Clinical trial NCT03829046: The Effects of Evolocumab in Patients With Diabetes and Atherosclerotic Vascular Disease
Official title: The Effects of Evolocumab on Endothelial and Inflammatory Biocellular Markers in Patients With Diabetes and Atherosclerotic Vascular Disease (METCHNIKOFF)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Atherosclerotic Vascular Disease
Type2 Diabetes
Microvascular Dysfunction
Keywords: PCSK9 inhibition
Evolocumab
Inflammatory Signals
Circulating monocyte subsets
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: Amgen
name: University of Toronto
name: University of Michigan
First posted: 2019-02-04
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: SUPPORTIVE_CARE

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. 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.

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.

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.

Primary outcomes:
measure: Number of Adverse Events
timeFrame: up to 12 weeks
Secondary outcomes:
measure: Seattle Angina Questionnaire
timeFrame: 12 weeks
measure: MDA Level
timeFrame: 12 weeks
measure: MPO Level
timeFrame: 12 weeks
measure: IL-6 Level
timeFrame: 12 weeks
measure: IL-18 Level
timeFrame: 12 weeks
measure: TNF-α Level
timeFrame: 12 weeks
measure: PECAM Level
timeFrame: 12 weeks
measure: ICAM Level
timeFrame: 12 weeks
measure: VCAM Level
timeFrame: 12 weeks
measure: Alpha5/Beta3 Activation Levels
timeFrame: 12 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Icahn School of Medicine at Mount Sinai
state: New York
city: Toronto
country: Canada
facility: St. Michael's - University of Toronto
state: Ontario
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: Robert Rosenson, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: St. Michael's Hospital at University of Toronto
name: Kim A Connelly, MD
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
citation: 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.
citation: 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.
citation: 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.