Conditions: Myocardial Infarction Hypercholesterolemia
Keywords: Myocardial Infarction Low Density Lipoprotein Cholesterol proprotein convertase subtilisin kexin 9, human alirocumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: alirocumab intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
Alirocumab in Patients with Acute 
Myocardial Infarction 
A Randomized Controlled Double-Blinded Study 
 
The VCU Alirocumab Response Trial 
 
 
 
 
Principal Investigator: Antonio Abbate, MD, PhD 
Sponsor: Virginia Commonwealth University  
Funding provided by: Regeneron Pharmaceuticals, Inc. and 
Sanofi U.S. 
 
    STUDY PROTOCOL   


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TABLE OF CONTENTS 
1) 
PERSONNEL 
2) 
PROTOCOL SUMMARY 
3) 
BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
4) 
OBJECTIVES 
4.1   Study objectives 
4.2   Study outcome measures  
4.3 
 Study endpoints 
5) 
STUDY DESIGN 
6) 
ENROLLMENT IN THE STUDY 
6.1   Inclusion criteria 
6.2   Exclusion criteria 
7) 
RANDOMIZATION 
8) 
TREATMENT WITH THE INVESTIGATIONAL DRUG 
9) 
STUDY ASSESSMENT 
10) 
POTENTIAL BENEFITS AND RISKS 
10.1   Alirocumab 
10.2  Social and psychological risks 
10.3   Testing Risks 
10.4 
Direct benefits to study participants 
11) 
ASSESSMENT OF SAFETY 
11.1   Reporting of Adverse Events 
12) 
DISCONTINUATION OF TREATMENT AND WITHDRAWAL 
13) 
STATISTICAL CONSIDERATIONS 
14) 
REFERENCES 
 
 


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1)  
PERSONNEL 
Name  
 
 
 
Role  
 
 
Institution/ Division 
Antonio Abbate, MD, PhD  
Principal Investigator 
VCU, Cardiology  
 
Amy Ladd, PhD 
 
 
Regulatory Coordinator  
VCU, Cardiology  
 
Cory Trankle, MD 
 
 
Investigator  
 
VCU, Cardiology 
 
Benjamin Van Tassell, PharmD 
Investigator  
 
VCU, School of Pharmacy 
Salvatore Carbone, MS 
 
Investigator  
 
VCU, Cardiology 
Leo Buckley, PharmD 
 
Investigator  
 
VCU, School of Pharmacy 
Justin Canada, MS  
 
Investigator  
 
VCU, Cardiology 
Dinesh Kadariya, MD 
 
Investigator  
 
VCU, Internal Medicine 
 
Robin Sculthorpe, PharmD 
Investigational Pharmacy VCU, School of Pharmacy 
 
 


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2) 
 PROTOCOL SUMMARY 
 
Title: 
Alirocumab in Patients with Acute Myocardial Infarction 
 
Population: 
20 patients aged ≥21 years presenting with an acute 
spontaneous 
non-ST 
elevation 
myocardial 
infarction 
(NSTEMI) who are already taking at least moderate intensity 
statin therapy at time of hospital admission 
 
Description:   
Phase IV clinical trial of the alirocumab, an inhibitor of the 
proprotein convertase subtilisin/kexin (PCSK9), or placebo 
added to high-intensity statin (atorvastatin 80 mg) in LDL 
cholesterol lowering during NSTEMI. 
 
 
 
 
 
Objectives: 
To determine the effectiveness of alirocumab in further 
lowering cholesterol LDL and inflammatory biomarkers when 
initiated acutely in patients with NSTEMI, in addition to high 
intensity statin, atorvastatin 80 mg. 
 
Primary Endpoint: 
Placebo-corrected percentage change in calculated LDL 
cholesterol from baseline to day 14. 
 
Secondary Endpoints: 
Placebo-corrected percentage change in calculated LDL 
cholesterol from baseline to 72 hours; placebo-corrected 
percentage change in PCSK9 levels from baseline to 72 hours 
and 14 days; placebo-corrected percentage change in 
lipoprotein(a) levels from baseline to 72 hours and 14 days; 
placebo-corrected percentage change in inflammatory 
markers (high-sensitivity CRP, IL-6, IL-10, and TNF-α) from 
baseline to 72 hours and 14 days; and safety and tolerability 
of alirocumab when initiated in the inpatient setting soon after 
an NSTEMI. 
 
Study Design: 
Randomized, double-blinded, placebo-controlled phase IV 
clinical trial of a single dose of Alirocumab 150 mg or matched 
placebo in a 1:1 ratio. Patients will be assessed at enrollment, 
72 hours and 14 days after treatment. 
 
