Cath Lab Digest

VASCULAR DISEASE MANAGEMENT 2010;7:E179–E180

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What is the purpose and scope of the RESTORE- CLI trial? How many patients and centers will be involved in the Phase 3 trial, and when will it be completed?

This study is designed to evaluate the safety and efficacy of autologous tissue repair cells (TRCs) for patients with peripheral arterial disease as a treatment for critical limb ischemia (CLI). RESTORE-CLI is a Phase 2b study and will complete patient follow-up in March of 2011. Pending company talks with the FDA, a Phase 3 clinical trial could start in 2011.

How is RESTORE-CLI designed?

RESTORE-CLI is a Phase 2b, multicenter, randomized, placebo-controlled, double-blind study. What is critically important to the RESTORE-CLI study design is that it is a randomized, blinded study which includes a placebo control. In addition, the protocol includes clinically meaningful and objectively measured outcomes (treatment failure composite endpoint defined as major amputation, doubling in wound size, de novo gangrene and all-cause mortality). Many other studies are single-center, unblinded and use more subjective outcome measures or surrogate endpoints (i.e., those that correlate with, but don’t necessarily predict clinical outcomes).

What do the interim results of RESTORE-CLI show?

According to the interim analysis, the safety profile was similar between the treatment and placebo patients. The analysis of time to first occurrence of treatment failure (including major amputations, doubling of wound size, all-cause mortality and new gangrene) indicated that patients receiving Aastrom’s autologous TRCs had a delay in treatment failure compared to placebo (p = 0.0053). Likewise, amputation-free survival (defined as time to major amputation or death) was statistically significant (p = 0.0376). Other clinically meaningful endpoints (e.g., major amputation rate, complete wound closure) approached but did not reach statistical significance at interim analysis. Forty-six CLI patients who underwent at least a 6-month follow-up, including 33 patients who completed 12-month follow-up, contributed to the interim analysis. Based on the interim findings, Aastrom concluded enrollment of new patients in order to complete the study as soon as possible, and to begin planning and discussions with the FDA for a Phase 3 clinical program.

Describe the technical aspects of TRC therapy to treat CLI. How are these autologous cells obtained and delivered in this particular application, and how do they repair tissue?

A small amount (about 60 ml) of a patient’s bone marrow is taken from the hip bone and transported to Aastrom. At Aastrom, the progenitor cells are enhanced using a special process which allows the key cells to be grown. After about 12 days, the patient’s enhanced cells are packaged and delivered to the patient’s doctor. The doctor then injects the cells back into the extremity affected by CLI. The cells are also bar-coded from when the bone marrow is taken from the patient to when the TRCs are injected to ensure that the patient receives his or her own cells back.

What role will TRCs play in treating CLI patients? Will it be a first-line therapy or limited to patients with end-stage disease?

Currently, most patients with CLI are assessed and treated by interventional procedures such as angioplasty and surgical graft placement. Rapid treatment is critical to improving the chances of limb survival. Because standard of care for treating CLI patients is to perform revascularization whenever possible, products such as TRCs have only been studied in patients who are not candidates for a vascular procedure. If TRCs are shown to decrease the morbidity associated with CLI in this patient group, I think it would make sense to evaluate the effects of the treatment on other types of CLI patients, perhaps as an adjunct to revasculariztion. That exploration may be a few years away.

Will TRCs be effective in treating CLI patients with severe, diffuse atherosclerotic disease?

They may be, given that replacing key cellular elements may not only improve blood flow to the extremities, but also decreases the inflammation associated with atherosclerotic disease. This remains to be proven.

Are other cellular therapies being studied for CLI at present? How does Aastrom’s TRC technology differ from these?

Yes, there are other cellular therapies currently being studied in CLI. Aastrom’s cellular growth technology allows TRC preparations to contain very high numbers of stem and other early lineage cell types that can be important in restoring adequate blood flow to the affected limb. The cell numbers are typically higher than those utilized by other products in the clinic and draw on a mixed-cell population rather than a single cell line that may be more physiologic. Also, the Aastrom therapy uses the patient’s own cells, which avoids adverse events and immunologic problems.

Do you think the ultimate results of RESTORE- CLI will change the landscape of CLI treatment?

If the early results of the Phase 2b study are duplicated in larger groups of patients, this therapy has the potential to alter the way in which we treat patients with severe CLI both as a standalone therapy and as an adjunct to surgical or endoluminal revascularization.

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Dr. Marston can be contacted via his assistant, Deborah Alberti, at: debbie_alberti@med.unc.edu