Conditions: Dyslipidemia Cardiovascular Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
B-HIVE is a Phase 3, double blind, placebo-controlled, randomized, parallel group study, designed to compare the efficacy and safety of bococizumab 150 mg subcutaneously every 2 weeks to bococizumab placebo subcutaneously every 2 weeks for LDL-C lowering in HIV-infected subjects.

Detailed description:
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 CVD risks by numerous epidemiological studies. Moreover, large prospective clinical outcome trials have demonstrated that lowering LDL-C decreases cardiovascular morbidity and mortality (1). A meta-analysis of 26 randomized clinical trials comprising 170,000 participants showed that more intensive statin therapy compared to less intensive regimens will reduce coronary deaths or myocardial infarction by an additional 13% (2).

HIV-infected individuals represent a unique and increasing subset of atherosclerosis. With the advent of antiretroviral therapy, HIV-infected individuals now have much improved survival and are faced with health issues related to aging, including cardiovascular disease. Individuals with HIV have higher rates of coronary events compared to controls even in the setting of treated and suppressed disease and a growing body of literature suggests that they are at increased risk for myocardial infarction, atherosclerosis, and sudden cardiac death (3-5). Many facets of atherosclerosis differ in HIV-infected individuals compared to uninfected individuals with atherosclerosis. HIV-infected patients with acute coronary syndromes are younger and more likely to be males and smokers, with low high density lipoprotein-cholesterol (HDL-C), compared to other acute coronary syndrome patients (6). With respect to pathophysiology, viral replication, antiretroviral drugs and inflammation all contribute to atherosclerosis (7,8).

HIV-associated inflammation induces pro-atherogenic lipid abnormalities and anti-retroviral therapy leads to the development of metabolic abnormalities such as dyslipidemia, lipodystrophy and insulin resistance (9,10) In a large cross-sectional study, 27% of subjects receiving combination therapy including a protease inhibitor had a total cholesterol level exceeding 240 mg/dl, compared to 8% of untreated HIV subjects, and 40% had triglyceride levels above 200 mg/dl, compared to 15% in untreated subjects (11). The prevalence and severity of dyslipidemia varies among different antiretroviral drugs; (9) however, hypertriglyceridemia and low HDL-cholesterol were associated with HIV infection even before the advent of antiretroviral therapy (12). Total, HDL-C, and LDL-C decrease at the time of HIV infection, and with antiretroviral treatment total and LDL-C levels increase to pre-infection levels while HDL-C remains low (13).

Abnormalities in body composition have been reported in 40-50% of HIV-infected patients, with higher rates in those receiving combination antiretroviral therapy (9). Subcutaneous lipoatrophy commonly affects the face, limbs, and buttocks, and is accompanied by central fat accumulation. Hyperinsulinemia is often also present. In a representative study, (14) diabetes was present in 7% of HIV-infected adults with fat accumulation or lipoatrophy, as compared to 0.5% of control subjects matched for age and BMI. The corresponding rates of glucose intolerance were 35% and 5% respectively (14). Compared to healthy control subjects, HIV-infected men treated with combination antiretroviral therapy were 4 times as likely to develop diabetes over a 3-year observation period (15).

The increased cardiovascular risk and dyslipidemia in HIV-infected individuals is difficult to treat for several reasons. Statins reduce LDL-C levels less in HIV-infected individuals compared to uninfected controls (16). Fibrates reduce triglyceride levels less in HIV-infected individuals compared to uninfected controls as well (16). Drug-drug interactions between statins and protease inhibitors increase the risk of adverse events (17,18). Due to these interactions, simvastatin and lovastatin are contraindicated among individuals receiving protease inhibitors and the dose of atorvastatin should not exceed 40 mg (17). Even interactions with rosuvastatin, which is not metabolized by the cytochrome P450 system, have been described (19,20).

As a consequence, physicians may avoid treating HIV-infected individuals who would benefit from statins, or use lower doses or less potent statins, reducing the potential for cardiovascular event reduction. High triglyceride levels in HIV-infected subjects are common, and the combination of a fibrate plus antiretroviral therapy increases the risk of drug-drug adverse events, even before consideration of a statin.

Statin treatment reduces lipid levels modestly in HIV subjects. Among 72 HIV-infected subjects in the SATURN-HIV trial randomized to rosuvastatin 10 mg/day, LDL-C was reduced by 25.3% by week 24 (21). In another study, of 83 HIV-infected subjects, rosuvastatin 10 mg and pravastatin 40 mg/day reduced LDL-C by 37% and 19% respectively at 45 days (22). Among 151 HIV-infected subjects randomized to rosuvastatin 10 mg, atorvastatin 10 mg, or pravastatin 40 mg/day, LDL-C reductions were greater with rosuvastatin at this dose, but all 3 statins significantly and similarly reduced serum levels of hs-CRP and TNF (23).

That statins might favorably influence the evolution of atherosclerosis in HIV-infected subjects is suggested by a recent trial where 40 HIV subjects with mild coronary atherosclerosis by CT angiography and aortic inflammation by FDG-PET imaging were randomized to atorvastatin 20-40 mg/day or placebo and were followed for 12 months (24). Atorvastatin significantly reduced non-calcified coronary plaque volume relative to placebo, as well as the number of high-risk plaques.

Approximately 1/3 of individuals with HIV-infection are co-infected with hepatitis C (25). Elevated hepatic enzymes due to hepatitis C represent a relative contraindication to statin therapy, and some evidence suggests that a statin might increase hepatitis C activity (26). Finally, HIV-infected patients often need many medications and have a large daily pill burden. Compliance suffers, but has been shown to improve when single tablet regimens reduce daily pill load.27 Long-acting injectable antiretroviral drugs are under development as a strategy to reduce pill burden and improve compliance (28). PCSK9 inhibitor injections would dovetail well with this approach. For these reasons, PCSK9 inhibitor therapy offers advantages over statin therapy in this unique population.

Bococizumab (RN316/PF-04950615) is a novel humanized PCSK9 monoclonal antibody. In a 24-week, multicenter, randomized, double-blind, placebo-controlled phase II trial, the LDL-C lowering effects of bococizumab, administered every 2 or 4 weeks in statin-treated adults with LDL-C ≥80 mg/dL was assessed (29). Subjects were randomized to placebo, bococizumab 50 mg, 100 mg, or 150 mg every 2 weeks, or placebo, bococizumab 200 mg or 300 mg monthly. The dose was reduced if LDL-C was ≤25 mg/dL. The primary analysis was the placebo-adjusted treatment difference for the change from baseline in LDL-C at week 12.

Overall, 354 patients were randomized, 351 received study treatment, and 299 completed the study. Bococizumab significantly reduced LDL-C across all doses. The placebo-adjusted LDL-C reduction at 12 weeks for the 2-weekly dosing regimen was 34.3% with 50 mg, 45.1% for 100 mg and 53.4% for 150 mg, and for the monthly dosing regimen was 27.6% for 200 mg and 44.9% for 300 mg. The incidence and profile of adverse events were similar across placebo and bococizumab groups.

Based on these findings, 150 mg every 2 weeks was selected as the dose for phase III trials, including this trial. Because multiple doses of bococizumab as high as 150 mg every 2 weeks and 300 mg every 4 weeks up to 12 weeks were safe and well tolerated, the primary rationale for dose selection was the pharmacokinetic/pharmacodynamic model that predicted LDL-C change from baseline. Based on population PK/PD modeling, a dose of 150 mg every 2 weeks in patients on a background of statins is estimated to be equivalent to approximately 80% of the maximal response for LDL-C lowering (-67%). Assuming an average LDL C at baseline of 100 mg/dL for HIV-infected individuals, the mean absolute LDL-C reduction is predicted to be approximately 60 mg/dL.

Arms:
arm 1: 150 mg bococizumab injected subcutaneously every 2 weeks for a duration of 52 weeks arm 2: 150 mg placebo injected subcutaneously every 2 weeks for a duration of 52 weeks

Interventions: intervention 1: Bococizumab intervention 2: Placebo
Intervention descriptions: intervention 1: PF-04950615 is a humanized monoclonal antibody against the proprotein convertase subtilisin kexin type 9 (PCSK9) enzyme responsible for the degradation of the low-density lipoprotein receptor (LDLR), being developed by Pfizer, Inc for the treatment of primary hyperlipidemia and mixed dyslipidemia. intervention 2: placebo

Protocol document:
Prot_SAP_000.pdf: 
Study WI204426 
B-HIVE Protocol, 10OCT16 
 
 
Bococizumab HIV Evaluation (B-HIVE) Study: 
A Phase 3, Double-Blind, Randomized, Placebo-Controlled 
Study to Assess the Efficacy and Safety of Bococizumab, 
a PCSK9 Inhibitor, in HIV-Infected Subjects 
 
IND Number: 128157 
CHR Number: 15-16405 
NCT Number: NCT02524106 
 
Priscilla Y. Hsue, MD, Principal Investigator 
Ahmed Tawakol, MD 
Miguel Hernandez Pampaloni, MD 
Michael Hope, MD 
Peter Ganz, MD 
Steven Deeks, MD 
Carl Grunfeld, MD 


