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

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.

Study Overview

• Status: Withdrawn
• Conditions: Pulmonary Emphysema
• Intervention / Treatment: Biological: Mesenchymal stem cells; Other: Reference therapy: 400 mL of 0.9% NaCl solution

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow Region
    • Moscow, Moscow Region, Russian Federation, 115682
      • Federal Research Clinical Center of Federal Medical and Biological Agency of Russia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: MSC group; 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; 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
PLACEBO_COMPARATOR: Control Group; 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

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Federal Research Clinical Center of Federal Medical & Biological Agency, Russia
• Investigators: Principal Investigator: Alexander V Averyanov, MD, PhD, Federal Research Clinical Center of Federal Medical and Biological Agency

Study record dates

Study Major Dates

• Study Start: March 1, 2014
• Primary Completion (ANTICIPATED): December 1, 2016
• Study Completion (ANTICIPATED): June 1, 2017

Study Registration Dates

• First Submitted: April 24, 2013
• First Submitted That Met QC Criteria: May 5, 2013
• First Posted (ESTIMATE): May 8, 2013

Study Record Updates

• Last Update Posted (ACTUAL): January 9, 2018
• Last Update Submitted That Met QC Criteria: January 8, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: Hypoxia; Mesenchymal stem cells; Emphysema
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Signs and Symptoms, Respiratory; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Emphysema; Hypoxia
• Other Study ID Numbers: MSC-HYP-01; FMBA-FRCC-MSC-01 (OTHER: Federal Medical&Biological Agency)