Effect of Evolocumab in Patients With Critical Limb Ischemia (Evol-CLI)

Study Overview
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Brief Summary
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Critical limb ischemia (CLI), is the most severe form of peripheral arterial disease (PAD), and clinically is characterized by pain at rest or non-healing ulcers of the lower extremities. Also, is associated with increased risk of cardiovascular death, myocardial infarction (MI), stroke and amputation. Feringa et al. demonstrated in a study of 1,374 patients with PAD that all cause and cardiac related mortality rates were lower in patients at higher statin dose and lower levels of low-density lipoprotein cholesterol (LDL). Patients with CLI statin therapy and lower LDL levels improve amputation-free survival and patency after revascularization procedures. In the FOURIER trial, LDL cholesterol reduction with the PCSK9 inhibitor evolocumab in patients with symptomatic PAD with or without prior myocardial infarction or stroke was associated with improved major adverse cardiac events (MACE) and major adverse limb events (MALE) at 2-years. The effect of evolocumab in patients with CLI , after a recent arterial revascularization and active wounds is not known, also it is not known whether the cholesterol lowering effect of evolocumab in this group of patients is equivalent to that of non-CLI PAD patients and what the effect is on arterial perfusion, wound healing and other biological markers of vascular physiology. This study aims to investigate the effect of evolocumab in patients with CLI on maximally tolerated lipid lowering therapy with a statin for one year after an index CLI event, requiring revascularization.

Detailed Description
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This is a double-blinded, prospective, randomized, pilot, study in thirty-two subjects with clinical CLI on background treatment with 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. There will be a treatment group and a placebo group, each with equal number of participants (n=16 patients in each group). After consent and enrollment, subjects will have a venous blood sample drawn to perform a lipid profile, serum vascular growth factors such as: vascular endothelial growth factor (VEGF), soluble VEGF receptor-1 (sVEGFR-1), soluble VEGF receptor-2 (sVEGFR-2), fibroblast growth factor (FGF), von Willebrand factor (vWF), tissue plasminogen activator (TPA) and plasminogen activator inhibitor -1 (PAI-1) and endothelial progenitor cells (EPCs). The investigators will then perform lower extremity arterial perfusion assessment of the affected and unaffected limb as rest ankle-brachial index (ABI), toe-brachial index (TBI), bilateral transcutaneous partial pressure of oxygen (TcPO2), spatial frequency domain imaging (SFDI), femoral studies (FMT, compliance, distensibility and stiffness), brachial endothelial function testing (FMD after hyperemia and maximal vasodilation). The study participant subjects will receive monthly subcutaneous injections of evolocumab 420 mg or placebo injections. The LDL cholesterol will be measured at the baseline and a blinded measurement will also be performed at 3 and 12 months. In patients with active wounds, healing will be evaluated at baseline and every month for six months by photographic analysis using planimetry and 2D/3D topographic analysis. The study participants patients will be seen at 3, 6, and 9 months for follow up. After 12 months +/- 2 weeks, all tests will be repeated.

Official Title
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Effect of Evolocumab in Patients With Critical Limb Ischemia

Conditions
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Critical Limb Ischemia

Intervention / Treatment
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* Drug: Evolocumab 140mg/mL Injector 1milliliter (mL) Pen x 3 for a monthly dose of 420 mg for 12 months.
* Other: Placebo 1 milliliter (mL) Injector Pen x 3 monthly for 12 months