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2 
 
David D. Waters, MD


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3 
 
PROTOCOL SUMMARY 
Indication 
PF-04950615 is a humanized monoclonal antibody against the proprotein convertase 
subtilisin kexin type 9 (PCSK9) enzyme responsible for the degradation of the low-
density lipoprotein receptor (LDLR), being developed by Pfizer, Inc. for the treatment of 
primary hyperlipidemia and mixed dyslipidemia.   
Background and Rationale 
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 CVD risks by numerous epidemiological studies. Moreover, 
large prospective clinical outcome trials have demonstrated that lowering LDL-C 
decreases cardiovascular morbidity and mortality.1 A meta-analysis of 26 randomized 
clinical trials comprising 170,000 participants showed that more intensive statin therapy 
compared to less intensive regimens will reduce coronary deaths or myocardial infarction 
by an additional 13%.2 
HIV-infected individuals represent a unique and increasing subset of atherosclerosis. 
With the advent of antiretroviral therapy, HIV-infected individuals now have much 
improved survival and are faced with health issues related to aging, including 
cardiovascular disease.  Individuals with HIV have higher rates of coronary events 
compared to controls even in the setting of treated and suppressed disease and a growing 
body of literature suggests that they are at increased risk for myocardial infarction, 
atherosclerosis, and sudden cardiac death.3-5  Many facets of atherosclerosis differ in 
HIV-infected individuals compared to uninfected individuals with atherosclerosis. HIV-
infected patients with acute coronary syndromes are younger and more likely to be males 
and smokers, with low high density lipoprotein-cholesterol (HDL-C), compared to other 
acute coronary syndrome patients.6  With respect to pathophysiology, viral replication, 
antiretroviral drugs and inflammation all contribute to atherosclerosis.7,8 
HIV-associated inflammation induces pro-atherogenic lipid abnormalities and anti-
retroviral therapy leads to the development of metabolic abnormalities such as 
dyslipidemia, lipodystrophy and insulin resistance.9,10  In a large cross-sectional study, 
27% of subjects receiving combination therapy including a protease inhibitor had a total 
cholesterol level exceeding 240 mg/dl, compared to 8% of untreated HIV subjects, and 
40% had triglyceride levels above 200 mg/dl, compared to 15% in untreated subjects.11  
The prevalence and severity of dyslipidemia varies among different antiretroviral drugs;9 
however, hypertriglyceridemia and low HDL-cholesterol were  associated with HIV 
infection even before the advent of antiretroviral therapy.12  Total, HDL-C, and LDL-C 
decrease at the time of HIV infection, and with antiretroviral treatment total and LDL-C 
levels increase to pre-infection levels while HDL-C remains low.13 
Abnormalities in body composition have been reported in 40-50% of HIV-infected 
patients, with higher rates in those receiving combination antiretroviral therapy.9 
Subcutaneous lipoatrophy commonly affects the face, limbs, and buttocks, and is 


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4 
 
accompanied by central fat accumulation.  Hyperinsulinemia is often also present. In a 
representative study,14 diabetes was present in 7% of HIV-infected adults with fat 
accumulation or lipoatrophy, as compared to 0.5% of control subjects matched for age 
and BMI.  The corresponding rates of glucose intolerance were 35% and 5% 
respectively.14  Compared to healthy control subjects, HIV-infected men treated with 
combination antiretroviral therapy were 4 times as likely to develop diabetes over a 3-
year observation period.15 
The increased cardiovascular risk and dyslipidemia in HIV-infected individuals is 
difficult to treat for several reasons. Statins reduce LDL-C levels less in HIV-infected 
individuals compared to uninfected controls.16  Fibrates reduce triglyceride levels less in 
HIV-infected individuals compared to uninfected controls as well.16  Drug-drug 
interactions between statins and protease inhibitors increase the risk of adverse 
events.17,18  Due to these interactions, simvastatin and lovastatin are contraindicated 
among individuals receiving protease inhibitors and the dose of atorvastatin should not 
exceed 40 mg.17  Even interactions with rosuvastatin, which is not metabolized by the 
cytochrome P450 system, have been described.19,20 
As a consequence, physicians may avoid treating HIV-infected individuals who would 
benefit from statins, or use lower doses or less potent statins, reducing the potential for 
cardiovascular event reduction.  High triglyceride levels in HIV-infected subjects are 
common, and the combination of a fibrate plus antiretroviral therapy increases the risk of 
drug-drug adverse events, even before consideration of a statin. 
Statin treatment reduces lipid levels modestly in HIV subjects.  Among 72 HIV-infected 
subjects in the SATURN-HIV trial randomized to rosuvastatin 10 mg/day, LDL-C was 
reduced by 25.3% by week 24.21  In another study, of 83 HIV-infected subjects, 
rosuvastatin 10 mg and pravastatin 40 mg/day reduced LDL-C by 37% and 19% 
respectively at 45 days.22  Among 151 HIV-infected subjects randomized to rosuvastatin 
10 mg, atorvastatin 10 mg, or pravastatin 40 mg/day, LDL-C reductions were greater 
with rosuvastatin at this dose, but all 3 statins significantly and similarly reduced serum 
levels of hs-CRP and TNF-.23 
That statins might favorably influence the evolution of atherosclerosis in HIV-infected 
subjects is suggested by a recent trial where 40 HIV subjects with mild coronary 
atherosclerosis by CT angiography and aortic inflammation by FDG-PET imaging were 
randomized to atorvastatin 20-40 mg/day or placebo and were followed for 12 months.24  
Atorvastatin significantly reduced non-calcified coronary plaque volume relative to 
placebo, as well as the number of high-risk plaques. 
Approximately 1/3 of individuals with HIV-infection are co-infected with hepatitis C.25  
Elevated hepatic enzymes due to hepatitis C represent a relative contraindication to statin 
therapy, and some evidence suggests that a statin might increase hepatitis C activity.26  
Finally, HIV-infected patients often need many medications and have a large daily pill 
burden.  Compliance suffers, but has been shown to improve when single tablet regimens 
reduce daily pill load.27  Long-acting injectable antiretroviral drugs are under 
development as a strategy to reduce pill burden and improve compliance.28  PCSK9 
inhibitor injections would dovetail well with this approach.  For these reasons, PCSK9 
inhibitor therapy offers advantages over statin therapy in this unique population. 


Study WI204426 
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5 
 
Bococizumab (RN316/PF-04950615) is a novel humanized PCSK9 monoclonal antibody. 
In a 24-week, multicenter, randomized, double-blind, placebo-controlled phase II trial, 
the LDL-C lowering effects of bococizumab, administered every 2 or 4 weeks in statin-
treated adults with LDL-C ≥80 mg/dL was assessed.29  Subjects were randomized to 
placebo, bococizumab 50 mg, 100 mg, or 150 mg every 2 weeks, or placebo, 
bococizumab 200 mg or 300 mg monthly.  The dose was reduced if LDL-C was ≤25 
mg/dL.  The primary analysis was the placebo-adjusted treatment difference for the 
change from baseline in LDL-C at week 12. 
Overall, 354 patients were randomized, 351 received study treatment, and 299 completed 
the study.  Bococizumab significantly reduced LDL-C across all doses.  The placebo-
adjusted LDL-C reduction at 12 weeks for the 2-weekly dosing regimen was 34.3% with 
50 mg, 45.1% for 100 mg and 53.4% for 150 mg, and for the monthly dosing regimen 
was 27.6% for 200 mg and 44.9% for 300 mg.  The incidence and profile of adverse 
events were similar across placebo and bococizumab groups. 
Based on these findings, 150 mg every 2 weeks was selected as the dose for phase III 
trials, including this trial.  Because multiple doses of bococizumab as high as 150 mg 
every 2 weeks and 300 mg every 4 weeks up to 12 weeks were safe and well tolerated, 
the primary rationale for dose selection was the pharmacokinetic/pharmacodynamic 
model that predicted LDL-C change from baseline.  Based on population PK/PD 
modeling, a dose of 150 mg every 2 weeks in patients on a background of statins is 
estimated to be equivalent to approximately 80% of the maximal response for LDL-C 
lowering (-67%).  Assuming an average LDL-C at baseline of 100 mg/dL for HIV-
infected individuals, the mean absolute LDL-C reduction is predicted to be approximately 
60 mg/dL. 
Objectives and Endpoints 
Objectives 
The primary objective of the study is to demonstrate the efficacy of LDL-C lowering with 
bococizumab 150 mg administered subcutaneously every 2 weeks compared to placebo, 
in HIV-infected subjects whose LDL-C is 70 mg/dL (1.81 mmol/L).  The secondary 
objectives will be to assess the effect of bococizumab compared to placebo on total 
cholesterol (TC), HDL-C, triglycerides, non-HDL-C, apolipoprotein B (ApoB), 
apolipoprotein A-I (ApoA-I), and lipoprotein (a) [Lp(a)], and to assess the safety and 
tolerability of bococizumab. 
The study has 3 important tertiary objectives.  The first is to determine whether 
bococizumab compared to placebo improves vascular inflammation in HIV-infected 
individuals, as assessed by FDG-PET/CT [(18)Fluorodeoxyglucose positron emission 
tomography/computed tomography].  The second is to determine whether changes in 
arterial FDG uptake are associated with changes in coronary plaques as measured by CT 
angiography.  The third tertiary objective is to determine whether bococizumab improves 
endothelial dysfunction among HIV-infected individuals as assessed by flow-mediated 
dilation of the brachial artery (FMD).  We will correlate these findings with changes in 
LDL-C, inflammatory markers, and Lp(a).   


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Endpoints 
The primary endpoint for the study is the percent change from baseline in fasting LDL-C 
at week 12. Key secondary endpoints are the percent change from baseline in fasting TC, 
ApoB, non HDL-C, HDL-C, and Lp(a) at week 12.  Secondary lipid efficacy endpoints 
are the percent change from baseline in fasting LDL-C, TC, ApoB, non HDL-C, HDL-C, 
and Lp(a) at week 24; the percent change from baseline in fasting TG, and ApoA-I, at 
week 12 and 24;  the absolute change from baseline in fasting TC / HDL-C ratio and 
ApoB / ApoA-I ratio at week 12 and 24, along with absolute change from baseline at 
week 12 in LDL-C, TC, ApoB, non-HDL-C, HDL-C and Lp(a); the proportion of 
subjects achieving fasting LDL-C 70 mg/dL (1.81 mmol/L) at week 12 and 24.  
Secondary safety endpoints are adverse events, and serious adverse events, including 
Type 1 and 3 hypersensitivity reactions and injection site reactions. 
Study Design 
This study is a Phase 3, double blind, placebo-controlled, randomized, parallel group 
study, designed to compare the efficacy and safety of bococizumab 150 mg 
subcutaneously every 2 weeks to bococizumab placebo subcutaneously every 2 weeks for 
LDL-C lowering in HIV-infected subjects.  The study will enroll approximately 200 
subjects in 2 treatment arms, randomized 1:1 to either bococizumab or placebo injections.  
Randomized subjects will receive study drug for 52 weeks. The primary comparison of 
interest is bococizumab 150 mg compared to placebo. Rates of discontinuation due to 
AEs and SAEs will be described for both treatment groups. 
After providing informed consent at the screening visit, subjects will be assessed to 
determine eligibility for the trial.  Eligible subjects will be considered enrolled and 
progress to the Baseline visit. Results from screening evaluations will be reviewed and 
only subjects who continue to meet all eligibility criteria will be randomized.  
Randomized subjects will enter the 52-week treatment period, followed by a 6-week 
follow-up, for a total of 58 weeks study participation. Subjects will attend clinic visits as 
shown in the Schedule of Activities.  Lipid levels will be blinded to the investigator and 
staff, subject and sponsor. 
Statistical Methods 
Statistical methods are described in detail in the Statistical Analysis Plan and are 
summarized in Section 9. For the primary endpoint of LDL-C change with bococizumab 
compared to placebo at 12 weeks, 54 subjects per treatment group will provide ≥99% 
power to detect an expected treatment difference. This calculation is based upon a 
previous bococizumab study29 and uses an =0.05 (two-sided), a common standard 
deviation of 25% (based upon a previous study29), and the normal approximation of the 
test statistic for the comparison between 2 means. We assume a dropout rate of 10% per 
group, and thus 60 subjects per group would need to be randomized for the primary lipid 
endpoint. We assume a similar LDL-C response in HIV subjects as that seen in other 
subjects.22 
For the FDG-PET/CT endpoint of difference of change in aortic TBR between the 
treatment groups, we calculate a sample size requirement of 120 subjects based upon the 


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following considerations: (1) 10% of subjects without inflammation at baseline will be 
excluded, (2) 8% of subjects will discontinue treatment or not return for repeat imaging, 
(3) 8% of subjects will be excluded due to insufficient image quality, leaving a total of 
90-92 subjects, (4) the anticipated average TBR will be 2.5, (5) the assumed standard 
deviation for change in TBR will be 0.29, and (6) the minimum expected change in TBR 
on treatment will be 7%. These assumptions are based upon previous studies, as 
described in section 9. Despite the calculated sample size of 90-92 subjects, FDG-PET 
imaging will be done in all study participants because of the uncertainties of the estimates 
used in the sample size calculation. No differences in FDG-PET images were seen in the 
aforementioned atorvastatin study;24 however, adequate images were available for only 
21 of the 40 study subjects. 
For the coronary CT angiography endpoints, little data is available for an accurate sample 
size calculation. In the atorvastatin HIV study of Lo et al,24 significant differences were 
seen for non-calcified plaque and high-risk plaque in a group of only 40 HIV-infected 
subjects, but all had mild coronary lesions by CT angiography at baseline. As with FDG-
PET, we plan to perform CT angiography on all of the study participants due to 
uncertainties in the sample size calculation. 
For the FMD endpoint of the difference between the bococizumab and placebo groups for 
the change in mean FMD between baseline and follow-up, approximately 25 subjects per 
group would provide an adequate sample size based on extrapolations from previous 
studies. We plan to measure FMD in all subjects because it is a simple, noninvasive and 
inexpensive test. We plan to correlated changes in FMD and changes in lipid parameters, 
as outlined in section 9. 
Safety will be assessed through adverse and serious adverse events, vital signs, and 
physical examination, 12-lead electrocardiograms (ECGs), and safety laboratory tests 
including hematology, ADAs and blood chemistry studies. 


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SCHEDULE OF ACTIVITIES 
The Schedule of Activities table 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 unplanned visits in addition to those listed on the schedule 
of activities, in order to conduct evaluations or assessments required to protect the 
wellbeing of the subject


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Study Phase 
Screen 
Rand 
Treatment 
 
 
Follow- Up 
Protocol Activity (Week) 
-8 
0 
4 
8 
12 
24 
30 
40 
52/EOSa 
58 
Visit Day 
-57 
1 
29 
57 
85 
169 
211 
281 
365 
407 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
CV risk factors, demographics, medical history 
X 
 
 
 
 
 
 
 
 
 
Vital Signs (HR, BP, temperature) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weight 
 
X 
 
 
 
X 
 
X 
X 
 
Physical examination 
X 
 
 
 
 
X 
 
X 
X 
 
Prior Medications 
X 
 
 
 
 
 
 
 
 
 
Concomitant medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
X 
 
 
X 
 
Review inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Laboratory  
 
 
 
 
 
 
 
 
 
 
  Fasting Lipid Profile 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diet and contraception advice 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Instruction on self-injection 
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Dispense study treatment 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Brachial artery FMD 
 
X,X 
 
 
 
X 
 
 
 
 
FDG-PET/CT 
 
Xb 
 
 
 
Xb 
 
 
 
 
Coronary CT angiography 
 
Xb 
 
 
 
 
 
 
Xb 
 
a. 
EOS = End of Study, procedures to be completed for subjects who have early study discontinuation. Visit day 365/EOS will usually require 2 days to complete because of the requirement to 
perform coronary CT angiography study 
b. 
FDG-PET/CT or coronary CT angiography reimage within 7 days if deemed necessary 


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TABLE OF CONTENTS 
1. INTRODUCTION ...............................................................................................................14 
1.1. Indication .................................................................................................................14 
1.2. Background and Rationale ......................................................................................14 
1.2.1. Atherosclerosis in HIV-Infected Individuals ..............................................14 
1.2.2. Bococizumab ..............................................................................................15 
1.2.3. FDG-PET/CT Imaging ...............................................................................16 
1.2.4. Coronary CT Angiography .........................................................................17 
1.2.5. Brachial Artery Flow-Mediated Dilation (FMD) .......................................17 
1.2.6. Benefits and Risks of Participation .............................................................18 
2. STUDY OBJECTIVES AND ENDPOINTS .......................................................................18 
2.1. Objectives ................................................................................................................18 
2.1.1. Primary Objectives .....................................................................................18 
2.1.2. Secondary Objectives .................................................................................18 
2.1.3. Tertiary Objectives .....................................................................................18 
2.1.4. FDG-PET Objectives ..................................................................................19 
2.1.5. Coronary CT Angiography Objectives .......................................................19 
2.1.6. FMD Objectives ..........................................................................................19 
2.2. Endpoints .................................................................................................................19 
2.2.1. Primary Endpoint ........................................................................................19 
2.2.2. Key Secondary Endpoints...........................................................................19 
2.2.3. Other Secondary Endpoints ........................................................................20 
2.2.4. Safety Evaluations: .....................................................................................20 
2.2.5. Exploratory Endpoints ................................................................................20 
2.2.6. FDG-PET/CT Endpoint ..............................................................................20 
2.2.7. Coronary CT Angiography Endpoints ........................................................20 
2.2.8. FMD Endpoint ............................................................................................21 
3. STUDY DESIGN.................................................................................................................21 
4. SUBJECT SELECTION ......................................................................................................22 
4.1. Inclusion Criteria .....................................................................................................22 
4.2. Exclusion Criteria ....................................................................................................24 
4.3. Randomization Criteria ...........................................................................................26 


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4.4. Lifestyle Guidelines ................................................................................................26 
4.4.1. Contraception ..............................................................................................26 
5. STUDY TREATMENTS .....................................................................................................26 
5.1. Allocation to Treatment ..........................................................................................27 
5.2. Breaking the Blind .................................................. Error! Bookmark not defined. 
5.3. Drug Supplies ..........................................................................................................27 
5.3.1. Formulation and Packaging ........................................................................27 
5.3.2. Preparation and Dispensing ........................................................................27 
5.3.3. Administration ............................................................................................27 
5.3.4. Compliance .................................................................................................27 
5.4. Drug Storage and Drug Accountability ...................................................................28 
5.5. Concomitant Medication(s) .....................................................................................28 
6. STUDY PROCEDURES .....................................................................................................28 
6.1. Screening Visit ........................................................................................................28 
6.1.1. Visit Day -57 (± 3 days) .............................................................................28 
6.2. Treatment Period .....................................................................................................29 
6.2.1. Visit Day 1 (±3 day) ...................................................................................29 
6.2.2. Visit Days 29, 57, 85, 169, 211, and 281 (±7 days) ...................................29 
6.2.3. Intermittent Bi-Weekly Study Visits If Applicable (± 3 days)Error! Bookmark not define
6.2.4. Visit Day 365/End of Study Visit (EOS) (± 3 days) ..................................30 
6.3. Follow-up Visit .......................................................................................................30 
6.3.1. Visit Day 407 (±3 days) ..............................................................................30 
6.4. Subject Withdrawal ................................................. Error! Bookmark not defined. 
6.4.1. Individual Subject Dosing Stopping CriteriaError! Bookmark not defined. 
7. ASSESSMENTS ..................................................................................................................31 
7.1. Efficacy ...................................................................................................................31 
7.1.1. Lipids ..........................................................................................................31 
7.1.2. FDG-PET/CT and CCTA Imaging .............................................................31 
7.1.3. Brachial Artery FMD ..................................................................................31 
7.1.4. Inflammatory Markers ................................................................................31 
7.2. Safety .......................................................................................................................31 
7.2.1. Laboratory ...................................................................................................31 
7.2.2. Pregnancy Testing ...................................... Error! Bookmark not defined. 


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12 
 
7.2.3. Cardiovascular Risk Factors and Medical History .....................................31 
7.2.4. 12-Lead ECG ..............................................................................................32 
7.2.5. Vital Signs ..................................................................................................32 
7.2.6. Weight and Height ...................................... Error! Bookmark not defined. 
7.2.7. Physical Exam ............................................ Error! Bookmark not defined. 
7.2.8. Adverse Events ...........................................................................................32 
7.2.9. Immunogenicity .......................................... Error! Bookmark not defined. 
7.2.10. Plasma for Analysis of Bococizumab and PCSK9Error! Bookmark not defined. 
7.2.11. Stored Specimen for Future Research ...... Error! Bookmark not defined. 
8. ADVERSE EVENT REPORTING......................................................................................32 
8.1. Adverse Events ........................................................................................................32 
8.2. Reporting Period ..................................................... Error! Bookmark not defined. 
8.3. Definition of an Adverse Event ............................... Error! Bookmark not defined. 
8.4. Medication Errors .................................................... Error! Bookmark not defined. 
8.5. Abnormal Test Findings ..........................................................................................32 
8.6. Serious Adverse Events ...........................................................................................33 
8.6.1. Potential Cases of Drug-Induced Liver InjuryError! Bookmark not defined. 
8.7. Hospitalization ........................................................ Error! Bookmark not defined. 
8.8. Severity Assessment ................................................ Error! Bookmark not defined. 
8.9. Causality Assessment .............................................. Error! Bookmark not defined. 
8.10. Exposure During Pregnancy .................................. Error! Bookmark not defined. 
8.11. Occupational Exposure ......................................... Error! Bookmark not defined. 
8.12. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal) ............................................................... Error! Bookmark not defined. 
8.13. Eliciting Adverse Event Information .................... Error! Bookmark not defined. 
8.14. Reporting Requirements ........................................................................................33 
8.14.1. Serious Adverse Event Reporting Requirements .....................................33 
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................33 
8.14.3. Medical Device Complaint Reporting RequirementsError! Bookmark not defined. 
8.14.4. Sponsor Reporting Requirements to Regulatory AuthoritiesError! Bookmark not define
9. DATA ANALYSIS/STATISTICAL METHODS ...............................................................33 
9.1. Sample Size Determinations ...................................................................................33 
9.2. Efficacy Analysis ....................................................................................................34 


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9.2.1. Analysis of Primary Endpoint ....................................................................34 
9.2.2. Analysis of Key Secondary Endpoints .......................................................34 
9.2.3. Analysis of Secondary Lipid Endpoints .....................................................34 
9.2.4. Analysis of Exploratory Lipid Endpoints ...................................................35 
9.2.5. Analysis of the FDG-PET/CT Endpoints ...................................................35 
9.2.6. Analysis of Brachial Artery FMD Endpoints .............................................35 
9.3. Analysis of Other Endpoints ...................................................................................36 
9.3.1. Pharmacokinetics and Pharmacodynamic Data ..........................................36 
9.4. Safety Analysis ........................................................................................................36 
9.5. Subgroup Analyses ..................................................................................................37 
9.6. Data Monitoring Committee ...................................................................................38 
10. REFERENCES ..................................................................................................................39 
 


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1. INTRODUCTION 
1.1. Indication 
Bococizumab is a humanized monoclonal antibody against the proprotein convertase 
subtilisin kexin type 9 (PCSK9) enzyme responsible for the degradation of the low-
density lipoprotein receptor (LDLR).  Bococizumab is being developed for the treatment 
of primary hyperlipidemia and mixed dyslipidemia. 
1.2. Background and Rationale 
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 CVD risks by numerous epidemiological studies.  Moreover, 
large prospective clinical outcome trials have demonstrated that lowering LDL-C 
decreases cardiovascular morbidity and mortality.1  A meta-analysis of 26 randomized 
clinical trials comprising 170,000 participants showed that more intensive statin therapy 
compared to less intensive regimens will reduce coronary deaths or myocardial infarction 
by an additional 13%.2 
1.2.1. Atherosclerosis in HIV-Infected Individuals 
HIV-infected individuals represent a unique and increasing subset of patients with 
atherosclerosis.  With the advent of antiretroviral therapy, HIV-infected individuals now 
have much improved survival and are faced with health issues related to aging, including 
cardiovascular disease.  Individuals with HIV have higher rates of coronary events 
compared to controls and a growing body of literature suggests that they are at increased 
risk for myocardial infarction, atherosclerosis, and sudden cardiac death.3-5  Many facets 
of atherosclerosis differ in HIV-infected individuals compared to uninfected individuals 
with atherosclerosis.  HIV-infected patients with acute coronary syndromes are younger 
and more likely to be males and smokers, with low high density lipoprotein-cholesterol 
(HDL-C), compared to other acute coronary syndrome patients.6  With respect to 
pathophysiology, viral replication, antiretroviral drugs and inflammation all contribute to 
atherosclerosis.7,8 
HIV-associated inflammation induces pro-atherogenic lipid abnormalities and anti-
retroviral therapy leads to the development of metabolic abnormalities such as 
dyslipidemia, lipodystrophy and insulin resistance.9,10 In a large cross-sectional study, 
27% of subjects receiving combination therapy including a protease inhibitor had a total 
cholesterol level exceeding 240 mg/dl, compared to 8% of untreated HIV subjects, and 
40% had triglyceride levels above 200 mg/dl, compared to 15% in untreated subjects.11 
The prevalence and severity of dyslipidemia varies among different antiretroviral drugs;9 
however, hypertriglyceridemia and low HDL-cholesterol were  associated with HIV 
infection even before the advent of antiretroviral therapy.12  Total, HDL-C, and LDL-C 
decrease at the time of HIV infection, and with antiretroviral treatment total and LDL-C 
levels increase to pre-infection levels while HDL-C remains low.13 
The increased cardiovascular risk and dyslipidemia in HIV-infected individuals is 
difficult to treat for several reasons.  Statins reduce LDL-C levels less in HIV-infected 


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individuals compared to uninfected controls.16 Fibrates reduce triglyceride levels less in 
HIV-infected individuals compared to uninfected controls as well.16  Drug-drug 
interactions between statins and protease inhibitors increase the risk of adverse 
events.17,18  Due to these interactions, simvastatin and lovastatin are contraindicated 
among individuals receiving protease inhibitors and the dose of atorvastatin should not 
exceed 40 mg.17 Even interactions with rosuvastatin, which is not metabolized by the 
cytochrome P450 system, have been described.19,20 
As a consequence, physicians may avoid treating HIV-infected individuals who would 
benefit from statins, or use lower doses or less potent statins, reducing the potential for 
cardiovascular event reduction.  High triglyceride levels in HIV-infected subjects are 
common, and the combination of a fibrate plus antiretroviral therapy increases the risk of 
drug-drug adverse events, even before consideration of a statin. 
Statin treatment reduces lipid levels modestly in HIV subjects.  Among 72 HIV-infected 
subjects in the SATURN-HIV trial randomized to rosuvastatin 10 mg/day, LDL-C was 
reduced by 25.3% by week 24.21 In another study, of 83 HIV-infected subjects, 
rosuvastatin 10 mg and pravastatin 40 mg/day reduced LDL-C by 37% and 19% 
respectively at 45 days.22  Among 151 HIV-infected subjects randomized to rosuvastatin 
10 mg, atorvastatin 10 mg, or pravastatin 40 mg/day, LDL-C reductions were greater 
with rosuvastatin at this dose, but all 3 statins significantly and similarly reduced serum 
levels of hs-CRP and TNF-.23 
That statins might favorably influence the evolution of atherosclerosis in HIV-infected 
subjects is suggested by a recent trial where 40 HIV subjects with mild coronary 
atherosclerosis by CT angiography and aortic inflammation by FDG-PET imaging were 
randomized to atorvastatin 20-40 mg/day or placebo and were followed for 12 months.24 
Atorvastatin significantly reduced non-calcified coronary plaque volume relative to 
placebo, as well as the number of high-risk plaques. 
Approximately 1/3 of individuals with HIV-infection are co-infected with hepatitis C.25 
Elevated hepatic enzymes due to hepatitis C represent a relative contraindication to statin 
therapy, and some evidence suggests that a statin might increase hepatitis C activity.26 
Finally, HIV-infected patients often need many medications and have a large daily pill 
burden. Compliance suffers, but has been shown to improve when single tablet regimens 
reduce daily pill load.27  Long-acting injectable antiretroviral drugs are under 
development as a strategy to reduce pill burden and improve compliance.28 PCSK9 
inhibitor injections would dovetail well with this approach. For these reasons, PCSK9 
inhibitor therapy offers advantages over statin therapy in this unique population. 
1.2.2. Bococizumab 
Bococizumab (RN316/PF-04950615) is a novel humanized PCSK9 monoclonal antibody 
targeting the evolutionarily conserved LDL receptor-binding domain of PCSK9 with high 
affinity. The constant region of bococizumab is based on the human IgG2 isotype bearing 
two amino acid mutations, called IgG2Δa, which have greatly reduced ability to bind to 
Fcγ receptors or fix complement.30,31  In nonclinical models, PF-04950615 binds to 
secreted PCSK9, effectively prevents PCSK9 from degrading LDLR, leading to 
improved LDL-C clearance in plasma and reduction of circulating LDL-C. 


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In a 24-week, multicenter, randomized, double-blind, placebo-controlled phase II trial, 
the LDL-C lowering effects of bococizumab, administered every 2 or 4 weeks in statin-
treated adults with LDL-C ≥80 mg/dL was assessed.29  Subjects were randomized to 
placebo, bococizumab 50 mg, 100 mg, or 150 mg every 2 weeks, or placebo, 
bococizumab 200 mg or 300 mg monthly. The dose was reduced if LDL-C was ≤25 
mg/dL.  The primary analysis was the placebo-adjusted treatment difference for the 
change from baseline in LDL-C at week 12. 
Overall, 354 patients were randomized, 351 received study treatment, and 299 completed 
the study. Bococizumab significantly reduced LDL-C across all doses. The placebo-
adjusted LDL-C reduction at 12 weeks for the 2-weekly dosing regimen was 34.3% with 
50 mg, 45.1% for 100 mg and 53.4% for 150 mg, and for the monthly dosing regimen 
was 27.6% for 200 mg and 44.9% for 300 mg.  The incidence and profile of adverse 
events were similar across placebo and bococizumab groups. The incidence of moderate 
and severe injection site reactions and of serious adverse events was low in all treatment 
groups. 
As of 1 December 2013, a total of 517 subjects had received at least one dose of 
bococizumab in completed studies, administered either as single or multiple dose both 
alone and in combination with current lipid lowering agents; bococizumab was generally 
well tolerated. No subjects in completed studies had drug-induced liver injury according 
to the Hy’s law definition.  Thirty-seven subjects (7%) exposed to bococizumab across all 
completed studies developed anti-drug antibodies but none were associated with any 
clinical signs or symptoms of hypersensitivity. 
Based on the findings of the study described above,29 150 mg every 2 weeks was selected 
as the dose for phase III trials, including this trial. Because multiple doses of 
bococizumab as high as 150 mg every 2 weeks and 300 mg every 4 weeks up to 12 weeks 
were safe and well tolerated, the primary rationale for dose selection was the 
pharmacokinetic/pharmacodynamic model that predicted LDL-C changes from baseline. 
Based on population PK/PD modeling, a dose of 150 mg every 2 weeks in patients on a 
background of statins is estimated to be equivalent to approximately 80% of the maximal 
response for LDL-C lowering (-67%). Assuming an average LDL-C at baseline of 100 
mg/dL for HIV-infected individuals, the mean absolute LDL-C reduction is predicted to 
be approximately -60 mg/dL. 
1.2.3. FDG-PET/CT Imaging 
FDG-PET/CT imaging is the best-validated imaging modality to detect and monitor 
arterial inflammation in humans.32-35 Arterial inflammation as assessed by FDG-PET/CT 
correlates with atherosclerotic plaque inflammatory cell content, CV risk factors, 
Framingham risk score, and inflammatory biomarkers.36-38 FDG-PET/CT predicts CV 
risk independently of traditional risk factors.39-41 FDG-PET/CT has been used 
successfully to detect reductions in arterial inflammation by drugs that reduce CV risk.42-
45 
Arterial uptake of FDG has been shown to be higher in HIV-infected adults than in HIV-
uninfected controls matched for age, gender, and Framingham risk score.46 Other 
investigators have confirmed that FDG-PET/CT imaging detects inflammation in HIV-
infected individuals.47 


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Several groups have demonstrated reductions in arterial FDG uptake in response to lipid 
lowering therapy.42,43 Tawakol et al demonstrated in a multicenter trial that both high and 
low-dose atorvastatin rapidly lower arterial inflammation, and that high-dose atorvastatin 
reduces arterial inflammation by twice as much as low-dose atorvastatin. FDG-PET/CT 
has been employed to demonstrate rapid reductions in arterial inflammation in response 
to non-pharmacologic lipid lowering as well.48 Specifically, in a recent study of 24 
patients with familial hypercholesterolemia (FH) and 12 controls, TBR by FDG-PET/CT 
was significantly higher in the FH group, and significantly correlated with LDL-C 
levels.48 Lipoprotein apheresis significantly lowered LDL-C in FH patients and 
significantly lowered TBR. Thus, FDG-PET/CT imaging is a well-established tool to 
evaluate and monitor arterial inflammation, and these results show that profound lipid 
lowering reduces arterial inflammation. 
1.2.4. Coronary CT Angiography 
Coronary CT angiography (CCTA) allows visualization of the coronary arteries while 
avoiding coronary arteriography, a much more invasive procedure. CCTA provides 
prognostic as well as diagnostic information: greater volumes of non-calcified plaque and 
vulnerable plaque morphology on CCTA have been associated with future major cardiac 
events.49 Studies in HIV-infected individuals have shown an increased prevalence of 
subclinical atherosclerosis, including a predominant increase in non-calcified plaque 
compared with patients without HIV, controlling for traditional coronary risk factors.50-52 
Noncalcified plaque is lipid-laden, has higher macrophage content, and is more 
vulnerable to rupture. 
In a recent randomized, double-blind, placebo-controlled trial using FDG-PET/CT and 
CCTA,24 we showed that one year of treatment with atorvastatin 20-40 mg/day 
significantly reduced non-calcified plaque volume and high-risk coronary plaque features 
in HIV-infected patients. Changes in non-calcified plaque volume were large, with 19.4% 
regression in the atorvastatin group and 20.4% progression in the placebo group.  
The 52-week treatment period in this trial may be too short to detect changes in coronary 
plaques. However, in our previous study with one year of treatment, 3 of 20 placebo-
treated patients had progression of clinically significant coronary stenoses. Coronary 
lesions appear to progress more rapidly in HIV-infected individuals compared to other 
patients with coronary disease. But statin treatment limits this rapid progression. Thus, 
CCTA endpoints in this study should be viewed as exploratory. 
1.2.5. Brachial Artery Flow-Mediated Dilation (FMD) 
Endothelial dysfunction is a key step in atherogenesis. FMD, a noninvasive marker of 
endothelial function, predicts CV risk in the general population; specifically, a 1% 
absolute difference in FMD is associated with an adjusted 14% reduction in CV risk.55,56  
Interventions such as statins57,58 and anti-hypertensive drugs53 that reduce CV events also 
improve FMD. 
FMD is markedly impaired in patients with HIV.59,60  Changes in FMD with antiretroviral 
therapy have been used as surrogate markers for change in CV risk.61-63 An improvement 
in FMD with bococizumab would parallel the improvement in FMD seen with statins, 
and would be expected to presage an improvement in CV events. 


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1.2.6. Benefits and Risks of Participation 
The benefit of participation in this study for all subjects is close monitoring of their 
medical condition and safety of their treatment. Those randomized to the active treatment 
group may benefit from lowering their LDL-C.  Those randomized to the placebo group 
are not expected to obtain any additional benefit, beyond close monitoring of their 
medical condition and safety of their treatment, which may itself be associated with 
improving lipid levels. 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. 
Complete information for this compound may be found in the bococizumab 
Investigator’s Brochure. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1. Objectives 
2.1.1. Primary Objectives 
The primary objective of the study is to demonstrate the efficacy of LDL-C lowering with 
bococizumab 150 mg administered subcutaneously every 2 weeks compared to placebo, 
in HIV-infected subjects whose LDL-C is 70 mg/dL (1.81 mmol/L). 
2.1.2. Secondary Objectives 
The secondary objectives will be to assess the effect of bococizumab compared to 
placebo on: 
 Total cholesterol (TC), HDL-C, TG, and non HDL-C; 
 Other lipid parameters, including ApoB, ApoA-I, and Lp(a). 
To compare the safety and tolerability of bococizumab 150 mg administered 
subcutaneously every 2 weeks compared to placebo, in HIV subjects whose LDL-C is 
≥70 mg/dL (1.81 mmol/L).   
2.1.3. Tertiary Objectives 
The study has 3 important tertiary objectives. The first is to determine whether 
bococizumab compared to placebo improves vascular inflammation in HIV-infected 
individuals, as assessed by FDG-PET/CT [(18)Fluorodeoxyglucose positron emission 
tomography/computed tomography]. The second is to correlate changes in coronary 
plaque characteristics as measured by CT angiography to changes in arterial FDG uptake 
as seen by PET, and to other parameters. The third tertiary objective is to determine 
whether bococizumab improves endothelial dysfunction among HIV-infected individuals 
as assessed by flow-mediated dilation of the brachial artery (FMD).  We will correlate 
these findings with changes in LDL-C, inflammatory markers, and Lp(a). 


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2.1.4. FDG-PET Objectives 
1. To compare changes in arterial inflammation (baseline to follow-up imaging) in 
individuals treated with bococizumab versus placebo. 
2. To compare changes in arterial inflammation: 
a. To change in LDL-C with treatment across all study subjects with serial 
FDG-PET/CT imaging. 
b. To change in FMD with treatment across all study subjects with serial 
FDG-PET/CT imaging and serial FMD measurements. 
c. To changes in inflammatory markers: Lp(a), hs-CRP, IL-6, fibrinogen, 
sCD14, sCD163, and D-dimers. 
2.1.5. Coronary CT Angiography Objectives 
To correlate the changes in coronary plaque characteristics to: 
1. Changes in arterial FDG uptake seen by PET. 
2. Changes in LDL-C. 
The coronary plaque characteristics that will be evaluated include: 
1. Change from baseline to follow-up in volume of non-calcified coronary plaque. 
2. Change from baseline to follow-up in volume of high-risk coronary plaque. 
3. Incidence of new coronary plaque. 
2.1.6. FMD Objectives 
1. To compare change in FMD with treatment to change in LDL-C with treatment 
across all study subjects with serial FMD measurements. 
2. To compare change in FMD with treatment to changes in inflammatory markers: 
Lp(a), hs-CRP, IL-6, fibrinogen, sCD14, sCD163 and D-dimers. 
2.2. Endpoints 
2.2.1. Primary Endpoint 
 Percent change from baseline in fasting LDL-C at week 12. 
2.2.2. Key Secondary Endpoints 
 Percent change from baseline in fasting TC, ApoB, and non HDL-C at week 12; 
 Percent change from baseline in fasting Lp(a) at week 12; 


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 Percent change from baseline in fasting HDL-C at week 12. 
2.2.3. Other Secondary Endpoints 
 Percent change from baseline in fasting LDL-C, TC, Apo B, non HDL-C, Lp(a) 
and HDL-C at week 24; 
 Percent change from baseline in fasting TG, and ApoA-I at week 12 and 24;  
 Absolute change from baseline in fasting LDL-C, TC, HDL-C, non HDL-C, TG, 
ApoB and Lp(a) at week 12;  
 Absolute change from baseline in fasting TC/HDL-C ratio and ApoB/ApoA-I 
ratio at week 12 and 24;  
 Proportion of subjects achieving fasting LDL-C ≤70 mg/dL (1.81 mmol/L) at 
week 12 and 24. 
2.2.4. Safety Evaluations: 
 Adverse events (including Type 1 and 3 hypersensitivity reactions, injection site 
reactions, and immunogenicity) 
2.2.5. Exploratory Endpoints 
 Proportion of subjects achieving fasting LDL-C ≤50 mg/dL (1.29 mmol/L) at 
week 12 and 24;  
 Absolute and percent change from baseline in PCSK9 concentrations at week 12 
and 24; 
 Plasma bococizumab concentration at week 12 and 24. 
2.2.6. FDG-PET/CT Endpoint 
 Change in TBR from baseline to follow-up study at 24 weeks. This will be 
performed for several arterial endpoints, as previously described. The main 
arterial endpoint for this exploratory substudy is the most diseased segment of the 
index vessel, as described in 7.1.2. 
2.2.7. Coronary CT Angiography Endpoints 
 Change in non-calcified plaque from baseline to follow-up study at 52 weeks. 
 Change in high-risk plaque from baseline to follow-up study at 52 weeks. 
 Incidence of new lesions from baseline to follow-up study at 52 weeks. 
 Correlations between change in LDL-C and 


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(a) change in volume of non-calcified coronary plaque 
(b) change in high-risk coronary plaque 
2.2.8. FMD Endpoint 
 Change in FMD from baseline to follow-up study among subjects with FMD 
studies. 
3. STUDY DESIGN 
This study is a Phase 3, double blind, placebo-controlled, randomized, parallel group 
study, designed to compare the efficacy and safety of bococizumab 150 mg 
subcutaneously every 2 weeks to bococizumab placebo subcutaneously every 2 weeks for 
LDL-C lowering in HIV-infected subjects.  The study will enroll approximately 200 
subjects in 2 treatment arms, randomized 1:1 to either bococizumab or placebo injections.  
Randomized subjects will receive study drug for 52 weeks.  Rates of discontinuation due 
to AEs and SAEs will be described for both treatment groups. 
After providing informed consent at the screening visit, subjects will be assessed to 
determine eligibility for the trial.  Eligible subjects will be considered enrolled and 
progress to the Baseline visit. Results from screening evaluations will be reviewed and 
only subjects who continue to meet all eligibility criteria will be randomized. 
Randomized subjects will enter the 52-week treatment period, followed by a 6-week 
follow-up, for a total of 58 weeks study participation.  Subjects will attend clinic visits as 
shown in the Schedule of Activities. Lipid levels will be blinded to the investigator and 
staff, and subjects. 


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4. SUBJECT SELECTION 
This study can fulfill its objectives only if appropriate subjects are 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 will be reviewed and documented by an appropriately qualified 
member of the investigator’s study team before subjects are included in the study. 
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study. 
(a) Subjects who lack the capacity to consent for themselves, e.g. consent 
provided by a legally authorized representative (LAR) will be excluded 
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures. 
3. Males and females  40 years of age. 
4. With documented HIV infection. 
5. HIV-1 RNA level below 200 copies/mL for at least 12 weeks prior to study entry and 
confirmed at study entry. The assay used for eligibility can be performed by any US 
laboratory that has a CLIA certification or its equivalent. 
6. Continuous ART for at least 12 weeks with no change in regimen prior to study entry. 
This is defined as continuous active therapy self-reported by subject with no 
treatment interruption longer than 7 consecutive days and adherence greater than 
90%. 
NOTE: Some modifications of ART doses during the 12 weeks prior to study entry are 
permitted. In addition, the change in formulation (e.g., from standard formulation to 
fixed-dose combination) is allowed within 12 weeks prior to study entry. A within 
class single drug substitution (e.g., switch from nevirapine to efavirenz or from 
atazanavir to darunavir) is allowed within 12 weeks prior to study entry, with the 
exception of a switch from any other NRTI to abacavir. No other changes in ART in 
the 12 weeks prior to study entry are permitted. 
OR if a subject is not on ART, they may be included if: 
HIV-1 RNA is < 2000 copies/mL for at least 52 weeks prior to study entry and 
confirmed within 12 weeks prior to study entry. The assay used for eligibility can be 
performed by an US Laboratory that has a CLIA certification or its equivalent. 
 


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7. Moderate or high CVD risk defined as: 
 
documented CVD as assessed by meeting at least 1 of 3 criteria below: 
(a) 
Coronary artery disease (CAD): prior MI due to atherosclerosis, coronary 
artery bypass graft surgery, percutaneous coronary intervention, or 
angiographic CAD with luminal diameter stenosis of at least one coronary 
artery at least 50%. 
(b) 
Cerebrovascular disease: prior ischemic stroke of carotid origin, carotid 
endarterectomy or stenting, or angiographic carotid stenosis of at least 
50%. 
(c) 
Peripheral arterial disease: prior lower extremity arterial surgical or 
percutaneous revascularization procedure, or angiographic lower 
extremity arterial stenosis of at least 50%.  
OR any one of the following CVD risk factors: 
(a) 
Controlled type II diabetes mellitus (HbA1C ≤ 8.0% within the past 90 
days prior to study entry, regardless of use of medications) 
(b) 
Family history: a first degree relative who had a heart attack, stroke, or 
documented CVD as defined in the previous section that occurred: 
a. When they were age 55 years or younger for males (father, uncle, or 
brother) 
b. When they were age 60 years or younger for females (mother, aunt, or 
sister) 
(c) 
Current smoking: participant report of smoking at least a half a pack of 
cigarettes a day, on average, in the past month. 
(d) 
Hypertension: two consecutive BP readings with either systolic >140 
mmHg or diastolic > 90 mmHg; or currently on antihypertensive 
medications. 
(e) 
Dyslipidemia: defined as or HDL-C ≤ 40 mg/dL for men or ≤ 50 mg/dL 
for women, regardless of medication use; or currently on lipid lowering 
medications. 
(f) 
A hsCRP ≥ 2mg/L at screening. 
8. Lipids at screening visit: 
 Fasting LDL-C ≥ 70 mg/dL (1.81 mmol/L);  
 Fasting TG ≤ 600 mg/dL (6.78 mmol/L). 
9. If subjects meet ACC/AHA criteria for statin therapy and are not currently on a statin, 
subjects must be taking a stable dose of statin for at least 4 weeks, unless they are 
statin intolerant, refuse to take a statin, or have a medical condition (e.g. chronic 
hepatitis) where a statin is contraindicated. 
10. Male and female subjects of childbearing potential must agree to use a highly 
effective method of contraception throughout the study and for at least 63 days after 


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the last dose of assigned treatment.  A subject is of childbearing potential if, in the 
opinion of the investigator, he/she is biologically capable of having children and is 
sexually active.   
Female subjects who are not of childbearing potential (i.e., meet at least one of the 
following criteria): 
 Have undergone a documented hysterectomy 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; and have a serum follicle stimulating hormone (FSH) level within the 
laboratory’s reference range for postmenopausal females. 
4.2. Exclusion Criteria 
Subjects presenting with any of the following will not be included in the study: 
1. 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. 
2. Participation in other studies involving small molecule investigational drug(s) 
(Phases 1-4) within 1 month 5 half lives, whichever is longer except for cholesteryl 
ester transfer protein (CETP) inhibitors (indefinitely), or biological agents within 6 
months or 5 half lives, whichever is longer before the current study begins and/or 
during study participation (the investigator should refer to documents provided by the 
subject on the other study to determine the investigational product half life). If the 
blind has been broken and the Investigator knows (with documentation) that the 
subject received placebo, he/she can be included.   
3. Subjects with prior exposure to bococizumab or another PCSK9 inhibitor. 
4. Subjects who are unable to receive injections, as either a self-injection, or 
administered by another person.   
5. History of a cardiovascular or cerebrovascular event or procedure (e.g., myocardial 
infarction, stroke, transient ischemic attack, angioplasty) during the past 90 days.   
6. Congestive heart failure, New York Heart Association functional class IV, or left 
ventricular ejection fraction measured by imaging known to be <25%. (Imaging not 
required for study inclusion). 
7. Poorly controlled hypertension (on or off treatment) at screening visit or at 
randomization (defined as the average of two systolic blood pressure (BP) 
measurements greater than 160 mm Hg or the average of two diastolic BP 
measurements greater than 100 mm Hg).   
8. Any history of hemorrhagic stroke or lacunar infarct. 
9. For individuals with undetectable HIV RNA and on stable anti-retroviral therapy, 
they will be excluded if CD4 is ≤ 50 cells/mm3 at screening visit. 


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10. Current untreated hypothyroidism or thyroid stimulating hormone (TSH) 
>1 X upper limit of normal (ULN) at screening. Subjects who are treated and well 
controlled should be on a stable dose of thyroid hormone for at least 6 months.   
11. Current history of alcoholism or drug addiction according to the Diagnostic and 
Statistical Manual of Mental Disorders (DSM) IV criteria within 12 months prior to 
screening. Use of any illicit drug confirmed by urine toxicology test at screening that 
would in the opinion of the investigator interfere with study procedures or results. 
12. History of cancer within the last 5 years (except for cutaneous basal cell or squamous 
cell cancer resolved by excision, or cervical carcinoma in situ).   
13. Any disease or condition that might compromise the hematological, renal, hepatic, 
pulmonary, endocrine, central nervous, immune, or gastrointestinal systems (unless 
deemed not clinically significant by the Investigator and/or the Sponsor) or confound 
the interpretation of the study results. Examples of such conditions include but are not 
limited to nephrotic syndrome, uncontrolled diabetes, excessive alcohol consumption, 
cholestatic liver disease, unstable mental illness. 
14. Undergoing apheresis or have a planned start of apheresis.   
15. Initiation of or change in non-lipid lowering prescription drugs, herbal medicine or 
supplements (including foods with added plant sterols and stanols) within 6 weeks of 
screening with the exception of initiation or change in multivitamins used for general 
health purposes. Short-term use of medications to treat acute conditions, and vaccines 
are allowed (e.g., antibiotics or allergy medication).   
16. History of allergic or anaphylactic reaction to any therapeutic or diagnostic 
monoclonal antibody (IgG protein) or molecules made of components of monoclonal 
antibodies (e.g., Enbrel® which contains the Fc portion of an antibody or Lucentis® 
which is a Fab).   
17. Any abnormal hematology values, clinical chemistries, or ECGs at screening judged 
by the Investigator as clinically significant, which could impact on subject safety, 
were the potential subject to be included in the study, or interfere with the 
interpretation of study results. 
18. Active phase hepatitis. Stable patients with hepatitis B or C infection >2 years before 
randomization are eligible. 
19. Aspartate transaminase (AST) or alanine transaminase (ALT) > 5 X ULN at 
screening.   
20. Direct bilirubin > 4 X ULN at screening.   
21. Calculated fibrosis-4 score > 3.25 (see section 7.2.1.1 for instructions on how to 
calculate). 
22. GFR1 < 30 mL/min/1.73m2 at screening or undergoing dialysis.   
23. Plans to donate blood during the study. 
                                                 
1 Calculated by Modification of Diet in Renal Disease (MDRD) formula 


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24. Pregnant females; breastfeeding females. 
25. Additional exclusion criteria for the FDG-PET/CT imaging (patients with these 
exclusions may participate in the rest of the trial): 
a. Significant radiation exposure during the year prior to randomization. Significant 
exposure is defined as i) more than 2 PCI procedures, ii) more than 2 myocardial 
perfusion studies, or iii) more than 2 CT angiograms. 
b. Any history of radiation therapy. 
c. Current insulin use. 
26. Additional exclusion criteria for CTA imaging (patients with these exclusions may 
participate in the rest of the trial): 
a. Significant radiation exposure during the year prior to randomization. Significant 
exposure is defined as i) more than 2 PCI procedures, ii) more than 2 myocardial 
perfusion studies, or iii) more than 2 CT angiograms (as with FDG-PET/CT). 
b. Any history of radiation therapy (as with FDG-PET/CT). 
c. Any contraindication to -blocker (atenolol and metoprolol) or nitroglycerin use, 
because these drugs are given as part of the standard cardiac CT protocol. 
d. Significant renal dysfunction (defined as an eGFR < 60 mL/min/1.73m2). 
e. Body weight > 300 pounds (136 Kg), because of the CT scanner table limitations. 
f. Allergy to iodine-containing contrast media. 
g. Any history of CABG. 
4.3. Randomization Criteria 
Subjects will be randomized into the trial based on a randomization scheme prepared for 
each site provided they have satisfied all subject selection criteria.  Subjects will be 
assigned to either bococizumab 150 mg subcutaneous injection every 2 weeks, or 
corresponding placebo injection. Subjects who do not complete the trial will not be 
replaced. 
4.4. Lifestyle Guidelines 
4.4.1. Contraception 
All male and female subjects who, in the opinion of the investigator, are biologically 
capable of having children and 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 subject, 
will select the most appropriate method of contraception from the permitted list of 
contraception methods.  The investigator will instruct the subject in its consistent and 
correct use. In addition, the investigator will instruct the subject to call immediately if the 
selected birth control method is discontinued or if pregnancy is known or suspected. 
5. STUDY TREATMENTS 
Subjects will be randomized into one of 2 parallel groups: 


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 Bococizumab 150 mg subcutaneously every 2 weeks (n=100); 
 Bococizumab placebo subcutaneously every 2 weeks (n=100); 
5.1. Allocation to Treatment 
Each subject will receive a 4 digit identification number at the screening visit.  A 
randomization scheme will be prepared for each study site.  The pharmacist at each site 
will assign blinded study drug according to the randomization scheme.  Subjects will self-
inject (or if unable to self-inject, receive an injection by a home care giver) 150 mg of 
bococizumab or bococizumab placebo subcutaneously every 2 weeks.  Subjects eligible 
to be randomized will be assigned a randomization number at week 0 (visit day 1).  The 
randomization will be stratified by statin use. Each subject will receive 26 subcutaneous 
injections over the period of 52 weeks.  
Subjects should adhere to their treatment schedule even if their scheduled clinic visit is 
rescheduled or missed due to unforeseen circumstances. 
5.2. Drug Supplies 
5.2.1. Formulation and Packaging 
Bococizumab is presented as a sterile solution for subcutaneous administration, packaged 
in a glass pre-filled syringe (PFS) with a fixed needle. Each PFS contains a sufficient 
amount of bococizumab to provide the intended dose of drug at a concentration of 100 
mg/mL. Each syringe contains bococizumab in an aqueous buffered solution.   
Placebo is presented as a sterile solution for subcutaneous administration, packaged in a 
glass PFS with a fixed needle for subcutaneous administration. Each syringe contains an 
aqueous buffered solution.   
Each PFS is for single use only. 
5.2.2. Preparation and Dispensing 
Bococizumab and placebo will be provided in PFS packaged in cartons with tamper 
evident seals. The cartons should not be opened until the drug is to be administered.  
Drug will be dispensed to subjects in the sealed cartons. 
5.2.3. Administration 
The drug may be injected into either an upper or lower quadrant of the abdominal wall, 
anterior aspect of the thigh or to the lateral aspect of the upper arm.  Study staff, 
caregivers and subjects should refer to the Subject Study Medication Dosing Booklet and 
Instruction for specific instructions on the handling and administration of study drug and 
placebo. 
5.2.4. Compliance 
Subjects will record their injections in a diary and all injections and dates will be 
collected in a data collection instrument (case-report form).   
. 


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5.3. Drug Storage  
All bococizumab should be stored at 2 to 8º centigrade and protected from excessive 
shaking. Syringes should remain in the protective carton until the time of dosing. Storage 
conditions stated in the single reference safety document (Investigator Brochure) will be 
superseded by the label storage. 
The investigational products must be stored as indicated. Deviations from the storage 
requirements, including any actions taken, must be documented and reported to Pfizer.  
5.4. Concomitant Medication(s) 
All subjects will be questioned about HIV and CV concomitant medications (from now 
on designated as medications) at each visit.  
Subjects should take prescribed permitted concomitant medication, as needed, prior to the 
clinic visit, if it can be administered with water only. Subjects taking a statin should 
remain on the same dose of the same statin throughout the study. In general, subjects 
should remain on stable dosages of concomitant medications throughout the study. 
Changes in doses are allowed if clinically indicated. 
6. STUDY PROCEDURES 
Subjects will be required to fast prior to all study visits.  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. Screening Visit 
6.1.1. Visit Day   
The following procedures and activities will be performed during this visit: 
Obtain written informed consent, obtain and record cardiovascular risk factors and 
cardiovascular medical history, Obtain and record demographics and general medical 
history, Measure and record vital signs: heart rate (HR), temperature and BP (Section 
7.2.5), Conduct physical examination (Section 7.2.7), Obtain and record prior 
medications and instruct subjects on the use of concomitant medications (Section 5.5), 
Conduct 12-lead ECG test (Section 7.2.4), Verify trial eligibility by checking and 
documenting inclusion and exclusion criteria (Section 4.1, Section 4.2). 
Collect specimens for laboratory exams: 
 Blood for hematology and chemistry 
 Urinalysis for toxicology screen (if necessary); 
Provide lifestyle and contraception recommendations (Section 4.4.1); 
Do practice injection with placebo to ensure patient is comfortable self-injecting; 
Determine if subject meets ACC/AHA criteria for statin therapy. 


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 If subject meets criteria and is not currently on statin therapy, the subject will be 
referred back to their PCP. 
6.2. Treatment Period 
6.2.1. Visit Day 1  
Visit day 1 will usually require up to 7 days to complete because of the requirement to 
perform the brachial artery reactivity flow-mediated dilation, coronary CT angiography, 
and FDG-PET/CT studies after randomization and before the first treatment. 
A qualified FDG-PET/CT and coronary CT angiography interpreter will measure the 
images. Study drug dispensing will be delayed until after the repeat scan is completed. 
Randomization: 
Perform brachial artery reactivity flow-mediated dilation study; 
Perform FDG-PET/CT imaging; 
Perform coronary CT angiography; 
Drug dispensation and dosing: 
Instruct subject to self-inject; 
Assessment during and after subject self-injection or injection by trained study nurse: 
Provide lifestyle and contraception recommendations (Section 4.4.1); 
6.2.2. Visit Days 29, 57, 85, 169, 211, and 281  
The following procedures and assessments should be made before subject self-injection: 
Review results from laboratory values; 
Measure and record vital signs: heart rate (HR), temperature and BP (Section 7.2.5); 
Obtain and record on-going medications and instruct subjects on the use of concomitant 
medications (Section 5.5); 
Inquire for and record adverse events; 
Collect specimens for laboratory exams: 
Provide diet and therapeutic lifestyle and contraception recommendations (Section 4.4.1); 
Administer optional depression questionnaire; 
Drug dispensation and dosing 


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6.2.3. Visit Day 365/End of Study Visit (EOS) (± 3 days) 
The following procedures apply to subjects attending for Visit Day 365 or an early 
discontinuation visit if subjects choose to discontinue participation before Day 365. As 
detailed in Subject Withdrawal (Section 6.4) every effort should be made to ensure that 
all subjects complete study participation.  Subjects who discontinue study treatment will 
be encouraged to continue participation in the study and complete all protocol 
assessments/evaluations.  If, however, subjects choose not to continue attending study 
visits subjects should be encouraged to attend an EOS Visit and the follow up visits if 
indicated.   
Review results from laboratory values; 
Measure and record vital signs: heart rate (HR), temperature and BP (Section 7.2.5); 
Conduct 12-lead ECG test (Section 7.2.4); 
Obtain and record on-going medications and instruct subjects on the use of concomitant 
medications (Section 5.5); 
Inquire for and record adverse events; 
Collect specimens for laboratory exams: 
Provide lifestyle and contraception recommendations (Section 4.4.1); 
Administer optional depression questionnaire; 
Collect all used and unused pre-filled syringe cartons. 
6.3. Follow-up Visit 
A follow up visit will be arranged for all randomized subjects, including those who 
discontinued early in which case the follow up visit will occur 42 days after EOS Visit. 
6.3.1. Visit Day 407 (±3 days) 
Review results from laboratory values; 
Measure and record vital signs: heart rate (HR), temperature and BP (Section 7.2.5); 
Obtain and record on-going medications and instruct subjects on the use of concomitant 
medications (Section 5.5); 
Inquire for and record adverse events; 
Collect specimens for laboratory exams: 
Provide lifestyle and contraception recommendations (Section 4.4.1,); 
Administer optional depression questionnaire. 


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7. ASSESSMENTS 
Every effort will 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 that 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.   
7.1. Efficacy 
7.1.1. Lipids 
Efficacy will be based on the percent change from baseline in fasting lipids, primarily 
LDL-C.  Other lipid efficacy measures will include TC, HDL-C, non-HDL-C, TG, ApoB, 
ApoA-I, and Lp(a). 
The investigators and clinical staff and the subject will remain blinded to lipid results for 
the duration of the study.   
A DMC review will be implemented on all patients with LDL-C levels ≤ 25 mg/dL. 
7.1.2. FDG-PET/CT and CCTA Imaging 
FDG-PET/CT and CCTA imaging will be performed in randomized subjects at the day 1 
visit and again at the day 184. 
Participants will have PET imaging after an overnight fast to reduce myocardial FDG 
uptake. PET imaging will be done 3 hours after administration of 10 mCi of fluorine-18-
labelled FDG.65 
7.1.3. Brachial Artery FMD 
The imaging will be done at the primary location of our study team. Analysis of digitized 
images is performed using dedicated software.  
7.1.4. Inflammatory Markers 
We will measure inflammatory markers including IL-6, hsCRP, fibrinogen and sCD14, a 
receptor for endotoxin, using well validated assays. Samples will be collected at the 
randomization visit and at the week 24/end of study visit.  
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.  
  
