The Effects of Evolocumab in Patients With Diabetes and Atherosclerotic Vascular Disease
Condition: Atherosclerotic Vascular Disease; Type2 Diabetes; Microvascular Dysfunction
MeSH terms: Vascular Diseases; Atherosclerosis; Diabetes Mellitus
Intervention: Placebo; Evolocumab
Intervention description: 12 weeks of treatment; 12 weeks of treatment
Intervention MeSH terms: Evolocumab
Phase: Phase 4
Study type: Interventional
Primary purpose: Supportive Care
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A 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 identity of the treatments will be concealed by the use of matching placebo to the study drug that are identical in packaging, labeling, appearance and schedule of administration.
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: The identity of the treatments will be concealed by the use of matching placebo to the study drug that are identical in packaging, labeling, appearance and schedule of administration.
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PCSK9 inhibition; Evolocumab; Inflammatory Signals; Circulating monocyte subsets

Summary:

      Experimental models have linked lipid lowering therapies with systemic inflammation; however,
      relatively little is known about this network in clinical populations and specifically how it
      changes with PCSK9 inhibition. The eligible subjects will have 6 visits in 13 to 16 weeks and
      will have Repatha/placebo 140mg subcutaneous every 4 weeks for 3 times since randomization
      visit, blood tests will be done in each visit to evaluate the effects of evolocumab upon
      biocellular markers potentially altered by PCSK9 inhibition in a population of type 2
      diabetes patients with microvascular dysfunction.

      Primary Aims:

      Determine the ACUTE and SHORT-TERM effects of PCSK9 inhibition with evolocumab on biocellular
      markers of inflammation, immune mediated thrombosis and rheology. The data from this trial
      will be used to support a clinical trial to assess the role of PCSK9 inhibition in type 2
      diabetes patients with cardiac microvascular dysfunction.

      Secondary Aims:

        1. To define the association between PCSK 9 concentrations and immune-related phenotype.

        2. To define the association between Lp(a) concentrations, oxidized phospholipids (OxPL),
           ApoB, biocellular markers of inflammation, tissue factor and immunothrombosis.
    

Eligibility criteria:

        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.