Effect of Evolocumab in Functional Status and LDL Oxidation of Patients With Peripheral Arterial Disease

Phase 4

• Conditions: Peripheral Arterial Disease
• Interventions: Drug: Evolocumab 140 mg/mL Subcutaneous Injection 1 milliliter (mL) pre-filled injector Pen x 3 for a monthly dose of 420 mg for 6 months.; Other: Placebo 1milliliter (mL) Subcutaneous Injection pre-filled injector Pen x 3 monthly for 6 months.

• Registration Number: NCT04306081
• Lead Sponsor: Leonardo Clavijo

Brief Summary

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerotic cardiovascular disease (ASCVD) and is associated with increase cardiovascular risk. PAD impairs quality of life due to symptoms of claudication, pain at rest or risk of limb loss.

All major societies recognize the importance of LDL reduction in patients with PAD.

Statin therapy improves cardiovascular end-points in patients with PAD and have been shown to improve symptoms of lower extremity intermittent claudication (pain free walking time), 6-minute walking time, ankle-brachial index (ABI), and endothelial function, while decreasing markers of atherosclerosis.

This study aims to demonstrate that in patients with PAD on stable maximal tolerated lipid lowering regimen with a statin, further reduction of LDL with the pro protein converts subtilisin/kexin type 9 (PCSK-9) inhibitor Evolocumab, improves functional status (pain free walking time in particular, but also maximal walking time), lower extremity arterial perfusion and endothelial function (brachial endothelial reactivity).

Detailed Description

This is a double-blinded, prospective, randomized, study in eighty-six subjects with clinical ASCVD with PAD on background treatment with maximal tolerated dose of a statin. Subjects will be assessed based on their medical history and physical examination. Eligible subjects must meet all inclusion criteria and none of the exclusion criteria (listed below). There will be a treatment group and a placebo group, each with equal number of participants (n=43 patients in each group). After consent and enrollment, subjects will have a venous blood sample drawn to perform serum circulating biomarkers of oxidative stress as oxidized low density lipoprotein (oxLDL), oxidized glutathione : reduced glutathione (GSH:GSSG) and soluble CD36 (sCD36). We will then perform: functional walking measurements, pain free walking time (PFWT), and (maximal walking time (MWT), lower extremity arterial perfusion assessment (rest ABI/TBI, post-exercise ABI and bilateral TcPO2), and brachial endothelial function testing (after hyperemia). Subjects will receive monthly subcutaneous injections of Evolocumab 420 mg or placebo injection. The study participants will be seen at three months and six months for follow up and a final assessment at 26 +/-2 weeks, all tests will be repeated for comparison from baseline and/or placebo.

Study Timeline

• Study Start: 2017-12-14
• Study First Submitted: 2020-02-21
• Status Verified: 2020-03
• Study First Submitted QC: 2020-03-11
• Last Update Submitted: 2020-03-11
• Study First Posted: 2020-03-12
• Last Update Posted: 2020-03-12
• Primary Completion: 2020-12-30
• Study Completion: 2021-03-30

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 86

Inclusion Criteria

• Signed informed consent.
• Age ≥40 to ≤85 years of age at the time of consent.
• Diagnosis of ASCVD with peripheral arterial disease, Rutherford class I-VI at the time of diagnosis, confirmed by ABI≤0.9 at rest or ABI≤0.8 after exercise, angiography, duplex ultrasound or history of lower extremity surgical or endovascular revascularization.
• At least 1 months from last intervention, including surgery or endovascular procedures.
• Stable on maximal tolerated doses of a lipid-lowering regimen for at least 4 weeks.
• Most recent fasting LDL-C ≥55 mg/dL or non-HDL-C ≥80 mg/dL.

Exclusion Criteria

• Subjects with active, non-healed wounds.
• Subjects with anticipated need of cardiac or surgical revascularization procedures.
• Subjects with chronic inflammatory conditions or requiring chronic systemic corticosteroids.
• New York Heart Association (NYHA) class III or IV heart failure, or known left ventricular ejection fraction <30%.
• Uncontrolled arrhythmia.
• Uncontrolled hypertension with systolic BP>180 mmHg or diastolic >100 mmHg.
• Untreated thyroid disease.
• Severe chronic renal disease with estimated glomerular filtration rate (eGFR) <20 mL/min.
• Liver disease with aspartame aminotransferase (AST) or alanine aminotransferase (ALT) ≥3 times the upper limit of normal.
• Status post-organ transplant.
• Pregnant and breastfeeding women
• Fertile age female not on appropriate birth control.
• Clinically significant disease that, in the opinion of the Principal Investigator, is likely to require surgery or immunotherapy that may interfere with the completion of the study.
• Active cancer or life expectancy of less than two years.
• Chronic anticoagulation or hypercoagulability disorder.
• Atrial fibrillation with a CHADS-VASc Score ≥2 or any clinical condition which, in the opinion of the Principal Investigator increases the risk of cerebrovascular events.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Treatment Arm	Evolocumab 140 mg/mL Subcutaneous Injection 1 milliliter (mL) pre-filled injector Pen x 3 for a monthly dose of 420 mg for 6 months.	43 Patients with lower extremities Peripheral Arterial Disease on maximum statin therapy will receive in addition a monthly dose of evolocumab 420 mg via subcutaneous injections for 6 months.
Control Arm	Placebo 1milliliter (mL) Subcutaneous Injection pre-filled injector Pen x 3 monthly for 6 months.	43 Patients with lower extremities Peripheral Arterial Disease on maximum statin therapy will receive in addition a monthly dose of placebo via subcutaneous injections for 6 months.

Primary Outcome Measures

Name	Time	Method
Evolocumab effect in pain free walking time (PFWT) in patients with PAD	six months	To evaluate change in pain free walking time (PFWT) in patients with PAD at baseline and after six months of therapy with Evolocumab.; PFWT will be measured in minutes, using a graded treadmill Gardner protocol with a constant speed of 2 miles per hour, increasing by 2% grade every 2 minutes.

Secondary Outcome Measures

Name	Time	Method
Evolocumab effect in maximal walking time (MWT) in patients with PAD	six months	To evaluate changes in maximal walking time (MWT) in patients with PAD at baseline and after six months of therapy with Evolocumab.; MWT will be measured in minutes, using a graded treadmill Gardner protocol with a constant speed of 2 miles per hour, increasing by 2% grade every 2 minutes.

Trial Locations

Locations (1)

University of Southern California; 🇺🇸 Los Angeles, California, United States