Phase 3 Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel Group Evaluation Of The Efficacy, Safety, And Tolerability Of Bococizumab (Pf-04950615) In Reducing The Occurrence Of Major Cardiovascular Events In High Risk Subjects.
Phase: PHASE3
Conditions: Cardiovascular Disease
Sponsor: Pfizer

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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PHASE 3 MULTI-CENTER, DOUBLE-BLIND, RANDOMIZED, 
PLACEBO-CONTROLLED, PARALLEL GROUP EVALUATION OF THE 
EFFICACY, SAFETY, AND TOLERABILITY OF BOCOCIZUMAB (PF-04950615), 
IN REDUCING THE OCCURRENCE OF MAJOR CARDIOVASCULAR EVENTS 
IN HIGH RISK SUBJECTS
SPIRE: STUDIES OF PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 
9 (PCSK9) INHIBITION AND THE REDUCTION OF VASCULAR 
EVENTS-SPIRE-1
Compound:
PF-04950615 (RN-316)
Compound Name:
Bococizumab
United States (US) Investigational New 
Drug (IND) Number:
104,872
European Clinical Trial Database 
(EudraCT) Number:
2013-002646-36
Universal Trial Number:
U1111-1151-0594
Protocol Number:
B1481022
Phase:
3

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 2
12-February-2016
Visit dates in months were replaced by visit dates 
in weeks, throughout the protocol, for clarity and 
consistency.
Unplanned visits were described as unscheduled 
visits, throughout the protocol, for clarity and 
consistency.
The protocol background information was updated 
to include more updated Phase 2 anti-drug 
antibody data based on a more sensitive assay, so 
as to provide additional safety information.
Clinical Secondary Objectives and Endpoints 
were updated to reflect an upgrading of the 
secondary endpoint of a composite endpoint of 
all-cause death, non-fatal MI and non-fatal stroke 
to a KEY secondary endpoint, in consideration of 
its clinical importance.  The secondary endpoint 
of nominal change in hs-CRP was changed to 
percent change in hs-CRP.
The schedule of activities and its footnotes were 
modified to describe more clearly which 
procedures were to be conducted and when they 
were to be conducted.
Statements have been added which state that 
unscheduled assessments limited to measures of 
creatine kinase (CK), liver function tests 
(including alanine amino transferase [ALT], 
aspartate amino transferase [AST], alkaline 
phosphatase, and total and direct bilirubin), 
hepatitis C polymerase chain reaction (PCR), or 
pregnancy testing, do not require fasting. 
The study design language was modified to clarify 
that the end of study visit should occur no sooner 
than 14 days after the last dose of investigational 
product (IP) was administered.  The safety 
follow-up period is 40 days after the last dose of 
IP was administered and if the EOS visit has taken 
place earlier than 40 days after the last dose of IP 

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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administration, subjects will receive a telephone 
call to determine if any serious adverse events 
have occurred.
The study design language was modified in 
consideration of the fact that subjects who qualify 
for this study, would no longer be allocated to 
study B1481038, if they had an LDL-C 
100 mg/dL or a non-HDL-C 130 mg/dL.
The proposed indication was modified so that the 
major cardiovascular events reflected components 
of the primary endpoint.
Section 1.2.2, Rationale was updated to include 
more recent references of PCSK9 inhibitors.
Section 1.2.6, Rationale for dose selection was 
expanded to include data relevant to subjects with 
LDL-C 100 mg/dL.
The summary of safety for completed studies with 
bococizumab was updated to reflect the updated 
Phase 2 anti-drug anti-body data based on a more 
sensitive assay, so as to provide additional safety 
information.
The safety reporting section was revised to reflect 
the fact that a Pfizer Internal Serious Adverse 
Event Triage Group will ensure the correct 
reporting of SAEs to the Pfizer Drug Safety Unit.
The protocol section describing external 
committees was updated to reflect the fact that the 
Joint Operations Committee and Joint Leadership 
Committee were merged into a single oversight 
committee.
Modifications were made to the study's inclusion 
criteria, as described below.  The inclusion criteria 
of the study were modified to also permit the 
inclusion of high risk subjects with LDL-C values 
100 mg/dL or non HDL-C values 130 mg/dL.  
The rationale for this change was to (1) complete 
the study sooner, so as to preserve the study's 
integrity, given the risk that subjects may be 
started on a marketed PCSK9 inhibitor during the 
conduct of the study, or drop out of the study if 

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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they suspect that they are receiving placebo (eg,  
if a primary care physician obtains lipid levels) 
and (2) to acquire additional long term efficacy 
and safety information in subjects with higher 
levels of lipids.
The inclusion criterion for age was modified to 
state that subjects who have not had a prior CVD 
event, but who have a conditions of elevated 
LDL-C, (heterozygous familial 
hypercholesterolemia [heFH] or a history of 
LDL-C 190 mg/dL [4.9 mmol/L]) should be 
35 years of age if a man, and 45 years of age, if 
a woman, given observational studies which 
demonstrate that it is at these ages at which 
patients with heFH have an increased risk of 
incurring a CV event.
Subjects with complete statin intolerance can no 
longer be enrolled in the study, given the fact that 
such subjects might be candidates for a marketed 
PCSK9 inhibitor.
Clarifying language was added to the 
requirements for background lipid lowering 
treatment, to permit the use of intermediate doses 
of statins.
Clarifying language was added to the inclusion 
criteria that the diagnosis of a prior myocardial 
infarction could not be made solely on the basis of 
the presence of new Q waves reported on an ECG.  
There would need to be additional evidence of a 
silent MI, such as imaging data showing a fixed 
regional wall motion abnormality which 
correlated with such ECG changes.
Clarifying language was added to indicate that a 
diagnostic arterial catheterization, without 
revascularization, did no qualify as a 
revascularization event.
The inclusion criterion of peripheral vascular 
disease was expanded to permit the inclusion of 
subjects with imaging evidence of a > 50% 
stenosis of a carotid or lower extremity artery or 
imaging evidence of a high carotid artery plaque 

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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burden.
Clarifying language as added to the inclusion 
criterion of imaging evidence of significant 
coronary artery disease which states that a 
previously stenotic coronary artery, which was 
subsequently revascularized, cannot be counted as 
a CVD risk factor.
Exclusion criteria were modified to exclude 
subjects who have an SAE of a cardiovascular 
disease event between Visit 0 and Visit 5.
The cerebral hemorrhage risk exclusion was 
modified to clarify that a prior lacunar infarct 
refers to a prior lacunar stroke, ie, a lacunar infarct 
which resulted in a stroke.  Imaging evidence of a 
lacunar infarct, in the absence of a historical 
neurologic deficit is not exclusionary.
Exclusion criteria were modified to exclude 
subjects who may take or have taken a marketed 
PCSK9 inhibitor, since such drugs are now 
available in some countries.
Exclusion criteria were modified to exclude 
subjects with a Patient Health Questionnaire score 
15 or who have a positive score in question 9 of 
that assessment, since such scores suggest a high 
risk of depression with suicidality.
The exclusion criterion of intramuscular injections 
was removed from the protocol, since the sole 
concern of these injections was the potential for 
triggering an elevated value of creatine kinase due 
to tissue trauma, which might complicate the 
analysis of safety.
A provision was added in the description of the 
hepatitis inclusion criterion, to permit a 
confirmatory hepatitis C polymerase chain 
reaction in subjects who have a positive hepatitis 
C screening test.
An exclusion criterion of gastric bypass surgery 
was added, since its presence could complicate the 
interpretation of metabolic efficacy and safety 

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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data.
The definition of investigational product was 
added to Section 5, Study Treatments.
The blood sampling schedule for levels of LDL-C, 
anti-drug antibodies, PCSK9, and bococizumab 
was modified to ensure that it takes place no 
sooner than 10 days after the last dose of 
bococizumab, so as to prevent the unnecessary 
triggering of dose modifications.
Lipid testing is no longer required at early 
discontinuation and EOS visits since the time 
intervals between the discontinuation of IP and the 
sampling will be highly variable and not reflective 
of the pre-specified dose administration schedule.
A requirement was added to the protocol that 
study sites contact the early discontinuation
hotline when they become aware of a potential 
discontinuation of a subject's participation, so as 
to enhance the retention of subjects in the study, 
for the purposes of maintaining the study's 
scientific integrity.
A requirement was added to the protocol that 
investigational product should not be 
administered, if a subject is prescribed a marketed 
PCSK9 inhibitor during the conduct of the study.
A provision was added to the study, for subjects 
who are traveling, to obtain study required lab 
tests when they cannot visit the study site.
Urine pregnancy tests were added to all visits, for 
women of childbearing potential.
The blood pressure measurement requirements 
were modified to reflect locally accepted practice, 
to enhance compliance.
The blood sampling requirements for creatine 
kinase (CK) testing were modified, such that such 
sampling should take place no sooner than one 
week after an intramuscular injection, to avoid 
spurious elevations of CK due to local muscle 

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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injury.
The requirements for anti-drug antibody blood 
sampling were modified so that anti-drug antibody 
measurements would be obtained for an injection 
site reaction that lasts more than 3 days.
Section 7.6, Triggered requirements was modified 
with the removal of the section describing the 
management of low-LDL-C with the concomitant
dose modification paradigm, since this would 
happen automatically, through the IRT system and 
would not require direct study site involvement. 
Section 7.6, Triggered requirements was modified 
with the removal of the section describing the 
management of positive ADAs, since the analysis
of ADA is done in the laboratory and not at the 
study site.
Section 7.6, Triggered requirements was modified 
with the removal of the section requiring the site 
to seek approval from the medical monitor, to 
continue dispensing investigational product if the 
subject experiences unexplained muscle 
tenderness or weakness in the absence of a CK 
elevation, since there is no known relationship 
between PCSK9 inhibition and myopathy.  While 
such symptoms are known to be related to statin 
administration, it is up to the investigator to 
follow local requirements for the administration of 
statins as described in the Section 5.8., 
concomitant medications.
In Safety Section 8.2, clarification was added that 
serious adverse event reporting includes the 
period between pre-screening and randomization.
Section 8.6.1 was modified to indicate that 
Protocol Specified Adverse Events were now to 
be described as Disease Related Efficacy 
Endpoints and that they would be identified by the 
Pfizer SAE triage group.
In Safety Section 8.14.1, Serious Adverse Event 
Reporting Requirements, the operations of an 
internal Pfizer Serious Adverse Event Triage 
Group are described, to improve the reporting of 

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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serious adverse events.
Section 9. Data Analysis/Statistical Methods, was 
updated to be consistent with other changes made 
for this amendment.  To be consistent with the 
way the study was randomized, a stratification 
factor for LDL-C (<100 mg/dL, 100 mg/dL) 
was incorporated into all analysis models.
The definition of the efficacy cutoff date was 
modified to accommodate the possibility of 
changes to the stopping criteria outlined in Section 
3.
As a result of EMA Scientific Advice, the 
minimum number of events required to perform 
subgroup analyses was deleted.  As a result, 
language was added to indicate that the subgroups 
would be finalized in the Statistical Analysis Plan.  
Also the language around the interaction p-value 
model was modified to include subjects from all 
subgroups.
The method of controlling Type 1 error for the 
key secondary endpoints was changed to fixed 
sequence testing from the Hochberg procedure, to 
increase the power for more important endpoints.
Minor additional modifications of text were made, 
to ensure compliance with the most current Pfizer 
protocol template for Phase 3 studies, dated 
16-Feb-2015.
The appendices were updated as follows:  
Appendix 3, Hepatitis B Assessment was 
modified to reflect the laboratory nomenclature 
for the central lab;
Appendix 4, Clinical Endpoints was modified to 
reflect the addition of the MI type 4c, stent 
stenosis;
Appendix 7, Safety algorithm: Myopathy, was 
modified so that it was no longer necessary for 
investigators to contact the study medical monitor 
to resume investigational product, for unexplained 
muscle symptoms without an elevation in creatine 

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 9
kinase levels.  Such events would be reported as 
adverse events usually would be, with clinical 
follow-up as needed;
Appendix 9 was modified to reflect the updated 
safety reporting processes;
Appendix 10 was modified to reflect updated 
inclusion criteria.
Amendment 1
01-Oct-2014
The generic name, bococizumab, replaces 
compound number PF-04950615;
Schedule of activities was modified to reflect 
changes in protocol and provide additional detail 
to study sites;
An efficacy endpoint of any stroke (fatal and 
non-fatal), of any etiology which includes 
hemorrhagic stroke, was added;
Modified inclusion and exclusion criteria
language to enhance study site compliance and 
acknowledge the inclusion of other factors known 
to confer cardiovascular risk;
Clarified language regarding background 
concomitant lipid lowering treatments, to enhance 
clarity for the investigators;
Modified contraception language in Inclusion 
Criteria (4.1) and Lifestyle Guidelines (4.4.2), to 
reflect additional pre-clinical reproductive safety 
data, and to enhance clarity for the investigators;
Modified study design to include a pre-screening 
direct low density lipoprotein cholesterol (LDL-C)
measurement, to permit investigators to identify 
subjects who might qualify for inclusion, before 
other study procedures are completed, so as to 
enhance the identification of subjects who are 
most appropriate for inclusion in each of the two 
cardiovascular outcomes studies and to reduce the 
need for rescreening;
Required that lipid assessments be done no sooner 
than 10 days after prior dose, to ensure that lipid 
values are evaluated at the end of the dosing 

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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period;
Added more frequent visits for assessment of 
direct LDL-C and adverse events (AEs)/serious 
adverse events (SAEs), for subjects who have had 
IP dose frequency modifications to Q4wks so that 
the data monitoring committee (DMC) can 
monitor more closely, lipid levels in subjects with 
a history of low levels of LDL-C during the trial;
Added endpoint of calculated remnant lipoprotein 
cholesterol, in consideration of scientific interest 
in this parameter;
Clarified that very low density lipoprotein 
cholesterol (VLDL-C) is a calculated value, so 
that reviewers understand the measurement was 
not made by ultracentrifugation;
Added depression assessments so as to capture 
baseline risk for the disorder, given that 
depression is found fairly frequently in subjects at 
high risk of cardiovascular events and its presence 
may alter performance on the planned cognitive 
assessments;
Added Hopkins Verbal Learning Testing to the 
cognitive assessment panel, to get additional 
information on the subjects’ memory function;
Added health care utilization assessments and 
endpoints, to evaluate the potential impact of
bococizumab on health care resource utilization;
Added to screening laboratory tests, hs-CRP and 
Lp(a) for subjects who had not had a prior 
cardiovascular event, since these are established 
risk factors for the occurrence of cardiovascular 
events;
Modified safety section to clarify further, how 
serious adverse events are to be reported;
Modified statistical assumptions, event rate and 
sample size as well as analysis plan, including 
subgroups, to enhance the scientific value of the 
study;
Added safety appendices that include flow charts 

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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describing actions which should occur in cases of 
potential drug induced liver injury or myopathy to 
clarify the intent of the protocol procedures, for 
the investigators;
Added an appendix facilitating the understanding 
of screening hepatitis serologies, to enhance the 
clarity of the protocol for the investigators;
Added Appendix 9, describing safety reporting 
and potential endpoint reporting, to enhance the 
clarity of the protocol for the investigators;
Added Appendix 10, describing the assessment of 
CVD risk for inclusion, to enhance the clarity of 
the protocol for the investigators.
Original protocol
26 August 2013
Not Applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc. 

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Final Protocol Amendment 2, 12 February 2016
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PROTOCOL SUMMARY
Background
Bococizumab (PF-04950615, previously numbered as RN-316 or J16) is a humanized 
monoclonal antibody against the proprotein convertase subtilisin kexin type 9 (PCSK9) 
enzyme responsible for the regulation of the low density lipoprotein receptor (LDLR), being 
developed for the following indications: (1) the treatment of primary hyperlipidemia or 
mixed dyslipidemia and (2) cardiovascular (CV) risk reduction, in subjects at high and very 
high risk of major cardiovascular events.
Cardiovascular disease (CVD) due to atherosclerosis continues to be the leading single cause 
of death in industrialized countries.  High serum lipid levels, and especially high low density 
lipoprotein cholesterol (LDL-C) levels, have been demonstrated to strongly and directly 
correlate with cardiovascular disease risks by numerous epidemiological studies.  Moreover, 
large prospective clinical outcome trials have demonstrated that lowering LDL-C decreases 
cardiovascular morbidity and mortality.45 Despite the availability of highly effective lipid 
lowering therapies such as statins and ezetimibe, a significant percentage of patients remain 
at high risk for CVD.
PCSK9 is the ninth member of the subtilisin family of kexin like proconvertases to be 
identified and is closely related to proteinase K.  PCSK9 is linked to serum LDL-C levels by 
binding to and down regulating LDLR levels on hepatocytes.  This reduction in LDLR 
results in reduced cellular uptake of LDL-C and, consequently, higher LDL-C levels in 
serum.17 In contrast, a decrease in active PCSK9 leads to an increase in hepatocyte LDLR, 
causing an increase in LDL uptake from circulation and consequently a subsequent reduction 
in serum LDL-C levels.15,16 Loss of function mutations lead to higher levels of the LDLR, 
and consequently lower plasma LDL-C levels, and protection from coronary heart 
disease.18-22 This loss of PCSK9 appears to have no discernible adverse consequences in the 
affected subjects.21,22
Bococizumab targets the evolutionarily conserved LDLR binding domain of PCSK9 with 
high affinity.  Bococizumab administered either as a single or multiple doses, either alone or
in combination with current lipid lowering agents, was generally well tolerated in completed 
studies.  No subjects in completed studies met the categorical criteria of drug-induced liver
injury according to the Hy’s law definition.  Using a highly sensitive and drug tolerant 
anti-drug antibody (ADA) assay, 42.5% of subjects (201/473) exposed to bococizumab in 
three recently completed studies (B1481024, B1481015, and B1481036) developed ADAs.  
The presence of ADAs was not associated with any clinical signs or symptoms of 
hypersensitivity. In 98.7% of ADA positive subjects treated with multiple doses of 
bococizumab, no adverse effects on clinical pharmacokinetics (PK) or pharmacodynamics 
(PD) were evident. A potential impact on PK and/or PD was noted in 5 of 398 subjects 
(1.3%) treated with multiple doses.

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Results from the completed Phase 2b study (Study B1481015) showed that bococizumab was 
generally well tolerated at each dose, with an adverse event profile similar to previous 
findings in the clinical program, and clear evidence of efficacy was established in all 
bococizumab treatment groups.
Study Objectives (Refer to Section 2.1 for Complete List)
Primary Objective
The primary objective of this clinical trial is to demonstrate the superior efficacy of 
bococizumab compared with placebo in reducing the risk of major CV events, a composite 
endpoint which includes adjudicated and confirmed CV death, non-fatal MI (myocardial 
infarction), non-fatal stroke, and hospitalization for unstable angina with urgent 
revascularization (as defined in Appendix 4), in subjects at high or very high risk of major 
CV events, who are on background lipid lowering treatment, and have an LDL-C 70 mg/dL 
(1.81 mmol/L) or non-HDL-C (non-high density lipoprotein cholesterol) 100 mg/dL 
(2.59 mmol/L).
Clinical Secondary Objectives
The key secondary objectives of this clinical trial are to demonstrate in subjects with high or 
very high risk of major CV events, who are on background lipid lowering treatment, and 
have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 100 mg/dL (2.59 mmol/L), the 
superior efficacy of bococizumab compared with placebo in reducing the risk of adjudicated 
and confirmed key secondary endpoints (as defined in Appendix 4) of: 

A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;

A composite endpoint of all-cause death,  non-fatal MI, non-fatal stroke, and 
hospitalization for unstable angina needing urgent revascularization;

A composite endpoint of all-cause death, non-fatal MI and non-fatal stroke;

Hospitalization for unstable angina needing urgent revascularization.
Additional clinical secondary objectives are to evaluate, in subjects with high or very high 
risk of major CV events, who are on background lipid lowering treatment, and have an 
LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 100 mg/dL (2.59 mmol/L), the efficacy 
of bococizumab compared with placebo in reducing the risk of other adjudicated and 
confirmed secondary endpoints (as defined in Appendix 4) of:

A composite endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalization 
for unstable angina;

CV death;

Any MI (fatal and non-fatal);

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
Fatal MI;

Non-fatal MI;

Any stroke (fatal and non-fatal);

Any stroke (fatal and non-fatal) of any etiology;

Fatal stroke;

Non-fatal stroke;

Hospitalization for unstable angina;

Hospitalization for congestive heart failure (CHF);

Any coronary revascularization procedure;

Coronary artery bypass graft surgery (CABG);

Percutaneous coronary intervention (PCI);

Any arterial revascularizations;

All-cause death.
Circulating Biomarker Objectives
A circulating lipid biomarker secondary objective is to evaluate bococizumab compared with 
placebo, for LDL-C, with respect to the percent change and nominal change from baseline at 
Week 14 and the percent change from baseline to the last available post randomization value 
of LDL-C (direct measure).
Additional circulating lipid biomarker objectives are evaluating the percent change from 
baseline at Week 14 in:

Non-HDL-C;

Total cholesterol;

Very low density lipoprotein cholesterol (VLDL-C);

Remnant lipoprotein cholesterol (RLP-C);

Apolipoprotein B (apo B);

Lipoprotein(a) (Lp(a));

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
Triglycerides;

HDL-C;

Apolipoprotein A-I (apo A-I).
The sole circulating inflammatory secondary objective is to evaluate bococizumab compared 
with placebo, for high sensitivity C-reactive protein (hs-CRP) with respect to its percent 
change from baseline at Week 14.
Health Care Resource Utilization Objectives
Health care resource utilization objectives include comparing bococizumab to placebo with 
respect to the following:

Incidence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition for all-cause 
hospitalizations;

Incidence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition for CV 
hospitalizations;

Incidence of emergency room visits;

Incidence of physician office visits;

Incidence of outpatient rehabilitation visits;

Incidence of all-cause hospitalizations within 30 days of a previous hospitalization, 
primary and secondary discharge diagnoses, length of stay, and discharge disposition;

Incidence of CV hospitalizations within 30 days of a previous hospitalization, 
primary and secondary discharge diagnoses, length of stay, and discharge disposition.
Safety Objectives
Safety objectives are to describe the safety, tolerability, and immunogenicity of bococizumab
and placebo, including assessments of adverse events (including Type 1 and 
3 hypersensitivity reactions and injection site reactions), serious adverse events, vital signs, 
physical and neurological examinations, cognitive testing, 12-lead electrocardiogram (ECG) 
recordings, and safety laboratory tests including hematology, urinalysis, blood chemistry 
studies, and anti-drug antibody (ADA) assessments.  See Section 7.2 for details.
Study Endpoints (refer to Section 2.2 for complete list and Appendix 4 for clinical endpoint 
definitions)

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Primary Endpoint
The primary endpoint is defined as the time from randomization to the first adjudicated and 
confirmed occurrence of a major CV event, a composite endpoint that includes CV death, 
non-fatal MI, non-fatal stroke, and hospitalization for unstable angina needing urgent 
revascularization.
Key Secondary Endpoints
Key secondary endpoints are defined as the times from randomization to the first adjudicated 
and confirmed occurrence of:

A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;

A composite endpoint of all-cause death, non-fatal MI, non-fatal stroke, and 
hospitalization for unstable angina needing urgent revascularization;

A composite endpoint of all-cause death, non-fatal MI and non-fatal stroke;

Hospitalization for unstable angina needing urgent revascularization.
Other Secondary Clinical Endpoints
The times from randomization to the first adjudicated and confirmed occurrence of the 
following endpoints:

A composite endpoint of CV death, non-fatal MI, and non-fatal stroke, and 
hospitalization for unstable angina;

CV death;

Any MI (fatal and non-fatal);

Fatal MI;

Non-fatal MI;

Any stroke (fatal and non-fatal);

Any stroke (fatal and non-fatal), of any etiology;

Fatal stroke;

Non-fatal stroke;

Hospitalization for unstable angina;

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
Hospitalization for congestive heart failure (CHF);

Any coronary revascularization procedure;

CABG;

PCI;

Any arterial revascularizations;

All-cause death.
Other Secondary Circulating Biomarker Endpoints
The LDL-C biomarker endpoints are the percent change and nominal change from baseline at 
Week 14 (Visit 8) and the percent change from baseline to the last available 
post-randomization value of LDL-C (direct measure).
Other lipid endpoints include the percent change from baseline at Week 14 (Visit 8) in levels 
of:

Non-HDL-C;

Total cholesterol;

VLDL-C;

RLP-C;

Apo B;

Lp(a);

Triglycerides;

HDL-C;

Apo A-I.
Inflammatory Biomarker Endpoint
The sole inflammatory biomarker endpoint is the percent change from baseline at Week 
14 (Visit 8), in levels of hs-CRP.
Health Care Resource Utilization Endpoints
Health care resource utilization endpoints being evaluated include:

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
The occurrence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition, of all-cause 
hospitalizations;

The occurrence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition, of CV 
hospitalizations;

The occurrence of emergency room visits;

The occurrence of physician office visits;

The occurrence of outpatient rehabilitation visits;

The occurrence of all-cause hospitalizations within 30 days of a previous 
hospitalization, primary and secondary discharge diagnoses, length of stay, and 
discharge disposition;

The occurrence of CV hospitalizations within 30 days of a previous hospitalization, 
primary and secondary discharge diagnoses, length of stay, and discharge disposition.
Safety Endpoints
Safety endpoints include investigator reported adverse events, (including Type 1 and 
3 hypersensitivity reactions and injection site reactions), serious adverse events, vital signs, 
examination observations (physical and neurological examinations and cognitive testing), 
12-lead ECG recordings, and safety laboratory tests, including hematology, blood chemistry 
studies (including liver function tests and creatine kinase tests), urinalysis studies, and ADA 
assessments.  See Section 7.2 for details.
Study Design (details found in Section 3)
This is an event driven, Phase 3 multi-center, double-blind, randomized parallel group 
evaluation of the efficacy, safety, and tolerability of bococizumab compared with placebo, in 
reducing the occurrence of major CV events in subjects at risk, who are on background lipid 
lowering treatment and have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 
100 mg/dL (2.59 mmol/L).  After obtaining informed consent, there will be a pre-screening 
visit.  At this visit subjects will have consented to have had lipid levels assessed and to 
provide medical records for review, only, so as to determine if the subject qualifies for this 
study.  The interactive response technologies (IRT) system will determine if the subject is 
eligible for the study or if the subject should be screen failed.  This will be followed by a 
screening visit, within 30 days, and a run-in period of up to 6 weeks, during which subjects 
will be fully assessed with respect to the trial enrollment criteria and compliance with the 
self-administration of subcutaneous injections.  The run-in period will be followed by the 
treatment period, the duration of which will be determined by the number of subjects with 
primary endpoint events, and concluded by a safety follow-up period, as illustrated in the 
schematic below.

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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Study Schematic
Approximately 85,000 subjects may be screened and approximately 17,000 subjects will be 
randomized.  The trial is intended to complete when approximately 844 subjects have 
accrued adjudicated and confirmed primary endpoint events, or 12 months following the 
randomization date of the last subject, whichever occurs later.  The duration of the trial is 
expected to be approximately 4.8 years (see Section 9.1).  The End of Study (EOS) will be 
announced to study sites, when the Sponsor estimates that criteria for stopping the study in 
Section 3 have been satisfied. EOS visits should be scheduled as soon as possible, after that 
announcement. The EOS visit should occur no sooner than 14 days after the last dose of 
investigational product (IP) was administered. The safety follow-up period is 40 days after 
the last dose of IP was administered.  If the EOS visit has taken place earlier than 40 days 
after the last dose of IP administration, subjects will receive a telephone call to determine if 
any serious adverse events have occurred.  All EOS procedures should be done for all 
randomized subjects when the study is completed, whether or not the subject is taking 
double-blind investigational product, when the study is terminated.
The sample size may be modified to shorten the expected duration of the trial or to improve 
the likelihood of attaining 70% power for the key secondary composite endpoint of CV 
death, non-fatal MI and non-fatal stroke. Prior to the end of enrollment, blinded assessments 
will be made of the expected duration of the trial and of the power for this endpoint, 
assuming a hazard ratio (HR) of 0.8 at a two-sided alpha of 0.05. The decision to make 
either or both modifications will be documented in the Trial Master File.  If the modification 
for the key secondary endpoint is made, the trial would be intended to complete when 
approximately 844 subjects have accrued adjudicated and confirmed primary endpoint 
events, 496 subjects have accrued adjudicated and confirmed events of the above key 
secondary endpoint, or 12 months following the randomization date of the last subject, 
whichever is last.
In addition, the sample size in certain subgroups, including diabetic subjects with no prior 
CVD event, may be modified or the trial duration may be extended to improve the likelihood 
that the estimated hazard ratios in the subgroups are less than one.  Prior to the end of 
enrollment, the sponsor will perform a blinded assessment of the probabilities, assuming a 
hazard ratio of 0.8.  If one or more of the probabilities are too small, the number of subjects 
in the corresponding subgroups may be modified, possibly increasing the total enrollment to 
do so.  Prior to the end of the study, the sponsor will include a second blinded assessment of 
the probabilities.  If one or more of these probabilities are too small, the duration of the trial 

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 20
may be extended.  If the latter modification is made, the criterion for stopping the trial will 
include accruing 58 primary endpoint events in the corresponding subgroups.  These 
decisions will be documented in the Trial Master File.
Because the trial is designed to assess the effect of PCSK9 inhibition on recurrent as well as 
first clinical events, it is expected that subjects who sustain a clinical event will remain on 
their assigned treatment and continue in the study, unless the investigator chooses to 
withdraw the subject or the subject declines continued participation in the study.
Potential endpoint events will be adjudicated by an independent and blinded adjudication 
committee.  Subject safety will be monitored by an independent data monitoring committee 
(DMC).  An independent statistical data analysis center will provide analyses to the DMC 
according to the DMC charter
Study Treatments
Subjects will be randomized to bococizumab 150 mg or placebo Q2wks in a 1:1 ratio.  
Randomization will be stratified by geographic region and LDL-C at the pre-screening visit 
(< 100 mg/dL, 100 mg/dL).  Subjects will self-inject, or if unable to self-inject, have 
investigational product administered by a caregiver (eg, a family member or health care 
assistant).
Statistical Methods and Sample Size Determination
Data analyses and statistical methods are described in Section 9.  A more detailed 
methodology for summary and statistical analyses of the data collected in this study will be 
documented in a Statistical Analysis Plan (SAP), which will be maintained by the sponsor. 
A sample size estimate of 17,000 randomized subjects (8,500 on bococizumab and 8,500 on 
placebo) has approximately 90% power to detect a 20% reduction in the risk of experiencing 
the primary endpoint, by means of a two-sided α = 0.05 log rank test.  The required number 
of subjects with an adjudicated and confirmed event is 844.  The sample size calculation is 
based on an annual event rate of 2.3% and a premature study discontinuation rate of 1% per 
year.  Assuming that the trial will recruit in 3.1 years, with approximately 50% of the 
subjects in the last ten months, the study will finish in another approximately 1.7 years, for 
trial duration of approximately 4.8 years.  These results were derived via the software 
package EaST® (version 6.3.1).
As above, the sample size may be modified to shorten expected the duration of the trial or to 
improve the likelihood of attaining 70% power for the key secondary composite endpoint of 
CV death, non-fatal MI and non-fatal stroke. In addition, the sample size in certain 
subgroups, including diabetic subjects with no prior CVD event, may be modified or the trial 
duration may be extended to improve the likelihood that the estimated hazard ratios in the 
subgroups are less than one.  As any adjustment to the sample size or duration of follow-up 
will be based on blinded data, the distribution of the test statistic for the primary analysis 
under the null hypothesis will not be affected and no alpha adjustment will be made.

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
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Primary Endpoint Event Rate Estimate
Given the power and the alpha level, the expected duration of the trial will be driven by the 
assumed rate of accrual of adjudicated and confirmed primary endpoint events in the placebo 
group, the assumed hazard ratio, the subject accrual rate and the premature study 
discontinuation rate.  To produce an estimate of the primary endpoint event rate in the 
placebo group, meta-analyses, published and unpublished, were considered and a review of 
lipid lowering clinical trial literature was conducted (Section 9.1.3).  These trials vary 
considerably with respect to their temporal execution, background cardioprotective 
medications, and differences in enrichment of various risk factors, any of which may impact 
CV event rates.  Furthermore, the component of the primary endpoint for the present study, 
hospitalization for unstable angina needing urgent revascularization did not appear to be a 
predefined component of the trials that were reviewed, some of which had endpoint 
components comprising hospitalization for unstable angina, irrespective of the need for 
revascularization, and for other clinical trials, revascularization rates were reported 
separately, as a secondary endpoint.
Given the uncertainty of the primary endpoint event rate in the placebo group, and 
enrichment of the study population with diabetic subjects without a prior CVD event who 
have a lower primary endpoint rate than the rest of the population, estimates of trial duration 
and event accrual will assume a placebo event rate of 2.3%/year, which is, slightly less than 
the lower bound of the 80% prediction interval for the estimated placebo event rate for 
baseline LDL-C of 80 mg/dL (2.1 mmol/L) from a unpublished meta-analysis. 
Efficacy Analysis
The primary analysis set for efficacy analyses will be the Full Analysis Set, which includes 
all randomized subjects and all post-randomization data.  The primary endpoint will be 
analyzed using a log rank test stratified by geographic region and LDL-C at the pre-screening 
visit (<100 mg/dL, 100 mg/dL) and a two-sided α=0.049 after a single Bonferroni 
adjustment for DMC reviews of all-cause death (see Section 9.6).  The hazard ratio and a 
95% confidence interval will be reported from a Cox proportional hazards model stratified by 
geographic region and LDL-C at the pre-screening visit (<100 mg/dL, 100 mg/dL) with 
treatment group as a covariate.  Kaplan-Meier estimates will be plotted.
A gatekeeping procedure will be applied; the key secondary endpoints will be formally tested 
only if the null hypothesis for the primary analysis is rejected (See Section 9.2.2 for details).  
A fixed sequence testing procedure with a two sided =0.049 will be applied for the key 
secondary endpoints.  Aside from the alpha level, the methodology for the key secondary 
endpoints will be the same as that for the primary endpoint.  The methodology for the 
remaining clinical endpoints will be identical to that for the primary endpoint except that an 
alpha=0.05 will be used.
Percent and/or nominal changes from baseline in circulating biomarkers, as indicated in the 
objectives, will be analyzed using a mixed model repeated measures (MMRM) model with 
fixed effects for treatment, scheduled visit time point (categorical), baseline value, interaction 

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 22
between the baseline value and scheduled visit time point, interaction between the treatment 
and scheduled visit time point and geographic region.  An unstructured covariance matrix 
will be used.  Estimates of the treatment group means and mean treatment group differences 
at each visit with corresponding 95% confidence intervals will be reported, as will the 
p-values for the mean treatment group differences.  The estimated treatment group means and 
the corresponding 95% confidence intervals will be plotted.  For Lp(a), triglycerides and 
hs-CRP, the same model will be fit for log-transformed data.  The estimated treatment group 
means and corresponding 95% confidence intervals will be transformed to percent changes 
for reporting.  The estimated treatment group differences will be transformed to the ratio of 
the mean percent changes and reported with 95% confidence intervals along with p-values.  
The estimated mean percent changes and corresponding 95% confidence intervals will be 
plotted.
Safety Analysis
Safety will be assessed through adverse events (including Type 1 and 3 hypersensitivity 
reactions and injection site reactions), serious adverse events, vital signs, examination results
(physical and neurologic examinations and cognitive testing),  12-lead ECG recordings, and 
safety laboratory tests including hematology, blood chemistry studies (including liver 
function tests and creatine kinase tests), urinalysis studies, and ADA assessments.  The 
Safety Analysis Set (SAS) includes all subjects who have received at least one dose of 
randomized study medication and will be used for all safety analyses, unless otherwise 
specified.  All summaries of safety data will be descriptive only, unless indicated otherwise.  
Details of the safety analysis are found in Section 9.4.

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Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 23
SCHEDULE OF ACTIVITIES
The Schedule of Activities Flowchart provides an overview of the protocol visits and 
procedures.  Refer to STUDY PROCEDURES and ASSESSMENTS sections of the protocol 
for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (designated in this protocol as unscheduled visits) in
addition to those listed on the schedule of activities, in order to conduct evaluations or 
assessments required to protect the well-being of the subject.

