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

Primary Purpose

Peripheral Arterial Disease

Status

Unknown status

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

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.

Placebo 1milliliter (mL) Subcutaneous Injection pre-filled injector Pen x 3 monthly for 6 months.

About this trial

This is an interventional treatment trial for Peripheral Arterial Disease focused on measuring PAD, Hyperlipidemia, Claudication

Eligibility Criteria

40 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Southern CaliforniaRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Treatment Arm

Control Arm

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT04306081

First Posted

February 21, 2020

Last Updated

March 11, 2020

Sponsor

Leonardo Clavijo

Collaborators

Amgen

1. Study Identification

Unique Protocol Identification Number

NCT04306081

Brief Title

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

Acronym

Evol-PAD

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2020

Overall Recruitment Status

Unknown status

Study Start Date

December 14, 2017 (Actual)

Primary Completion Date

December 30, 2020 (Anticipated)

Study Completion Date

March 30, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Leonardo Clavijo

Collaborators

Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Peripheral Arterial Disease

Keywords

PAD, Hyperlipidemia, Claudication

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Model Description

This is a double-blinded, prospective, randomized, placebo-controlled study.

Masking

ParticipantCare ProviderInvestigator

Masking Description

Study subjects will be randomized, to receive either evolocumab or placebo. Each participant will have equal chance of receiving evolocumab or placebo. The study participant, the care provider and the investigator will not know to which study arm the participant was assigned.

Allocation

Randomized

Enrollment

86 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Treatment Arm

Arm Type

Experimental

Arm Description

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.

Arm Title

Control Arm

Arm Type

Placebo Comparator

Arm Description

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.

Intervention Type

Drug

Intervention Name(s)

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 Intervention Name(s)

Repatha

Intervention Description

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

Intervention Type

Other

Intervention Name(s)

Placebo 1milliliter (mL) Subcutaneous Injection pre-filled injector Pen x 3 monthly for 6 months.

Other Intervention Name(s)

Control

Intervention Description

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

Primary Outcome Measure Information:

Title

Evolocumab effect in pain free walking time (PFWT) in patients with PAD

Description

Time Frame

six months

Secondary Outcome Measure Information:

Title

Evolocumab effect in maximal walking time (MWT) in patients with PAD

Description

Time Frame

six months

Other Pre-specified Outcome Measures:

Title

Evolocumab effect in lower extremity arterial perfusion in ankle-brachial indices (ABI).

Description

Time Frame

six months

Title

Evolocumab effect in lower extremity arterial perfusion pressure in post-exercise ankle-brachial indices.

Description

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.

Time Frame

six months

Title

Evolocumab effect in lower extremity arterial perfusion pressure in Toe-Brachial pressure indices.

Description

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.

Time Frame

six months

Title

Evolocumab effect in lower extremity arterial perfusion in transcutaneous oxygen changes.

Description

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.

Time Frame

six months

Title

Evolocumab effect in brachial endothelial function by changes in Flow Mediated Dilation (FMD).

Description

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.

Time Frame

six months

Title

Evolocumab effect in serum circulating biomarker oxidative LDL

Description

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.

Time Frame

six months

Title

Evolocumab effect in serum circulating biomarker soluble CD36 (sCD36).

Description

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.

Time Frame

six months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

40 Years

Maximum Age & Unit of Time

85 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jorge Caro, MPH

Phone

323-382-7646

Jorge.Caro@med.usc.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Melissa Ramos, RN

Phone

323-442-7983

Melissa.Ramos@med.usc.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Leonardo Clavijo, MD, PhD

Organizational Affiliation

University of Southern California

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of Southern California

City

Los Angeles

State/Province

California

ZIP/Postal Code

90033

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Jorge Caro, MPH

Phone

323-382-7646

Jorge.Caro@med.usc.edu

First Name & Middle Initial & Last Name & Degree

Melissa Ramos, RN

Phone

323-442-7983

Melissa.Ramos@med.usc.edu

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

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

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