms of transplantation. After the success of pilot studies have started clinical trials. Currently, the website http://www. ClinicalTrials.gov reported three studies evaluating the efficacy and safety of MSC transplantation in patients with COPD and emphysema. Two of them have already been completed and the results of the first pilot project published. Authors on the example of 4 patients showed a complete absence of adverse effects, improved quality of life and stability of functional parameters at 12 months after starting treatment One of the problems of MSC transplantation in patients with respiratory failure is an accelerated apoptosis of transplanted cells under the influence of proinflammatory cytokines and oxidative stress. Since it is proved that preconditioning MSCs under hypoxia increases their survival in hypoxic conditions, increases the expression of growth factors and antiinflammatory cytokines, we suppose that MSCs grown in hypoxic medium may have a significant positive effect on the disease.

Official Title
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Clinical Study of the Efficacy and Safety of the Application of Allogeneic Mesenchymal (Stromal) Cells of Bone Marrow, Cultured Under the Hypoxia in the Treatment of Patients With Severe Pulmonary Emphysema

Conditions
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Pulmonary Emphysema

Intervention / Treatment
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* Biological: Mesenchymal stem cells
* Other: Reference therapy: 400 mL of 0.9% NaCl solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HRCT-confirmed diagnosis of lung emphysema by two independent radiologists post-bronchodilator FEV1/FVC ratio < 0.7 post-bronchodilator FEV1 % predicted value ≥ 20% and < 50% age 35 and 75 years of, of either sex, and of any race current or ex-smoker, with a cigarette smoking history ≥ 10 pack-years Exclusion Criteria: • asthma or other clinically relevant lung disease other than COPD (e.g. restrictive lung diseases, sarcoidosis, tuberculosis, idiopathic pulmonary fibrosis, or lung cancer) α1-Antitrypsin deficiency Presence of bullae (more than 10 cm in the diameter) active infection within 4 weeks of screening significant exacerbation of COPD or has required mechanical ventilation within 4 weeks of screening clinically relevant uncontrolled medical condition not associated with COPD documented history of uncontrolled heart failure pulmonary hypertension due to left heart condition Subject has evidence of active malignancy, or prior history of active malignancy Subject has a life expectancy of < 6 months

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: MSC group<br>Intravenous infusion of MSC suspension, pre-conditioned under 1% oxygen, in the amount of 200 mln. cells per 400 mL of sodium chloride physiological solution. Infusions will be performed every 2 months for 1 year | Biological: Mesenchymal stem cells<br>* Intravenous infusion of MSC suspension, pre-conditioned under 1% oxygen, in the amount of 200 mln. cells per 400 mL of sodium chloride physiological solution<br>|
| Placebo Comparator: Control Group<br>400 mL of 0.9% NaCl solution. Infusions will be performed every 2 months for 1 year | Other: Reference therapy: 400 mL of 0.9% NaCl solution<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety compared with placebo | Mortality (Baseline and 2 years after procedure) Adverse effects and reactions to the treatment(Baseline and 2 years after procedure). Vital signs (pulse rate, systolic and diastolic arterial blood pressure) (Baseline and 2 years after procedure) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the lung tissue density measured by CT-densitometry at6, 12, 24 months |  | 2 years | 
| DLCO change from baseline at 6, 12, 24 months |  | 2 years | 
| Change from baseline in the functional parameters (FEV1, TLC, RV, FEV1/FVC) at 6,12,18,24 months |  | 2 years | 
| Dynamics of the physical capacity (by the 6-min test results) |  | 2 years | 
| Dynamics of the blood gas composition (PaO2, PaCO2) |  | 2 years | 
| Dynamics of serum level IL-6, TNF-α, Leptin |  | 2 years | 
| Quality of life indices by the questionnaire (SF-36) |  | 2 years | 
| Number and frequency of exacerbations |  | 2 years | 
| Body mass index |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mesenchymal stem cells, Hypoxia, Emphysema