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 24
Visit Schedule/Flowchart:
Study Period
Pre
Scr
Run in period
R
VISITS1
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
EDC28/EOS29
Week1
NA
NA
-6
-4
-2
0
4
8
14
26
40
52
70
86
104
122
140
156
174
192
208
Informed Consents1
X
X
Contact IRT2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical hx/Demog.
X
Inclusion/exclusion 
X
X
X
X
Counseling3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs,T, BP/PR4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Exam5
X
X
X
X
X
X
Cognitive assessment6
X
X
X
X
X
X
12 Lead ECG7
X
X
X
X
X
X
Laboratory
Chemistry Group8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Liver function9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatine kinase10
X
X
X
X
X
X
X
ADA/PK/PCSK911
X
X
X
X
X
X
X
X
X
X
Hematology12
X
X
X
X
X
X
X
Urinalysis13
X
X
X
X
X
X
X
Pregnancy Test14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biospecimens15
X
X
Lipid Profile16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Special Studies17
X
X
X
X
HbA1c18
X
X
X
Hepatitis19
X
X
Dispense IP20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Injection in clinic20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Con Med  Check21
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Event/SAE 
Collection22
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Potential Endpoint 
Assessment22
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Compliance Check23
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Contraception Chk.24
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D assessment25
X
X
X
X
X
X
X
X
PHQ-2/PHQ-926
X
X
X
X
X
X
HCRU assessment27
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 25
Key: Pre=pre-screening visit; Scr = screening; R = randomization visit; EDC = early discontinuation of investigational product; EOS = End of 
Study/Study Completion; IRT= Interactive Response Technology System; T = temperature; BP=blood pressure; PR=pulse rate; hx= history;
ECG=electrocardiogram; ADA/PK/PCSK9=anti-drug antibody/pharmacokinetic; and PCSK9 sampling; IP=investigational product; Con 
Med=concomitant medication; EQ-5D= EuroQol Group quality of life assessment; HCRU=health care resource utilization; PHQ-2/PHQ-9 = 
patient health questionnaire for depression; Chk.= check
Footnotes:
1.
Visit Schedule:  
Visits should be scheduled by the numbered weeks above.
Subjects should be fasting for at least 10 hours prior to all visits during which fasting blood samples will be collected, with the following exceptions.  
Unscheduled assessments limited to measures of creatine kinase (CK), liver function tests (including alanine amino transferase [ALT], aspartate amino 
transferase [AST], alkaline phosphatase, and total and direct bilirubin), hepatitis C polymerase chain reaction (PCR), or pregnancy testing, do not require 
fasting.  At Visit 0, where required, or where pre-clinic visit fasting is not the general practice, subjects will need to return for Visit 0 blood sampling, at a 
subsequent unscheduled visit, so that 10 hour fasting only takes place after informed consent has been obtained.  Subjects are permitted to take concomitant 
medications, on the morning of a visit, taken as prescribed with water. When a subject has missed a scheduled visit, every attempt should be made to contact 
him/her, to reschedule the visit, by phone, e-mail, text message, and if necessary, by letter and/or certified mail, in instances where the subject is not 
responsive to contact attempts.
Informed consent:
The subject should be consented prior to any pre-screening procedures being completed at Visit 0.  A study specific informed consent will be obtained at 
Visit 1, the screening visit if not obtained previously.  Some study sites may have alternative informed consent requirements as specified by their 
institutional review board (IRB)/ethics committee (EC), but the general principle is that informed consent must have been obtained prior to the conduct of 
any study procedure.
Visit 0, Pre-screening visit:
A pre-screening visit will be conducted to collect data which will help the investigator ascertain if a potential subject qualifies for this study.  The subject 
should be consented prior to any pre-screening procedures being completed at Visit 0.  At this visit, subjects will have consented to have had lipid levels 
assessed and provide medical records for review, only, so as to determine if the subject qualifies for this study.  The investigator will register the subject in 
the Interactive Response Technology (IRT) system. At Visit 0, where required, or where pre-clinic visit fasting is not the general practice, subjects will need 
to return for Visit 0 blood sampling, at a subsequent unscheduled visit, so that 10 hour fasting only takes place after informed consent has been obtained.  No 
data for the subject will be recorded in the pre-randomization visit case report form (CRF) until the cholesterol laboratory results are received, unless the 
subject experiences an AE or SAE
The time interval between the Pre-screening Visit (Visit 0), and Visit 1 is a maximum of 30 days.
Visit 1:
Visit 1, the screening visit, should be scheduled after the pre-screening data (lipid results and medical records) are available to ascertain eligibility for the 
study.  Study-specific informed consent should be obtained at Visit 1 before all other procedures, if not obtained previously.  Starting at Visit 1, study 
centers should attempt to schedule each subject’s visits at the same time of day, and day of the week for that subject, if possible.  Visits should be scheduled 

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 26
based on the week in the Schedule of Activities table and coordinated with the subject’s dosing schedule, so that the visit day is coordinated with a subject’s 
relevant dose day, if possible.  Starting at Visit 5 (randomization/baseline visit), and all subsequent visits, if a visit coincides with a scheduled injection of 
investigational product, the injection should be performed after all other study procedures have been completed.
Lipid, ADA, PK, and PCSK9 testing requirements after randomization:
Lipid (direct LDL-C and lipid panel), ADA, PK, and PCSK9 testing, after randomization, when required, should be scheduled no sooner than 10 days after 
the subject’s prior dose, even if this requires an unscheduled visit.  If a subject has a visit that is scheduled less than 10 days after the last dose, the visit 
procedures may take place, but lipid, ADA, PK, and PCSK9 testing should be postponed and performed at the earliest possible time, at an unscheduled visit, 
no sooner than 10 days after the subject's last dose.  A lipid profile will not be collected at EDC/EOS visits.  ADA, PK, and PCSK9 samples will be collected 
at EDC/EOS visits.
Visit windows: 
The run-in period is of up to 6 weeks duration, starting at Visit 2, so that there is some flexibility for scheduling the subjects.  The run-in visits should take 
place no less than 7 and no more than 14 days apart.  The run-in period continues until Visit 5, randomization.  Visit 5 should be scheduled no more than 
14 days after Visit 4, the final run-in visit.
After Visit 5, all visits will have a visit window 14 days, except for Visits 8 (the Week 14 visit), 11 (the Week 52 visit), both which will have visit window 
of 3 days, and EDC/EOS visits, which will not have visit windows.  It will be important to ascertain that the lipid level testing requirement stated above, is 
met.
Dosing windows:
After randomization, investigational product dosing windows are 1 day before or up to 4 days after the scheduled dosing date.  If more than 4 days after the 
scheduled day have passed, the subject should skip the dose and resume dosing following the dosing schedule provided by site personnel for the next 
injection.
Visit 2, start of run-in: Run-in Visit 2 can occur up to 14 days after Visit 1, depending upon the availability of Visit 1 lab results, additional medical records, 
if they are needed, and the schedule of the subject and clinical site. At Run-in Visit 2, the initiation of the run-in period, the subject will be shown how to 
self-inject investigational product (placebo).  Only during the run-in period (Visits 2, 3, and 4), subjects will be seen up to two weeks apart, to ascertain the 
subjects’ ability to self-inject investigational product.  The other run-in procedures specified in this Schedule of Activities will be adhered to.
Visit sequences: After Visit 5 (Week 0) subjects will be seen at Visit 6 (Week 4), Visit 7 (Week 8), Visit 8 (Week 14), Visit 9 (week 26), Visit 10 (week 
40), and Visit 11 (week 52).  After Visit 11, subjects will be seen, as indicated in the Schedule of Activities, until study completion (EOS).  Subjects who 
discontinue investigational product early (EDC), will be encouraged to be followed, according to the visit schedule and activities, until study completion 
(EOS).  If the study is not completed by Visit 20, visits will continue in accordance with the Schedule of Activities for annual (Visits 11, 14, 17, 20) and 
interim visits (eg, Visits 12, 13, 15, 16, 18, and 19), until study completion (EOS).  The study may end sooner than Visit 20, if the primary endpoint event 
accrual rate is faster than anticipated or the trial is terminated for other reasons.  Subjects who have had an investigational product (IP) dose frequency 
modification to dosing every 4 weeks, will need to have their visit frequency increased to every 8 weeks, approximately, for the purposes of direct LDL-C 
measurement and an assessment for adverse events, both serious and non-serious (Section 6.4.5).  If the per-protocol scheduled visit falls within the 8 week 
window, the scheduled visit will reset the scheduling of the next 8 week direct LDL-C measurement visits.
2.
IRT.  The subjects’ visits will be registered at Visit 0 and every visit thereafter, unless they have discontinued treatment with investigational product.
3.
Counseling: drug self-injection counseling and therapeutic lifestyle change counseling (diet, exercise) as per NCEP-ATP III or ESC/EAS guidelines or per 
local medical practice.

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Final Protocol Amendment 2, 12 February 2016
Page 27
4.
Vital Signs: Vital signs (temperature, pulse rate and blood pressure) shall be recorded at each visit, except for Visits 2, 3, and 4 (unless clinically indicated),
as described in Section 7.2.3.1.
5.
Physical Exam:  Periodic examinations, including a physical exam and basic neurology exam will be performed at baseline (Visit 5), annually, and at the 
EDC or EOS visit.  The physical exam will include the measurement of weight, height and waist circumference at Visit 5 (Section 7.2.3.2.1).  Waist 
circumference will also be measured at EOS or EDC.  Whenever a physical exam is performed, it must include the measurement of weight and a basic 
neurology exam as described in Section 7.2.3.2.
6.
Cognitive Testing:  Cognitive testing will be performed in a subset of designated North American (U.S. and Canada) study sites, at baseline (Visit 5), 
annually, and EDC or EOS visits only as described in Section 7.2.3.4.
7.
ECG: Regularly scheduled ECGs are to be recorded locally, anonymized, saved in the study file, and a copy of the ECG should be sent to the study central 
ECG file for storage.  If a subject experiences a nonfatal adjudicated and confirmed CV event after randomization, a new baseline ECG should be performed 
following the event.  It may be done at a regularly scheduled visit if the visit is to occur within that time frame.  If not, a new ECG should be performed at an 
unscheduled study visit.
8.
Chemistry Group: At indicated visits only: sodium, potassium, chloride, bicarbonate, creatinine, blood urea nitrogen (BUN; serum urea), glucose.  All 
chemistry studies are to be performed by central laboratory.
9.
Liver function tests:  Liver function tests, including ALT, AST, alkaline phosphatase, and total and direct bilirubin, should be performed at the designated 
visits.  Unscheduled visits for reassessing liver function test abnormalities may be required (Section 8.6.2 and Appendix 8) and do not require fasting.
10. Creatine Kinase:  Scheduled CK tests are only drawn at screening, baseline, and, annually thereafter.  If a subject complains of muscle discomfort at a visit, a 
CK level should be drawn.  If at any time a CK level is > 5X the upper limit of normal (ULN), an unscheduled visit should be scheduled for a repeat CK, 
within 48 hours if possible, with CK fractionation for isozymes (to assess CK-MM and CK-MB) and urine dipstick.  Unscheduled measurements of CK do 
not require fasting.  See Section 7.2.5, Section 7.6 and Appendix 7.
Prior to obtaining blood for a CK assessment, investigators should enquire about recent intramuscular injections, heavy exercise, or recent musculoskeletal 
trauma, and defer CK testing until the next visit or repeat testing at an unscheduled visit, no less than 7 days after the IM injection or musculoskeletal 
trauma, so as to avoid spuriously elevated values.
11. ADA/PK/PCSK9 sampling: Anti-drug antibody (ADA), bococizumab drug, and PCSK9 blood samples should be collected in all subjects, at the baseline and 
designated visits as described in Section 6. For Visit 3, only a PCSK9 sample is needed.  No PK or ADA sample is needed at Visit 3.  After randomization, 
if lipid sampling has been postponed to an unscheduled visit, the corresponding ADA/PK/PCSK9 samples should be postponed as well, and collected at the 
same time as the rescheduled lipid sample collection.  ADA, PK, and PCSK9 samples will be collected at EDC/EOS visits.
12. Hematology: Complete blood count (CBC) with white blood cell (WBC) and red blood cell (RBC) counts, hemoglobin, hematocrit, WBC differential and 
platelet count.  All hematology studies are to be performed by central laboratory.
13. Urinalysis: Dipstick urinalysis will be performed by study site, locally.  Details describing what is evaluated in the urinalysis are described in 
Section 7.2.1.2, Table 2.  At the screening visit a central lab urine albumin/creatine ratio assessment may be evaluated, in subjects who have had a 
cardiovascular event more than 5 years prior to screening and in subjects without a prior qualifying cardiovascular event.
14. Pregnancy Test: A woman is of childbearing potential if, in the opinion of the investigator, she is biologically capable of having children, with her partner,
and is sexually active (Section 4.1, inclusion criterion 8).  For women of childbearing potential, serum pregnancy tests, performed at the central laboratory, 
and urine pregnancy tests, tested locally, are performed at the screening visit (Visit 1), before investigational product administration at the baseline visit
(Visit 5), at all visits after randomization, and at the EDC/EOS visit.  Subjects who have missed a menstrual period or who show an indeterminate or positive 

Bococizumab
Protocol B1481022
Final Protocol Amendment 2, 12 February 2016
Page 28
result on the urine test may not further progress in the study until pregnancy is ruled out using further diagnostic testing (eg, a negative quantitative serum 
pregnancy test conducted at the central laboratory).  At all visits, a negative urine pregnancy result is required before the subject may receive the 
investigational product.  In the case of a positive confirmed pregnancy, the subject will be withdrawn from study medication but may remain in the study.  In 
addition, pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active treatment period (or when potential pregnancy is 
otherwise suspected).  Pregnancy tests may also be repeated as per request of IRBs/ECs or if required by local regulations.  Unscheduled visits for pregnancy 
testing do not require fasting.
15. Biospecimens: Banked biospecimen collection will include a 4 mL whole blood specimen at Visit 5, and 10 mL blood samples processed to plasma at Visits 
5 and 11, as specified in Section 7.5.
16. Lipid profile: The fasting lipid profile includes total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), 
very low density lipoprotein cholesterol (VLDL-C), remnant lipoprotein cholesterol (RLP-C), and triglycerides, performed by a central laboratory.  After 
randomization lipid level tests should be scheduled no sooner than 10 days after the subject’s prior dose, even if this requires an unscheduled visit.  If a 
subject has a visit that is scheduled less than 10 days after the last dose, the visit procedures may take place, but lipid testing should be postponed and
performed at the earliest possible time, at an unscheduled visit, no sooner than 10 days after the subject's last dose.  Subjects who have had an IP dose 
frequency modification to dosing every 4 weeks, will need to have their visit frequency increased to every 8 weeks, approximately, for the purposes of direct 
LDL-C measurement.  A lipid profile will not be collected at EDC/EOS visits.
17. Special Lipid and Efficacy Assessments:  At the screening visit hs-CRP and Lp(a) assessment may be evaluated, in subjects who have had a cardiovascular 
event more than 5 years prior to screening and in subjects without a prior qualifying cardiovascular event.  Apolipoprotein (apo) B and apo A-I will not be 
collected at the screening visit.  Special lipid and efficacy blood samples will be collected in all subjects, at Visits 5, 8, and 11, for apo B, apo A-I, Lp(a), and 
hs-CRP, as described in Section 6, and measured by a central laboratory.
18. HbA1c: HbA1c will be collected, for all subjects, at baseline, Visit 11, and EDC or EOS.  HbA1c may be collected at any time, at an unscheduled visit, if 
necessary for additional safety assessments, as determined by the investigator.
19. Viral hepatitis serologies. Hepatitis B and hepatitis C virus screening serologies will be collected at Visit 1 in all subjects and evaluated as per Appendix 3.  
Hepatitis C virus serologies will be collected at the EDC/EOS visit only for subjects from study sites in Canada.  A positive or indeterminate hepatitis C 
serology may trigger a hepatitis C polymerase chain reaction (PCR) test for confirmation.  Unscheduled visits for hepatitis C PCR testing do not require 
fasting.
20. Dispense investigational product:  Investigational product will be dispensed as designated in the table.  During the run-in period (Visits 2, 3, and 4) subjects 
will self-administer or be administered study drug by a caregiver, during the study visit.  At Visit 5, Subjects will be observed during injection of 
investigational product, either by self-injection, or as performed by a care giver and observed for a period of 30 minutes, to determine if any signs or 
symptoms develop.  The observation period may be extended, if any signs or symptoms become apparent.  After Visit 5, the randomization visit, study sites 
should try to coordinate the visit schedule with the subject’s dosing schedule, when possible.  After study procedures are completed, at each visit, subjects 
should self-inject investigation product only after blood samples have been collected and the physical exam has been performed.
21. Con Med Check:  Concomitant medication assessment, including assessment of background lipid lowering medication (see Section 5.8).
22. Adverse events and Potential Endpoint Assessments:  Adverse events (AEs) will be reported at every visit.  Serious adverse events (SAEs) events will be 
reported from the time of informed consent (see Section 8.2).  Potential disease-related efficacy endpoint assessment will be done at every visit after 
randomization.

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23. Compliance Check:  The subject’s compliance with investigational product administration will be assessed as described in Section 5.3.  After the 
randomization visit, subjects will be directed to bring any used and unused syringe cartons to each visit.  Used syringes will be returned to the study center in 
a biohazard container, as needed.  Compliance with lifestyle guidelines should also be reviewed (Section 4.4) and recorded in the CRF.
24. Contraception Check:  A contraception check should be made for male and female subjects, who, with their partner(s), are of childbearing potential 
(Section 4.4.2).
25. EQ-5D:  EuroQol Group quality of life (EQ-5D) assessments (Section 7.3.1) at visits 5, 8, 9, 11, 14, 17, 20, and EDC or EOS.
26. Patient Health Questionnaire:  A Patient Health Questionnaire 2 (PHQ-2) will be performed at Visit 5 (Section 7.3.2), in all subjects, and in the subset of 
subjects with cognitive assessments, only, it will also be performed annually, and at EDC or EOS.  If at the baseline PHQ-2 assessment, a subject scores 2, 
the remaining 7 questions of the PHQ-9 will be answered.  If the PHQ-9 score is 10, the subject should be referred back to his/her primary care physician 
for further assessment and/or treatment of potential major depression.  If the PHQ-9 score is 15 or there is a positive score in question 9, the subject should 
be excluded from participation, the subject’s primary care physician (PCP) should be informed, and the subject should be referred to a mental health 
professional, either by the PCP or the investigator.  Such subjects may be rescreened, at a later date, if they were evaluated and treated as appropriate, and 
the repeat PHQ scores permit inclusion.  Any adverse events should be documented in the case report form as appropriate. 
Only subjects participating in the cognitive assessment sub-study will have annual, and end of treatment or end of study PHQ assessments, in addition to the 
baseline assessment.  If at any the visits after the baseline assessment, a subject scores 2, the remaining 7 questions of the PHQ-9 will be answered.  If the 
PHQ-9 score is 10, consideration should be given to referring the subject back to his/her primary care physician for further assessment of potential major 
depression and recommendations.  If the PHQ-9 score is 15 or there is a positive score in question 9, the subject’s primary care physician (PCP) should be 
informed, and the subject should be referred to a mental health professional, either by the PCP or the investigator.  Any adverse events should be 
documented in the case report form as appropriate.
27. Health care resource utilization:  Subjects will be queried for hospitalizations, emergency room visits, and physician office visits, and the appropriate CRFs
completed.
28. Early discontinuation (EDC) procedures should be done upon the permanent early discontinuation of double-blind investigational product.  Study sites must 
contact the study retention team, or delegate, or EDC retention hotline (by telephone or email) for all potential or actual EDC subjects.  Subjects should 
continue to have visits (either in person or via phone visit) with study personnel according to the study schedule until study completion.  Subjects who 
continue in the study, after EDC, should also complete EOS procedures, at the time of study completion.
29. The EOS visit will be announced to study sites, when the Sponsor estimates that criteria for stopping the study in Section 3 have been satisfied. EOS visits 
should be scheduled as soon as possible after that announcement.  The EOS visit should occur no sooner than 14 days after the last dose of investigational 
product was administered for subjects taking IP.  The safety follow-up period is 40 days after the last dose of IP was administered.  If their EOS visit has 
occurred less than 40 days after the last dose of IP was administered, subjects should be contacted by telephone to determine if any serious adverse events 
have occurred.  All EOS procedures should be done for all randomized subjects when the study is completed, whether or not the subject is taking 
double-blind investigational product.

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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................36
LIST OF FIGURES .................................................................................................................36
APPENDICES .........................................................................................................................36
1. INTRODUCTION ...............................................................................................................37
1.1. Indication.................................................................................................................37
1.2. Background and Rationale ......................................................................................37
1.2.1. Overview of the Disease State....................................................................37
1.2.2. Rationale.....................................................................................................38
1.2.3. Summary of Safety from Completed Studies with Bococizumab..............40
1.2.4. Benefits and Risks of Participation.............................................................40
1.2.5. Interim Analysis from Study B1481015.....................................................40
1.2.6. Rationale for Dose Selection ......................................................................41
1.2.6.1. For subjects with LDL-C 70 mg/dL (1.81 mmol/L) and 
< 100 mg/dL (2.59 mmol/L)..............................................................42
1.2.6.2. For subjects with LDL-C 100 mg/dL (2.59 mmol/L) ............42
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................43
2.1. Objectives................................................................................................................43
2.1.1. Primary Objective.......................................................................................43
2.1.2. Secondary Objectives .................................................................................43
2.1.2.1. Clinical Secondary Objectives ..................................................43
2.1.2.2. Circulating Biomarker Secondary Objectives...........................44
2.1.2.3. Health Care Resource Utilization Objectives............................45
2.1.2.4. Safety Objectives.......................................................................46
2.2. Endpoints.................................................................................................................46
2.2.1. Primary Endpoint........................................................................................46
2.2.2. Key Secondary Endpoints...........................................................................46
2.2.3. Other Clinical Secondary Endpoints ..........................................................46
2.2.3.1. Circulating Biomarker Endpoints..............................................47
2.2.3.2. Health Care Resource Utilization Endpoints ............................48
2.2.4. Safety Endpoints.........................................................................................48
2.2.5. Assessment of Clinical Efficacy and Safety Endpoints..............................49

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3. STUDY DESIGN.................................................................................................................49
3.1. Number and Location of Study Sites ......................................................................51
3.2. Study Population .....................................................................................................51
3.3. Treatment Periods ...................................................................................................51
3.3.1. Pre-screening Visit......................................................................................51
3.3.2. Screening Visit............................................................................................51
3.3.3. Run-In Period..............................................................................................51
3.3.4. Active Treatment Period.............................................................................52
3.3.5. Safety follow-up period ..............................................................................52
3.4. External Committees...............................................................................................52
3.4.1. Executive Committee..................................................................................52
3.4.2. Adjudication Committee.............................................................................52
3.4.3. Data Monitoring Committee.......................................................................52
3.4.4. Steering Committee ....................................................................................53
3.4.5. Joint Leadership/Operations Committee ....................................................53
4. SUBJECT SELECTION......................................................................................................53
4.1. Inclusion Criteria.....................................................................................................53
4.2. Exclusion Criteria....................................................................................................60
4.3. Randomization Criteria ...........................................................................................64
4.4. Life Style Guidelines...............................................................................................64
4.4.1. Nutritional Counseling................................................................................64
4.4.2. Contraception..............................................................................................64
4.5. Sponsor Qualified Medical Personnel.....................................................................65
5. STUDY TREATMENTS.....................................................................................................65
5.1. Allocation to Treatment ..........................................................................................66
5.1.1. Interactive Response Technology Registration ..........................................66
5.1.2. Visit 0, Pre-screening Visit.........................................................................66
5.1.3. Visit 1, Screening Visit and Run-In Period ................................................66
5.1.4. Run-in Period Visits ...................................................................................66
5.1.5. Visit 5, Randomization Visit and Active Treatment Period.......................67
5.2. Breaking the Blind ..................................................................................................68
5.3. Subject Compliance.................................................................................................68

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5.4. Investigational Product............................................................................................69
5.4.1. Dosage Form and Packaging ......................................................................69
5.4.1.1. Dose Adjustments .....................................................................70
5.4.2. Preparation and Dispensing........................................................................70
5.5. Administration.........................................................................................................70
5.6. Investigational Product Storage ..............................................................................71
5.7. Investigational Product Accountability...................................................................72
5.7.1. Destruction of Investigational Product.......................................................72
5.8. Concomitant Medication(s).....................................................................................72
5.8.1. Lipid Lowering Medication(s)....................................................................72
5.8.1.1. Statin Intolerance.......................................................................73
5.8.2. Other Concomitant Medication(s) ..............................................................73
6. STUDY PROCEDURES .....................................................................................................73
6.1. Visit 0: Pre-screening visit ......................................................................................74
6.2. Visit 1:  Screening Visit ..........................................................................................74
6.3. Run-in Period ..........................................................................................................76
6.3.1. Visit 2:  Run-in Visit...................................................................................77
6.3.2. Visit 3:  Run-in Visit...................................................................................78
6.3.3. Visit 4:  Run-in Visit...................................................................................79
6.4. Treatment Period.....................................................................................................79
6.4.1. Visit 5 (Week 0) Randomization (Baseline) Visit......................................80
6.4.2. Visits 6 (Week 4) and 7 (Week 8) ..............................................................82
6.4.3. Visits 8, 9, 10, 12, 13, 15, 16, 18, and 19 ...................................................83
6.4.4. Visits 11, 14, 17, 20, and Early Study Discontinuation or End of 
Study Visit .......................................................................................................85
6.4.5. Visits after second dose modification of Investigational Product ..............88
6.4.6. Discontinuation of Investigational Product ................................................88
6.5. Subject Withdrawal.................................................................................................89
6.5.1. Withdrawal of Consent...............................................................................89
6.5.2. Lost to Follow-Up.......................................................................................90
6.5.3. Individual Subject Dosing Stopping Criteria..............................................90
7. ASSESSMENTS..................................................................................................................91

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7.1. Efficacy Assessments..............................................................................................91
7.1.1. Clinical Endpoints ......................................................................................91
7.1.1.1. Primary Clinical Endpoint.........................................................91
7.1.1.2. Key Secondary Clinical Endpoints ...........................................92
7.1.1.3. Other Clinical Secondary Endpoints.........................................92
7.1.2. Biomarker Efficacy Endpoints ...................................................................93
7.1.2.1. Lipid profile...............................................................................93
7.1.2.2. Special Lipid and Efficacy Assessments...................................94
7.2. Safety.......................................................................................................................94
7.2.1. Laboratory...................................................................................................94
7.2.1.1. Local Laboratory Tests..............................................................95
7.2.1.2. Central Laboratory Tests...........................................................95
7.2.2. 12-Lead Electrocardiogram ........................................................................96
7.2.3. Examinations ..............................................................................................97
7.2.3.1. Vital Signs.................................................................................97
7.2.3.2. Physical Exam...........................................................................97
7.2.3.3. Neurological Exam....................................................................98
7.2.3.4. Cognitive Testing ......................................................................98
7.2.4. Injection Site Reactions..............................................................................99
7.2.5. Creatine Kinase (CK) / Symptomatic Myopathy Monitoring ....................99
7.2.6. LDL-C monitoring....................................................................................100
7.2.6.1. LDL-C < 25 mg/dL (0.65 mmol/L).........................................100
7.2.6.2. Subjects with a History of LDL-C 10 mg/dL 
(0.26 mmol/L)..................................................................................100
7.2.7. Immunogenicity........................................................................................100
7.2.7.1. Anti-drug Antibodies...............................................................100
7.2.7.2. Hypersensitivity Types 1 and 3 Reactions ..............................101
7.3. Health-Related Quality of Life and Depression Assessments. .............................101
7.3.1. EQ-5D Health Questionnaire....................................................................101
7.3.2. Patient Health Questionnaire Depression Module....................................102
7.4. Pharmacokinetics ..................................................................................................103
7.4.1. Plasma for Analysis of bococizumab and PCSK9....................................103

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7.5. Banked Biospecimens ...........................................................................................103
7.5.1. Markers of Drug Response.......................................................................103
7.5.2. Additional Research..................................................................................105
7.6. Triggered Requirements........................................................................................105
7.7. Health Care Resource Utilization Assessments ....................................................107
8. ADVERSE EVENT REPORTING....................................................................................108
8.1. Adverse Events......................................................................................................108
8.2. Reporting Period ...................................................................................................109
8.3. Definition of an Adverse Event.............................................................................109
8.4. Medication Errors..................................................................................................110
8.5. Abnormal Test Findings........................................................................................110
8.6. Serious Adverse Events.........................................................................................111
8.6.1. Disease-Related Efficacy Endpoints.........................................................112
8.6.2. Potential Cases of Drug-Induced Liver Injury..........................................112
8.7. Hospitalization ......................................................................................................113
8.8. Severity Assessment..............................................................................................115
8.9. Causality Assessment............................................................................................115
8.10. Exposure During Pregnancy................................................................................115
8.11. Occupational Exposure .......................................................................................117
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal).............................................................................................................117
8.13. Eliciting Adverse Event Information ..................................................................117
8.14. Reporting Requirements......................................................................................117
8.14.1. Serious Adverse Event Reporting Requirements ...................................117
8.14.2. Non-Serious Adverse Event Reporting Requirements ...........................118
8.14.3. Medical Device Complaint Reporting Requirements.............................118
8.14.4. Sponsor's Reporting Requirements to Regulatory Authorities...............119
9. DATA ANALYSIS/STATISTICAL METHODS.............................................................119
9.1. Sample Size Determination...................................................................................119
9.1.1. Cognitive Testing Sample Size.................................................................120
9.1.2. Primary Endpoint Placebo Event Rate Estimate ......................................120
9.1.3. Representative Analyses of Event Rates ..................................................121

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9.1.3.1. Event Rates in Diabetics Without a Prior CVD Event............123
9.2. Efficacy Analysis ..................................................................................................124
9.2.1. Analysis of Primary Endpoint ..................................................................124
9.2.1.1. Subgroup Analyses..................................................................126
9.2.2. Analysis of Secondary Endpoints.............................................................127
9.2.2.1. Secondary Endpoints for Clinical Outcomes ..........................127
9.2.2.2. Secondary Endpoints for Circulating Biomarkers ..................129
9.3. Analysis of Other Endpoints .................................................................................131
9.3.1. Health –Related Quality of Life and Health Care Resource Use .............131
9.3.2. Analysis of Pharmacokinetic and Pharmacodynamic Endpoints .............131
9.4. Safety Analysis......................................................................................................132
9.5. Interim Analyses ...................................................................................................133
9.6. Data Monitoring Committee .................................................................................134
10. QUALITY CONTROL AND QUALITY ASSURANCE...............................................134
11. DATA HANDLING AND RECORD KEEPING ...........................................................135
11.1. Case Report Forms/Electronic Data Record .......................................................135
11.2. Record Retention.................................................................................................135
12. ETHICS............................................................................................................................136
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..........136
12.2. Ethical Conduct of the Study ..............................................................................136
12.3. Subject Information and Consent........................................................................136
12.4. Subject Recruitment ............................................................................................137
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................137
13. DEFINITION OF END OF TRIAL.................................................................................138
13.1. End of Trial in a Member State...........................................................................138
13.2. End of Trial in all Other Participating Countries ................................................138
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................138
15. PUBLICATION OF STUDY RESULTS........................................................................138
15.1. Communication of Results by Pfizer ..................................................................138
15.2. Publications by Investigators ..............................................................................139
16. REFERENCES ................................................................................................................141

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LIST OF TABLES
Table 1.
Treatments ............................................................................................................67
Table 2.
Laboratory Tests ...................................................................................................95
Table 3.
Precision Estimates for Cognitive Assessments.................................................120
Table 4.
CTTC Statin Lipid Lowering Trials and Event* Rate Estimates, %/Year.........121
Table 5.
CTTC Statin Lipid Lowering Trial Event Rates (%/year) by LDL Level..........122
Table 6.
Estimates of Expected CV Event Rates by Baseline LDL-C .............................123
LIST OF FIGURES
Figure 1.
Study B1481015 LS-Mean Treatment Difference (mg/dL) and 95% 
Confidence Interval ..............................................................................................41
Figure 2
B1481022 Study Diagram ....................................................................................50
APPENDICES
Appendix 1. Abbreviations....................................................................................................149
Appendix 2. Criteria for Diagnosis of Heterozygous Familial Hypercholesterolemia..........153
Appendix 3. Hepatitis B Assessment.....................................................................................154
Appendix 4. Clinical Endpoints.............................................................................................155
Appendix 5. Data Monitoring Committee Stopping Rules....................................................157
Appendix 6. EQ-5D Health Questionnaire............................................................................161
Appendix 7. Safety algorithm: Myopathy .............................................................................163
Appendix 8. Potential Drug Induced Liver Injury Assessment .............................................164
Appendix 8.1. Liver function assessment in subjects with normal baseline liver 
function...............................................................................................................164
Appendix 8.2. Liver function assessment in subjects with abnormal baseline liver 
function...............................................................................................................165
Appendix 9. Adverse Event and Potential Outcome Event Flowchart..................................166
Appendix 10. Categories of Cardiovascular Risk..................................................................167
Appendix 10.1. Flow Chart....................................................................................................167
Appendix 10.2. Cardiovascular Disease Risk Conditions and Risk Factors .........................168

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1. INTRODUCTION
Bococizumab (previously numbered as PF-04950615, RN-316, and J16) is a humanized 
monoclonal antibody that is a potent and selective inhibitor of proprotein convertase kexin 
(PCSK9).  Bococizumab enhances the expression of LDL receptors on hepatocytes, lowering
LDL-C levels substantially, with or without concomitant statin treatment.  It has the potential 
to be an effective therapy for patients with primary hyperlipidemia or mixed dyslipidemia,
and may reduce the occurrence of cardiovascular (CV) events. The purpose of this study is 
to establish the superior efficacy and safety of bococizumab, compared to placebo, in 
reducing the risk of major CV events in subjects at high or very high risk of incurring a CV 
event, who are on background lipid lowering therapy, and have an LDL-C 70 mg/dL 
(1.81 mmol/L) or non-HDL-C 100 mg/dL (2.59 mmol/L).
1.1. Indication
In patients at high risk of coronary events due to a history of CV disease (myocardial 
infarction, ischemic stroke, or arterial revascularization) or in high-risk patients without CV
disease (diabetes mellitus, familial hypercholesterolemia, symptomatic peripheral vascular 
disease, or chronic kidney disease), bococizumab, when added to the existing standard of 
care, is indicated to reduce the risk of the following major CV events: 

CV death;

Non-fatal myocardial infarction;

Non-fatal stroke; 
and

Hospitalization for unstable angina needing urgent revascularization
1.2. Background and Rationale
1.2.1. Overview of the Disease State
Cardiovascular disease due to atherosclerosis (CVD), including myocardial infarction and 
stroke, is currently the leading cause of morbidity and premature mortality worldwide, 
contributing 17 million (8.6 million among women) deaths annually and 10% of the global 
disease burden, despite the availability of highly effective treatments.1,2 By the year 2020, 
heart disease and stroke are estimated to become the leading causes of both death and 
disability, worldwide, with the number of fatalities projected to increase to over 20 million a 
year.3,4
Risk factors for CVD are well characterized and include age, gender, family history of CVD, 
hypertension, diabetes, smoking, dyslipidemia (increased levels of low density lipoprotein 
cholesterol [LDL-C] and non-high density lipoprotein cholesterol [non-HDL-C], and low 
levels of high density lipoprotein cholesterol [HDL-C]), and elevated levels of high 
sensitivity C-reactive protein (hs-CRP) a circulating biomarker of vascular inflammation.5,6
Various vascular imaging modalities have also been used to identify the risk of CVD.7