 
 


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3) BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
Acute myocardial infarction (AMI) remains a leading cause of mortality and morbidity 
across the nation and worldwide.  While major advances in reperfusion strategies over 
the past several decades have significantly reduced early mortality rates after AMI, 
patients who survive the index event are increasingly at risk for adverse cardiac 
remodeling and the sequelae of heart failure and sudden cardiac death1.  The aging 
population accelerates this problem, making heart failure a major public health concern. 
Heart failure, indeed, currently affects approximately five million Americans with 
increasing rates of prevalence and incidence. 
 
Anticoagulants, antiplatelet agents, and neurohormonal blockers have become standard 
of care in the treatment of patients with AMI, given their established effects on mortality. 
Cholesterol-lowering drugs, primarily HMG-coA reductase inhibitors – statins – have been 
studied as a means not only to reduce LDL cholesterol (and hence the incidence of a first 
or recurrent AMI) but also as an adjunct to acute AMI therapy. In the MIRACL trial, 
atorvastatin 80mg was administered within 24 to 96 hours after presentation with acute 
coronary syndrome (ACS).  When compared to placebo, the atorvastatin group had a 
reduction in the primary endpoint (composite of death, nonfatal AMI, cardiac arrest with 
resuscitation, or recurrent symptomatic myocardial infarction) from 17.4% to 14.8% 
(relative risk = 0.84 [0.70 – 1.00], p=0.048)2. 
 
The ARMYDA trial showed that loading with high dose statins for 7 days prior to elective 
percutaneous intervention (PCI) significantly reduced periprocedural myocardial 
infarction (MI) rates from 18% to 5% (p=0.025)3. This was followed by the ARMYDA-ACS 
trial, showing that initiation of high dose statin therapy in patients presenting with non-ST 
elevation ACS sent to early (<48 hours) angiography reduced the composite primary 
endpoint of death, MI, or target vessel revascularization from 17% to 5% compared to 
placebo (p=0.010) at 30 days4. 
 
Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors are emerging as a promising 
new treatment strategy for LDL cholesterol lowering, demonstrating potent LDL lowering 
effects in addition to or compared to statins, in stable patients in primary or secondary 
prevention 5–9.  PCSK9 is predominantly produced in the liver, intestine, and kidney, 
where it is secreted into the plasma and binds the extracellular component of LDL 
receptors (LDLR).  Once bound, the LDLR-PCSK9 complex is internalized and directed 
it to the lysosome for degradation10.  PCSK9 inhibitors have been formulated as 
monoclonal antibodies, designed to bind PCSK9 and prevent this series of events.  As an 
effect, LDLR concentrations on the surface of hepatocytes are increased, and more LDL 
is removed from the circulation. 
 
Alirocumab (Praluent) is the first FDA-approved PCSK9 inhibitor, approved for primary 
prevention in patients with heterozygous familial hypercholesterolemia or secondary 
prevention in patients with clinically stable atherosclerotic cardiovascular disease who 
require additional lowering of LDL-cholesterol11. 
 


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To date, there have been no studies of alirocumab or any other PCSK9 inhibitor given 
acutely in patients with acute myocardial infarction (AMI). 
 
Considering the residual risk of complications and death in patients with AMI, there is an 
urgent clinical need to investigate new strategies for risk reduction in AMI.  A rapid 
reduction of LDL cholesterol within 2-4 weeks of an AMI may provide additional benefit 
on top of standard care, including high-dose statins. 
 
Moreover, a cross-talk between lipoprotein metabolism and systemic inflammation exists.  
In multiple in vitro studies, PCSK9 has demonstrated influence on receptors other than 
LDLR, including the LDLR-related protein 1 (LRP-1)12 and CD3613.  LRP-1 has been 
shown to have anti-inflammatory effects, at least in part due to its indirect control on the 
IKK/NF-κB pathway by downregulation of the cell surface expression of tumor necrosis 
factor-114.  PCSK9 appears to have a similar effect on LRP-1 as it does on LDLR (i.e. 
facilitating LRP-1 degradation)15, suggesting that PCSK9 inhibition would prevent this 
process and could have an anti-inflammatory effect. 
 
