Hypercholesterolemia, Myocardial Infarction
Conditions
Keywords
Myocardial Infarction, Low Density Lipoprotein Cholesterol, proprotein convertase subtilisin kexin 9, human, alirocumab
Brief summary
Phase IV investigator initiated clinical trial to study the effectiveness of alirocumab, an inhibitor of proprotein convertase subtilisin/kexin (PCSK9), versus placebo added to high-intensity statin (atorvastatin 80 mg) in lowering low density lipoprotein (LDL) cholesterol during non-ST segment elevation myocardial infarction (NSTEMI).
Detailed description
This research will study the effects of early initiation of alirocumab in addition to high intensity statin therapy in patients who have previously been treated with high intensity statins with poor response, who present with a type I (spontaneous) acute NSTEMI. Patients will be dosed with drug or placebo once during the first day of their hospital admission. Blood samples will be collected at baseline, 3 days and 14 days after randomization for biomarker testing. Particular attention will be paid to additional LDL lowering effects, as well as the effects on PCSK9 levels and inflammatory biomarkers. Safety and tolerability will be monitored with complete blood count + differential and complete metabolic panels at each study visit.
Interventions
DRUGalirocumab
DRUGplacebo
Sponsors
Regeneron Pharmaceuticals
Sanofi
Virginia Commonwealth University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Acute type I (spontaneous) NSTEMI defined as chest pain (or equivalent) with an onset of symptoms within 12 hours of presentation, a duration of \>15 minutes, and elevated cardiac troponin I levels, with or without electrocardiographic changes \[with the exclusion of ST elevation\]; 2. On medical therapy with high intensity statin prior to admission (either atorvastatin 40-80 mg or rosuvastatin 20-40 mg) as documented by hospital or pharmacy records and with known LDL cholesterol ≥70 mg/dL within the prior 12 months.
Exclusion criteria
1. Age \<21 years of age 2. Inability to give informed consent 3. Previous, current or planned treatment with a PCSK9 inhibitor 4. Known history of loss of function of PCSK9 (genetic mutation or sequence variation) 5. Patient with homozygous familial hypercholesterolemia (clinically or by previous genotyping) 6. Recent (\<14 days) or active use of immunosuppressive drugs (including but not limited to high-dose corticosteroids \[\>1mg/kg of prednisone equivalent\], Tumor Necrosis Factor-α blockers, cyclosporine) not including non-steroidal antinflammatory drugs or corticosteroids used for IV dye allergy or corticosteroids used as replacement therapy for pituitary/adrenal disease with a stable regimen for at least 6 weeks prior to randomization (note: topical, intra-articular, nasal, inhaled, and ophthalmic steroid therapies are not considered systemic and are allowed); 7. Chronic auto-immune or auto-inflammatory disease (including but not limited to rheumatoid arthritis, systemic lupus erythematosus); 8. History of cancer within the past 5 years, except for adequately treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer; 9. Known chronic hepatitis B or C infection (excluding patients with a positive antibody who were successfully treated or who have demonstrated no viral load); 10. Known human immunodeficiency virus infection. 11. Use of fibrates other than fenofibrate within 6 weeks of the screening visit. 12. Uncontrolled hypothyroidism. Note: patients on thyroid replacement therapy can be included if the dosage of thyroxin has been stable for at least 12 weeks prior to screening. 13. Known history of a hemorrhagic stroke. 14. Has been previously treated with at least 1 dose of alirocumab or any other anti-PCSK9 monoclonal antibody in other clinical studies. 15. Conditions/situations such as: 1. Any clinically significant abnormality identified at the time of screening that in the judgment of the investigator or any sub-investigator would preclude safe completion of the study or constrain assessment of endpoints, such as major systemic diseases or patients with short life expectancy. 2. Patients considered by the investigator or any sub-investigator to be inappropriate for this study for any reason: i. Those patients deemed unable to meet specific protocol requirements, such as scheduled visits. ii. Those patients the investigator deems unable to administer or tolerate long-term injections. c. Investigator or any sub-investigator, pharmacist, study coordinator, other study staff, or relative thereof directly involved in the conduct of the protocol. d. Presence of any other conditions (geographic or social), actual or anticipated, that the investigator feels would restrict or limit the patient's participation for the duration of the study. 16. Thyroid-stimulating hormone (TSH) \< lower limit of normal (LLN) or \> upper limit of normal (ULN); if TSH is abnormal due to controlled hypothyroidism (patient is on a stable dose of thyroid replacement therapy), the patient may be enrolled into the study; 17.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Low-density Lipoprotein (LDL) Cholesterol | baseline and 14 days | Placebo-corrected percentage change in calculated LDL cholesterol from baseline to day 14 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Inflammatory Markers (hsCRP) | baseline to 3 days | Placebo-corrected percentage change in inflammatory markers (hsCRP) from baseline to 3 days |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Alirocumab Alirocumab (150 mg) will be administered by subcutaneous injection once, within the first day of the patient's diagnosis of NSTEMI. Patients will also receive an 80 mg dose of atorvastatin.
alirocumab | 10 |
| Placebo Placebo (sterile saline) will be administered by subcutaneous injection once, within the first day of the patient's diagnosis of NSTEMI. Patients will also receive an 80 mg dose of atorvastatin.
placebo | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Alirocumab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60 years | 56 years | 59 years |
| body mass index | 27.8 kilograms per meters squared | 31.9 kilograms per meters squared | 30.9 kilograms per meters squared |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 9 Participants | 16 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 | 3 Participants | 1 Participants | 4 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 4 Participants | 9 Participants | 13 Participants |
| Sex: Female, Male Male | 6 Participants | 1 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 4 / 10 | 1 / 10 |
Outcome results
Primary
Changes in Low-density Lipoprotein (LDL) Cholesterol
Placebo-corrected percentage change in calculated LDL cholesterol from baseline to day 14
Time frame: baseline and 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alirocumab | Changes in Low-density Lipoprotein (LDL) Cholesterol | -73 percent change |
| Placebo | Changes in Low-density Lipoprotein (LDL) Cholesterol | 2 percent change |
p-value: <0.01ANOVA
Secondary
Change in Inflammatory Markers (hsCRP)
Placebo-corrected percentage change in inflammatory markers (hsCRP) from baseline to 3 days
Time frame: baseline to 3 days
Population: Research team was unable to collect samples from 2 Alirocumab participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alirocumab | Change in Inflammatory Markers (hsCRP) | 58 percent change |
| Placebo | Change in Inflammatory Markers (hsCRP) | 55 percent change |
p-value: >0.2ANOVA
Secondary
Change in Inflammatory Markers (hsCRP)
Placebo-corrected Percentage Change in Inflammatory Markers (hsCRP) From Baseline to 14 Days
Time frame: baseline to 14 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alirocumab | Change in Inflammatory Markers (hsCRP) | -4 percent change |
| Placebo | Change in Inflammatory Markers (hsCRP) | -33 percent change |
p-value: >0.2ANOVA