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Cholesterol, an insoluble fat, is transported through the bloodstream on lipoproteins.  
Non-HDL-C, and its components, very low density lipoprotein cholesterol (VLDL-C)
intermediate density lipoprotein cholesterol (IDL-C), remnant lipoprotein cholesterol
(RLP-C), and LDL-C represent those moieties that lead to the development of 
atherosclerosis.  LDL-C is the main contributor to the accumulation of cholesterol in arterial 
walls and the cause of systemic atherosclerosis.8 Low-density lipoprotein (LDL) particles 
within the vessel wall can become oxidized and modified, within monocyte/macrophages, 
leading to local inflammation and vessel injury.9 When the intravascular accumulation of 
plaque becomes unstable, plaque rupture can be triggered, leading to thrombotic occlusion of 
a vessel and potential irreversible end organ damage to the heart or brain.10
LDL-C cholesterol is presently a key treatment target for reducing the risk of CVD event 
occurrence.5,6 Over the decades, numerous studies assessing the safety and efficacy of 
different treatments that lower total cholesterol (TC) and LDL-C have consistently shown a 
strong relationship between LDL-C lowering a reduction in the risk of major CV events.11
As dyslipidemia treatments have become more potent, leading to lower LDL-C on-treatment 
values and lower CV event rates, the LDL-C treatment recommendations continue to 
evolve.5,6,12,13
The most effective LDL-C lowering treatments, for the prevention of cardiovascular events, 
to date, are statins.  They reduce levels of LDL-C by inhibiting hepatocyte 
3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase and the intracellular 
synthesis of cholesterol.  This action triggers the production of more hepatocyte LDL 
receptors, which remove circulating LDL-C from the bloodstream.  The cholesterol is 
ultimately excreted in the bile.  Statins also reduce levels of non-HDL-C, which includes 
VLDL-C and triglyceride rich remnant lipoproteins, and modestly increase levels of HDL-C.
1.2.2. Rationale
Despite currently available treatments for dyslipidemia, many patients do not reach 
therapeutic LDL-C goals and others sustain major CV events, even while being treated with 
adequate doses of medication.  LDL-C lowering by inhibiting the action of proprotein 
convertase subtilisin kexin type 9 (PCSK9) appears to be a promising new dyslipidemia 
treatment.  Among the genetic polymorphisms that alter LDL metabolism and LDL-C levels 
are mutations of the PCSK9 gene.  PCSK9 is the ninth member of the subtilisin family of 
kexin-like proconvertases to be identified and is closely related to proteinase K.14 It is 
expressed in liver, neuronal tissue, kidney, and intestinal cells.  The PCSK9 gene is regulated 
by sterols and regulates the level of LDL receptor.  The mechanism by which PCSK9 is 
linked to serum LDL-C levels has been elucidated by biochemical and genetic studies in cell 
cultures and rodents.  These studies have demonstrated that PCSK9 binds to and down 
regulates LDL receptor (LDLR) levels on hepatocytes.  This reduction in LDL receptor 
density results in reduced cellular uptake of LDL cholesterol and, consequently, higher levels 
of LDL-C.  In contrast, a decrease in active PCSK9 leads to an increase in the number of 
hepatocyte LDL receptors, causing an increase in LDL uptake from circulation and lower 
levels of LDL-C.15,16

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As would be predicted, naturally occurring gain of function mutations in PCSK9 reduce 
LDLR levels in the liver, resulting in high levels of plasma LDL-C in the plasma and 
increased susceptibility to coronary heart disease.17 Loss of function mutations lead to higher 
levels of the LDLR, and consequently lower plasma LDL-C levels, and protection from 
coronary heart disease.18-22 This loss of PCSK9 appears to have no discernible adverse 
consequences in the affected subjects. 21, 22
The LDLR and PCSK9 are coordinately regulated by sterol regulatory element binding 
protein 2 (SREBP 2), a transcription factor that activates many genes involved in cholesterol 
metabolism in a coordinated manner.23,24 Statin administration, in addition to the HMG-CoA 
inhibition of cholesterol synthesis, induces SREBP 2 expression, which induces the 
expression of LDLR.25,26 However, the statin induction of SREBP 2 also increases 
PCSK9 messenger ribonucleic acid (mRNA) expression and protein levels.27,28   The increase 
in PCSK9 expression would be expected to attenuate the LDL cholesterol lowering effect of 
statins.  Thus, the pharmacologic inhibition of PCSK9 activity may augment statin induced 
LDLR expression and increase LDL-C clearance, as was observed when statins were 
administered to PCSK9 knockout mice.27 This hypothesis, combined with the supportive 
epidemiologic findings in patients with loss of function PCSK9 mutations, underlies the 
development of LDL-C lowering pharmacologic inhibitors of PCSK9.29,30,31 The Phase 
1 Phase 2, and Phase 3 published studies of injectable antibody inhibitors of PCSK9, in 
normal subjects and subjects with dyslipidemia have shown robust LDL-C lowering, with 
and without background statin therapy.32-38,70-78 There is also evidence from meta-analyses 
of some of those studies, that suggests that PCSK9 inhibitors may reduce the occurrence of 
CV events.78,79
Bococizumab is a humanized monoclonal antibody that is a potent and selective inhibitor of 
PCSK9.39 Bococizumab lowers LDL-C levels substantially, with or without concomitant 
statin treatment.39,40,77 It has the potential to be an effective therapy for patients with 
dyslipidemia and may reduce the risk of major CV events including CV death, non-fatal 
myocardial infarction (MI), non-fatal stroke, and hospitalization for unstable angina needing 
urgent revascularization.
Consequently, the proposed target population for this study is subjects at high or very high 
risk of incurring a CV event, who are on background lipid lowering therapy, and have an 
LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 100 mg/dL (2.59 mmol/L).  The clinical 
characteristics of the study population are based on the key features of published guidance 
documents and prognostic tools used to determine CV risk including the American Heart 
Association/American College of Cardiology Foundation (AHA/ACCF) guidelines of 
201113, National Cholesterol Education Program/Adult Treatment Panel (NCEP/ATP) III 
guidelines of 2004,12 the European Society of Cardiology/European Atherosclerosis Society 
(ESC/EAS) guidelines for the treatment of dyslipidemia, published in 2011,5 and are 
consistent with the more recent European Guidelines on Cardiovascular Disease Prevention 
in Clinical Practice, published in 2012,59 and the International Atherosclerosis Society Global 
Recommendations for the Management of Dyslipidemia, published in 2014.60

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1.2.3. Summary of Safety from Completed Studies with Bococizumab
Bococizumab administered either as a single or multiple doses, either alone or in 
combination with current lipid lowering agents, was generally well tolerated in completed 
studies.  No subjects in completed studies met the categorical criteria of drug-induced liver 
injury according to the Hy’s law definition.  Using a highly sensitive and drug tolerant
anti-drug antibody (ADA) assay, 42.5% of subjects (201/473) exposed to bococizumab in 
three recently completed studies (B1481024, B1481015, and B1481036) developed ADAs.  
The presence of ADAs was not associated with any clinical signs or symptoms of 
hypersensitivity.  In 98.7% of ADA positive subjects treated with multiple doses of 
bococizumab, no adverse effects on clinical pharmacokinetics (PK) or pharmacodynamics 
(PD) were evident. A potential impact on PK and/or PD was noted in 5 of 398 subjects 
(1.3%) treated with multiple doses.
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the Investigators Brochure. 
Complete information for background treatments may be found in the country specific local 
label (such as the United States Package Insert [USPI], Summary of Product Characteristics 
[SPC] or Local Product Document [LPD]).
1.2.4. Benefits and Risks of Participation
The potential benefit of participation, for all subjects in this study is close monitoring of their 
medical condition and safety.  Those randomized to the active treatment arm may have a 
benefit of a lower risk of major CV events.  Those randomized to the placebo arm are not 
expected to obtain any additional benefit, beyond close monitoring of their medical condition 
and safety.  A potential risk of participation, for all subjects, is the occurrence of injection 
site reactions. For those receiving active treatment, there may be an additional risk of 
achieving a very low LDL-C.  It is not known if there are any risks associated with very low 
LDL-C. 
1.2.5. Interim Analysis from Study B1481015
An interim analysis, for the primary endpoint of the now completed study B1481015, was 
conducted after subjects completed 12 weeks of treatment, for the purpose of Phase 3 dose 
selection.  The study was a randomized, double-blind, placebo-controlled, parallel-group, 
dose-ranging trial that enrolled 354 subjects, with a treatment duration of 24 weeks.  Subjects 
were randomized to one of 7 dose groups (placebo, 50, 100, 150, once every 2 weeks 
[Q2wks] and placebo, 200, 300 mg, once every 4 weeks [Q4wks]) delivered by the 
subcutaneous (SC) route.  The dosing strategy in this study allowed for downward dose 
adjustment when LDL-C 25mg/dL (0.65mmol/L).  The primary efficacy endpoint was the 
absolute change in LDL-C at 12 weeks following Q2wks or Q4wks dosing as compared to 
study Day 1 pre-dose baseline LDL-C. 
Clear evidence of efficacy was established in all bococizumab treatment groups as shown in 
Figure 1, below.  At the primary timepoint of Week 12, the Q2wks adjusted mean treatment 
group differences for change in LDL-C from baseline ranged from −30.4 to −54.9 mg/dL at 

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the end of the dosing period (Q14d in Figure 1).  The Q4wks adjusted mean treatment group 
differences for change in LDL-C ranged from −27.8 to −45.2 mg/dL at the end of the dosing 
period (Q28d in Figure 1).  The Q4wk LDL-C adjusted mean treatment group difference, 
based on the means of the observed nadir (week10, peak effect) and trough (week 12, end of 
dosing period) values ranged from −46.8 to −55.5 mg/dL (Q28d AVG in Figure 1).
Figure 1.
Study B1481015 LS-Mean Treatment Difference (mg/dL) and 95% 
Confidence Interval
LS-Mean Treatment Difference (mg/dL) and 95% Confidence Interval
Bococizumab was generally well tolerated at each dose, with an adverse event profile similar 
to previous findings in the clinical program.  The overall proportion of subjects experiencing 
adverse events was similar among all treatment groups.  The incidence of moderate and 
severe injection site reactions and of serious adverse events was low in all treatment groups.  
Downward-dosing titrations were more frequent in higher dose groups. 
1.2.6. Rationale for Dose Selection
The dose selected for Phase 3 is a starting dose of 150 mg administered SC, every two weeks 
(Q2wks), with a potential modification to a dose of 75 mg Q2wks for subjects with two 
consecutive low LDL-C concentrations (≤ 10 mg/dL or 0.26 mmol/L) at the end of the 

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dosing interval.  Additionally, subjects with two consecutive low LDL-C concentrations 
≤10 mg/dL (0.26 mmol/L), even after a dose reduction, will have their dose frequency 
modified to 75 mg every four weeks (Q4wks). 
In study B1481015, multiple subcutaneous (SC) doses of bococizumab as high as 150 mg 
Q2wks and 300 mg Q4wks (up to 24 weeks) were safe and well-tolerated.  The primary 
rationale for dose selection was based on the pharmacokinetic/pharmacodynamic (PK/PD)
model-predicted LDL-C percent change from baseline (CFB) and the estimate of the 
proportion of subjects with very low LDL-C at the end of the dosing interval.  The 
probability of achieving a target effect (risk reduction in CV events) was also estimated by 
taking into consideration the uncertainty in the dose response profile, clinical relevance of the 
magnitude of effect, and the desired level of confidence in the effect size.
Based on population PK/PD modeling, a dose of 150 mg Q2wks is approximately equivalent 
to the dose associated with 80% of the maximum LDL-C response (~ED80).  This dose is 
predicted to result in LDL-C lowering of approximately -67 percent CFB.
1.2.6.1. For subjects with LDL-C 70 mg/dL (1.81 mmol/L) and < 100 mg/dL 
(2.59 mmol/L) 
For subjects with LDL-C 70 mg/dL (1.81 mmol/L) and < 100 mg/dL (2.59 mmol/L), a 
dose of 150 mg Q2wks is expected to result in approximately 12% of subjects having LDL-C 
concentrations ≤10 mg/dL (0.26 mmol/L) at the end of a dosing interval.  Clinical trial 
simulations where the proposed dose modification rules for this protocol are implemented for 
subjects with LDL-C ≤10 mg/dL predict that 18.1% of subjects in this population will be 
titrated to 75 mg Q2wks and a further 1.7% will have dose frequency modified to 75 mg 
Q4wks.  Assuming a mean LDL-C baseline of 82 mg/dL (2.12 mmol/L), which is expected 
with an LDL-C inclusion criterion of ≥70 to <100 mg/dL( ≥1.81 mmol/L to <2.59 mmol/L), 
the mean absolute LDL-C change from baseline is predicted to be -51 mg/dL (1.32 mmol/L), 
for this population.
A model-based meta-analysis of the relationship between on-trial LDL-C differences and 
relative risk (RR) for (1) “any” CV event (a composite endpoint of CV death, MI, stroke, and 
hospitalization for unstable angina or coronary revascularization) and (2) CV events with end 
organ injury (a composite endpoint limited to CV death, MI, and stroke, sometimes described
as a “hard” endpoint) was used to simulate the probability distribution of risk reduction for 
CV events for bococizumab vs. control, given the trial design and patient characteristics 
proposed for this population.  The estimated RR for “any” CV event was 0.72 (90%PI: 0.64, 
0.82) with a 90.7% probability of an observed RR ≤ 0.80 (one-sided α=0.025).  The 
estimated RR for CV events with end organ injury was 0.72 (90% PI: 0.61, 0.84) with an 
87.5% probability of an observed RR ≤0.80 (one-sided α=0.025).
1.2.6.2. For subjects with LDL-C 100 mg/dL (2.59 mmol/L) 
For subjects with LDL-C 100 mg/dL (2.59 mmol/L), a dose of 150 mg Q2wks is expected 
to result in approximately 5% of subjects having LDL-C concentrations 10 mg/dL 
(0.26 mmol/L), at the end of a dosing interval.  Clinical trial simulations where the proposed 

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dose modification rules for this are implemented for subjects with an LDL-C 10 mg/dL 
(0.26 mmol/L) predict that 7.7% of subjects in this population will be titrated to 75 mg 
Q2wks and a further 0.4% will have dose frequency modified to 75 mg Q4wks.  Assuming a 
mean LDL-C baseline of 119 mg/dL (3.08 mmol/L), which is expected with an LDL-C 
inclusion criterion of 100 mg/dL (2.59 mmol/L), the mean absolute LDL-C change from 
baseline for this population is predicted to be -79.5 mg/dL (2.06 mmol/L). 
Based on the predicted LDL-C reduction, the estimated RR for “any” CV event was 
0.61 (90% PI: 0.50, 0.76) with an 85.4% probability the observed RR 0.70 (one-sided 
=0.025).  The estimated RR for CV events with end organ injury was 0.62 (90% PI: 0.48, 
0.81) with a 77.4% probability the observed RR 0.70 (one-sided =0.025).
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective
The primary objective of this clinical trial is to demonstrate the superior efficacy of 
bococizumab compared with placebo in reducing the risk of major CV events, a composite 
endpoint which includes adjudicated and confirmed CV death, non-fatal MI, non-fatal stroke, 
and hospitalization for unstable angina with urgent revascularization (as defined in
Appendix 4), in subjects at high or very high risk of major CV events, who are on 
background lipid lowering treatment, and have an LDL-C 70 mg/dL (1.81 mmol/L) or 
non-HDL-C 100 mg/dL (2.59 mmol/L).
2.1.2. Secondary Objectives
2.1.2.1. Clinical Secondary Objectives
The key secondary objectives of this clinical trial are to demonstrate in subjects with high or 
very high risk of major CV events, who are on background lipid lowering treatment, and
have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 100 mg/dL (2.59 mmol/L), the
superior efficacy of bococizumab compared with placebo in reducing the risk of adjudicated 
and confirmed key secondary endpoints (as defined in Appendix 4) of:

A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;

A composite endpoint of all-cause death, non-fatal MI, non-fatal stroke, and 
hospitalization for unstable angina needing urgent revascularization;

A composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke;

Hospitalization for unstable angina needing urgent revascularization.
Additional clinical secondary objectives are to evaluate, in subjects with high or very high 
risk of major CV events, who are on background lipid lowering treatment, and have an
LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 100 mg/dL (2.59 mmol/L), the efficacy 
of bococizumab compared with placebo in reducing the risk of other adjudicated and 
confirmed secondary endpoints (as defined in Appendix 4) of: 

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
A composite endpoint of CV death, non-fatal MI, non-fatal stroke, and 
hospitalization for unstable angina;

CV death;

Any MI (fatal and non-fatal);

Fatal MI;

Non-fatal MI;

Any stroke (fatal and non-fatal);

Any stroke (fatal and non-fatal), of any etiology;

Fatal stroke;

Non-fatal stroke;

Hospitalization for unstable angina;

Hospitalization for congestive heart failure (CHF);

Any coronary revascularization procedure;

Coronary artery bypass graft surgery (CABG);

Percutaneous coronary intervention (PCI);

Any arterial revascularizations;

All-cause death.
2.1.2.2. Circulating Biomarker Secondary Objectives
2.1.2.2.1. LDL-C
To evaluate, in subjects at high or very high risk of major CV events, who are on background 
lipid lowering treatment, and have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 
100 mg/dL (2.59 mmol/L), bococizumab compared with placebo, with respect to the 
circulating lipid biomarker LDL-C (direct measure): its percent change and nominal change 
from baseline at Week 14 and its percent change from baseline to the last available post 
randomization measure.
2.1.2.2.2. Other circulating lipid biomarkers
To evaluate, in subjects at high or very high risk of major CV events, who are on background 
lipid lowering treatment, and have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 
100 mg/dL (2.59 mmol/L), bococizumab compared with placebo, with respect to the 
following circulating lipid biomarkers, and their percent change from baseline at Week 14:

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
Non-HDL-C;

Total cholesterol;

Very low density lipoprotein cholesterol (VLDL-C);

Remnant lipoprotein cholesterol (RLP-C);

Apolipoprotein B (apo B);

Lipoprotein(a) (Lp(a));

Triglycerides;

HDL-C;

Apolipoprotein (apo A-I).
2.1.2.2.3. Inflammatory circulating biomarker
To evaluate in subjects at high or very high risk of major CV events, who are on background 
lipid lowering treatment, and have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 
100 mg/dL (2.59 mmol/L), bococizumab compared with placebo, with respect to high 
sensitivity C-reactive protein (hs-CRP) and its percent change from baseline at Week 14.
2.1.2.3. Health Care Resource Utilization Objectives
To evaluate in subjects at high or very high risk of major CV events, who are on background 
lipid lowering treatment, and have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 
100 mg/dL (2.59 mmol/L), the comparison of health care resource utilization (HCRU) 
associated with bococizumab versus placebo, the following:

Incidence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition, for 
all-cause hospitalizations;

Incidence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition, for CV
hospitalizations;

Incidence of emergency room visits;

Incidence of physician office visits;

Incidence of outpatient rehabilitation visits;

Incidence of all-cause hospitalizations within 30 days of a previous hospitalization, 
primary and secondary discharge diagnoses, length of stay, and discharge disposition;

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
Incidence of CV hospitalizations within 30 days of a previous hospitalization, 
primary and secondary discharge diagnoses, length of stay, and discharge disposition.
2.1.2.4. Safety Objectives
To describe in subjects at high or very high risk of major CV events, who are on background 
lipid lowering treatment, and have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 
100 mg/dL (2.59 mmol/L), the safety, tolerability and immunogenicity of bococizumab or 
placebo, including the assessment of adverse events (including Type 1 and 3 hypersensitivity 
reactions and injection site reactions), serious adverse events, vital signs, examinations
(physical and neurological examinations and cognitive testing), 12-lead ECG recordings, and 
safety laboratory tests, including hematology, blood chemistry studies (including liver 
function tests and creatine kinase tests), and urinalysis studies, and ADA assessments.
2.2. Endpoints
This protocol will use an independent endpoint adjudication committee to determine whether 
certain investigator-reported events meet the definition of disease-related efficacy endpoints, 
using pre-defined endpoint criteria.  For all clinical endpoints listed below, a description of 
qualifying outcome events can be found in Appendix 4.  The criteria determining whether a 
potential clinical event qualifies as an adjudicated and confirmed clinical outcome event are 
defined in the Adjudication Committee Charter.
2.2.1. Primary Endpoint
The primary endpoint is defined as the time from randomization to the first adjudicated and 
confirmed occurrence of a major CV event, a composite endpoint that includes CV death, 
non-fatal MI, non-fatal stroke, and hospitalization for unstable angina needing urgent
revascularization.
2.2.2. Key Secondary Endpoints
Key secondary endpoints are defined as the times from randomization to the first adjudicated 
and confirmed occurrence of:

A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;

A composite endpoint of all-cause death, non-fatal MI, non-fatal stroke, and 
hospitalization for unstable angina needing urgent revascularization;

A composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke;

Hospitalization for unstable angina needing urgent revascularization.
2.2.3. Other Clinical Secondary Endpoints
Other clinical secondary endpoints are defined as the times from randomization to the first 
adjudicated and confirmed occurrence of:

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
A composite endpoint of CV death, non-fatal MI, and non-fatal stroke, and 
hospitalization for unstable angina;

CV death;

Any MI (fatal and non-fatal);

Fatal MI;

Non-fatal MI;

Any stroke (fatal and non-fatal);

Any stroke (fatal and non-fatal), of any etiology;

Fatal stroke;

Non-fatal stroke;

Hospitalization for unstable angina;

Hospitalization for CHF;

Any coronary revascularization procedure;

CABG;

PCI;

Any arterial revascularizations;

All-cause death.
2.2.3.1. Circulating Biomarker Endpoints
2.2.3.1.1. LDL-C
The percent change and nominal change, from baseline at Week 14 and percent change from 
baseline to the last available post-randomization value, in LDL-C (direct measurement).
2.2.3.1.2. Other circulating lipid biomarker endpoints
The percent change from baseline at Week 14 in levels of:

Non-HDL-C;

Total cholesterol;

VLDL-C;

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
RLP-C;

Apo B;

Lp(a);

Triglycerides;

HDL-C;

Apo A-I.
2.2.3.1.3. Inflammatory circulating biomarker

The percent change from baseline at Week 14 in levels of hs-CRP.
2.2.3.2. Health Care Resource Utilization Endpoints
The HCRU endpoints include:

The occurrence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition, of all-cause 
hospitalizations;

The occurrence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition of CV 
hospitalizations;

The occurrence of emergency room visits;

The occurrence of physician office visits;

The occurrence of outpatient rehabilitation visits;

The occurrence of all-cause hospitalizations within 30 days of a previous 
hospitalization, primary and secondary discharge diagnoses, length of stay, and 
discharge disposition;

The occurrence of CV hospitalizations within 30 days of a previous hospitalization, 
primary and secondary discharge diagnoses, length of stay, and discharge disposition.
2.2.4. Safety Endpoints
Safety endpoints include investigator reported adverse events, (including Type 1 and 
3 hypersensitivity reactions and injection site reactions), serious adverse events, vital signs, 
examination observations (physical and neurological examinations and cognitive testing), 
12-lead ECG recordings, and safety laboratory tests, hematology, blood chemistry studies 
(including liver function tests and creatine kinase tests), urinalysis studies, and ADA 
assessments.  See Section 7.2 for details.

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2.2.5. Assessment of Clinical Efficacy and Safety Endpoints
This protocol will use an independent blinded Adjudication Committee wherein, to maintain 
scientific integrity, adjudication of disease-related efficacy endpoints will be performed.  The
Adjudication Committee will adjudicate potential disease-related efficacy endpoints, 
including CV deaths, all-cause death, MI, stroke, hospitalization for unstable angina needing 
urgent revascularization (as defined above), hospitalization for unstable angina, 
hospitalization for CHF, and arterial revascularization procedures including percutaneous 
coronary interventions, CABG, and all other arterial revascularization procedures, as 
described in Appendix 4.  The Adjudication Committee will confirm whether potential
disease-related efficacy endpoints meet the pre-specified clinical criteria defined in the 
Adjudication Committee charter.  The definition of MI, for the purposes of adjudication will 
conform to the Third Universal Definition of Myocardial Infarction.41 Other endpoint 
definitions will be based upon the Standardized Definitions for Cardiovascular and Stroke 
End Point Events in Clinical Trials.42
For those Serious Adverse Events (SAEs) that are handled as disease-related efficacy 
endpoints (which includes death), a data monitoring committee (DMC) will conduct 
unblinded reviews on a regular basis throughout the trial (see the Data Monitoring 
Committee Section 3.4.3).  The DMC is responsible for ongoing analysis of these events and 
for informing the sponsor of recommendations made (eg, to continue the study or to stop the 
study).  Disease-related efficacy endpoints are described in Section 8.6.1.
Pfizer will utilize an internal serious adverse event (SAE) triage group to ensure the correct 
reporting of SAEs to the Pfizer Drug Safety Unit (as defined in Section 8.14.1).
3. STUDY DESIGN
This is an event driven, Phase 3 multi-center, double-blind, randomized parallel group 
evaluation of the efficacy, safety, and tolerability of bococizumab compared with placebo, in 
reducing the occurrence of major CV events in subjects at risk, who are on background lipid 
lowering treatment and have an LDL-C 70 mg/dL (1.81 mmol/L) or non-HDL-C 
100 mg/dL (2.59 mmol/L).  After obtaining informed consent, there will be a pre-screening
visit.  At this visit subjects will have consented to have had lipid levels assessed and to 
provide medical records for review, only, so as to determine if the subject qualifies for this 
study.  The interactive response technologies (IRT) system will determine if the subject is 
eligible for the study or if the subject should be screen failed.  This will be followed within
30 days, by a screening visit, and a run-in period of up to 6 weeks, during which subjects will 
be fully assessed with respect to the trial enrollment criteria and compliance with the 
self-administration of subcutaneous injections.  The run-in period will be followed by the 
treatment period, the duration of which will be determined by the number of subjects with 
primary endpoint events, and concluded by a safety follow-up period, as illustrated in the 
schematic below (Figure 2).

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Figure 2
B1481022 Study Diagram
Approximately 85,000 subjects may be screened and approximately 17,000 subjects will be 
randomized.  Subjects will be randomized to bococizumab 150 mg or placebo Q2wks in a 
1:1 ratio.  Subjects will self-inject, or if unable to self-inject, have investigational product 
administered by a caregiver (eg, a family member or health care assistant).  Randomization 
will be stratified by geographic region and LDL-C at the pre-screening visit (<100 mg/dL, 
100 mg/dL). 
The trial is intended to complete when approximately 844 subjects have accrued adjudicated 
and confirmed primary endpoint events, or 12 months following the randomization date of 
the last subject, whichever occurs later.  The duration of the trial is expected to be
approximately 4.8 years (see Section 9.1).  The End of Study (EOS) will be announced to 
study sites, when the Sponsor estimates that criteria for stopping the study in Section 3 have 
been satisfied. EOS visits should be scheduled as soon as possible, after that announcement.
The EOS visit should occur no sooner than 14 days after the last dose of IP was administered 
for subjects taking IP. The safety follow-up period is 40 days after the last dose of IP was 
administered.  If the EOS visit has taken place earlier than 40 days after the last dose of IP 
administration, subjects will receive a telephone call to determine if any serious adverse 
events have taken place.  All EOS procedures should be done for all randomized subjects 
when the study is completed, whether or not the subject is taking double-blind investigational 
product.
The sample size may be modified to shorten the expected duration of the trial or to improve 
the likelihood of attaining 70% power, for the key secondary composite endpoint of CV 
death, non-fatal MI and non-fatal stroke. Prior to the end of enrollment, blinded assessments
will be made of the expected duration of the trial and of the power for this endpoint, 
assuming a hazard ratio (HR) of 0.8 at a two-sided alpha of 0.05. The decision to make 
either or both modifications will be documented in the Trial Master File.  If the modification
for the key secondary endpoint is made, the trial would be intended to complete when 
approximately 844 subjects have accrued adjudicated and confirmed primary endpoint 
events, 496 subjects have accrued adjudicated and confirmed events of the above key 
secondary endpoint, or 12 months following the randomization date of the last subject, 
whichever is last.
In addition, the sample size in certain subgroups, including diabetic subjects with no prior 
CVD event, may be modified or the trial duration may be extended to improve the likelihood 
that the estimated hazard ratios in the subgroups are less than one.  Prior to the end of 
enrollment, the sponsor will perform a blinded assessment of the probabilities, assuming a 

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hazard ratio of 0.8.  If one or more of the probabilities are too small, the number of subjects 
in the corresponding subgroups may be modified, possibly increasing the total enrollment to 
do so.  Prior to the end of the study, the sponsor will perform a second blinded assessment of 
the probabilities.  If one or more of these probabilities are too small, the duration of the trial 
may be extended.  If the latter modification is made, the criterion for stopping the trial will 
include accruing 58 primary endpoint events in the corresponding subgroups.  These 
decisions will be documented in the Trial Master File.
Because the trial is designed to assess the effect of PCSK9 inhibition on recurrent as well as 
first clinical events, it is expected that subjects who sustain a clinical event will remain on 
their assigned treatment and continue in the study, unless the investigator chooses to 
withdraw the subject or the subject declines continued participation in the study.
3.1. Number and Location of Study Sites
The study will be conducted in North America, Latin America, Europe, Africa, Asia, and 
Australia in approximately forty countries.
3.2. Study Population
Subjects will be men and women with a high risk or very high risk of incurring major CV 
events based on the study inclusion and exclusion criteria (Section 4).
3.3. Treatment Periods
3.3.1. Pre-screening Visit
A pre-screening visit is required for all subjects.  Sites will obtain informed consent from 
potential subjects to evaluate baseline lipids and obtain medical records for review, only, so 
as to determine if the subject qualifies for this study.  The IRT system will determine if the 
subject is eligible for the study or if the subject should be screen failed.  The lipid 
assessments will be done using the central laboratory.
3.3.2. Screening Visit
The time interval between the Pre-screening Visit (Visit 0) and the Screening Visit (Visit 1) 
is a maximum of 30 days.  At the screening visit, after obtaining consent for participation in 
study B1481022, potential subjects will be fully evaluated for eligibility, based on the
prescreening lipid values and medical records obtained after the pre-screening visit, and a 
review of the complete study specific inclusion/exclusion criteria, as described in Section 4.
3.3.3. Run-In Period
After the screening visit, qualified subjects will begin a run-in period of up to six weeks 
duration during which they will receive SC injections of open-label placebo investigational 
product (IP) no less than 7 and no more than 14 days apart. 

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The primary objectives of the run-in period are to ensure (1) compliance with the SC
administration of a parenteral agent, (2) that subjects meet inclusion and exclusion criteria 
and (3) can follow study procedures.
3.3.4. Active Treatment Period
At the randomization visit, the subject will be assigned to either active treatment or placebo
IP in a blinded fashion.  IP will be administered SC by self-injection, or by a trained 
caregiver, every Q2wks during the course of the study, unless there has been an IP dose 
modification to a frequency of Q4wks (Section 5.4.1.1).  Subsequent visits for assessments of 
efficacy, safety, and tolerability will be scheduled according to the Schedule of Activities, 
unless there has been an IP dose modification to Q4wks, in which case subjects will be seen 
every 8 weeks, approximately, until the completion of the study.
Subjects may return to the study site for unscheduled visits, or to replenish investigational 
product supplies, if necessary.  Subjects who discontinue investigational product will be 
followed until the completion of the study.  Randomized subjects who withdraw from the 
study will have consented, at the onset of the study, to provide vital status information to the 
study site at the completion of the study.
3.3.5. Safety follow-up period
The safety follow-up period will comprise 40 calendar days after the last administration of 
the investigational product.
3.4. External Committees
3.4.1. Executive Committee
An Executive Committee will be responsible for providing overall guidance to Pfizer on the 
study protocol.  This will include evaluation of the scientific merit of proposed sub-studies, 
execution of the trial, review of recommendations from the Data Monitoring Committee 
(DMC) and oversight of study publications.  A separate charter will document specific 
policies and procedures of the Executive Committee.
3.4.2. Adjudication Committee
An Adjudication Committee will perform a blinded review of all potential primary, 
secondary, and tertiary endpoints (as specified in the Adjudication Committee Charter) to 
confirm that the data support the endpoint designation.  The Adjudication Committee Charter 
describes the Adjudication Committee’s responsibilities and how it will function.
3.4.3. Data Monitoring Committee
Subject safety will be monitored by an independent data monitoring committee (DMC).  An 
independent statistical data analysis center will provide analyses to the DMC according to the 
DMC charter.  Refer to Section 9.6 for a full description of the functions of the DMC.

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3.4.4. Steering Committee
The Steering Committee comprises medical representatives from each country of study 
operations and will oversee recruitment, retention and quality issues within the country.  This 
committee will work jointly with the Executive Committee, to ensure that operational issues 
are effectively addressed on a national level.
3.4.5. Joint Leadership/Operations Committee
The Joint Leadership/Operations Committee will be responsible for the operational aspects of 
study execution, global site initiation and monitoring, recruitment and data quality issues
across the different academic and clinical research organizations.  It will make 
recommendations to the Executive Committee and Steering Committee members on quality 
issues within countries or across regions.  A separate charter will document specific policies 
and procedures of the Joint Leadership/Operations Committee.
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled and followed 
throughout the completion of the trial irrespective of whether they are maintained on 
investigational product.  All efforts should be made to follow all subjects for the entire 
duration of the study.  Importantly, discontinuation of investigational product does not imply 
or constitute withdrawal of the subject from the study.  Section 6.5 describes the follow-up 
procedures for Subjects who withdraw from investigational product.  In general, 
Investigators should try to obtain the most complete collection of data as possible from 
subjects who discontinue investigational product, weighing the subject’s willingness to 
participate with the scientific integrity of the protocol.  Those subjects who are a priori 
unwilling to agree to the collection of this information in the event that they discontinue 
investigational product should not be enrolled.
The following eligibility criteria are designed to select subjects for whom protocol treatment 
is considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether this protocol is suitable for a particular subject.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team, before subjects are included in the study.  Appropriately 
qualified members of the investigator's study team are defined in the study site's delegation 
of authority log.
A key element of eligibility is the investigator’s documentation that the subject is at high or 
very high risk of incurring a CVD event.  Adequate documentation of objective evidence of 
the criterion that qualifies the subject as being at high risk or very high risk for CVD events 
must be available in the investigational site’s source documents including medical records, 
copies of such records from other institutions, or a letter from a referring physician that 
specifically provides diagnostic information and/or a diagnosis and the date of a qualifying 
CVD event, when relevant.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:

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1. Informed Consent
There must be evidence of personally signed and dated, informed consent documents for both 
the pre-screening and screening visits indicating that the subject (or a legal representative) 
has been informed of all pertinent aspects of the study.  The pre-screening visit informed 
consent form will be limited to study activities up until the screening visit.  The screening 
visit informed consent form will cover all aspects of the study.  Subjects should be 
reconsented if there are modifications to the original informed consent document, at the next 
available opportunity.
2. Compliance
Subjects must be willing and able to comply with scheduled visits, treatment plan, laboratory 
tests, and other study procedures.
3. Age
Subjects who have had a prior CVD event, must be men or women age the legal age of 
majority (legal adulthood), in the subject’s country.
Subjects who have not had a prior CVD event must be age 50 years, if a man, and must be 
age 60 years, if a woman, with the following exception:
Subjects who have not had a prior CVD event, but who have a condition of elevated LDL-C, 
(heterozygous familial hypercholesterolemia [heFH] or a history of LDL-C 190 mg/dL 
[4.9 mmol/L]) should be 35 years of age if a man, and 45 years of age, if a woman.
4. Acceptance of administration of investigational product
Subjects must be willing and able to self-administer or be administered sub-cutaneous 
injections of investigational product.
5. Requirements for background lipid lowering treatment
There should be no plans at the time of pre-screening and randomization to modify the dose 
of statin for the duration of the trial.  Unless the background lipid lowering treatment 
exceptions described below are met, subjects must be treated with one of the following 
highly effective statins at the specified daily doses for 4 weeks prior to the pre-screening 
visit:

atorvastatin, at least 40 milligrams (mg) once a day;

rosuvastatin, at least 20 mg, once a day;

simvastatin, at least 40 mg, once a day or, if a subject has been on that dose for > 
1 year, 80 mg, once a day.
Combination medications that contain atorvastatin, rosuvastatin, or simvastatin components 
described at the aforementioned doses will be permitted. 

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Background lipid lowering treatment exceptions
The following background lipid lowering treatment exceptions are permitted:

Lower doses of statins due to partial statin intolerance
Subjects may be on a lower dose of one of the highly effective statins described 
above if there is documented intolerance to any one of them (atorvastatin, 
rosuvastatin, or simvastatin) at the aforementioned, or lower, doses. 
Intolerance to any dose of any statin must be documented as historical adverse 
events attributed to the statin in question, in the source documentation and case 
report form (CRF).

Regulatory limitations
Subjects may be on a lower dose of one of the highly effective statins described 
above if the highest locally approved dose for one of the stated statins is lower 
than those doses shown above (eg, in Japan, atorvastatin 20 mg, once a day, is the 
highest locally approved dose) or due to label restrictions.

