RESTORE-CLI Interim Results - February 24, 2010
What is critical limb ischemia?
Critical limb ischemia (CLI) is typically identified as the end stage of peripheral arterial disease. People with CLI face a high risk of amputation and in some cases death. Approximately 1 million patients in the U.S. suffer from CLI. The disease results in more than 160,000 amputations each year.
How is CLI currently treated?
Treatment for CLI might include surgical revascularization, local wound treatment or amputation. No drugs are currently approved for the treatment of CLI. Approximately 25% of all CLI patients die within a year of diagnosis.
What is the treatment used in this study?
Patients in the RESTORE-CLI study were treated with vascular repair cells (VRCs). These are autologous bone marrow-derived cells that are expanded using Aastrom's proprietary technology. Once expanded, they are administered to patients in treatment.
What were the results of the RESTORE-CLI trial?
Click here for the Aastrom press release announcing the interim results of the RESTORE-CLI trial.
As reported, the interim analysis results showed positive trends in favor of the VRC treatment group in terms of the most clinically meaningful endpoints, i.e., amputation rates and wound healing. These trends were consistent over time and the effect was sustained over the entire observation period. Because the study included a relatively small number of patients, isolated results related to amputation and wound healing, while positive, are not statistically significant. However, review of the composite endpoint which includes amputation and wound-based endpoints does reach statistical significance at this interim analysis.
In this study, the composite endpoint includes the incidence of major amputation, doubling of wound size, de novo gangrene and revascularization. The composite endpoint from our study is similar to a composite endpoint used by Conte and colleagues (J Vasc Surg 2009; 50(6): 1462-73) which addresses overall survival, limb preservation, avoidance of interventions, and quality of life. The FDA has commented on this approach (Kumar, et al. J Vasc Surg 2009; 50(6): 1474-6).
The interim results from the RESTORE-CLI trial, together with other relevant research, indicate that a mixture of cell types from the patient's bone marrow can improve circulation in the affected limb in patients with CLI. VRCs contain a very large number of stem and progenitor cells that have been implicated in improving blood flow and in removing scar tissue that may create a barrier for key nutrients to reach the tissues in the limb.
We hope to present the interim data from the RESTORE-CLI trial at an appropriate scientific meeting later this year.
What is the next step in the clinical development program for VRCs?
The interim analysis has provided us with sufficient clinical information to design appropriate pivotal trials for VRCs. Additional data collected in the continuing patient follow-up period could provide additional insights to further support pivotal study design. The ability to see an efficacy signal in a trial of this size gives us confidence in advancing to a pivotal phase 3 study for VRCs at this stage. Analysis of the 6 month data from all randomized patients should occur by Q4 2010. If necessary, a final analysis when all patients have completed a 12-month follow-up is planned for Q2 2011.
Our goal is to discuss our interim analysis results with the FDA by Q3 2010, and we expect further discussions will take place by Q1 2011. The endpoints for a pivotal phase 3 study will be based on these discussion and final agreement with the FDA, although at this stage we can conclude that assessment of amputation rate as well as other key components are likely to be included.
The Aastrom RESTORE-CLI clinical trial differs from other clinical research in CLI in several important ways:
- Nearly 400 patients have been treated with TRC-based products thus far, providing us with a strong database of safety information.
- Our data positions us to target clear efficacy endpoints. It also allows us design phase 3 trials based on clinical experience rather than conjecture.
- RESTORE-CLI was one of the very few double-blinded, placebo controlled studies ever conducted in cellular therapy.
- We used adult autologous cells in the development of VRCs.
- VRCs include a mixture of the specific cell types thought to be critical to the development of vascular structures, rather than a single cell type product.
With a robust, multi-center, placebo-controlled design, the RESTORE-CLI trial was able to demonstrate statistically significant results in CLI patients most in need of a treatment option. Survival analysis of time to treatment failure based on the events of amputation, doubling of wound size, and new gangrene over a full year of follow-up shows fewer clinically relevant, meaningful events with treatment in comparison to placebo(P < 0.05). Although not statistically significant, the following showed favorable differences. At 6 months, 19% treated versus 25% of placebo patients had an amputation event. At 12 months, the treated group remained at a 19% amputation rate while 33% of the placebo group experienced an amputation. Likewise only 13% of placebo patients had complete wound healing versus 31% of treated patients.
How does the RESTORE-CLI trial relate to some of the previous research done on CLI treatment?
While previous research involving the use of cell therapy to treat CLI is limited, results from a study by Tateishi-Yuyama for the Therapeutic Angiogenesis using Cell Transplantation (TACT) was published in The Lancet in 2002. This study did provide strong support for the development of cell therapy for CLI patients. However, the RESTORE-CLI trial both builds on and differs from this earlier research in several important ways.
The process associated with obtaining bone marrow may be less risky to CLI patients. In the TACT study, researchers extracted 500 mLs of bone marrow in a procedure that required general anesthesia. Treatment with VRCs requires the removal of a much smaller bone marrow sample, roughly 50 mLs, in an outpatient procedure, which does not involve the risks of general anesthesia.
The Tateishi-Yuyama et al. study measured surrogate endpoints. They did not measure clinical outcomes, nor was the study large enough to perform that evaluation. Experts in vascular surgery, as well as the FDA have described valid scientific evaluations of hard clinical endpoints that will be used to judge the efficacy of CLI treatments (Conte MS, et al. J Vasc Surg 2009; 50(6): 1462-73. Kumar, et al., J Vasc Surg 2009; 50(6): 1474-6). These event endpoints include, among other things, amputation rate and effects on wound formation and healing. These endpoints are assessed in the RESTORE-CLI trial.
There are also some important differences in study design between these two studies. The TACT investigators used each patient as their own control (one leg injected with bone marrow mononuclear cells and the other with peripheral blood mononuclear cells), which significantly reduces variability. The RESTORE-CLI trial used a parallel control group -- a more robust standard to support regulatory and clinical acceptance. There were also differences in the patient population for each trial. The RESTORE-CLI trial included diabetic patients with an HbA1c less than 10% versus the highly controlled HbA1c of < 6.5% in the TACT investigator's trial. RESTORE-CLI also included hemodialysis patients.