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

• Status: Recruiting
• Trial end date: 2021-12-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Robert Rosenson
• Collaborators: Amgen; University of Michigan; University of Toronto
• Treatments: Antibodies, Monoclonal; Evolocumab

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.