A Trial of Alirocumab and Plaque Regression in Peripheral Arterial Disease
A Trial of Alirocumab and Plaque Regression in Peripheral Arterial Disease
Peripheral arterial disease (PAD) is characterized by lower limb arterial obstruction due to
 atherosclerosis. Magnetic resonance imaging (MRI) methods can accurately quantify
 atherosclerotic plaque in the superficial femoral artery (SFA) in patients with PAD. Such
 techniques have demonstrated plaque regression with statin therapy over 1 year. Alirocumab is
 a PCSK9 inhibitor that effectively reduces LDL cholesterol up to 70% in patients on statins
 or intolerant to statins. The investigators hypothesize that effective low density
 lipoprotein (LDL) lowering with Alirocumab 150m subcutaneously (SQ) every 2 weeks will
 regress atherosclerotic plaque in the SFA in patients with PAD over one year compared to
 placebo. 54 patients with mild-moderate PAD (ankle brachial index or ABI 0.4-0.9) will be
 randomized to alirocumab 150 mg SQ every 2 weeks or matching placebo at the University of
 Virginia (UVA) (n=34) and Northwestern (n=20). The primary endpoint is change in
 atherosclerotic plaque volume in the superficial femoral artery over the 1 year treatment
 period. Secondary endpoints include changes in peak calf muscle perfusion after thigh cuff
 occlusion/hyperemia, 6-minute walk distance, and blood biomarkers (LDL cholesterol,
 fibrinogen, high sensitivity c-reactive protein (hs-CRP), and lipoprotein(a).
PAD is characterized by lower limb arterial obstruction due to atherosclerosis. There are
 over 8.5 million people with PAD in the U.S. Recent data in a general population over 40
 demonstrated an incidence of PAD defined by ankle brachial index (ABI) of 4.3%. Another study
 of over 3000 patients, mean age 59, demonstrated a prevalence of 3.9%. The prevalence is
 age-dependent, rising to 14.5% in those over 70. In populations at risk including diabetics
 or smokers, the incidence is nearly 30%. Standard cardiovascular (CV) risk factors are also
 risks for PAD, especially smoking, diabetes, hypertension, African-American race and chronic
 kidney disease. The annual rate of CV events including myocardial infarction, stroke, and CV
 death is 5-7%. The adjusted risk of dying of a CV event is 2-fold higher than those without
 PAD.

 Magnetic resonance imaging (MRI) methods can accurately quantify atherosclerotic plaque in
 the superficial femoral artery (SFA) in patients with PAD. These measures can be performed
 rapidly and reproducibly with an intraclass correlation of 0.997 for intraobserver
 reproducibility, 0.987 for intraobserver, and 0.996 for test-retest reproducibility, Plaque
 regression with statins have been shown using these techniques in PAD.

 Alirocumab is a PCSK9 inhibitor that effectively reduces LDL cholesterol up to 70% in
 patients on statins or intolerant to statins. This injectable agent has proven safe and
 well-tolerated, but has not yet been studied specifically in patients with peripheral
 arterial disease.The study will be a double blind, placebo-controlled, randomized study of
 Alirocumab vs. placebo in 54 patients with PAD.

 Baseline visit: Informed consent will be signed. Vital signs will be taken and blood drawn
 fasting for baseline values. A MRI would be performed with black blood imaging of the SFA of
 both legs. Approximately 10-15 cm of each leg would be covered, using a specifically designed
 surface coil (Machnet, Leiden, NL). The imaging would start at the bifurcation of the common
 femoral and proceed distally. The pulse sequence used will be a black blood turbo spin echo
 proton density weighted sequence with 3mm slice thickness and 3mm gaps that will be
 subsequently interleaved. A single slice with an extensive amount of plaque will be chosen
 for imaging of plaque characteristics including T1- and T2-W imaging. Finally, a calf muscle
 perfusion study will be performed in the leg that is most symptomatic and/or has the lowest
 ABI in the absence of claudication symptoms. The calf will be wrapped in a flexible surface
 coil in a 3T scanner. Subjects will be placed supine in the MR scanner with the calf at the
 magnet isocenter. A thigh cuff will be inflated up to 250 mmHg for 5 min. Arterial spin
 labeling images of the mid-calf will be obtained immediately after release of the
 cuff.Regions of interest will be drawn on the relative blood flow maps corresponding to calf
 muscle groups to measure perfusion in ml/min/100g.

 Randomization: The study statistician will do a block randomization and let the pharmacy
 know. Patients in the treatment group will begin treatment with alirocumab or matching
 placebo, 150 mg subcutaneously every 2 weeks. Treatment will continue for 26 treatments or 1
 year.

 Final Visit: This will be a repeat of the initial visit with vital signs, blood draw for
 lipid panel, and repeat MRI with the exact same protocol as on the initial visit.
Inclusion Criteria:

 -  Age 35-85

 -  Clinical diagnosis of peripheral arterial disease

 -  Ankle brachial index of 0.4-0.9

 -  Either on statin for at least 6 months or statin intolerant. The statin used should be
 a high potency statin (Crestor, Lipitor) or high dose of a lower potency statin (e.g.
 Zocor 40-80mg, Pravachol 40-80 mg)

 Exclusion Criteria:

 -  rest pain

 -  critical limb ischemia

 -  known or planned stent in the SFA

 -  known occlusion of the SFA

 -  planned revascularization within the next year

 -  inability to lie flat

 -  known contraindications to MRI including pacemaker, implantable cardioverter
 defibrillators, certain intracranial aneurysm clips, claustrophobia

 -  pregnancy

 -  known allergy to alirocumab