Familial Hypercholesterolemia
Conditions
Keywords
Hyperlipidemia, Hypercholesterolemia, atherothrombosis
Brief summary
The primary goal is to assess the impact of Evolocumab therapy on platelet function of familial hypercholesterolemia (FH) patients in a randomized, double blind study. Evolocumab is a humanized monoclonal antibody that targets circulating PCSK9, increases hepatic LDL receptor, decreases plasma LDL cholesterol and reduces risk of cardiovascular events. Evolocumab (brand name Rapatha) has been approved by FDA along with diet and maximally tolerated statin therapy in adults with FH or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol. The secondary goal is to determine if platelet activation or the response to Evolocumab therapy is modified by rs3184504 polymorphism. The investigators believe that these investigations will complement ongoing studies to demonstrate that Evolocumab reduces athero-thrombotic risk and aid the decision-making as to whether Evolocumab can reduce the atherothrombotic risk in acute coronary syndrome (ACS) patients.
Detailed description
Hyperlipidemia as exemplified by familial hypercholesterolemia is associated with increased platelet activation and an underlying pro-coagulant state. Hyperlipidemia primes platelets and increases platelet activation in response to various agonists. Plasma cholesterol levels appear to have a critical role in modulating platelet activity as hypercholesterolemia increases platelet activation more potently than hypertriglyceridemia. Increased platelet reactivity may contribute to the increased risk of atherothrombosis associated with hypercholesterolemia. Plasma levels of platelet activation markers such as thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), soluble CD40L (sCD40L) or P-selectin exposure at surface of platelets are increased in hypercholesterolemic patients. Increased levels of the platelet activation markers are associated with increased platelet membrane cholesterol content in hypercholesterolemia.Statins may show antithrombotic properties.
Interventions
DRUGEvolocumab
140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia
Sponsors
Amgen
Columbia University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects who have a clinical diagnosis of familial hypercholesterolemia (FH) * Subjects who are referred to Dr. Ginsberg's Lipid Practice for treatment with PCSK9 inhibitor * Subjects with LDL cholesterol levels \>100 mg/dl on baseline treatment with statins and/or ezetimibe
Exclusion criteria
* Children under 18 years of age
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | Day 7, Day 14, Day 21, Day 28, Day 84 | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU |
| Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Day 7, Day 14, Day 21, Day 28, Day 84 | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Evolocumab Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196.
Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia | 2 |
| Placebo Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196.
Evolocumab: 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia | 2 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Due to Covid-19 pandemic, the trial was prematurely terminated | 2 | 2 |
Baseline characteristics
| Characteristic | Evolocumab | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 2 participants | 2 participants | 4 participants |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU))
ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU)
Time frame: Day 7, Day 14, Day 21, Day 28, Day 84
Population: Adult male and female subjects who have a clinical diagnosis of familial hypercholesterolemia and referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe. Of the four participants reported in this study, one participant per arm had ADP assessed by PRU Test (evolocumab and placebo arms) and one participant per arm had ADP assessed by Aspirin assay (evolocumab and placebo arms).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 21 | 533 ARU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 28 | 530 ARU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test Day 14 | 608 ARU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 84 | 406 ARU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 7 | 521 ARU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 84 | 386 ARU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 7 | 432 ARU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test Day 14 | 401 ARU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 28 | 512 ARU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | Aspirin Test, Day 21 | 490 ARU |
Primary
Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU))
ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU
Time frame: Day 7, Day 14, Day 21, Day 28, Day 84
Population: Adult male and female subjects who have a clinical diagnosis of familial hypercholesterolemia and referred for treatment with PCSK9 inhibitor, with LDL cholesterol levels ≥70 mg/dl on baseline treatment with statins and/or ezetimibe or intolerant to statin and/or ezetimibe. Of the four participants reported in this study, one participant per arm had ADP assessed by PRU Test (evolocumab and placebo arms) and one participant per arm had ADP assessed by Aspirin assay (evolocumab and placebo arms).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 14 | 268 PRU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 28 | 276 PRU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 test, Day 21 | 268 PRU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 84 | 256 PRU |
| Evolocumab | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 7 | 266 PRU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 84 | 267 PRU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 7 | 216 PRU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 14 | 226 PRU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 test, Day 21 | 233 PRU |
| Placebo | Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | P2Y12 Test, Day 28 | 225 PRU |