A Trial of Alirocumab and Plaque Regression in Peripheral Arterial Disease
Condition: Peripheral Arterial Disease
MeSH terms: Peripheral Arterial Disease; Peripheral Vascular Diseases
Study type: Interventional
Phase: Phase 4

Summary: 
      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).
    

Detailed description: 
      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.
    

Intervention name(s): Alirocumab; Matching placebo
Intervention type(s): Drug; Drug
Intervention description(s): 150mg SQ every 2 weeks; SQ every 2 weeks
Other intervention name(s): Praluent
Intervention MeSH terms: Alirocumab
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: MRI; PCSK9 inhibition; LDL cholesterol