Alternative statins
Subjects may be treated with other statins (pravastatin, fluvastatin, pitavastatin, or 
lovastatin), different from the highly effective statins listed above, if there is 
documented intolerance to any two different highly effective statins (atorvastatin, 
rosuvastatin, simvastatin) at the lowest available dose, for at least one of those 
highly effective statins.  Intolerance to any statin must be documented as 
historical adverse events attributed to the statin in question, in the source 
documentation and CRF.
6. Qualifying cardiovascular disease risk
Qualifying cardiovascular disease (CVD) risk must be documented by supporting source
documentation such as, but not limited to, copies of a hospital discharge summary, copies of 
medical records, or other documents that can be used to confirm the qualifying CVD risk 
event or diagnosis and its approximate date of occurrence or onset.  Ideally, this 
documentation should be acquired before Visit 1.  A subject may qualify for inclusion 
according to the following (see Appendix 10):
a. Myocardial infarction

A subject may qualify for inclusion if he/she had a prior myocardial infarction, > 
30 days and 5 years, prior to screening;  

A subject may qualify for inclusion if he/she had an MI > 5 years before screening if 
he/she also has an additional CVD risk condition and one additional CVD risk factor, 
two additional CVD risk conditions, or two additional CVD risk factors (CVD risk 
conditions and CVD risk factors are described below in e);

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
The diagnosis of a silent MI based solely on ECG criteria of new Q waves, without 
additional imaging evidence showing a corresponding fixed regional wall motion 
abnormality, is not considered sufficient evidence for a qualifying MI CV event;
OR
b. Ischemic stroke

A subject may qualify for inclusion if he/she had a prior ischemic stroke, as 
documented by hospital discharge summary or medical records which have evidence 
of confirmatory brain scan imaging, > 30 days, and 5 years prior to screening;

A subject may qualify for inclusion if he/she had a prior ischemic stroke, as 
documented by hospital discharge summary or medical records which have evidence 
of confirmatory brain scan imaging, > 5 years before screening, if he/she has an 
additional CVD risk condition and one additional CV risk factor, two additional CVD 
risk conditions, or two additional risk factors (CVD risk conditions and CVD risk 
factors are described below in e);
OR
c.
Coronary artery revascularization

A subject may qualify for inclusion if he/she had a prior coronary artery 
revascularization > 90 days, but 5 years prior to screening, including PCI, 
thrombolysis, or CABG, as documented by hospital discharge summary or medical 
records.  For a PCI performed during the same hospitalization as an MI, the date of 
the PCI (not the date of the MI) determines whether the subject is qualified for 
inclusion);  

If the prior coronary artery revascularization was > 5 years before screening, the 
subject may qualify for inclusion if he/she has an additional CVD risk condition and 
one additional CVD risk factor, two additional CVD risk conditions, or two additional 
CVD risk factors (CVD risk conditions and CVD risk factors are described below in 
e);

A purely diagnostic coronary angiogram or cardiac catheterization without 
revascularization (eg, angioplasty, stent placement, or thrombolysis) does not qualify 
as a prior CV event;
OR
d. Prior non-coronary arterial revascularization

A subject may qualify for inclusion if he/she had a prior non-coronary arterial 
revascularization, > 30 days, and 5 years prior to screening documented as a 
carotid, abdominal aortic aneurysm repair, or peripheral artery revascularization, by 
either open surgery, endovascular catheterization, or thrombolysis, with or without
stent placement;

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
A purely diagnostic angiogram or catheterization without revascularization (eg, 
angioplasty, stent placement, or thrombolysis) does not qualify as a prior CV event;

If the prior non-coronary arterial revascularization was more than five years before 
screening, the subject may qualify for inclusion if he/she has an additional CVD risk 
condition and one additional CVD risk factor, two additional CVD risk conditions, or 
two additional CVD risk factors (CVD risk conditions and CVD risk factors are 
described below in e);

A purely diagnostic coronary angiogram or cardiac catheterization without 
revascularization (eg, angioplasty, stent placement, or thrombolysis) does not qualify 
as a prior CV event.
OR
e.
CVD risk conditions

Subjects may qualify for inclusion if they have two CVD risk conditions;
OR 

one CVD risk condition and two CV risk factors (described below);
OR 

a condition of elevated LDL-C as specified below.

CVD Risk Conditions

Diabetes
A subject may qualify for inclusion if he/she has Type I or Type II diabetes 
mellitus, (as defined per local diabetes guidelines, eg, American Diabetes 
Association in the United States of America (USA)., European Association for the 
Study of Diabetes [EASD] in the European Union [EU]) and one other CVD risk 
condition listed here, or two additional CVD risk factors (see below);

Peripheral vascular disease
A subject may qualify for inclusion if he/she has:

peripheral vascular disease with current or historical documentation of a 
measured ankle brachial index (ABI) of < 0.85; or

significant (> 50%, or reported as hemodynamically significant) peripheral 
artery stenosis in at least one limb, using any kind of imaging technology; or

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
a prior amputation for peripheral vascular disease; or

imaging evidence of a significant (>50%) stenosis in at least one carotid 
artery, or

a high carotid plaque burden, using ultrasound, with a total plaque area 
>119 mm2 of plaque or equivalent plaque volume; and
one other CVD risk condition listed here, or two additional CVD risk factors (see 
below);

Chronic kidney disease
A subject may qualify for inclusion if he/she has chronic kidney disease with an 
estimated glomerular filtration rate of 30 and 60 mL/min/1.73m2, based on the
screening visit measurement of creatinine, as calculated by the Modification of 
Diet in Renal Disease [MDRD] formula, and not on dialysis and one other CVD 
risk condition listed here, or two additional CVD risk factors (see below).

Conditions of elevated LDL-C
Conditions of elevated LDL-C are defined as:

a history of heterozygous familial hypercholesterolemia (heFH) as 
described in Appendix 2
or

a history of LDL-C 190 mg/dL (4.9 mmol/L) regardless of whether or 
not the subject was taking background lipid lowering therapy at the time 
the measurement was made.
Subjects with a condition of elevated LDL-C and a prior CV event only need to 
be of legal age.  For subjects with a condition of elevated LDL-C and without a 
prior CV event, they should be at least 35 years old if a man and 45 years old if a 
woman as specified in the age criteria, above.
Subjects who have a condition of elevated LDL-C and a pre-screening direct 
measure of LDL-C 100 mg/dL (2.59 mmol/L), without a prior CV event,
must have at least one additional risk condition or risk factor, and they must meet 
the age criteria as specified above.
Subjects who have a condition of elevated LDL-C and a pre-screening direct 
measure of LDL-C < 100 mg/dL (2.59 mmol/L), without a prior CV event,
must have any combination of two risk conditions and/or risk factors (eg, one 
additional risk condition and risk factor, any two risk factors, or any two risk 
conditions) and they must meet the age criteria as specified above.

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
CVD risk factors

Imaging evidence of significant coronary artery disease
Current or historical evidence of coronary artery stenoses of > 50% narrowing in
the left main coronary artery or at least two major coronary arteries (left anterior 
descending, circumflex, or right coronary arteries) as documented by any type of 
coronary artery imaging with the exception that a previously stenotic coronary 
artery, which was subsequently revascularized, cannot be counted as a CVD risk 
factor;
or 
A coronary artery calcium score of 300 Agatston units or 75th percentile for 
age, sex, and ethnicity;

Smoking
Current cigarette smoking, defined as smoking for 30 days or more (any number 
of cigarettes) at the time of screening;

Low levels of HDL-C
HDL-C < 40 mg/dL (< 1.03 mmol/L) as measured at the pre-screening visit;

Elevated levels of hs-CRP
hs-CRP > 2.0 mg/L documented within one year of the screening visit;

Microabluminuria
A positive measure of microalbuminuria (a spot urine albumin-to-creatinine ratio 
> 30 mg/g) at the screening visit;

Lipoprotein (a)
Any history of Lp(a) cholesterol 50 mg/dL.
7. Qualifying lipid levels (LDL-C or non-HDL-C)
Subjects must have a direct LDL-C measurement of 70 mg/dL (1.81 mmol/L) or 
non-HDL-C 100 mg/dL (2.59 mmol/L) at the pre-screening visit, to qualify for inclusion in 
the study.  The lipid values collected at Visit 3 are not used for qualification.
8. Contraception requirements
Male subjects able to father children and female subjects of childbearing potential, who (with 
their partners) are at risk for pregnancy, or male subjects with pregnant partners who are 
sexually active, must agree to use a highly effective method of contraception throughout the 
study and for at least 63 days after the last dose of assigned treatment.  A male subject need 
not use contraception with his partner who is not of childbearing potential as defined below.

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Female subjects who are not of childbearing potential should meet at least one of the 
following criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure, or 

Achieved post-menopausal status, defined as: cessation of regular menses for at least 
12 consecutive months with no alternative pathological or physiological cause; status 
may be confirmed by having a serum follicle stimulating hormone (FSH) level within 
the laboratory’s reference range for postmenopausal females.
All other female subjects (including female subjects with tubal ligations) will be 
considered to be of childbearing potential.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Personnel involved in the conduct of the study
Subjects who are investigational site staff members directly involved in the conduct of 
the trial and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of the 
trial.
2. Exclusionary prior CV events or planned revascularization procedures
A planned coronary (PCI or CABG) or other arterial revascularization;
Myocardial infarction, stroke, or any non-coronary arterial revascularization 30 days 
prior to screening;
Coronary revascularization 90 days prior to screening;
Subjects with SAEs that would have potentially met the criteria for a CVD event (as 
defined in Appendix 4), between Visit 0 and Visit 5, should be excluded.  Such subjects 
may be rescreened at a later date.
3. Participation in prior clinical research studies
Participation in other studies involving small molecule investigational drug(s) (Phases 
1-4) within 1 month, or five half-lives, of Visit 1, whichever is longer; any participation 
in a cholesteryl ester transfer protein (CETP) inhibitor trial within 1 year of Visit 1; or 
any biological agents within 6 months or 5 half-lives, of Visit 1, whichever is longer (the 
investigator should refer to documents provided by the subject on the other study to 
determine the investigational product half-life).  If the blind of the prior study has been 
broken and the investigator provides documentation that the subject received placebo, the 
potential subject can be included, regardless of when participation occurred.

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4. Other exclusionary conditions
Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or investigational product 
administration or may interfere with the interpretation of study results and, in the 
judgment of the investigator, would make the subject inappropriate for entry into this 
study.
5. Childbearing potential and/or breast feeding
Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant who are sexually active; male subjects able to father children and 
female subjects of childbearing potential, who are at risk of pregnancy with their partners
and are unwilling or unable to use a highly effective method of contraception as outlined 
in this protocol for the duration of the study and for 63 days after last dose of 
investigational product (refer to Section 4.4.2).
6. Latex sensitivity
Latex sensitive individuals (due to potential for exposure to natural dry rubber in the 
pre-filled syringe cap of investigational product, during administration).
7. Apheresis
Undergoing lipid apheresis, within 6 weeks of pre-screening, or planned start of lipid 
apheresis.
8. Severe congestive heart failure
Congestive heart failure of New York Heart Association (NYHA) Class IV, or if there is 
prior documentation of left ventricular ejection fraction (LVEF) of < 25%, measured by 
imaging.  For subjects who have had serial assessments of LVEF, only the most recent 
study is used for the purposes of this exclusion requirement.
9. Dialysis
Potential subjects with end stage renal disease on dialysis.
10. Chronic renal insufficiency
Potential subjects with an eGFR of < 30 ml/min/1.73m2 by MDRD formula at Visit 1.
11. Hypertension
Poorly controlled hypertension at any screening visit or at randomization, defined as the 
average of two systolic blood pressure (BP) measurements > 180 mmHg or the average 
of two diastolic BP measurements > 110 mmHg even with treatment.  Subjects who have 
hypertension and are controlled on stable doses of anti-hypertensive medications may be 

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included.  An additional BP measurement may be performed within the hour or at the 
completion of the office visit, to determine if a subject may be included in the study, 
given the potential for “white coat hypertension.”  The final set of measurements will be 
the measurements of record.
12. Cerebral hemorrhage risk
A prior history of hemorrhagic stroke or lacunar infarct resulting in a stroke (a lacunar 
infarct which was seen with cerebral imaging is not exclusionary in the absence of a 
clinical stroke).  A prior ischemic stroke which resulted in hemorrhagic transformation is 
not exclusionary.
13. Tissue donation
Plans to donate any tissues (eg, blood, sperm, or other tissues, including participating in 
in vitro fertilization) during the study.
14. Substance abuse
Current history of alcoholism or drug addiction according to diagnostic and statistical 
manual of mental disorders (DSM) IV criteria within 12 months prior to screening.  Use 
of any recreational drugs within 12 months prior to screening.
15. Human immunodeficiency virus
Medical history of positive testing for human immunodeficiency virus (HIV).
16. Prior or anticipated exposure to a PCSK9 inhibitor
Subjects with prior exposure to bococizumab or PCSK9 inhibitors;
Subjects who, in the opinion of the investigator, are likely to be treated with a marketed 
PCSK9 inhibitor at any time during the conduct of the study.
17. Depression
If the subject's Patient Health Questionnaire (PHQ-9) score is 15 or there is a positive 
score in question 9 (Section 7.3.2), the subject should be excluded from participation, the 
subject’s primary care physician (PCP) should be informed, and the subject should be 
referred to a mental health professional, either by the PCP or the investigator.  Such 
subjects may be rescreened, at a later date, if they were evaluated and treated as 
appropriate, and the repeat PHQ scores permit inclusion.  Any adverse events should be 
documented in the case report form as appropriate.
18. Hypersensitivity to monoclonal antibodies
History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal 
antibody (immunoglobulin G [IgG] protein) or molecules made of components of 
monoclonal antibodies (eg, Enbrel® which contains the fragment crystallizable [Fc]
portion of an antibody or Lucentis® which is a monoclonal antibody fragment).

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19. Hepatitis

Hepatitis B
Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc), or 
tests indicative of present or prior infection.  NOTE: If a subject tests negative for 
HBsAg, but positive for anti-HBc, the subject would be considered eligible only if the 
subject tests positive for antibody to HBsAg (anti-HBs) upon reflex testing (see 
Appendix 3).

Hepatitis C
Serologic tests indicative of past or present hepatitis C virus infection.  A positive or 
indeterminate hepatitis C serology may trigger a hepatitis C polymerase chain reaction 
(PCR) test for confirmation.  If the hepatitis C PCR is negative, the subject may be 
included.
20. Creatine kinase elevations
Creatine kinase (CK) 3.0 x upper limit of normal (ULN) at Visit 1.  A measurement 
3.0 x ULN may be repeated once, no later than Visit 2, and if <3.0 x ULN the subject is 
eligible.
21. Amino transferase elevation
Alanine amino transferase (ALT) or aspartate amino transferase (AST) > 2 x ULN, at 
Visit 1.  These labs may be repeated once for values > 2 x ULN, no later than Visit 2, and 
if 2 x ULN the subject is eligible.
22. Bilirubin elevation
Direct bilirubin > 1.5 X ULN, at Visit 1.  This may be repeated once for values > 1.5 X 
ULN, no later than Visit 2, and if 1.5 x ULN the subject is eligible.
23. Malignancy
Subjects with cancer who are actively receiving chemotherapy.  Potential subjects with a 
prior history of malignancy should have thorough documentation of the malignancy type 
and the extent of disease.  Potential subjects considered at high risk of recurrence or the 
development of metastatic disease within the time frame of the conduct of the clinical 
trial should be excluded.
24. Gastric bypass surgery
Planned or prior gastric bypass surgery.
25. Subjects not taking a statin
Subjects with complete statin intolerance, ie, subjects not taking a background statin, are 
excluded from enrollment in this study, with this protocol amendment 2.

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4.3. Randomization Criteria 
Subjects will be randomized into the trial upon satisfactory completion of the run-in period if 
they have demonstrated 100% compliance with all injections of placebo and satisfied all 
subject selection criteria (Section 4.1 and 4.2) , unless there are extenuating circumstances 
which require further evaluation (see Section 5.1.5).  A computer-generated randomization 
schedule will be used to assign subjects to treatment with bococizumab or placebo in a 
1:1 ratio.  The randomization schedule will be stratified by geographic region and LDL-C at 
the pre-screening visit (<100 mg/dL, 100 mg/dL).
4.4. Life Style Guidelines 
During protocol feasibility activities, study teams should become familiar with acceptable 
contraception wording in the countries in which the protocol will be conducted to ensure 
protocol acceptability during the Ethics review. 
4.4.1. Nutritional Counseling
All subjects will be provided with counseling for diet and therapeutic lifestyle change 
recommendations for the prevention of CV disease, in accordance with ESC/EAS5 or 
NCEP-ATP-III6 guidelines at all study visits, from screening to end of study.  Documentation 
of such counseling will be recorded in the CRF for each visit.
4.4.2. Contraception
All male subjects able to father children and female subjects of childbearing potential, who, 
in the opinion of the investigator, are biologically capable of having children and are sexually 
active, and are at risk for pregnancy with their partners, and male subjects with pregnant 
partners who are sexually active, must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and
for at least 63 days after the last dose of investigational product. The investigator or his/her 
designee, in consultation with the subject, will confirm the subject has selected the most 
appropriate method of contraception, for the individual subject, from the permitted list of 
contraception methods (see below) and instruct the subject in its consistent and correct use.  
Subjects must affirm that they meet the criteria for the correct use of at least one of the 
selected methods of contraception.  The investigator or his/her designee will discuss with the 
subject the need to use highly effective contraception consistently and correctly.  These 
discussions will take place according to the Schedule of Activities (SOA) will be 
documented in the subject’s chart.  In addition, the investigator or his/her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject, or the subject's partner.
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of hormonal methods of contraception associated with oral inhibition of 
ovulation (eg, inserted, injected, implanted, or transdermal) provided the female subject 
or male subject's partner plans to remain on the same treatment throughout the entire 
study and has been using that hormonal contraceptive for an adequate period of time to 
ensure effectiveness.

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2. Correctly placed copper containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).  For countries where spermicide is not available or condom plus spermicide 
is not accepted as highly effective contraception, this option is not appropriate: eg, for 
male subjects from Denmark, condom use WITH a spermicide is acceptable.  For female 
subjects from Denmark, condom use WITH a spermicide is not acceptable and other 
highly effective methods of contraception described in this section should be used.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device's label).
4.5. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
trial is documented in the study contact list located in the coordinator’s manual.
Appropriately qualified members of the investigator's study team are defined in the study 
site's delegation of authority log.  To facilitate access to appropriately qualified medical 
personnel, on study related medical questions or problems, subjects are provided with a 
contact card. The contact card contains, at a minimum, protocol and investigational 
compound identifiers, subject study number, contact information for the investigational site 
and contact details for a help desk in the event that the investigational site staff cannot be 
reached to provide advice on a medical question or problem originating from another 
healthcare professional not involved in the subject’s participation in the study. The help desk 
number can also be used by investigational staff if they are seeking advice on medical 
questions or problems, however it should only be used in the event that the established 
communication pathways between the investigational site and the study team are not 
available. It is therefore intended to augment, but not replace the established communication 
pathways between the investigational site and study team for advice on medical questions or 
problems that may arise during the study. The help desk number is not intended for use by 
the subject directly and if a subject calls that number they will be directed back to the 
investigational site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
Investigational product will comprise placebo and bococizumab.  During the run-in period, 
subjects will be receiving placebo.  After completion of the run-in period the subjects will be 
randomized into two parallel groups.  One group will receive bococizumab and the other 
group will continue to receive placebo, both delivered by the SC route every two weeks. 

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During the run-in and treatment periods, subjects will be taking their prescribed background 
lipid lowering treatment(s).  Lipid lowering treatment doses, frequency, and changes in dose 
or frequency will be recorded in the CRF at each visit.  When background lipid lowering 
treatment changes occur, the reason for those changes should be documented in both the 
source documentation and CRF.
5.1. Allocation to Treatment
5.1.1. Interactive Response Technology Registration
Allocation of subjects to treatment groups will proceed through the use of an Interactive 
Response Technology (IRT) System (Interactive Web Response [IWR]/Interactive Voice 
Response [IVR] system). The site personnel (study coordinator or specified designee) will 
be required to enter or select information including, but not limited to, the user’s 
identification (ID) and password, and protocol number to access the system.  For each 
subject, at the initial registration call, the site personnel will be provided with a subject 
identification number that will be used to track the subject throughout the study. 
At each study visit, the site personnel will be provided with a treatment assignment as a
dispensable unit (DU) number.  The IRT system will provide a confirmation report 
containing the subject number and DU or container number assigned.  The confirmation 
report must be stored in the site’s files. 
There is a 24 hour a day, 7 days a week, IRT helpdesk available for any questions or issues.  
The study specific IRT reference manual will provide the contact information and further 
details on the use of the IRT. 
An IRT operations manual will be provided to the study site.  The IRT operations manual
will describe the IRT functions for each visit, and will serve as the reference manual 
throughout the conduct of the study.
5.1.2. Visit 0, Pre-screening Visit
Each subject will be assigned a unique identifier number at Visit 0 by the IRT for Study 
B1481022.
5.1.3. Visit 1, Screening Visit and Run-In Period
If the subject continues to qualify for this study, based on the pre-screening lipid values and 
medical history, the subject will continue to be assigned to Study B1481022, otherwise the 
subject will be screen failed.
5.1.4. Run-in Period Visits
For subjects continuing in Study B1481022, the run-in period starts at Visit 2.  The 
objectives of the run in period are to ensure (1) compliance with the SC administration of a 
parenteral agent, (2) that subjects meet inclusion and exclusion criteria and (3) can follow 
study procedures.  There will be IRT interactions at each run-in visit.

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5.1.5. Visit 5, Randomization Visit and Active Treatment Period
At Visit 5, if the subject meets all randomization criteria and has 100 percent compliance 
with injections during the run-in period, the system will randomize the subject to receive the 
administration of subcutaneous injections of IP, either bococizumab (I) or placebo (II) 
(Table 1).  If extenuating circumstances arise during run-in phase preventing 100 percent 
compliance with injections (eg, the subject is prevented from getting to a scheduled study site 
visit or the study site is unable to provide investigational product), such cases should be 
discussed with the Sponsor to determine if the subject should continue on to randomization.  
Randomization will use a permuted block design stratified by geographic region and LDL-C 
at the pre-screening visit (<100 mg/dL, 100 mg/dL).  Subjects, who are disqualified from 
allocation to blinded treatment, will be registered as screen failures in the system.
Table 1.
Treatments
Group
I
bococizumab, 150 mg SC, Q2wks
II
Placebo injection, SC, Q2wks
The IRT system will be used for each study visit during the active treatment period, to assign 
investigational product for each subject.  For subjects who are randomized to the active 
treatment arm, blinded bococizumab will initially be administered at a dose of 150 mg SC 
Q2wks.  For subjects who are randomized to placebo, blinded placebo will initially be 
administered SC Q2wks.  Blinded dose modifications may take place, through the IRT 
system, based on trigger measurements of LDL-C (5.4.1.1).
At Visit 5, after the subject has been randomized, and all other procedures and assessments 
completed, the first active treatment period dose will be self-injected or injected by a 
care-giver at the clinic. The subject will be observed, at the study site, by the study site 
personnel, for 30 minutes after the injection. Subjects will be provided with a dosing 
schedule by site personnel based on the date of randomization.  Subjects will receive 
sufficient pre-filled syringes (PFSs) to self-inject between clinic visits. As noted in the 
Schedule of Activities, many of the scheduled doses will also coincide with scheduled visits.  
When a scheduled dose occurs on the same day as a scheduled visit, subjects should hold 
their self-injected dose until they are at the clinic and self-inject or be administered an 
injection by a care provider only after all other study procedures for that visit have been 
completed. 
Injections 1 day before or up to 4 days past the scheduled day of administration are allowed.  
If more than 4 days after the scheduled day have passed, the subject should skip the dose and 
resume dosing following the dosing schedule provided by site personnel for the next 
injection.
Subjects should adhere to their treatment schedule even if their scheduled clinic visit is 
rescheduled or missed due to unforeseen circumstances.

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Subjects will continue to receive their prescribed, background lipid lowering therapy, at the 
dose that they had taken at the last visit of the run-in period prior to the randomization visit.
5.2. Breaking the Blind
The study will be subject, investigator, and sponsor blinded.
At the initiation of the study, the study site will be instructed on the method for breaking the 
blind.  When appropriate, the Principal Investigator or designee must interact with the IRT to 
obtain the treatment assigned to the subject.  Blinding codes should only be broken in 
emergency situations for reasons of subject safety.  Whenever possible, the investigator or 
sub-investigator should contact a member of the study team, prior to breaking the blind.  It is 
understood that in an emergency situation, it may not be possible to communicate with the 
study team, prior to breaking the blind.  The safety of the subject should be of primary 
concern.  When the blinding code is broken, the reason must be fully documented and 
entered on the CRF.
To protect the blind, the subject, investigator, sub-investigators, and sponsor should be 
blinded with respect to lipid values and under no circumstances should more than one carton 
of investigational product be opened to compare unused syringe fill volumes, at any one 
time.  In addition, to protect the blind, any IP dose adjustments made in the blinded active 
treatment arm, will be matched by a sham dose adjustment in the blinded placebo arm,
through the IRT system.
5.3. Subject Compliance
Compliance will be evaluated at all visits beginning with Visit 2.  During the run-in period 
visits (Visits 2, 3, 4) and at the randomization visit (Visit 5), compliance refers to the 
observation of the correct administration of study drug, since dose administration will be 
observed at the study site.  The criterion for acceptable investigational product compliance 
during the run-in period is as follows:
Run-in period compliance will be checked at each visit after Visit 2 (beginning of the run-in 
period).  Any subject found to be taking less than 100 percent of the prescribed 
investigational product will be considered non-compliant and should be discontinued prior to 
randomization, unless there are extenuating circumstances which require further evaluation 
(see Section 5.1.5).
From Visit 5, the randomization visit, onward, subjects will be dispensed study drug, to take 
home with them.  After the randomization visit, subjects will be directed to bring any used 
and unused syringe cartons to each visit.  Used syringes will be returned to the study center 
in a biohazard container, when it is full, to receive a new container, and when directed by the 
study site. 
Compliance is calculated as the percent of planned IP doses that were actually taken.  
Cartons lost prior to the administration of IP, or damaged and unused syringes, should not be 
counted as completed dose administrations.  From this information, compliance, based on the 
dosing schedule, will be calculated as follows:

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Compliance = 100%  x 
        actual dose administrations
      dose administrations planned
Following randomization, should subjects have less than 100% compliance, the investigator 
or designee should assess potential factors leading to less than complete compliance and take 
steps to improve compliance.
In the event of an adverse event (AE) or reaction, subjects may be counseled to interrupt 
dosing permanently or temporarily.  Doses not taken in such instances do not count as 
planned dose administrations and do not constitute lack of compliance.
5.4. Investigational Product
5.4.1. Dosage Form and Packaging
Blinded investigational product, placebo or bococizumab 100 mg/mL, will be presented as a 
sterile solution, in pre-filled syringes, for subcutaneous injection, throughout the trial.  Each 
syringe will be packaged in an individual carton and sealed with a tamper-evident closure.  
Both syringes and cartons will be labeled in accordance with local regulations.  The cartons 
should not be opened until the drug is to be administered.  Each subject should receive 
enough pre-filled syringes to cover the number of doses until the next scheduled clinic visit.
Prefilled syringes containing sterile blinded investigational product (placebo solution), for 
subcutaneous injection will also be provided during the run-in period.  The run-in period 
syringes may be of different volumes compared to those provided during the treatment 
period.
Dose volumes for investigational product (placebo or active treatment arms) may change 
during the conduct of the study when dose modifications in the active treatment arm occur 
(Section 5.4.1.1) and comparable sham dose modifications are triggered by the IRT in the 
placebo treatment arm.
Protection of the blind is to be ensured by the guidance that (1) no more than one syringe 
carton should be opened at any one time, (2) syringes should be discarded, into the provided 
biohazard sharps container, immediately after use, (3) the subject and the members of study 
site and study team should remain blinded to lipid values, and by the design elements 
whereby (1) investigational product dose modifications are made in both the active and 
placebo treatment arms of the trial and (2) active and placebo are blinded in appearance, 
packaging, labeling, and storage conditions.
The subjects will continue to take their prescribed lipid lowering and other treatments as 
background medications.  None of these treatments will be provided as clinical trial drug 
supply.

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5.4.1.1. Dose Adjustments
Lipid levels will be blinded to the investigator and staff, subject and sponsor study team.  
Lipid level values from study visits will be transmitted directly from the central laboratory to 
the IRT system.  Dose modifications will be conducted through the IRT system to preserve 
the study blind. 
If a subject randomized to bococizumab has two consecutive end of dosing interval LDL-C 
measurements ≤10 mg/dL (0.26 mmol/L), the dose of bococizumab, for that subject, will be 
adjusted to 75 mg SC Q2wks.  If a bococizumab subject, again, has two consecutive end of 
dosing interval LDL-C measurements ≤10 mg/dL (0.26 mmol/L), after a dose modification to 
75 mg SC Q2wks, the dose frequency will be modified to bococizumab, 75mg SC Q4wks for 
the remainder of the study.  For each bococizumab subject who has a dose adjustment or 
dose frequency change, a placebo subject with similar baseline LDL-C will be selected for 
the same dose adjustment or dose frequency change at the visit with the same visit number.
5.4.2. Preparation and Dispensing
See the Dosage and Administration Instructions (DAI), package insert or equivalent, for 
instructions in how to prepare the investigational product for administration.  Investigational 
product should be prepared and dispensed by an appropriately qualified and experienced 
member of the study staff (eg, physician, nurse, physician’s assistant, practitioner, or 
pharmacist) as allowed by local, state, and institutional guidance.  Only qualified personnel 
(Section 4.5) should dispense investigational product to subjects.  At each study visit, 
subjects will be given multiple cartons of investigational product, for the purpose of ongoing 
treatment.  Since some study visit intervals are as long as 18 weeks after the first year of 
treatment, subjects may need to return to the study site for re-supply, so that they have a 
sufficient quantity of investigational product to continue dosing, prior to each study visit.
The following procedures should be followed to help protect the blind:
Under no circumstances should more than one syringe carton be opened at a study center, at 
any one time Similarly, neither the subject, nor the caregiver, should open more than one 
syringe carton, at any one time, in any location.  Used syringes should be placed immediately 
after use, whenever or wherever dosing occurs, in a biohazard sharps container and the 
container will be returned to the study site, as needed, eg, when the biohazard sharps 
container is full, or at early discontinuation (EDC)/EOS visits.
5.5. Administration
In general, it is expected that subjects will self-administer investigational product during the 
run-in period and after randomization. 
Qualified study site personnel will be trained on how to instruct subjects or care-giver in the 
proper administration of investigational product.  Subjects, who are not capable of the 
self-administration of investigational product, may have the injections administered by a 
caregiver who has been trained in the procedure, during the run-in period.  New or 
replacement caregivers will be trained for the administration of IP to a subject.

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Instructions on the administration of investigational product will be provided at Visit 2,
during the run-in period, and after randomization if re-training is necessary.  Investigational 
product will be administered as a single SC injection as outlined on the subject dosing cards.  
The drug will be injected into the upper or lower quadrant of the abdominal wall.  Study 
staff, care givers, and subjects should refer to the subject dosing instructions on the handling 
and administration of investigational product.
5.6. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.
Investigational product should be stored in its original container and in accordance with the 
drug label.  See the package label for storage conditions of the product.  All investigational 
product should be stored at 2 to 8º centigrade and protected from excessive shaking.  Single 
use syringes should remain in the protective carton until the time of dosing.
Storage conditions stated in the SRSD (Investigator Brochure) will be superseded by the 
storage conditions stated in the labeling.
Site systems must be capable of measuring and documenting, at a minimum, daily minimum 
and maximum temperatures for all site storage locations.  This should be captured from the 
time of investigational product receipt throughout the study.  Even for continuous monitoring 
systems, a log or site procedure that ensures active daily evaluation for excursions should be 
available.  The operation of the temperature monitoring device and storage unit (for example, 
refrigerator), as applicable, should be regularly inspected to ensure it is maintained in 
working order. 
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to labeled storage 
conditions, as described in the labeling, as soon as possible.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion. Use of the investigational product 
prior to sponsor approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site.
Site staff will instruct subjects on the proper storage requirements for take home 
investigational products.

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5.7. Investigational Product Accountability 
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of investigational product supplies.  All unused investigational product 
(kits, prefilled syringes, used and unused) must be returned to the investigator by the subject.
5.7.1. Destruction of Investigational Product
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site).  If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer, and all destruction must be adequately documented.
5.8. Concomitant Medication(s)
All permitted concomitant medication administration, as described below, should be recorded 
at each study visit; details as specified on the CRF and/or the CRF completion guidelines.
Subjects should take prescribed permitted concomitant medication, as needed, prior to the 
clinic visit, if it can be administered with water only.  Prescribed permitted concomitant 
medications that must be taken with food or after meals should not be taken until after the 
visit procedures have been completed.
5.8.1. Lipid Lowering Medication(s)
Subjects will continue to take their prescribed background lipid lowering treatment.  It is
expected that statin treatment (type, dose, and frequency) will not be modified for the 
duration of the trial.  Each subject’s primary health care provider needs to be informed that 
the subject’s lipid levels should not be checked outside the clinical trial and prescribed lipid 
lowering treatment doses should not be changed on the basis of an unblinded measurement of 
lipid levels.  If a dose adjustment in prescribed background lipid lowering therapy needs to 
take place because of an AE, such as partial or complete statin intolerance, the dose change 
and AE must be recorded in the appropriate CRF (Section 5.8.1.1).
During the study, subjects may continue to take additional, locally approved, non-statin lipid 
lowering treatment (eg, ezetimibe), during the conduct of the study, if they were taking such 
treatment at the time of screening. 
During the study, if subjects are prescribed a commercially available PCSK9 inhibitor, they 
must not take investigational product at the same time.  Wherever possible, these subjects 
should remain in the study and have all study procedures, until the study is concluded.  
Should a subject discontinue a prescribed commercially available PCSK9 inhibitor, they may 
resume treatment with investigational product, after consultation with the study team, 
regarding the timing of doing so.

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5.8.1.1. Statin Intolerance
It is possible, that, during the clinical trial, subjects will become statin intolerant due to AEs 
attributed to the background statin treatment.  Subjects, who develop statin intolerance, due 
to a documented AE, may be switched to another locally approved statin treatment or, if 
intolerant to two statins, due to documented AEs, treatment with other approved lipid 
lowering therapies such as niacin, ezetimibe, or bile acid sequestrants.  During the trial, 
subjects who are only able to tolerate a submaximal dose of any statin, due to a documented 
AE, will be designated as partially statin intolerant.  During the trial, subjects who are not 
able to tolerate two different statins, due to documented AEs, will be designated as 
completely statin intolerant.  In instances of partial or complete statin intolerance, the 
causative AEs triggering (background statin dose adjustments, changes in background statin 
type, or complete discontinuation of background statin treatment) must be recorded in the 
CRF.
5.8.2. Other Concomitant Medication(s)
The administration of concomitant medications required to treat concurrent medical 
conditions is permitted during the course of the study, consistent with local regulatory 
labeling, at the discretion of the investigator.  Medications that are contraindicated with 
concomitant lipid lowering therapy, according to local regulatory labeling, should be 
avoided.  In these subjects at high risk or very high risk of CV events, it is expected that 
subjects will be treated according to local guidelines, in the absence of contraindications.
6. STUDY PROCEDURES 
The specific procedures (including specific laboratory tests) to be performed at all study 
visits are shown in the Visit Schedule/Flowchart. 
Scheduling:
The visit window for all post randomization visits will be 14 days, except for visits 8, 11, 
for which the visits windows are 3 days, and EDC/EOS visits, which will not have visit 
windows.  Study sites should attempt to schedule each subject’s visits at the same time of day 
for that subject.  Visits should be scheduled based on the week in the Schedule of Activity
Table and coordinated with the subject’s dosing schedule, so that the visit day is coordinated 
with a subject’s relevant dose day, if possible.  Starting at Visit 5, and all subsequent visits, if 
a visit coincides with a scheduled injection of investigational product, the injection should be 
performed after all other study procedures have been completed.
Ideally, after randomization, visits should be scheduled to take place on a dosing day, so that 
dosing can take place at the end of the study visit.  Lipid level tests (direct LDL-C and lipid 
panel) should be scheduled no sooner than 10 days after the subject’s prior dose, even if this 
requires an unscheduled visit.  If a subject has a visit that is scheduled less than 10 days after 
the last dose, the visit procedures may take place, but lipid labs should be postponed and 
drawn at the earliest possible time, at an unscheduled visit, no sooner than 10 days after the 
last dose.

