A Trial of Alirocumab and Plaque Regression in Peripheral Arterial Disease

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