Macrophages play an important role in atherosclerosis formation and the associated 
inflammatory pathways.  Increased levels of plasma LDL lead to oxidative modification of 
the LDL particles by macrophages in the arterial intima (forming oxLDL), which is then 
recognizable to scavenger receptors (SR), principally SR-CD36 and SR-A16.  Once CD36 
binds oxLDL, it interacts with Toll-like receptor 4 (TLR4) and TLR6 to activate NF-κB and 
ultimately the inflammasome complex17.  PCSK9 has been shown not only to increase 
levels of circulating LDL, which then promotes CD36 stimulation/upregulation18, but also 
to directly increase the expression of surface CD3619,20.  Thus, CD36 appears to have a 
net proinflammatory effect that is stimulated by PCSK9, and in this manner, PCSK9 
inhibition could again have anti-inflammatory effects. 
 
Overlapping pathways between lipoprotein metabolism and inflammation has a 
theoretical basis in the immune response to pathologic lipoproteic signals (i.e. cell debris 
during myocardial injury or lipopolysaccharide in Gram negative bacteria). Indeed, in a 
mouse model of septic shock, PCSK9 knockout mice or mice receiving PCSK9 
modulators had a more favorable outcome than their counterparts. Accordingly, 
retrospective evidence from a large clinical study of septic shock showed a correlation 
between estimated PCSK9 activity (extrapolated from detected gain of function or loss of 
function genetic mutations), the measured inflammatory biomarker levels, and survival 
during septic shock21.  
 
PCSK9 inhibitors have not been tested in acute settings such as AMI. The effects of the 
PCSK9 inhibitors on LDL cholesterol and on the systemic inflammation in AMI are 
unknown.  It has been shown that persistently high levels of IL-6 and CRP during 
admission for acute coronary syndrome and at discharge are associated with worse 
outcomes 21,22. In the PROVE-IT trial, despite optimal medical care including high intensity 
statin therapy during the time of an ACS, more than 40% of patients had CRP levels 
>2mg/L at 30 days from the index events, and such patients were at increased risk of 
adverse outcomes23. 


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4) 
OBJECTIVES 
 
 
4.1  
Study Objectives 
We propose to study the effects of early initiation of alirocumab in addition to high intensity 
statin therapy in patients who have previously been treated with moderate-high intensity 
statins, who present with a type I (spontaneous) acute non-ST segment elevation MI 
(NSTEMI).  Particular attention will be paid to additional LDL lowering effects, as well as 
the effects on PCSK9 levels and inflammatory biomarkers. 
 
Biomarkers will be collected at baseline, 3 days, and 14 days after randomization. 
 
4.2 
Study Outcome Measures 
LDL cholesterol levels. We will administer one dose of alirocumab 150 mg 
subcutaneously in addition to atorvastatin 80 mg given as standard of care, then monitor 
the change in LDL cholesterol at baseline, 3 days, and 14 days when compared to control 
subjects who receive placebo in addition to atorvastatin 80 mg. 
 
PCSK9 levels. PCSK9 levels will also be measured at each time point, to monitor the 
effectiveness of alirocumab in lowering those levels when initiated acutely during an 
NSTEMI.  We expect PCSK9 levels to rise with high intensity statin treatment alone but 
be lowered by treatment with alirocumab. 
 
Lipoprotein(a). Levels of lipoprotein(a) [Lp(a)], another well-validated cardiovascular risk 
marker, will be measured at each time point.  We expect a marked reduction in Lp(a) 
levels, as was observed in prior trials using alirocumab. 
 
Inflammatory biomarkers. High-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-
6), IL-10, and tumor necrosis factor-α (TNF-α) will be measured at each time point.  We 
expect an inflammatory response after an NSTEMI, with a peak in many of the markers 
at 72 hours after the onset of symptoms.  We suspect that treatment with alirocumab may 
blunt this inflammatory response. 
 
Safety and tolerability. Although Alirocumab is already approved as an adjunct to diet and 
maximally tolerated statins for the treatment of patients with familial hypercholesterolemia 
and for patients with clinical atherosclerotic cardiovascular disease who require additional 
lowering of LDL-cholesterol, the current study represents the first clinical trial in which 
alirocumab will be given in patients with acute NSTEMI in the inpatient setting. Subjects 
will be screened for any adverse side effects or events thought potentially related to 
alirocumab treatment immediately after administration of the study injection, at 3 days, 
and at 14 days after the dose.  A complete blood count with differential and complete 
metabolic panel will be drawn at each time point, as well. 
 
 
 
 


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4.3 
Study Endpoints 
Primary Endpoint: 
 Placebo-corrected percentage change in calculated LDL cholesterol from baseline 
to day 14. 
Secondary Endpoints: 
 Placebo-corrected percentage change in calculated LDL cholesterol from baseline 
to 72 hours; 
 Placebo-corrected percentage change in PCSK9 levels from baseline to 72 hours 
and 14 days; 
 Placebo-corrected percentage change in Lp(a) levels from baseline to 72 hours 
and 14 days; 
 Placebo-corrected percentage change in inflammatory markers (hsCRP, IL-6, IL-
10, and TNF-α) from baseline to 72 hours and 14 days; 
 Safety and tolerability of alirocumab when initiated in the inpatient setting soon 
after an NSTEMI. 
 
