Stage III COPD, severe emphysema, eligible for LVRS ()
Design
Single center, single arm, open-label, safety study
Multicenter, placebo-controlled, randomized, double-blind, Phase II safety & efficacy study
Single arm, open-label, safety study
Treatment (cells, dose & delivery route)
Autologous BMMC 1 × 108/ml, one IV dose (brachial)
Allogenic MSC 1 × 108/ml, four IV infusions monthly
Autologous BM-MSC 1-2 × 106 cells/kg, two IV infusions 1 week apart, 4 & 3 weeks before 2nd LVRS
Study year (follow-up)
May 2009 (1 and 3 years)
April 2008 (2 years)
October 2010 (1 year)
Primary outcomes
Lung function: FVC; FEV1; VC
AEs during infusion or by physician/lab assessment ECGs during study & follow-up COPD exacerbations
Safety: AEs ≤ 3 weeks after infusion (WHO criteria) Feasibility: quantities of expanded MSCs versus BM collected; passages needed & time to reach target dose
Secondary outcomes
Arterial blood gases: PaO2; PaCO2
Lung function: FEV1, FVC, FEV1/FVC, total capacity, DLCO, 6MWT, dyspnea (Borg scale) QoL: SGRQ & global assessment Exacerbations: time to 1st exacerbation; exacerbation rate ratio between study arms Inflammation markers: TNF-α, IFN-γ, IL-2, TGF-β, IL-4, IL-5, IL-10, and CRP
Difference (days) between post-LVRS transpleural air leak after 1st versus 2nd LVRS Immunohistochemistry of markers of inflammation, fibrosis, and repair in resected lung tissue
Other markers
Cell concentration & markers: NC, BMMC, CD34+, and CD133+
SaO2 (before & after 6MWT), CRP, and TGF-β
Clinical: spirometry, gas transfer, lung volumes, and CT-derived lung densitometry at baseline & 1 year Immunohistochemistry: CD3, CD4, CD8, CD31, CD68, Ki-67, or SP-C Gene expression: growth factors, immune mediators, proliferation markers, and lung cell markers
Safety results
Safe, no significant AEs
AEs mostly mild to moderate (MSC 56.6%; placebo 65.6%) and unlikely to be procedure-related (MSC 63.3%; placebo 68.8%)
Safety: stable vital functions and no change in WHO-toxicity; no infusion-related symptoms Feasibility: 7/10 patients completed the study; BM could be aspirated from nine (mean 158 ± 64 ml); target MSC number was obtained with 3 expansion cycles in eight
Efficacy results
Slightly improved lung function ≤30 days after infusion, declined thereafter, but not to baseline Three-year expiratory tests in two patients predicted FVC increase from 21% to 36.5% and 34% to 58%; all patients reported significantly improved emotional and physical status
COPD exacerbations: MSC 66.7% versus placebo 46.9% Median time to 1st exacerbation: MSC 6.7 months versus placebo not estimated (too few events) Exacerbation-free at 1 and 2 years: MSC 46.0% & 31.9% versus placebo 56.3% & 52.7%
Clinical: FEV1 rose by 390 ± 240 ml from baseline at 1-year follow-up (P = 0.03) Patients’ weight significantly increased: mean 4.6 kg (range 1–10 kg; P = 0.016) Immunohistochemistry: alveolar septa showed tripled expression of CD31 (P = 0.016) Significantly higher CD3+ T cell count in alveolar septa after LVRS + BM-MSC versus before (P = 0.016); CD4+ T cell count in alveolar septa increased in all but one patient after LVRS + BM-MSC (P = 0.30; fold change P = 0.047) Gene expression: higher mRNA expression of IL10 and TSG6 in biopsy tissue after versus before LVRS + BM-MSC (P = 0.06)
