A placebo-controlled, randomized trial of mesenchymal stem cells in COPD

Abstract

Background: COPD is a devastating disease affecting millions worldwide. As disease pathogenesis includes both chronic pulmonary and systemic inflammation, antiinflammatory effects of systemically administered mesenchymal stem cells (MSCs) may decrease inflammation, resulting in improved lung function and quality of life. The goal of this study was to assess safety and to perform an initial evaluation of the potential efficacy of systemic MSC administration to patients with moderate to severe COPD.

Methods: Sixty-two patients at six sites were randomized to double-blinded IV infusions of either allogeneic MSCs (Prochymal; Osiris Therapeutics Inc) or vehicle control. Patients received four monthly infusions (100 × 10⁶ cells/infusion) and were subsequently followed for 2 years after the first infusion. End points included comprehensive safety evaluation, pulmonary function testing (PFT), and quality-of-life indicators including questionnaires, 6MWT, and assessments of systemic inflammation.

Results: All study patients completed the full infusion protocol, and 74% completed the 2-year follow-up. There were no infusional toxicities and no deaths or serious adverse events deemed related to MSC administration. There were no significant differences in the overall number of adverse events, frequency of COPD exacerbations, or worsening of disease in patients treated with MSCs. There were no significant differences in PFTs or quality-of-life indicators; however, an early, significant decrease in levels of circulating C-reactive protein (CRP) was observed in patients treated with MSCs who had elevated CRP levels at study entry.

Conclusions: Systemic MSC administration appears to be safe in patients with moderate to severe COPD and provides a basis for subsequent cell therapy investigations.

Trial registry: ClinicalTrials.gov; No.: NCT00683722; URL: www.clinicaltrials.gov.

Figures

Figure 1.

Schematics of study design and patient disposition. Time of study-drug infusions are marked by upward arrows. [1] The intent-to-treat set consists of all randomized subjects analyzed in the group to which they were randomized, regardless of actual treatment received. [2] The per-protocol set consists of all randomized subjects who received the correct randomized treatment and did not have major protocol violations. [3] The safety set consists of all randomized subjects who received at least one dose of the study drug, analyzed according to the treatment they received, regardless of randomization. [4] Percentages based on number of randomized subjects (intent-to-treat set). [5] Percentages based on the number of subjects who discontinued prematurely. *One subject failed exclusion criteria due to a > 225 mL change in FEV1 from visit 1 (screening) to visit 2 (day 0), but was randomized and received the first infusion before the study sponsor (Osiris Therapeutics Inc) was made aware of the deviation. The subject continued in the study, but was excluded from the per-protocol population. **One patient in the placebo group died 2 weeks after the final 2-year study visit and was considered to have completed the study. PHI=protected health information.

Figure 2.

A-F, Changes in (A) FEV1% predicted, (B) FVC % predicted, (C) FEV1/FVC, (D) 6MWT, (E) Borg dyspnea scale, and (F) circulating CRP levels in the study populations. Changes in circulating CRP levels are shown only for those who had elevated levels at screening (> 4.0 mg/L). *P < .05. 6MWT=6-min walk test; CRP=c-reactive protein.

Figure 2.

A-F, Changes in (A) FEV1% predicted, (B) FVC % predicted, (C) FEV1/FVC, (D) 6MWT, (E) Borg dyspnea scale, and (F) circulating CRP levels in the study populations. Changes in circulating CRP levels are shown only for those who had elevated levels at screening (> 4.0 mg/L). *P < .05. 6MWT=6-min walk test; CRP=c-reactive protein.