5) 
STUDY DESIGN 
We designed an active-controlled, double-blinded study of alirocumab versus placebo in 
addition to high intensity statin, atorvastatin 80 mg, in patients who present with acute 
type I (spontaneous) NSTEMI and who are already taking a moderate-high intensity statin 
prior to admission.   
 
 


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The study is composed of two treatment arms exploring: 
 
a) Alirocumab 150 mg given as a single dose subcutaneously + Atorvastatin 80 
mg orally daily; 
 
b) Matching placebo injection subcutaneously + Atorvastatin 80 mg daily.  
 
 
6) 
ENROLLMENT IN THE STUDY  
Patients who are admitted to the Pauley Heart Center in the VCU Medical Center will be 
screened for inclusion and exclusion criteria based on a cursory evaluation of the 
information available in their medical charts. This approach is supported by a partial 
waiver of informed consent for authorization to access protected health information to 
allow identification of the subjects. After identifying the potential subjects, the 
investigators will approach the subjects in a private manner and review the informed 
consent form approved by the Institutional Review Board.  Any additional information 
about their medical history that is unclear or incomplete from the medical charts will be 
clarified by speaking with the patients and obtaining confirmatory outside medical records, 
with the consent of the patients, if deemed necessary. 
 
Patients agreeing to participate in the study will sign the informed consent form and will 
be given a copy of the consent form signed by the investigator performing the informed 
consent process. No study procedures will occur prior to the subject signing the approved 
informed consent.  
 
6.1 
Inclusion Criteria 
Both criteria must be met for enrollment of the patient into the study 
1) Acute type I (spontaneous) non-ST elevation AMI 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 moderate-high intensity statin prior to admission (either 
atorvastatin 20, 40 or 80 mg, or simvastatin 20, 40 or 80 mg or rosuvastatin 20 or 40 
mg) as documented by hospital or pharmacy records and with known LDL cholesterol 
≥70 mg/dL within the prior 12 months. 
 
6.2  
Exclusion Criteria 
Subjects will not be eligible if they meet any of the following 11 exclusion criteria 
1. Age <21 years of age (NIH standard); 
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 (i.e., genetic mutation or sequence 
variation); 
5. Patient with homozygous FH (clinically or by previous genotyping); 


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6. Recent (<14 days) or active use of immunosuppressive drugs (including but not limited 
to high-dose corticosteroids [>1mg/kg of prednisone equivalent], TNF-α blockers, 
cyclosporine) not including NSAIDs 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: 
a. 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. 
b. Patients considered by the investigator or any sub-investigator to be 
inappropriate for this study for any reason, eg: 
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 (eg, 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; 


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17. Exclusion Criteria Related to the Active Comparator and/or Mandatory Background 
Therapies: All contraindications to the background therapies or warnings/precautions 
of use (when appropriate) as displayed in the respective national product labeling. 
18. Exclusion Criteria Related to the Current Knowledge of Alirocumab 
a. Known hypersensitivity to monoclonal antibody therapeutics 
b. Pregnant or breastfeeding women 
19. Women of childbearing potential who are not protected by highly effective method(s) 
of birth control (as defined in the informed consent form [ICF] and/or in a local 
protocol addendum) and/or who are unwilling or unable to be tested for pregnancy. 
Note:  Women of childbearing potential must have a confirmed negative pregnancy 
test at the screening and randomization visits.  They must use an effective 
contraceptive method throughout the entire duration of study treatment and for 10 
weeks after the last dose of study drug, and agree to repeat urine pregnancy testing 
at designated visits.  The applied methods of contraception must meet the criteria for 
a highly effective method of birth control according to International Conference on 
Harmonisation (ICH)guideline M3(R2) “Nonclinical Safety Studies for the Conduct of 
Human Clinical Trials and Marketing Authorization for Pharmaceuticals” 
(EMA/CPMP/ICH/286/95),which is available at the following Internet address:  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/
09/WC500002720.pdf . Postmenopausal women must be amenorrheic for at least 
12 months. 
7) 
RANDOMIZATION  
 
The Investigational Pharmacist (Robin Sculthorpe, RPh) who will not be involved in 
patient care, data gathering, or data analysis, will be in charge of randomization. Patients 
will be randomized 1:1 to Alirocumab 150 mg or placebo.  
 