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Subjects will be required to fast (water only) for at least 10 hours prior to all study visits
during which blood samples will be collected, with the following exceptions.  Unscheduled 
assessments limited to measures of CK, liver function tests (including ALT, AST, alkaline 
phosphatase, and total and direct bilirubin), hepatitis C PCR testing, or pregnancy testing, do 
not require fasting.  Subjects should take prescribed permitted concomitant medication, as 
needed, prior to each study visit if it can be administered with water only; prescribed 
permitted concomitant medications that must be taken with food or after meals should NOT 
be taken until after the visit procedures have been completed.  Subjects who do not fast will 
be required to return for fasting laboratory tests, at the earliest possible time, before the next 
scheduled study visit.
6.1. Visit 0: Pre-screening visit
A pre-screening visit should be conducted to collect data which will help the investigator 
ascertain if a potential subject qualifies for this study.  The subject should be consented prior 
to any pre-screening procedures being completed at Visit 0.  At this visit, subjects will have 
consented to have had lipid levels assessed and provide medical records for review, only, so 
as to determine if the subject qualifies for this study.  The IRT system will determine if the 
subject is eligible for the study or if the subject should be screen failed.  The following 
activities should take place at this visit:

Obtain informed consent for access to historical records and lipid laboratory testing;  
At Visit 0, where required, or where pre-clinic visit fasting is not the general practice, 
subjects will need to return for Visit 0 blood sampling, at a subsequent unscheduled 
visit, so that 10 hour fasting only takes place after informed consent has been 
obtained;

Register the subject in the IRT system;

Obtain a fasting lipid blood sample (per Section 7.1.2.1) for analysis of LDL-C and 
non-HDL-C; 

Evaluate the subject for adverse and serious adverse events.
No data for the subject will be recorded in the pre-screening visit CRF until the cholesterol 
laboratory results are received, unless the subject experiences an AE or SAE.
The Pre-screening Visit 0 and Screening Visit 1, may be up to 30 days apart, since it may 
take time for the study site to obtain the subject’s medical records.
6.2. Visit 1: Screening Visit
Visit 1, the screening visit, should be scheduled after the pre-screening data (lipid results and 
medical records) are available to ascertain eligibility for the study.  The time interval 
between the Pre-screening Visit (Visit 0) and the Screening Visit (Visit 1) is a maximum of 
30 days. 

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Study specific informed consent should be obtained at Visit 1, before all other procedures, if 
not obtained previously.  Some study sites may have alternative informed consent 
requirements as specified by their institutional review board (IRB)/ethics committee (EC), 
but the general principle is that informed consent must have been obtained prior to the 
conduct of any study procedure.
Starting at Visit 1, study centers should attempt to schedule each subject’s visits at the same 
time of day and day of the week for that subject.
Investigator Level Assessments

Informed Consent: At Visit 1, the investigator will obtain written informed consent 
from each subject or the subject's legally acceptable representative before any 
study-specific activity is performed (see Section 12.3).  This informed consent covers 
the period from Visit 1 until the end of the subject’s participation in the study.  The 
investigator should ascertain that the subject’s primary care provider has been 
informed of the subject’s participation in the trial, that safety will be monitored, and 
that it will be important for the health care provider to not perform lipid chemistry 
analyses during the subject’s participation in the trial.

Demographics: Information such as date of birth, race, and gender will be collected.

Criteria for Eligibility: If the subject meets all the applicable inclusion criteria (see 
Section 4.1) and none of the exclusion criteria apply (see Section 4.2), the subject 
should be scheduled for Visit 2 to occur no more than 14 days after the screening 
visit.

Medical History: Qualifying cardiovascular disease (CVD) risk must be documented 
by supporting source documentation such as, but not limited to, copies of a hospital 
discharge summary, copies of medical records, or other documents that can be used to 
confirm the qualifying CVD risk event or diagnosis and its approximate date of 
occurrence or onset.  Ideally, this documentation should be acquired before Visit 1. 

Vital Signs: (1) Temperature, (2) pulse rate (PR), and (3) BP will be recorded as 
described in Section 7.2.3.1.

Prior and Concomitant Medications: Any medications (over-the-counter or 
prescribed), including lipid lowering medications, vitamins, and herbal supplements 
taken in the last 3 months should be recorded.  Start and stop dates for medications 
should be recorded as accurately as possible. 

IRT interaction:  Subjects will be registered in the IRT, Visit 1, Screening Visit, and 
assigned a screening number by the system.

Laboratory tests: At Visit 1, laboratory specimens will be obtained for analysis as 
specified in the Schedule of Activities (Visit Schedule/Flowchart and Section 7.2.1): 
chemistry group tests (including liver function tests [LFTs] and creatine kinase [CK]), 

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hematology tests, urinalysis, and urine and serum pregnancy tests (in female subjects 
of childbearing potential, only).  At the screening visit hs-CRP, Lp(a), and a central 
lab urine albumin/creatine ratio may be evaluated, only in subjects who have had a 
cardiovascular event more than 5 years prior to screening and in subjects without a 
prior qualifying cardiovascular event. Hepatitis B and C virus serologies will be 
collected for all subjects at the screening visit.  A positive or indeterminate hepatitis 
C serology may trigger a hepatitis C PCR test for confirmation.

Adverse Events (including SAEs): Subjects will be asked if any AEs have occurred.  
SAEs should be reported as per the safety requirements of the study (Section 8.6).  
During the run-in period, AEs (serious and non serious) should be recorded on the 
CRF.  SAEs should be reported as per the safety requirements of the study 
(Section 8.6).  Subjects should be questioned, specifically, about the occurrence of 
potential new cardiovascular events, since their occurrence, after screening but before 
randomization, might be exclusionary (Section 4).

Lifestyle guidance: Subjects will be provided with educational information 
describing therapeutic life style change guidelines that are recommended for patients 
at risk of major CV events (Section 4.4).  The particular guidelines used will be 
documented in the CRF, and their review with the subject by the investigator or 
his/her designee Run-in period visits.

Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2).
Re-screening is permitted for subjects who were screened previously, but now meet 
inclusion/exclusion criteria.  Rescreening is also permitted in the event of lost or damaged 
laboratory samples, in which case only the lost or damaged laboratory tests need to be 
replaced.  Additionally, subjects who cannot complete screening procedures between the date 
of screening and the planned Visit 2 date, due to unforeseen circumstances, such as but not 
limited to, delays in study drug shipment to the clinical site or acts of nature (eg, weather 
disasters), may be re-screened.  In this case all eligibility criteria need to be reviewed, and the 
fasting lipid profile, pregnancy test (if applicable), medical history and concomitant 
medications need to be redone/updated.
6.3. Run-in Period
The primary objectives of the run-in period are to ensure (1) compliance with the SC 
administration of a parenteral agent, (2) that subjects meet inclusion and exclusion criteria 
and (3) can follow study procedures.
For run-in Visits 2, up to and including Visit 5 (the randomization visit), visits should be 
scheduled no less than 7 and no more than 14 days apart.  The run-in period continues until 
Visit 5, randomization.  Visit 5 should be scheduled no more than 14 days after Visit 4, the 
final run-in visit

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All subjects will be assessed for AEs, SAEs and CV events at every visit during the trial, 
including the run-in period.
6.3.1. Visit 2: Run-in Visit
The following procedures should be completed:

Assessment of inclusion/exclusion criteria: Subjects should be reassessed to 
confirm that they meet the applicable inclusion/exclusion criteria.

Concomitant medication assessment: Subjects will have a concomitant medication 
assessment which will include prescribed background lipid lowering treatment.  The 
medication names and doses will be recorded in the CRF.

Assessment of AEs (including SAEs):  Subjects will be asked if any AEs have 
occurred.  SAEs should be reported as per the safety requirements of the study 
(Section 8.6).  During the run-in period, AEs (serious and non serious) should be 
recorded on the CRF. SAEs should be reported as per the safety requirements of the 
study (Section 8.6).  Subjects should be questioned, specifically, about the occurrence 
of potential new cardiovascular events, since their occurrence, after screening but 
before randomization, might be exclusionary (Section 4).

Vital signs (only if clinically indicated): Temperature, PR, and BP will be measured 
and recorded in the CRF as described in Section 7.2.3.1.

IRT interaction:  At the time of the visit, the visit will be registered in the IRT which 
will trigger an allocation of investigational product (placebo) for the subject.

Dispensing of open-label placebo investigational product: At Visit 2, subjects or 
their care giver, will be instructed on the storage and administration of the injectable 
investigational product.  They will not be provided with investigational product to 
take home at this visit.  They will be given the opportunity to practice self-injection
during the study visit.  They will also be instructed on what to do with used injection 
materials after the administration of investigational product.  They will be informed 
on how to identify and report potential injection site reactions.  Optimally, subjects 
should be able to self-inject the investigational product, but if that is not possible, a 
trained care giver may administer the investigational product. 
Subjects will be informed on how the investigational product will be supplied and 
that there may be a need for interval trips to the study site, solely for the purpose of 
drug re-supply, during the conduct of the study.  Documentation of investigational 
product usage will be recorded in the CRF and the IRT.

Compliance check:  The subject’s compliance with investigational product 
administration, as described in Section 5.3, will be assessed Compliance with lifestyle 
guidelines should also be reviewed (Section 4.4) and recorded in the CRF. 

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
Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2).
6.3.2. Visit 3:  Run-in Visit
The following procedures and assessments should be made before subject self-injection:

Concomitant medication assessment: Subjects will have a concomitant medication 
assessment which will include prescribed background lipid lowering treatment.  The 
medication names and doses will be recorded in the CRF.

Assessment of AEs (including SAEs):  Subjects will be asked if any AEs have 
occurred. During the run-in period AEs (serious and non serious) should be recorded 
on the CRF.  SAEs should be reported as per the safety requirements of the study 
(Section 8.6).  Subjects should be questioned, specifically, about the occurrence of 
potential new cardiovascular events (Section 8.6.1) since their occurrence, after 
screening but before randomization, might be exclusionary (Section 4).

Vital signs (only if clinically indicated):  Temperature, PR, and BP will be 
measured and recorded in the CRF as described in Section 7.2.3.1.

Laboratory tests: All subjects will have a fasting lipid profile measured.  These 
values will not be used to ascertain lipid eligibility for the study, but will be used in 
the calculation of the baseline lipid values.  A blood specimen should be acquired for 
analysis of a PCSK9 level.

IRT interaction:  At the time of the visit, the visit will be registered in the IRT which 
will trigger an allocation of investigational product (placebo) for the subject.

Dispensing of open-label placebo investigational product:  At Visit 3, subjects or 
their care- giver, will be re-instructed on the storage and administration of the 
injectable investigational product.  They will not be provided with investigational 
product to take home at this visit.  They will be given the opportunity to practice 
self-injection during the study visit.  They will also be instructed on what to do with 
used injection materials after the administration of investigational product.  They will 
be re-instructed on how to identify and report potential injection site reactions.  
Documentation of investigational product usage (placebo), will be recorded in the 
CRF and the IRT

Compliance check: The subject’s compliance with investigational product 
administration, as described in Section 5.3 will be assessed.  Compliance with 
lifestyle guidelines should also be reviewed (Section 4.4) and recorded in the CRF. 

Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2).

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6.3.3. Visit 4:  Run-in Visit
The following procedures and assessments should be made before subject self-injection:

Concomitant medication assessment: Subjects will have a concomitant medication 
assessment.  The medication names and doses will be recorded in the CRF.

Assessment of AEs (including SAEs):  Subjects will be asked if any AEs have 
occurred.  During the run-in period AEs (serious and non serious) should be recorded 
on the CRF.  SAEs should be reported as per the safety requirements of the study 
(Section 8.6).  Subjects should be questioned, specifically, about the occurrence of 
potential new cardiovascular events (Section 8.6.1) since their occurrence, after 
screening but before randomization, might be exclusionary (Section 4).

Vital signs (only if clinically indicated): Temperature, PR, and BP will be measured 
and recorded in the CRF as described in Section 7.2.3.1.

IRT interaction:  At the time of the visit, the visit will be registered in the IRT which 
will trigger an allocation of investigational product (placebo) for the subject.

Dispensing of open-label placebo investigational product:  At Visit 4, subjects or 
their care giver, will be re-instructed on the storage and administration of the 
injectable investigational product.  They will not be provided with investigational 
product to take home at this visit.  They will be given the opportunity to practice 
self-injection during the study visit.  They will also be instructed on what to do with 
used injection materials after the administration of investigational product.  They will 
be re-instructed on how to identify and report potential injection site reactions.  
Documentation of investigational product usage (placebo) will be recorded in the 
CRF and the IRT.

Compliance check:  The subject’s compliance with investigational product 
administration, as described in Section 5.3, will be assessed.  Compliance with 
lifestyle guidelines should also be reviewed (Section 4.4) and recorded in the CRF. 

Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2). 

Review of inclusion/exclusion criteria:  At Visit 4 a determination will be made to 
confirm if the subject fulfills all inclusion criteria (Section 4.1), and that there are no 
exclusion criteria present (Section 4.2).
6.4. Treatment Period
Visit windows for the treatment period are 14 days for all visits except Visit 8 (Week 14)
and Visit 11 (Week 52), each of which has a visit window of 3 days.
After Visit 5 (Week 0) subjects will be seen at Visit 6 (Week 4), Visit 7 (Week 8), Visit 
8 (Week 14), Visit 9 (Week 26), Visit 10 (Week 40), and Visit 11 (Week 52).  After Visit 11,
subjects will be seen as indicated in the Schedule of Activities, until study completion and 
the EOS.  Subjects who discontinue investigational product early (EDC), will be encouraged 

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to be followed, according to the Schedule of Activities, until study EOS.  If the study is not 
completed by Visit 20, visits will continue in accordance with the Schedule of Activities for 
annual visits (Visits 11, 14, 17, 20) and interim visits (eg, Visits 12, 13, 15, 16, 18, and 19),
until EOS.  The study may end sooner than Visit 20, if the primary endpoint event accrual 
rate is faster than anticipated or the trial is terminated for other reasons.
Subjects who have had an IP dose frequency modification to dosing every 4 weeks, will need 
to have their visit frequency increased to every 8 weeks, approximately, for the purposes of 
direct LDL-C measurement (Section 5.4.1.1) and an assessment for adverse events, both 
serious and non-serious (Section 6.4.5).  These more frequent visits should be instituted after 
the visit at which the subject was informed of the decreased dose frequency.  Such subjects 
should maintain the original visit schedule, with an additional visit scheduled approximately 
half-way between the already scheduled visits.
6.4.1. Visit 5 (Week 0) Randomization (Baseline) Visit
The following procedures and assessments should be made before subject self-injection of 
investigational product:

Assessment of inclusion/exclusion criteria:  The subject should be re-evaluated to 
ensure that he/she have met the inclusion/exclusion criteria, for the study, prior to 
randomization using the IRT system.

IRT interaction: At the randomization visit, the subject will be registered in the IRT 
and assigned a randomization number by the system.  The IRT will assign the subject 
to blinded investigational product.

Concomitant medication assessment: Subjects will have a concomitant medication 
assessment. At the randomization visit, and all subsequent visits, subjects should 
continue their prescribed background medications, including their lipid lowering 
treatment.  Any changes in background medications should be recorded in the CRF.

Assessment of AEs (including SAEs) or potential CVD outcome events: Subjects 
will be asked if any AEs have occurred.  AEs (serious and non serious), with an onset 
during the run-in period, should be recorded on the CRF.  SAEs should be reported as 
per the safety requirements of the study (Section 8.6).  Subjects should be specifically 
interrogated with respect to the occurrence of potential outcome events.  Potential 
CVD outcome events should be reported as required (Section 8.6.1).  Subjects with 
SAEs that would have potentially met the criteria for a CVD event (as defined in 
Appendix 4), between Visit 0 and Visit 5, should be excluded.  Such subjects may be 
rescreened at a later date.

Vital signs: Temperature, PR, and BP will be measured and recorded in the CRF as 
described in Section 7.2.3.1.

Examinations: Randomized subjects will have a complete physical exam and a 
neurologic exam, as described in Section 7.2.3.2.  Cognitive assessments are only to 
be performed at designated study sites (Section 7.2.3.4).  The subject’s weight, 
height, and waist circumference will also be measured as described in 
Section 7.2.3.2.1.  All findings will be recorded in the CRF.

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
Laboratory tests:  At the randomization visit subjects will have the following 
laboratory tests: chemistry group tests (including LFTs and CK level), hematology 
tests, urinalysis, urine and serum pregnancy tests (in female subjects of childbearing 
potential only), fasting lipid profile, special lipid and efficacy studies, and 
hemoglobin A1c (HbA1c).

Blood specimens:  Blood specimens will be acquired for ADA, bococizumab level, 
and PCSK9 level.

Biospecimens:  Biospecimens will be collected as described in Section 7.5.

12-Lead ECG: A 12-lead ECG should be recorded and saved (Section 7.2.2).

EuroQol 5-Dimensions Health State Profile (EQ-5D): Subjects will complete a
brief EQ-5D questionnaire as described in Section 7.3.1.  Results will be transcribed 
to the CRF.

Depression assessment:  A Patient Health Care Questionnaire 2 (PHQ-2) will be 
completed at the randomization visit in all subjects and if the score is 2, the 
remaining 7 PHQ questions will be completed as the PHQ-9 (see Section 7.3.2).  If 
the PHQ-9 score is 10, the subject should be referred back to his/her primary care 
physician for further assessment and/or treatment of potential major depression.  If 
the PHQ-9 score is 15 or there is a positive score in question 9, the subject should 
excluded from participation, the subject’s primary care physician (PCP) should be 
informed, and the subject should be referred to a mental health professional, either by 
the PCP or the investigator.  Such subjects may be rescreened, at a later date, if they 
were evaluated and treated as appropriate, and the repeat PHQ scores permit 
inclusion.  Any adverse events should be documented in the case report form as 
appropriate.

Dispensing of investigational product:  At Visit 5, Subjects will be dispensed 
investigational product according to the IRT allocation.  At the visit, subjects or their 
care giver, will be re-instructed on the storage and administration of the injectable 
investigational product, as well as how to store, safely, used injection materials, after
the administration of investigational product.  The self-injection process will be 
reviewed with the subject.  Subjects will be observed, at the visit, during injection of 
investigational product, either by self-injection, or as performed by a care giver and 
observed for a period of 30 minutes, to determine if any signs or symptoms develop.  
The observation period may be extended, if any signs or symptoms become apparent.  
They will be re-instructed on how to identify and report potential injection site or
hypersensitivity reactions.

Compliance check:  The subject’s compliance with investigational product 
administration, as described in Section 5.3 will be assessed.  Subjects will be 
instructed to bring any used and unused syringe cartons to each visit.  Used syringes 
will be returned to the study center in a biohazard container, when it is full, to receive 

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a new container, and when directed by the study site, as described in Section 5.3.  
Compliance with lifestyle guidelines should also be reviewed (Section 4.4) and 
recorded in the CRF. 

Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2). 
6.4.2. Visits 6 (Week 4) and 7 (Week 8)
The following procedures and assessments should be made before subject self-injection:

Laboratory test review:  There should be a review of results from laboratory values 
of the previous visit.

Vital signs: Temperature, PR, and BP will be measured and recorded in the CRF as 
described in Section 7.2.3.1.

Concomitant medications:  Background prescribed lipid lowering treatment (drug 
name and dose) and all other concomitant treatments will be recorded in the CRF.  
Instruct subjects on the use of concomitant medications (Section 5.8).

Health care resource utilization: Assessment of health care resource utilization 
(Section 7.7)

Assessment of AEs (including SAEs) or potential CVD outcome events: Subjects 
will be asked if any AEs have occurred.  AEs (serious and non serious) should be 
recorded on the CRF.  SAEs should be reported as per the safety requirements of the 
study (Section 8.6).  Subjects should be specifically interrogated with respect to the 
occurrence of potential outcome events.  Potential CVD outcome events should be 
reported as required (Section 8.6.1).

IRT interaction:  At the time of the visit, the visit will be registered in the IRT which 
will trigger an allocation of investigational product for the subject.

Investigational product:  Dispense investigational product based on IRT 
randomization code.  If there is dosing during the visit, subjects will be observed, at 
the visit, during the injection of investigational product, either by self-injection, or as 
performed by a care giver, after all other procedures have been completed.  Subjects
will be provided with investigational product kits to bring home with them and will 
be reminded about storage conditions.

Compliance check:  The subject’s compliance with investigational product 
administration, as described in Section 5.3 will be assessed.  Subjects will be 
instructed to bring any used and unused syringe cartons to each visit.  Used syringes 
will be returned to the study center in a biohazard container, when it is full, to receive 
a new container, and when directed by the study site, as described in Section 5.3.  
Compliance with lifestyle guidelines should also be reviewed (Section 4.4) and 
recorded in the CRF.

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
Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2).
The following laboratory tests will be collected:

Blood for fasting lipid profile: 
Lipid level tests should be scheduled no sooner than 10 days after the subject’s prior 
dose, even if this requires an unscheduled visit;  
If a subject has a visit that is scheduled less than 10 days after the last dose, the visit 
procedures may take place, but lipid testing should be postponed and performed at the 
earliest possible time, at an unscheduled visit, no sooner than 10 days after the 
subject's last dose;

LFTs;

Blood specimens acquired for ADA, bococizumab level, and PCSK9 level in all 
subjects at Visit 6 only;
After randomization, if lipid sampling has been postponed to an unscheduled visit, the 
corresponding ADA/PK/PCSK9 samples should be postponed as well, and collected 
at the same time as the rescheduled lipid sample collection;

Urine and serum for pregnancy testing (if indicated).
6.4.3. Visits 8, 9, 10, 12, 13, 15, 16, 18, and 19
At weeks 14, 26, 40, 70, 86, 122, 140, 174, and 192, the following procedures and 
assessments should be made before subject self-injection:

Laboratory test review:  There should be a review of results from laboratory values 
of the previous visit.

Vital signs: Temperature, PR, and BP will be measured and recorded in the CRF as 
described in Section 7.2.3.1.

Concomitant medications:  Background prescribed lipid lowering treatment (drug 
name and dose) and all other concomitant treatments will be recorded in the CRF.  
Instruct subjects on the use of concomitant medications (Section 5.8).

Health care resource utilization:  Assessment of healthcare resource utilization 
(Section 7.7).

Assessment of AEs (including SAEs) or potential CVD outcome events: Subjects 
will be asked if any AEs have occurred.  AEs (serious and non serious) should be 
recorded on the CRF. SAEs should be reported as per the safety requirements of the 

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study (Section 8.6).  Subjects should be specifically interrogated with respect to the 
occurrence of potential outcome events.  Potential CVD outcome events should be 
reported as required (Section 8.6.1).

EQ-5D: Subjects will complete a brief questionnaire as described in Section 7.3 at 
visits 8 and 9 only. Results will be transcribed to the CRF.

IRT interaction:  At the time of the visit, the visit will be registered in the IRT which 
will trigger an allocation of investigational product for the subject.

Investigational product:  Dispense investigational product based on IRT 
randomization code.  If there is dosing during the visit, subjects will be observed, at 
the visit, during the injection of investigational product, either by self-injection, or as 
performed by a care giver, after all other procedures have been completed.

Subjects will be provided with investigational product kits to bring home with them 
and will be reminded about storage conditions.

Compliance check:  The subject’s compliance with investigational product 
administration, as described in Section 5.3 will be assessed.  Subjects will be 
instructed to bring any used and unused syringe cartons to each visit.  Used syringes 
will be returned to the study center in a biohazard container, when it is full, to receive 
a new container, and when directed by the study site, as described in Section 5.3.  
Compliance with lifestyle guidelines should also be reviewed (Section 4.4) and 
recorded in the CRF. 

Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2). 
The following laboratory tests should be collected:

Blood for fasting lipid profile: 
Lipid level tests should be scheduled no sooner than 10 days after the subject’s prior 
dose, even if this requires an unscheduled visit;  
If a subject has a visit that is scheduled less than 10 days after the last dose, the visit 
procedures may take place, but lipid testing should be postponed and performed at the 
earliest possible time, at an unscheduled visit, no sooner than 10 days after the 
subject's last dose;

Special lipid and efficacy studies, as described in Section 7.1.2.2, will be collected at 
Week 14, Visit 8.

Chemistry group;

LFTs;

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
Blood specimens acquired for ADA, bococizumab level (PK), and PCSK9 level in all 
subjects at Visits 8, 10, and 12;  
After randomization, if lipid sampling has been postponed to an unscheduled visit, the 
corresponding ADA/PK/PCSK9 samples should be postponed as well, and collected 
at the same time as the rescheduled lipid sample collection;

Urine and serum for pregnancy testing (if indicated).
6.4.4. Visits 11, 14, 17, 20, and Early Study Discontinuation or End of Study Visit
At the annual visits (Weeks 52, 104, 156, and 208) or early study discontinuation or end of 
study visit, the following procedures and assessments should be completed.  Except for the 
early discontinuation or end of study visits, all of the procedures should be completed before 
the self-administration of investigational product.
When the criteria for stopping the trial outlined in Section 3 have been met, the study sites 
will be contacted by the study team and told to instruct their subjects to discontinue taking 
IP.  EOS visits should be scheduled as soon as possible after that announcement.  The EOS 
visit should be scheduled to occur no sooner than 14 days after the last dose of 
investigational product was administered.  The safety follow-up period is 40 days after the 
last dose of IP was administered. If their EOS visit has occurred less than 40 days after the 
last dose of IP was administered, subjects will receive a telephone call to determine if any 
serious adverse events have taken place. All EOS procedures should be done for all 
randomized subjects when the study is completed whether or not the subject is taking 
double-blind investigational product.
All EDC procedures should be done upon the permanent early discontinuation of 
double-blind investigational product.  Subjects should continue to have visits with study 
personnel according to the study schedule until study completion.  If a subject has not fully 
withdrawn consent for further contact with the study site, the subject should be encouraged to 
remain in contact with the investigator, either by attending study visits or via phone visit, 
throughout the remainder of the study. The study management team will provide to the study 
site, an EDC retention hotline, and a study retention toolkit, to define potential levels of the 
subject's continued participation in the study. Every effort must be made to retain subjects in 
the study, even if they are no longer taking investigational product.

Laboratory test review:  There should be a review of results from laboratory values 
of the previous visit.

Vital signs: Temperature, PR, and BP will be measured and recorded in the CRF as 
described in Section 7.2.3.1.

Examinations:  Subjects will have a complete physical exam and a neurologic exam, 
as described in Section 7.2.3.  Waist circumference will be measured only at the EDC 
or EOS visits.  Cognitive assessments are only to be performed at designated study 
sites, in those subjects who had baseline assessments (Section 7.2.3.4), annually and 
at EDC and/or EOS visits. 

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
12 Lead ECG:  A 12 Lead ECG will be recorded (Section 7.2.2).

Concomitant medications:  Background prescribed lipid lowering treatment (drug 
name and dose) and all other concomitant treatments will be recorded in the CRF.  
Instruct subjects on the use of concomitant medications (Section 5.8).

Health care resource utilization:  Assessment of healthcare resource utilization
(Section 7.7)

Assessment of AEs (including SAEs) or potential CVD outcome events: Subjects 
will be asked if any AEs have occurred.  AEs (serious and non serious) should be 
recorded on the CRF.  SAEs should be reported as per the safety requirements of the 
study (Section 8.6).  Subjects should be specifically interrogated with respect to the 
occurrence of potential outcome events.  Potential CVD outcome events should be 
reported as required (Section 8.6.1)

EQ-5D: Subjects will complete a brief questionnaire as described in Section 7.3.  
Results will be transcribed to the CRF.

Depression assessment:  Only subjects participating in the cognitive assessment 
sub-study will have annual, and end of treatment or end of study PHQ assessments, in 
addition to the baseline assessment (Section 7.3.2).  If at any the visits after the 
baseline assessment, a subject scores 2, the remaining 7 questions of the 
PHQ-9 will be answered.  If the PHQ-9 score is 10, consideration should be given 
to referring the subject back to his/her primary care physician for further assessment 
of potential major depression and recommendations.  If the PHQ-9 score is 15 or 
there is a positive score in question 9, the subject’s primary care physician (PCP) 
should be informed, and the subject should be referred to a mental health 
professional, either by the PCP or the investigator.  Any adverse events should be 
documented in the case report form as appropriate.

IRT interaction:  At the time of the visit, the visit will be registered in the IRT which 
will trigger an allocation of investigational product for the subject, except at the EDC 
or EOS visit.  At the EDC or EOS visit, the EDC or EOS status will be registered.

Investigational product:  Dispense investigational product based on IRT 
randomization code (except for EDC or EOS visit).  If there is dosing during the visit, 
subjects will be observed, at the visit, during the injection of investigational product, 
either by self-injection, or as performed by a care giver, after all other procedures 
have been completed.  Except for EDC or EOS visit, subjects will be provided with 
investigational product kits to bring home with them and will be reminded about 
storage conditions.

Compliance check:  The subject’s compliance with investigational product 
administration, as described in Section 5.3, will be assessed.  Subjects will be 
instructed to bring any used and unused syringe cartons to each visit.  Used syringes 

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will be returned to the study center in a biohazard container, when it is full, to receive 
a new container, and when directed by the study site, as described in Section 5.3.  
Compliance with lifestyle guidelines should also be reviewed (Section 4.4) and 
recorded in the CRF. 

Contraception check:  A contraception check should be made for male and female 
subjects, who, with their partner, are of childbearing potential (Section 4.4.2). 
The following laboratory tests will be collected:

Blood for fasting lipid profile: 
Lipid level tests should be scheduled no sooner than 10 days after the subject’s prior 
dose, even if this requires an unscheduled visit;  
If a subject has a visit that is scheduled less than 10 days after the last dose, the visit 
procedures may take place, but lipid testing should be postponed and performed at the 
earliest possible time, at an unscheduled visit, no sooner than 10 days after the 
subject's last dose;
A lipid profile will not be collected at EDC/EOS visits;

Special lipid and efficacy studies as described in Section 7.1.2.2, at Week 52, Visit 
11;

Biospecimens as described in Section 7.5, at Week 52, Visit 11;

Chemistry group (including LFTs and CK level);

Hematology;

Urinalysis;

HbA1c for all subjects at Visit 11 and EDC and/or EOS;

Blood specimens acquired for ADA, bococizumab level, and PCSK9 level in all 
subjects at Visits 14, 17, 20, and EDC or EOS;
After randomization, if lipid sampling has been postponed to an unscheduled visit, the 
corresponding ADA/PK/PCSK9 samples should be postponed as well, and collected 
at the same time as the rescheduled lipid sample collection;

Urine and serum for pregnancy testing (if indicated);

Hepatitis C virus serologies will be collected at the EDC or EOS visit for subjects at 
study sites in Canada.  A positive or indeterminate hepatitis C serology may trigger a 
hepatitis C polymerase chain reaction (PCR) test for confirmation.

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6.4.5. Visits after second dose modification of Investigational Product
Subjects who have had dosing of IP modified by the IRT system to Q4wks (Section 5.4.1.1), 
will need to have their visit frequency changed to obtain a direct LDL-C level every 8 weeks 
(Q8wks), approximately.  Such subjects should maintain the original visit schedule, with an 
additional visit scheduled approximately half-way between the already scheduled visits.  This 
will permit the DMC to perform an independent safety review, in an ongoing fashion so as to 
ascertain if there are any potential safety issues, consequent to the modification of IP dosing. 
The direct measurement of LDL-C tests should be scheduled no sooner than 10 days after the 
subject’s prior dose, even if this requires an unscheduled visit.  If a subject has a visit that is 
scheduled less than 10 days after the last dose, the visit procedures may take place, but lipid, 
ADA, PK, and PCSK9 testing should be postponed and performed at the earliest possible 
time, at an unscheduled visit, no sooner than 10 days after the subject's last dose.
Since all subjects with a dose frequency modification (both those on placebo and those 
receiving bococizumab) will have more frequent direct LDL-C monitoring, the blinding of 
the study should be preserved.
At these visits for direct LDL-C assessment the following additional assessments should take 
place:

Health care resource utilization:  Assessment of healthcare resource utilization 
(Section 7.7).

Assessment of AEs (including SAEs) or potential CVD outcome events: Subjects 
will be asked if any AEs have occurred.  AEs (serious and non serious) should be 
recorded on the CRF.  SAEs should be reported as per the safety requirements of the 
study (Section 8.6).  Subjects should be specifically interrogated with respect to the 
occurrence of potential outcome events.  Potential CVD outcome events should be 
reported as required (Section 8.6.1)

Compliance check:  The subject’s compliance with investigational product 
administration, as described in Section 5.3, will be assessed.  Collect all used and 
unused syringes in a biohazards container, as needed.  Compliance with lifestyle 
guidelines should also be reviewed (Section 4.4) and recorded in the CRF. 

Contraception check:  At these visits, a contraception check should be made for 
male and female subjects, who, with their partner, are of childbearing potential 
(Section 4.4.2). 
6.4.6. Discontinuation of Investigational Product
Subjects, who temporarily or permanently discontinue investigational product, should remain 
in the study and continue to be followed at all scheduled visits, for the duration of the study.  
Subjects with the temporary discontinuation of investigational product should resume its 
administration when deemed appropriate by the investigator and, if necessary, with 
consultation of the Sponsor.  Only subjects who have permanently discontinued

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investigational product are classified as Off Drug In Study (ODIS) subjects.  ODIS subjects
are those not expected to, or planned to resume the administration of investigational product.  
ODIS subjects should remain in contact with the investigator, either by attending study visits 
or via phone visit, throughout the remainder of the study. The sole exception to continuing 
some level of contact with the investigator is if a subject fully withdraws consent, as 
described in Section 6.5.  Temporary or permanent discontinuation of investigational product
and/or resumption of investigational product after a temporary discontinuation must be 
registered in the IRT.
For all ODIS and Withdrawn Consent subjects the study site must discuss the case with a 
study team member, ie, retention hotline or delegate to discuss the subject status and ensure 
continued follow-up in the study.  The study management team will provide to the study site, 
an EDC retention hotline and a study retention toolkit, to define potential levels of the 
subject's continued participation in the study, even if the subject is no longer taking 
investigational product (ie, an ODIS subject). Every effort must be made to retain subjects in 
the study, even if they are no longer taking investigational product.
6.5. Subject Withdrawal
6.5.1. Withdrawal of Consent
Subjects who withdraw consent are defined as those subjects who refuse any further contact 
with the investigator or persons authorized by the subject, previously, to receive the subject's 
study information.  Subjects should notify the investigator of the decision to withdraw 
consent from future follow-up in writing, whenever possible.  The reason for withdrawal of 
consent should be explained in detail in the medical records by the investigator, as to whether 
the withdrawal is from further treatment with study drug only or also from study procedures 
and/or post treatment study follow-up, and entered on the appropriate CRF page.  The 
investigator should document thoroughly, the efforts by the site to retain the subject by 
offering the subject the opportunity to remain in the study as an ODIS subject with complete 
study visits or lesser degrees of follow up (ie, phone contact). In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available information 
should be used to determine vital status only as appropriately directed in accordance with 
local law.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site, with the exception noted in Section 6.5.3.  In such 
circumstances, subjects should be encouraged to remain in contact with the investigator, and 
to be followed as ODIS subjects, either by attending study visits or via phone visit 
throughout the remainder of the study in order to provide safety information as it occurs.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.

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6.5.2. Lost to Follow-Up
Lost to follow-up is defined by the inability to reach the subject by the end of the study, only.  
No subject should be considered lost to follow-up, until the study has been completed. If a 
subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  Attempts to reschedule the visit should be completed by phone, e-mail, text 
message, and if necessary, by letter and/or certified mail, in instances where the subject is not 
responsive to contact attempts. This includes follow-up with persons authorized by the 
subject as noted above.  The study retention team must be contacted, through the retention 
hotline or delegate, to discuss strategies available for assistance with locating subjects who 
are potentially lost to follow-up.  All efforts to retain a subject, should continue throughout 
the course of the study and should be documented in the subject’s medical source records.  
Every effort should be made to have the subject complete an EDC or EOS visit and to
document subject's vital status, if possible. 
If it is determined that the subject has died, the site will use permissible local methods to 
obtain the date and cause of death.  If investigator’s use of third-party representative to assist 
in the follow-up portion of the study has been included in the subject’s informed consent, 
then the investigator may use a Sponsor retained third-party representative to assist site staff 
with obtaining subject’s contact information or other public vital status data necessary to 
complete the follow-up portion of the study.  The site staff and representative will consult 
publicly available sources, such as public health registries and databases, in order to obtain 
updated contact information.  If after all attempts, the subject remains lost to follow-up, then 
the last known alive date as determined by the investigator should be reported and 
documented in the subject’s medical records.
6.5.3. Individual Subject Dosing Stopping Criteria
No subjects will be withdrawn from the study by the investigator or the sponsor because of 
lack of compliance with investigational product administration (Section 5.3).
During the double-blind, active treatment phase subjects will have clinic visits at regular 
intervals.  The following individual dosing stopping criteria will be followed:

Dosing with blinded investigational product (bococizumab, matching placebo) may 
be temporarily discontinued or stopped for intolerable adverse events, or if the 
Investigator believes that continuing dosing will be detrimental to the subject’s 
mental or physical health;

Dosing with blinded investigational product should be stopped if the subject starts 
taking a marketed PCSK9 inhibitor;  

Subjects with CK values >5 x ULN confirmed by repeat test (Refer to Section 7.2.5), 
for whom the CK elevation is associated with muscle pain, muscle tenderness and/or 
muscle weakness, or new onset renal dysfunction, must be discontinued from study 
treatment and asked to complete the remainder of the scheduled visits without 
receiving blinded investigational product (bococizumab or placebo). 

