Ixmyelocel-T is a patient-specific, expanded, multicellular therapy evaluated in patients with lower extremity critical limb ischemia (CLI) with no options for revascularization. This randomized, double-blind, placebo-controlled, phase 2 trial (RESTORE-CLI) compared the efficacy and safety of intramuscular injections of ixmyelocel-T with placebo. Patients received one-time injections over 20 locations in a single leg and were followed for 12 months. Safety assessments included occurrence of adverse events. Efficacy assessments included time to first occurrence of treatment failure (TTF; major amputation of injected leg; all-cause mortality; doubling of total wound surface area from baseline; de novo gangrene) and amputation-free survival (AFS; major amputation of injected leg; all-cause mortality). A total of 77 patients underwent bone marrow or sham aspiration; 72 patients received ixmyelocel-T (48 patients) or placebo (24 patients). Adverse event rates were similar. Ixmyelocel-T treatment led to a significantly prolonged TTF (P = 0.0032, logrank test). AFS had a clinically meaningful 32% reduction in event rate that was not statistically significant (P = 0.3880, logrank test). Treatment effect in post hoc analyses of patients with baseline wounds was more pronounced (TTF: P < 0.0001, AFS: P = 0.0802, logrank test). Ixmyelocel-T treatment was well tolerated and may offer a potential new treatment option.
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.
Conduct of a large, multicenter trial of the aldose reductase inhibitor zenarestat provided data on the reproducibility of multiple electrophysiologic (nerve conduction studies, NCS) and quantitative sensory (QST) tests. Baseline and 12-month electrophysiologic data from approximately 1100 patients at multiple centers were available for analysis. Intersite variability contributed minimally to overall test variance. All NCS tests were highly reproducible. Cool thermal and vibration QST thresholds, as measured by CASE IV instrumentation, were also highly reproducible. Intersubject variance accounted for the majority of variance for all parameters measured. Repeating NCS and QST measures decreased sample sizes needed to show statistical significance. Consideration of these observations, particularly with regard to QST, should aid in the design of future clinical trials investigating neuropathy.
Aastrom Biosciences has developed a proprietary cell-processing technology that enables the manufacture of ixmyelocel-T, a patient-specific multicellular therapy expanded from a small sample of a patient's own bone marrow. Ixmyelocel-T is produced under current good manufacturing practices (cGMP) in a fully closed, automated system that expands mesenchymal stem cells (MSCs) and macrophages. While the cell types in ixmyelocel-T are the same as those found in the bone marrow, the numbers of MSCs and alternative macrophages are greater in ixmyelocel-T. We propose that the mixture of expanded MSCs and alternatively activated macrophages promote long-term tissue repair of ischemic tissue. The multiple cell types in ixmyelocel-T have a range of biological activities that are likely to contribute to a complex mechanism of action. Clinical trial data collected to date support the potential for ixmyelocel-T as an efficacious and safe treatment for ischemic cardiovascular indications, including critical limb ischemia (CLI) and a severe form of heart failure, dilated cardiomyopathy (DCM). The CLI clinical program has completed phase 2 and has reached concurrence with the Food and Drug Administration (FDA) on a phase 3 study (REVIVE) through the Special Protocol Assessment (SPA) process. The phase 3 study began screening patients in February 2012. The DCM clinical program will initiate phase 2b in 2012.
OBJECTIVE -The aim of this study was to report the baseline and natural progression of diabetic peripheral neuropathy over 12 months in a large mild-to-moderate neuropathy population.RESEARCH DESIGN AND METHODS -Patients from a multicentered trial of zenarestat, an aldose reductase inhibitor, had serial measures of neurologic function, including nerve conduction studies (NCSs), quantitative sensory testing (QST), and clinical neuropathy rating scores at baseline and at 12 months. Baseline population descriptors and changes in neurologic function in placebo-treated patients were analyzed. CONCLUSIONS -The neurologic decline over 12 months is evident when measured by NCS and cool thermal QST. Other measures (vibration QST, neuropathy rating scores, monofilament examination) are insensitive to changes over 12 months in a mild-to-moderate affected population of this size. RESULTS Diabetes Care 27:1153-1159, 2004D iabetic peripheral neuropathy (DPN) is a debilitating condition affecting as many as one-half of all patients with diabetes during the course of their disease (1). The progressive, irreversible course of the disease ultimately leads to an increased incidence of ulceration and limb amputations (2).Currently, therapy is limited to intensive glycemic control and symptomatic treatments. It is critical to identify the appropriate study population within the broad continuum of the disease when evaluating potential therapies. For example, pancreatic islet transplantation work suggests that severe neuropathy is not amenable to therapy (3,4). Defining a mildto-moderate, perhaps more responsive, DPN population may be helpful in identifying new therapeutic modalities (5).Objective, yet clinically meaningful, data characterizing the natural progression of mild-to-moderate DPN are also lacking. One issue is the uncertain rate of disease progression (6,7). Another is lack of agreement regarding the clinical relevance of the available scientifically rigorous measures of DPN. The San Antonio neuropathy consensus called for study designs requiring multiple, often expensive electrophysiologic, sensory, and clinical tools to document disease progression and response to therapy (8,9). Only a fraction of these tools translate directly to patient outcomes. None are widely used in clinical practice or are accessible to primary care practitioners.Increased nerve sorbitol and fructose associated with hyperglycemia remain a hypothesized causal mechanism of DPN. Inhibition of aldose reductase, the enzyme responsible for converting glucose to sorbitol, demonstrates reduced nerve degeneration and improved nerve conduction in animal models and humans (10). Previous aldose reductase inhibitors (ARIs) have been plagued with problems, including occasional marginal efficacy, lack of tissue permeability, and a variety of toxicities lacking a common causal mechanism.Zenarestat, a highly potent ARI, was evaluated in a large phase 3 trial of mild distal symmetrical DPN, using guidelines provided by the consensus panels (8,9,11). This study was ...
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