Access to randomization log will be restricted and allowed only on an emergency basis, 
or at the end of the study including all data collection. In case of an emergency, a 
physician treating any patient enrolled in the study may request un-blinding of that 
individual patient if the physician determines that un-blinding is necessary to make a 
treatment decision. The PI will contact the VCU Investigational Pharmacy to provide the 
treatment allocation to the PI, who will then relay the information to the treating physician. 
Upon completion of the study (including completion of all data collection and event 
adjudication), the PI will request the complete randomization log from the VCU 
Investigational Pharmacy. 
 
8) 
TREATMENT WITH THE INVESTIGATIONAL DRUG  
 
After signing of the informed consent, verification of the inclusion/exclusion criteria, 
obtaining baseline laboratory samples, and randomization, patients will receive their 


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injection of either alirocumab 150 mg or matching placebo administered subcutaneously.  
The dose will be administered by a nurse or an investigator appropriately using a 
dedicated auto-injector. The syringes and auto-injectors are prepared in a manner in 
which the active drug will be indistinguishable from the placebo, to ensure blinding of the 
providers and subjects. 
 
To avoid prescribers prescribing additional PCSK9 inhibitors during the study, we will 
write a note in the clinical chart of each study subject informing providers about the 
enrollment in the study and the recommendation to not prescribe PCSK9 inhibitors until 
completion of the trial protocol (2 weeks).  This will avoid patients being treated with two 
different PCSK9 inhibitors or with overlapping doses of alirocumab. 
 
 
9) 
STUDY ASSESSMENTS  
 
 
Baseline 
(Day 0) 
Day 3 
(Or Discharge) 
Follow Up 
(14 ± 3 days) 
Screening 
X 
 
 
Consent 
X 
 
 
Administer Med 
X 
 
 
History 
X 
 
X 
Physical Exam 
X 
 
X 
Medication List 
X 
X 
X 
Biomarkers 
X 
X 
X 
 
Patient will have blood samples (approximately 30 mL) drawn at baseline after signing 
the informed consent form but before receiving the study injection.  The panel of 
biomarkers will include a lipid panel (total cholesterol, LDL-C, HDL-C, triglyceride levels, 
and Lp[a]), PCSK9 levels, inflammatory biomarkers (including hsCRP, IL-6, IL-10, and 
TNF-α), complete blood count (CBC), and complete metabolic panel (CMP). 
 
After 3 days, or at the time of patient discharge (whichever occurs first), blood samples 
(approximately 30 mL) will be drawn again to re-measure the biomarkers listed above, 
and the patient will be given an appointment for a visit 143 days from enrollment.  At 
their follow up visit, patients will undergo a repeat history and physical exam, and blood 
samples (approximately 30 mL) will again be drawn to re-measure the biomarkers listed 
above.  This will complete the participation of the subjects in the clinical trial. The patient’s 
clinical care will then continue on a regular basis, according to standard of care.  
 
Biomarkers will be measured by LabCorp (Cincinnati, OH).  The tubes will be collected 
by trained personnel, and immediately inverted 8-10 times after being drawn. Samples 
are then processed, refrigerated and shipped within 24 hours. The results from LabCorp 
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For the measurement of the PCSK9 levels, not available commercially, we will collect 
samples, process them, and store them in a freezer located our lab for single batch 
analysis by Regeneron Pharmaceuticals, Inc. and Sanofi U.S.  
 
10) 
POTENTIAL BENEFITS AND RISKS  
 
 
10.1  Alirocumab  
Alirocumab is a PCSK9 inhibitor which has been shown to significantly lower LDL-
cholesterol, both in patients with heterozygous familial hypercholesteremia (HeFH) and 
in patients without HeFH who have clinical atherosclerotic disease.  It is subcutaneously 
administered by means of an auto-injector.  Its safety and efficacy have been broadly 
investigated multiple clinical trials in patients with or without HeFH who are already on 
maximally tolerated statins, with or without additional lipid-lowering agents5–8.  Patients in 
this study will similarly be required to have been on at least moderate-intensity statin 
therapy prior to presentation for acute MI, and they will receive a single dose of 
alirocumab 150 mg subcutaneously or placebo.  There are no dose-adjustments needed 
based on age or weight. Drug-to-drug interactions are minimal and not expected to be 
clinically relevant. 
 
Side effects have been reported with alirocumab.  Adverse reactions recorded in the 
current reference document for alirocumab are: injection site reactions (including 
erythema/redness, itching, swelling, pain, tenderness), upper respiratory tract signs and 
symptoms (including mainly oropharyngeal pain, rhinorrhea, sneezing), pruritis, 
hypersensitivity, eczema nummular, urticarial, and hypersensitivity vasculitis. 
 
