GPAD-II: Cell therapy may improve walking performance in patients with PAD

Issue: February 2014

DALLAS ─ Patients with peripheral arterial disease who undergo cell therapy may improve walking performance at 3 months compared with controls, according to findings from a phase 2 study.

Perspective from John H. Rundback, MD, FAHA, FSVM, FSIR

Cell therapy was associated with improvement in certain secondary outcomes in patients with claudication, and with improvement in the primary outcome in patients with greater mobilization of the cells, which may suggest avenues for future study, Arshed A. Quyyumi, MD, said at a presentation at AHA 2013.

According to the study background, animal studies had shown that bone marrow progenitor cells were associated with improved perfusion in ischemic hind limbs, but the way that the study was performed in humans led to a marginal result that may require further study.

Potential therapy for claudication

Quyyumi, of Emory University School of Medicine, Atlanta, and colleagues enrolled patients with intermittent claudication (n=159; median age, 64 years; 87% male; 37% with diabetes) in GPAD-II, a double blind, placebo-controlled phase 2 study. One group (n=80) received 500 mcg/day three times a week via subcutaneous injections of granulocyte-macrophage colony-stimulating factor (leukine) for four weeks; the other group (n=79) received placebo. Both groups were advised to walk to claudication three times per day.

The primary outcome was peak treadmill walking time at 3 months. Secondary outcomes included treadmill walking time at 6 months, changes in circulating progenitor-cell levels, changes in ankle-brachial index, walking impairment questionnaire score and 36-item Short Form Health Survey score.

In the treatment group, mean peak treadmill walking time increased from 296 seconds (standard deviation, 151) to 405 seconds (standard deviation, 248) at 3 months, for a mean change of 109 seconds (95% CI, 67-151). In the control group, mean peak treadmill walking time increased from 308 seconds (standard deviation, 161) to 376 seconds (standard deviation, 182), for a mean change of 56 seconds (95% CI, 14-98). The mean difference between the two groups in change in mean peak treadmill walking time was 53 seconds (95% CI, –6 to 112).

However, Quyyumi said, a per-protocol analysis that excluded the results of four participants who during the study period became unable to exercise for various reasons showed that the treatment group had a significantly greater change in mean peak treadmill walking time compared with the placebo group at 3 months (P=.02) and 6 months (P=.02).

Patients who had an increase in progenitor cells of more than 100% performed better in peak walking time at 3 months than those whose increase was 100% or less (P=.04). “People who had greater mobilization of progenitor cells tended to have greater improvement in their peak walking time compared to those who didn’t, and this was also sustained at 6 months,” Quyyumi said.

There were no differences between the groups in changes in ankle-brachial index, the stair-climbing and speed scores in the walking impairment questionnaire, the mental and physical components of the 36-item Short Form Health Survey score or claudication onset time.

Some secondary outcomes significant

However, granulocyte-macrophage colony-stimulating factor was associated with an improvement in the physical functioning subscore of the Short Form Health Survey questionnaire. At 3 months, the treatment group improved 11.4 (95% CI, 6.7-16.1) compared with 4.8 (95% CI, –0.1 to 9.6) for the control group. The mean difference in change between groups was 7.5 (95% CI, 1-14).

Granulocyte-macrophage colony-stimulating factor was also associated with an improvement in the distance score of the walking impairment questionnaire. It improved by 12.5 (95% CI, 6.4-18.7) in the treatment group vs. 4.8 (95% CI, –0.2 to 9.8) in the control group, for a mean difference in change of 7.9 (95% CI, 0.2-15.7).

There were 18 serious adverse events, equally distributed between the groups, “but none of those were attributed to being on the study,” Quyyumi said. Non-serious adverse events more common in the treatment group than in the placebo group were headaches, rash around the injection site, gastrointestinal issues and tiredness. – by Erik Swain

For more information:

Poole J. JAMA. 2013;doi:10.1001/jama.2013.282540.

Quyyumi AA. CS.01. Application of cell-based therapies to treat cardiac and peripheral diseases. Presented at: the American Heart Association Scientific Sessions; Nov. 16-20, 2013; Dallas.

Disclosure: The granulocyte-macrophage colony-stimulating factor was supplied by Sanofi-Aventis. Quyyumi reports financial ties with Amgen, Amorcyte, Forest, Genzyme, Soteria and Stemedica.

Perspective

John H. Rundback, MD, FAHA, FSVM, FSIR

This was a very interesting trial, particularly in light of the fact that we are finding an increasing percentage of patients in whom contemporary methods of revascularization are unsatisfactory, either because of complex anatomic patterns and/or high rates of restenosis with current technology. We’re all very interested in finding alternative therapeutic options for these patients. The idea that stem cells, even in this early evolution, might provide benefit to this cohort of patients is intriguing.

There are other trials underway for patients with critical limb ischemia as well as the claudication population that was studied in this particular trial. Although there have been a large number of trials, we have yet to really refine the underlying putative mechanism whereby cell therapies work. What that means is there is the ability to hone these technologies so we can assess benefit and durable benefit. It was interesting that there was a high rate of circulating progenitor cells in patients for whom walking distance was improved, but what the physiologic substrates were for that at the target muscle cellular level remain to be determined.

I think there was a bimodal response here. On one hand, this study represents a population of patient in whom the cellular response to administration of this therapy is going to be positive and beneficial, and will result in prolonged clinical response. On the other hand, there will be a population in whom for some reason you don’t see the same cellular up-regulation and response to therapy. We need to glean why that happens. Another aspect of this bimodal evaluation is the expectation of response. It’s interesting that there’s only a modest difference in peak walking distance and no difference in initial claudication distance, but when you look at physical domain scores on the quality-of-life evaluation, there were differences. I don’t know how much that reflects expectation of outcomes or a placebo effect, but there are other factors at play here which need to be delineated.

It’s interesting that they took this approach (e.g. intramuscularly administering unmodified bone marrow pluripotential cells). Other researchers, particularly in critical limb ischemia, have looked at different strategies whereby they take the multiple clonal cell population and then do amplification of a particular cellular subset for administration. It would be interesting to look at the cellular response in claudication patients compared with critical limb ischemia population, in whom up-regulation of angiogenesis might be more beneficial. If that’s the case, amplification strategies might be better in this group.

John H. Rundback, MD, FAHA, FSVM, FSIR

Medical Director, Interventional Institute at Holy Name Medical Center

Managing Partner, Advanced Interventional Radiology Services LLP, Teaneck, N.J.

Disclosures: Rundback is a board member of VIVA Physicians, a not-for-profit 501(c)(3) organization; a consultant for Bard, Biotronik, Covidien/ev3, Simbionix and St. Jude Medical; receives options from Sil Vascular; is on the speakers bureaus for Cook, Covidien, CSI and Terumo; is an unpaid consultant for Bluegrass Technologies, Boston Scientific and Ekos; and receives institutional research support but no compensation from Atrium, Bard/Lutonix, Cardiovascular Systems Inc., Cordis/Flexible Stenting Solutions, Daiichi Sankyo, Ekos and Terumo/Harvest.