Immune modulation with Celacade appears to reduce chronic inflammation underlying peripheral arterial disease, significantly decreasing C-reactive protein levels, but it does not appear to significantly improve function in these patients, according to results of the SIMPADICO Trial presented at the annual meeting of the American College of Cardiology.

SIMPADICO was a phase III trial in which 947 patients were screened for eligibility and 553 adults were randomized to Celacade or placebo. Although patients in the active arm not reach the primary endpoint of change in maximal treadmill walking distance, Celacade significantly reduced high sensitivity C-reactive protein (hs-CRP), a pre-specified endpoint and a widely recognized marker of systemic inflammation.

"We are obviously disappointed that Celacade was not shown to improve walking distance in peripheral arterial disease, one of the most difficult endpoints in which to demonstrate a therapeutic benefit," said Jeffrey Olin, MD, principal investigator and presenter of the study. "It is very interesting to note, however, the finding of a significant reduction in C-reactive protein, a well recognized inflammatory marker that is associated with increased risk of cardiovascular events."

Measurement of hs-CRP was included in SIMPADICO as a pre-specified endpoint to assess impact on systemic inflammation. The mean levels of hs-CRP at baseline were well matched at 4.15 mg/L and 4.81 mg/L in the placebo and Celacade groups, respectively; these levels are consistent with a patient population at moderate-to-high risk for cardiovascular and peripheral arterial disease events.
Mean hs-CRP was reduced by 0.93 mg/L in the Celacade group, while it increased by 0.50 mg/L in the placebo group. A majority of patients were on anti- platelet therapy (82.1% placebo, 77.5% Celacade), predominantly aspirin, and were receiving lipid-lowering therapy (81.3% placebo, 79.8% Celacade), predominantly statins, which are known to reduce hs-CRP levels in cardiovascular conditions, providing evidence that Celacade significantly reduces hs-CRP levels on top of anti-inflammatory pharmaceuticals.

The modified intention-to-treat population (535) that was used for primary data analysis consisted of all patients randomized who received at least one study treatment and had at least one post-randomization treadmill test. The placebo (273) and Celacade (262) groups were well balanced for all important baseline characteristics, including demographics, maximal treadmill walking distance (absolute claudication distance, 321 meters placebo, 303 meters Celacade), smoking history, comorbid medical conditions, and medications.

The percentage increase in absolute claudication distance between baseline and 26 weeks was not significantly different between Celacade and placebo groups. Similarly, there were no significant differences in the pain-free treadmill walking distance (initial claudication distance) between groups.

In a time-to-first-event analysis, 84 patients experienced a peripheral arterial disease-related or cardiovascular outcome event during the course of the study, 46 in the placebo group and 38 in the Celacade group. In a similar analysis of only peripheral arterial disease-related outcome events, 20 patients experienced an event, 14 in the placebo group and 6 in the Celacade group. Fifteen of these patients progressed to critical limb ischemia, 12 in the placebo group and 3 in the Celacade group, a significant difference.

While changes in quality of life and ankle-brachial index did not reach significance, exploratory analysis in the per-protocol group (patients with no major protocol violations and who received a pre-designated number of treatments, 416) showed significant changes in several measures.

Quality of life analysis (SF-36, v2), showed a significant difference between Celacade and placebo in the Physical Functioning and Social Functioning Scores. On the Walking Impairment Questionnaire, Celacade was also associated with significant improvements in the Distance and Speed domains. There was also a small but statistically significant improvement in ankle-brachial index at 26 weeks in the Celacade group.

Celacade was shown to be well tolerated in this patient population, who were receiving standard-of-care medications for atherosclerosis and peripheral arterial disease including statins, beta-blockers, anti-platelet agents, and angiotensin converting enzyme-inhibitors.