10.2 Social and psychological risks 
 
There is a social/psychological risk in this study of breaching confidentiality and having a 
patient’s diagnosis discovered. The likelihood of this occurring is very low, and will be 
further lowered by creating a database that does not link patients’ identity with their clinical 
data. Loss of confidentiality is a potential risk. However, except when required by law, 
patients will not be identified by name, social security number, address, or any other 
personal identifier.  
 
10.3 Testing risks 
 
The only study-related testing risks will be those of a venous blood draw, which involves 
minor bleeding (rare) and infection (extremely rare) at the puncture site. 
 
10.4 Potential benefits to study participants 
The hypothesis being tested is that alirocumab will be well tolerated when initiated in the 
inpatient setting during an acute MI, and that it will be effective in further lowering LDL-C 
levels in addition to standard of care, possibly with the additional effect of attenuating the 
inflammatory response during acute myocardial infarction. There is no guarantee, 
however, that there is a benefit of using alirocumab in the setting of acute myocardial 


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infarction. There is however, also, no guarantee that the subject will receive alirocumab 
as 50% of subjects will receive placebo. Finally, we also cannot exclude the possibility, 
although highly unlikely, that alirocumab will provide harm in the investigated population. 
In the ODYSSEY Long-Term analysis, indeed, fewer patients experienced an acute 
myocardial infarction on alirocumab vs placebo (0.9% vs 2.3%, P=0.01), and there is no 
evidence suggesting that the patients who experienced an acute myocardial infarction 
while on alirocumab had a worse outcome than those on placebo, as shown by a trend 
toward reduced cardiac mortality with alirocumab (0.3% vs 0.9%)5. 
 
11)  
ASSESSMENT OF SAFETY 
Safety parameters will include data deriving from history and physical examination 
performed at each encounter, laboratory data, and results of functional and imaging tests 
obtained as part of standard clinical care. The patient will be encouraged to contact the 
research team at any time with any concern or change. 
Disease-related data will be assessed including change in symptoms (or new symptoms), 
change in functional capacity, vital signs, and significant changes in medications. 
Data specific to the treatment will also be assessed. The patient will be asked about 
symptoms. Changes to treatment for side-effects or unanticipated problems will be 
performed without breaking the randomization code, unless deemed necessary for the 
treatment of the individual patient by the physician caring for him, in which case the 
physician will be made aware while the remainder of the team, especially the investigators 
performing and interpreting the tests, will be maintained blinded, if possible.  
The risks of the tests performed have been described above. In order to reduce risk, the 
procedures will be performed by skilled practitioners in the standard clinical fashion.  
11.1 Reporting of Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject 
administered a medicinal (investigational or non-investigational) product. An AE does not 
necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational or non- investigational) 
product, whether or not related to that medicinal (investigational or non-investigational) 
product.  
The occurrence of an AE may come to the attention of study personnel during study 
encounters and interviews of a study recipient for medical care, or upon review by an 
investigator and/or study coordinator. All events considered AEs including local and 
systemic reactions will be recorded on the appropriate AE form. Information to be 
collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study intervention (assessed only by those with the training and authority 
to make a diagnosis, which would include a physician) and time of resolution/stabilization 
of the event. All AEs occurring while on study must be documented appropriately 
regardless of relationship. All AEs will be followed to adequate resolution. All AEs must 
be graded for severity and relationship to study product. 


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Severity of Event. All AEs will be assessed by the clinician as: 
 Mild: events require minimal or no treatment and do not interfere with the daily 
activities. 
 Moderate: events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning and may 
require local or systemic drug therapy. 
 Severe: events interrupt a patient’s usual daily activity and will likely require systemic 
drug therapy or other treatment. Severe events are usually incapacitating. 
 Life threatening: any adverse drug experience that places the patient or subject, in the 
view of the investigator, at immediate risk of death from the reaction as it occurred (it 
does not include a reaction that had it occurred in a more severe form, might have 
caused death). 
 
Relationship to the intervention. All suspected AEs must have their relationship to study 
intervention assessed using the terms: associated or not associated.  
 
 Definitely related: The event is temporally related to the administration of the study 
intervention and, in the opinion of the investigator, no other etiology explains the event. 
 Probably related: The event is temporally related to the administration of the study 
intervention and represents, in the opinion of the investigator, the most plausible 
explanation of the event. 
 Possibly related: The event is temporally related to the administration of the study 
intervention but, in the opinion of the investigator, it does not represent the most likely 
explanation of the event. 
 Definitely Unrelated: The event is temporally independent of study intervention and/or 
the event appears, in the opinion of the investigator, to be explained by another 
etiology. 
 