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7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described. However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator, which may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.
The study team will be informed of these incidents in a timely fashion.
In order to completely and accurately assess the primary and secondary clinical efficacy 
endpoints and the safety profile of the treatment groups, the vital status of each randomized 
subject must be obtained at the completion of the study.  The occurrence of potential clinical 
outcome events as defined in Section 2.2 will trigger the compilation of a dossier that 
includes anonymized supporting medical record information that will be sent to the clinical 
Adjudication Committee.
7.1. Efficacy Assessments
7.1.1. Clinical Endpoints
Clinical endpoints defined as primary or secondary efficacy parameters will be assessed 
beginning with the day of randomization.  Cardiovascular adverse events occurring between 
pre-screening (the time of pre-screening informed consent) and randomization should be 
reported as adverse events and not submitted for adjudication.  All potential disease-related 
efficacy endpoints occurring after randomization, through study completion/end of study 
visit, should be reported as an adverse event and submitted for adjudication, whether or not 
the subject is on double-blind investigational product.  A complete description of these 
endpoints, their definition, the documentation that needs to be provided for review, and the 
processes whereby the documentation is prepared and transmitted for adjudication by the 
Adjudication Committee are detailed in a separate Adjudication Committee Charter.  
Potential endpoint documentation should include, but is not limited to, any of the following:  
hospital discharge summaries, operative reports, clinic notes, ECGs, diagnostic test data 
and/or results, autopsy reports and death certificate information.
The identification of a potential disease-related efficacy endpoint will be made by the study 
site and communicated to Pfizer or designated representative immediately (within 24 hours). 
7.1.1.1. Primary Clinical Endpoint
The primary endpoint is the time from randomization to the first occurrence of the 
adjudicated and confirmed occurrence of a major CV event, a composite endpoint which 
includes CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina 
needing urgent revascularization (as defined in Appendix 4).

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7.1.1.2. Key Secondary Clinical Endpoints
The times from randomization to the first adjudicated and confirmed occurrence of the 
endpoints below (as defined in Appendix 4):

A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;

A composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke, and 
hospitalization for unstable angina needing urgent revascularization;

A composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke;

Hospitalization for unstable angina needing urgent revascularization;
7.1.1.3. Other Clinical Secondary Endpoints
The times from randomization to the first adjudicated and confirmed occurrence of the 
endpoints below (as defined in Appendix 4): 

A composite endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalization 
for unstable angina;

CV death;

Any MI (fatal and non-fatal);

Fatal MI;

Non-fatal MI;

Any stroke (fatal and non-fatal);

Any stroke (fatal and non-fatal), of any etiology;

Fatal stroke;

Non-fatal stroke;

Hospitalization for unstable angina;

Hospitalization for congestive heart failure (CHF);

Any coronary revascularization procedure;

CABG;

PCI;

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
Any arterial revascularizations;

All-cause death.
7.1.2. Biomarker Efficacy Endpoints
Circulating biomarker endpoints are secondary efficacy endpoints and include the lipid and 
inflammatory parameters listed below.  Lipid parameters will be evaluated as percent change 
from baseline.  In addition, LDL-C will be evaluated as nominal change from baseline.  The 
inflammatory parameter, hs-CRP will be evaluated as the percent change from baseline.
The subject, sponsor, investigators and clinical staff and the subject will remain blinded to all 
circulating efficacy biomarker laboratory findings. Once all subjects have completed
participation and the study is unblinded, results of the fasting lipid tests for each study 
participant will be sent to the investigator. 
Investigators should inform the study subject’s primary care physician (PCP) of the study 
design and the importance of maintaining the blind for lipid laboratory results.  If possible, 
PCPs should refrain from measuring lipids while the subject is a participant in the study, if 
possible, but if measurement is necessary, they should refrain from informing the subject of 
the results.  Subjects will be provided an information card to give to a health provider, when 
being seen for medical care or when undergoing phlebotomy that is not study related.  The 
information card will explain the nature of the subject’s participation in the study and that 
lipid and other biomarker data is being reviewed, to maintain the safety of the subject during 
the conduct of the trial.
7.1.2.1. Lipid profile
Fasting lipid profile plasma samples will be collected at the pre-screening visit, Visit 3, 5 (the 
randomization visit), and every visit thereafter, except for EDC or EOS visits.  After 
randomization, lipid level tests should be scheduled no sooner than 10 days after the 
subject’s prior dose, even if this requires an unscheduled visit.  If a subject has a visit that is
scheduled less than 10 days after the last dose, the visit procedures may take place, but lipid 
testing should be postponed and performed at the earliest possible time, at an unscheduled
visit, no sooner than 10 days after the subject's last dose. Subjects who have had an IP dose 
frequency modification to dosing every 4 weeks, will need to have their visit frequency 
increased to every 8 weeks, approximately, for the purposes of direct LDL-C measurement.  
Lipid analyses will be performed by a central laboratory and include:

LDL-C;

Total cholesterol;

HDL-C;

Triglycerides;

Non-HDL-C (calculated as total cholesterol – HDL-C);

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
Friedewald LDL-C (calculated as total cholesterol – HDL-C – [triglyceride x 0.2] 
when using mg/dL or as total cholesterol – HDL-C – [triglyceride x 0.458)] when 
using mmol/L);43,66

VLDL-C (calculated as triglycerides x 0.2, when using mg/dL or triglycerides x 
0.458,  when using mmol/L);43,66

RLP-C (calculated as total cholesterol – [HDL-C + LDL-C]).
7.1.2.2. Special Lipid and Efficacy Assessments
At the screening visit hs-CRP, Lp(a), and a urinary microalbuminuria assessment may be 
evaluated, in subjects without a prior qualifying CV event or those subjects who had a CV 
event more than 5 years prior to screening.  Apo B and apo A-I will not be collected at the 
screening visit. 
Special lipid and efficacy assessments will be analyzed by a central laboratory or assessed as 
calculated parameters based on analyses of lipid profile measurements.  Special lipid and 
efficacy blood samples will be collected, and stored for later analysis, by the central 
laboratory or values will be calculated for them, for Visits 5, 8, and 11, only.  These 
assessments include:

Apo-A-I;

Apo-B;

Lp(a);

hs-CRP.
7.2. Safety
7.2.1. Laboratory
Laboratory tests for safety will be performed at times defined in the Schedule of Activities of 
this protocol.  Subject eligibility based on these tests will be determined at screening. 
Every effort should be made to collect laboratory test samples at the investigator’s study site
where the subject was consented, for sending to the central laboratory for analysis.  However, 
in the event that the subject is travelling long distance for an extended period of time, the 
subject must be made aware that laboratory test sample can be collected at a local laboratory
chosen by the investigator or at a local investigator study site that is also participating in the 
study, located in the area where the subject is travelling.  The study site should consult with 
the study management team on how to proceed with this process.  Laboratory test 
measurements are performed by the central lab and laboratory reports are communicated to 
the original investigator.  No other study visit procedures will be conducted at these visits 
other than laboratory test collections. 

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Laboratory test collection that occurs at a local laboratory and or at another investigator study 
site will require the original investigator follow up with the subject for any safety AE/SAEs.  
Investigators who have subjects that will have laboratory test collection at a local laboratory
and or another investigator study site should communicate to the appropriate study
management team regarding any subjects that will be travelling and will be gone for an 
extended period of time so that they can work with the investigator on the logistics.
7.2.1.1. Local Laboratory Tests
Urine dipstick assessments and urine pregnancy tests should be performed locally at times 
defined in the Schedule of Activities and Section 6 of this protocol.  A serum pregnancy test 
is always submitted for analysis to the central laboratory, whenever a urine pregnancy test is 
performed.
7.2.1.2. Central Laboratory Tests
A central laboratory will be used to analyze hematology and blood chemistry tests (as listed 
in the table below) to ensure accuracy and consistency in test results.  Serum pregnancy tests 
are performed centrally as specified in the Schedule of Activities.  The central laboratory will 
transmit all results for protocol tests, scheduled and unscheduled, to the sponsor for inclusion 
in the clinical data base.
The following laboratory tests will be performed at times defined in the Schedule of 
Activities and Section 6 of this protocol.  Additional tests not listed here may be performed 
as needed, with the approval of the clinical study team.
Table 2.
Laboratory Tests
Hematology
Chemistry
Urinalysis***
Additional
Hemoglobin
Hematocrit
RBC count
Mean corpuscular
volume (MCV)
Mean corpuscular
hemoglobin (MCH)
Mean corpuscular
hemoglobin 
concentration (MCHC)
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
Creatinine
Glucose
Ca++
Na+, K+, Cl 
Total 
CO2 (Bicarbonate)
Uric acid
Albumin
Total protein
LDH
Magnesium
Phosphorus
CK
CK-isozymes*
eGFR
HbA1c*
Liver function:
AST/ALT
Gamma-glutamyl 
transferase (GGT)*
Total bilirubin
Direct bilirubin
pH
Specific gravity
Bilirubin
Urobilinogen
Nitrite
Leukocytes
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Urine 
albumin/creatinine 
ratio*
Serum pregnancy 
(WCBP)*
Urine pregnancy***
(WCBP)*
Hepatitis panel**
ADA*
PCSK9*
bococizumab*

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Table 2.
Laboratory Tests
Hematology
Chemistry
Urinalysis***
Additional
Indirect bilirubin
Alkaline phosphatase
Lipid profile (total 
cholesterol, LDL-C, 
non-HDL-C, HDL-C, 
RLP-C, VLDL-C, 
triglycerides)*
Special chemistry 
assessments (hs-CRP, 
Lp(a), Apo B, Apo A-I)*
*      Where applicable and according to the SOA
**    Hepatitis B and C virus serologies at screening for all subjects and Hepatitis C virus serologies will 
be collected at EDC/EOS only for subjects from study sites in Canada.  A positive or indeterminate 
hepatitis C serology may trigger a hepatitis C PCR test for confirmation.
*** Performed locally
Qual = qualitative; WCBP= women of childbearing potential
7.2.1.2.1. Pregnancy Testing (Local and Central Laboratory)
For women of childbearing potential, serum pregnancy tests, performed at the central 
laboratory, and urine pregnancy tests, tested locally, are performed at the screening visit 
(Visit 1), before investigational product administration, at the baseline visit (Visit 5), at all 
visits after randomization, and at the EDC/EOS visit.  For female subjects of childbearing 
potential, serum and urine pregnancy tests, with sensitivity of at least 25 mIU/mL, will be 
performed.  The urine pregnancy test is conducted with the test kit provided by the central 
laboratory in accordance with instructions provided in its package insert.
Subjects who have missed a menstrual period or who show an indeterminate or positive 
result on the urine test may not further progress in the study until pregnancy is ruled out 
using further diagnostic testing (eg, a negative quantitative serum pregnancy test conducted 
at the central laboratory).  At all visits, a negative pregnancy result is required before the 
subject may receive the investigational product.  In the case of a positive confirmed 
pregnancy, the subject will be withdrawn from study medication but may remain in the study.  
In addition, pregnancy tests will also be done whenever 1 menstrual cycle is missed during 
the active treatment period (or when potential pregnancy is otherwise suspected).  Pregnancy 
tests may also be repeated as per request of institutional review boards (IRBs)/ethics 
committees (ECs) or if required by local regulations.
7.2.2. 12-Lead Electrocardiogram
A 12-lead electrocardiogram (ECG) will be obtained at Visit 5, and annually thereafter.  
ECGs will be locally assessed and interpreted and stored at the study site and a copy will be 
stored centrally.  ECGs may be recorded, at scheduled or unscheduled visits, for safety 
purposes, if needed.  Clinically significant ECG abnormalities at any visit will be recorded in 
the CRF.

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If a subject experiences a nonfatal adjudicated and confirmed CV event after randomization, 
a new baseline ECG should be performed following the event.  It may be done at a regularly 
scheduled visit if the visit is to occur within that time frame.  If not, a new ECG should be 
performed at an unscheduled study visit.
7.2.3. Examinations
7.2.3.1. Vital Signs
Temperature, PR, and BP will be measured at visits specified in the Schedule of Activities of 
this protocol.  Additional measurements of PR and BP rate will be permitted, as necessary, to 
ensure appropriate collection of safety data.
Sitting BP should be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) should be used throughout the study.  The same size BP cuff, 
which has been properly sized and calibrated, should be used to measure BP each time.  The 
use of automated devices for measuring PR and BP is preferred, although, when done 
manually, PR should be measured in the brachial/radial artery for at least 30 seconds.  When 
the timing of these measurements coincides with a blood collection, PR and BP should be 
obtained prior to the nominal time of the blood collection.
Baseline BP is defined as the mean of the average systolic and diastolic BP measures at the 
Randomization visit and will serve as the comparator for average values obtained at later 
visits.  At each visit sitting systolic and diastolic PR and BP will be measured in duplicates.  
The second measurement should be taken after the first measurement, according to the local 
standard of care.  The first and second measurements will be recorded on the CRF and their 
average will serve as the value for that visit.
7.2.3.2. Physical Exam
Physical exam will be performed at baseline (Visit 5), annually, and at EDC and/or EOS.  
Abnormal changes from baseline, deemed clinically significant by the Investigator should be 
recorded as AEs.
7.2.3.2.1. Weight, Height, and Waist Circumference
Height will be measured without shoes at the baseline visit (Visit 5).
Body weight will be measured at the baseline visit (Visit 5), annually, and at EDC and/or 
EOS.  Body weight will be measured in indoor clothing without shoes.
Waist circumference will be measured at baseline (Visit 5) and at EDC and/or EOS.  To 
measure waist circumference, place a tape measure around the subject’s bare abdomen just 
above the subject’s hip bone (at the level of the subject’s navel).  Be sure that the tape is 
snug, but does not compress the subject’s skin, and is parallel to the floor.  Have the subject 
relax, exhale, and measure the subject’s waist.

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7.2.3.3. Neurological Exam
A basic neurological panel consists of clinical tests of selected cranial nerves, sensation, 
coordination, and peripheral reflexes and will be performed at baseline (Visit 5), annually, 
and at EDC and/or EOS, as part of the physical exam.  These tests can be performed by 
individuals with basic medical training and do not require specialized equipment.  Abnormal 
changes from baseline, deemed clinically significant by the Investigator should be recorded 
as AEs.
7.2.3.4. Cognitive Testing
Cognitive testing will be performed at baseline (Visit 5), annually, and at the EDC and/or
EOS visits at a subset of designated study sites in approximately 500 subjects (250/treatment 
group).  This number of subjects is based on feasibility of sites with the appropriate staff and 
workspace to administer the testing accurately, which have the trained personnel and 
facilities to perform the tests.
The cognitive testing battery will comprise the following assessments:

Wechsler Adult Intelligence Scale (WAIS-III) - Digit Span (Forward and 
Backward)55,56
Digit Span is a test of working memory using paper and pencil.  Participants are read 
a sequence of digits increasing in length from two to nine digits.  In the Digit Span 
Forward test, subjects are asked to repeat the digits as they are presented, and in the 
Digit Span Backward test, subjects are asked to repeat the digits in reverse.  The 
length of the digit sequence is increased across trials until there has been a failure 
across two consecutive trials of a particular length.

Wechsler Adult Intelligence Scale (WAIS-III) - Digit Symbol-Coding55,56
Digit Symbol - Coding is a brief motor skill and cognition test using paper and pencil.  
It consists of a series of numbers, each of which is paired with its own corresponding 
hieroglyphic-like symbol. Using a key, the subject writes the symbol corresponding 
to its number. The subject’s score is determined by the number of symbols correctly 
drawn within a 120-second time limit.  Subjects are encouraged to perform the task as 
quickly and accurately as possible. 

Trail Making Test (Parts A and B)57
The Trail Making Test (TMT) is a measure of attention, speed, and mental flexibility 
using paper and pencil. The TMT also tests spatial organization, visual pursuits, 
recall, and recognition. It consists of 25 circles distributed over a sheet of paper. In 
Part A of the test, the circles are numbered 1-25 and the subject is required to draw 
lines to connect the 25 numbered circles in ascending order.  Part A tests visual 
scanning, numeric sequencing, and visuomotor speed.  In Part B, the circles include 
both numbers (1-13) and letters (A-L).  Part B of the test is similar to Part A except 
the subject must alternate between connecting the numbered and lettered circles (ie, 

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1-A-2-B-3-C, etc.), and it is believed to be more difficult and takes longer to 
complete.  Part B tests cognitive demands including visual motor and visual spatial 
abilities and mental flexibility. Part A and Part B are timed, and scores represents the 
total time required to complete the tasks. Subjects are instructed to connect the 
circles as quickly as possible, without lifting the pen or pencil from the page.

Hopkins Verbal Learning Test64,65
The Hopkins Verbal Learning Test (HVLT) - Revised is a relatively brief test of 
verbal learning and memory to be used when serial testing is desired. It is composed 
of 12 items, organized into three semantic categories, and is presented over three 
consecutive learning trials as the Immediate Recall test.  The subjects are asked to 
recall as many words as they can remember in any order.  The same list of words is 
utilized in the consecutive trials.  Delayed Recall is assessed 20 to 25 minutes after 
completion of the Immediate Recall test, with the subjects again to recall as many 
words as they can in any order.  Immediately after administration of the Delayed 
Recall trial, a forced-choice Recognition test is administered. The Recognition test 
includes the 12 target words, plus 12 distractors (six semantically-related and six 
semantically-unrelated words).  The numbers of words correctly recalled for each of 
the three Learning Trials are summed for the Total Recall score, which ranges from 
0 to 36.  The Delayed Recall Trial score, is the number of words correctly recalled on 
the delayed trial, and ranges from 0 to 12.  The Recognition test score is the sum of 
the number of words correctly identified on the list for the Immediate Recall Test and 
the number correctly identified as not being on the list.  The Recognition test score 
ranges from 0 to 24.  On these assessments, higher scores indicate greater verbal 
learning and recall.  Test administration time is about seven minutes for the 
Immediate Recall test and three minutes for the Delayed Recall and Recognition tests.
7.2.4. Injection Site Reactions
In case of acute injection site reactions, the Investigator should institute treatment measures 
deemed medically appropriate such as topical therapy at the injection site.  Such events and 
treatments are to be captured and reported as AEs.  The Investigator should provide a clear 
description of the observed or reported AE including location and severity.  All concomitant 
treatments used to treat injection site reactions should be recorded and captured in the CRF, 
together with the AE of injection site reactions.  AEs should be reported as serious per the 
criteria in Section 8.6 of this protocol.
7.2.5. Creatine Kinase (CK) / Symptomatic Myopathy Monitoring
If at any clinic visit after screening, a subject experiences unexplained (ie, not associated 
temporally with recent trauma, intra muscular injections, heavy exercise or physically 
strenuous activity) CK values >5x ULN, then the subject must return to the clinic for repeat 
CK testing preferably within 48 hours of when results are made available to the Investigator. 
At the time of repeat testing, CK isozymes (to assess CK-MM and CK-MB fractions) and a 
serum creatinine will be obtained, as well as a urine dipstick. If the repeat testing confirms 
CK values >5x ULN, and the CK elevation is associated with muscle pain, muscle tenderness 

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and/or muscle weakness, or new onset renal dysfunction, then the subject must be 
discontinued from study treatment and asked to complete the remainder of the scheduled 
visits without receiving bococizumab or placebo.  If completing the remainder of the trial 
without study treatment is not possible, end of study evaluations must be performed. 
The Sponsor must be notified of any CK >5x ULN within 24 hours.  If the subject’s CK 
value is >5x ULN on repeat testing, without muscle pain, muscle tenderness, and/or muscle 
weakness, or new onset renal dysfunction, the subject may continue on study therapy if 
approved by Pfizer’s Medical Monitor, who may request additional assessments.  At the time 
of repeat testing, CK isozymes (to assess CK-MM and CK-MB fractions) and a serum 
creatinine will be obtained. The subject’s CK levels should continue to be monitored, 
pending resolution of the CK elevation. 
Prior to obtaining blood for a CK assessment, investigators should enquire about recent 
intramuscular injections, heavy exercise, or recent musculoskeletal trauma, and defer CK 
testing until the next visit or repeat testing at an unscheduled visit, no less than 7 days after 
the IM injection or musculoskeletal trauma, so as to avoid spuriously elevated values.
7.2.6. LDL-C monitoring
7.2.6.1. LDL-C < 25 mg/dL (0.65 mmol/L)
Some subjects may have LDL-C measurements below 25 mg/dL (0.65 mmol/L). An 
independent safety review of AEs and laboratory results will be conducted by the DMC for 
all subjects presenting with LDL-C < 25 mg/dL (0.65mmol/L).
7.2.6.2. Subjects with a History of LDL-C 10 mg/dL (0.26 mmol/L)
Subjects who have had dosing of IP modified by the IRT system to Q4wks (Section 5.4.1.1), 
will have their visit frequency changed to obtain a direct LDL-C level every 8 weeks 
(Q8wks).  The first visit of increased frequency should take place 6 weeks after the visit at 
which the subject was informed of the change in IP dose frequency. This will permit the 
DMC to perform an independent safety review, in an ongoing fashion so as to ascertain if 
there are any potential safety issues, consequent to the modification of IP dosing.  Since all 
subjects with a dose frequency modification (both those on placebo and those receiving 
bococizumab) will have more frequent direct LDL-C monitoring, the blinding of the study 
should be preserved.
7.2.7. Immunogenicity 
7.2.7.1. Anti-drug Antibodies
Blood samples will be collected and assayed for development of ADAs to bococizumab.  
This monitoring will take place at regular intervals as described in the Schedule of Activities.  
After randomization, if lipid sampling has been postponed to an unscheduled visit, the 
corresponding ADA, PK, PCSK9 samples should be postponed as well, and collected at the 
at the same time as the rescheduled lipid sample collection.  ADA, PK, and PCSK9 samples 
will be collected at EDC and EOS visits.

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ADA samples will be analyzed using a tiered testing strategy.  All ADA samples that are 
positive in a screening assay, will be confirmed for antibody specificity.  Confirmed positive 
samples will be characterized further for titer and neutralizing antibody response, if 
appropriate. 
Blood samples for anti-bococizumab antibody analysis (4 ml to provide approximately 
1.5 ml of plasma) will be collected into appropriately labeled tubes containing potassium 
ethylenediaminetetraacetic acid (K2EDTA). 
Samples for anti-bococizumab antibody will be analyzed using validated analytical methods 
in compliance with Pfizer standard operating procedures.
As part of understanding the immunogenicity of the study drug, samples may be used for 
evaluation of the bioanalytical method.  These data will be used for internal (ie, Pfizer) 
exploratory purposes and will not be included in the clinical report.
7.2.7.2. Hypersensitivity Types 1 and 3 Reactions
Type 1 hypersensitivity or allergic (eg, shortness of breath, urticaria, anaphylaxis, 
angioedema) reactions are theoretically possible in response to any injected protein.  Immune 
complex mediated Type 3 hypersensitivity reactions are similar to the adverse events (AEs) 
of Type 1 reactions but are likely to be delayed from the time of injection and may include 
symptoms such as rash, urticaria, polyarthritis, myalgias, polysynovitis, fever, and, if severe, 
glomerulonephritis. 
In the case of a hypersensitivity reaction, the subject will be treated symptomatically with 
supportive care, further monitoring, and treatment with anti-histamines and/or 
corticosteroids.  Study injections may be stopped and the subject will be followed until the 
end of the study. At the time of any hypersensitivity reaction an ADA, PK, and 
PCSK9 specimen should be collected, and another sample collected at the next visit, as per 
the Schedule of Activities.
If a subject reports an injection site reaction that has not resolved by the end of the third day, 
after dosing, an unscheduled visit should be performed, to collect an ADA, PK, and 
PCSK9 sample.
7.3. Health-Related Quality of Life and Depression Assessments.
7.3.1. EQ-5D Health Questionnaire
A health-related quality of life assessment, the EQ-5D Health Questionnaire, is administered 
at visits 5 (baseline), 8, 9, 11, 14, 17, 20, and at early discontinuation from study or end of 
study visit.  See Appendix 6.
The EQ-5D is a generic measure of health-related quality of life.44 The EQ-5D is a subject 
completed instrument designed to assess impact on quality of life in five domains: mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression.  Additionally, scores from 
the five domains may be used to calculate a single index value. The EuroQol EQ-5D Visual 

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Analogue Scale (VAS) is a patient-completed 20 cm scale designed to rate an individual’s 
current health state. The Health State Profile will be administered concurrently with the 
VAS - HEALTH STATE component of the EuroQol EQ-5D instrument.
The health outcomes assessment survey (EQ-5D) evaluates the subject’s own perceptions. In 
order to gain the most objective results possible, subjects should complete the EQ-5D prior to 
performing any other study-related procedure for the visit and prior to any study-specific 
discussion of how they are feeling. The investigator must not influence the subject’s 
assessments. Every effort should be made to maintain an unbiased assessment. All subject 
self-assessments should be reviewed for completeness while the subject is still present for the 
study visit.
7.3.2. Patient Health Questionnaire Depression Module
Depression is an affective disorder that sometimes occurs in patients with CV disease.  The 
assessment of depression in patients with CV disease is recommended since it may impact 
the quality of life and adherence to medical treatment.62 The Patient Health Questionnaire 
(PHQ) depression assessment is a validated tool to assess the presence of depression and its 
severity.  It will be used to evaluate subjects for clinical evidence of depression in this study.
The PHQ-2 consists of the first two items of the PHQ-9, and constitutes the two core 
DSM-IV items for major depressive disorder.  The PHQ-2 score ranges from 0 to 6. The 
operating characteristics of this ultra-brief measure are quite good; the recommended 
cut-point when used as a screening test is a score of 3 or greater.63 This study will use a 
screening test score of 2 or greater, as a trigger for completion of the PHQ-9 assessment, as a 
more conservative approach to identifying the presence of a major depressive disorder.  The 
PHQ-2 provides depressive scores and can be used as a screening assessment for depression;
the remaining 7 questions of the PHQ-9 evaluate the severity of depression. The severity is 
calculated by assigning scores of 0, 1, 2, and 3, to the response categories of “not at all”,
“several days”, “more than half the days”, and “nearly every day”, respectively.  PHQ-9 total 
score ranges from 0 to 27.  Scores of 1-4, 5-9, 10-14, 15-19, and 20-27 represent minimal,
mild, moderate, moderately severe, and severe depression, respectively.
The PHQ-2 will be performed in all subjects at Visit 5 (randomization), and in subjects with 
cognitive assessments only, it will be performed annually, and at EDC or EOS. 
If at the baseline PHQ-2 assessment, a subject scores 2, the remaining 7 questions of the 
PHQ-9 will be answered.  If the PHQ-9 score is 10, the subject should be referred back to 
his/her primary care physician for further assessment and/or treatment of potential major 
depression.  If the PHQ-9 score is 15 or there is a positive score in question 9, the subject 
should excluded from participation, the subject’s primary care physician (PCP) should be 
informed, and the subject should be referred to a mental health professional, either by the 
PCP or the investigator.  Such subjects may be rescreened, at a later date, if they were 
evaluated and treated as appropriate, and the repeat PHQ scores permit inclusion.  Any 
adverse events should be documented in the case report form as appropriate.

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Only subjects participating in the cognitive assessment sub-study will have annual, and end 
of treatment or end of study PHQ assessments, in addition to the baseline assessment.  If at 
any of the visits after the baseline assessment, a subject scores 2, the remaining 7 questions 
of the PHQ-9 will be answered.  If the PHQ-9 score is 10, consideration should be given to 
referring the subject back to his/her primary care physician for further assessment of 
potential major depression and recommendations.  If the PHQ-9 score is 15 or there is a 
positive score in question 9, the subject’s primary care physician (PCP) should be informed, 
and the subject should be referred to a mental health professional, either by the PCP or the 
investigator.  Any adverse events should be documented in the case report form as 
appropriate. 
7.4. Pharmacokinetics
7.4.1. Plasma for Analysis of bococizumab and PCSK9
Blood samples for bococizumab and PCSK9 will be collected as specified in the Schedule of 
Activities.  On all bococizumab/PCSK9 blood sample collection days, samples must be 
collected prior to bococizumab dosing. After randomization, if lipid sampling has been 
postponed to an unscheduled visit, the corresponding ADA, PK, and PCSK9 samples should 
be postponed as well, and collected at the at the same time as the rescheduled lipid sample 
collection.  Bococizumab/PCSK9 blood samples will be collected from all subjects, but only 
analyzed, if needed, to help understand the PK, PD, and safety response of bococizumab in 
this study population.  In addition, baseline PCSK9 samples collected on Visits 3 and 5 may
be analyzed in a randomly selected subset of subjects (N=1,200).
Blood samples (4 mL) to provide a minimum of 1.5 mL of plasma for pharmacokinetic 
analysis will be collected into appropriately labeled tubes containing K2EDTA at times 
specified above.
Samples for bococizumab and PCSK9, if analyzed, will be measured using a validated 
analytical method in compliance with Pfizer standard operating procedures.
Detailed instructions for the preparation and shipment of the samples may be found in the 
Laboratory Manual supplied by the Central Laboratory.
As part of understanding the pharmacokinetics/pharmacodynamics of the investigational 
product, samples may be used for evaluation of the bioanalytical methods.  These data will 
be used for internal (ie, Pfizer) exploratory purposes and will not be included in the clinical 
report.
7.5. Banked Biospecimens
7.5.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA), protein, and metabolite variation patterns of subjects who respond 
well and those who respond poorly to treatment may help to better define the most 

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appropriate group of patients in which to target a given treatment. Collecting biospecimens 
for exploratory pharmacogenomic/biomarker analyses and retaining them in the Pfizer 
BioBank makes it possible to better understand the drug’s mechanism of action and to seek 
explanations for differences in, for example, exposure, efficacy, tolerability, or safety not 
anticipated prior to the beginning of the study. Providing these biospecimens is a required 
study activity for study sites and subjects, unless prohibited as such by local regulations or 
ethics committee decision. 
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study ID number. Samples will be kept in a facility 
accessible only by badge-swipe. Data will be stored on password-protected computer 
systems. The key between the code and the subject’s personal identifiers will be held at the 
study site; the researchers using the biospecimens and data generated from them will not 
have access to the key nor any personally identifying information. Biospecimens will only 
be used for the purposes described here and in the informed consent document/patient 
information sheet; any other uses require additional ethical approval. Unless a time 
limitation is required by local regulations or ethical requirements, biospecimens will be 
stored indefinitely to allow for future research on the topics described here, including 
research conducted during the lengthy drug development process and also post-marketing 
research. Subjects can withdraw their consent for the use of their biospecimens at any time 
by making a request to the investigator, in which event any remaining biospecimen will be 
destroyed; data already generated from the biospecimens will continue to be stored to protect 
the integrity of existing analyses. It is very unlikely that results generated from the 
biospecimens will have any clinical, diagnostic, or therapeutic implications for the individual 
study participants. Subjects are notified in the informed consent document/patient 
information sheet that their results will not be given to them, unless required by local laws or 
regulations, in which case results will be returned via the investigator. Results will not be 
provided to family members or other physicians; nor will they be recorded in the subject’s 
medical record. There is no intention to contact subjects after completion of the clinical 
study.
The following biospecimens will be retained for potential exploratory 
pharmacogenomic/biomarker analyses related to drug response, unless prohibited by local 
regulations or ethics committee decision. For example, putative safety biomarkers, drug 
metabolizing enzyme genes, drug transport protein genes, or genes or biomarkers thought to 
be related to the mechanism of drug action may be examined. The biospecimens include:

Prep D1 (K2 edetic acid (ethylenediaminetetraacetic acid) (EDTA) whole blood 
collection optimized for DNA analysis): a 4 ml blood biospecimen will be collected 
at the baseline visit (Visit 5);

Prep B1 (K2 EDTA plasma collection optimized for
biomarker/proteomic/metabonomic analysis): a 10 mL blood biospecimen will be 
collected at baseline (Visit 5) and at the 12 month visit (Visit 11).

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The Banked Biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage and 
shipment instructions are provided in the central laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/patient information sheet that 
they will not be compensated in this event.
7.5.2. Additional Research
Unless prohibited by local regulations, subjects will be asked to indicate on the consent form 
whether they will allow the Banked Biospecimens to also be used for the following research:

Investigations of the disease under study in the clinical trial, and related conditions;

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation amongst people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to Pharmacogenomics/biomarkers. 
Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in Markers of Drug Response Section will be used.  Subjects may still 
participate in the clinical trial if they elect not to allow their Banked Biospecimens to be used 
for the additional purposes described in this section.
7.6. Triggered Requirements
Condition
Action
Reduction of IP Dosing Frequency
If a subject has IP dosing reduced to Q4wks
The subject will have direct LDL-C measurements 
approximately Q8 wks, for the duration of the 
study.
Management of Hypertriglyceridemia
If the fasting triglyceride result is 600 mg/dL 
(6.78 mmol/L) and < 800 mg/dL (9.03 mmol/L) on one 
occasion; and it is determined that the subject was NOT 
fasting a minimum of 10 hours
The subject does NOT need to have an 
unscheduled visit for a repeat triglyceride 
assessment, and should return to the study site at 
the next scheduled visit time.
The investigator should reinforce the importance 
of dietary compliance and fasting for 10 hours, 
prior to laboratory testing.
If the fasting triglyceride result is 600 mg/dL 
(6.78 mmol/L) and < 800 mg/dL (9.03 mmol/L) on one 
occasion; and it is determined that the subject was 
fasting a minimum of 10 hours
The subject should have an unscheduled visit for a 
repeat triglyceride assessment, to confirm the 
elevation.
The investigator should reinforce the importance 
of dietary compliance and refer the subject for the 
treatment of hypertriglyceridemia and/or prescribe 
therapy in accordance with accepted local 
treatment guidelines.

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Condition
Action
If the triglyceride result is 800 mg/dL (9.03 mmol/L), 
and it was determined that the subject was fasting a 
minimum of 10 hours 
The investigator should reinforce the importance 
of dietary compliance.  The subject must be 
prescribed additional therapy to manage 
hypertriglyceridemia.  More specifically, fibrates, 
or niacin or fish oil, in accordance with clinical 
practice.
If the subject is diabetic glycemic control should 
be optimized.
Symptomatic Myopathy Monitoring/CK
If at any study visit after screening, a subject 
experiences unexplained (ie, not associated temporally 
with recent trauma, intra muscular injections, heavy 
exercise or physically strenuous activity) CK values >5x 
ULN,
If completing the remainder of the trial without study 
treatment is not possible, end of study evaluations must 
be performed. 
The subject must return to the clinical research site 
for repeat CK testing preferably within 48 hours of 
when results are made available to the 
Investigator.  Continued follow up for the lab 
abnormality should be conducted in accordance 
with the Adverse Events section of the protocol 
(Section 8) and Appendix 7.
At the time of repeat testing, a CK isozyme 
assessment (to assess CK MM and MB fractions) 
should be performed, a urine dipstick should be 
performed, and a serum creatinine specimen 
should also be obtained.  If the repeat testing 
confirms CK values >5x ULN, and the CK 
elevation is associated with muscle pain, muscle 
tenderness and/or muscle weakness, or new onset 
renal dysfunction, then the subject must be 
discontinued from study treatment and asked to 
complete the remainder of the scheduled visits 
without receiving bococizumab or placebo. 
If completing the remainder of the trial without 
study treatment is not possible, end of study 
evaluations must be performed.  
If a subject has a CK >5x ULN,
The Sponsor must be notified of any CK >5x ULN 
within 24 hours. Continued follow up for the lab 
abnormality should be conducted in accordance 
with the Adverse Events section of the protocol 
(Section 8) and Appendix 7.
If the subject’s CK value is >5x ULN on repeat 
testing, without muscle pain, muscle tenderness, 
and/or muscle weakness, or new onset renal 
dysfunction,  the subject may continue on study 
therapy if approved by Pfizer’s Medical Monitor 
or designated representative, who may request 
additional assessments. 
At the time of repeat testing, CK isozymes (to 
assess CK-MM and CK-MB fractions), a urine 
dipstick, and a serum creatinine will be obtained. 
The subject’s CK levels should continue to be 
monitored, pending resolution of the CK elevation.

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7.7. Health Care Resource Utilization Assessments
At each visit after Visit 5 (Randomization) an assessment will be made of HCRU.  
Specifically, subjects will be asked if they have utilized health care resources.  Should health 
care resources have been utilized, the investigator obtains a release of medical records, so 
that HCRU data can be obtained and extracted for completion of the HCRU CRF.  It is quite 
possible that this HCRU data will identify AEs and or SAEs which will also require 
appropriate safety reporting (Section 8.14). 
HCRU assessments will take place at each visit to collect data on the following:

The occurrence, overall length of stay, primary and secondary discharge diagnoses,
duration of stay in different medical care units, and discharge disposition for all-cause 
hospitalizations;

The occurrence, primary and secondary discharge diagnoses, overall length of stay, 
duration of stay in different medical care units, and discharge disposition for CV
hospitalizations;

The occurrence of emergency room visits;

The occurrence of physician office visits;

The occurrence of outpatient rehabilitation visits;

The occurrence of all-cause hospitalizations within 30 days of a previous 
hospitalization, primary and secondary discharge diagnoses, length of stay, and 
discharge disposition;

The occurrence of CV hospitalizations within 30 days of a previous hospitalization, 
primary and secondary discharge diagnoses, length of stay, and discharge disposition.
The medical care units being assessed for these objectives include:

Cardiac Care Unit (CCU);

Medical Intensive Care Unit (MICU);

Neurology Intensive Care Unit (NICU);

Surgical Intensive Care Unit (SICU);

Thoracic Intensive Care Unit (TICU);

Cardiac Step-down Unit;

Pulmonary Step-down Unit;

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
General ward;

Dialysis Unit;

Chemotherapy Unit;

Infections disease isolation unit;

Other.
Discharge care disposition entities being evaluated for HCRU include:

Home self-care;

Home health care;

Nursing home care/skilled nursing facility;

Rehabilitation facility;

Hospice care;

Death;

And other potential disposition entities.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study. 

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8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 40 calendar days after the last 
administration of the investigational product.  This period includes the period between 
pre-screening (the time of pre-screening informed consent) and randomization, as well as the 
run-in visits, when the subject is receiving placebo injections.  Serious adverse events 
occurring to a subject after the active reporting period has ended should be reported to the 
Sponsor if the investigator becomes aware of them; at a minimum, all serious adverse events 
that the investigator believes have at least a reasonable possibility of being related to 
investigational product are to be reported to the Sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has signed the informed consent document through the last subject visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

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
Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from the administration of the wrong product by
the wrong subject, at the wrong time, or at the wrong dosage strength.  Such medication 
errors occurring to a study participant are to be captured on the medication error CRF, which 
is a specific version of the AE page, and on the SAE form when appropriate.  In the event of 
medication dosing error, the sponsor should be notified immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the adverse 
event (AE) page and, if applicable, any associated AE(s) are captured on an AE CRF page.
A single missed dose is not automatically considered a medication error.  In the event of a 
medication dosing error, the sponsor should be notified immediately.  If a single dose is 
outside of the injection window and there are at least 7 days separation between this dose and 
the nearest dose (previous and/or subsequent), this would not be considered a medication 
error.  If the subject repeats this out of window administration again in the study, it would 
still not be recorded as a medication error as long as the out of window administrations are 
not consecutive.  If the subject repeats their out of window administration consecutively or 
the minimum time (7 days) between doses is not maintained, this will be considered a 
medication error.  Subjects should return to their original dosing schedule.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

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
Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
An SAE is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
Medical device complaints may meet the SAE reporting requirement criteria (see the section 
on Medical Device Complaint Reporting Requirements).  An incident is any malfunction (ie, 
the failure of a device to meet its performance specifications or to perform as intended; 
performance specifications include all claims made in the labeling for the device) that, 
directly or indirectly, might lead to or might have led to the death of a subject, or user, or of 
other persons, or to a serious deterioration in their state of health. 
A serious injury that can cause a serious deterioration in state of health can include:

a life-threatening illness, even if temporary in nature;

a permanent impairment of a body function or permanent damage to a body structure; 

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
a condition necessitating medical or surgical intervention to prevent the above 
2 bulleted items.
Examples: clinically relevant increase in the duration of a surgical procedure, a condition that 
requires hospitalization or significant prolongation of existing hospitalization;

any indirect harm as a consequence of an incorrect diagnostic or in vitro diagnostic 
device test results when used within the manufacturer’s instructions for use;

fetal distress, fetal death, or any congenital abnormality or birth defects.
8.6.1. Disease-Related Efficacy Endpoints
The Pfizer SAE Triage Group will identify potential disease-related efficacy endpoints (listed 
below) that are considered by the investigator to be causally related to study drug and report 
these into the Pfizer Drug Safety Unit (DSU) (as shown in Appendix 9):

Myocardial infarction, fatal or non-fatal.

CV death.

All-cause death.

Hospitalization for unstable angina needing urgent revascularization (PCI or CABG).

Stroke, fatal or non-fatal.

Hospitalization for unstable angina.

Hospitalization for congestive heart failure.

Arterial revascularization of any kind (eg, PCI, CABG, peripheral vascular surgery, 
carotid artery surgery).
8.6.2. Potential Cases of Drug-Induced Liver Injury
Abnormal values in aspartate aminotransaminase (AST) and/or alanine aminotransaminase 
(ALT) levels concurrent with abnormal elevations in total bilirubin level that meet the 
criteria outlined below in the absence of other causes of liver injury are considered potential 
cases of drug-induced liver injury (potential Hy’s Law cases) and should always be 
considered important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

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
Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (X ULN) concurrent with a total bilirubin values 2 X ULN with no evidence 
of hemolysis and an alkaline phosphatase value 2 X ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 X ULN, or 8 X ULN 
(whichever is smaller).

Concurrent with:

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin levels increased from baseline by an amount of at least one time 
the upper limit of normal or if the values reaches ≥3 times the upper limit of 
normal (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/International Normalized Ratio (INR), and 
alkaline phosphatase.  A detailed history, including relevant information, such as review of 
ethanol, acetaminophen, recreational drug and supplement consumption, family history, 
occupational exposure, sexual history, travel history, history of contact with a jaundiced 
person, surgery, blood transfusion, history of liver or allergic disease, and work exposure, 
should be collected.  Further testing for acute hepatitis A, B, or C infection and liver imaging 
(eg, biliary tract) may be warranted.  All cases confirmed on repeat testing as meeting the 
laboratory criteria defined above, with no other cause for liver function test (LFT)
abnormalities identified at the time should be considered potential Hy’s Law cases 
irrespective of availability of all the results of the investigations performed to determine 
etiology of the abnormal LFTs.  Such potential Hy’s Law cases should be reported as SAEs.
Training and a flowchart is provided to the study sites, to explain the reporting process for 
potential drug induced liver injury events (see Appendix 8).
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 

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tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.

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8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the Sponsor (see the Section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product", 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 

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An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer SAE Triage Group, on an SAE report form and Exposure During 
Pregnancy (EDP) supplemental form, regardless of whether an SAE has occurred.  In 
addition, the investigator must submit information regarding environmental exposure to a 
Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant and has been 
exposed to a cytotoxic product by inhalation or spillage) using the EDP supplemental form.  
This must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the exposure.  The information submitted should include the anticipated date of 
delivery (see below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  In the case of a live birth, the structural integrity of the 
neonate can be assessed at the time of birth.  In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.

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8.11. Occupational Exposure
An occupational exposure occurs when during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an adverse event.
An occupational exposure is reported to the Pfizer SAE Triage Group within 24 hours of the 
investigator’s awareness, using the SAE Report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF, however a copy of the completed SAE Report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject. In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
All SAEs will be reported on the AE eCRF (marked as serious) and on the Clinical Trial 
SAE report form (available in Firecrest) to be submitted to the Pfizer SAE Triage Group, 
within 24 hours of investigator’s awareness.  The form must be completed fully, including an 
assessment of SAE causality on the submitted forms (see Section 8.9).  The Pfizer SAE 
Triage Group will identify potential disease-related efficacy endpoint SAEs as defined in 
Section 8.6.1.  The identified potential disease-related efficacy endpoints will not be 
reported, by the Pfizer SAE Triage Group, into the Pfizer DSU unless the investigator 
believes there is a causal relationship between study drug and a potential disease-related 
efficacy endpoint.  Other SAEs that are not potential disease-related efficacy endpoints will 
be reported to the DSU, by the Pfizer SAE Triage Group.
In particular, if the SAE is fatal or life-threatening, notification to the Pfizer SAE Triage 
Group must be made immediately, irrespective of the extent of available AE information.  
This time frame also applies to additional new information (follow-up) on previously 
forwarded SAE reports as well as to the initial and follow-up reporting of exposure during 
pregnancy, exposure via breastfeeding and occupational exposure cases. 

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If a potential disease-related efficacy endpoint SAE is subsequently adjudicated not to be an 
endpoint, the site will be contacted by the Adjudication Committee and asked to submit an 
updated SAE form.  The form should be revised to show the awareness date (the date of 
notification by the Adjudication Committee).  This form should be submitted to the Pfizer 
SAE Triage Group within 24 hours of the notification from the Adjudication Committee.  
This process is shown in Appendix 9.
SAEs must be reported for all subjects (including screen failures) from the time of signing 
informed consent up to and including 40 days after discontinuing study drug, with this 
period, including events occurring between pre-screening (the time of pre-screening 
informed consent) and randomization. 
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  Follow up information for 
previously forwarded SAE reports, should be reported directly to the DSU within 24 hours of 
investigator awareness. In addition, an investigator may be requested by Pfizer to obtain 
specific additional follow-up information in an expedited fashion.  This information collected 
for SAEs is more detailed than that captured on the AE CRF.  In general, this will include a 
description of the AE in sufficient detail to allow for a complete medical assessment of the 
case and independent determination of possible causality.  Information on other possible 
causes of the event, such as concomitant medications, vaccines, and/or illnesses, must be 
provided.  In the case of a subject death, a summary of available autopsy findings must be 
submitted as soon as possible to Pfizer or its designated representative.
In the rare event that the investigator does not become aware of the occurrence of an SAE 
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event to the Pfizer SAE Triage Group within 24 hours after 
learning of it and document the time of his or her first awareness of the SAE.
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Medical Device Complaint Reporting Requirements
All medical device complaints, regardless of whether the medical device complaint is 
associated with an AE, will be collected on the applicable pages within the CRF.  This 
includes potential incidents or malfunctions associated with the use of a medical device 
product.  An incident or malfunction is an event that might have led to death or serious 
deterioration in health, or if it occurred again might have led to death or serious deterioration 
in health.
Pfizer is to be notified of all medical device complaints within 24 hours of the investigator’s 
awareness of the event.

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8.14.4. Sponsor's Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summaries and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP), which will be maintained by 
the sponsor.  This document may modify the plans outlined in the protocol; however, any
major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment.
9.1. Sample Size Determination
A sample size estimate of 17,000 randomized subjects (8,500 on bococizumab and 8,500 on 
placebo) has approximately 90% power to detect a 20% reduction in the risk of experiencing 
the primary endpoint, by means of a two-sided α = 0.05 log rank test. The required number 
of subjects with an adjudicated and confirmed event is 844.  The sample size calculation is 
based on an annual event rate of 2.3% and a premature study discontinuation rate of 1% per 
year.  The trial is intended to complete after approximately 844 subjects have accrued an 
adjudicated and confirmed primary endpoint event (as defined in Section 2.2.1) or 12 months 
following the date that the last subject is randomized, whichever occurs later.  Assuming that 
the trial will recruit in 3.1 years, with approximately 50% of the subjects in the last ten 
months, the study will finish in another approximately 1.7 years, for trial duration of 
approximately 4.8 years.
The sample size may be modified to shorten the expected duration of the trial or to improve 
the likelihood of attaining 70% power for the key secondary composite endpoint of CV 
death, non-fatal MI and non-fatal stroke. Prior to the end of enrollment, blinded assessments
will be made of the expected duration of the trial and the power for this endpoint, assuming a 
hazard ratio of 0.8 and a two sided-alpha of 0.05. Under these assumptions, 496 confirmed 
and adjudicated events will provide approximately 70% power.
In addition, the sample size in certain subgroups, including diabetic subjects with no prior 
CVD event, may be modified or the trial duration may be extended to improve the likelihood 
that the estimated hazard ratios in the subgroups are less than one.  Prior to the end of 
enrollment, the sponsor will perform a blinded assessment of the probabilities, assuming a 
hazard ratio of 0.8.  Under this assumption, 58 events will provide approximately 80% 
probability that a point estimate is less than one.
As any adjustment to the sample size or duration of follow-up will be based on blinded data, 
the distribution of the test statistic for the primary analysis under the null hypothesis will not 
be affected and no alpha adjustment will be made.
These power and trial duration calculations were done with the software package EaST
(version 6.3.1).

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9.1.1. Cognitive Testing Sample Size
One of the objectives for this trial is to describe the safety of bococizumab and placebo with 
respect to assessments of cognitive testing. Cognitive testing will be performed at baseline 
(Visit 5), annually, and at the EDC and EOS visits at a subset of designated study sites in 
approximately 500 subjects (250/treatment group).  This number of subjects is based on 
feasibility of sites with the appropriate staff and workspace to administer the testing 
accurately. 
Assuming 80% of the 500 subjects will have cognitive testing performed at Visit 11 (Week 
52) and 70% at Visit 14 (Week 104), it is expected that 400 subjects (200/group) will have 
cognitive testing at Week 52 and 350 subjects (175/group) at Week 104. Precision estimates 
are defined as the half-width of the 95% confidence interval for these assumed sample sizes 
at Week 52 and Week 104 for each cognitive test and are displayed in the table below.
Table 3.
Precision Estimates for Cognitive Assessments
Cognitive Test
Visit
N/group
SD*
Precision
Digit Span (Forward)
Week 52
200
2
±0.39
Week 104
175
2
±0.42
Digit Span (Backward)
Week 52
200
2
±0.39
Week 104
175
2
±0.42
Digit Symbol Substitution Test
Week 52
200
9
±1.76
Week 104
175
9
±1.89
Trail Making A
Week 52
200
22
±4.31
Week 104
175
22
±4.61
Trail Making B
Week 52
200
40
±7.84
Week 104
175
40
±8.38
HVLT Learning
Week 52
200
4
±0.78
Week 104
175
4
±0.84
HVLT Delayed Recall
Week 52
200
2
±0.39
Week 104
175
2
±0.42
* Based on data for cognitively normal subjects from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 
study except for HVLT which is based on data for placebo subjects from Pfizer Study A4091004.
9.1.2. Primary Endpoint Placebo Event Rate Estimate
Given the power and the alpha level, the expected duration of the trial will be driven by the 
assumed rate of accrual of adjudicated and confirmed primary endpoint events in the placebo 
group, the assumed hazard ratio, the subject accrual rate and the premature study 
discontinuation rate.  To produce an estimate of the primary endpoint event rate in the 
placebo group, meta-analyses, published and unpublished, were considered and a review of 
lipid lowering clinical trial literature was conducted (Section 9.1.3).  These trials vary 
considerably with respect to their temporal execution, background cardioprotective 
medications, and differences in enrichment of various risk factors, any of which may impact 
CV event rates.  Furthermore, the component of the primary endpoint for the present study, 
hospitalization for unstable angina needing urgent revascularization did not appear to be a 

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predefined component of the trials that were reviewed, some of which had endpoint 
components comprising hospitalization for unstable angina, irrespective of the need for 
revascularization, and for other clinical trials, revascularization rates were reported 
separately, as a secondary endpoint.
Given the uncertainty of the primary endpoint event rate in the placebo group, and 
enrichment of the study population with diabetic subjects without a prior CVD event who 
have a lower primary endpoint rate than the rest of the population, estimates of trial duration 
and event accrual will assume a placebo event rate of 2.3%/year, which is, slightly less than
the lower bound of the 80% prediction interval for the estimated placebo event rate for 
baseline LDL-C of 80 mg/dL (2.1 mmol/L) from a unpublished meta-analysis. 
9.1.3. Representative Analyses of Event Rates
The Cholesterol Treatment Trialists’ Collaboration (CTTC) meta-analysis showed an average 
major vascular event rate of 4.5%/year, for trials that compared more intensive to less 
intensive statin therapy (Table 4).45 These event rates are expected to be somewhat higher 
than what would be expected for this study, for which only unscheduled urgent 
revascularizations, rather than any revascularizations serve as an element of the primary 
endpoint.
Table 4.
CTTC Statin Lipid Lowering Trials and Event* Rate Estimates, 
%/Year
CTTC trial meta-analysis
Statin more intensive
Statin less intensive
Trial name
PROVE-IT46
11.3
13.1
A to Z47
4.0
5.4
TNT48
5.2
6.3
IDEAL49
3.6
3.8
SEARCH50
7.2
8.1
Mean
4.5
5.3
*Major vascular events CHD death, non-fatal MI, any revascularization, any stroke
The Cholesterol Treatment Trialists’ Collaboration (CTTC) meta-analysis also evaluated 
event rates by the baseline level of LDL (Table 5).The analysis did not demonstrate a trend 
by baseline LDL-C level (Trend 2 = 2.04, p = 0.2).45

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Table 5.
CTTC Statin Lipid Lowering Trial Event Rates (%/year) by LDL Level
mg/dL
mmol/L
Statin more intensive
Statin less intensive
< 77
<2.0
4.6
5.2
≥ 77 to < 97
≥ 2.0 to < 2.5
4.2
4.8
≥ 97 to < 116
≥ 2.5 to < 3.0
4.5
5.0
≥ 116 to < 135
≥ 3.0 to < 3.5
5.7
7.8
≥ 135
≥ 3.5
4.5
5.3
The statin treatment control arm event rate of two recent trials assessing the efficacy and 
safety of treatments increasing levels of HDL-C were also informative and would be 
considered near, contemporaneous, with expected event rates for the present trial.  The 
AIM-HIGH study of subjects at risk of CVD with low levels of HDL-C, with a baseline 
LDL-C of 74 mg/dL (1.9 mmol/L) taking simvastatin, had a somewhat broader primary 
endpoint than the present study (death from coronary heart disease, nonfatal myocardial 
infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or 
symptom-driven coronary or cerebral revascularization).51 The investigators reported an 
event rate of 16% over a mean of 3 years, or an approximate rate of 5.4%/year.51
The dal-OUTCOMES assessment of dalcetrapib in subjects with recent acute coronary 
syndrome had a primary endpoint which was a composite of death from coronary heart 
disease, nonfatal myocardial infarction, ischemic stroke, unstable angina, or cardiac arrest 
with resuscitation.52 The mean LDL-C level reported in that study was 76 mg/dL 
(2.0 mmol/L) and the investigators reported a primary endpoint incidence of 9.1 % (95% CI 
8.4-9.9) or approximately 3%/year.
An independent, unpublished meta-analysis of CV event rates, was performed by 
Quantitative Solutions, Inc.  It evaluated the occurrence of CV events observed in a large 
number of lipid lowering studies.  The analysis included a simulation of a Phase 3 outcomes 
trial similar to the current study design and assumed a population comprising 60% CHD 
subjects and 40% with diabetes, an HDL-C of 47 mg/dL and a body mass index (BMI) of 
29 kg/m2.  The analysis demonstrated a 4.5 year cumulative incidence of 8.3% (1.8%/year) 
for major cardiovascular events (CV death, non-fatal MI, and non-fatal stroke) and 14.5% 
(3.3%/year) for any CV event (major CV events as described, and coronary 
revascularization).53
An evaluation of whether or not the level of baseline LDL-C contributed to the event rate 
estimates (with 80% prediction interval [PI]) suggested a trend toward a modestly higher rate 
with increasing levels of baseline LDL-C, but there was considerable variation in the 
estimates (Table 6).53

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Table 6.
Estimates of Expected CV Event Rates by Baseline LDL-C
Baseline LDL mg/dL
Baseline LDL mmol/L
CV events with End 
Organ Injury
[80% PI]
Any CV event
[80% PI]
80
2.1
1.9 [1.4-2.7]
3.3 [2.4-4.5]
90
2.3
2.0 [1.4-2.8]
3.5 [2.5-4.8]
100
2.6
2.2 [1.5-3.0]
3.8 [2.7-5.1]
110
2.8
2.3 [1.6-3.2]
4.0 [2.9-5.4]
120
3.1
2.4 [1.7-3.4]
4.3 [3.1-5.7]
PI = Prediction Interval
9.1.3.1. Event Rates in Diabetics Without a Prior CVD Event
Subjects with diabetes without a prior CVD event have been considered at high risk of 
incurring such events, since the NCEP ATPIII guidelines of 2002.6 Evidence-based clinical 
guidelines continue to support the treatment of high risk diabetics who have not had a prior 
CVD event with high dose statin therapy.5,12,13,59,60 Clinical trials, both observational and 
interventional, have demonstrated a wide range (0.6%/year to 7.7%/year) of CVD event 
rates, albeit with different definitions of major CV events, in this important, high risk 
primary prevention population.67,68,69   The differences in event rates reported in diabetics 
without a prior CV event may be related to differences in the presence of co-morbidities, 
background treatments, demographics, referral patterns of subjects, and the level of 
follow-up for event detection.  These event rates are generally lower than those observed for 
the population represented in Table 6 for subjects with baseline LDL-C of 80 mg/dL 
(2.1 mmol/L).
In the Collaborative Atorvastatin Diabetes Study (CARDS), 2,838 primary prevention 
diabetic subjects were evaluated and randomized either to placebo or atorvastatin 
10 mg/day.67 The trial was terminated 2 years earlier than expected because the pre-specified 
early stopping rule for efficacy had been met.  The median duration of follow-up was 
3.9 years (Interquartile range 3.0–4.7).  127 subjects randomized to placebo (2.46 per 
100 person-years at risk) and 83 randomized to atorvastatin (1.54 per 100 person-years at 
risk) had at least one major cardiovascular event (rate reduction 37% [95% CI –52 to –17], 
p=0.001).  The incidence of acute coronary heart disease events was 1.47 per 
100 person-years at risk for subjects randomized to placebo and 0.94 per 100 person-years at 
risk for those randomized to atorvastatin. If unstable angina is excluded from the definition 
of non-surgical acute coronary events (to allow comparison with other major clinical trials),
the incidence was 1.31 per 100 person-years at risk for placebo and 0.88 per 
100 person-years at risk for atorvastatin. For acute coronary heart disease events plus 
revascularizations, the incidence was 1.93 per 100 person-years at risk for placebo and 
1.18 per 100 person-years at risk for atorvastatin.
In a population of diabetic subjects without known CVD who were referred for cardiac 
radionuclide imaging, after a median follow-up of 2 years, 98 MI or cardiac death events 
occurred in 1430 subjects, for an annual event rate of 3.1%.68 Asymptomatic subjects, 

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subjects with angina, and subjects with shortness of breath had annual MI or cardiac death
rates of 2.2%, 3.2%, and 7.7%, respectively.68 It should be noted that an endpoint of 
hospitalization for unstable angina with urgent revascularization was not evaluated in this 
study.
The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study, a randomized 
controlled trial in which 1,123 diabetic participants, not referred for imaging, were randomly 
assigned either to be systematically screened with stress myocardial perfusion imaging or not 
to be screened to test the hypothesis that systematic screening would identify higher-risk 
individuals and beneficially affect their risk of myocardial infarction or cardiac death.  In the 
DIAD study the average event rate was 0.6%/year.69 The DIAD study did not evaluate an
endpoint of hospitalization for unstable angina requiring urgent revascularization.
9.2. Efficacy Analysis
Efficacy analyses, unless otherwise indicated, will be performed according to the 
intention-to-treat (ITT) principle.  The Full Analysis Set (FAS) includes all subjects who 
were randomized and will be the primary analysis set for the analysis of efficacy data.  
Subjects will be analyzed according to their randomized dose regardless of any change in 
dose.  Data will not be excluded from the FAS due to changes in dose or adherence to, or 
discontinuation of, study medication.  For time-to-event analyses of clinical efficacy 
endpoints, all data through the efficacy cutoff date will be included, unless specified 
otherwise.  For all other efficacy analyses, all data will be included. 
9.2.1. Analysis of Primary Endpoint
The primary objective is to demonstrate superiority of bococizumab compared to placebo 
with respect to the primary endpoint, the time from randomization to the first adjudicated and 
confirmed occurrence of a major cardiovascular event, a composite endpoint which includes 
CV death, non-fatal MI, non-fatal stroke, and hospitalization for unstable angina needing 
urgent revascularization (as defined in Appendix 4).  Subjects who discontinue randomized 
study medication prematurely and have not withdrawn consent will continue to be followed 
in the study to assess the occurrence of endpoints.  Subjects who do not experience any of the 
components of the primary endpoint will be censored on the efficacy cutoff date, or on the 
date of last contact, whichever is earlier.  The efficacy cutoff date is defined as the estimated 
date that the criteria in Section 3 for ending the study, excluding continuing the study for at 
least 12 months after the last randomization, will be met.  This date will be determined 
during the conduct of the study, prior to unblinding.  The date of last contact is defined as the 
date of death, if the date is not missing. Otherwise, the date of last contact is defined as the 
study discontinuation date, the onset date of the last AE, or the randomization date, 
whichever occurs last. The primary endpoint will be analyzed in the FAS using a log rank 
test stratified by geographic region and LDL-C at the pre-screening visit (<100 mg/dL, 
100 mg/dL).  The overall alpha level for this trial is 0.05.  The two-sided alpha level for this 
log rank test will be adjusted for DMC reviews of all-cause death (see Section 9.6), resulting 
in a two-sided alpha of 0.049.  A Cox proportional hazards model will be fit with treatment 
group as a covariate and geographic region and LDL-C at the pre-screening visit 

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(<100 mg/dL, 100 mg/dL) as stratification factors.  If the model fitting fails to converge, 
LDL-C at pre-screening will be removed as a stratification factor.  The hazard ratio will be 
presented along with a 95% confidence interval.  The goodness of fit of the Cox proportional
hazards model will be assessed with an Arjas plot.80 Kaplan-Meier estimates of time to first 
major cardiovascular event will be plotted.
In order to aid in the assessment of the impact of premature discontinuation from the study 
on the primary analysis, time from randomization to premature discontinuation from the 
study will be analyzed.  The p-value from a log rank test will be presented.  A Cox 
proportional hazards model will be fit with treatment group as a covariate and geographic 
region and LDL-C at the pre-screening visit (<100 mg/dL, 100 mg/dL) as stratification 
factors.  If the model fitting fails to converge, LDL-C at pre-screening will be removed as a 
stratification factor.  The hazard ratio and a 95% CI will be presented.  Kaplan-Meier 
estimates of time to premature discontinuation from the study will be plotted.
The impact of informative censoring on the primary analysis will be evaluated through 
multiple imputations.  Imputations will only be done for subjects who withdrew consent to be 
followed prior to the efficacy cutoff date, and did not have a primary endpoint event.  Several 
imputation models for informative censoring will be used.  Each model will incorporate 
possible explanatory variables for premature study discontinuation.  In a conservative 
approach, the imputation model for subjects in both treatment groups will be based only on 
data from placebo subjects.  In one approach, the imputation model will incorporate reasons 
for premature study discontinuation.  In a second approach, the imputation model will 
incorporate the incidence of targeted medical events associated with the mechanism of action 
of bococizumab.
In a supplemental analysis, the log rank test and Cox proportional hazards model analysis for 
the primary endpoint will be repeated incorporating all adjudicated and confirmed events, 
including events after the efficacy cutoff date.
In a second supplemental analysis, time to recurrent primary endpoint events will be 
analyzed using the Wei-Lin-Weissfeld methodology with treatment group as a covariate and 
geographic region and LDL-C at the pre-screening visit (<100 mg/dL, 100 mg/dL) as 
stratification factors.58 If the model fitting fails to converge, LDL-C at pre-screening will be 
removed as a stratification factor.  The common hazard ratio, 95% confidence interval, and 
p-value will be presented.
An additional supplemental analysis of the primary endpoint will assess the efficacy of 
bococizumab for subjects who adhere to treatment.  Only subjects who have been treated for 
at least 26 weeks will be included.  Adherence to treatment will be defined as attaining an 
LDL-C level at or below 30 mg/dL at Visit 11 (Week 52).  Treatment-adherent bococizumab
subjects, non-treatment-adherent bococizumab subjects and placebo subjects will be 
compared using the above Cox proportional hazards model with additional covariates 
including smoking status, age, BMI, and relevant baseline history. 

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9.2.1.1. Subgroup Analyses
Cox regression for the primary endpoint will be performed in a subset of the subgroups of the 
FAS listed below.  The subgroup analyses will be finalized in the Statistical Analysis Plan 
prior to final unblinding.

Gender;

Age (<65, 65-74, ≥75); 

Race; 

Ethnicity; 

Geographic region; 

BMI (<25 kg/m2, ≥25 kg/m2– <30 kg/m2, ≥30 kg/m2); 

Smoking status.

Baseline history of:

Atherosclerotic/cardiovascular event;

Hypertension; 

MI; 

Coronary heart disease; 

Diabetes;

Diabetes and atherosclerotic/cardiovascular event;

Coronary revascularization;

Peripheral artery revascularization;

heFH/LDL-C190 mg/dL (4.9 mmol/L), historically or at pre-screening;

Peripheral vascular disease;

CHF;

Statin intolerance; 

Microalbuminuria;

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
eGFR (≥30 ml/min/1.73m2 to <60 ml/min/1.73m2 [moderate renal impairment], 
≥60 ml/min/1.73m2 to <90 ml/min/1.73m2 [mild renal impairment], 
≥90 ml/min/1.73m2 [no renal impairment]) (as calculated by MDRD equations);

Any renal impairment and baseline history of an atherosclerotic/cardiovascular 
event

LDL-C at the pre-screening visit (<100 mg/dL, 100 mg/dL)

Baseline triglycerides (<200 mg/dL, ≥ 200 mg/dL); 

Baseline hs-CRP (< 2.0 mg/L, ≥ 2.0 mg/L); 

Baseline Lp(a) (< 50 mg/dL, ≥ 50 mg/dL);

Additional background lipid lowering treatments;

Time from atherosclerotic/cardiovascular event (1 year, > 1 year).
Geographic region and LDL-C at the pre-screening visit (<100 mg/dL, 100 mg/dL) will be 
stratification factors in the Cox regressions, as appropriate.  If the model fitting fails to 
converge, LDL-C at the pre-screening visit will be removed as a stratification factor.  The 
hazard ratios and 95% confidence intervals will be reported and plotted.  For each categorical 
variable used to define subgroups, an additional Cox proportional hazards model will be fit.  
This Cox model will also include the categorical variable and an interaction between the 
categorical variable and treatment group.  The interaction p-value will be reported.
In addition, the primary endpoint will be summarized by the number of dose adjustments.  
The subjects randomized to bococizumab with 0, 1 and 2 dose adjustments will be tabulated 
with all placebo subjects; subgroups will not be taken of the placebo subjects.
9.2.2. Analysis of Secondary Endpoints
The experimentwise Type 1 error rate, after a single Bonferroni adjustment for DMC reviews 
of all-cause death (see Section 9.6), will be controlled by using a gatekeeping procedure 
followed by a fixed sequence testing procedure.  Key secondary endpoints will be formally 
tested only if the null hypothesis for the primary analysis is rejected.  The fixed sequence 
testing procedure will be applied to the key secondary endpoints with a two-sided =0.049, 
using the sequence indicated in Section 2.2.2.  All other statistical tests for secondary 
endpoints will be performed at the two-sided =0.05 level; no further corrections will be 
made for multiple endpoints.
9.2.2.1. Secondary Endpoints for Clinical Outcomes
The secondary endpoints for clinical outcomes include the times from randomization to the 
first occurrence of the adjudicated and confirmed clinical endpoints described below 
(Section 9.2.2.1.1 and Section 9.2.2.1.2).  Time to each of these endpoints will be tested in
the FAS with a log rank test stratified by geographic region and LDL-C at the pre-screening 

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visit (<100 mg/dL, 100 mg/dL).  For the key secondary endpoints, the fixed sequence 
testing procedure with a two-sided α=0.049 will be used for the log rank test of each 
endpoint.  The sequence indicated in Section 2.2.2 will be used.  For other secondary 
endpoints, and for analyses of the key secondary endpoints other than the log rank test, a 
two-sided α=0.05 will be used.  A Cox proportional hazards regression model for each 
endpoint will be fit with treatment group as a covariate and geographic region and LDL-C at 
the pre-screening visit (<100 mg/dL, 100 mg/dL) as stratification factors.  If the model 
fitting fails to converge, LDL-C at the pre-screening visit will be removed as a stratification 
factor.  The hazard ratio and 95% confidence intervals will be reported.  For each endpoint, 
Kaplan-Meier estimates of time to first event will be plotted.
For each of the key secondary endpoints and for all-cause death, the log rank test and Cox 
proportional hazards model analysis will be repeated incorporating all adjudicated and 
confirmed events, including events after the efficacy cutoff date.
Times to recurrent events for each of the key secondary endpoints and the remaining 
composite endpoint will be analyzed using the Wei-Lin-Weissfeld methodology with 
treatment group as a covariate and geographic region and LDL-C at the pre-screening visit 
(<100 mg/dL, 100 mg/dL) as stratification factors.  If the model fitting fails to converge, 
LDL-C at the pre-screening visit will be removed as a stratification factor.  The common 
hazard ratios, 95% confidence intervals, and p-values will be presented.
In addition, an adherent subject analysis will be performed for all-cause death and for the 
composite endpoint of CV death, non-fatal MI and non-fatal stroke using the same 
methodology as for the primary endpoint (Section 9.2.1).
9.2.2.1.1. Key Secondary Endpoints
The key secondary endpoints (as defined in Appendix 4) are the times from randomization to 
the first adjudicated and confirmed occurrence of:

A composite endpoint of CV death, non-fatal MI, and non-fatal stroke;

A composite endpoint of all-cause death, non-fatal MI, and non-fatal stroke, and 
hospitalization for unstable angina needing urgent revascularization;

A composite endpoint of all-cause death, non-fatal MI and non-fatal stroke;

Hospitalization for unstable angina needing urgent revascularization.
9.2.2.1.2. Other clinical secondary endpoints
Other clinical secondary endpoints (as defined in Appendix 4) are the times from 
randomization to the first adjudicated and confirmed occurrence of:

A composite endpoint of CV death, non-fatal MI, non-fatal stroke, and hospitalization 
for unstable angina;

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
CV death;

Any MI (fatal and non-fatal);

Fatal MI;

Non-fatal MI;

Any stroke (fatal and non-fatal);

Any stroke (fatal and non-fatal) of any etiology;

Fatal stroke;

Non-fatal stroke;

Hospitalization for unstable angina;

Hospitalization for congestive heart failure (CHF);

Any coronary revascularization procedure;

CABG;

PCI;

Any arterial revascularization;

All-cause death.
9.2.2.2. Secondary Endpoints for Circulating Biomarkers
Percent changes from baseline in all lipid endpoints and hs-CRP, and nominal change from 
baseline in LDL-C will be analyzed using a mixed model repeated measures (MMRM) 
model with fixed effects for treatment (categorical variable), scheduled visit time point 
(categorical variable), baseline value (continuous variable), interaction between baseline 
value and scheduled visit time point, interaction between treatment and scheduled visit time 
point, and geographic region (categorical variable) , and LDL-C at the pre-screening visit 
(<100 mg/dL, 100 mg/dL, as appropriate).  Baseline will be calculated as the mean of the 
last two non-missing values prior to and including the randomization date.
Restricted Maximum Likelihood (REML) estimation will be used, and the default covariance 
structure will be unstructured.  If the model fitting fails to converge with an unstructured 
covariance matrix, a spatial power covariance will be used.  If the model fails to converge 
with this covariance structure, compound symmetry will be used.  Consistent with MMRM 
model fitting, no explicit imputation of missing assessments will be performed.  Estimates of 
treatment group means and mean treatment group differences at Week 14 and each other 

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visit, corresponding 95% confidence intervals, and p-values for the mean differences will be 
provided.  The least-squares mean treatment group estimates and 95% confidence intervals 
will be plotted longitudinally. 
For Lp(a), triglycerides and hs-CRP, the same model will be fit in the same manner for 
log-transformed nominal changes from baseline.  The data will be log transformed prior to 
calculating changes.  Any zero values will be replaced with 0.0001 to enable taking the 
logarithm.  The estimated treatment group means and corresponding 95% confidence 
intervals from the analysis of the log transformed data will be transformed to percent changes 
for reporting.  The estimated treatment group differences will be transformed to the ratio of 
the mean percent changes and reported with 95% confidence intervals along with 
untransformed p-values.  The transformed estimated mean percent changes and 
corresponding transformed 95% confidence intervals will be plotted.
The percent changes from baseline to last non-missing post-baseline measurement in LDL-C 
will be analyzed using an analysis of covariance model with treatment group and baseline 
value as covariates and geographic region as a factor.  Least squares means with 
corresponding 95% confidence intervals, the least-squares mean differences and 
corresponding 95% confidence intervals, and p-values will be presented.
Secondary endpoints for circulating biomarkers are:

The percent and nominal change from baseline at Week 14 (Visit 8) and percent 
change from baseline to the last available post-baseline observation in LDL-C (direct 
measurement).

