Atherosclerotic Vascular Disease, Microvascular Dysfunction, Type2 Diabetes
Conditions
Keywords
PCSK9 inhibition, Evolocumab, Inflammatory Signals, Circulating monocyte subsets
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.
Interventions
DRUGPlacebo
12 weeks of treatment
DRUGEvolocumab
12 weeks of treatment
Sponsors
Robert Rosenson
Amgen
University of Toronto
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
TRIPLE (Subject, Caregiver, 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.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | up to 12 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Seattle Angina Questionnaire | 12 weeks | 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. |
| MDA Level | 12 weeks | Malondialdehyde levels to measure oxidative stress |
| MPO Level | 12 weeks | Myeloperoxidase level to measure inflammation |
| IL-6 Level | 12 weeks | Interleukin-6 levels to measure cytokines |
| IL-18 Level | 12 weeks | Interleukin-8 levels to measure cytokines |
| TNF-α Level | 12 weeks | Tumor necrosis factor alpha levels to measure cytokines |
| PECAM Level | 12 weeks | Platelet endothelial cell adhesion molecule levels to measure vascular endothelial activation |
| ICAM Level | 12 weeks | Intercellular adhesion molecule levels to measure vascular endothelial activation |
| VCAM Level | 12 weeks | Vascular cell adhesion molecule levels to measure vascular endothelial activation |
| Alpha5/Beta3 Activation Levels | 12 weeks | Alpha 5/Beta 3 levels to measure vascular endothelial activation |
Countries
Canada, United States
Contacts
PRINCIPAL_INVESTIGATORRobert Rosenson, MD
Icahn School of Medicine at Mount Sinai
PRINCIPAL_INVESTIGATORKim A Connelly, MD
St. Michael's Hospital at University of Toronto
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo SC QM x 12 weeks of treatment | 19 |
| Evolocumab Evolocumab SC 420mg/dL QM x 12 weeks of treatment | 21 |
| Total | 40 |
Baseline characteristics
| Characteristic | Placebo | Evolocumab | Total |
|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 9.3 | 65.9 years STANDARD_DEVIATION 7.7 | 65.7 years STANDARD_DEVIATION 8.2 |
| Albumin | 4.4 g/dL STANDARD_DEVIATION 0.3 | 4.4 g/dL STANDARD_DEVIATION 0.3 | 4.4 g/dL STANDARD_DEVIATION 0.3 |
| Cardiovascular Disease (CVD) Carotid Disease | 2 Participants | 2 Participants | 4 Participants |
| Cardiovascular Disease (CVD) Coronary Artery Disease (CAD) | 11 Participants | 15 Participants | 26 Participants |
| Cardiovascular Disease (CVD) Peripheral Artery Disease (PAD) | 6 Participants | 4 Participants | 10 Participants |
| Cholesterol Panel HDL | 51.6 mg/dL STANDARD_DEVIATION 17.8 | 44.9 mg/dL STANDARD_DEVIATION 11.9 | 48.1 mg/dL STANDARD_DEVIATION 15 |
| Cholesterol Panel LDL-C | 114.2 mg/dL STANDARD_DEVIATION 30.4 | 107.7 mg/dL STANDARD_DEVIATION 32 | 110.8 mg/dL STANDARD_DEVIATION 30.6 |
| Cholesterol Panel Total Cholesterol | 189.9 mg/dL STANDARD_DEVIATION 39.1 | 180.0 mg/dL STANDARD_DEVIATION 34.7 | 184.7 mg/dL STANDARD_DEVIATION 36.2 |
| Cholesterol Panel Triglycerides | 129.2 mg/dL STANDARD_DEVIATION 56 | 145.0 mg/dL STANDARD_DEVIATION 59.2 | 137.5 mg/dL STANDARD_DEVIATION 56.8 |
| Diabetes | 19 Participants | 21 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 15 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Family History No premature CAD | 15 Participants | 19 Participants | 34 Participants |
| Family History Premature CAD | 4 Participants | 2 Participants | 6 Participants |
| Fibrinogen | 329.9 mg/dL STANDARD_DEVIATION 80.6 | 317.5 mg/dL STANDARD_DEVIATION 131.1 | 323.4 mg/dL STANDARD_DEVIATION 107.5 |
| HbA1c (glycated hemoglobin) | 7.0 percentage of hgb coated with glucose STANDARD_DEVIATION 1.2 | 7.0 percentage of hgb coated with glucose STANDARD_DEVIATION 1.1 | 7.0 percentage of hgb coated with glucose STANDARD_DEVIATION 1.1 |
| Hypertension | 17 Participants | 21 Participants | 38 Participants |
| Medication Use Antidiabetics | 18 Participants | 20 Participants | 38 Participants |
| Medication Use Antihypertensive | 17 Participants | 21 Participants | 38 Participants |
| Medication Use High intensity Statins | 11 Participants | 12 Participants | 23 Participants |
| Medication Use Low to moderate intensity Statins | 6 Participants | 5 Participants | 11 Participants |
| Medication Use No Statin (Statin intolerance) | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 9 Participants | 20 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 20 Participants |
| Sex: Female, Male Male | 8 Participants | 12 Participants | 20 Participants |
| Smoking Current | 5 Participants | 2 Participants | 7 Participants |
| Smoking Former | 9 Participants | 9 Participants | 18 Participants |
| Smoking Never smoker | 5 Participants | 10 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 21 |
| other Total, other adverse events | 10 / 19 | 9 / 21 |
| serious Total, serious adverse events | 3 / 19 | 4 / 21 |
Outcome results
Primary
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.
Time frame: up to 12 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Adverse Events | 13 events |
| Evolocumab | Number of Adverse Events | 13 events |
Secondary
Alpha5/Beta3 Activation Levels
Alpha 5/Beta 3 levels to measure vascular endothelial activation
Time frame: 12 weeks
Secondary
ICAM Level
Intercellular adhesion molecule levels to measure vascular endothelial activation
Time frame: 12 weeks
Secondary
IL-18 Level
Interleukin-8 levels to measure cytokines
Time frame: 12 weeks
Secondary
IL-6 Level
Interleukin-6 levels to measure cytokines
Time frame: 12 weeks
Secondary
MDA Level
Malondialdehyde levels to measure oxidative stress
Time frame: 12 weeks
Secondary
MPO Level
Myeloperoxidase level to measure inflammation
Time frame: 12 weeks
Secondary
PECAM Level
Platelet endothelial cell adhesion molecule levels to measure vascular endothelial activation
Time frame: 12 weeks
Secondary
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.
Time frame: 12 weeks
Secondary
TNF-α Level
Tumor necrosis factor alpha levels to measure cytokines
Time frame: 12 weeks
Secondary
VCAM Level
Vascular cell adhesion molecule levels to measure vascular endothelial activation
Time frame: 12 weeks