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A Trial of Alirocumab and Plaque Regression in Peripheral Arterial Disease

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ClinicalTrials.gov Identifier: NCT02959047
Recruitment Status : Recruiting
First Posted : November 8, 2016
Last Update Posted : October 11, 2018
Sponsor:
Collaborator:
Northwestern University
Information provided by (Responsible Party):
Christopher Kramer, University of Virginia

Tracking Information
First Submitted Date  ICMJE November 4, 2016
First Posted Date  ICMJE November 8, 2016
Last Update Posted Date October 11, 2018
Actual Study Start Date  ICMJE July 17, 2017
Estimated Primary Completion Date July 17, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 7, 2016)
Change in superficial femoral plaque volume (summed from both legs) [ Time Frame: 1 year ]
Measured by black blood MRI, expressed in cm3
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 7, 2016)
  • Change in calf muscle perfusion in the most symptomatic leg [ Time Frame: 1 year ]
    Measured by arterial spin labeling MRI, expressed in ml/min/100g
  • Change in plaque characteristics [ Time Frame: 1 year ]
    % lipid in one slice from each leg
  • Change in 6-minute walk test [ Time Frame: 1 year ]
    expressed in feet
  • Change in LDL cholesterol [ Time Frame: 1 year ]
  • Change in high sensitivity c-reactive protein [ Time Frame: 1 year ]
  • Change in fibrinogen [ Time Frame: 1 year ]
  • Change in lipoprotein (a) [ Time Frame: 1 year ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial of Alirocumab and Plaque Regression in Peripheral Arterial Disease
Official Title  ICMJE A Double Blind, Randomized Trial of Alirocumab and Plaque Regression in Peripheral Arterial Disease
Brief 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Peripheral Arterial Disease
Intervention  ICMJE
  • Drug: Alirocumab
    150mg SQ every 2 weeks
    Other Name: Praluent
  • Drug: Matching placebo
    SQ every 2 weeks
Study Arms  ICMJE
  • Experimental: Alirocumab
    Alirocumab 150mg SQ every 2 weeks
    Intervention: Drug: Alirocumab
  • Placebo Comparator: Placebo
    Matched placebo
    Intervention: Drug: Matching placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 7, 2016)
54
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE July 17, 2021
Estimated Primary Completion Date July 17, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 35 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Christopher M Kramer, MD 4342430736 ckramer@virginia.edu
Contact: Jennifer R Kay, BSN 4342439937 jrh2g@virginia.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02959047
Other Study ID Numbers  ICMJE 19404
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Christopher Kramer, University of Virginia
Study Sponsor  ICMJE University of Virginia
Collaborators  ICMJE Northwestern University
Investigators  ICMJE
Principal Investigator: Christopher M Kramer, MD University of Virginia Health System
PRS Account University of Virginia
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP