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

The Effects of Evolocumab on Endothelial and Inflammatory Biocellular Markers in Patients With Diabetes and Atherosclerotic Vascular Disease (METCHNIKOFF)

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.

Study Overview

• Status: Completed
• Conditions: Type2 Diabetes; Microvascular Dysfunction; Atherosclerotic Vascular Disease
• Intervention / Treatment: Drug: Placebo; Drug: Evolocumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B1W8
      • St. Michael's - University of Toronto
• United States
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo SC QM	Drug: Placebo; 12 weeks of treatment
Active Comparator: Evolocumab; Evolocumab SC 420mg/dL QM	Drug: Evolocumab; 12 weeks of treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events	Safety as measured by number of adverse events, defined as any untoward medical occurrence in a subject who has been administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.	up to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seattle Angina Questionnaire	The Seattle Angina Questionnaire is a quality-of-life measure for patients with coronary artery disease. The SAQ is a self-report instrument with 19 items that yields five subscale scores: physical limitation, angina stability, angina frequency, treatment satisfaction, and disease perception. The possible range of scores for each of the five subscales is 0 to 100, with higher scores indicating better quality of life. There is no summary score generated.	12 weeks
MDA Level	Malondialdehyde levels to measure oxidative stress	12 weeks
MPO Level	Myeloperoxidase level to measure inflammation	12 weeks
IL-6 Level	Interleukin-6 levels to measure cytokines	12 weeks
IL-18 Level	Interleukin-8 levels to measure cytokines	12 weeks
TNF-α Level	Tumor necrosis factor alpha levels to measure cytokines	12 weeks
PECAM Level	Platelet endothelial cell adhesion molecule levels to measure vascular endothelial activation	12 weeks
ICAM Level	Intercellular adhesion molecule levels to measure vascular endothelial activation	12 weeks
VCAM Level	Vascular cell adhesion molecule levels to measure vascular endothelial activation	12 weeks
Alpha5/Beta3 Activation Levels	Alpha 5/Beta 3 levels to measure vascular endothelial activation	12 weeks

Collaborators and Investigators

• Sponsor: Robert Rosenson
• Collaborators: University of Michigan; University of Toronto; Amgen
• Investigators: Principal Investigator: Robert Rosenson, MD, Icahn School of Medicine at Mount Sinai; Principal Investigator: Kim A Connelly, MD, St. Michael's Hospital at University of Toronto

Publications and helpful links

General Publications

• Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007 Jun 26;49(25):2379-93. doi: 10.1016/j.jacc.2007.02.059. Epub 2007 Jun 8.
• Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015 Feb;15(2):104-16. doi: 10.1038/nri3793.
• Dai G, Kaazempur-Mofrad MR, Natarajan S, Zhang Y, Vaughn S, Blackman BR, Kamm RD, Garcia-Cardena G, Gimbrone MA Jr. Distinct endothelial phenotypes evoked by arterial waveforms derived from atherosclerosis-susceptible and -resistant regions of human vasculature. Proc Natl Acad Sci U S A. 2004 Oct 12;101(41):14871-6. doi: 10.1073/pnas.0406073101. Epub 2004 Oct 4.
• Traub O, Berk BC. Laminar shear stress: mechanisms by which endothelial cells transduce an atheroprotective force. Arterioscler Thromb Vasc Biol. 1998 May;18(5):677-85. doi: 10.1161/01.atv.18.5.677.
• Nahrendorf M, Pittet MJ, Swirski FK. Monocytes: protagonists of infarct inflammation and repair after myocardial infarction. Circulation. 2010 Jun 8;121(22):2437-45. doi: 10.1161/CIRCULATIONAHA.109.916346. No abstract available.
• Chang HN, Leroueil PR, Selwa K, Gasper CJ, Tsuchida RE, Wang JJ, McHugh WM, Cornell TT, Baker JR Jr, Goonewardena SN. Profiling inflammatory responses with microfluidic immunoblotting. PLoS One. 2013 Nov 27;8(11):e81889. doi: 10.1371/journal.pone.0081889. eCollection 2013.

Helpful Links

• Inflammation in atherosclerosis
• Hemodynamic Shear Stress via ROS Modulates PCSK9 Expression in Human Vascular Endothelial and Smooth Muscle Cells and Along the Mouse Aorta.
• Local effects of human PCSK9 on the atherosclerotic lesion.

Study record dates

Study Major Dates

• Study Start (Actual): June 3, 2019
• Primary Completion (Actual): November 15, 2021
• Study Completion (Actual): November 15, 2021

Study Registration Dates

• First Submitted: February 1, 2019
• First Submitted That Met QC Criteria: February 1, 2019
• First Posted (Actual): February 4, 2019

Study Record Updates

• Last Update Posted (Actual): July 13, 2022
• Last Update Submitted That Met QC Criteria: July 11, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Evolocumab; PCSK9 inhibition; Inflammatory Signals; Circulating monocyte subsets
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Diabetes Mellitus; Vascular Diseases; Atherosclerosis; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Evolocumab
• Other Study ID Numbers: GCO 18-1412; 20167719 (Other Identifier: Amgen)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: This is a pilot study and all data from this trial will be used to support a bigger clinical trial to assess the role of PCSK9 inhibition in type 2 diabetes patients with cardiac microvascular dysfunction.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes