Conditions: Human Immunodeficiency Virus
Keywords: Treated Progressors Immune Activation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 53
Healthy volunteers: no

Brief summary:
Background:

\- The immune system protects the body from infection. But it can also cause harm. For example, the clotting system makes blood clot and protects from bleeding. But blood clots are sometimes harmful. People with human immunodeficiency virus (HIV) infection have increased inflammation and clotting. This may increase their risk for diseases like stroke or heart attack. Researchers want to know how aspirin or HMG-CoA reductase inhibitors (so-called statin medications) affect the immune and clotting systems of people with HIV. Aspirin is a medicine to decrease clotting. Statins are medications given to lower cholesterol and decrease inflammation.

Objectives:

\- To see how aspirin or statins change immune and clotting systems in people with HIV.

Eligibility:

\- Adults 18 and older with HIV and a low viral load, not on aspirin or a statin medication. They must also have either: (1) never taken anti-HIV medications (ARVs), have a suppressed viral load, have stable CD4 counts, and never had an opportunistic infection; or (2) been taking ARVs for 5 continuous years and have a suppressed viral load for more than 3 years.

Design:

* Participants will be screened with medical history, physical exam, and blood and lab tests.
* Participants will repeat screening tests and have an MRI. An MRI is a way to visualize blood vessels in the neck and head. Participants will lie on a table that slides in and out of a cylinder surrounded by a magnetic field.
* Participants will take either study drug once daily for 9 months.
* Participants will have a blood procedure twice. Blood will be removed through a needle in one arm and circulated through a machine that removes white blood cells. The blood, minus white blood cells, is returned through a needle in the other arm.
* All participants will be observed for 3 months before and after treatment.

Detailed description:
Despite dramatic improvements in mortality with antiretroviral therapy (ART), HIV-infected persons remain at risk of developing non-infectious complications, including cardiovascular, renal, and neurological disease. A small subset of the HIV-infected population achieve durable control of HIV virus in the absence of ART. These individuals, termed elite controllers (ECs), remain ART na(SqrRoot) ve, have stable CD4 T cell counts for many years and have no history of opportunistic infections. Despite the lack of AIDS complications, recent evidence suggests ECs may exhibit heightened immune activation that may contribute to a potentially increased risk for non-infectious complications, similar to successfully treated progressors.

In the current 2 group, randomized, open label trial, we intend to study the effects of a lipid lowering agent vs aspirin (ASA) on immune activation in HIV-1 infected participants. One group will consist of ECs who are HIV-1 infected, maintain HIV-RNA levels of less than the LLD of commercially available assays in the absence of ART, have no history of ART or opportunistic infections (OIs) and have stable CD4 T cell counts for greater than 3 years. The second group will enroll HIV-1 infected Treated Progressors (henceforth referred to as ART \<50) who have maintained HIV-RNA below the limit of detection in commercially available assays (\<40, \<48, or \<50 copies/mL) for greater than 3 years on ART (treatment duration greater than 4 years). Up to 2 months after the screening and enrollment visit, each group will enter a 3 month observation period (to establish baseline values for biomarkers/cellular markers). After 3 months, participants from each group will be randomized to either ASA, 81 mg PO daily, or atorvastatin (ATV), 40 mg (dose adjusted for subjects on antiretroviral regimens with significant interactions, and will be treated for 9 months, followed by 3 months of a wash out period (see Figure 1). The primary end point will be change of sCD14 after 9 months of study intervention from Month 3 to Month 12 in each treatment arm, with groups combined (EC and ART \<50). Secondary objectives will be to compare changes in soluble biomarkers (sCD14, IL-6, D-dimer, hsCRP, sTF, sCD163 and other relevad treatment arms (ASA vs statin and EC vs ART\<50 and with groups combined), to evaluate cardiovascular (CV) disease prevalence in EC vs ART\<50 and with groups combined), to evaluate cardiovascular (CV) disease prevalence in EC vs ART \<50 by MR imaging of carotids, to determine MR measurements and correlations with biomarkers and cellular activation markers, and to investigate changes in plasma viremia as measured by single copy assay over time.

Arms:
arm 1: Elite controllers not on ART arm 2: HIV infected on ART

Interventions: intervention 1: Aspirin intervention 2: Atorvastatin
Intervention descriptions: intervention 1: Daily Asprin daily intervention 2: Daily Atorvastatin Daily

Protocol document:
Prot_SAP_000.pdf: 
 
 
Elite Controller and ART-treated HIV+ Statin versus ASA Treatment Intervention 
Study (ECSTATIN)  
 
NIAID Protocol Number: 14-I-0039 
 
Sponsored by:  
National Institute of Allergy and Infectious Diseases (NIAID) 
 
Pharmaceutical Support Provided by: NIH Pharmacy Development Service 
 
 
Principal Investigator: 
Irini Sereti, MD, MHS 
CMRS/LIR/NIAID 
Phone: 301-496-5533 
Email: isereti@niaid.nih.gov 
  
Accountable Investigator: 
Irini Sereti, MD, MHS 
CMRS/LIR/NIAID 
Phone: 301-496-5533 
Email: isereti@niaid.nih.gov 
Z Number: AI001121-01 
 
 
Version Number 
V.15 
Day Month Year: 
 
SEPTEMBER 21,  2018


EC and Immune Activation, V.15 
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Page 2 of 83 
 
STUDY STAFF ROSTER 
 
Principal Investigator:  
 
Irini Sereti, MD, MHS 
CMRS/LIR/NIAID 
Phone: 301-496-5533 
E-mail: isereti@niaid.nih.gov 
 
Accountable Investigator:  
Irini Sereti, MD, MHS 
CMRS/LIR/NIAID 
Phone: 301-496-5533 
E-mail: isereti@niaid.nih.gov 
 
Research Contact/ 
Study Coordinator:   
 
April Poole, RN 
 
 
 
 
 
Phone: (301) 435-8007 
 
 
 
 
 
Pooleal@niaid.nih.gov 
 
 
Associate Investigators:  
 
Stephen Migueles, MD 
NIAID/LIR 
 
Colleen Hadigan, MD, MPH 
NIAID/LIR 
 
Jason Baker, MD, MSCR 
Division of Infectious Diseases 
University of Minnesota 
Hennepin County Medical Center 
 
Ahmed Gharib, MD 
NIDDK/Biomedical & Metabolic Imaging Branch 
 
 
Alice Pau, PharmD 
NIAID/ICMOB 
 
JoAnn Mican, MD 
NIAID/ICMOB 
 
Andrea Lisco, MD, PhD 
NIAID/LIR 
 
Maura Manion, MD 
NIAID/LIR 
 
Elizabeth Laidlaw, PA-C, MPH 


EC and Immune Activation, V.15 
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Page 3 of 83 
 
 
Collaborator:  
 
 
Sonya Krishnan, BA 
 
 
 
 
 
Nicolas Patronas, MD  
 
 
 
 
 
Virginia Sheikh, MD 
 
 
 
 
 
Eleanor Wilson, MD 
 
 
 
 
 
 
 
 
 
 
 
Elena Martinelli, PhD MPH 
Scientist II, Population Council Center for 
Biomedical Research 
1188 York Ave, 10065, New York 
Phone: 212-327-7329 
She will use anonymized PBMC samples to test activity of an antibody in testing.  
 
Michaela Muller Trutwin, PhD 
Institut Pasteur Department of Virology 
Tele. +33140613969 
Email: mmuller@pasteur.fr 
She will study NK cell phenotype and function in various categories of HIV+ individuals. 
 
 
 
Statistician:   
 
 
Rebecca DerSimonian, ScD 
NIAID/BRB 
Phone: 301-435-7181 
E-mail: rdersimonian@niaid.nih.gov 
RESEARCH SITES 
 
National Institutes of Health, Clinical Center 
National Institutes of Allergy and Infectious Diseases – HIV Clinic 
Building 10, CRC, OP-8 
10 Center Drive 
Bethesda, MD 20892 
USA 
 
Hennepin County Medical Center 
701 Park Avenue 
Minneapolis, MN 55415 
USA 
 


EC and Immune Activation, V. 15 
 
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TABLE OF CONTENTS 
 
AUGUST 21, 2014 ............................................ ERROR! BOOKMARK NOT DEFINED. 
STUDY STAFF ROSTER ................................................................................................ 2 
RESEARCH SITES .......................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................. 4 
TABLE OF FIGURES AND TABLES ........................................................................... 6 
LIST OF ABBREVIATIONS .......................................................................................... 7 
PROTOCOL SUMMARY ............................................................................................... 9 
1 PRÉCIS ...................................................................................................................... 12 
2 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............. 13 
2.1 
BACKGROUND INFORMATION ........................................................................................................... 13 
2.1.1 
Immune Activation in HIV-infected Persons ........................................................................... 13 
2.1.2 
Immune Activation in Elite Controllers ................................................................................... 13 
2.1.3 
Imaging and Cardiovascular Disease ..................................................................................... 13 
2.1.4 
Effects of Statins on Cardiovascular Disease and Immune Activation ................................... 14 
2.1.5 
Platelet Aggregation and HIV ................................................................................................. 14 
2.1.6 
Effect of Aspirin on Cardiovascular Disease and Immune Activation .................................... 15 
2.1.7 
Targeting Cardiovascular Disease in HIV-infected Persons .................................................. 15 
2.1.8 
Gut microbiome and inflammation in HIV infected persons ................................................... 15 
2.2 
RATIONALE ...................................................................................................................................... 16 
3 STUDY OBJECTIVES ............................................................................................. 16 
3.1 
PRIMARY OBJECTIVE ........................................................................................................................ 17 
3.2 
SECONDARY OBJECTIVES ................................................................................................................. 17 
3.3 
DESCRIPTION OF THE STUDY DESIGN ............................................................................................... 17 
3.4 
STUDY ENDPOINTS ........................................................................................................................... 19 
3.4.1 
Primary Endpoint .................................................................................................................... 19 
3.4.2 
Secondary Endpoints ............................................................................................................... 19 
3.4.3 
Exploratory Endpoints ............................................................................................................. 19 
4 STUDY POPULATION ........................................................................................... 19 
4.1 
RATIONALE FOR SUBJECT SELECTION .............................................................................................. 19 
4.2 
RECRUITMENT PLAN ........................................................................................................................ 20 
4.3 
SUBJECT INCLUSION CRITERIA ......................................................................................................... 20 
4.4 
PARTICIPATION OF WOMEN: ............................................................................................................ 21 
4.5 
SUBJECT EXCLUSION CRITERIA ........................................................................................................ 22 
4.6 
JUSTIFICATION FOR EXCLUSION OF WOMEN AND CHILDREN (SPECIAL POPULATIONS) ................... 22 
4.6.1 
Exclusion of Women ................................................................................................................ 22 
4.6.2 
Exclusion of Children .............................................................................................................. 23 
5 STUDY AGENT/INTERVENTIONS ..................................................................... 23 
5.1 
DISPOSITION AND DISPENSATION ..................................................................................................... 23 
5.1.1 
Formulation, Packaging, and Labeling ................................................................................... 23 
5.2 
STUDY AGENT STORAGE AND STABILITY ........................................................................................ 23 
5.3 
PREPARATION, ADMINISTRATION, AND DOSAGE OF STUDY AGENT/INTERVENTION(S) ................... 23 
Deleted: ERRO
Deleted: 16
Deleted: 17


EC and Immune Activation, V.15 
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5.3.1 
Study Agent : atorvastatin ....................................................................................................... 23 
5.3.2 
Study Agent: aspirin ................................................................................................................ 24 
5.4 
STUDY PRODUCT ACCOUNTABILITY PROCEDURES .......................................................................... 25 
5.5 
ASSESSMENT OF SUBJECT COMPLIANCE WITH STUDY AGENT/INTERVENTION(S) ............................ 25 
5.6 
CONCOMITANT MEDICATIONS AND PROCEDURES ............................................................................ 25 
5.7 
PROHIBITED MEDICATIONS AND PROCEDURES ................................................................................ 25 
6 STUDY SCHEDULE ................................................................................................ 25 
6.1 
SCREENING ....................................................................................................................................... 25 
6.2 
ENROLLMENT/BASELINE (MONTH 0) ............................................................................................... 26 
6.3 
RANDOMIZATION ............................................................................................................................. 26 
6.4 
STUDY PHASE – MONTH 3 (± 2 WEEKS) ........................................................................................... 26 
6.5 
STUDY PHASE – MONTH 6 AND MONTH 9 ( ± 2 WEEKS) ................................................................... 27 
6.6 
WASHOUT PHASE – MONTH 12  (± 2 WEEKS) ................................................................................... 27 
6.7 
END OF STUDY VISIT – MONTH 15  (± 2 WEEKS) .............................................................................. 28 
6.8 
EARLY TERMINATION VISIT ............................................................................................................. 28 
6.9 
PREGNANCY AND FOLLOW-UP VISIT ................................................................................................ 28 
6.10 
RECONTACT OF SUBJECTS AFTER TRIAL TERMINATION ................................................................ 29 
7 STUDY PROCEDURES/EVALUATIONS ............................................................ 29 
7.1 
CLINICAL EVALUATIONS .................................................................................................................. 29 
7.2 
LABORATORY EVALUATIONS ........................................................................................................... 29 
7.2.1 
Clinical and Research Laboratory Evaluations and Specimen Collection ............................. 29 
7.3 
MRI EVALUATIONS .......................................................................................................................... 30 
8 POTENTIAL RISKS AND BENEFITS ................................................................. 30 
8.1 
POTENTIAL RISKS ............................................................................................................................. 30 
8.2 
POTENTIAL BENEFITS ....................................................................................................................... 32 
9 RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA
 
32 
10 REMUNERATION PLAN FOR SUBJECTS ...................................................... 33 
11 ASSESSMENT OF SAFETY ................................................................................. 33 
11.1 
TOXICITY SCALE ............................................................................................................................ 33 
11.2 
SPECIFICATION OF SAFETY PARAMETERS ...................................................................................... 33 
11.3 
RECORDING/DOCUMENTATION ...................................................................................................... 34 
11.4 
DEFINITIONS ................................................................................................................................... 35 
11.5 
REPORTING PROCEDURES ............................................................................................................... 36 
11.5.1 
Expedited Reporting to the NIAID IRB ................................................................................. 36 
11.5.2 
Annual Reporting to the NIAID IRB ...................................................................................... 36 
11.6 
REPORTING OF PREGNANCY ........................................................................................................... 37 
11.7 
TYPE AND DURATION OF THE FOLLOW-UP OF SUBJECTS AFTER ADVERSE EVENTS ....................... 37 
11.8 
MODIFICATION OF STUDY AGENT(S)/INTERVENTION(S) FOR A SUBJECT ....................................... 37 
11.9 
PAUSING RULES FOR THE PROTOCOL ............................................................................................. 37 
11.10 
STOPPING RULES FOR AN INDIVIDUAL SUBJECT/COHORT ............................................................ 37 
11.11 
PREMATURE WITHDRAWAL OF A SUBJECT ................................................................................... 38 
11.12 
REPLACEMENT OF A SUBJECT WHO DISCONTINUES STUDY TREATMENT .................................... 38 
12 CLINICAL MONITORING STRUCTURE ........................................................ 38 
12.1 
SAFETY MONITORING PLAN ........................................................................................................... 38 
13 STATISTICAL CONSIDERATIONS .................................................................. 38 
13.1 
STUDY HYPOTHESES ...................................................................................................................... 38 
Deleted: 36


EC and Immune Activation, V.15 
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13.2 
SAMPLE SIZE JUSTIFICATION .......................................................................................................... 38 
13.3 
SAFETY ANALYSIS ......................................................................................................................... 39 
13.4 
PLANNED INTERIM ANALYSES ....................................................................................................... 39 
13.5 
EFFICACY ANALYSIS ...................................................................................................................... 39 
14 ETHICS/PROTECTION OF HUMAN SUBJECTS ........................................... 39 
14.1 
INFORMED CONSENT PROCESS ....................................................................................................... 39 
14.1.1 
Remote Site Consent Process ................................................................................................. 40 
14.2 
SUBJECT CONFIDENTIALITY ........................................................................................................... 40 
15 DATA HANDLING AND RECORD KEEPING ................................................. 40 
15.1 
DATA CAPTURE AND MANAGEMENT ............................................................................................. 40 
15.2 
RECORD RETENTION ...................................................................................................................... 41 
APPENDIX A: SCIENTIFIC REFERENCES ............................................................ 42 
APPENDIX B: SCHEDULE OF PROCEDURES/EVALUATIONS ........................ 50 
APPENDIX C: BLOOD VOLUMES FOR SPECIMEN COLLECTION ................ 51 
APPENDIX D: ATORVASTATIN PACKAGE INSERT .......................................... 53 
APPENDIX E: ASPIRIN PACKAGE INSERT .......................................................... 75 
 
TABLE OF FIGURES AND TABLES 
Figure 1. Study Schema .................................................................................................... 18 
 
Table 1. Atorvastatin Interactions with Selected Antiretrovirals and Dosing 
Recommendations ............................................................................................................. 24 
 


EC and immune activation, V 15 
 
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LIST OF ABBREVIATIONS  
 
AE 
 
Adverse Event/Adverse Experience 
ART  
Antiretroviral Therapy 
ASA  
Aspirin 
ATV  
Atorvastatin 
AUC  
Area under the curve 
BRB  
Biostatistics Research Branch 
CRP 
 
C-Reactive Protein 
CMRS  
Clinical and Molecular Retrovirology Section  
CRIMSON 
Clinical Research Information Management System of the NIAID 
CV 
 
Cardiovascular 
EC 
 
Elite Controller 
FDA  
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
HAV IgG 
Hepatitis A Virus Immunoglobin G 
HAV IgM 
Hepatitis A Virus Immunoglobin M 
HBcAb 
Hepatitis B Core Antibody 
HBsAb 
Hepatitis B Surface Antibody 
HBsAg 
Hepatitis B Surface Antigen 
HCMC 
Hennepin County Medical Center 
HCV Ab 
Hepatitis C antibody 
HLA  
Human Leukocyte Antigen 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
ICMOB 
Intramural Clinical Management and Operations Branch  
IMT 
 
Intima-Media Thickness 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
LLD 
 
Lower limit of detection 
LIR 
 
Laboratory of Immunoregulation 
mL 
 
Milleliter 
MR 
 
Magnetic Resonance 
N 
 
Number (typically refers to number of subjects/sample size) 
NIAID  
National Institute of Allergy and Infectious Diseases  
NIH 
 
National Institutes of Health 
NSAID  
nonsteroidal anti-inflammatory drugs  
OHRP  
Office for Human Research Protections 
PBMC  
Peripheral Mononuclear Cells 
PCR 
 
Polymerase Chain Reaction 
PI 
 
Principal Investigator 
RCHSPB 
Regulatory Compliance and Human Subjects Protection Branch 
RNA  
Ribonucleic Acid 
SAE 
 
Serious Adverse Event 
sTF 
 
soluable tissue factor  


EC and Immune Activation, V 15 
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SVR 
 
Sustained virologic response 
ULN  
Upper Limit of Normal 
UP 
 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 


EC and Immune Activation, V 15 
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PROTOCOL SUMMARY 
 
Full Title: 
Elite Controller and ART-treated HIV+ Statin versus ASA 
Treatment Intervention Study (ECSTATIN) 
Short Title:  
 
Immune Activation in Elite Controllers 
Clinical Phase: 
Phase 1 
Protocol 
 
 
14-I-0039 
Conducted by: 
 
NIAID-DIR 
Principal Investigator: 
Irini Sereti, M.D. 
Sample Size: 
N=80 
 
Elite Controller (EC) Group: N=40  
Randomization arms: 
 
aspirin (ASA): N=20  
atorvastatin (ATV): N=20 
 
 
Treated Progressor Group (ART<50): N=40  
Randomization arms:  
 
ASA: N=20 
 
ATV: N=20 
Accrual Ceiling: 
N=120 
Study Population: 
 
Subjects (≥18 years) infected with the human immune-
deficiency virus type 1 (HIV-1) grouped ECs (no 
opportunistic infections [OIs], no antiretroviral therapy 
[ART], stable CD4 T cell counts greater than 3 years, HIV-
RNA less than the lower limit of detection (LLD) of 
commercially available assays) OR on continuous 
combination ART >4 years with HIV-RNA less than the 
lower limit of detection (LLD) of commercially available 
assays). Transient measurements of detectable viremia, or 
“blips,” are allowed, if flanked by viral loads less than the 
lower limit of detection. 
Accrual Period: 
 
4 Years 
Study Design: 
 
This is an open-label, randomized controlled trial intended 
to study potential modifiers of immune activation in HIV-1 
infected ECs (no OIs, no ART, stable CD4 T cell counts 
greater than 3 years, viral load less than the LLD of the assay 
used) (EC group) and treated progressers on continuous 
combination ART for > 4 years with HIV-RNA below the 
limit of detection in commercially available assays (<40, 
<48, or <50 copies/mL, depending on the assay used) for 
greater than 3 years (ART <50 group). After screening at 


EC and Immune Activation, V 15 
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Page 10 of 83 
either Hennepin County Medical Center or the NIH Clinical 
Center, subjects will be enrolled on study at the NIH Clinical 
Center and will enter a 3 month observation period (to 
establish baseline values for biomarkers/cellular markers). 
At Month 3, participants will be randomized within each 
group to receive once daily oral dose of ASA 81 mg or ATV 
40 mg (dose adjusted for subjects on antiretroviral regimens 
with significant interactions, see Section 5.3.1) and will be 
treated for 9 months, followed by 3 months of 
discontinuation of study drug.  
Study Duration: 
 
Start Date:  November 2013 
 
 
End Date: November 2019 
Study Agent/  
Intervention Description: 
- ASA, 81 mg, once daily, PO for 9 months 
 
 
- ATV, 40 mg (dose adjusted for subjects on antiretroviral 
regimens with significant interactions, see Section 5.3.1), 
once daily, PO for 9 months 
Primary Objective:  
To evaluate changes from baseline in sCD14 after 9 months 
of treatment with ASA or ATV, in EC and Treated 
Progressor (ART <50) groups combined. 
 
Secondary Objectives:  
 
• To evaluate changes in soluble biomarkers including 
sCD14, IL-6, D-dimer, hsCRP, soluable tissue factor (sTF), 
sCD163 and other related markers of inflammation and 
coagulation in EC and ART <50 copies/mL groups treated 
with ASA or ATV with groups combined as well as 
independently within each group and arm, at 6, 9, and 12 
months. 
• To evaluate changes in T cell activation (measured by 
HLA-DR/CD38 co-expression), monocyte immune 
activation (measured by activated monocyte subsets 
expressing either CD14++CD16+ and CD14varCD16+ and 
markers of activation, CCR5 and TF, and migration, CCR2 
and CX3CR1 and other relevant markers), at 6, 9, and 12 
months. 
• Assess if a 3-month wash out period (at Month 15) 
following 9 months of study drug results in biomarker and 
cellular activation changes. 
• To compare changes of biomarkers and cellular markers 
between EC and ART <50 groups. 
• To compare changes of biomarkers and cellular markers 
between ASA and ATV arms of each group and in both 
groups combined. 


EC and Immune Activation, V 15 
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• To evaluate changes in plasma viral load, as measured by 
single copy assay in EC and ART <50 groups treated with 
ASA or ATV from baseline, to months 3 and 12. 
• Assess tolerance of ASA and ATV treatment for 6 months 
in HIV+ participants without clinical indication for these 
drugs. 
• Assess prevalent atherosclerotic disease in EC vs ART <50 
groups by MR imaging of carotids at baseline. 
• Assess changes in MR imaging of carotids after 9 months of 
ASA or ATV in EC or ART <50 groups, and both groups 
combined. 
• Correlate MR vascular imaging with soluble and cellular 
biomarkers of inflammation. 
• To assess in an exploratory study the microbiome of EC 
versus ART<50 groups and the possible influence of ASA 
or statin therapy 
 
 
 
 
 
 


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1 
PRÉCIS 
 
Despite dramatic improvements in mortality with antiretroviral therapy (ART), HIV-
infected persons remain at risk of developing non-infectious complications, including 
cardiovascular, renal, and neurological disease. A small subset of the HIV-infected 
population achieve durable control of HIV virus in the absence of ART. These individuals, 
termed elite controllers (ECs), remain ART naïve, have stable CD4 T cell counts for many 
years and have no history of opportunistic infections. Despite the lack of AIDS 
complications, recent evidence suggests ECs may exhibit heightened immune activation 
that may contribute to a potentially increased risk for non-infectious complications, similar 
to successfully treated progressors. 
 
In the current 2 group, randomized, open label trial, we intend to study the effects of a lipid 
lowering agent vs aspirin (ASA) on immune activation in HIV-1 infected participants. One 
group will consist of ECs who are HIV-1 infected, maintain HIV-RNA levels less than the 
LLD of commercially available assays in the absence of ART, have no history of ART or 
opportunistic infections (OIs) and have stable CD4 T cell counts for greater than 3 years. 
The second group will enroll HIV-1 infected Treated Progressors (henceforth referred to 
as ART <50) who have maintained HIV-RNA below the limit of detection in commercially 
available assays (<40, <48, or <50 copies/mL) for greater than 3 years on ART (treatment 
duration greater than 4 years). Up to 2 months after the screening and enrollment visit, each 
group will enter a 3 month observation period (to establish baseline values for 
biomarkers/cellular markers). After 3 months, participants from each group will be 
randomized to either ASA, 81 mg PO daily, or atorvastatin (ATV), 40 mg (dose adjusted 
for subjects on antiretroviral regimens with significant interactions, see Section 5.3.1), and 
will be treated for 9 months, followed by 3 months of a wash out period (see Figure 1). The 
primary end point will be change of sCD14 after 9 months of study intervention from 
Month 3 to Month 12 in each treatment arm, with groups combined (EC and ART <50). 
Secondary objectives will be to compare changes in soluble biomarkers (sCD14, IL-6, D-
dimer, hsCRP, sTF, sCD163 and other relevant markers of inflammation and coagulation) 
and cellular activation markers between study groups and treatment arms (ASA vs statin 
and EC vs ART<50 and with groups combined), to evaluate cardiovascular (CV) disease 
prevalence in EC vs ART <50 by MR imaging of carotids, to determine MR measurements 
and correlations with biomarkers and cellular activation markers, and to investigate 
changes in plasma viremia as measured by single copy assay over time. 
 


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2 
 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
2.1 
Background Information 
2.1.1 Immune Activation in HIV-infected Persons 
HIV-infected individuals are currently at increased risk for non-infectious complications, 
including cardiovascular, renal and hepatic disease, bone loss and neurocognitive 
impairment, despite decreased risk of AIDS due to the development of ART [1, 2]. 
Biomarkers linked to non-AIDS complications (venous thromboembolism, cardiovascular 
disease and renal disease) including D-dimer, soluble (s) tissue factor (TF), sCD14, C-
reactive protein (CRP), and proinflammatory cytokines have been observed at higher levels 
in HIV seropositive compared to seronegative persons [3-7]. Furthermore, elevated levels 
of biomarkers associated with inflammation, coagulation and monocyte activation (D-
dimer, CRP, IL-6, and sCD14) have been found to be independent predictors of all-cause 
mortality and increased risk of AIDS [8-10]. Even in the presence of ART-induced viral 
suppression, HIV-infected individuals remain at a heightened risk of atherosclerotic 
disease and increased carotid intima-media thickness (IMT) and show increased 
inflammation and monocyte activation [11, 12] [13]. In HIV-negative subjects, the 
CD14++CD16+ activated monocyte phenotype independently predicts cardiovascular 
disease [14]. Monocytes are known to migrate to developing atherosclerotic plaques by 
chemotaxis and differentiate into macrophages on site. Macrophage activation leads to the 
production of oxygen radicals, inflammatory cytokines, and chemokines, ultimately 
causing  deleterious tissue damage and increased inflammation [15]. 
2.1.2 Immune Activation in Elite Controllers 
A small subset of the HIV-infected population (<0.5 percent) are able to maintain stable 
CD4 T cell counts and suppressed HIV RNA below the limit of detection in the absence of 
ART for decades [16-18]. Now termed elite controllers (ECs), these individuals are thought 
to control HIV replication through protective class I HLA haplotypes [19-21] and strong 
HIV-specific CD8 T cell responses [22-24]. However, despite suppression of viral 
replication below the limits of detection, ECs have higher rates of immune activation as 
measured by soluble biomarkers of inflammation such as D-dimer, IL-6, CRP, and markers 
of monocyte activation including soluble (s) CD163 and TF (tissue factor) [25-28] 
compared to healthy controls. In some cases, ECs have been noted to have higher levels of 
immune activation than those observed in HIV-infected progressors on effective ART (D-
dimer and sTF) [29] and may possibly be at increased risk for cardiovascular complications 
[27].  
2.1.3 Imaging and Cardiovascular Disease 
For decades, imaging techniques have been used to quantify the degree of cardiovascular 
disease and atherosclerosis through evaluation of IMT, lumen diameter, and the presence 
of plaques in the coronary and carotid arteries [30, 31] [32]. Imaging studies initially 
utilizing B-mode ultrasonography, established an association between carotid IMT and 
cardiovascular events, namely increased risk of stroke and myocardial infarction [33-35]. 
Increasingly, carotid IMT has been used as a surrogate marker of atherosclerosis and has 
been shown to be a predictor of future cardiac events [32, 36]. Given the rising cost of 
health care in the United States, carotid ultrasonography is now being ultilized to determine 


EC and Immune Activation, V 15 
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Page 14 of 83 
the degree of atherosclerosis in populations at increased risk for cardiovascular disease 
(HIV-seropostive, diabetics, autoimmune connective tissue diseases, etc) [13, 37, 38]. 
Consistent with previous findings that HIV-infected individuals have increased levels of 
biomarkers and inflammation linked to cardiovascular disease (see Section 2.1.2), HIV-
infected subjects also have a greater mean carotid IMT compared to HIV-negative controls 
[13]. Furthermore, HIV infection has been shown to be an independent risk factor of carotid 
IMT [13]. These findings have been extended to ECs, who have also been shown to have 
higher levels of carotid IMT than HIV-seronegative controls [28] and increased coronary 
atherosclerosis (determined by CT) [27]. Recently, the use of magnetic resonance (MR) 
imaging to measure atherosclerosis has been explored and compared to carotid 
ultrasonography [39]. MR imaging offers high spatial resolution and has been established 
as accurate and sensitive for measuring plaque size and carotid IMT [40-42]. 
2.1.4 Effects of Statins on Cardiovascular Disease and Immune Activation 
HMG-CoA reductase inhibitors, or statins, are the current first-line treatment for reduction 
of low-denisty lipoprotein (LDL) cholesterol [43] and have been shown to prevent 
cardiovascular disease, myocardial infarction and stroke in both patients with established 
cardiovascular disease and subclinical disease [44, 45]. Statins greatly decrease all-cause 
mortality and act to reduce low-density lipoprotein cholesterol and C reactive protein, 
known independent predictors of cardiovascular events [46-50]. Studies have also focused 
on the ability of statins to impede or reverse progression of cardiovascular disease, 
measured by atheroma volume and carotid IMT. Among the statins currently available on 
the market, atorvastatin (ATV) has emerged as a statin of choice in studying the effects of 
statins on cardiovascular disease regression, given it’s availability as a generic medication, 
the widespread familiarity with its use, and well-characterized safety profile [51, 52]. 
While atorvastatin is a CYP3A substrate, less potent drug interactions have been observed 
with CYP3A inhibitors than with other statins metabolized through this pathway [53]). 
ATV has been shown to have a comparable ability to lower LDL cholesterol and raise HDL 
cholesterol compared with other statins and has been associated with a reduction in 
cardiovascular events [53-57]. In a study of atorvastatin in patients with stable 
cardiovascular disease, regression of carotid IMT was noted that correlated with changes 
in inflammation, thrombosis and endothelial activation profiles [58] and atorvastatin has 
been associated with reductions in pro-inflammatory cytokines, including CRP [59] and 
sCD14 [60] in high risk patients. 
2.1.5 Platelet Aggregation and HIV 
Platelets aggregate and adhere to the site of vascular injury and secrete products such as 
adenosine diphosphate, thrombin, epinephrine, and thromboxane A2 that mediate clot 
formation and amplify the platelet response [61]. While platelets play a critical role in the 
maintenance of the endothelium and homeostasis through plug formation, exhuberant 
platelet activation is associated with increased carotid IMT [62, 63] and ultimately 
increased arterial and venous thromboembolic events [64, 65]. Increased thromboxane 
metabolites, a secretion product of activated platelets, have been linked to accelerated 
atherogenesis and acute coronary syndromes [66-68]. Increased platelet aggregation is also 
associated independently with mortality and cardiovascular events [69]. Given that HIV-
infected individuals have increased risk of thrombotic and cardiovascular events, it is not 
surprising that they exhibit heightened platelet activation. Specifically, HIV-infected 


EC and Immune Activation, V 15 
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Page 15 of 83 
individuals are known to have increased expression of P-selectin, a marker of platelet 
activation that is critical in the recuirment and adhesion of pro-inflammatory leukocytes to 
the site of endothelial injury [70]. In a case control matched study, we found that soluble 
vascular cell adhesion molecule-1 (sVCAM-1), a biomarker upregulated by vascular 
endothelial cells in response to proinflammatory cytokines, was significantly elevated in 
HIV-infected individuals preceding an incident cardiovascular event compared to HIV-
infected controls [7]. Furthermore, HIV-infected individuals have increased circulating 
platelet-monocyte complexes, an additional marker of platelet activation [71, 72]. 
2.1.6 Effect of Aspirin on Cardiovascular Disease and Immune Activation 
Aspirin (ASA) is a potent COX-1 inhibitor that prevents the formation of prostaglandin H2 
and thus thromboxane A2, a vasoconstrictor important in recruitment of circulating 
platelets and granule secretion [73]. In HIV-uninfected individuals, ASA has been used for 
decades to prevent cardiovascular disease, including incidence of myocardial infarction 
and stroke [73-75]. Numerous placebo-controlled trials with doses ranging from 50 mg 
daily to 1300 mg daily have confirmed the antithrombotic properties of ASA [76], with 81 
mg or 325 mg the most commonly prescribed doses in the United States. However, ASA 
usage (even 100 mg on alternate days) is associated with increased risk of gastrointestinal 
(GI) bleeding [75, 77]. Despite the adverse GI effects of ASA, it has a favorable safety 
profile at low doses and remains one of the most commonly used drugs worldwide [74, 
78]. 
2.1.7 Targeting Cardiovascular Disease in HIV-infected Persons 
A new study proposed by the AIDS Clinical Trial Group (ACTG) is designed to target 
immune activation in ECs through treatment with ART (A5308, NCT 01777997), with a 
primary endpoint looking at co-expression of HLA-DR and CD38 on CD8 T cells at 24 
and 48 weeks on ART. ART may pose some risks in terms of side effects and may cause a 
potential decrease or even loss of HIV-specific responses in this unique population. 
Recently, studies have shown a trend towards decreased mortality with HMG Co-A 
reductase inhibitors (or statin) therapy [79] and decreased markers of immune activation, 
as measured by sCD14, with ASA [80] and with statin therapy in HIV positive individuals 
[81]. In a substudy of the SATURN-HIV trial (a randomized, double-blind trial of ATV in 
HIV positive individuals, targeting subclinical cardiovascular disease), significant 
reductions were observed in soluble and cellular markers of monocyte activation after as 
little as 6 months (24 weeks) on therapy [81], and in a subanalysis of the SMART study, 
sCD14 was associated with mortality [10]. Additionally, it has been recently reported in a 
preliminary study that statin use (predominately rosuvastatin and pravastatin) reduces the 
risk of cancer in HIV-infected persons [82]. We propose to target immune activation with 
low-dose ASA or ATV therapy in both ECs and ART-treated HIV+ patients with 
suppressed viremia (ART <50), with change from month 3 in sCD14 as a primary outcome 
after 9 months of intervention (ASA vs ATV). 
 
2.1.8 Gut microbiome and inflammation in HIV infected persons 


EC and Immune Activation, V 15 
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Page 16 of 83 
The gut microbiome in HIV infected people may be playing a role in inflammatory 
responses (STM McCune) and to investigate this we will study stool microbiome 
at baseline [86]. 
 
 
2.2 
Rationale 
It is well-established that HIV-seropositive persons are at increased risk of cardiovascular 
disease. Within the HIV-infected population, there exists a unique subset of HIV-infected 
individuals, termed ECs, who maintain stable CD4 T cells counts and suppressed plasma 
HIV-RNA in the absence of antiretroviral therapy (ART). Despite their ability to control 
HIV viral replication, recent studies have demonstrated heightened immune activation and 
atherosclerosis in ECs compared to HIV-uninfected individuals [27, 28]. While ART is 
known to decrease immune activation in HIV-infected persons, it is costly, poses some risk 
of adverse effects, and may decrease HIV-specific immune responses in this group. In 
addition, as ART-treated persons still maintain higher levels of biomarkers that are linked 
to all cause mortality and have excess cardiovascular risk, it is feasible that ART alone in 
EC will not reverse the small decrease of inflammation and may necessitate treatment with 
both ART and an additional anti-inflammatory intervention. ATV and ASA are 2 well-
studied and well-tolerated drugs known to decrease immune activation and prevent 
cardiovascular events with minimal side effects.  
We propose to study the effects of ATV and ASA on biomarkers and cellular markers of 
immune activation and carotid-intima thickness. ECs and HIV-infected persons with 
suppressed HIV-RNA on ART (Treated Progressors) will be randomized to either a ATV 
or ASA open-labeled study arm. Because ATV bioavailability is increased when co-
administered with certain antiretrovirals [53] the study dose would be adjusted in subjects 
on antiretroviral regimens with significant interactions (see Section 5.3.1). ASA will be 
dosed at 81 mg daily. At these doses, there is limited risk for adverse effects from either 
medication despite good anticipated efficacy. 
The impact of 9 months of ATV or ASA therapy will be assessed through changes in 
biomarkers and cellular markers of activation, with the primary endpoint set as a change in 
sCD14, which has been linked to all-cause mortality in HIV-infected individuals. 
Additional biomarkers will include high sensitivity C reactive protein (hsCRP), soluble 
Tissue Factor (sTF), IL-6 and D-dimer. Furthermore, markers of T cell and monocyte 
activation will also be investigated. Lastly, we will observe the impact of therapy on 
cardiovascular disease progression through MR imaging of the carotid arteries. This study 
is utilzing MR imaging over carotid ultrasonography as it offers increased resolution, is 
free of radiation and provides similar results to ultrasonography. A washout period is 
included to elucidate if changes in biomarkers and cellular markers can be attributed to 
either ATV or ASA. 
 
 
3 
STUDY OBJECTIVES 


EC and Immune Activation, V 15 
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Page 17 of 83 
3.1 
Primary Objective 
• 
To evaluate changes from baseline in sCD14 after 9 months of treatment with ASA, 
or ATV, in ECs and in Treated Progressors (ART <50), with the groups combined. 
3.2 
Secondary Objectives 
• 
Compare changes in soluble biomarkers (sCD14, IL-6, D-dimer, hsCRP, sTF, 
sCD163 and other relevant markers of inflammation and coagulation) and cellular 
activation markers between study groups and treatment arms (ASA vs statin and 
EC vs ART<50 and with groups combined) at 6, 9, 12 months, and after 3 month 
washout at 15 months. Comparisons between EC and ART<50 will be adjusted for 
CD4, smoking status and age. 
• 
Evaluate cardiovascular (CV) disease prevalence in EC vs ART <50 by MR 
imaging of carotids at baseline and follow how it changes over time 
• 
Determine MR measurements and correlations with biomarkers and cellular 
activation markers 
• 
Investigate changes in plasma viremia as measured by single copy assay 
• 
To assess in an exploratory sudy the microbiome of EC versus ART<50 groups and 
the possible influence of ASA or statin therapy 
• 
 
 
3.3 
Description of the Study Design 
We propose a study of 40 ECs and 40 Treated Progressors (ART <50) who between 
screening and 2 months after screening will enter a 3-month observation period to establish 
baseline values for biomarkers/cellular markers. At Month 3, subjects will be randomized 
to either ASA, 81 mg daily, or ATV, 40 mg (dose adjusted for subjects on antiretroviral 
regimens with significant interactions, see Section 5.3.1).  
 
Study treatment will continue for 9 months until month 12 (primary end point), followed by a 3 month washout 
period (see  
 
 
 
 
 
 
 
 
Figure 1).  
 
Deleted: ¶
¶
¶
¶
¶
¶
¶
¶
¶
Figure 1


EC and Immune Activation, V 15 
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Page 18 of 83 
 
 
 
 
 
 
 
 
 
 
Figure 1. Study Schema 
 
 
 
 
 
Screening/H&P,
Month,0,
Month,12,,Washout,,
<2#months#
Randomized#
Aspirin,,81mg,daily,
AtorvastaAn,,40mg,daily*,
Month,15,
End,of,study,
• 
Caro2d#MRI#
• 
Apheresis#
• 
Research#Flow#
• 
Rectal#Swab#
• 
Research#Flow#
• 
Caro2d#MRI#
• 
Research#Flow###
• 
Rectal#Swab#
• 
Dietary#Ques2onnaire#
• 
Apheresis#
• 
Research#Flow#
Month,3,
• 
Research#Flow#
Month,6,
*#ATV#will#be#dose#adjusted#for#subjects#on#ART#regimens#with#signiﬁcant#interac2ons.#
**PBMCs,#Serum,#Plasma,#Safety#Labs,#and#Fas2ng#Lipid#Proﬁle#will#be#collected#at#each#study#visit.#
#
• 
Research#Flow#
Month,9,


EC and Immune Activation, V 15 
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Page 19 of 83 
3.4 
Study Endpoints 
3.4.1 Primary Endpoint 
The primary end point will be change of sCD14 from Month 3 to Month 12 in the 2 groups 
combined (EC and ART <50). 
3.4.2 Secondary Endpoints 
• 
To evaluate changes in soluble biomarkers (sCD14, IL-6, D-dimer, hsCRP, 
sCD163, sTF as well as other relevant markers of inflammation and coagulation) in 
EC and ART <50 groups treated with ASA or ATV, independently within each 
group and arm and with groups combined, at 6, 9, and 12 months. 
• 
To evaluate changes in T cell activation (measured by HLA-DR/CD38 co-
expression), monocyte immune activation (measured by activated monocyte subsets 
expressing either CD14++CD16+ and CD14varCD16+ and markers of activation, 
CCR5 and TF, and migration, CCR2 and CX3CR1), at 6, 9, 12 months of study. 
• 
To investigate differences in HLA type, which has been implicated as a mechanism 
of viremic control in ECs, between groups and treatment arms, as it relates to 
treatment response. 
• 
Assess if a wash out period following 9 months of therapy results in biomarker and 
cellular activation changes after 3 months (Month 15). 
• 
To compare changes of biomarkers and cellular markers between EC and ART <50 
groups after adjusting for smoking, CD4 counts and age. 
• 
To compare changes of biomarkers and cellular markers between ATV and ASA 
arms of each group and in both groups combined. 
• 
To evaluate changes in plasma viral load, as measured by single copy assay in EC 
and ART <50 groups treated with ASA or ATV at baseline, 3 and 12 months. 
• 
Assess toxicity profile of ASA versus ATV in the study population. 
• 
Assess prevalent atherosclerotic disease in EC vs ART<50 by MR imaging of 
carotids. 
• 
Assess changes in MR imaging of carotids after 9 months of statin or ASA in each 
group and both groups combined. 
• 
Correlate MR vascular imaging with soluble and cellular biomarkers of 
inflammation. 
3.4.3 Exploratory Endpoints 
Change in carotid IMT by MR between Month 0 and Month 9. 
4 
STUDY POPULATION 
4.1 
Rationale for Subject Selection 
Selection criteria for ECs were created based on the well-established definition that 
EC/Long-term Non-progressors are HIV-1 infected subjects with a suppressed viral load 
of <40 (or <48 or <50) copies/mL (depending on the assay used) in the absence of ART. 
Additionally, they have no history of opportunistic infections and stable CD4 T cells 
counts [83]. Selection criteria for Treated Progressors (ART <50) are based on the 


EC and Immune Activation, V 15 
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Page 20 of 83 
accepted standard that HIV-1 infected individuals on ART who achieve virological 
suppression have a HIV-RNA level of <40 (or <48 or <50) copies/mL. 
 
Since this study is seeking to establish the biomarker, cellular and cardiovascular effects 
of treatment with ATV and ASA, participants must not have received statin or ASA therapy 
for 6 months prior to the screening visit. In order to eliminate any confounding effects, 
patients will also be excluded if they have received any immunomodulating therapy, 
systemic corticosteroids or chronic daily nonsteroidal anti-inflammatory drugs (NSAID) 
use unless discussed with and approved by the study investigator. 
4.2 
Recruitment Plan  
Subjects will be recruited from the NIH Clinical Center, particularly from the NIH 
CCMD/NIAID OP8 Clinic, and from University of Minnesota Hennepin County Medical 
Center. The study may also be advertised through web based campaign as study visits are 
infrequent and we may need to recruit from outside the local area.   
Subjects recruited from University of Minnesota, Hennepin County will sign consents at 
this site and all screeining procedures including initial history and physical Assesments, 
lab work to determine eligibility will be done before sending them to NIH clinical Center 
OP8 clinic. These subjects will continue into month 0 and complete the rest of the study 
visits at NIH.  
Prior to study implementation, sites must obtain Institutional Review Board (IRB) 
approvals. Health care providers and research personnel at participating institutions will 
identify potentially eligible subjects. Once a subject for study entry is identified and 
expresses interest in learning about the study, the subject will be approached by the study 
team about participation in the protocol. If the subject remains interested, study details and 
the informed consent form (ICF) will be reviewed with the candidate by the study 
PI/designee. If the subject is willing to participate in the study, he or she will be provided 
with a copy of the informed consent to review. If a subject requires more time to consider 
the study, the staff member will give them a copy of the informed consent along with the 
staff member’s contact information, so that subjects may take the documents home for 
further review. After questions related to the study and the informed consent has been 
answered to the subject’s satisfaction, subjects will be asked to sign the IRB-approved 
consent form.  
4.3 
Subject Inclusion Criteria 
EC Arm 
1. 
Age ≥18 years. 
2. 
Documented HIV-1 infection confirmed by enzyme-linked immunosorbent assay 
(ELISA) and Western blot tests (will not be repeated if performed previously at 
NIH). 
3. 
Categorized as a long term non-progressor EC as defined by viral loads typically 
less than the LLD of commercially available assays and clinical and laboratory 
criteria (no OIs, no ART, stable CD4 T cell counts for more than 3 years). Viral 
load “blips” are allowed as long as they are <500 copies/mL and flanked by viral 


EC and Immune Activation, V 15 
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Page 21 of 83 
load measurements less than limit of detection of the commercially available assay. 
Viral load <100c/mL will be acceptable for eligibility at screening. 
4. 
In women of childbearing potential, with no plans for pregnancy for the next 15 
months and willing to use 2 investigator approved highly reliable methods of birth 
control consistently while on the study or in 3 month follow up. 
5. 
Willingness to have samples stored for future research.  
6. 
Not on a statin or ASA for the past 6 months. 
 
 
ART <50 Arm 
1. 
Age ≥18 years. 
2. 
Documented HIV-1 infection confirmed by enzyme-linked immunosorbent assay 
(ELISA) and Western blot tests. 
3. 
In women of childbearing potential, with no plans for pregnancy for the next 15 
months and willing to use 2 investigator approved highly reliable methods of birth 
control consistently while on the study or in 3 month follow up.  
4. 
On continuous combination ART >4years. 
5. 
HIV RNA <50 copies/mL (or <40 or <48 copies/mL, depending on the lower limit 
of detection of the assay used; transient periods of low level (<300) detectable 
virus, “blips,” acceptable if isolated and followed by <50 copies/mL values) >3 
years and current HIV-RNA less than the LLD of the commercially available assay 
used. Subject will be rescreened if HIV detectable at screening visit. 
6. 
Willingness to have samples stored for future research.  
7. 
Not on a statin or ASA for the past 6 months.  
4.4 
Participation of Women:   
Decreased cholesterol synthesis caused by ATV may cause fetal harm when administered 
to women who are pregnant; ATV has been listed as a pregnancy category X drug. ASA 
has been listed as a pregnancy category D drug by the Food and Drug Administration 
(FDA) due to the potential for known teratogenic or abortifacient effects on the developing 
fetus. Subjects must agree not to become pregnant. Females of childbearing potential must 
have a pregnancy test before initiating the study agent and at each study visit. Because of 
the risk involved, sexually active subjects and their partners must use 2 methods of birth 
control, one of which must be a barrier method. They must continue to use both methods 
until the end of study visit (Month 15). The methods of birth control may be selected from 
the list included below:  
• 
Hormonal contraception  
• 
Male or female condoms with or without a spermicide 
• 
Diaphragm or cervical cap with a spermicide  
• 
Intrauterine device (IUD) 


EC and Immune Activation, V 15 
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Page 22 of 83 
• 
Male partner with a vasectomy 
If pregnancy is suspected or should occur, subjects must notify the study staff immediately.  
4.5 
Subject Exclusion Criteria 
1. 
Diagnosis of cardiovascular disease or hypercholesterolemia (LDL cholesterol >.190 
mg/dL). 
2. 
Known hypersensitivity or allergy to ATV or ASA, including a history of myositis 
or rhabdomyolysis with statin or ASA use. 
3. 
Other contraindication for ASA or statin therapy (active liver disease, peptic ulcer 
disease, etc.). 
4. 
Women who are lactating, pregnant, or actively trying to become pregnant or 
considering pregnancy over the likely span of the study (including women of 
childbearing potential who are unwilling to use adequate contraception throughout 
the study). 
5. 
Any chronic inflammatory condition either requiring anti-inflammatory medication 
(systemic corticosteroids, daily NSAID use,immunomodulating medications) which 
may, in the opinion of the investigator, confound the interpretation of soluble 
inflammatory biomarkers.  While on study, short term (less than 5 days) NSAID use 
will be allowed at the discretion of the investigator.   
6. 
Active drug use or alcohol abuse that, in the opinion of the investigator, may interfere 
with the ability of the subject to participate in the study or that may unacceptably 
increase the risk of the study intervention.. 
7. 
Safety laboratory cut offs: coagulation (INR >2 upper limit of normal [ULN], 
PLT<75K), renal function (GFR<60), liver function (ALT or Alkaline phosphatase 
or direct bilirubin >2x ULN), aldolase <1.5 ULN and anemia (Hg <9 mg/dL). 
8. 
Antiretroviral therapy with tipranivir, or any therapy which combines non-nucleoside 
reverse transcriptase inhibitors with protease inhibitors. 
9. 
Chronic hepatitis C co-infection.  However, if a subject has more than 24 weeks of 
sustained virologic response (SVR), the subject can be considered for eligibility. 
10. If either MR or apheresis is contraindicated, subject may still participate without this 
procedure. In the case of missed apheresis, a 30 mL research blood draw will be 
substituted (see Appendices B and C). 
11. If statin initiation is indicated per current guidelines, subject will be counseled to 
consult with their PMD. If the  subject then chooses to take part in the study, we will 
provide their PMD with all pertinent lab results during the course of the study, if 
requested. 
 
Co-enrollment Guidelines: Co-enrollment in other trials will be restricted, other than 
enrollment on observational studies. Study staff should be notified of co-enrollment as it 
may require the approval of the Investigator. 
4.6 
Justification for Exclusion of Women and Children (Special Populations)  
4.6.1 Exclusion of Women  
• Pregnancy: Pregnant women are excluded from this study because there are known 
adverse effects of ATV, a pregnancy category X drug, on the developing human fetus. 


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Page 23 of 83 
ASA has been listed as a pregnancy category D drug by the FDA due to the potential 
for known teratogenic or abortifacient effects on the developing fetus. 
• Breast-feeding: Because there is an unknown but potential risk for adverse events 
(AEs) in nursing infants secondary to treatment of the mother with ATV, breastfeeding 
should be discontinued if the mother will be treated with ATV. There is a known risk 
for AEs in nursing infants secondary to treatment of the mother with ASA, therefore 
breastfeeding should be discontinued if the mother will be treated with ASA. 
4.6.2 Exclusion of Children  
Because there are insufficient data regarding dosing or AEs available in HIV-infected 
adults to judge the potential risk in HIV-infected children, children are excluded from this 
study.  
 
5 
STUDY AGENT/INTERVENTIONS  
5.1 
Disposition and Dispensation  
Study agents will be distributed via the NIH Central Pharmacy according to standard 
pharmacy procedures. 
5.1.1 Formulation, Packaging, and Labeling 
Each bottle will be individually labeled with the participant ID number, dosing instructions, 
recommended storage conditions, the name and address of the manufacturer, 
randomization number, and that the agent should be kept out of reach of children. 
5.2 
Study Agent Storage and Stability 
Both ATV and ASA should be stored at room temperature, 20-25°C (68-77°F). 
5.3 
Preparation, Administration, and Dosage of Study Agent/Intervention(s) 
5.3.1 Study Agent : atorvastatin 
Description 
Dosing and Administration: 40 mg tablet, daily. In subjects on certain 
antiretroviral medications, ATV dosing will be adjusted in accordance with 
DHHS guidelines [84]. See Table 1 below for list of antiretroviral agents 
requiring adjustment. Briefly, in subjects on cobicistat -or ritonavir- boosted 
protease inhibitor or elvitegravir-based regimens, the atorvastatin AUC can 
increase  by 3-6 fold [87].  In subjects on protease inhibitor (other than tipranavir) 
or elvitegravir-based regimens, the atorvastatin dose will be decreased to 20mg 
daily.  In subjects on efavirenz or etravirine-based regimens, atorvastatin AUC 
can decrease from 32 to 43%.  Therefore, in subjects on efavirenz or etravirine-
based regimens, the dose of atorvastatin will be increased to 80mg daily. Dosing 
of ATV with other ART regimens will also be made in accordance with DHHS 
guidelines [84]. 
 


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Table 1. Atorvastatin Interactions with Selected Antiretrovirals and Dosing Recommendations 
Antiretroviral Medication 
Effect on Atorvastatin 
Adjusted Atorvastatin 
Atazanavir, Atazanavir with 
Ritonavir or Cobicistat 
Increased Atorvastatin possible 
20mg,daily 
Darunavir with Ritonavir or 
Cobicistat 
DRV/r + Atorvastatin  
10mg similar to Atorvastatin  
40mg administered alone 
20mg daily 
Elvitegravir with Cobicistat  o
(or  Ritonavir) 
Increased Atorvastatin possible 
20mg, daily 
Lopinavir with ritonavir 
Increased AtorvastatinAUC 488% 20mg daily 
Efavirenz, Etravirine 
Decreased Atorvastatin  
AUC 32-43% 
80mg daily 
Rilpivirine 
Atorvastatin AUC unchanged 
40mg daily 
 
Route of Administration: PO 
Duration of Therapy: 9 months 
Tracking of Dose: pill count and participant stated compliance. 
Limitations on Prior Therapy: Prior statin therapy allowable if therapy ceased 
at least 6 months prior to the screening visit. 
Subject Access to Study Agent at Study Closure: ATV is only available by 
prescription, and subjects will be counseled to consult with their primary 
physician before considering chronic therapy. 
5.3.2 Study Agent: aspirin 
Description 
Dosing and Administration: 81 mg tablet, daily 
Route of Administration: PO 
Duration of Therapy: 9 months 
Tracking of Dose: pill count and participant stated compliance. 
Limitations on Prior Therapy: Prior chronic asprin use allowable if therapy 
ceased at least 6 months prior to the screening visit. 
Use of Ancillary Medications/OTC Products/Foods: Use of systemic 
corticosteroids, daily NSAID use or immunomodulating medications prohibited at 
the discretion of the principal investigator (PI)  


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Subject Access to Study Agent at Study Closure: While ASA is available over-
the-counter, subjects will be counseled to consult with their primary physician 
before considering chronic ASA therapy.  
5.4 
Study Product Accountability Procedures 
We will follow the NIH Central Pharmacy study product accountability procedures. 
5.5 
Assessment of Subject Compliance with Study Agent/Intervention(s)  
Particpants will be asked about missing pills at each visit and a pill count will be 
performed.  
5.6 
Concomitant Medications and Procedures 
All concomitant prescription medications taken during study participation will be 
documented in the Clinical Research Information Management System of NIAID 
(CRIMSON). For this protocol, a prescription medication is defined as a medication that 
can be prescribed only by a properly authorized/licensed clinician.  Medications to be 
reported in CRIMSON are concomitant prescription medications, over-the-counter 
medications and non-prescription medications taken at the time of AEs (all grades except 
grade 1). 
5.7 
Prohibited Medications and Procedures 
Treatment with immunomodulating agents, systemic corticosteroids and daily NSAIDs 
will not be permitted unless discussed with and approved by the study investigator. 
Subjects treated with a statin or ASA daily up to 6 months prior to the screening visit will 
also be excluded. Treatment with tipranavir will be prohibited because ATV is 
contraindicated in these patients. Treatment with any ART regimen combining a non-
nucleoside reverse transcriptase inhibitor with a protease inhibitor will be prohibited 
because of the lack of data concerning drug interactions with ATV. 
6 
STUDY SCHEDULE 
 
For the purposes of this study, a month is a calendar month.  A window of up to ± 2 
weeks will be acceptable for all visits after the baseline visit. Visits that include 
procedures (MRI or pheresis) may be completed in more than one day. 
6.1 
Screening  
Subjects will be screened at either the NIH Clinical Center or Hennepin County Medical 
Center and undergo the following procedures subsequent to signing informed consent: 
• Review patient eligibility  
• Physical examination, medical history and medication history (including herbal 
supplements) 
• HIV RNA, CD4 
• Pregnancy testing (urine or serum) in women of child-bearing potential 
• Safety labs (Hematology, PT/PTT, Chemistry, Liver Function Tests, Urinalysis, 
Creatine Kinase, Aldolase) 


EC and Immune Activation, V 15 
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• Hepatitis serology (HBsAg, anti-HBcAb and anti-HBsAb, anti-HAV IgG, HCV 
Ab and HCV PCR) HCV Ab testing accepted from outside lab if performed 
within 2 months of Baseline Month 0 visit. 
• D-dimer, fibrinogen, Protein C and S, antithrombin III,  
• Fasting lipid profile 
• Documentation of HIV infection status 
6.2 
Enrollment/Baseline (Month 0) 
This visit, and all subsequent visits, will take place at the NIH Clinical Center only.  This 
Enrollment/Baseline Month 0 Visit will occur between 2 days and 2 months of screening, 
At Month 0, enrolled subjects will undergo the following procedures: 
• Physical examination, medical history and medication history (including herbal 
supplements) 
• Laboratory data for HIV RNA, CD4 
• Research flow cytometry 
• PBMCs, serum and plasma for research and storage 
• Safety labs (Hematology, PT/PTT/D-dimer, Chemistry/CRP, Liver Function 
Tests, Urinalysis, Pregnancy Testing, Creatine Kinase, Aldolase) 
• D-dimer, fibrinogen, Protein C and S, antithrombin III 
• Fasting lipid profile  
• Hemoglobin A1c 
• HLA typing (if not previously performed at NIH) 
• Carotid MRI 
• ELISA and Western Blot (if not previously performed at NIH) 
• Rectal swab and dietary questionnaire for microbiome studies 
• Framingham Risk Score Calculation 
 
6.3 
Randomization  
The NIH Pharmacy Department will carry out blocked, open-label, randomization using a 
random number generator. At the Month 3 study visit, ECs and Treated Progressors will 
be separately randomized 1:1 to open label ASA or ATV arms.  
6.4 
Study Phase – Month 3 (± 2 weeks) 
Following randomization, study participants will initiate study drug and the following 
procedures at this vist: 
• Initiation of open label ATV 40 mg (dose adjusted for subjects on antiretroviral 
regimens with significant interactions, see Section 5.3.1) or ASA 81 mg PO daily,  


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• Targeted physical examination, medical history and medication history (including 
over the counter medications and herbal supplements) 
• HIV RNA, CD4 
• Research flow cytometry  
• PBMCs, serum and plasma for research and storage 
• Safety labs (Hematology, PT/PTT/D-dimer, Chemistry/CRP, Liver Function 
Tests, Urinalysis, Pregnancy Testing (for females of childbearing potential), 
Creatine Kinase, Aldolase) 
• D-dimer, fibrinogen, Protein C and S, antithrombin III 
• Fasting lipid profile  
• Hemoglobin A1c 
• 1 L leukapheresis (prior to drug initiation) 
6.5 
Study Phase – Month 6 and Month 9 ( ± 2 weeks) 
Study participants will continue study drug and will undergo the following procedures at 
this visit: 
• Targeted physical examination, medical history and medication history (including 
over the counter medications and herbal supplements) 
• HIV RNA, CD4 
• Research flow cytometry  
• PBMCs, serum and plasma for research and storage 
• Safety labs (Hematology, PT/PTT/D-dimer, Chemistry/CRP, Liver Function 
Tests, Urinalysis, Pregnancy Testing (for females of childbearing potential), 
Creatine Kinase, Aldolase) 
• D-dimer, fibrinogen, Protein C and S, antithrombin III 
• Fasting lipid profile  
• Hemoglobin A1c 
6.6 
Washout Phase – Month 12  (± 2 weeks) 
The follow procedures will be completed at Month 12: 
• Discontinuation of ATV and ASA therapy 
• Targeted physical examination, medical history and medication history (including 
over the counter medications and herbal supplements) 
• HIV RNA, CD4 
• Research flow cytometry  
• PBMCs, serum and plasma for research and storage 


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• Safety labs (Hematology, PT/PTT/D-dimer, Chemistry/CRP, Liver Function 
Tests, Urinalysis, Pregnancy Testing (for females of childbearing potential), 
Creatine Kinase, Aldolase) 
• D-dimer, fibrinogen, Protein C and S, antithrombin III 
• Fasting lipid profile 
• Hemoglobin A1c 
• Carotid MRI 
• 1 L leukapheresis 
• Rectal swab 
6.7 
End of Study Visit – Month 15  (± 2 weeks) 
• Targeted physical examination, medical history and medication history (including 
over the counter medications and herbal supplements) 
• HIV RNA, CD4 
• Research flow cytometry  
• PBMCs, serum and plasma for research and storage 
• Safety labs (Hematology, PT/PTT/D-dimer, Chemistry/CRP, Liver Function 
Tests, Urinalysis, Pregnancy Testing (for females of childbearing potential), 
Creatine Kinase, Aldolase) 
• D-dimer, fibrinogen, Protein C and S, antithrombin III 
• Fasting lipid profile 
• Hemoglobin A1c 
6.8 
Early Termination Visit 
If a subject becomes pregnant (see section 6.9) or experiences a life-threatening adverse 
reaction related to either ATV or ASA and is forced to terminate study drug, the subject 
will continue to be followed at the established study time points until Month 15, with only 
safety laboratory tests drawn.  
6.9 
Pregnancy and Follow-up Visit 
Urine or serum pregnancy tests will be performed for all female participants of childbearing 
potential at each study visit. All pregnancy tests must be negative in order to continue 
participating in the protocol. The following actions will be taken if the PI is notified that a 
female participant becomes pregnant while on study: 
• Withdrawal of the participant from the study if the pregnancy occurs before drug 
administration. 
• Discontinuation of study drug (both ATV and ASA) immediately if the pregnancy 
occurs during the treatment phase. The patient will be referred to a maternal fetal 
medicine specialist.  The patient will be followed as necessary by the study team 


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throughout the remainder of the study period or until the time of birth (whichever 
occurs later), for safety assessments and labs.  
6.10 
Recontact of Subjects After Trial Termination 
Subjects may be recontacted after trial termination to be informed about study results and 
possibly to be notified about potential similar follow-up studies. 
7 
STUDY PROCEDURES/EVALUATIONS 
7.1 
Clinical Evaluations 
• Medical/medication/social history with complete or targeted physical examination. 
Physical examination will include: 
o Vital signs (temperature, pulse, resting blood pressure, respiratory rate, oxygen 
saturation) 
o Skin  
o Head, ears, eyes, nose, and throat 
o Oral mucosa 
o Lymph nodes (including cervical, axillary, clavicular, and inguinal) 
o Respiratory system 
o Cardiovascular system 
o Abdominal area  
o Neurological system 
o Musculoskeletal system 
 
• Targeted examination will take place at study time points after screening and Month 
0 visits. 
 
• Participants with a contraindication for MR will not be required to undergo the 
procedure. 
7.2 
Laboratory Evaluations 
• Apheresis: Participants with inadequate venous access will only undergo an 
additional 30 mL blood draw (see Appendices B and C). 
• Phlebotomy: Collection of blood for safety lab tests, fasting lipid prolife, hepatitis 
serology, hemoglobin A1c, coagulation studies, HIV-1 serology and storage. 
• Research flow cytometry: activation of T cells and monocytes at study time points 
• CD4, HIV-RNA levels, HLA typing 
• Microbiome studies which consists of a rectal swab and dietary history questionnaire. 
 
 
7.2.1 Clinical and Research Laboratory Evaluations and Specimen Collection 
All safety labs will be performed at the NIH Clinical Center, as well as hsCRP and 
D-dimer. Testing for research chemokines (such as IP-10), cytokines (ie IL-6, 


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TNA-α, and IL-10), soluble biomarkers (including sCD14, IL-6, and sTF) and flow 
cytometry will be batched and performed at Leidos Biomedical Research, Inc.   
Leidos Biomedical Research, Inc. will also process and organize research 
 stored samples.  
 
 
 
7.3 
MRI Evaluations 
All MRIs will be reviewed by the NIH Clinical Center radiologist according to standard 
clinical protocols and the read entered into the patient chart. If an individual participant is 
found to have clinically significant abnormalities as a result of participation in this study, 
the findings will be reviewed with the patient in detail by the study team. This will include 
any clinical recommendations for future care or follow-up testing, and this information will 
also be provided to the subject’s doctor(s) when indicated.  
 
In order to answer the research objective, an MR reading for research with IMT 
measurement will be performed by Dr Gharib or Dr Patronas (study collaborator) who will 
not be involved in he clinical care of the patients.  
 
8 
POTENTIAL RISKS AND BENEFITS 
8.1 
Potential Risks 
 
Atorvastatin: 
Per the package insert (Appendix D), the following warnings and precautions should be 
considered: 
• Skeletal Muscle Effects: Rare cases of rhabdomyolysis with acute renal failure 
secondary to myoglobinuria have been reported with atorvastatin calcium tablets and 
with other drugs in this class.  Atorvastatin, like other statins, occasionally causes 
myopathy,, defined as muscle aches or weakness in conjunction with increases in 
CPK values >10 times ULN.The comcomitant use of higher doses of atorvastatin  
with certain drugs such as cyclosporine and strong CYP3A4 inhibitors  (e.g. 
clarithromycin, itraconazole, and HIV protease inhibitors) increases the risk of 
myopathy/rahbdomyolysis.  
• Liver Dysfunction: Persistent elevations (<3 time ULN occurring on 2 or more 
occasions in serum transaminases occurred in 0.7% of patients who received 
atorvastatin calcium tablets in clinical trails. 
• Endocrine Effects: “Increases in HbA1c and fasting serum glucose levels have been 
reported with HMG-CoA reductase inhibitors,” including ATV. 
 
 
 


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Aspirin: 
According to the ASA package insert (Appendix E),  the following warnings and 
precautions should be considered in patients with the following morbidities: 
• Alcohol Warning: Increased bleeding risks may occur in patients who consume 3 or 
more alcoholic drinks a day. 
• Coagulation Abnormalities: “Even low doses of ASA can inhibit platelet function 
leading to an increase in bleeding time. This can adversely affect patients with 
inherited (hemophilia) or acquired (liver disease or vitamin K deficiency) bleeding 
disorders.” 
• GI Side Effects: “GI side effects include stomach pain, heartburn, nausea, vomiting, 
and gross GI bleeding.” 
• Peptic Ulcer Disease: ASA can cause gastric mucosal irriation and bleeding so 
patients with a history of active peptic ulcer disease should avoid use. 
• Renal Failure: Patients with glomerular filtration rates less that 10 mL/minute 
should avoid use. 
• Hepatic Insufficiency: Avoid use in patients with hepatic insufficiency. 
• Sodium Restricted Diet: The high sodium content in buffered ASA preparations 
should be avoided in patients with sodium retaining states (ie congestive heart failure 
or renal failure). 
Phlebotomy  
The risks associated with phlebotomy include discomfort, bruising, local hematoma 
formation and, on rare occasions, infections, lightheadedness, and fainting. The amount of 
blood drawn for research purposes will be within the limits allowed for adult subjects at 
the NIH Clinical Center (Medical Administrative Policy 95-9: Guidelines for Limits of 
Blood 
Drawn 
for 
Research 
Purposes 
in 
the 
Clinical 
Center: 
http://cc-
internal.cc.nih.gov/policies/PDF/M95-9.pdf). 
 
Apheresis 
The potential risks associated with apheresis include lightheadedness, dizziness, possible 
fainting, tingling around the mouth and in the fingers and toes, nausea, chills, vomiting, 
mild muscle cramps, loss of <1 pint of blood, or pain, bruising, or discomfort at the needle 
insertion sites. More serious, but rare, complications include nerve damage at the needle 
insertion site, seizures and air embolism. Most procedures are performed without an 
incident. Blood components removed during apheresis are generally replaced by the body 
within a few hours or a few days. No infections associated with this procedure have been 
reported in thousands of cases performed over the last 10 years at the NIH.   
 
Magnetic Resonance Imaging 
Patients with pacemakers, aneurysm clips (metal clips on the wall of a large artery), 
metallic prostheses (including heart valves and cochlear implants), or shrapnel fragments 
in critical sites, such as the orbit or the brain are at risk of injury from MR imaging. Welders 
and metal workers are also at risk for injury because of possible metallic foreign bodies in 


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the eye. The patient will lie flat in a long metal cylinder. No pain will be felt, but this may 
be uncomfortable if the patient fears closed spaces. An operator will be present at all times 
for observation and assistance if necessary. If requested, removal from the machine can 
occur at any time.  
 
Rectal Swabs 
Participant may experience pressure as the swab is inserted into the rectum, but the test is 
usually not painful. 
 
8.2 
Potential Benefits 
Participation in the study provides no direct benefit to volunteer participants, although 
similar treatments have been of benefit in other patients with increased cardiovascular risk. 
Currently, no treatment exists that addresses increased immune activation and 
cardiovascular disease in HIV-infected individuals; therefore this study may benefit future 
populations of HIV-infected persons with risk of cardiovascular events.  
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR 
DATA 
 
• 
Intended Use: Samples and data collected under this protocol may be used to study 
biomarkers and cellular markers of activation or other immune measurements that are 
relevant to HIV infection or similar immunodeficiencies as well as cardiovascular 
disease. Any other research or experimental treatments will be done under this or other 
protocols for which separate signed informed consent documents will be obtained. 
• 
Storage:  Access to stored samples will be limited using either a locked room or a 
locked freezer. Samples and data will be stored using codes assigned by the 
investigators. Data will be kept in password-protected computers. Only investigators 
will have access to the samples and data.  
• 
Tracking: Samples will be tracked utilizing the NCI at Frederick Central repository operated 
by Leidos Biomedical Research, Inc. Data will be stored and maintained in the CRIMSON 
database. 
 
• 
Disposition at the Completion of the Protocol:  
o In the future, other investigators (both at NIH and outside) may wish to study these 
samples and/or data. In that case, IRB approval must be sought prior to any sharing 
of samples and/or data.  Any clinical information shared about the sample would 
similarly require prior IRB approval.  
o At the completion of the protocol (termination), samples and data will either be 
destroyed, or after IRB approval, transferred to another existing protocol.  
 
• 
Reporting the Loss or Destruction of Samples/Specimens/Data to the IRB: 
Any loss or unanticipated destruction of samples (for example, due to freezer 
malfunction) or data (for example, misplacing a printout of data with identifiers) 
that meets the definition of a Protocol Deviation, Unanticipated Problem, and/or 
compromises the scientific integrity of the data collected for the study, will be 
reported to the NIAID IRB. 


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•    Additionally, subjects may decide at any point not to have their samples stored.    
In this case, the principal investigator will destroy all known remaining samples 
and report what was done to both the subject and to the IRB.  This decision will not 
affect the subject’s participation in this protocol or any other protocols at NIH. (If 
applicable). 
10 REMUNERATION PLAN FOR SUBJECTS 
 
Eligible subjects will be compensated for travel according to the NIAID/NIH travel policy. 
Compensation for time inconvenience will be provided for participants who attempt or 
complete leukapheresis procedures ($150); carotid MRI ($150); dietary questionnaire 
($70), rectal swab ($30); phlebotomy $40 and clinic visit $20 . If a subject does not qualify 
for leukapheresis, an additional research blood draw of 30 mL will be added (see Appendix 
C), and in that case, compensation for time and inconvenience will be provided for this 
procedure ($40). If a subject completes all study visits, the subject  will receive a study 
completion compensation of $200 at the end of the study for their time and inconvenience.   
 
 
11 ASSESSMENT OF SAFETY 
11.1 
Toxicity Scale 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
Toxicity (Version 1.0 - December 2004 (Clarification dated August 2009)) will be used 
to grade each AE: 
 
http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx 
All AEs will be recorded regardless of grade. Only grade 2 and above AEs will be 
reported. 
 
11.2 
Specification of Safety Parameters 
Atorvastatin: 
The following most common adverse reactions have been reported with ATV use, 
according to the package insert: 
• Nasopharyngitis (8.3%) 
• Arthralgia (6.9%) 
• Diarrhea (6.8%) 
• Pain in extremity (6.0%) 
• Urinary tract infection (5.7%) 
 
These events, should they occur, would constitute expected adverse events.  
 
 


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Aspirin 
Abormalities in the following laboratory tests have been associated with ASA use: 
• “Elevated hepatic enzymes, blood nitrogen, urea nitrogen, serum creatinine, 
hyperkalemia, proteinuria, and prolonged bleeding time.” 
The following adverse reactions have been noted to occur with ASA use (note that these 
adverse reactions are usually dose related and more frequently occur at higher doses 
compared to the 81 mg dose used in this study): 
• “Body as a Whole: Fever, hypothermia, thirst. 
• Cardiovascular: Dysrhythmias, hypotension, tachycardia. 
• Central Nervous System: Agitation, cerebral edema, coma, confusion, dizziness, 
headache, subdural or intracranial hemorrhage, lethargy, seizures. 
• Fluid and Electrolyte: Dehydration, hyperkalemia, metabolic acidosis, repiratory 
alkalosis. 
• Gastrointestinal: Dyspepsia, GI bleeding, ulceration and perforation, nausea, 
vomiting, transient elevations of hepatic enzymes, hepatitis, Reye’s syndrome, 
pancreatitis. 
• Hematologic: Prolongation of the prothrombin time, disseminated intravascular 
coagulation, coagulopathy, thrombocytopenia. 
• Hypersensitivity: Acute anaphylaxis, angioedema, asthma, bronchospasm, 
laryngeal edema, urticarial. 
• Musculoskeletal: Rhabdomyolysis. 
• Metabolism: Hypoglycemia (in children), hyperglycemia. 
• Reproductive: Prolonged pregnancy and labor, stillbirths, lower birth weight 
infants, antepartum and postpartum bleeding. 
• Respiratory: Hyperpnea, pulmonary edema, tachypnea. 
• Special Senses: Hearing loss, tinnitus. Patients with higher frequency hearing loss 
may have difficulty perceiving tinnitus. In these patients, tinnitus cannot be used 
as a clinical indicator of salicylism.  
• Urogential: Interstitial nephritis, papillary necrosis, proteinuria, renal 
insufficiency and failure.” 
These events, should they occur, would constitute expected adverse events.  
 
11.3 
Recording/Documentation 
At each contact with the subject, information regarding adverse events will be elicited by 
appropriate questioning and examinations.  All events, both expected/unexpected and 
related/unrelated  will be recorded on a source document. Source documents will include: 
progress notes, laboratory reports, consult notes, phone call summaries, survey tools and 


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data collection tools. Source documents will be reviewed in a timely manner by the 
research team. All reportable adverse events  that are identified will be recorded in 
CRIMSON. The start date, the stop date, the severity of each reportable event, and the PI’s 
judgment of the AEs relationship and expectedness to the study agent/intervention will also 
be recorded in CRIMSON. 
11.4 
Definitions 
 
 
Adverse Event: Any untoward medical occurrence in a human subject, that includes any 
abnormal sign symptom, or disease, temporally associated with the subject’s participation 
in the research, whether or not considered related to the research. 
 
Serious adverse event: Any AE that 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• results in a congenital anomaly/birth defect; or 
• based upon appropriate medical judgment, may jeopardize the subject’s health and 
may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. (examples of such events include allergic bronchospasm 
requiring intensive treatment in the emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse) 
 
Protocol Deviation: Any change, divergence, or departure from the IRB approved study 
procedures in a research protocol. Protocol deviations are designated as serious or non-
serious and further characterized as 
1. Those that occur because a member of the research team deviates from the protocol. 
2. Those that are identified before they occur, but cannot be prevented. 
3. Those that are discovered after they occur 
 
Serious Protocol Deviation: A deviation that meets the definition of a Serious Adverse 
Event or compromises the safety, welfare or rights of subjects or others. 
 
Non-compliance: The failure to comply with applicable NIH HRPP policies, IRB 
requirements, or regulatory requirements for the protection of human subjects. Non-
compliance is further characterized as 
1. Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH-HRPP 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 


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3. Minor: Non-compliance that, is neither serious nor continuing. 
 
 
Unanticipated Problem: (UP)Any incident, experience, or outcome that meets all three 
of the following criteria would be considered a serious UP: 
 
1. unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure (IB) or other study 
documents; and 
b. the characteristics of the subject population being studied; and 
2. related or possibly related to participation in the research; and 
3. suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized.  
Unanticipated problem that is not an Adverse Event (UPnonAE): An unanticipated 
problem that does not fit the definition of an adverse event, but which may, in the 
opinion of the investigator, involve risk to the subject, affect others in the research 
study, or significantly impact the integrity of research data.  Such events would be 
considered a non-serious UP. For example, we will report occurrences of breaches of 
confidentiality, accidental destruction of study records, or unaccounted-for study drug. 
 
11.5 
Reporting Procedures  
11.5.1 Expedited Reporting to the NIAID IRB 
 
Serious and non-serious Unanticipated Problems, deaths, serious deviations, and serious 
or continuing non-compliance will be reported within 7 calendar days of investigator 
awareness. Serious Adverse Events that are possibly, probably, or definitely related to the 
research will be reported to the NIAID IRB within 7 calendar days of investigator’s 
awareness, regardless of expectedness. 
 
11.5.2 Annual Reporting to the NIAID IRB 
 
The following items will be reported to the NIAID IRB in summary at the time of 
Continuing Review: 
 
- 
Serious and non-serious unanticipated  
- 
Expected SAEs that are possibly, probably, or definitely related to the research 
- 
SAEs that are not related to the research 
- 
All adverse events, except expected AEs and deaths granted a waiver of reporting 
- 
Serious and non-serious protocol deviations 
- 
Serious, continuing, and minor non-compliance 
- 
Any trends or events which in the opinion of the investigator should be reported 
- 
Grade 1 AEs will not be reported. 


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11.6 
Reporting of Pregnancy  
Pregnancy itself is not an AE. Pregnancies and complications of pregnancies will be 
reported as information items and in summary at the time of CR. 
11.7 
Type and Duration of the Follow-up of Subjects after Adverse Events 
• The participant will be withdrawn from the study if the AE occurs before drug 
administration, at the discretion of the principal investigator. 
• The study drug (both ATV and ASA) will be discontinued immediately if the AE 
occurs during the treatment phase at the discretion of the investigator. The participant 
will be followed as necessary throughout the remainder of the study period for safety 
assessments and labs.  
11.8 
Modification of Study Agent(s)/Intervention(s) for a Subject 
If a participant is unable to tolerate ATV or ASA, they  will discontinue study drug and 
will be withdrawn from study. No dose adjustment will occur during the course of this 
study. See 11.7 for AEs. 
11.9 
Pausing Rules for the Protocol  
The study drugs are very commonly used medications with wide experience and ASA is 
also an over the counter medication. The study will be monitored by the study team and if 
an unusual number of SAEs or grade 3 or 4 events occur related to participation in the 
research, the study will be paused in consultation with the IRB until the events are better 
evaluated. 
11.10 Stopping Rules for an Individual Subject/Cohort 
A study subject will be discontinued from further Study Agent(s)/Intervention(s) 
administration for: 
• Any clinical AE, laboratory abnormality, intercurrent illness, other medical condition 
or situation occurs such that continued participation in the study would not be in the 
best interest of the subject. 
• Development of any exclusion criteria may be cause for discontinuation. 
• Grade 3 or 4 adverse reactions to the study drug, including myalgia, abdominal pain, 
and nausea. 
• Grade 3 elevation of hepatic transaminases that is confirmed by repeated testing and is 
considered related to study drug. 
• New pregnancy (see Section 6.9). 
• Development of allergy or hypersensitivity to study drug. 
• Request by participant to withdraw from study. 
• Development of a medical condition that requires administration of the following 
prohibited concomittent medications: 
o Systemic corticosteroids 
o Daily NSAIDs 


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o Immunomodulating medication 
• Subject is judged to be at risk of failing to adhere to the study provisions to such a 
degree that, in the opinion of the investigator, the integrity of the study results might 
become compromised. 
For all subjects withdrawn from study, the PI will evaluate on an individual basis if it is in 
the best interest of the participant to be followed by the protocol team with follow-up visits 
that include safety laboratory tests. 
11.11 Premature Withdrawal of a Subject 
If a subject elects to withdraw, end of study evaluations will be performed at the time of 
their withdrawal. Leukapheresis and MR carotid imaging may be performed if the study 
participation is nearing completion. 
11.12 Replacement of a Subject Who Discontinues Study Treatment 
Subjects who receive less than 6 months of study drug will be replaced. 
12 CLINICAL MONITORING STRUCTURE 
12.1 
Safety Monitoring Plan 
Study staff will review laboratory and study test results as they become available. Review 
of test results and communication of findings will be in accordance with OP8 Clinic 
Operations Standard Operating Procedure for review and assessment of test results. When 
medically indicated, appropriate follow-up testing and treatment will be offered to 
participants utilizing the resources and expertise available at the NIH Clinical Center. 
 
13 STATISTICAL CONSIDERATIONS 
13.1 
Study Hypotheses 
Based on the evidence presented above on the impact of statins and ASA on the biomarkers 
related to inflammation, the coagulation cascade and on cellular markers of activation, we 
hypothesize that both EC and ART <50 will exhibit reductions in biomarkers and cellular 
markers of activation and could be grouped for the purposes of the primary end point 
analysis.  
13.2 
Sample Size Justification   
Those who died in the SMART study had a baseline median sCD14 level of 2.47 µg/mL 
(IQR 2.19 – 2.91), while matched controls had lower levels at 2.23 µg/mL (IQR 2.01 -
2.63).  We powered our study to exhibit a similar effect size. 
  
Assuming a mean of 2.45 µg/mL and a standard deviation of 0.45 µg/mL observed in ART 
treated subjects in the SMART study (personal communication Dr. Sandler) and a 
correlation coefficient of 0.71 (personal communication Dr. Sandler and Dr. Funderburg), 
a trial with a total of 40 patients (per treatment arm) has a power of 95% (with type I error 
of 0.05 based on a one-sample paired difference t test, two-sided) for detecting a 0.20 
difference in sCD14 levels between Month 3 and Month 12 visits. This power reduces to 


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74% when N = 20 and we consider each randomization arm within each group separately 
(a secondary end point). 
13.3 
Safety Analysis  
Descriptive statistics with a summary of AEs will be completed at the end of study. 
13.4 
Planned Interim Analyses  
There will be no interim analysis. 
13.5 
  Efficacy Analysis 
The primary endpoint will be set as a change in sCD14 after 9 months of treatment with 
ASA or ATV, in ECs and in Treated Progressors (ART <50) combined. Assuming 40 
patients enroll in each treatment arm, with a mean sCD14 of 2.45 µg/mL and a standard 
deviation of 0.45 µg/mL, the study has 95% power to detect a reduction of 0.20 in sCD14 
levels (See Section 13.2) after 9 months of treatment. The significance of paired differences 
within each group will be evaluated using two-sided nonparametric (one-sample signed 
rank) test. As discussed above, this power decreases to 74% when treatment arms are 
compared individually within each group (as a secondary endpoint, see below). Adjustment 
for differences in CD4, age and smoking status will be done in any between group (EC vs 
ART<50) comparisons. 
Secondary endpoints, including group comparisons (ASA vs statin and EC vs ART<50) of 
changes in biomarkers and T cell activation, cardiovascular disease prevalence, and 
changes in plasma viremia will be evaluated  using  two-sided nonparametric (Wilcoxon 
rank-sum) tests. Exploratory analyses comparing paired differences of carotid IMT 
thickness at Month 0 and Month 12 within each group will be assessed by two-sided 
nonparametric (one-sample signed rank) tests. Associations between continuous variables 
(MR measurements and biomarks and cellular activation markers ) will be assessed using 
Spearman rank order correlation coefficients. Linear regression models will be used to 
control for factors such as age, smoking, and inflammatory biomarkers.  For all evaluations, 
type I error will be set at 0.05. 
14 ETHICS/PROTECTION OF HUMAN SUBJECTS 
14.1 
Informed Consent Process 
Informed consent is a process where information is presented to enable persons to 
voluntarily decide whether or not to participate as a research subject. It is an on-going 
conversation between the human research subject and the researchers which begins before 
consent is given and continues until the end of the subject's involvement in the research. 
Discussions about the research will provide essential information about the study and 
include: purpose, duration, experimental procedures, alternatives, risks and benefits. 
Subjects will be given the opportunity to ask questions and have them answered.  
The subjects will sign the informed consent document prior to undergoing any research 
procedures. The subjects may withdraw consent at any time throughout the course of the 
trial. A copy of the informed consent document will be given to the subjects for their 
records. The researcher will document the signing of the consent form in the subject’s 
medical record. The rights and welfare of the subjects will be protected by emphasizing to 


EC and Immune Activation, V 15 
SEPTEMBER 21, 2018 
 
Page 40 of 83 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. For Non-English–Speaking Participants the Investigator obtaining 
consent will document the consent process in the participant’s electronic medical record, 
including the name of the interpreter. Further, all instances of use of the CC Short Written 
Consent Form will be reported to the IRB at the time of annual review. If the CC Short 
Written Consent Form is used three times or more for the same language, this will be 
reported to the IRB immediately, and the consent will need to be translated into that 
language. 
14.1.1 Remote Site Consent Process 
Screening may take place at either the NIH Clinical Center or the Hennepin County 
Medical Center (HCMC). For patients recruited from HCMC, the following consent 
process will be followed: 
a) The signed, witnessed, and dated consent must be completed by the Associate 
Investigator at Hennepin County prior to any screening labs.  The original  
document will be maintained at the site and a copy sent to NIH. 
b) The consent will be checked for accuracy. The copy of the signed consent will be 
filed in the medical record. 
c) Participants recruited from HCMC will sign the NIH consent document separately 
upon arrival at the NIH Clinical Center and this signed consent will be filed in the 
medical record as well.  
14.2 
Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state and local law. 
The study monitors and other authorized representatives of the Sponsor may inspect all 
documents and records required to be maintained by the Investigator, including but not 
limited to, medical records. Records will be kept locked and all computer entry and 
networking programs will be done with coded numbers only. Clinical information will not 
be released without written permission of the subject, except as necessary for monitoring 
by IRB, NIAID, or the Office for Human Research Protections (OHRP). 
15  DATA HANDLING AND RECORD KEEPING 
15.1 
Data Capture and Management  
Study data will be maintained in CRIMSON and collected directly from subjects during 
study visits and telephone calls, or will be abstracted from subjects’ medical records. 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary to confirm the data abstracted for this study. Source 
documentation (the point of initial recording of information) should support the data 
collected and must be signed and dated by the person recording and/or reviewing the data.   
Data entry into CRIMSON will be performed by authorized individuals. The Investigator 
is responsible for assuring that the data collected are complete, accurate, and recorded in 
a timely manner.  Corrections to electronic data systems shall be tracked electronically 
(password protected) with time, date, individual making the correction, and what was 
changed. 
 


EC and Immune Activation, V 15 
SEPTEMBER 21, 2018 
 
Page 41 of 83 
15.2 
Record Retention 
The investigator is responsible for retaining all essential documents listed in the ICH Good 
Clinical Practice (GCP) Guideline. Study records will be maintained by the PI for a 
minimum of 3 years and in compliance with institutional, IRB, state, and federal medical 
records retention requirements, whichever is longest. All stored records will be kept 
confidential to the extent required by federal, state, and local law. 
 
Should the investigator wish to assign the study records to another party and/or move them 
to another location, the investigator will provide written notification of such intent to 
Regulatory Compliance and Human Subjects Protection Branch (RCHSPB)/NIAID with 
the name of the person who will accept responsibility for the transferred records and/or 
their new location. Destruction or relocation of research records will not proceed without 
written permission from RCHSPB/NAID. 
 


EC and immune activation V 12 
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Page 42 of 83 
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individual participant data. Lancet 2012,379:2053-2062. 
37. 
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APPENDIX B: SCHEDULE OF PROCEDURES/EVALUATIONS  
  
 
 
 
 
 
 
(After baseline, all visit windows ± 2 weeks) 
Evaluation 
Screening 
(0 days– -2 
months) 
Baseline 
(Month 0) 
Month 3 
Month 6 
Month 9 
Month 12 
Month 15 
Medical/Medication History 
X 
X 
X 
X 
X 
X 
X 
Clinical Assessment 
X 
X 
X 
X 
X 
X 
X 
Physical Exam1 
X 
X 
X 
X 
X 
X 
X 
Carotid MRI2 
 
X 
 
 
 
X 
 
Rectal swab & dietary questionnaire 
 
X 
 
 
 
X (swab only) 
 
Apheresis (2-Pass)3 
 
 
X 
 
 
X 
 
CBC, differential, platelets 
X 
X 
X 
X 
X 
X 
X 
PT/PTT/D-dimer 
X 
X 
X 
X 
X 
X 
X 
Acute Care/Hepatic Panel/Mineral 
Panel/hsCRP/CK/Aldolase 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
Pregnancy Testing 
X 
X 
X 
X 
X 
X 
X 
CD4/HIV-1 RNA 
X 
X 
X 
X 
X 
X 
X 
Hemoglobin A1c 
 
X 
X 
X 
X 
X 
X 
Lipid Panel (fasting) 
X 
X 
X 
X 
X 
X 
X 
Hepatitis Serology 
X 
 
 
 
 
 
 
ELISA/Western Blot 
 X4 
 
 
 
 
 
 
Research Storage (Plasma, PBMC, 
Serum) 
 
X 
X 
X 
X 
X 
X 
Research Flow Cytometry 
 
X 
X 
X 
X 
X 
X 
Atorvastatin or Aspirin Dispensed 
 
 
X 
X 
X 
 
 
Pill Count  
 
 
X 
X 
X 
X 
 
1 Targeted physical exam for acute presentations following screening visit. 
2 Can occur any time on or between the M0 and M3 visits, based on MR availability. 
3 If adequate venous access and Hg>9g/dL and PLT>50,000. If inadequate venous access, 30mL of additional blood will be drawn in lieu of apheresis (3-10mL green tops 
4If not previously performed at NIH


EC and Immune Activation, V.12 
April 27th  2017 
 
Page 51 of 83 
APPENDIX C: BLOOD VOLUMES FOR SPECIMEN COLLECTION 
 
1 Visit 
Tube Type 
Screening  
6Baseline 
 
 
 
 
End of 
Study 
Month (M) of Study 
 
 
M 0 
M 3 
M 6 
M 9 
M 12 
M 15 
Clinical 
 
 
 
 
 
  
 
 
CBC, differential, platelets 
3mL Light lavender top 
3 
3 
3 
3 
3 
3 
3 
PT, aPTT, D-dimer, fibrinogen, 
protein C and S, antithrombin III 
4.5 mL Light blue top 
4.5 
4.5 
4.5 
4.5 
4.5 
4.5 
4.5 
Pregnancy test: urine  
 
 
 
 
 
 
 
 
Acute Care, Hepatic and Mineral 
Panel 
8mL Green top(lithium 
heparin) 
8 
8 
8 
8 
8 
8 
8 
Creatine Kinase, Aldolase, hsCRP 
Same tube 
X 
X 
X 
X 
X 
X 
X 
HBsAg, anti-HBcAb, anti-HBsAb, 
anti-HAV IgG, HCV Ab and HCV 
PCR2 
8mL SST 
8 
 
 
 
 
 
 
ELISA/Western Blot 3 
4mL SST 
4 
 
 
 
 
 
 
Lipid Panel 
4 mL Green top 
(lithium heparin)  
4 
4 
4 
4 
4 
4 
4 
HIV-1 RNA 
6mL Purple top 
6 
6 
6 
6 
6 
6 
6 
Hemoglobin A1c 
3mL Light lavender top 
 
3 
3 
3 
3 
3 
3 
HLA typ3 
10ml Purple top 
 
10 
 
 
 
 
 
Research 
 
 
 
 
 
 
 
 
PBMC Storage4 
6mL Green top 
 
55 
60 
60 
60 
60 
60 
Plasma Storage 
6mL Dark lavender top 
 
12 
12 
12 
12 
12 
12 
Serum Storage  
8mL SST 
 
8 
8 
8 
8 
8 
8 
Single Copy Assay 
(3) 9ml Purple top 
 
27 
27 
 
 
27 
 
Flow Cytometry 
6mL Purple top 
6 
6 
6 
6 
6 
6 
6 
Daily Volume (mL) 
 
43.5 
146.5 
141.5 
114.5 
114.5 
141.5 
114.5 
4Cumulative Volume (mL) 
 
 
190 
331.5 
446 
560.5 
702 
816.5 
1 Visit Windows: All visit windows ± 2 weeks after baseline 
2  HCV Ab will be accepted from an outside lab if performed within 2 months of of Month 0 
3 Only if not previously done at NIH 
4 An additional 30mL(3-10mL green tops) of PBMC storage will be collected if patient is unable to undergo apheresis at the designated study visits . 
5Per NIH MEC Policy M95-9, maximum blood volumes drawn for research purposes for an adult subject (aged 18 years or older) may not exceed: 10.5 mL/kg or 550 mL, 
whichever is smaller, over any eight week period. Exceptions to this policy shall be approved by the IRB. 


EC and Immune Activation, V.12 
April 27th  2017 
 
Page 52 of 83 
6 M 0 evaluations are the baseline for subsequent safety assessments. Visit must occur 0 days – 2 months after screening. 


EC and Immune Activation, V.12 
April  27th  2017 
 
Page 53 of 83 
APPENDIX D: ATORVASTATIN PACKAGE INSERT 
 
 
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
atorvastatin calcium tablets safely and etTecHvely. See full prescribing
information for atorvastatin calcium tablets.
AtorvastaNn Calcium Tablets for oral administration
Initial U.S. Approval: 1996
RECENT MAJOR CHANGES------___~____
Dosage and Administration (2.6) 
11/2012
Warnings and Precautions (5.1) 
11/2012
Drug Interactions (7) 
02/2012
-- --------------------INDICATIONS AND USAGE--------------------
Atorvastatin calcium is an inhibitor of HMG-CoA reductase (statin) indicated
as an adjunct therapy to diet to:
• Reduce the risk of MI, stroke, revascularization procedures, and angina
in patients without CHD, but with multiple risk factors (1.1).
• Reduce the risk of MI and stroke in patients with type 2 diabetes without
CHD, but with multiple risk factors (L 1).
• Reduce the risk of non-fatal MI, fatal and non-fatal sVoke,
revascularization procedures, hospitalization for CHF, and angina in
patients with CHD 
(1.1).
• Reduce elevated total-C, LDL-C, apo B, and TG levels and increase
HDL-C in adult patients with primary hyperlipidemia (heterozygous
familial and nonfamilial) and mixed dyslipidemia (12).
Reduce elevated TG in patients with hypertriglyceridemiaand primary
dysbetalipoproteinemia (1.2).
• 
Reduce total-C and LDL-C in patients with homozygous familial
hypercholesterolemia (HoFH) 
(1.2).
• 
Reduce elevated total-C, LDL-C, and apo B levels in boys and
postmenarchal girls, 10 to ] 
7 years of age, with heterozygous familial
hypercholesterolemiaaher failing an adequate trial of diet therapy (1.2).
Limitations of Use
Atorvastatin calcium tablets have not been studied in Fredrickson Types I and
V dysfipidemias.
____________________DOSAGE AND ADMINISTRATION--------____________
Dose range: 10 to 80 mg once daily (2.1).
Recommended start dose: 10 or 20 mg once daily (2.1).
Patients requiring lazge LDL-C reduction (>45%) may start at 40 mg once
daily (2.1).
Pediatric starting dose: 10 mg once daily; maa~imum recommended dose: 20
mg once daily (2.2).
-----------------DOSAGE FORMS AND STRENGTHS--_________________
10, 20, 40, and 80 mg tablets (3).
----------------------------CONTRAINDICATIONS-----------------------
Active liver disease, which may include unexplained persistent elevations in
hepatic transaminase levels (4.1).
Women who are pregnant or may become pregnant (43).
Nursing mothers (4.4).
Hypersensitivity to any component of this medication (4.2).
-------------------WARNINGS AND PRECAUTIONS---------------------
Skeletal muscle effects {e.g., myopathy and rhabdomyolysis): Risks increase
when higher doses aze used concomitantly with cyclosporine and sVong
CYP3A4 inhibitors (e.g., clazithromycin, itraconazole, HIV protease
inhibitors). Predisposing factors include advanced age (> 65), uncontrolled
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Prevention of Cardiovascular Disease
1.2 Hyperlipidemia
13 Limitations of Use
hypothyroidism, and renal impairment. Rare cases of rhabdomyolysis with
acute renal failure secondary to myoglobinuria have been reported. Advise
patients to promptly report to their physician unexplained and/or persistent
muscle pain, tenderness, or weakness. Atorvastatin therapy should be
discontinued if myopathy is diagnosed or suspected (5.1, 8.5).
Liver enzyme abnormalities: Persistent elevations in hepatic transaminases
can occur. Check liver enzyme tests before initiating therapy and as clinically
indicated thereafter (5.2).
A higher incidence of hemorrhagic stroke was seen in patients without CHD
but with stroke or TIA within the previous 6 months in the atorvasta[in
calcium tablets 80 mg group vs. placebo (5.5).
- ADVERSE REACTIONS-------------------------
The most commonly reported adverse reactions (incidence > 2%) 
in patients
treated with atorvastatin calcium tablets in placebo-controlled Vials regardless
of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and
urinary Vact infection (6.1).
To report SUSPECTED ADVERSE REACTIONS, 
contact Greenstone
LLC at 1-500-438-1985 or FDA at 1-800-FDA-1088 or
www.fdagov/medwatch.
-------------------------DRUG INTERACTTONS--------------------------
Drug Interactions Associated with Increased
Risk of Mvopathv/Rhabdomyolysis (2.6, 5.1, 7, l23)
Interactin A ents
Prescribin Recommendations
Cyclosporine, HIV protease inhibitors
(tipranavir plus ritonavir), hepatitis C
Avoid atorvastatin
rotease inhibitor tela revir
HN protease inhibitor (lopinavir plus
Use with caution and lowest dose
ritonavir)
necess
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir plus
ritonavir, darunavir plus ritonavir,
Do not exceed 20 mg atorvastatin
fosamprenavir, fosamprenavir plus
daily
rito~avir
HIV protease inhibitor (nelfinavir)
Hepatitis C protease inhibitor
Do not exceed 40 mg atorvastatin
(bore revir
daily
• Other Lipid-Lowering Medications: Use with fibrate products or lipid-
modifying doses (>_1 g/day) of niacin increases the risk of adverse
skeletal muscle effecu. Caution should be used when prescribing with
atorvastatin calcium tablets (7).
• Digoxin: Patients should be monitored appropriately (7.8).
• Oral Contraceptives: Values for norethindrone and ethinyl estradiol may
be increased (7.9).
• Rifampin should be simultaneously co-administered with atorvastatin
calcium kablets (7.7).
---------------------USE IN SPECIFIC POPULATIONS---------------------
• Hepatic impairment: Plasma concentrations mazkedly increased in
patients with chronic alcoholic liver disease (123).
See 17 for PA'Y'[F,NT COUNSELING INFORMATION
Revised: X11/2012]
DOSAGE AND ADMINISTRATION
2.1 Hyperlipidemia
2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients
23 Homozygous Familial Hypercholesterolemia
2.4 Concomitant Lipid-Lowering Therapy
2.5 Dosage in Patients With Renal Impairment
2.6 Dosage in Patients Taking Cyclosporine, Gazithromycin, IVaconazole, or Certain Protease Inhibitors


EC and Immune Activation, V 12 
April 27th 2017 
 
Page 54 of 83 
 
 
 
 
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
4. l 
Active Liver Disease which may include Unexplained Persistent Elevations of
Hepatic Transaminase Levels
4.2 Hypersensitivity to any Component of this Medication
4.3 Pregnancy
4.4 Nursing Mothers
5 WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle
5.2 Liver Dysfunction
5.3 Endocrine Function
5.4 CNS Toxicity
5.5 Use in Patients with Recent Stroke or TIA
6 ADVERSE REACTIONS
6.1 Clinical Trial Adverse Experiences
6.2 Postintroduction Reports
6.3 Pediatric Patients (ages 10-17 yeazs)
7 DRUG INTERACTIONS
7.1 Strong Inhibitors of Cytochrome P450 3A4:
Clarithromycin
Combination of Protease Inhibitors
ltraconazole
7.2 Grapefruit Juice
7.3 Cyclosporine
7.4 Gemfibrozil
7.5 Other Fibrates
7.6 Niacin
7.7 Rifampin or other Inducers of Cytochrome P450 3A4
7.8 Digoxin
7.9 Oral Contraceptives
7.10 Warfazin
7.11 Colchicine
S USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
123 Phannacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Cazcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 
Prevention of Cardiovascular Disease
14.2 
Hyperlipidemia and Mixed Dyslipidemia
143 Hypertriglyceridemia
14.4 
Dysbetalipoproteinemia
14.5 
Homozygous Familial Hypercholesterolemia
14.6 
Heterozygous Familial Hypercholesterolemia in Pediatric Patients
15 REFERENCES
16 HOW Sl1PPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 
Muscle Pain
17.2 Liver Enzymes
17.3 Pregnancy
17.4 Breastfeeding
*Sections or subsections omitted from the full prescribing information are not listed.


EC and Immune Activation, V 12 
April 27th 2017 
 
Page 55 of 83 
 
 
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly
increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet
when the response to a diet restricted in saturated fat and cholesterol and other nonphannacologic measures alone has been inadequate.
In patients with CHD or multiple risk factors for CHD, atorvastatin calcium tablets can be started simultaneously with diet.
1.1 Prevention of Cardiovascular Disease
In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age,
smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to:
• Reduce the risk of myocardial infarction
• Reduce the risk of stroke
• Reduce the risk for revascularization procedures and angina
In patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart
disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:
• Reduce the risk of myocardial infarction
• Reduce the risk of stroke
In patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:
• Reduce the risk of non-fatal myocardial infarction
• Reduce the risk of fatal and non-fatal stroke
• Reduce the risk for revascularization procedures
• Reduce the risk of hospitalization for CHF
• Reduce the risk of angina
1.2 Hyperlipidemia
Atorvastatin calcium tablets are indicated:
■ 
As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in patients with
primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and
IIb);
■ 
As an adjunct to diet for the treatment of patients with elevated serum TG levels (Fredrickson Type IV);
■ 
For the treatment of patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to
diet;
■ 
To reduce total-C and LDL-C in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-
lowering treatments (e.g., LDL apheresis) or if such treatments are unavailable;
■ 
As an adjunct to diet to reduce total-C, LDL-C, and apo B levels in boys and postmenarchai girls, 10 to 17 years of age, with
heterozygous familial hypercholesterolemia if after an adequate trial of diet therapy the following findings are present:
a. LDL-C remains >_ 190 Ong/dL or
b. LDL-C remains >_ 160 mg/dL and:
• there is a positive family history of premature cardiovascular disease or
• two or more other CVD risk factors are present in the pediatric patient
1.3 Limitations of Use
Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons
(Fredrickson Types I and V).


EC and Immune Activation, V 12 
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2 DOSAGE AND ADMINISTRATION
2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
The recommended starting dose of atorvastatin calcium. tablets is 10 or 20 mg once daily. Patients who require a large reduction in
LDL-C (more than 45%) may be started at 40 mg once daily. The dosage range of atorvastatin calcium tablets is 10 to 80 mg once
daily. Atorvastatin calcium tablets can be administered as a single dose at any time of the day, with or without food. The starting dose
and maintenance doses of atorvastatin calcium tablets should be individualized according to patient characteristics such as goal of
therapy and response (see current NCEP Guidelines). After initiation and/or upon titration of atorvastatin calcium tablets, lipid levels
should be analyzed within 2 to 4 weeks and dosage adjusted accordingly.
2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10-17 years of age)
The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the maximum recommended dose is 20 mg/day (doses
greater than 20 mg have not been studied in this patient population). Doses should be individualized according to the recommended
goal of therapy [see current NCEP Pediatric Panel Guidelines, Clinical Pharmacology (12), and Indications and Usage (1.2)].
Adjustments should be made at intervals of 4 weeks or more.
2.3 Homozygous Familial Hypercholesterolemia
The dosage of atorvastatin calcium tablets in patients with homozygous FH is 10 to 80 mg daily. Atorvastatin calcium tablets should
be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable.
2.4 Concomitant Lipid-Lowering Therapy
Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and
fibrates should generally be used with caution [see Warnings and Precautions, Skeletal Muscle (S. 1), Drug Interactions (7)].
2.5 Dosage in Patients With Renal Impairment
Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment
in patients with renal dysfunction is not necessary [see Warnings and Precautions, Skeletal Muscle (S. 1), Clinical Pharmacology,
Pharmacokinetics (12.3)].
2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, ltraconazole, or Certain Protease Inhibitors
In patients taking cyclosporine or the HIV protease inhibitors (tipranavir plus ritonavir) or the hepatitis C protease inhibitor
(telaprevir), therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, caution
should be used when prescribing atorvastatin calcium tablets and the lowest dose necessary employed. In patients taking
clarithromycin, itraconazole, or in patients with H1V taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir,
fosamprenavir, or fosamprenavir plus ritonavir, therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate
clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is employed. In patients
taking the H1V protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, therapy with atorvastatin calcium tablets
should be limited to 40 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of
atorvastatin calcium tablets is employed [see Warnings and Precautions, Skeletal Muscle (S. 1), Drug Interactions (7)].
3 DOSAGE FORMS AND STRENGTHS
White, elliptical, film-coated tablets containing 10, 20, 40, and 80 mg atorvastatin calcium.
4 CONTRAINDICATIONS
4.1 Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels
4.2 Hypersensitivity to any component of this medication
4.3 Pregnancy
Women who are pregnant or may become pregnant Atorvastatin calcium tablets may cause fetal hann when administered to a
pregnant woman. Serum cholesterol and triglycerides increase during normal pregnancy, and cholesterol or cholesterol derivatives are
essential for fetal development. Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy
should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. There are no adequate and well-


EC and Immune Activation, V 12 
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controlled studies of atorvastatin calcium tablets use during pregnancy; however in rare reports, congenital anomalies were observed
following intrauterine exposure to statins. In rat and rabbit animal reproduction studies, atorvastatin revealed no evidence of
teratogenicity. ATORVASTATIN CALCIUM TABLETS SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING
AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TQ CONCEIVE AND HAVE BEEN INFORMED OF THE
POTENTIAL HAZARDS. If the patient becomes pregnant while taking this drug, atorvastatin calcium tablets should be discontinued
immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)].
4.4 Nursing mothers
It is not known whether atorvastatin is excreted into human milk; however a small amount of another drug in this class does pass into
breast milk. Because statins have the potential for serious adverse reactions in nursing infants, women who require atorvastatin
calcium tablets treatment should not breastfeed their infants [see Use in Specific Populations (8.3)J.
5 WARNINGS AND PRECAUTIONS
5.1 Skeletal Muscle
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin
calcium tablets and with other drugs in this class. A history of renal impairment may be a risk factor for the development of
rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with
increases in creative phosphokinase (CPK) values > 10 times ULN. The concomitant use of higher doses of atorvastatin with certain
drugs such as cyclosporine and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease inhibitors) increases
the risk of myopathy/rhabdomyolysis.
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin
use. IMNM is characterized by: proximal muscle weakness and elevated serum creative kinase, which persist despite discontinuation
of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with
immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of
CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by
malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin calcium tablets. Atorvastatin therapy should
be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of cyclosporine, fabric acid
derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors,
including saquinavir plus ritonavir, lopinavir plus ritonavir, tipranavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, and
fosamprenavir plus ritonavir, niacin, or azole antifungals. Physicians considering combined therapy with atorvastatin and fabric acid
derivatives, erythromycin, clarithromycin, a combination of saquinavir plus ritonavir, lopinavir plus ritonavir, darunavir plus ritonavir,
fosamprenavir, or fosamprenavir plus ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the
potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness,
particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and
maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs (see Drug
Interactions (7)). Periodic creative phosphokinase (CPK) determinations may be considered in such situations, but there is no
assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 1 [see also Dosage and Administration (2. ~, Drug
Interactions (7), Clinical Pharmacology (12.3)].


EC and Immune Activation, V 12 
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Table 1. Drug Interactions Associated with Increased Risk of
Mvopathv/Rhabdomyolysis
Interacting Agents
Prescribing
Recommendations
Cyclosporine, HIV protease
inhibitors (tipranavir plus ritonavir),
avoid atorvastatin
hepatitis C protease inhibitor
(telaprevir)
HIV protease inhibitor (lopinavir
Use with caution and
plus ritonavir)
lowest dose necess
Clarithromycin, itraconazole,
HIV protease inhibitors (saquinavir
Do not exceed 20 mg
plus ritonavir*, darunavir plus
atorvastatin daily
ritonavir, fosamprenavir,
fosam renavir lus ritonavir)
H1V protease inhibitor (nelfmavir)
Do not exceed 40 mg
Hepatitis C protease inhibitor
atorvastatin daily
(boce revir)
*Use with caution and with the lowest dose necessary (12.3)
Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with colchicine, and caution
should be exercised when prescribing atorvastatin with colchicine [see Drug Interactions (7.11)].
Atorvastatin therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive
of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g.,
severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and
uncontrolled seizures).
5.2 Liver Dysfunction
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent
elevations (>3 times the upper limit of normal ~ULN] occurring on 2 or more occasions) in serum transaminases occurred in
0.7% of patients who received atorvastatin calcium tablets in clinical trials. The incidence of these abnormalities was 0.2%,
0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with
jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned
to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a
reduced dose of atorvastatin calcium tablets.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium tablets and repeated as
clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins,
including atorvastatin.lf serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment
with atorvastatin calcium tablets, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin calcium
tablets.
Atorvastatin calcium tablets should be used with caution in patients who consume substantial quantities of alcohol and/or have a
history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of
atorvastatin calcium tablets [see Contraindications (4.1)].
5.3 Endocrine Function
increases in HbAlc and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin
calcium tablets.
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies
have shown that atorvastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve. T'he effects of statins on
male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in
premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may
decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.


EC and Immune Activation, V 12 
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5.4 CNS Toxicity
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation
were seen in another female dog that was sacrificed in moribund condition after 1 l weeks of escalating doses up to 280 mg/kg/day.
The l20 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0-24
hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each. of 2 male dogs (one treated at 10
mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to
2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 1 l times (mouse) and 8 to 16
times (rat) the human AUC (0-24) based on the maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces,
have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve
degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in adose-dependent fashion at a dose that
produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
5.5 Use in Patients with Recent Stroke or TIA
in a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) 
study where atorvastatin
calcium tablets 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6
months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium tablets 80 mg group compared to placebo (55,
23% atorvastatin vs. 33, 1.4%placebo; HR: 1.68, 95% CI: 1.09, 2.59; p=0.0168). The incidence of fatal hemorrhagic stroke was
similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal
hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some
baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of
hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)].
6 ADVERSE REACTIONS
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy [see Warnings and Precautions (S. 1)]
Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
6.1 Clinical Trial Adverse Experiences
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical studies of a
drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical
practice.
In the atorvastatin calcium tablets placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium tablets vs.
73l 1 placebo; age range 10-93 years, 39%women, 91 %Caucasians, 3%Blacks, 2%Asians, 4% other) with a median treatment
duration of 53 weeks, 9.7% of patients on atorvastatin calcium tablets and 9.5% of the patients on placebo discontinued due to adverse
reactions regardless of causality. The five most common adverse reactions in patients treated with atprvastatin calcium tablets that led
to treahnent discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine
aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).
'The most commonly reported adverse reactions (incidence > 2%and greater than placebo) regardless of causality, in patients treated
with atorvastatin calcium tablets in placebo controlled trials (n=8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea
(6.8%), pain in extremity (6.0%), and urinary tract infection (5.7%).
Table 2 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in > 2% and at a rate greater than
placebo in patients treated with atorvastatin calcium tablets (n=8755), from seventeen placebo-controlled trials.
Table 2. Clinical adverse reactions occurring in > 2% 
in patients treated with any dose of
atorvastatin calcium tablets and at an incidence greater than placebo regardless of
causality (% 
of patients).
Adverse Reaction.* 
Any dose 
10 mg 
20 mg 
40 mg 
80 mg 
Placebo
N=8755 
N=3908 
N=188 
N=604 
N=4055 
N=7311
Nasopharyngitis 
8.3 
12.9 
5.3 
7.0 
4.2 
8.2
Arthralgia 
6.9 
8.9 
11.7 
10.6 
43 
6.5


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Diarrhea
6.8
7.3
6.4
14.1
5.2
6.3
Pain in extremity
6.0
8.5
3.7
9.3
3.1
5.9
Urinary tract
5 ~
6.9
6.4
8.0
4.l
5.6
infection
Dyspepsia
4.7
5.9
3.2
6.0
33
43
Nausea
4.0
3.7
3.7
7.1
3.8
3.5
Musculoskeletal
3.8
5.2
3.2
5.1
2 3
3.6
pain
Muscle Spasms
3.6
4.6
4.8
5.1
2.4
3.0
Myalgia
3.5
3.6
5.9
8.4
2.7
3.1
Insomnia
3.0
2.8
1.1
5.3
2.8
2.9
Pharyngolaryngeal
2 3
3.9
1.6
2.8
0.7
2.1
ain
* Adverse Reaction > 2° /a in any dose greater than placebo
Other adverse reactions reported in placebo-controlled studies include:
Body as a whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, hepatitis, cholestasis;
Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck pain, joint swelling; Metabolic and nutritional system:
transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creative phosphokinase increase,
hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin and appendages: urticaria; Special senses: vision
blurred, tinnitus; Urogenital system: white blood cells urine positive.
Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)
In ASCOT [see Clinical Studies (14.1)] involving 10,305 participants (age range 40-80 years, 19%women; 94.6% Caucasians, 2.6%
Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin calcium tablets 10 mg daily (n=5,168) or placebo (n=5,137),
the safety and tolerability profile of the group treated with atorvastatin calcium tablets was comparable to that of the group treated
with placebo during a median of 33 years of follow-up.
Collaborative Atorvastatin Diabetes Study (CARDS)
In CARDS [see Clinical Studies (14.1)] involving 2,838 subjects (age range 39-77 years, 32%women; 94.3% Caucasians, 2.4%
South Asians, 2.3%Afro-Caribbean, 1.0% other) with type 2 diabetes treated with atorvastatin calcium tablets 10 mg daily (n=1,428)
or placebo (n=1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the
treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.
Treating to New Targets Study (TNT)
In TTiT [see Clinical Studies (14.1)] involving 10,001. subjects (age range 29-78 years, 19% women; 94.1 %Caucasians, 2.9%Blacks,
1.0% Asians, 2.0%other) with clinically evident CHD treated with atorvastatin calcium tablets 10 mg daily (n=5006) or atorvastatin
calcium tablets 80 mg daily (n=495), there were more serious adverse reactions and discontinuations due to adverse reactions in the
high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%,
respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (>_3 x LTLN twice within 4-10 days) occurred
in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (> 10 x
ULN) were low overall, but were higher in the high-dose atorvastatin treatment goup (13, 0.3%) compared to the low-dose
atorvastatin group (6, 0.1%).
Incremental Decrease in Endpoints through Aggressive Lipid Lowerdng Study (IDF.~1L)
In IDEAL [see Clinical Studies (14.1)] involving 8,888 subjects (age range 26-80 years, 19%women; 993% Caucasians, 0.4%
Asians, 0.3%Blacks, 0.04% other) treated with atorvastatin calcium tablets 80 mg/day (n=4439) or sicnvastatin 20-40 mg daily
(n=4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment
groups during a median follow-up of 4.8 years.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
In SPARCL involving 4731 subjects (age range 21-92 years, 40%women; 93.3% Caucasians, 3.0° /a Blacks, 0.6% Asians, 3.1%other)
without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with
atorvastatin calcium tablets 80 mg (n=2365) or placebo (n=2366) for a median follow-up of 49 years, there was a higher incidence of
persistent hepatic transaminase elevations (>_ 3 x ULN twice within 4-10 days) in the atorvastatin group (0.9%) compared to placebo
(0.1 %). Elevations of CK (>10 x ULN) 
were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0.0%).
Diabetes was reported as an adverse reaction in 144 subjects (~.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo
group [see Warnings and Precautions (S.5)].
In a post-hoc analysis, atorvastatin calcium tablets 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366,
11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, l .4%) compared to placebo. The incidence of


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fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium tablets vs. 18 placebo). The incidence of non-fatal
hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo
group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk
for hemorrhagic stroke [7 (16%) atorvastatin calcium tablets vs. 2 (4%) placebo].
There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin calcium
tablets 80 mg/day group vs. 211 (8.9%) in the placebo group. The proporkions of subjects who experienced cardiovascular death were
numerically smaller in the atorvastatin calcium tablets 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of
subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin calcium tablets 80 mg group (5.0%)
than in the placebo group (4.0%).
6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of atorvastatin calcium tablets. Because these reactions
are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a
causal relationship to drug exposure.
Adverse reactions associated with atorvastatin therapy reported since market introduction, that are not listed above, regardless of
causality assessment, include the following: anaphylaxis, angioneurotic edema, bullous rashes (including erythema multiforme,
Stevens-Johnson syndrome, and toxic epidermal necrolysis), rhabdomyolysis, fatigue, tendon rupture, fatal and non-fatal hepatic
failure, dizziness, depression, peripheral neuropathy, and pancreatitis.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions
(S.1)].
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment,
confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious,
and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of
3 weeks).
6.3 Pediatric Patients (ages 10-17 years)
Ina 26-week controlled study in boys and postmenarchal girls (n=140, 31%female; 92% Caucasians, 1.6%Blacks, 1.6%Asians,
4.8%other), the safety and tolerability profile of atorvastatin calcium tablets 10 to 20 mg daily was generally similar to that of placebo
[see Clinical Studies (14.6) and Use in Special Populations, Pediatric Use (8.4)].
7 DRUG INTERACTIONS
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-
modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and
itraconazole) [see Warnings and Precautions, Skeletal Muscle (5.1) and Clinical Pharmacology (12.3)].
7.1 Strong Inhibitors of CYP 3A4: Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant administration of
atorvastatin calcium tablets with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The
extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
Clarithromycin: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium tablets
80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium tablets. alone [see Clinical
Pharmacology (12.3)]. Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin dose exceeds 20
mg [see Warnings and Precautions, Skeletal Muscle (S. 1) and Dosage and Administration (2.6)j.
Combination of Protease Inhibitors: Atorvastatin AUC was significantly increased with concomitant administration of
atorvastatin calcium tablets with several combinations of HIV protease inhibitors, as well as with the hepatitis C protease inhibitor
telaprevir, compared to that of atorvastatin calcium tablets alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking
the HIV protease inhibitor tipranavir plus ritonavir, or the hepatitis C protease inhibitor telaprevir, concomitant use of atorvastatin
calcium tablets should be avoided. Inpatients taking the HIV protease inhibitor lopinavir plus ritonavir, caution should be used
when prescribing atorvastatin calcium tablets and the lowest dose necessary should be used. In patients taking the HIV protease
inhibitors saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, the dose of
atorvastatin calcium tablets should not exceed 20 mg and should be used with caution [see Warnings and Precautions, Skeletal
Muscle (5.1) and Dosage and Administration (2.6)]. Inpatients taking the HIV protease inhibitor nelfinavir or the hepatitis C
protease inhibitor boceprevir, the dose of atorvastatin calcium tablets should not exceed 40 mg and close clinical monitoring is
recommended.


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ltraconazole: Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium tablets 40
mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)]. Therefore, in patients taking itraconazole, caution should be
used when the atorvastatin dose exceeds 20 mg [see Warnings and Precautions, Skeletal Muscle (S. 1) and Dosage and
Administration (2.6)].
7.2 Grapefruit Juice: Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of
atorvastatin, especially with excessive grapefruit juice consumption (>1.21iters per day).
7.3 Cyclosporine: Atorvastatin and atorvastatin-metabolites are substrates of the OATPIBI transporter. Inhibitors of the OATPIBI
(e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant
administration of atorvastatin calcium tablets 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin calcium tablets
alone [see Clinical Pharmacology (12.3)]. The co-administration of atorvastatin calcium tablets with cyclosporine should be avoided
[see Warnings and Precautions, Skeletal Muscle (S.1)].
7.4 Gemfibrozil: Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered
with gemfibrozil, concomitant administration of atorvastatin calcium tablets with gemfibrozil should be avoided [see Warnings and
Precautions (5.1)].
7.5 Other Fibrates: Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is
increased with concurrent administration of other fibrates, atorvastatin calcium tablets should be administered with caution when used
concomitantly with other fibrates [see Warnings and Precautions (5.1)].
7.6 Niacin: The risk of skeletal muscle effects may be enhanced when atorvastatin calcium tablets are used in combination with
niacin; a reduction in atorvastatin calciwn tablets dosage should be considered in this setting [see Warnings and Precautions (S.1)].
7.7 Rifampin or other Inducers of Cytochrome P450 3A4: Concomitant administration of atorvastatin calcium tablets with
inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin.
Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin calcium tablets with rifampin is
recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant
reduction in atorvastatin plasma concentrations.
7.8 Digoxin: When multiple doses of atorvastatin calcium tablets and digoxin were coadministered, steady state plasma digoxin
concentrations increased by approximately 20%. Patients taking digoxin should be monitored appropriately.
7.9 Oral Contraceptives: Co-administration of atorvastatin calcium tablets and an oral contraceptive increased AUC values for
norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)]. These increases should be considered when selecting an oral.
contraceptive for a woman taking atorvastatin.
7.10 Warfarin: Atorvastatin calcium tablets had no clinically significant effect on prothrombin time when administered to patients
receiving chronic warfarin treatment.
7.11 Colchicine: Cases of myopathy, including rhabdomyolysis, have been reported with atorvastatin co-administered with
colchicine, and caution should be exercised when prescribing atorvastatin with colchicine.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category X
Atorvastatin calcium tablets are contraindicated in women who are or may become pregnant. Serum cholesterol and triglycerides
increase during normal pregnancy. Lipid lowering drugs offer no benefit during pregnancy because cholesterol and cholesterol
derivatives are needed for normal fetal development. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering drugs
during pregnancy should have little impact on long-term outcomes of primary hypercholesterolemia therapy.
There are no adequate and well-controlled studies of atorvastatin use during pregnancy. There have been rare reports of congenital.
anomalies following intrauterine exposure to statins. In a review of about 100 prospectively followed pregnancies in women exposed
to other statins, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed the rate
expected in the general population. However, this study was only able to exclude athree-to-four-fold increased risk of congenital
anomalies over background incidence. In 89% of these cases, drug treatment started before pregnancy and stopped during the first
trimester when pregnancy was identified.


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Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was not
teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about
30 times (rat) or 20 times (rabbit) the human exposure based on surface area (mg/mz) 
[see Contraindications, Pregnancy (4.3)J.
In a study in rats given 20, 100, or 225 mg/kg/day, from gestation day 7 through to lactation day 21 (weaning), there was decreased
pup survival at birth, neonate, weaning, and maturity in pups of mothers dosed with 225 mg/kg/day. Body weight was decreased on
days 4 and 21 in pups of mothers dosed at 100 mg/kg/day; pub body weight was decreased at birth and at days 4, 21, and 9l at 225
mg/kg/day. Pup development was delayed (rotorod performance at 100 mg/kg/day and acoustic startle at 225 mg/kg/day; pinnae
detachment and eye-opening at 225 mg/kg/day). These doses correspond to 6 times (100 mg/kg) and 22 times (225 mg/kg) the human
AUC at 80 mg/day.
Statins may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium tablets should be administered to women
of childbearing potential only when such patients are highly unlikely to conceive and have been informed of the potential hazards. If
the woman becomes pregnant while taking atorvastatin, it should be discontinued immediately and the patient advised again as to the
potential hazards to the fetus and the lack of known clinical benefit with continued use during pregnancy.
8.3 Nursing Mothers
It is not known whether atorvastatin is excreted in human milk, but a small amount of another drug in this class does pass into breast
milk. Nursing rat pups had plasma and liver drug levels of 50% and 40%, respectively, of that in their mother's milk. Animal breast
milk drug levels may not accurately reflect human breast milk levels. Because another drug in this class passes into human milk and
because statins have a potential to cause serious adverse reactions in nursing infants, women requiring atorvastatin treatment should be
advised not to nurse their infants [see Contraindications (4)].
8.4 Pediatric Use
Safety and effectiveness in patients 10-17 years of age with heterorygous familial hypercholesterolemia have been evaluated in a
controlled clinical trial of 6 months' duration in adolescent boys and postmenarchal girls. Patients treated with atorvastatin calcium
tablets had an adverse experience profile generally similar to that of patients treated with placebo. T'he most common adverse
experiences observed in both groups, regardless of causality assessment, were infections. Doses greater than 20 mg have not been
studied in this patient population. In this limited controlled study, there was no significant effect on growth or sexual maturation in
boys or on menstrual cycle length in girls [see Clinical Studies (14.6); Adverse Reactions, Pediatric Patients (ages 10-17 years) (6.3);
and Dosage and Administration, Heterorygous Familial Hypercholesterolemia in Pediatric Patients (JO-17 years of age) (2.2)].
Adolescent females should be counseled on appropriate contraceptive methods while on atorvastatin therapy [see Contraindications,
Pregnancy (4.3) and Use in Specific Populations, Pregnancy (8.1)]. Atorvastatin calcium tablets have not been studied in
controlled clinical trials involving pre-pubertal patients or patients younger than 10 years of age.
Clinical. efficacy with doses up to 80 mg/day for ]year have been evaluated in an uncontrolled study of patients with homozygous FH
including 8 pediatric patients [see Clinical Studies, Homorygous Familial Hypercholesterolemia (14.5)].
8.5 Geriatric Use
Of the 39,828 patients who received atorvastatin calcium tablets in clinical studies, 15,813 (40%) were _>65 years old and 2,800 (7%)
were >_75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and
other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater
sensitivity of some older adults cannot be ruled out. Since advanced age (>_65 years) is a predisposing factor for myopathy,
atorvastatin should be prescribed with caution in the elderly.
8.6 Hepatic Impairment
Atorvastatin calcium tablets are contraindicated in patients with active liver disease which may include unexplained persistent
elevations in hepatic transaminase levels [see Contraindications (4) and Pharmacokinetics (12.3)].
10 OVERDOSAGE
There is no specific treatment for atorvastatin overdosage. In the event of an overdose, the patient should be treated symptomatically,
and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to
significantly enhance atorvastatin clearance.
11 DESCRIPTION


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Atorvastatin calcium is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A
(HMG-CoA) 
reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in
cholesterol biosynthesis.
Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-f3, S-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-
pyrrole-l-heptanoic acid, calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is (C33H3a FNz05)zCa•3H2O and
its molecular weight is 1209.42. Its structural formula is:
/ ~ N
~~ 
H3
CH
~H 
~k
O
CHx,~C~~CH
~GFFz 
C#i
~CH? 
C`O~
~~82~
• 
3F{z0
2
Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in aqueous solutions of pH 4 and below. Atorvastatin
calcium is very slightly soluble in distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and freely
soluble in methanol.
Atorvastatin calcium tablets for oral administration contain 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients:
calcium carbonate, USP; candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, NF; lactose monohydrate, NF;
magnesium stearate, NF; microcrystalline cellulose, NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium
dioxide); polysorbate 80, NF; simethicone emulsion.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-
methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. Cholesterol and triglycerides circulate in the
bloodstream as part of lipoprotein complexes. With ultracentrifugation, these complexes separate into HDL 
(high-density lipoprotein),
IDL (intermediate-density lipoprotein), LDL (low-density lipoprotein), and VLDL (very-low-density lipoprotein) fractions.
Triglycerides (TG) and cholesterol in the liver are incorporated into VLDL and released into the plasma for delivery to peripheral
tissues. LDL is formed from VLDL and is catabolized primarily through the high-affinity LDL receptor. Clinical and pathologic
studies show that elevated plasma levels of total cholesterol (total-C), LDL-cholesterol (LDL-C), and apolipoprotein B 
(apo B)
promote human atherosclerosis and are risk factors for developing cardiovascular disease, while increased levels of HDL-C are
associated with a decreased cardiovascular risk.
In animal models, atorvastatin lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol
.synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of
LDL; atorvastatin also reduces LDL production and the number of LDL particles. Atorvastatin reduces LDL-C in some patients with
homozygous familial hypercholesterolemia (FH), a population that rarely responds to other lipid-lowering medication(s).
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B (a membrane complex for LDL-C)
promote human atherosclerosis. Similarly, decreased levels of HDL-C (and its transport complex, apo A) 
are associated with the
development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary
directly with the level of total-C and LDL-C, and inversely with the level of HDL-C.
Atorvastatin reduces total-C, LDL-C, and apo B in patients with homozygous and heterozygous FH, nonfamilial forms of
hypercholesterolemia, and mixed dyslipidemia. Atarvastatin also reduces VLDL-C and TG and produces variable increases in HDL-C
and apolipoprotein A-1. Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, TG, and non-HDL-C, and increases HDL-C in
patients with isolated hypeririglyceridemia. Atorvastatin reduces intermediate density lipoprotein cholesterol (IDL-C) in patients with
dysbetalipoproteinem ia.
Like LDL, cholesterol-enriched triglyceride-rich lipoproteins, including VLDL, intermediate density lipoprotein (IDL), and remnants,
can also promote atherosclerosis. Elevated plasma triglycerides are frequently found in a triad with low HDL-C levels and small LDL
particles, as well as in association with non-lipid metabolic risk factors for coronary heart disease. As such, total plasma TG has not


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consistently been shown to be an independent risk factor for CHD. Furthermore, the independent effect of raising HDL or lowering
TG on the risk of caronary and cardiovascular morbidity and mortality has not been determined.
12.2 Pharmacodynamics
Atorvastatin calcium, as well as some of its metabolites, is pharmacologically active in humans. The liver is the primary site of action
and the principal site of cholesterol synthesis and LDL clearance. Drug dosage, rather than systemic drug concentration, correlates
better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response [see Dosage and
Administration (2)].
12.3 Pharmacokinetics
Absorption: Atorvastatin calcium tablets are rapidly absorbed after oral administration; maximum. plasma concentrations occur within
1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin
(parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%.
The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism.
Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, 
respectively, as assessed by Cmax and
AUC, LDL-C reduction is similar whether atorvastatin calcium tablets are given with or without food. Plasma atorvastatin
concentrations are lower (approximately 30% for Cmax and AUC) 
following evening drug administration compared with morning.
However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].
Distribution: Mean volume of distribution of atorvastatin is approximately 381 liters. Atorvastatin is >98%bound to plasma proteins.
A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats,
atorvastatin is likely to be secreted in human milk [see Contraindications, Nursing Mothers (4.4) and Use in Specific Populations,
Nursing Mothers (8.3)].
Metabolism: Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products.
In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metaboBtes is equivalent to that of atorvastatin.
Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies
suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of
atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions
(7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism;
however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans
is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution. of
active metabolites. Less than 2% of a dose of atorvastatin calcium tablets is recovered in urine following oral administration.
Specific Populations
Geriatric: Plasma concentrations of atorvastatin are higher (approximately 40% for Cm~ and 30% for AUC) 
in healthy elderly
subjects (age >65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the
elderly patient population compared to younger adults [see Use in Speciftc Populations, Geriatric Use (8. S)].
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: Plasma concentrations of atorvastatin in women differ from those in men (approximately 20%higher for Cmax and 10%
lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin; thus, dose
adjusrinent in patients with renal dysfunction is not necessary [see Dosage and Administration, Dosage in Patients with Renal
Impairment (2.5), Warnings and Precautions, Skeletal Muscle (S.1)].
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to
significantly enhance clearance of atorvastatin since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin are markedly increased.
Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-
foldincreased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4.1)].
TABLE 3. Effect of Co-administered Drugs on the Pharmacokinetics of Atorvastatin


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Co-administered drug and
dosin re imen
Atorvastatin
Dose (mg)
Chan~e in
AUC
Change in
Cmax&
Cyclosporine 5.2 mg/kg/day, stable dose
10 mg QD for 28 days
T 8.7 fold
1' ] 
0.7 fold
Tipranavir 500 mg BID/ritonavir 200
m BID, 7 da s
10 mg, SD
T 9.4 fold
T 8.6 fold
Telaprevir 750 mg q8h, 10 days
20 mg, SD
T 7.88 fold
T 10.6 fold
• •Saquinavir 400 mg BID/ ritonavir
400 m B1D, 15 da s
40 mg QD for 4 days
T 3.9 fold
1' 4.3 fold
Clarithromycin 500 mg BID, 9 days
80 mg QD for 8 days
T 4.4 fold
T 5.4 fold
Darunavir 300 mg BID/ritonavir 100 mg
BID, 9 da s
10 mg QD for 4 days
T 3.4 fold
T 2.25 fold
Itraconazole 200 mg QD, 4 days
40 mg SD
T 3.3 fold
T 20%
Fosamprenavir 700 mg BID/ritonavir
100 m BID, 14 da s
10 mg QD for 4 days
T 2.53 fold
T 2.84 fold
Fosamprenavir ].400 mg BID, 14 days
10 mg QD for 4 days
T 23 fold
T 4.04 fold
Nelfinavir 1250 mg BID, 14 days
10 mg QD for 28 days
T 74%
T 2.2 fold
Grapefruit Juice, 240 mL QD *
40 mg, SD
T 37%
T 16%
Diltiazem 240 mg QD, 28 days
40 mg, SD
T 51%
No change
Erythromycin 500 mg Q1D, 7 days
10 mg, SD
T 33%
T 38%
Amlodipine 10 mg, single dose
80 mg, SD
T 15%
~. 12
Cimetidine 300 mg QD, 4 weeks
10 mg QD for 2 weeks
~. Less than 1%
J. 11%
Colestipol 10 mg BID, 28 weeks
40 mg QD for 28 weeks
Not determined
.~ 26%*
Maalox TC~ 30 mL QD, 17 days
10 mg QD for 15 days
~ 33%
.~ 34%
Efavirenz 600 mg QD, 14 days
10 mg for 3 days
~ 4l%
~ 1
Rifampin 600 mg QD, 7 days (co-
administered t
40 mg SD
T 30%
T 2.7 fold
Rifampin 600 mg QD, 5 days (doses
se crated) t
40 mg SD
~. 80%
.L 40%
Gemfibrozi1600mg BID, 7 days
40mg SD
T 35%
~ Less
than 1
Fenofibrate 160m 
D, 7 da s
40m SD
3%
2%
Boce revir 800 m T1D, 7 da s
40 m SD
T2.30 fold
T2.66 fold
& Data given as x-fold change represent a simple ratio between co-administration and atorvastatin alone (i.e., 1-fold = no
change). Data given as %change represent %difference relative to atorvastatin alone (i.e., 0% = no change).
" See Sections 5.1 and 7 for clinical significance.
* Greater increases in AUC 
(up to 2.5 fold) and/or Cma~c (up to 71%) have been reported with excessive grapefruit
consumption (>_ 750 mL - 1.2 liters per day).
** Single sample taken 8-16 h post dose.
t Due to the dual interactiop mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is
recommended, as delayed administration of atorvastatin after administration of rifampin has been associated. with a
significant reduction in atorvastatin plasma concentrations.
~ T'he dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when
used clinically is likely tq be higher than what was observed in this study. Therefore, caution should be applied and the
lowest dose necessary should be used.
TABLE 4. Effect of Atorvastatin on the Pharmacokinetics of Co-administered Arugs
Atorvastatin
Co-administered dru and dosin re imen
Dru /Dose m
Chan e in AUC
Chan e in Cmax
80 mg QD for 15 days
Antipyrine, 600 mg SD
T 3%
,~ 11%
80 mg QD for 14 days
Digoxin 0.25 mg QD, 20 days
T 15%
T 20
40 mg QD for 22 days
Oral contraceptive QD, 2 months
- norethindrone lmg
T 28%
T 23%


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- ethin 1 estradio135
T 19%
T 30%
10 mg, SD
Tipranavir 500 mg BID/ritonavir
No change
No change
200 m BID, 7 da s
10 mg QD for 4 days
'
aassmprenavir 1400 mg BID 14
°
~ 27 ~o
~ 18%
Fosamprenavir 700 mg
10 mg QD for 4 days
BID/ritonavir 100 mg BID, 14
No change
No change
da s
# See Section 7 for clinical significance.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Ina 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose
females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0-24)
value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.
A 2-year carcinogenicity study in mice given 100, 200, or 400 mg/kg/day resulted in a significant increase in liver adenomas in high-
dose males and liver carcinomas in high-dose females. These findings occurred at plasma AUC (0-24) values of approximately 6
times the mean human plasma drug exposure after an 80 mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with
Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the
chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.
Studies in rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia
and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at
the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male
rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased
abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given
doses of 10, 40, or 120 mg/kg for two years.
14 CLINICAL STUDIES
14.1 Prevention of Cardiovascular Disease
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin on fatal and non-fatal. coronary heart disease
was assessed in 10,305 hypertensive patients 40-80 years of age (mean of 63 years), without a previous myocardial infarction and
with TC levels <251 mg/dL (6.5 mmol/L). Additionally, all patients had ~t least 3 of the following cardiovascular risk factors: male
gender (81.1%), age >55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in afirst-degree relative (26%), TC:HDL
>6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific
ECG abnormality (143%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with
anti-hypertensive therapy (Goal BP <140/90 mm Hg for non-diabetic patients; <130/80 mm Hg for diabetic patients) and allocated to
either atorvastatin calcium tablets 10 mg daily (n=5168) or placebo (n=5137), using a covariate adaptive method which took into
account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those
characteristics across the groups. Patients were followed for a median duration of 3.3 years.
The effect of 10 mg/day of atorvastatin calcium tablets on lipid levels was similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of coronary events [either fata.} coronary heart disease (46 events in the placebo group vs.
40 events in the atorvastatin calcium tablets group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin
calcium tablets goup)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium tablets vs. 3.0%
for placebo), p=0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of
renal dysfunction. The effect of atorvastatin was seen regardless of baseline LDL levels. Due to the small number of events, results for
women. were inconclusive.


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Figure 1: Effect of Atorvastatin 10 mg/day on Cumulative Incidence of Non-Fatal Myocardial Infarction or Coronary Heart
Disease Death (in ASCOT-LLA)
4.(~
.~
_.
3.D 
.— 
~fi~t~ ~~~rti 
- ~;
_.
,r
~,e
,f
-a 
_,.=
~,,~
,.
,_1
,.
1,0 
.~+1~1
~r
~+
O.D 
HR=0.84 (D,5#~D.$3) p=~.~(!3
~.~ 
Q.5 
1.Q 
1.~ 
2.Q 
~.5 
~.0 
~.5 Yeaes
Atorvastatin also significantly decreased the relative risk for revascularization procedures by 42%. Although the reduction of fatal and
non-fatal strokes did not reach apre-defined significance level (p=0.01), a favorable trend was observed with a 26%relative risk
reduction (incidences of 1.7% for atorvastatin calcium tablets and 2.3%for placebo). There was no significant difference between the
treatment groups for death due to cardiovascular causes (p=0.51) or noncardiovascular causes (p=0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin on cardiovascular disease (CVD) 
endpoints was
assessed in 2838 subjects (94% white, 68%male), ages 40-75 with type 2 diabetes based on WHO 
criteria, without prior history of
cardiovascular disease and with LDL < 160 mg/dL and TG <_ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the
following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbutninuria (9%) or
macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind
clinical trial, subjects were randomly allocated to either atorvastatin calcium tablets l0 mg daily (1429) or placebo (1411) in a 1:1
ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major
cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary
analysis was the time to first occurrence of the primary endpoint.
Baseline characteristics of subjects were: mean age of 62 years, mean HbA,~ 7.7%; median LDL-C 120 mg/dL; median TC
207 mg/dL; median TG 151 mg/dL; median HDL-C 52 mg/dL.
The effect of atorvastatin 10 mg/day on lipid levels was similar to that seen in previous clinical trials.
Atorvastatin significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin
calcium tablets group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83)
(p=0.001) (see Figure 2). An effect of atorvastatin calcium tablets was seen regardless of age, sex, or baseline lipid levels.
Atorvastatin significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium tablets group vs. 39 events in the
placebo group), HR 0.52, 95% CI (0.31, 0.89) (p=0.016) and reduced the risk of Mi by 42% (38 events in the atorvastatin calcium.
tablets group vs. 64 events in the placebo group), HR 0.58, 95.1 % 
CI (0.39, 0.86) (p=0.007). There was no significant difference
between the treatment groups for angina, revascularization procedures, and acute CHD death.
There were 6] deaths in the atorvastatin calcium tablets group vs. 82 deaths in the placebo group (HR 0.73, p=0.059).


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Figure 2: Effect of Atorvastatin 10 mg/day on Time to Occurrence of Major Cardiovascular Event (myocardial infarction,
acute CHD death, unstable angina, coronary revascularization, or stroke) in CARDS
,5
Placebo
Atorvastatin
a
v
m 10
NN
N
.~
7
~ 5
U
~ ;J~ 
HR 0.63 (0.4&0.83) p=0.001
1 
2 
3 
4 
5
Time to First Primary Endpoint Through Four (4) Years of Follow-up (Years)
In the Treating to New Targets Study (TTTT), the effect of atorvastatin calcium tablets 80 mg/day vs. atorvastatin calcium tablets
10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81 % 
male, 38% >65 years) with
clinically evident coronary heart disease who had achieved a target LDL-C level <130 mg/dL after completing an 8-week, open-label,
run-in period with atorvastatin calcium tablets l0 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of
atorvastatin calcium tablets and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of
any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial. infarction, resuscitated cardiac
arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145,
1.28, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium tablets and 99, 177, 152, 129, and 48 mg/dL during
treatment with 10 mg of atorvastatin calcium tablets.
Treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate of MCVE 
(434 events in the 80 mg/day group vs.
548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p=0.0002 (see Figure 3 and
Table 5). T'he overall risk reduction was consistent regardless of age (<65, >65) or gender.
Figure 3: Effect of Atorvastatin 80 mg/day vs. 10 mg/day on Time to Occurrence of Major Cardiovascular Events (TNT)
0.2
c
w 
Atorvastatin 10 mg ----
c 
Atorvastatin 80 mg —
~UC
N
..+"r
x 0.1~
,,,,.~„~~ 
HR 0.78 (0.69-0.89) P=0.0002
0 
1 
2 
3 
4
Time to First Major Cardiovascular Endpoint (Years)


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TABLE 5.Overview of Efficacy Results in TNT
Endpoint
Atorvastatin
10 mg
(N=5006)
Atorvastatin
80 mg
(N=4995)
HRe (95%CI)
PRIMARY ENDPOINT
n
(%)
n
(%)
First ma'or cardiovascular end oint
548
(10.9
434
(8.7)
0.78 (0.69, 0.89)
Com onents of the Primar End oint
CHD death
127
(2.5)
101
(2.0)
0.80 (0.61, 1.03)
Non-fatal, non- rocedure related MI
308
(6.2)
243
(4.9)
0.78 (0.66, 0.93)
Resuscitated cardiac arrest
26
(0.5)
25
(0.5)
0.96 (0.56, 1.67)
Stroke (fatal and non-fatal)
155
(3.1)
117
(2.3)
0.75 (0.59, 0.96)
SECONDARY ENDPOINTS*
First CHF with hospitalization
1.64
(3.3)
122
(2.4)
0.74 (0.59, 0.94)
First PVD end oint
282
(5.6)
275
(5.5)
0.97 (0.83, 1.15)
First CABG or other coronary
revascularization procedureb
904
(18.1)
667
(13.4)
0.72 (0.65, 0.80)
First documented angina endpoint
615
(12.3)
545
(10.9)
0.88 (0.79, 0.99)
All-cause mortali
282
(5.6)
284
(5.7)
1.01 (0.85, 1.19)
Com onents of All-Cause Mortalit
Cardiovascular death
155
(3.1)
126
(2.5)
0.81 (0.64, 1.03)
Noncardiovascular death
127
(2.5)
158
(3.2)
1..25 (0.99, 1.57)
Cancer death
75
(1.5)
85
(1.7)
1.13 (0.83, 1.55)
Other non-CV death
43
(0.9)
58
(1.2)
1.35 (0.91, 2.00)
Suicide, homicide, and other
traumatic non-CV death
9
(0.2)
15
(0.3)
1.67 (0.73, 3.82)
a Atorvastatin 80 mg: atorvastatin 10 mg
b Component of other secondary endpoints
* Secondary endpoints not included in primary endpoint
HR=hazard ratio; CHD=coronary heart disease; CI=confidence interval; MI=myocardial infarction; CHF=congestive heart failure;
CV=cardiovascular; PVD~eripheral vascular disease; CABG=coronary artery bypass graft
Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium tablets 80 mg/day significantly
reduced the rate ofnon-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest
(Table 5). Of the predefined secondary endpoints, treatment with atorvastatin calcium tablets 80 mg/day significantly reduced the rate
of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the
rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.
There was no significant difference between the treatment groups for all-cause mortality (Table 5). The proportions of subjects who
experienced cardiovascular death, including the components of CHD death and fatal stroke, were numerically smaller in the
atorvastatin calcium tablets 80 mg group than in the atorvastatin calcium tablets 10 mg treatment group. The proportions of subjects
who experienced noncardiovascular death were numerically larger in the atorvastatin calcium tablets 80 mg group than in the
atorvastatin calcium tablets 10 mg treatment group.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin calcium
tablets 80 mg/day was compared to treatment with simvastatin 20-40 mg/day in 8,888 subjects up to 80 years of age with a history of
CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of
61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76%were on statin therapy. In this prospective, randomized,
open-label, blinded endpoint (PRQBE) 
trial with no run-in period, subjects were followed for a median duration of 4.8 years. The
mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment
with 80 mg of atorvastatin calcium tablets and 105, l 79, ] 
42, 47, and 132 mg/dL during treatment with 20-40 mg of simvastatin.
There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal.
CHD, non-fatal MI, and resuscitated cardiac arrest): 41.1 (9.3%) in the atorvastatin calcium tablets 80 mg/day group vs. 463 (1.0.4%)
in the simvastatin 20-40 mg/day group, HR 0.89, 95% CI (0.78, 1.01), p=0.07.


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There were no significant differences between the treahnent groups for all-cause mortality: 366 (8.2%) in the atorvastatin calcium
tablets 80 mg/day group vs. 374 (8.4%) in the simvastatin 200 
mg/day group. The proportions of subjects who experienced CV or
non-CV death were similar for the atorvastatin calcium tablets 80 mg group and the simvastatin 20-40 mg group.
14.2 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
Atorvastatin reduces total-C, LDL-C, VLDL-C, apo B, and TG, and increases HDL-C inpatients with hyperlipidemia and mixed
dyslipidemia. Therapeutic response is seen within 2 weeks, and maximum response is usually achieved within 4 weeks and maintained
during chronic therapy.
Atorvastatin calcium tablets are effective in a wide variety of patient populations with hyperlipidemia, with and without
hyperniglyceridemia, in men and women, and in the elderly.
In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, atorvastatin calcium tablets given as a
single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 6.)
TABLE 6. Dose Response in Patients With Primary Hyperlipidemia (Adjusted Mean %Change From Baseline)°
Dose 
N 
TC LDL-C Apo B TG HDL-C Non-HDL-
C/ HDL-C
Placebo
21
4
4
3
10
-3
7
10
22
-29
-39
-32
-19
6
-34
20
20
-33
-43
-35
-26
9
-41
40
21
-37
-50
-42
-29
6
-45
80
23
-45
-60
-50
-37
5
-53
Results are pooled from 2dose-response studies.
In patients with Fredrickson Types Ila and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25`x' 
and 75`x'
percentile) percent changes from baseline in HDL-C for atorvastatin calcium tablets 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0,
17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant
decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
In three multicenter, double-blind studies in patients with hyperlipidemia, atorvastatin was compared to other statins. After
randomization, patients were treated for 16 weeks with either atorvastatin calcium tablets 10 mg per day or a fixed dose of the
comparative agent (Table 7).


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TABLE 7. Mean Percentage Change From Baseline at Endpoint (Double-Blind, Randomized, Active-Controlled Trials)
Treatment
Non-HDL-C/
(Daily Dose)
N
Total-C
LDL-C
Apo B
TG
HDL-C
HDL-C
Study 1
Atorvastatin 10 mg
707
-27a
-36a
-28a
-17a
+7
-37a
Lovastatin 20 mg
191
-19
-27
-20
-6
+7
-28
95% CI for Diff
-9.2, -6.5
-10.7, -7. ]
-10.0, -6.5
-15.2, -7.1
-1.7, 2.0
-11..1, -7. l
Study 2
Atorvastatin 10 mg
2.2.2.
-?Sb
-3Sb
-Z~Ib
-176
+6
-366
Pravastatin 20 mg
77
-17
-23
-17
-9
+8
-28
95% CI for Diffl
-10.8, -6.1
-14.5, -8.2
-13.4, -7.4
-14.1, -0.7
-4.9, 1.6
-11.5, -4.1
Study 3
Atorvastatin 10 mg
132
-29`
-37`
-34°
-23°
+7
-39°
Simvastatin 10 mg
45
-24
-30
-30
-15
+7
-33
95% CI for Diff`
-8.7, -2.7
-10.1, -2.6
-8.0, -1.1
-15.1, -0.7
-43, 3.9
-9.6, -1.9
' 
A negative value for the 95% Cl for the difference between treatments favors atorvastatin for all except HDL-C, for which a positive
value favors atorvastatin. If the range does not include 0, this indicates a statistically significant difference.
e Significantly different from lovastatin, ANCOVA, p <_0.05
b Significantly different from pravastatin, ANCOVA, p <_0.05
Significantly different from sunvastatin, ANCOVA, p 50.05
The impact on clinical outcomes of the differences in lipid-altering effects between trearinents shown in Table 7 is not known. Table 7
does not contain data comparing the effects of atorvastatin 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The
drugs compared in the studies summarized in the table are not necessarily interchangeable.
1.4.3 Hypertriglyceridemia (Fredrickson Type I~
The response to atorvastatin in 64 patients with isolated hypertriglyceridemia treated across several clinical trials is shown in the table
below (Table 8). For the atorvastatin calcium tablets-treated patients, median (min, max) baseline TG level was 565 (267-1502).
TABLE 8. Combined Patients With Isolated Elevated TG: Median (din, max) Percentage Change From Baseline
Placebo 
atorvastatin 10 mg 
atorvastatin 20 mg 
atorvastatin 80 mg
(N=12) 
(N=3 7) 
(N=13) 
(N=14)
Triglycerides 
-12.4 (-36.6, 82.7) 
-41.0 (-76.2, 49.4) 
-38.7 (-62.7, 29.5) 
-51.8 (-82.8, 41.3)
Total-C 
-2.3 (-15.5, 24.4) 
-28.2 (-44.9, -6.8) 
-34.9 (-49.6, -15.2) 
-44.4 (-63.5, -3.8)
LDL-C 
3.6 (-31.3, 31.6) 
-26.5 (-57.7, 9.8) 
-30.4 (-53.9, 0.3) 
-40.5 (-60.6, -13.8)
HDL-C 
3.8 (-18.6, 13.4) 
13.8 (-9.7, 61.5) 
11.0 (-3.2, 25.2) 
7.5 (-10.8, 37.2)
VLDL-C 
-1.0 (-31.9, 53.2) 
-48.8 (-85.8, 57.3) 
-44.6 (-62.2, -10.8) 
-62.0 (-88.2, 37.6)
non-HDL-C 
-2.8 (-17.6, 30.0) 
-33.0 (-52.1, -13.3) 
-42.7 (-53.7, -17.4) 
-51.5 (-72.9, -43)
14.4 Dysbetalipoproteinemia (Fredrickson Type IIn
The results of an open-label crossover study of 16 patients (genotypes: 14 apo E2/E2 and 2 apo E3/E2) with dysbetalipoproteinemia
(Fredrickson Type III) are shown in the table below (Table 9).
TABLE 9. Open-Label Crossover Study of 16 Patients With Dysbetalipoproteinemia (Fredrfckson Type iIn
Median %Change (min, max)
Median. (min, max) at
atorvastatin
atorvastatin
Baseline (mg/dL)
10 mg
80 mg
Total-C 
442 (225, 1.320)
-37 (-85, 17)
-58 (-90, -31)
Triglycerides 
678 (273, 5990)
-39 (-92, -8)
-53 (-95, -30)
IDL-C + VLDL-C 
215 (111, 613)
-32 (-76, 9)
-63 (-90, -8)
non-HDL-C 
411 (218, 1272)
-43 (-87, -19)
-64 (-92, -36)


