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

NCT03829046 | Completed Phase 4 Results FDA Drug

• 2 other identifiers: GCO 18-141220167719
• Study Type: interventional
• Target: 41
• Locations: 2 countries
• Sites: 2

Brief 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. 1.To define the association between PCSK 9 concentrations and immune-related phenotype.
2. 2.To define the association between Lp(a) concentrations, oxidized phospholipids (OxPL), ApoB, biocellular markers of inflammation, tissue factor and immunothrombosis.

Conditions

Atherosclerotic Vascular Disease; Type2 Diabetes; Microvascular Dysfunction

Keywords

PCSK9 inhibition; Evolocumab; Inflammatory Signals; Circulating monocyte subsets

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• Seattle Angina Questionnaire

  12 weeks

• MDA Level

  12 weeks

• MPO Level

  12 weeks

• IL-6 Level

  12 weeks

• IL-18 Level

  12 weeks

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo SC QM

Drug: Placebo

Evolocumab

ACTIVE COMPARATOR

Evolocumab SC 420mg/dL QM

Drug: Evolocumab

Interventions

Placebo DRUG

12 weeks of treatment

Placebo

Evolocumab DRUG

12 weeks of treatment

Evolocumab

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Both: male and female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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;
• 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);

Sponsors & Collaborators

• Robert Rosenson: lead
• Amgen: collaborator
• University of Toronto: collaborator
• University of Michigan: collaborator

Study Sites (2)

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

St. Michael's - University of Toronto

Toronto, Ontario, M5B1W8, Canada

Location

Related Publications (7)

• Tall AR, Yvan-Charvet L. Cholesterol, inflammation and innate immunity. Nat Rev Immunol. 2015 Feb;15(2):104-16. doi: 10.1038/nri3793.

  PMID: 25614320 BACKGROUND

• 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.

  PMID: 17599600 BACKGROUND

• 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.

  PMID: 15466704 BACKGROUND

• 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.

  PMID: 9598824 BACKGROUND

• 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.

  PMID: 20530020 BACKGROUND

• 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.

  PMID: 24312374 BACKGROUND

• Rosenson RS, Tate A, Mar P, Grushko O, Chen Q, Goonewardena SN. Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects. Atherosclerosis. 2024 May;392:117529. doi: 10.1016/j.atherosclerosis.2024.117529. Epub 2024 Mar 25.

  PMID: 38583289 DERIVED

Related 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.

MeSH Terms

Conditions

Atherosclerosis

Interventions

evolocumab

Condition Hierarchy (Ancestors)

Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Dr. Robert S. Rosenson
• Organization: Icahn School of Medicine at Mount Sinai

robert.rosenson@mssm.edu

212-241-9101

Study Officials

• Robert Rosenson, MD

  Icahn School of Medicine at Mount Sinai

  PRINCIPAL INVESTIGATOR

• Kim A Connelly, MD

  St. Michael's Hospital at University of Toronto

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: 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.
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: February 1, 2019
• First Posted: February 4, 2019
• Study Start: June 3, 2019
• Primary Completion: November 15, 2021
• Study Completion: November 15, 2021
• Last Updated: April 28, 2026
• Results First Posted: March 8, 2023

Record last verified: 2026-04

Locations

CA (1); US (1)