Effect of Evolocumab on Vascular Function (EVO)

This is an interventional treatment trial for Atherosclerotic Cardiovascular Disease focused on measuring CVD, LDL, heart failure, PCSK9 Read More

Inclusion Criteria:

• Signed informed consent in written form
• Male or female 40 - 80 years
• History of clinically evident atherosclerotic cardiovascular disease as evidenced by ANY of the following:
• diagnosis of coronary artery disease as evidenced by acute coronary syndrome, myocardial infarction (MI), coronary stent implantation, coronary stenosis ≥50% by coronary angiography
• diagnosis of non-hemorrhagic stroke or transient ischemic attack (TIA)
• symptomatic peripheral arterial disease (PAD), as evidenced by intermittent claudication with ankle-brachial index (ABI) < 0.85, or peripheral arterial revascularization procedure, or amputation due to atherosclerotic disease, or artery stenosis ≥50% by angiography
• Fasting LDL-C ≥ 70 mg/dL (≥ 1.8 mmol/L) or non-HDL-C ≥ 100 mg/dL (≥ 2.6mmol/L) on optimized background lipid lowering therapy (please see Appendix 14.3.)
• Stable background lipid lowering therapy for at least 4 weeks (please see Appendix 14.3)
• Most recent fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) by central laboratory before randomization

Exclusion Criteria:

• Inability to image the brachial artery and to perform FMD
• Subjects with statin intolerance
• Known or suspected homozygous familial hypercholesterolemia (FH)
• Subject must not be randomized within 4 weeks of their most recent MI or stroke
• NYHA class III or IV, or last known left ventricular ejection fraction < 30%
• Atrial fibrillation
• Known hemorrhagic stroke at any time
• Uncontrolled or recurrent ventricular tachycardia
• Planned or expected cardiac surgery or revascularization within 3 months after randomization
• Uncontrolled hypertension defined as sitting pSBP > 180 mmHg or pDBP > 110 mmHg
• Use of cholesteryl ester transfer protein (CETP) inhibition treatment, mipomersen, or lomitapide within 12 months prior to randomization. Fenofibrate therapy must be stable for at least 6 weeks prior to final screening at a dose that is appropriate for the duration of the study in the judgment of the investigator. Other fibrate therapy (and derivatives) are prohibited
• Prior use of PCSK9 inhibition treatment other than evolocumab or use of evolocumab < 12 weeks prior to final lipid screening
• Untreated or inadequately treated hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, and free thyroxine (T4) levels that are outside normal range at final screening
• Severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m2 at final screening
• Active liver disease or hepatic dysfunction, defined as serum Glutamate-Oxaloacetate-Transaminase (SGOT) or serum Glutamate-Pyruvate-Transaminase (SGPT)> 3 times the ULN as determined by central laboratory analysis at final screening
• Recipient of any major organ transplant (eg, lung, liver, heart, bone marrow, renal)
• Personal or family history of hereditary muscular disorders
• LDL or plasma apheresis within 12 months prior to randomization
• Severe, concomitant non-CV disease that is expected to reduce life expectancy to less than 3 years
• Creatinine Kinase (CK) > 5 times the ULN at final screening
• Known major active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction in the judgment of the investigator
• Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 10 years
• Subject has received drugs via a systemic route that have known major interactions with background statin therapy (see Appendix 14.4.) within 1 month prior to randomization or is likely to require such treatment during the study period
• Currently enrolled in another investigational device or drug study, or less than 30 days since ending another investigational device or drug study(s), or less than 5 fold of half-live time of the investigational drug, or receiving other investigational agent(s)

• Female subject who has either (1) not used acceptable method(s) of birth control for at least 1 month prior to screening or (2) is not willing to use such a method during treatment with IP and for an additional 15 weeks after the end of treatment with IP, unless the subject is sterilized or postmenopausal;

  • menopause is defined as 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years old or 12 months of spontaneous and continuous amenorrhea with a follicle-stimulating hormone (FSH) level > 40 IU/L (or according to the definition of "postmenopausal range" for the laboratory involved) in a female < 55 years old unless the subject has undergone bilateral oophorectomy
  • acceptable methods of preventing pregnancy include not having intercourse, birth control pills, injections, implants, or patches, intrauterine devices (IUDs), tubal ligation/occlusion, sexual activity with a male partner who has had a vasectomy, condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicide
• Subject is pregnant or breast feeding, or planning to become pregnant or to breastfeed during treatment with IP and/ or within 15 weeks after the end of treatment with IP
• Known sensitivity to any of the active substances or their excipients to be administered during dosing
• Subject likely to not be available to complete all protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge