The Effects of Evolocumab in Patients With Diabetes and Atherosclerotic Vascular Disease

Multi-center, double-blind, randomized, placebo-controlled, parallel group Phase IV study with two treatment arms: evolocumab SC 420 mg/dL QM or matching placebo. The population will include 40 participants with documented Atherosclerotic Vascular Disease (CAD, Stroke, PAD) and type 2 diabetes who receive treatment with maximal tolerated statin therapy and stable doses of anti-hyperglycemic therapy.

Subjects will be followed for 12 weeks during the treatment phase, maintaining the double-blind throughout. Assessments of ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular markers of endothelial function will be measured at baseline, Week 2, and Week 12. Safety assessments will be undertaken at each study visit.

Inclusion criteria

• Subjects ≥18 years of age signing of informed consent;
• A history of clinical ASCVD, which is defined as: acute coronary syndrome, or a history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral arterial disease presumed to be of atherosclerotic origin;
• Clinical diagnosis of type 2 diabetes according to ADA/ CDA guidelines;
• Subject on stable dose of maximally-tolerated statin therapy for ≥4 weeks prior to screening and LDL-c ≥70mg/dL. For subjects whose maximally tolerated dose of statin is no type or dose (i.e. determined to be statin intolerant by primary investigator), background lipid-lowering therapy is not required;
• Fasting triglycerides ≤400mg/dL (4.52mmol/L) by central laboratory at screening;
• Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures;
• Abnormal urinary Albumin Creatinine Ratio (ACR) as defined by an ACR ≥2;
• Subject tolerates screening placebo injection.

Exclusion criteria

• Personal or family history of hereditary muscular disorders;
• NYHA III or IV heart failure, or last know left ventricular ejection fraction (LVEF) <30%;
• Uncontrolled serious cardiac arrhythmia defined as recurrent and highly symptomatic ventricular tachycardia, atrial fibrillation with rapid ventricular response, or supraventricular tachycardia that are not controlled by medications, in the past 6 weeks prior to randomization;
• Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery graft (CABG) or stroke within 3 months prior to randomization;
• Planned cardiac surgery or revascularization;
• Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) <30mL/min/1.73m2 at screening;
• Type 1 diabetes, poorly controlled type 2 diabetes (HbA1c >10%), newly diagnosed type 2 diabetes (within 6 months of randomization), or laboratory evidence of diabetes during screening (fasting serum glucose ≥126mg/dL [7.0mmol/L] or HbA1c ≥6.5% without prior diagnosis of diabetes;
• Uncontrolled hypertension, defined as sitting systolic blood pressure (SBP) >160mmHg or diastolic BP (DBP) >100mmHg;
• Subject who has taken a cholesterol easter transfer protein (CETP) inhibitor in the last 12 months prior to LDL-c screening, such as: anacetrapib, dalcetrapib or evacetrapib;
• Treatment in the last 3 months prior to LDL-c screening with any of the following drugs: systemic cyclosporine, systemic steroids (e.g. IV, intramuscular [IM], or PO) (Note: hormone replacement therapy is permitted), vitamin A derivatives and retinol derivatives for the treatment of dermatologic conditions (e.g. Accutane); (Note: vitamin A in a multivitamin preparation is permitted). Topical retinol prescription and non-prescription derivatives or creams are permitted;
• Uncontrolled hypothyroidism or hyperthyroidism as defined by thyroid stimulating hormone (TSH) <1.0 time the lower limit of normal or >1.5 times the ULN, respectively, at screening. Potential subjects with TSH <1.0 time the lower limit of normal due to thyroid replacement therapy is not considered an exclusion;
• Active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times the ULN as determined by central laboratory analysis at screening;
• Known active infection or major hematologic, renal metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator;
• Diagnosis of deep vein thrombosis or pulmonary embolism within 3 months prior to randomization;
• Unreliability as a study participant based on the investigator's (or designee's) knowledge of the subject (e.g. alcohol or other drug abuse);
• Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or receiving other investigational agent(s);
• Female subject who has either (1) not used at least 1 highly effective method of contraception for at least 1 month prior to screening or (2) is not willing to use such a method during treatment and for an additional 15 weeks after the end of treatment, unless the subject is sterilized or postmenopausal;
• Subject who is pregnant or breast feeding, or planning to become pregnant during treatment and/ or within 15 weeks after the end of treatment;
• Use of PCSK9 inhibitor within 10 weeks from screening;
• Subject who has any kind of disorder that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent and/or to comply with all required study procedures;
• Malignancy except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years;
• Subject who has known sensitivity to any of the products or components to be administered during dosing;
• Subject who is likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject and investigator's knowledge;
• History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the principal investigator would pose a risk to subject or interfere with the study evaluation, procedures or completion;
• Blood donation 4 weeks prior to screening, or stated intention to donate blood or blood products during the period of the study or within one month following completion of the study;
• Subjects who have participated in other studies within 30 days prior to screening, or have five times the plasma half-life (if known) of the investigational drug, whichever is longer;
• BMI>40kg/m2.