An unexpected event means an event, the nature or severity of which is not consistent 
with the applicable product information.  An expected adverse drug reaction with a fatal 
outcome should be considered unexpected unless the local/regional product labelling 
specifically states that the event might be associated with a fatal outcome. 
 
A serious adverse event (SAE) is any adverse event/experience occurring between 
baseline assessments and the patients final study visit that results in any of the following 
outcomes and is considered by the investigator(s) to be unexpected or not consistent with 
the natural history of the disease: 
 Death; 
 Life threatening (subject at immediate risk of death); 
 Requires inpatient hospitalization or prolongation of existing hospitalization; 
 Results in a persistent or significant disability or incapacity; 
 Is a congenital anomaly/birth defect; 
 Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical 


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judgment, may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
 
For reports of hospitalization, it is the sign, symptom or diagnosis which led to the 
hospitalization, that is, the serious event for which details must be provided. 
 
Any event requiring in-patient hospital admission (or the prolongation of hospitalization) 
must be reported as a SAE.  
 
Admissions to the hospital that do not meet the criteria for SAE reporting are: 
 Social reasons, e.g. overnight stay because of distance between home and hospital 
 Surgery or procedure planned and documented prior to entry into the study 
 
All serious adverse events that have not resolved by the end of the study, or that have 
not resolved upon discontinuation of the subject's participation in the study, must be 
followed until any of the following occurs: 
 The event resolves 
 The event stabilizes 
 The event returns to baseline, if a baseline value/status is available 
 The event can be attributed to agents other than the study drug or to factors unrelated 
to study conduct 
 It becomes unlikely that any additional information can be obtained (subject or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts) 
 
Adverse Event of Special Interest (AESI): An adverse event of special interest (AESI) 
is an adverse event (serious or non-serious) of scientific and medical concern specific to 
the investigational medicinal product (IMP), for which ongoing monitoring and rapid 
communication by the Investigator to the Marketing Administration Holder (MAH) may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. AESIs may be added or removed during a study by protocol 
amendment. 
For this study, the AESI are: 
o Increase in alanine aminotransferase (ALT): 
 
ALT >3 x the ULN unless associated with aspartate aminotransferase (AST) 
increase (AST>ALT) and clearly attributed to cardiac cause. 
o Allergic events. 
 
Allergic drug reactions and/or local injection site reactions deemed to be 
allergic by the Investigator (or have an allergic component), that require 
consultation 
with 
another 
physician 
for 
further 
evaluation 
of 
hypersensitivity/allergy as per the Investigator’s medical judgment should be 
reported as an AESI. 
o Pregnancy: 
 
Pregnancy occurring in a female patient enrolled in the study will be recorded 
as a pre-specified AE with immediate notification in all cases, and IMP should 


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be discontinued in all cases. It will be qualified as an SAE only if it fulfills the 
SAE criteria. The follow-up of the pregnancy will be mandatory until the 
outcome of the pregnancy has been determined. 
 
Pregnancy occurring in the female partner of a male patient included in the 
clinical trial: if permitted by the female partner and by local regulatory policies, 
it will be recorded as a pre-specified AE with immediate notification (SAE if it 
fulfills the SAE criteria), and pregnancy should be followed-up until the 
outcome has been determined. 
o Symptomatic overdose with IMP: 
 
An overdose (accidental or intentional) is an event suspected by the 
Investigator or spontaneously notified by the patient (not based on systematic 
injection counts) and defined as at least twice of the intended dose within the 
intended therapeutic interval (ie, 2 or more injections are administered in <7 
calendar days), to be reported using the Term “symptomatic OVERDOSE 
(accidental or intentional), indicating the circumstance in parentheses (eg, 
“symptomatic overdose [accidental]” or “symptomatic overdose [intentional]”). 
The patient should be monitored and appropriate symptomatic treatment 
instituted. 
 
The circumstances of the overdose should be clearly specified in the verbatim. 
o Neurologic events: 
 
Neurologic events that require additional examinations/procedures and/or 
referral to a specialist should be reported as an AESI. If the event does not 
require additional examinations/procedures and/or referral to a specialist, it 
should be reported as a standard AE. 
o Neurocognitive events 
 
All neurocognitive events will be considered as AESI 
 
 New Safety Finding means any (other than reportable individual case safety report 
(ICSR)) safety issue that may require expedited reporting because providing 
information that may lead to a change in the known risk-benefit balance for the product 
and as mentioned, but not limited to, in the following regulatory texts: Europe: Volume 
9A of the Rules Governing Medicinal products in the European Union (September 
2008) Section 4.1; and US: FDA: 21 CFR Parts 312 Investigational New Drug 
Application- Section 312.32, (c) (1) IND safety reports. 
 
