Effect of Evolocumab in Functional Status and LDL Oxidation of Patients With Peripheral Arterial Disease (Evol-PAD)

Effect of Evolocumab in Functional Status and LDL Oxidation of Patients With Peripheral Arterial Disease (Evol-PAD)

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).

Study Overview

• Status: Unknown
• Conditions: Peripheral Arterial Disease
• Intervention / Treatment: 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.

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 Type: Interventional
• Enrollment (Anticipated): 86
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • University of Southern California

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 85 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment Arm; 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.	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.; The study subjects randomized to the treatment study arm will receive monthly subcutaneous injections of evolocumab 420 mg in the abdomen, thigh or upper arm. The study drug (evolocumab) prefilled injector pens are provided by Amgen; Other Names: Repatha
PLACEBO_COMPARATOR: Control Arm; 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.	Other: Placebo 1milliliter (mL) Subcutaneous Injection pre-filled injector Pen x 3 monthly for 6 months.; The study subjects randomized to the treatment study arm will receive monthly subcutaneous injections of Placebo in the abdomen, thigh or upper arm. The Placebo prefilled injector pens are provided by Amgen; Other Names: Control

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolocumab effect in pain free walking time (PFWT) in patients with PAD	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.	six months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolocumab effect in maximal walking time (MWT) in patients with PAD	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.	six months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evolocumab effect in lower extremity arterial perfusion in ankle-brachial indices (ABI).	To evaluate changes in lower extremity arterial perfusion in patients with PAD at baseline and after 6 month therapy with evolocumab, measured by systolic pressure rate changes in ankle-brachial indices (ABI). The rest ABI will be calculated by the dorsalis pedis and posterior tibialis arteries highest systolic pressure value (in mmHg) of each foot divided by the brachial artery highest systolic pressure (in mmHg) of both arms.	six months
Evolocumab effect in lower extremity arterial perfusion pressure in post-exercise ankle-brachial indices.	To evaluate changes in lower extremity arterial perfusion in patients with PAD at baseline and after 6 month therapy with evolocumab, measured by systolic pressure rate changes in post-exercise ankle-brachial indices (ABI). The post-exercise ABI will be calculated by the dorsalis pedis and posterior tibialis arteries highest systolic pressure value (in mmHg) of each foot divided by the brachial artery highest systolic pressure (in mmHg) of both arms and assessed by using a standardized treadmill walking protocol at a 2% progressive grade every 2 minutes and 2 miles per hour until symptoms force the subject to stop.	six months
Evolocumab effect in lower extremity arterial perfusion pressure in Toe-Brachial pressure indices.	To evaluate changes in lower extremity arterial perfusion in patients with PAD at baseline and after 6 month therapy with evolocumab, measured by systolic pressure rate changes toe-brachial indices (TBI). The TBI will be determined by the great toe pressure value (in mmHg) of each foot divided by the brachial artery highest systolic pressure (in mmHg) of both arms.	six months
Evolocumab effect in lower extremity arterial perfusion in transcutaneous oxygen changes.	To evaluate lower extremity arterial perfusion determined by changes in transcutaneous oxygen tension in the skin (in tcpo2 mmHg) at baseline and after 6 month therapy with evolocumab in patients with PAD. Transcutaneous oxygen will be performed by placing electrodes on the skin at different levels of each leg, foot and chest for reference.	six months
Evolocumab effect in brachial endothelial function by changes in Flow Mediated Dilation (FMD).	To evaluate changes in brachial endothelial function FMD determined by brachial artery diameter in response to shear stress of both arms in patients with PAD at baseline and after six months of therapy with Evolocumab compared with placebo. The FMD will be measured as the percentage (%) change in brachial artery diameter from baseline in response to the increase flow achieved after the inflation of a pneumatic cuff to supra-systolic pressure for 5 minutes. The ultrasound brachial images will be acquired using a LOGIQ eR7 ultrasound and a 12-L-RS linear array transducer and the images will be analyzed by the QUIPU automated cardiovascular suite, FMD studio software.	six months
Evolocumab effect in serum circulating biomarker oxidative LDL	To evaluate changes on LDL oxidation by measuring oxidized LDL levels (oxLDL), performed using a sandwich ELISA method in patients with PAD at baseline and after six months of therapy with Evolocumab.	six months
Evolocumab effect in serum circulating biomarker soluble CD36 (sCD36).	To evaluate changes on human soluble CD36 levels at baseline and after 6 month therapy with evolocumab in patients with PAD by using a quantitative sandwich ELISA format.	six months

Collaborators and Investigators

• Sponsor: Leonardo Clavijo
• Collaborators: Amgen

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 14, 2017
• Primary Completion (ANTICIPATED): December 30, 2020
• Study Completion (ANTICIPATED): March 30, 2021

Study Registration Dates

• First Submitted: February 21, 2020
• First Submitted That Met QC Criteria: March 11, 2020
• First Posted (ACTUAL): March 12, 2020

Study Record Updates

• Last Update Posted (ACTUAL): March 12, 2020
• Last Update Submitted That Met QC Criteria: March 11, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: PAD; Claudication; Hyperlipidemia
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Arterial Disease; Peripheral Vascular Diseases; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: 20167764; HS-16-00965 (OTHER: University of Southern California)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No