The percent change from baseline to Week 14 (Visit 8) in:

Non-HDL-C;

VLDL-C;

RLP-C;

Lp(a);

Apo-B;

HDL-C;

apo-A-I;

Total cholesterol;

Triglycerides;

The percent change from baseline to Week 14 (Visit 8) in hs-CRP.
Friedewald LDL-C will be summarized by treatment group and visit according to sponsor 
standards.

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9.3. Analysis of Other Endpoints
Demographics, alcohol and tobacco use, cardiovascular risk factors, medical history, 
pretreatment and concomitant lipid-lowering medications, other pretreatment and 
concomitant medications and non-drug treatments, protocol deviations, compliance with 
study medication, exposure to study medication and reasons for discontinuation from 
treatment and from the study will be tabulated by treatment group according to sponsor 
standards.
9.3.1. Health –Related Quality of Life and Health Care Resource Use
Observed values and changes from baseline in the health index score and the health state 
score and the observed value of individual EQ-5D items will be summarized according to the 
sponsor standards.
Health care resource utilization will be summarized by treatment group according to sponsor 
standards.  Additional analyses, including comparisons of the bococizumab treatment group 
to the placebo treatment group, will be prespecified in a separate analysis plan.
9.3.2. Analysis of Pharmacokinetic and Pharmacodynamic Endpoints
If data permit, the following analyses may be performed for plasma bococizumab
concentration data and PCSK9 concentration data:
1. A listing of all plasma bococizumab concentrations by subject at nominal time post 
dose. This listing will also include actual times post dose. 
2. A descriptive summary of plasma bococizumab concentrations.  Summary statistics 
of arithmetic mean, geometric mean, % coefficient of variation, standard deviation, 
median, minimum, and maximum will be tabulated by visit. 
3. A listing of all plasma PCSK9 concentrations by subject at nominal time post dose.  
This listing will also include actual times post dose. 
4. Descriptive summaries for observed PCSK9 concentrations, absolute and percentage 
change from baseline in PCSK9 concentrations.  Summary statistics of arithmetic 
mean, % coefficient of variation, standard deviation, median, minimum and 
maximum will be tabulated by visit. 
5. Baseline PCSK9 concentration will be defined as the mean of the last two 
non-missing values prior to and including randomization.
Details on the PK/PCSK9 analyses may be found in the Statistical Analysis Plan.
In addition, PK/PD (LDL-C and PCSK9) data from this study may be combined with data 
from other studies for population PK/PD analysis.

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9.4. Safety Analysis
Safety will be assessed through adverse events (including Type 1 and 3 hypersensitivity 
reactions and injection site reactions), serious adverse events, vital signs, examination results
(physical and neurologic examinations and cognitive testing), 12-lead ECG recordings, and 
safety laboratory tests including hematology, blood chemistry studies (including liver 
function tests and creatine kinase tests), urinalysis studies, and ADA assessments.  The 
Safety Analysis Set (SAS) includes all subjects who have received at least one dose of 
randomized study medication and will be used for all safety analyses, unless otherwise 
specified.  All summaries of safety data will be descriptive only, unless indicated otherwise.
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify all AEs 
with respect to system organ class and preferred term.  AEs, AEs leading to discontinuation 
from treatment, AEs leading to temporary discontinuation, and SAEs will be tabulated by 
treatment group.  Out of concern for appropriate reporting of adverse events associated with 
the prefilled syringe, adverse events and SAEs will be reported separately during the 
screening period and after the first dose of randomized study medication, without any 
requirement that the intensity increase after the first dose of study medication.  AEs leading 
to discontinuation from treatment and leading to temporary discontinuation will only be 
summarized after the first dose of study medication.  Summaries will also be provided by 
severity and relationship to study therapy.  In addition, a 3-tier approach will be used.  Tier 
1 AEs are AEs of special clinical interest, including Type 1 and Type 3 hypersensitivity
reactions and injection site reactions, and will be specified in the Safety Risk Plan.  For these 
events, the number and percentage of subjects with AEs with onset after the first dose of 
study medication, the risk difference versus placebo, the associated 95% confidence interval, 
and p-value will be provided.  The confidence intervals and p-values are not adjusted for 
multiplicity and are provided for screening purposes only.  Tier 2 AEs are those that are not 
Tier 1, but are common, occurring in 5% of subjects in any treatment arm.  For these 
events, the number and percentage of subjects with AEs with onset after the first dose of 
study medication, the risk difference versus placebo and the associated 95% confidence 
interval will be provided.  The confidence intervals are for estimation purposes only.  All 
events are Tier 3 events and will be summarized as described above.
Observed values and changes from baseline in systolic BP, diastolic BP, PR, weight, and 
waist circumference will be tabulated by visit according to sponsor standards.  Mean changes 
from baseline will be plotted longitudinally for selected laboratory parameters according to 
sponsor standards.  Observations of potential clinical concern at any time during the study for 
these parameters will be tabulated according to sponsor standards.  Height and temperature 
will be listed. 
Observed values and changes from baseline in hematology, blood chemistry, and quantitative 
urinalysis parameters will be tabulated by visit according to sponsor standards.  Mean 
changes from baseline will be plotted longitudinally according to sponsor standards.  
Observations of potential clinical concern after the first dose of study medication for 
hematology, blood chemistry and all urinalysis parameters will be tabulated by treatment 
group according to sponsor standards.  In addition, the number and percentage of subjects 
with positive ADAs and neutralizing ADAs will be tabulated for bococizumab-treated 
subjects. 

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12-lead ECGs will be locally read and the interpretations will be kept at the investigation 
sites as source documents.  Any clinically significant ECG abnormalities will be reported as 
AEs. 
Physical examination findings will be listed.  Neurological exam findings will be 
summarized according to sponsor standards. 
Changes from baseline in cognitive test results, including the Digit Span Forward score, 
Digit Span Backward Score, Digit Symbol - Coding score, Trail Making A score, Trail 
Making B score, HVLT Total Recall score, HVLT Delayed Recall Trial score, and the 
HVLT Recognition score will be analyzed using an MMRM model.  The fixed effects will be 
treatment group (categorical variable), scheduled visit time point (categorical variable), 
baseline value (continuous variable), interaction between treatment group and visit and 
interaction between treatment group and baseline value.  Baseline value will be the last 
non-missing value on or before the day of randomization.  REML estimation will be used and 
the default covariance structure will be unstructured.  If the model fitting fails to converge, 
compound symmetry will be used as the covariance structure.  Consistent with MMRM 
model fitting, no explicit imputation of missing assessments will be performed.  Estimates of 
treatment group means and mean treatment group differences at each visit along with 
corresponding 95% confidence intervals will be provided.  The confidence intervals are for 
estimation purposes only.
The PHQ-2 score and PHQ-9 score will be summarized by treatment group at baseline 
according to sponsor standards.
Time-to-event analyses of all-cause death will be repeated in the SAS.  Adjudicated and 
confirmed causes of death will be tabulated by treatment group.
AEs with onset after the first dose of study medication will be tabulated for subjects in 
subgroups defined by age (<65, 65-74, ≥75), gender, number of dose adjustments and having 
a post-baseline LDL-C ≤ 25 mg/dL at the end of a dosing interval.  For the number of dose 
adjustments, the subjects receiving bococizumab with 0, 1 and 2 dose adjustments will be 
tabulated along with all placebo subjects; subgroups will not be taken of the placebo subjects.  
Similarly, subjects receiving bococizumab having a post-baseline LDL-C ≤ 25 mg/dL and 
not having a post-baseline LDL-C ≤ 25 mg/dL will be tabulated along with all placebo 
subjects.
Adverse events with onset after the first dose of study medication, Tier 1 AEs, SAEs and 
selected lab parameters will be summarized by treatment group according to sponsor 
standards for the adherent subject treatment groups defined in Section 9.2.1.
9.5. Interim Analyses 
Prior to the completion of this study, analyses of time to the primary endpoint and time to 
all-cause death, which includes data pooled from the two Phase 3 CV outcomes studies 
(B1481022 and B1481038), will be done to support an overall safety assessment, prior to a 
regulatory submission for the treatment of hyperlipidemia.  These analyses will be conducted 

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by a group external to the sponsor and sent to the DMC for review.  Regulators will not 
receive the results of the analyses, but instead the DMC recommended actions with respect to 
the ongoing trials, which are blinded; no individual at the sponsor will be unblinded or 
exposed to the results of these analyses.  Access to the unblinded data will be described in the 
DMC Charter.  More information about DMC analyses is in Section 9.6.
As there is no possibility of this study stopping early for success as a result of this interim 
analysis and no individual at the sponsor will be unblinded or exposed to the results of this 
analysis, no adjustment to the experimentwise Type 1 error will be made.
9.6. Data Monitoring Committee 
This study will use an external DMC.  The DMC will be responsible for ongoing monitoring 
of the safety of subjects in the study and will meet periodically to review the safety data 
according to the DMC Charter.  As part of the periodic safety reviews, the DMC will review 
analyses of the primary endpoint and all-cause death.  These analyses will be conducted by a 
group external to the sponsor; no individual with the sponsor will be unblinded or exposed to 
the results of these analyses.  The DMC Charter contains pre-defined rules for stopping the 
trial.  Those rules are described in Appendix 5 of this protocol. The trial will not be stopped 
to declare success or futility on the primary endpoint; however, the DMC may recommend 
terminating the trial early due to a benefit on all-cause death, based on a pre-defined stopping 
rule which appears in Appendix 5.  The recommendations made by the DMC to continue the 
study as planned or alter the conduct of the study will be forwarded to Pfizer and the 
Executive Committee leadership for final decision.  Pfizer will make the final decision and 
will forward such decisions, which may include summaries of aggregate analyses of endpoint 
events and of safety data which are not endpoints, to regulatory authorities, as appropriate. 
The trial will not incorporate provisions for stopping early for success based on the primary 
endpoint, but may be stopped early for success on all-cause death.  As cardiovascular death 
counts towards both the primary endpoint and all-cause death, an alpha of 0.001 will be set 
aside for the DMC reviews of all-cause death.  The alpha spending function for these 
analyses is described in Appendix 5.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits, during study conduct, to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the IRB/IEC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.

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The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs, source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject’s chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 

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correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Conference on Harmonisation (ICH), 
local regulations, or as specified in the Clinical Study Agreement (CSA), whichever is 
longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 and 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data is compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code consisting 
of a numbering system provided by Pfizer in order to de-identify study subjects.  The study 

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site will maintain a confidential list of subjects who participated in the study linking their 
numerical code to the subject’s actual identity.  In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of subject personal data consistent with 
applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, or his or her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. 
Whenever consent is obtained from a subject’s her legally acceptable representative, the 
subject’s assent (affirmative agreement) must subsequently be obtained when the subject has 
the capacity to provide assent, as determined by the IRB/EC.  If the investigator determines 
that a subject’s decisional capacity is so limited he/she cannot reasonably be consulted, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, then 
the subject’s assent may be waived with source documentation of the reason assent was not 
obtained.  If the study subject does not provide his/her own consent, the source documents 
must record why the subject did not provide consent (eg, minor, decisionally impaired adult), 
how the investigator determined that the person signing the consent was the subject’s legally 
acceptable representative, the consent signer’s relationship to the study subject (eg, parent, 
spouse) and that the subject’s assent was obtained, or waived.  If assent is obtained verbally it 
must be documented in the source documents.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject’s legally acceptable representative, when applicable, 
before any study-specific activity is performed.  The investigator will retain the original of 
each subject’s signed consent document.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. 
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used. 
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 

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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State
End of Trial in a Member State of the European Union is defined as the time at which it is 
deemed that sufficient subjects have been recruited and completed the study as stated in the 
regulatory application (ie, Clinical Trial Application [CTA]) and ethics application in the 
Member State.  Poor recruitment (recruiting less than the anticipated number in the CTA) by 
a Member State is not a reason for premature termination but is considered a normal 
conclusion to the study in that Member State.
13.2. End of Trial in all Other Participating Countries
End of Trial in all other participating countries is defined as Last Subject Last Visit (LSLV).  
LSLV in all other participating countries is defined as the date the investigator reviews the 
last subject’s final safety data and determines that no further evaluation is required for the 
subject to complete the trial.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of bococizumab at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 30 days of the notification.  Final study visits 
should occur within 30 days of subject contact.  As directed by Pfizer, all study materials 
must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and other public registries in accordance with applicable local 
laws/regulations.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov

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Pfizer posts US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer product, 
regardless of the geographical location in which the study is conducted.  US Basic Results 
are submitted for posting within 1 year of the primary completion date for studies in adult 
populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary Completion Date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by the 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product. 
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively "Publication") 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, Investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 

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has not been submitted for publication within 12 months of completion or termination of the 
Study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.

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Shapiro AM, Benedict RH, Schretien D. Brandt J.  Construct and concurrent validity of 
the Hopkins Verbal Learning Test-revised.  Clin. Neuropsychol.  1999;13(3)348-358.
66.
DeLong DM, DeLong ER, Wood PD, Lippel K, Rifkind BM.  A comparison of 
methods for the estimation of plasma low- and very low-density lipoprotein cholesterol. 
The Lipid Research Clinics Prevalence Study.  JAMA. 1986 Nov 7;256(17):2372-7.
67.
Colhoun HM, Thomason MJ, Mackness MI, Maton SM, Betteridge DJ, Durrington PN, 
Hitman GA, Neil HA, Fuller JH; Collaborative AtoRvastatin Diabetes Study (CARDS).  
Design of the Collaborative AtoRvastatin Diabetes Study (CARDS) in patients with 
type 2 diabetes.  Diabet Med. 2002 Mar;19(3):201-211.
68.
Zellweger MJ, Hachamovitch R, Kang X, Hayes SW, Friedman JD, Germano G, 
Pfisterer ME, Berman DS.  Prognostic relevance of symptoms versus objective evidence 
of coronary artery disease in diabetic patients.  Eur Heart J. 2004 Apr;25(7):543-450.
69.
Young LH, Wackers FJ, Chyun DA, Davey JA, Barrett EJ, Taillefer R, Heller GV, 
Iskandrian AE, Wittlin SD, Filipchuk N, Ratner RE, Inzucchi SE; DIAD Investigators.   
Cardiac outcomes after screening for asymptomatic coronary artery disease in patients 
with type 2 diabetes: the DIAD study: a randomized controlled trial.  JAMA. 2009 Apr 
15;301(15):1547-1555.
70.
Raal F, Scott R, Somaratne R, et al.  Low-density lipoprotein cholesterol-lowering 
effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin 
type 9 serine protease in patients with heterozygous familial hypercholesterolemia. The 
reduction of LDL-c with PCSK9 inhibition in heterozygous familial 
hypercholesterolemia disorder (RUTHERFORD) randomized trial. Circulation. 
2012;126:2408-17.
71.
Sullivan D, Olsson AG, Scott R, et al. Effect of monoclonal antibody to PCSK9 on low-
density lipoprotein cholesterol levels in statin-intolerant patients. The GAUSS 
randomized trial. JAMA. 2012;308:2497-506.
72.
Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to 
PCSK9 in primary hypercholesterolemia.  N Engl J Med. 2012;367:1891-900.
73.
Koren MJ, Lundqvist P, Bolognese M, et al.  Anti-PCSK9 monotherapy for 
hypercholesterolemia; the MENDEL-2 randomized, controlled phase III clinical trial of 
evolocumab.  J Am Coll Cardiol. 2014;63:2531-40.

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74.
Blom DJ, Hala T, Bolognese M, et al.  A 52-week placebo-controlled trial of 
evolocumab in hyperlipidemia. N Engl J Med.  2014;370:1809-19.
75.
Schwartz GG, Bessac L, Berden LG, et al. Effect of alirocumab, a monoclonal antibody 
to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: 
rationale and design of the ODYSSEY Outcomes trial. Am Heart J.  2014;168:682-9.
76.
Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe 
added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with 
hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 
2014;311:1870-8.
77.
Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal 
antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, 
placebo-controlled, dose-ranging study in statin-treated subjects with 
hypercholesterolemia.  Am J Cardiol.  2015;115(9):1212-21.
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Sabatine MS, Giugliano RP, Wiviott SD, et al.  Efficacy and safety of evolocumab in 
reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-9.
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Robinson JG, Farnier M, Krempf M, et al.  Efficacy and safety of alirocumab in 
reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1488-99.
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Arjas E. A graphical method for assessing goodness of fit in Cox’s proportional hazards 
model. Journal of the American Statistical Association. 1988; 83:204-212.
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Cook TD, Benner RJ, Fisher MR. “The WIZARD trial as a case study of flexible 
clinical trial design,” Drug Information Journal, 2006;40: 345-53.

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Appendix 1. Abbreviations
Ab
Antibody
ABI
Ankle brachial index
Abs
Absolute
ACCF
American College of Cardiology Foundation
Apo
Apolipoprotein
ADA
Anti-drug antibodies
ADAs
Anti-drug antibodies
ADNI
Alzheimer’s Disease Neuroimaging Initiative
AHA
American Heart Association
AE
Adverse event
ALT
Alanine aminotransaminase
AntiHBc
Hepatitis B core antigen antibody
Anti-HBs
Hepatitis surface antigen antibody
AST
Aspartate aminotransaminase
BMI
Body Mass Index
BP
Blood pressure
C
Centigrade
CABG
Coronary artery bypass graft surgery
CARDS
Collaborative AtoRvastatin Diabetes Study
CCU
Cardiac care unit
CETP
Cholesteryl ester transfer protein
CFB
Change from baseline
CHD
Coronary heart disease
CHF
Congestive heart failure
CI
Confidence interval
CK
Creatine kinase (also known as CPK, creatine phosphokinase)
CKD
Chronic kidney disease
CK-MB
Creatine kinase heart isoenzyme
CK-MM
Creatine kinase muscle isoenzyme
Con Med
Concomitant medication
CPK
Creatine phosphokinase (also known as CK, creatine kinase)
CRF
Case report form
CSA
Clinical Study Agreement
CTA
Clinical trial application
CTTC
The Cholesterol Treatment Trialists’ Collaboration
CVD
Cardiovascular disease
CV
Cardiovascular
DAI
Dosing and administration instructions
DIAD
Detection of Ischemia in Asymptomatic Diabetics study
DSM
Diagnostic and statistical manual of mental disorders
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DSU
Drug Safety Unit
DU
Dispensible unit
EASD
European Association for the Study of Diabetes
ECG
Electrocardiogram

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ED80
80% of the maximal response
EDC
Early discontinuation of study drug
EDP
Exposure during pregnancy
ELISA
Enzyme-linked immunosorbent assay
EOS
End of study
ESC/EAS
European Society of Cardiology/European Society of Atherosclerosis
EQ-5D
EuroQol 5-Dimensions Health State Profile
EU
European Union
FAS
Full analysis set
Fc
Fragment crystallizable
FDA
Food and Drug Administration
FDAAA
US Food and Drug Administration Amendments Act of 2007
FH
Familial hypercholesterolemia
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
eGFR
Estimated glomerular filtration rate
HbA1c
Glycated hemoglobin
HBsAg
Hepatitis B surface antigen
hCG
Human Chorionic Gonadotropin
HCRU
Health Care Resource Utilization
HDL
High density lipoprotein
HDL-C
High density lipoprotein cholesterol
heFH
Heterozygous familial hypercholesterolemia
HIV
Human immunodeficiency virus
HMG-CoA
3-hydroxy-3-methyl-glutaryl-coenzyme A
HR
Hazard ratio
hs-CRP
High sensitivity C-reactive protein
HVLT
Hopkins Verbal Learning Test
IEC
Independent Ethics committee
ICD
Informed consent document
ID
Identification
IDL-C
Intermediate density lipoprotein cholesterol
ICH
International Conference on Harmonization
IgG
Immunoglobulin G
IM
Intramuscular
IND
Investigational new drug
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technologies
ITT
Intent to treat
IUD
Intrauterine device
IVR
Interactive voice response
IWR
Interactive web response
K2EDTA
Potassium ethylenediaminetetraacetic acid
LDH
Lactate Dehydrogenase
LDL
Low density lipoprotein
LDL-C
Low density lipoprotein cholesterol
LDLR
Low density lipoprotein receptor 

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LFTs
Liver function tests
Lp(a)
Lipoprotein (a)
LPD
Local Product Document
LSLV
Last subject last visit
LVEF
Left ventricular ejection fraction
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MICU
Medical intensive care unit
Mg
Milligrams
MI
Myocardial infarction
mL
Milliliter
mm Hg
millimeters of mercury
MMRM
Mixed models repeated measures
mRNA
Messenger ribonucleic acid
NCEP ATPIII
National Cholesterol Education Program Adult Treatment Panel III
NICU
Neurology intensive care unit
NYHA
New York Heart Association
ODIS
Off drug in study
PCI
Percutaneous coronary intervention
PCD
Primary completion date
PCP
Primary care physician
PCR
Polymerase chain reaction
PCSK9
Proprotein convertase subtilisin kexin type 9
PD
Pharmacodynamic
PHQ
Patient Health Questionnaire
PI
Predictive Index
PK
Pharmacokinetic
PR
Pulse rate
RC
Risk condition
REML
Restricted Maximum Likelihood
RF
Risk factor
RLP
Remnant lipoprotein
RNA
Ribonucleic acid
RR
Relative risk
Q2wks
Every 2 weeks
Q4wks
Every 4 weeks
QOL
Quality of life
SAE
Serious adverse event
SAP
Statistical analysis plan
SAS
Safety Analysis Set
SC
Subcutaneous
SICU
Surgical intensive care unit
SPC
Summary of Product Characteristics
SREBP 2
Sterol regulatory element binding protein 2
SRSD
Single Reference Safety Document
TC
Total cholesterol
TG
Triglycerides
TIA
Transient ischemic attack

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TICU
Thoracic intensive care unit
TMT
Trail Making Test
ULN
Upper limit of normal
US
United States
USA
United States of America
USPI
United States Package Insert 
VLDL
Very low density lipoprotein
VLDL-C
Very low density lipoprotein cholesterol
VAS
Visual Analogue Scale
WAIS
Wechsler Adult Intelligence Scale
WCBP
Women of childbearing potential

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Appendix 2. Criteria for Diagnosis of Heterozygous Familial Hypercholesterolemia
For the purposes of this study, the diagnosis of heFH should be based on historically having 
met the Simon Broome criteria (on or off treatment) as defined below (revised to add 
measures of cholesterol levels in mg/dL).54
A diagnosis of definite familial hypercholesterolemia (FH) requires:
Cholesterol above 290 mg/dL (7.5 mmol/l) or LDL cholesterol above 189 mg/dL 
(4.9 mmol/l) in an adult.
PLUS
Tendon xanthomas in patient or a 1st degree relative (parent, sibling, child), or in a 
2nd degree relative (grandparent, uncle, aunt).
OR
DNA-based evidence of an LDL receptor mutation, familial defective apoB-100, or a 
PCSK9 mutation.
A diagnosis of possible FH requires:
Cholesterol above 290 mg/dL (7.5 mmol/l) or LDL cholesterol above 189 mg/dL 
(4.9 mmol/l) in an adult.
PLUS
Family history of myocardial infarction (MI): Before 50 years in a 2nd degree relative 
or below age 60 in a 1st degree relative.
OR
Family history of raised total cholesterol: Above 290 mg/dL (7.5mmol/l) in adult 1st 
or 2nd degree relative or above 259 mg/dL (6.7 mmol/l) in a child or sibling aged 
under 16 years.

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Appendix 3. Hepatitis B Assessment
Interpretation of hepatitis B serology results.
Serologic Marker
Hepatitis B 
Surface Antigen 
(HBsAg)
Hepatitis B Core 
Antibody 
(Anti-HBc)
Hepatitis B Surface 
Antibody
(Anti-HBs)
Interpretation
Inclusion
–
–
–
Never infected
Permitted
+
–
–
Early infection or post 
vaccination
Not permitted
+
+
–
Acute infection
Not permitted
–
+
–
Acute resolving infection
Not permitted
–
+
+
Recovered from past 
infection and immune
Permitted
+
+
–
Chronic infection
Not permitted
–
+
–
Exposed and susceptible
Not permitted
–
–
+
immune
Permitted
Key
– : negative serology
+ :  positive serology

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Appendix 4. Clinical Endpoints
The specific criteria for clinical endpoint definitions outlined below, and the source 
documentation necessary to qualify for the adjudication and confirmation of a clinical 
endpoint event, are described in the Adjudication Committee Charter.
Cardiovascular Death
Cardiovascular death is defined as sudden cardiac death, fatal myocardial infarction (MI), 
death due to heart failure, death due to stroke (fatal ischemic stroke or fatal stroke of 
undetermined etiology), or death due to other cardiovascular causes. 
Myocardial Infarction
The MI categories contributing to the MI endpoints for this study are those defined in the 
Third Universal Definition of Myocardial Infarction, as Type 1 (plaque rupture with 
thrombus), Type 2, (MI due to an ischemic imbalance, ie, an increase in oxygen demand or a 
decrease in oxygen supply resulting in cardiac injury), Type 3 (MI resulting in cardiac death, 
when symptoms of ischemia, or ECG evidence of ischemia are present, but death occurred 
before biomarkers could be obtained), Type 4 (MI related to PCI [Type 4a], stent thrombosis
[Type 4b]), or stent restenosis [Type 4c]), or Type 5 (MI related to CABG), consistent with 
the draft endpoint definitions of the Standardized Data Collection for Cardiovascular Trials 
Initiative.41,42
Hospitalization for unstable angina needing urgent revascularization
Hospitalization for unstable angina needing urgent revascularization is defined as an 
unscheduled hospitalization for unstable angina in a subject needing urgent coronary 
revascularization. This criteria and documentation requirements for this endpoint are defined 
by the Adjudication Committee Charter and the draft endpoint definitions of the Standardized 
Data Collection for Cardiovascular Trials Initiative.42
Coronary revascularization
Coronary revascularization for the purpose of this study comprises procedures of coronary 
artery bypass grafting (CABG) or percutaneous coronary intervention (PCI).
Stroke
For the purposes of this study, any stroke is defined as events of ischemic or undetermined 
etiology, including strokes of ischemic etiology that have had subsequent hemorrhagic 
transformation.42 Stroke of any etiology will include all of the above and hemorrhagic 
stroke.  Hemorrhagic stroke events will also be reported as a safety endpoint.
Arterial revascularizations
For the purposes of this study, arterial revascularizations will comprise any peripheral artery 
revascularization of any type.

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Hospitalization for unstable angina
Hospitalization for unstable angina must be qualified as being with or without urgent 
revascularization.  The criteria for the diagnosis of hospitalization for unstable angina include 
clinical symptoms and ECG or imaging evidence of ischemia, in the absence of evidence of 
permanent myocardial injury.
Hospitalization for congestive heart failure
The criteria for hospitalization for congestive heart failure include a constellation of 
symptoms, physical examination findings, laboratory evidence, of heart failure, as well as the 
institution of heart failure therapy.

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Appendix 5. Data Monitoring Committee Stopping Rules
The Data Monitoring Committee (DMC) will use all available evidence and its collective 
judgment in making a recommendation to (1) stop or modify any of the ongoing studies in 
the bococizumab Phase 3 Clinical Development Program for safety or to (2) make a 
recommendation to stop for early benefit on all-cause death in either of the CV outcomes 
studies.  These statistical considerations are not a substitute for the committee’s medical, 
scientific, or statistical expertise.
Major CV events for safety
At each periodic review, a flag based on p0.001 for harm will be used to assess major CV 
events in bococizumab versus placebo.  This flag would signal further examination of all 
available data by the committee with consideration of altering the conduct or terminating any 
of the ongoing studies in the bococizumab Phase 3 Clinical Development Program.  This flag 
would be applied to chi-square tests for each study; a Cochran-Mantel-Haenszel (CMH) 
general association test across all studies; and log-rank tests for the CV outcomes studies, 
performed separately and in a pooled test with stratification by study.
All-cause death for safety
At each periodic review, a flag based on p0.01 for harm will be used to assess all-cause 
death in bococizumab versus placebo.  This flag would signal further examination of all 
available data by the committee with consideration of altering the conduct or terminating any 
of the ongoing studies in the bococizumab Phase 3 Clinical Development Program.  This flag 
would be applied to chi-square tests for each study; a Cochran-Mantel-Haenszel (CMH) 
general association test across all studies; and log-rank tests for the CV outcomes studies, 
performed separately and in a pooled test with stratification by study.
All-cause death for benefit in each CV outcomes study
Each CV outcomes study is designed to provide evidence in a specific population that 
LDL-C lowering with bococizumab compared to placebo will reduce the occurrence of the 
primary endpoint of major CV outcomes (a composite endpoint of cardiovascular death, 
non-fatal MI, non-fatal stroke, or hospitalization for unstable angina needing urgent 
revascularization). 
The minutes of the End of Phase 2 Meeting with the United States Food and Drug 
Administration include the following regarding DMC analyses of the primary endpoint and 
all-cause death:
The sponsor stated that the DMC will periodically look at the comparison between treatment 
arms on the primary endpoint.  These looks are intended for safety. FDA advised allowing 
for a small alpha to test for a mortality advantage at the interim analysis. The sponsor may 
want to consider having formal interim analyses on all-cause mortality.

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There will be no interim monitoring for the purposes of stopping early for efficacy for the 
primary endpoint in either CV outcomes study.  However, the DMC will consider evidence 
for overwhelming benefit for all-cause death (one of the non-key secondary endpoints) in 
each CV outcomes study as a potential reason to recommend early termination for efficacy.
When considering evidence to support a recommendation to stop early for overwhelming 
benefit for all-cause death, each CV outcomes study will be evaluated separately starting 
only when at least 33% of the study’s targeted adjudicated primary endpoint events have 
occurred and subject to a minimum of 8000 patient-years of follow-up (total in both arms in 
the trial) for B1481022 and 2750 patient-years of follow-up for B1481038.  The following 
procedure will be used to control overall Type 1 error.
In each CV outcomes study, the total (two-sided) Type 1 error of 0.050 will be partitioned, 
allocating 0.049 to the primary endpoint and 0.001 to all-cause death.  The primary endpoint 
will not be subject to interim monitoring for benefit, and the final analysis will use a critical 
value of 0.049.  Once the conditions above are met (33% of adjudicated primary events and 
8000 or 2750 patient-years of follow-up for B1481022 and B1481038, respectively), 
all-cause death will be subject to interim monitoring for benefit using a linear alpha spending 
function (t) = 0.001t with final alpha (1) = 0.001.  Depending on the number of looks, 
this choice of alpha-spending function corresponds to an approximately constant monitoring 
boundary of Z=3.4 to 3.6 (nominal p=0.0003 to 0.0006).  Because the total alpha spent in 
interim monitoring of all-cause death will be bounded above by the final alpha value 0.001, 
the experimentwise Type 1 error will be bounded above by 0.049 + 0.001 = 0.05, preserving 
overall Type 1 error. 
Because the trial is designed around a target number of primary endpoint events and the 
corresponding final number of all-cause death events is difficult to estimate with precision, at 
each interim analysis, the current cumulative alpha (t) will be calculated based on an 
information fraction t equal to the aggregate number of observed adjudicated primary 
endpoint events divided by the target event count, and critical values will be calculated based 
on correlations determined from observed aggregate counts of all-cause death at the current 
and previous interim analyses (as in the WIZARD study; Cook, Benner, and Fisher, 2006).81
Once the conditions above are met to begin interim monitoring for benefit for a particular 
trial, a formal interim monitoring calculation will be performed for that trial for every DMC 
report (including safety reports not associated with meetings or teleconferences).  The 
analysis will be based on a log-rank test of all-cause death from all data sources.  Missing 
death dates will be imputed based on date of last contact.
When the test for all-cause death meets the above guideline for stopping a particular study 
early for overwhelming efficacy, the DMC will consider the all-cause death evidence within 
the context of all available efficacy and safety information in making their recommendation.  
In addition, the DMC may wish to give consideration to continuing the study, even where the 
all-cause death analysis meets the above criteria for benefit at an interim analysis, if the study 
is nearing completion (eg, where 90% of targeted primary endpoint events have occurred).

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The table below indicates the percent risk reduction associated with nominal p-values of 
0.0003 and 0.0006 for various numbers of events, along with the probability of observing the 
reduction if the true risk reduction is 10%.  Note that if the true risk reduction is 0% (no 
treatment effect) the probability of stopping is equal to the nominal p-value.
Table 1.  Risk Reductions for Various Numbers of Events with Corresponding Probabilities
α = 0.0003
α = 0.0006
Number of 
Deaths
Percent Risk 
Reduction
Probability if 
10% Risk 
Reduction
Percent Risk 
Reduction
Probability if 
10% Risk 
Reduction
50
68.4%
0.07%
64.9%
0.16%
100
52.9%
0.11%
50.7%
0.20%
150
45.4%
0.14%
43.8%
0.24%
200
40.0%
0.22%
38.7%
0.34%
250
36.6%
0.27%
34.4%
0.57%
300
33.3%
0.42%
32.4%
0.59%
350
31.7%
0.43%
30.1%
0.78%
400
29.8%
0.55%
28.3%
0.95%
Planned interim safety analysis of the Cardiovascular Outcome Studies’ primary 
endpoint
Prior to the regulatory filing for hyperlipidemia and mixed dyslipidemia indications, a single 
planned interim safety analysis of the primary endpoint for the Cardiovascular Outcome 
Studies will be included in the committee report for review at a schedule meeting.  This 
analysis will include Major Cardiovascular Events from each of the studies in the 
bococizumab Phase 3 Clinical Development Program.  The DMC’s recommendation with 
respect to the cardiovascular outcome studies, based on this analysis as well as all available 
safety information, will be included in the regulatory filing.
For all randomized subjects in each study in the bococizumab Phase 3 Clinical Development 
Program, the time to the first adjudicated and confirmed occurrence of the a major CV event 
will be analyzed using a log rank test stratified by protocol and geographic region within a 
protocol.  A major CV event is defined as a composite endpoint which includes 
cardiovascular (CV) death, non-fatal MI, non-fatal stroke, and hospitalization for unstable 

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angina needing urgent revascularization.  Subjects who do not experience any of the 
components of the primary endpoint will be censored on the earlier of the date of death or the 
date of data transfer for this analysis.  A flag based on p<0.001 for harm of bococizumab
would signal further examination of all available data by the DMC and consideration of 
recommendation not to continue the Cardiovascular Outcome Studies.

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Appendix 6. EQ-5D Health Questionnaire
By placing a checkmark in one box in each group below, please indicate which statements 
best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (eg, work, study, housework, family or
leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed


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To help people say how good or bad a health state is, we have drawn a 
scale (rather like a thermometer) on which the best state you can 
imagine is marked 100 and the worst state you can imagine is marked 0.
We would like you to indicate on this scale how good or bad your own 
health is today, in your opinion.  Please do this by drawing a line from 
the box below to whichever point on the scale indicates how good or 
bad your health state is today.
1998 EuroQol Group. EQ-5D™
Your own
health state
today
9
8 0
7 0
6 0
5 0
4 0
3 0
2 0
1 0
100
Worst imaginable
health state
0
Best imaginable
health state

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Appendix 7. Safety algorithm: Myopathy
The following process illustrates the decision tree for evaluating potential myopathy related 
AEs and/or CK elevations.

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Appendix 8. Potential Drug Induced Liver Injury Assessment
Appendix 8.1. Liver function assessment in subjects with normal baseline liver function

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Appendix 8.2. Liver function assessment in subjects with abnormal baseline liver 
function

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Appendix 9. Adverse Event and Potential Outcome Event Flowchart

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Appendix 10. Categories of Cardiovascular Risk
Appendix 10.1. Flow Chart

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Appendix 10.2. Cardiovascular Disease Risk Conditions and Risk Factors