Instructions: 
 All Serious Adverse Events (SAEs) regardless of the relationship to a 
Regeneron/Sanofi product and all Adverse Events of Special Interest (AESIs) must 
be reported to Regeneron/Sanofi within 24 hours of becoming aware of the event  
 
Reports by E-MAIL should be sent to: CL-CPV-Receipt@sanofi.com or Fax: 908-547-
8000, within 24 hours of receipt by investigator/sponsor. E-Mail or Fax transmission 
should include the following:  
Investigator-Sponsored (IST #) study number:___________________  


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Study Title:____________________________________________  
Name of Principal Investigator:____________________________ 
 
 The Sponsor must provide to Regenron/Sanofi upon request, results of any relevant 
complementary exams performed to obtain the final diagnosis of any SAE or AESI  
(e.g. hospital discharge summary, autopsy, consultation). 
 
 The sponsor shall be responsible for ensuring submission of required expedited and 
periodic reports to the appropriate Regulatory Authority (RA), the Ethics Committee 
and investigators of each country participating in the Investigator-Sponsored Study 
(ISS, based on applicable regulations).  
 
 Any Periodic reports (e.g. Development Safety Update Report (DSUR)), submitted to 
Regulatory Authority must first be transmitted to Regeneron/Sanofi for review and 
comment 
 
 The Sponsor must provide to Regeneron/Sanofi any New Safety Findings pertaining 
to safety of the Investigational product within one (1) business day (e.g. Data Safety 
Monitoring Board recommendations). 
 
 
12)  
DISCONTINUATION OF STUDY PARTICIPATION AND WITHDRAWAL 
 
Patients may withdraw from the study at any time. The patient can decide to forgo any 
study procedures that makes him/her uncomfortable or wish not to complete. The study 
doctor may however stop the participation of the patient in this study at any time for many 
reasons including (but not limited to) the study doctor thinks it is necessary for patient 
health or safety, the patient has not followed study instructions, or administrative reasons 
requiring withdrawal.  
 
Loss to follow-up can occur due to patients’ withdrawal or death. If patients are lost to 
follow up and their clinical condition cannot be established (alive vs dead, hospitalized vs 
not), they will be excluded from the initial analysis, and then reintroduced for sensitivity 
analysis considering all potential outcomes. A 10% attrition rate is a reasonable 
assumption. 
 
13)  
STATISTICAL CONSIDERATIONS  
 
13.1 Sample Size 
 
In the ODYSSEY Long Term trial, the addition of alirocumab 150 mg to maximally 
tolerated statin therapy resulted in a reduction of LDL cholesterol of approximately 60% 
at 4 weeks5.  Similar LDL reductions were seen even when used in statin-intolerant 


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patients, as demonstrated in the ODYSSEY Alternative trial24.  We anticipate that patients 
will have baseline LDL levels of approximately 124 mg/dL on first presentation2, and that 
a >40% in LDL reduction will be observed after treatment with alirocumab + atorvastatin 
80 mg on top of what is seen with placebo + atorvastatin 80 mg at 2 weeks (primary 
endpoint), with a standard deviation of approximately 25%.  These estimates lead to a 
predicted power >99% (=0.01) with a sample size of 20 patients, and of >95% with a 
25% loss to follow up at 14 days.  We also expect that patients with an acute myocardial 
infarction to have increased CRP levels, peaking at 72 hours22,23. A sample size of 20 
patients will also provide a power of 65-85% to detect a reduction of 33-50% in CRP or 
IL-6 plasma levels at 72 hours or 14 days with alirocumab + atorvastatin 80 mg on top of 
placebo + atorvastatin 80 mg (secondary endpoint). 
13.2 Analysis of the data 
Continuous variables will be reported as median and interquartile, because of potential 
deviation from Gaussian distribution. Discrete variables will be reported as N and %. For 
the primary endpoint, the comparison in the interval change in LDL cholesterol between 
alirocumab and placebo will be completed using an ANOVA for repeated measures and 
assessing the P value for time_x_group allocation. P values <0.05 will be considered 
significant. Missing data will not be input. For the purpose of safety analysis, all patients 
receiving the investigational drug will be considered, independent of missing data. 
 
14)  
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