Interim analysis results from the RESTORE-CLI, a randomized, double-blind multicenter phase II trial comparing expanded autologous bone marrow-derived tissue repair cells and placebo in patients with critical limb ischemia

Richard J. Powell, Anthony J. Comerota, Scott A. Berceli, Raul Guzman, Timothy D. Henry, Edith Tzeng, Omaida Velazquez, William A. Marston, Ronnda L. Bartel, Amy Longcore, Theresa Stern, Sharon Watling

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85 Scopus citations


Objectives: Cell therapy is a novel experimental treatment modality for patients with critical limb ischemia (CLI) of the lower extremities and no other established treatment options. This study was conducted to assess the safety and clinical efficacy of intramuscular injection of autologous tissue repair cells (TRCs). Methods: A prospective, randomized double-blinded, placebo controlled, multicenter study (RESTORE-CLI) was conducted at 18 centers in the United States in patients with CLI and no option for revascularization. Enrollment of 86 patients began in April 2007 and ended in February 2010. For the prospectively planned interim analysis, conducted in February 2010, 33 patients had the opportunity to complete the trial (12 months of follow-up), and 46 patients had completed at least 6 months of follow-up. The interim analysis included analysis of both patient populations. An independent physician performed the bone marrow or sham control aspiration. The aspirate was processed in a closed, automated cell manufacturing system for approximately 12 days to generate the TRC population of stem and progenitor cells. An average of 136 ± 41 × 10 6 total viable cells or electrolyte (control) solution were injected into 20 sites in the ischemic lower extremity. The primary end point was safety as evaluated by adverse events, and serious adverse events as assessed at multiple follow-up time points. Clinical efficacy end points included major amputation-free survival and time to first occurrence of treatment failure (defined as any of the following: major amputation, death, de novo gangrene, or doubling of wound size), as well as major amputation rate and measures of wound healing. Results: There was no difference in adverse or serious adverse events between the two groups. Statistical analysis revealed a significant increase in time to treatment failure (log-rank test, P =.0053) and amputation-free survival in patients receiving TRC treatment, (log-rank test, P =.038). Major amputation occurred in 19% of TRC-treated patients compared to 43% of controls (P =.14, Fisher exact test). There was evidence of improved wound healing in the TRC-treated patients when compared with controls at 12 months. Conclusions: Intramuscular injection of autologous bone marrow-derived TRCs is safe and decreases the occurrence of clinical events associated with disease progression when compared to placebo in patients with lower extremity CLI and no revascularization options.

Original languageEnglish (US)
Pages (from-to)1032-1041
Number of pages10
JournalJournal of vascular surgery
Issue number4
StatePublished - Oct 2011
Externally publishedYes

Bibliographical note

Funding Information:
The study “Use of Tissue Repair Cells (TRCs-Autologous Bone Marrow Cells) in Patients with Peripheral Arterial Disease to Treat Critical Limb Ischemia” (RESTORE-CLI) is a prospective, randomized, double-blinded, placebo-controlled multicenter study that compares intramuscular injections of expanded autologous bone marrow cells (“tissue repair cells” or TRCs) that are suspended in physiological electrolyte solution with injections of the same electrolyte solution without cells in patients with lower extremity CLI. The study was sponsored by Aastrom Biosciences Inc in Ann Arbor, Michigan. The protocol was reviewed by the Center of Biologics Evaluation and Research (CBER) of the Federal FDA and the institutional review boards of the participating centers. All participants provided written voluntary consent. An independent Data Safety Monitoring Board (DSMB), consisting of three expert physicians and one statistician who were not involved in any other aspect of the study, monitored the safety of participants in the study according to the DSMB charter specifically developed for RESTORE-CLI.


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