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent. Age ≥40 to ≤85 years of age at the time of consent. Diagnosis CLI, Rutherford class IV to VI at the time of diagnosis, toe pressure ≤30 mmHg in non-diabetics or ≤40 mmHg in diabetics, angiography, duplex ultrasound or history of lower extremity surgical or endovascular revascularization for CLI. Stable on maximal tolerated dose of a statin, defined as the highest dose of statin (preferably atorvastatin or rosuvastatin) tolerated by the patient without side effects for at least one month. Exclusion Criteria: Less than 1 month from last revascularization procedure including surgery or endovascular procedures. Subjects with active infection. Diabetes therapy with canagliflozin Subjects who in the opinion of the Principal Investigator will likely require additional. amputation or revascularization procedures during the duration of the study. 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 aspartate 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a double-blinded, prospective, randomized, pilot, study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment arm<br>16 Patients with Critical Limb Ischemia on maximum statin therapy will receive in addition the study intervention involving a monthly subcutaneous injection of evolocumab 420 mg for 12 months | Drug: Evolocumab 140mg/mL Injector 1milliliter (mL) Pen x 3 for a monthly dose of 420 mg for 12 months.<br>* 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 to be provided by Amgen.<br>* Other names: Repatha;|
| Placebo Comparator: Control arm<br>16 Patients with Critical Limb Ischemia on maximum statin therapy will receive in addition a Placebo subcutaneous injection for 12 months. | Other: Placebo 1 milliliter (mL) Injector Pen x 3 monthly for 12 months<br>* The study subjects randomized to the control study arm will receive monthly subcutaneous injections of placebo 1 mL x 3 in the abdomen, thigh or upper arm. The study placebo prefilled injector pens are to be provided by Amgen.<br>* Other names: Control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolocumab effect on LDL cholesterol changes in patients with Critical Limb Ischemia | To evaluate LDL cholesterol values in mg/dL in patients with Critical Limb Ischemia at baseline and after receiving three month therapy of Evolocumab compared to placebo. The LDL cholesterol value changes will be measured as least-squares mean percentage | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evolocumab effect on Lower extremity arterial perfusion changes on ankle-brachial indices (ABI). | To evaluate lower extremity arterial perfusion of the affected and unaffected limb in patients with CLI at baseline and after a 12 month therapy with evolocumab, measured by rate changes in ankle-brachial indices (ABI). The ABI will be determined 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. | 12 months | 
| Evolocumab effect on Lower extremity arterial perfusion pressure changes on toe-brachial indices (TBI). | To evaluate lower extremity arterial perfusion of the affected and unaffected limb in patients with CLI at baseline and after a 12 month therapy with evolocumab, measured by rate changes in toe-brachial indices (TBI). The TBI will be determined by the great toe pressure (in mmHg) of each foot divided by the brachial artery highest systolic pressure (in mmHg) of both arms. | 12 months | 
| Evolocumab effect on Lower extremity microvascular perfusion changes. | To evaluate lower extremity microvascular perfusion of the affected and unaffected limb in patients with CLI at baseline and after a 12 month therapy with evolocumab compared with placebo, measured by tcpo2 mmHg changes in transcutaneous oxygen tension in the skin. Transcutaneous oxygen will be performed by placing electrodes on the skin at different levels of each leg, foot and chest for reference. | 12 months | 
| Evolocumab effect on foot perfusion changes. | To evaluate transcutaneous oxy-hemoglobin and deoxy-hemoglobin foot perfusion of the affected and unaffected foot in patients with CLI at baseline and after 6 month therapy with evolocumab compared with placebo, assessed by spatial frequency domain imaging (SFDI) mapping changes measured in percentage %. Transcutaneous oxy-hemoglobin and deoxy-hemoglobin will be performed by obtaining SFDI images on the skin at different levels of each foot. | 6 months | 
| Evolocumab effect on Femoral arterial distensibility changes. | To evaluate common femoral artery distensibility of the affected and unaffected limb in patients with CLI at baseline and after 12 month therapy with evolocumab compared with placebo, measured by the relative change in lumen area during systole for a given pressure change ( 10-3 x kPa-1). Femoral distensibility will be performed by correlating systemic blood pressure and continuously recording by linear ultrasound using a LOGIQ eR7 ultrasound and a 12-L-RS linear array transducer and images analyzed by the QUIPU automated cardiovascular suite, carotid studio imaging software. | 12 months | 
| Evolocumab effect on Femoral artery Medial Thickness (FMT) changes. | To evaluate common femoral artery medial thickness changes of the affected and unaffected limb in patients with CLI at baseline and after 12 month therapy with evolocumab compared with placebo. The common femoral artery medial thickness will be measured in millimeters (mm) and performed by correlating systemic blood pressure and continuously recording by linear ultrasound using a LOGIQ eR7 ultrasound and a 12-L-RS linear array transducer and images analyzed by the QUIPU automated cardiovascular suite, carotid studio imaging software. | 12 months | 
| Evolocumab effect on endothelial function by Flow Mediated Dilation (FMD) changes. | To evaluate brachial artery flow mediated dilation (brachial artery diameter in response to shear stress) of both arms in patients with CLI, at baseline and after 12 month 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. Images will be analyzed by the QUIPU automated cardiovascular suite, FMD studio imaging software. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CLI, Gangrene, Ischemia, Amputation