7.2.2. Cardiovascular Risk Factors and Medical History 
Cardiovascular risk factors and CV medical history will be collected through a dedicated 
case report form (CRF). 


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7.2.3. 12-Lead ECG 
A 12-lead ECG will be obtained at time points indicated in the Schedule of Activities. 
ECGs will be kept at the study site as part of subject’s records. Clinically significant 
abnormalities present at baseline will be recorded on the medical history CRF.  
Additional ECGs may be performed for the evaluation of adverse events at the discretion 
of the investigator. Clinically significant abnormal findings occurring after baseline 
should be captured in the adverse event (AE) CRF. 
7.2.4. Vital Signs 
Temperature, heart rate (HR) and BP will be measured at times specified in the Schedule 
of Activities. 
7.2.5. Adverse Events 
All AEs will be recorded in the AE CRF from the time the subject receives the first dose 
of study drug to the end of study visit. 
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 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. 
8.2. 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 
 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. 


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8.3. 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. 
8.4. 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. 
8.4.1. Serious Adverse Event Reporting Requirements 
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event  
8.4.2. Non-Serious Adverse Event Reporting Requirements 
All AEs will be reported on the AE page(s) of the CRF.  
9. DATA ANALYSIS/STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this 
study will be documented in a Statistical Analysis Plan (SAP). 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 Determinations 
Approximately 200 subjects will be enrolled into the trial to provide comprehensive 
safety data for bococizumab in HIV-infected subjects.  Sample size calculations indicate 
that smaller numbers are required to demonstrate efficacy for the main study endpoints. 
The primary endpoint is percent change from baseline to week 12 in fasting LDL-C and 
the primary comparison of interest is bococizumab 150 mg compared to placebo. 
Assuming a dropout rate of 10% for the first 3 months, 54 subjects per treatment group 
provide more than sufficient power (≥99%) to detect expected treatment differences 
based on the results of a previous study.29 These calculations are based on α=0.05 (two-
sided), a common standard deviation of 25% (based on previous study results29), and on 


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using the normal approximation of the test statistic for the comparison between two 
means.  
9.2. Efficacy Analysis 
The full analysis set (FAS) will be the primary analysis set for the analysis of efficacy 
data in this study.  The FAS includes all subjects who were randomized.  Subjects will be 
analyzed according to their randomized treatment group.  The comparison of 
bococizumab to placebo at week 12 is the primary lipid comparison of interest. 
The experiment-wise Type I error of α=0.05 (two-sided) for the primary lipid comparison 
of interest for the primary endpoint and the key secondary lipid endpoints will be 
controlled by using gatekeeping and Hochberg procedures.  Key secondary lipid 
endpoints will be formally tested only if the null hypothesis for the primary analysis is 
rejected.  The Hochberg procedure will be applied to the key lipid secondary endpoints.  
All other statistical tests for secondary lipid endpoints will be performed at the two-sided 
=0.05 level; no further corrections will be made for multiple endpoints.        
9.2.1. Analysis of Primary Endpoint 
Percent change from baseline to week 12 in fasting LDL-C by direct method will be 
analyzed with a mixed model repeated measures (MMRM) approach. 
The MMRM analysis is unbiased under data missing at random, a common and plausible 
scenario in large confirmatory clinical trials. To support the robustness of the conclusions 
drawn from this analysis, several sensitivity analyses will be performed to explore the 
dropout pattern and its possible impact on treatment comparisons.  
9.2.2. Analysis of Key Secondary Endpoints 
Key secondary lipid endpoints include the following: 
 Percent change from baseline in fasting TC, non HDL-C, and ApoB at week 12; 
 Percent change from baseline in fasting Lp(a) at week 12; 
 Percent change from baseline in fasting HDL-C at week 12. 
The above key secondary endpoints will be analyzed in a similar manner as the primary 
endpoint, where an MMRM model will be used.  
 
9.2.3. Analysis of Secondary Lipid Endpoints 
Secondary lipid endpoints include the following: 
 Percent change from baseline in fasting LDL-C, TC, Apo B, non HDL-C, Lp(a), 
and HDL-C at week 24; 
 Percent change from baseline in fasting TG and ApoA-I at week 12 and week 24;  


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 Absolute change from baseline in fasting LDL-C, TC, HDL-C, non HDL-C, TG, 
ApoB, ApoA-I, and Lp(a) at week 12;  
 Absolute change from baseline in fasting TC / HDL-C ratio and ApoB / ApoA-I 
ratio at week 12 and week 24;  
 Proportion of subjects achieving fasting LDL-C ≤70 mg/dL (1.81 mmol/L) at 
week 12 and week 24;  
Endpoints of change and percent change from baseline will be analyzed in a similar 
manner as the primary lipid endpoint, where an MMRM model will be used.  
  
9.2.4. Analysis of Exploratory Lipid Endpoints 
Exploratory endpoints include the following: 
 Proportion of subjects achieving fasting LDL-C ≤50 mg/dL (1.29 mmol/L) at 
week 12 and week 24;  
 Absolute and percent change from baseline in PCSK9 at week 12 and week 24; 
 Plasma bococizumab exposure at week 12 and week 24. 
Endpoints of change and percent change from baseline will be analyzed in a similar 
manner as the primary lipid endpoint, where an MMRM model will be used.  
 
9.2.5. Analysis of the FDG-PET/CT Endpoints 
The main FDG-PET/CT endpoint will be the relative mean change from baseline to 24 
weeks in the arterial FDG-PET signal, assessed as a TBR within the most diseased MDS 
TBR to 24 weeks/end of study will be compared between treatments using an analysis of 
covariance model including terms for treatment and baseline covariates. The week 24 
geometric mean fold change from baseline in the mean of the maximum TBR of segment 
(MDS) of the index vessel. The week 24 geometric mean fold change from baseline in 
the mean of the maximum TBR of the MDS will be estimated for each of the two 
treatment groups and assessed for statistical significance between groups. Data will be 
log transformed as pre-specified in the Statistical Analysis Plan. Differences between 
treatments will be assessed based on the observed data values, without adjusting for 
missing data. Additional sensitivity analyses may be performed using multiple imputation 
to attempt to correct for any missing data. 
The secondary FDG-PET/CT endpoint will be the relative change in the whole vessel 
TBR within the index vessel.  
9.2.6. Analysis of Brachial Artery FMD Endpoints 
The main FMD endpoint is the difference between treatment groups in change in FMD 
between baseline and 24 weeks. Multivariate models will be constructed to assess the 


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effect of other variables on change in FMD, including traditional coronary risk factors, 
statin use, and HIV characteristics including current CD4 count, nadir CD4 count, current 
use of abacavir, didanosine, tenofovir or protease inhibitors, and duration of antiviral 
therapy and protease inhibitor therapy. 
9.3. Analysis of Other Endpoints 
9.3.1. Pharmacokinetics and Pharmacodynamic Data 
If data permit, the following analyses will be performed for plasma bococizumab 
concentration data and PCSK9 concentration: 
 A listing of all plasma PF-04950615 concentrations by patient at nominal time 
post dose. This listing will also include actual times post dose.   
 A descriptive summary of plasma bococizumab concentrations.  
 A listing of all plasma PCSK9 concentrations by patient at nominal time post 
dose. This listing will also include actual times post dose.  
 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 study day.   
If data permit, plasma bococizumb, PCSK9 and LDL-C concentrations will also be 
analyzed by ADA status and neutralizing antibody (nAb) status.   
9.4. Safety Analysis 
Safety will be assessed through adverse and serious adverse events, vital signs, and 
physical examination, 12-lead ECG recordings, and safety laboratory tests including anti-
drug antibodies, hematology, and blood chemistry studies. Unless otherwise specified, 
safety analyses will be done in the Safety Analysis Set, which is comprised of all subjects 
who have received at least one dose of randomized study medication. All summaries of 
safety data will be descriptive only, unless indicated otherwise. 
UCSF CHR/HRPP guidelines will be utilized when reporting adverse events.  Adverse 
events, adverse events leading to discontinuation from treatment, and serious adverse 
events will be tabulated by treatment group. Summaries will also be provided by severity 
and relationship to study therapy.  
Mean observed and mean change from baseline in systolic blood pressure, diastolic blood 
pressure, heart rate, and weight will be tabulated by visit according to sponsor standards.  
Observations of potential clinical concern for these parameters will be tabulated 
according to sponsor standards.  Height and temperature will be listed.   
Mean observed and mean change from baseline in hematology and blood chemistry 
parameters will be tabulated by visit according to sponsor standards. Observations of 
potential clinical concern for hematology and blood chemistry parameters will be 


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tabulated by treatment group according to sponsor standards. In addition, the proportion 
of subjects with anti-drug antibodies will be tabulated by treatment group.   
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 adverse events. Physical examination findings will be listed.   
9.5. Subgroup Analyses 
Subgroups of interest include: 
 Age (<65 versus 65 years) 
 Gender 
 Any post-baseline LDL-C <25 mg/dL 
 HIV status, CD4+ T-cell count above and below the median, specific 
antiretroviral therapy 
 HCV status 
 Triglyceride, Lp(a), PCSK9, hs-CRP, IL-6, fibrinogen, sCD14, sCD163 and D-
dimer levels above versus below the median. 


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9.6. Data Monitoring Committee  
A Data Monitoring Committee will be composed of an expert in HIV medicine, a lipid 
expert and a statistician 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. The recommendations made by the DMC (i.e., to alter the conduct of the 
study, continue as planned, etc.) will be shared between the principal investigator and the 
sponsor. Pfizer will forward such decisions, which may include summaries of aggregate 
analyses of endpoint events and of safety data that are not endpoints, to regulatory 
authorities, as appropriate. 


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10. REFERENCES 
1. 
Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of 
cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 
participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. 
2. 
Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more 
intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 
participants in 26 randomised trials. Lancet 2010;376:1670–81. 
3. 
Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, Waters DD. 
Progression of atherosclerosis as assessed by carotid intima-media thickness in 
patients with HIV infection. Circulation 2004;109:1603-8. 
4. 
Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, Butt 
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