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14.5 Homozygous Familial Hypercholesterolemia
In a study without a concurrent control group, 29 patients ages 6 to 37 years with homorygous FH received maximum daily doses of
20 to 80 mg of atorvastatin calcium tablets. The mean LDL-C reduction in this study was 18%. Twenty-five patients with a reduction
in LDL-C had a mean response of 20% (range of 7% to 53%, median of 24%); the remaining 4 patients had 7% to 24% increases in
LDL-C. Five of the 29 patients had absent LDL-receptor function. Of these, 2 patients also had a portacaval shunt and had no
significant reduction in LDL-C. The remaining 3receptor-negative patients had a mean LDL-C reduction of 22%.
14.6 Heterozygous Familial Hypercholesterolemia in Pediatric Patients
In adouble-blind, placebo-controlled study followed by an open-label phase, l87 boys and postmenarchal girls 10-17 years of age
(mean age 1.4.1. years) with heterorygous familial hypercholesterolemia (FH) or severe hypercholesterolemia, were randomized to
atorvastatin calcium tablets (n=140) or placebo (n=47) for 26 weeks and then all received atorvastatin calcium tablets for 26 weeks.
Inclusion in the study required 1) a baseline LDL-C level >_ 190 mg/dL or 2) a baseline LDL-C level >_ 160 mg/dL and positive family
history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value
was 218.6 mg/dL (range: 138.5-385.0 mg/dL) in the atorvastatin calcium tablets group compared to 230A mg/dL (range: 160.4-324.5
mg/dL) in the placebo group. The dosage of atorvastatin calcium tablets (once daily) was 10 mg for the first 4 weeks and uptitrated to
20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium tablets-treated patients who required uptitration to 20
mg after Week 4 during the double-blind phase was 80 (57.1%).
Atorvastatin significantly decreased plasma levels of total-C, LDI.-C, triglycerides, and apolipoprotein B during the 26-week double-
blind phase (see Table ] 
0).
TABLE 10. Lipid-altering Effects of Atorvastatin in Adolescent Boys and Girls with Heterozygous Familial
Hypercholesterolemia or Severe Hypercholesterolemia (Mean Percentage Change From Baseline at Endpoint in
Intention-to-Treat Population)
DOSAGE 
N 
Total- 
LDL- 
HDL-C 
TG 
Apolipoprotein B
C 
C
Placebo 
47 
-1.5 
-0.4 
-1.9 
1.0 
0.7
Atorvastatin 
140 
-3 ] 
.4 
-39.6 
2.8 
-12.0 
-34.0
The mean achieved LDL-C value was 130.7 mg/dL (range: 70.0-242.0 mg/dL) in the atorvastatin group compared to 228.5 mg/dL
(range: 152.0-385A mg/dL) in the placebo group during the 26-week double-blind phase.
The safety and efficacy of doses above 20 mg have not been studied in controlled trials in children. The long-term efficacy of
atorvastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
15 REFERENCES
~ National Cholesterol Education Program (NCEP): Highlights of the Report of the Expert Panel on Blood Cholesterol Levels in
Children and Adolescents, Pediatrics. 89(3):495-501. ] 
992.
16 HOW SUPPLIED/STORAGE AND HANDLING
10 mg tablets: coded "PD 155" on one side and "10" on the other.
NDC 59762-0155-1 
bottles of 90
NDC 59762-0155-2 
bottles of 1000
20 mg tablets: coded "PD 156" on one side and "20" on the other.
NDC 59762-0156-1 
bottles of 90
NDC 59762-0156-2 
bottles of 1000
40 mg tablets: coded "PD 157" on one side and "40" on the other.
NDC 59762-0157-1 
bottles of 90
NDC 59762-0157-2 
bottles of 500
80 mg tablets: coded "PD 158" on one side and "80" on the other.
NDC 59762-0158-1 
bottles of 90
NDC 59762-0158-2 
bottles of 500


EC and Immune Activation, V 12 
April 27th 2017 
 
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Storage
Store at controlled room temperature 20 - 25° C (68 - 77° F) [see USP].
17 PATIENT COUNSELING INFORMATION
Patients taking atorvastatin calcium tablets should be advised that cholesterol is a chronic condition and they should adhere to their
medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as
appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with atorvastatin [see Warnings and
Precautions (5.1)J. Patients should also be advised to inform other healthcare professionals prescribing a new medication
that they are taking atorvastatin calcium tablets.
17.1 Muscle Pain
All patients starting therapy with atorvastatin calcium tablets should be advised of the risk of myopathy and told to report promptly
any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or
symptoms persist after discontinuing atorvastatin calcium tablets. T'he risk of this occurring is increased when taking certain types
of medication or consuming larger quantities (>1 liter) of grapefruit juice. They should discuss all medication, both prescription
and over the counter, with their healthcare professional.
17.2 Liver Enzymes
It is recommended that liver enzyme tests be performed before the initiation of atorvastatin calcium tablets and if signs or
symptoms of liver injury occur. All patients treated with atorvastatin calcium tablets should be advised to report promptly any
symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. .
17.3 Pregnancy
Women of childbearing age should be advised to use an effective method of birth control to prevent pregnancy while using
atorvastatin calcium tablets. Discuss future pregnancy plans with your patients, and discuss when to stop atorvastatin calcium
tablets if they are trying to conceive. Patients should be advised that if they become pregnant, they should stop taking atorvastatin
calcium tablets and call their healthcare professional.
17.4 Breastfeeding
Women who are breastfeeding should be advised to not use atorvastatin calcium tablets. Patients who have a lipid disorder and are
breastfeeding, should be advised to discuss the options with their healthcare professional.
G
GREENSTONE~BRAND
Distributed by:
Greenstone LLC
Peapack, NJ 07977
LAB-0644-1.0


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APPENDIX E: ASPIRIN PACKAGE INSERT 
 
 
Aspirin
Comprehensive
Prescribing
Information
DESCRIPTION
BAYER®SAFETYCOATEDASPIRIN
Delayed ReleaseEntericAspirin for Oral Administration
Regular Strength 325 mg Caplets end Low Strength
81 mg Tablets
Inactive
Ingredients
Regular Strength 325 mg- CarnaubaWax, Cellulose, D&CYellow #10 Aluminum Lake, FD&C
Yellow #6 Aluminum Lake, Hypromellose, Iron Oxides, Methacrylic Acid Copolymer, Polysorbate
80, Propylene Glycol, Shellac,Sodium Lauryl Sulfate, Starch, Titanium Dioxide, Triacetin.
Low Strength 81 mg -Black
Iron Oxide, Brown Iron Oxide, Carnauba Wax, Corn Starch,
Croscarmellose Sodium, D&CYellow #10 Aluminum Lake, FD&CYellow #6 Aluminum Lake,
Hypromellose, Lactose Monohydrate, Methacrylic Acid Copolymer, Microcrystalline Cellulose,
Polysorbate 80, Powdered Cellulose, Pregelatinized Starch, Propylene Glycol, Shellac, Sodium
Lauryl Sulfate, Titanium Dioxide, Triacetin.
AnUplatelet_
Antiarthritic
COOH
Aspirin
/CH 3
o
C9H804
Mol. Wt.:
180.16
C 60.00
%;
H 4.48
%;
0 35.52%
Aspirin is an odorless white, needle-like crystalline or powdery substance. When exposed to
moisture, aspirin hydrolyzes into salicylic and acetic acids, and gives off a vinegary-odor. I1:is
highly lipid soluble and slightly soluble in water.
CLINICAL
PHARMACOLOGY
Mechanism of Action
Aspirin is a more potent inhibitor of both prostaglandin synthesis and platelet aggregation than
other' salicylic acid derivatives. The differences in activity between aspirin and salicylic acid are
thought to be due to the acetyl group on the aspirin molecule. This acetyl group is responsible for
the inactivation of cyclo-oxygenasevia acetylation.
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PharmacokineU(:s
Absorption:
In general, immediate release aspirin is well and completely absorbed from the
gastrointestinal (GI) tract. Following absorption, aspirin is hydrotyzed to salicylic acid with peak
plasma levels of salicylic acid occurring within 1-2 hours of dosing (see Pharmacoldnetics-
Metabolism). The rate of absorption from the G1tract is dependent upon the dosage form, the
presence or absenceof food, gastric pH (the presence or absence of GI antacids or buffering
agents), and other physiologic factors. Enteric coated aspirin products are erratically absorbed
from the GI tract.
Distribution:
Salicylic acid is widely distributed to all tissues and fluids in the body including the
central nervous system (CNS), breast milk and fetal tissues. The highest concentrations are found
in the plasma, liver, renal cortex, heart and lungs. The protein binding of salicylate is
concentration-dependent, i,e., non-linear. At low concentrations (< 100 micrograms/milliliter
(mcg/mL)), approximately 90 percent of plasma salicylate is bound to albumin while at higher
concentrations (> 400 mcg/mL), only about 75 percent is bound. The early signs of salicylic
overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma concentrations
approximating 200 mcg/mL. Severe toxic effects are associated with levels > 400 mcg/mL. (See
Adverse Reactions and Overdosage,)
Metabolism:
Aspirin is rapidly hydrolyzed in the plasma to salicylic acid such that plasma levels
of aspirin are essentially undetectable 1-2 hours after dosing. Salicylic acid is primarily conjugated
in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of
minor metabolitas. Salicylic acid has a plasma half-life of approximately 6 hours. Salicylate
metabolism is saturable and total body clearance decreases at higher serum concentrations due to
the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic
doses (10-20 grams (g)), the plasma half-life may be increased to over 20 hours.
Elimination:
The elimination of salicylic add follows zero order pharmacokinetics; (i.e., the rate
of drug elimination is constant in relation to plasma concentration}. Renal excretion of unchanged
drug depends upon urine pH. As urinary pH dses above 6.5, the renal clearance of free salicylate
increases from < 5 percent to > 80 percent. Alkalinization of the urine is a key concept in the
management of salicylate overdose. (See Overdosage.)
Following therapeutic doses,
approximately 10 percent is found excreted in the urine as salicylic acid, 75 percent as salicyluric
acid, 10 percent and 5 percent as the phenolic and acyl glucuronides, respectively.
Pharmacodynamics
Aspidn affects platelet aggregation by irreversibly inhibitingprostaglandin cyclo-oxygenase. This
effect lasts for the life of the platelet and prevents the formation of the platelet aggregating factor
thromboxane Az. Non-acetylated salicylates do not inhibit this enzyme and have no effect on
platelet aggregation. At somewhat higher doses, aspirin reversibly inhibits the formation of
prostaglandin Iz (prostacyclin), which is an arterial vasodilator and inhibits platelet aggregation.
At higher dosesaspidn is an effective anti-inflammatory agent, partially due to inhibition of
inflammatory mediators via cyclo-oxygenase inhibition in peripheral tissues. In vitro studies
suggest that other mediators of inflammation may also be suppressed by aspirin administration,
although the precise mechanismof action has not been eluc!dated. It is this nonspecific
suppression of cyclo-oxygenaseactivity in peripheral tissues.following large doses that leads to its
primary side effect of gastric irritation. (See Adverse Reactions,)
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CLINICAL
STUDIES
Ischemi¢ Stroke and Transient Ischemic
Attack (_A):
In clinical trials of subjects with
TIAs due to fibrin platelet emboli or ischemic stroke, aspirin has been shown to significantly reduce
the risk of the combined endpoint of stroke or death and the combined eedpoint of TIA, stroke, or
death by about 13-18 percent.
Suspected Acute MyocardialInfarction
(MI):
In a large, multi-canter study of aspirin,
streptokinase, and the combination of aspirin and stmptokinase in 17,187 patients with suspected
acute MI, aspirin treatment produced a 23 percent reduction in the risk of vascular mortality.
Aspirin was also shown to have an additional benefit in patients given a thrombolytic agent.
Prevention
of Recurrent MI and Unstable Angina Pectoris: These indications are
supported by the results of six large,randomized, multi-center, placebo-controlled trials of
predominantly male post-Ml subjects and one randomized placebo-controlled study of men with
unstable angina pectoris. Aspirin therapy in MI subjects was associated with a significant reduction
(about 20 percent) in the risk of the combined endpoint of subsequent death and/or nonfatal
reinfarction in these patients. In aspirin-treated unstable angina patients the event rate was
reduced to 5 percent from the 10 percent rate in the placebo group.
Chronic Stable Angina Pectoris: In a randomized, multi-center, double-blind trial designed to
assessthe role of aspirin for prevention of MI in patients with chronic stable angina pectoris,
aspirin significantly reduced the primary combined endpoint of nonfatal MI, fatal MI, and sudden
death by 34 percent. The secondary eedpoint for vascular events (the first'occurrenca of MI,
stroke, or vascular death) was also significantly reduced (32 percent).
Revasculariza_on
Procedures:
Mostpatients who undergo coronary artery revascularization
procedures have already had symptomatic coronary artery disease for which aspirin is indicated.
Similarly, patients with lesions of the carotid bifurcation sufficient to require carotid
endarterectomy are likely to have had a precedent event. Aspirin is recommended for patients who
undergo revascularization procedures if there is a preexisting condition for which aspirin is already
indicated.
Rheumatologic Diseases: In clinical studies in patients with rheumatoid arthritis, juvenile
rheumatoid arthritis, anlo/Iosing spondylitis and osteoarthritis, aspirin has been shown to be
effective in controlling various indices of clinical disease activity.
ANIMAL
TOXICOLOGY
The acute oral 50 percent lethal dose in rats is about 1.5 g/kilogram (kg) and in mice 1.1 g/kg.
Renal papillary necrosis and decreased urinary concentrating ability occur in rodents chronically
administered high doses. Dose-dependent gastric mucosal injury occurs in rats and humans.
Mammalsmay develop aspirin toxicosis associated with GI symptoms, circulatory effects, and
central nervous system depression. (See Overdosage.)
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INDICATIONS
AND
USAGE
Vascular Indications (Ischemic
Stoke,
TIA, Acute MI, Prevention
of Recurrent MI,
Unstable Angina Pectoris, and Chronic Stable Angina Pectoris) : Aspirin is indicated to: (1)
Reducethe combined risk of death and nonfatal stroke in patients who have had ischemic stroke
or transient ischemia of the brain due to fibrin platelet emboli, (2) reduce the risk of vascular
mortality in patients with a suspected acute MI, (3) reduce the combined risk of death and nonfatal
MI in patients with a previous MI or unstable angina pectoris, and (4) reduce the combined risk of
HI and sudden death in patients with chronic stable angina pectoris.
Revascularization
Procedures (Coronary Artery Bypass Graft (CABG), Percutaneous
Translumina! CoronaryAngioplasty
(PTCA), and Carotid Endarterectorny):
Aspirin is
indicated in patients who have undergone revascularization procedures (i.e., CABG,PTCA,or
carotid endarterectomy) when there is a preexisting condition for which aspirin is already
indicated.
Rheumatologic
Disease Indications
(Rheumatoid Arthrib's, Juvenile Rheumatoid
Arthritis, Spondyloarthrepathies,
Osteoarthritis,
and the Arthritis and Pleurisy of
Systemic Lupus Elythematosus
(SLE)):
Aspirin is indicated for the relief of the signs and
symptoms of rheumatoid arthritis, juvenile rheumatoid arthritis, osteearthritis,
spondyloarthmpathies, and arthritis and pleurisy associated with SLE.
CONTRAINDICATIONS
Allergy:
Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-
inflammatory drug products and in patients with the syndrome of asthma, rhinitis, and nasal
polyps. Aspirin may cause severe urticaria, angioedema, or bronchospasm (asthma).
Reye'sSyndrome:
Aspirin should not be used in children or teenagers for viral infections, with
or without fever, becauseof the risk of Reye's syndrome with concomitant use of aspirin in certain
viral illnesses.
WARNINGS
Alcahol Wal_ing:
Patients who consume three or more alcoholic drinks every day should be
counseled about the bleeding risks involved with chronic, heavy alcohol use while taking aspirin.
CoagulaUon A_normalities;
Even low doses of aspirin can inhibit platelet function leading to
an increase in bleeding time. This can adversely affect patients with inherited (hemophilia) or
acquired (liver disease or vitamin K deficiency) bleeding disorders.
GI Side Effects;
GI side effects include stomach pain, heartburn, nausea, vomiting, and gross
GI bleeding. Although minor upper GI symptoms, such as dyspepsia, are common and can occur
anytime during therapy, physiciansshould remain alert for signs of ulceration and bleeding, even
in the absence of previous GI symptoms. Physiciansshould inform patients about the signs and
symptoms of GI side effects and what steps to take if they occur.
Peptic Ulcer Disease;
Patients with a history of active peptic ulcer disease should avoid using
aspirin, which can causegastric mucosal irritation and bleeding.
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i
PRECAUTIONS
General
RenalFailure:
Avoid aspirin in patients with severe renal failure (glomerular filtration rate less
than 10 mL/minute).
HepaticInsuffiden_f:
Avoid aspirin in patients with severe hepatic insufficiency.
Sodium Restricted Diets., Patients with sodium-retaining states, such as congestive heart
failure or renal failure, should avoid sodium-containing buffered aspirin preparations because of
their high sodium content.
Laboratory Tests
Aspirin has been associated with elevated hepatic enzymes, blood urea nitrogen and serum
creatinine, hyperkalemia, proteinuria, and prolonged bleeding time.
Drug
Interactions
Angiotensin Converting Enzyme (ACE) Inhibitor_.
The hyponatremic and hypotensive
• effects of ACEinhibitors may be diminished by the concomitant administration of aspirin due to its
indirect effect on the renin-angiotensin conversion pathway.
Acetazolamid_.
Concurrent use of aspirin and ecetezolamide can lead to high serum
concentrations of acatezolamide (and toxicity) due to competition at the renal tubule for secretion.
Anticoagulant
Therapy (Heparin and Warfarin):
Patients on anticoagulation therapy are at
increased risk for bleeding becauseof drug-drug interactions and the effect on platelets. Aspirin
can displacewarfarin from protein binding sites, leading to prolongation of both the prothrombin
time and the bleeding Lime.Aspirin can increase the anticoagulant activity of heparin, increasing
bleeding risk.
Anticonvulsants:
Salicylate can displace protein-bound phenytoin and valproic add, leading te
decrease in _e total concentration of phenytoin and an increase in serum valproie acid levels.
BetaBIockel_:
The hypotensive effects of beta blockers may be diminished by the concomitant
administration of aspirin due to inhibition of renal prostaglandins, leading to decreased renal blood
flow, and salt and fluid retention.
Diuretic:
The effectiveness of diuretics in patients with underlying renal or cardiovascular
disease may be diminished by the concomitant administration of aspirin due to inhibition of renal
prostaglandins, leading to decreased renal blood flow, and salt and fluid retention.
Methotrexate:
Salicylate can inhibit renal clearance of methotrexate, leading to bone marrow
toxicity, especially in the elderly or renal impaired.
NonsteroidalAnti-inflammatory
Drugs (NSAIDs):
The concurrent use of aspirin with other
NSAIDs should be avoided becausethis may increasebleeding or leadte decreased renal function.
OralHypoglycemics:
Moderate doses of aspirin may increase the effectiveness of oral
hypoglycemic drugs, leadingto hypoglycemia.
Uricosuric Agents (Probenedd
and Sultinpyrazone):
Salicylates antagonize the uricosuric
action of uricosuric agents.
Carcinogenesis, Mutagenesis, Impairment
of Fertility
Administration of aspirin for 68 weeks at 0,5 percent in the feed of rats was not carcinogenic. In
theAmes Salmonellaassay,aspirin
was notmutagenic;however,aspirin
didinducechromosome
aberrations
inculturedhuman fibroblasts.
Aspirininhibits
ovulation
inrats.(SeePregnancy).
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Pregnancy
Pregnantwomenshould only take aspirin if clearly needed. Becauseof the known effects.of
HSAIDson the fetal cardiovascular system (closure of the ductus arteriosus), use during the third
trimester of pregnancy should be avoided. Salicylate products have also been associated with
alterations in maternal and neonatal hemostasis mechanisms, decreased birth weight, and with
pednatal mortality.
Labor and Delivery
Aspidn should be avoided 1 week prior to and during laborand delivery because it can result in
excessive blood lossat delivery. Prolonged gestation and prolonged labor due to prostaglandin
inhibition have been reported.
Nursing Mothers
Nursing mothers should avoid using aspirin becausesaticylate is excreted in breast milk. Useof
high doses may lead to rashes, platelet abnormalities, and bleeding in nursing infants.
Pediatric
Use
Pediatric dosing recommendations for juvenile rheumatoid arthritis are based on well-controlled
clinical studies. An initial dose of 90-130 mg/kg/day in divided doses, with an increase as needed
for anti-inflammatory efficacy (target plasma salicylate levelsof 150-300 mcg/mL) are effective. At
high doses (i.e., plasma levels of greater than 200 mcg/mL), the incidence of toxicity increases.
ADVERSE
REACTIONS
Many adverse reactions due to aspirin ingestion are dose-related. The following is a list of adverse
reactions that have been reported in the literature. (SeeWarnings.)
Bodyasa
Whole: Fever, hypothermia, thirst.
Cardiova_ular:
Dysrhythmias, hypotension, tachycardia.
CentraINervous
5_lstem:
Agitation, cerebral edema, coma, confusion, dizziness, headache,
subdural or Intracranial hemorrhage, lethargy, seizures.
Fiuidand
Electtvlyte:
Dehydration, hyperkalemia, metabolic acidosis, respiratory alkalosis.
Ga_tmintestlnal:
Dyspepsia, GI bleeding, ulceration and perforation, nausea, vomiting,
transient elevations of hepatic enzymes, hepatitis, Reye's syndrome, pancreatitis.
Hematologic." Prolongation of the prothrombin time, disseminated intravascular coagulation,
coagulopathy, thrombocytopenia.
Hypel_en$itivity:
Acute anaphylaxis, angioedema, asthma, bronchospasm, laryngeal edema,
urticaria.
M_culoskeletal:
Rhabdomyolysis.
Metabolism:
Hypoglycemia (in children), hyperglycemia.
Reproductive:
Prolonged pregnancy and labor, stillbirths, lower birth weight infants,
antepartum and postpartum bleeding.
Respirately:
Hyperpnea, pulmonary edema, tachypnea.
SpedalSense$:
Hearing loss, tinnitus. Patients with higher frequency hearing lossmay have
difficulty perceivingtinnitus. In these patients, tinnitus cannot be used as a clinical indicator of
salicylism.
Ulvgenital:
Interstitial nephritis, papillary necrosis, proteinuria, renal insufficiency and failure.
Page 6 of 9


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DRUG
ABUSE
AND
DEPENDENCE
Aspirin is non-narcotic. There is no known potential for addiction associated with the use of
aspirin.
OVERDOSAGE
Salicylate toxicity may result from acute ingestion (overdose) or chronic intoxication. The early
signs of salicylic overdose (salicylism), including tinnitus (ringing in the ears), occur at plasma
concentrations approaching 200 mcg/mL. Plasma concentrations of aspirin above 300 mcg/mL are
clearly toxic. Severe toxic effects are associated with levels above 400 mcg/mL. (See Clinical
Pharmao_logy). A single lethal dose of aspirin in adults in not known with certainty but death
may be expected at 30 g. For real or suspected overdose, a Poison Control Center should be
contacted immediately. Careful medical management is essential.
Signs and_ymptom$:
In acute overdose, severe acid-base and electrolyte disturbances may
occur and are complicated by hyperthermia and dehydration. Respiratory alkalosis occurs early
while hyperventilation is present, but is quickly followed by metabolic acidosis.
Treatment:
Treatment consists primarily of supporting vital functions, increasing salicylate
elimination, and correcting the acid-base disturbance. Gastric emptying and/or lavage is
recommended as soon as possible after ingestion, even if the patient has vomited spontaneously.
After lavage and/or emesis, administration of activated charcoal, as a slurry, is benefidal, if less
than 3 hours have passedsince ingestion. Charcoal adsorption should not be employed prior to
emesis and lavage.
Severity of aspirin intoxication is determined by measuring the blood salicylate level. Acid-base
status should be closely followed with serial blood gas and serum pH measurements. Fluid and
electrolyte balance should also be maintained. In severe cases, hyperthermia and hypovolemia are
the major immediate threats to life. Children should be sponged with tepid water. Replacement
fluid should be administered intravenously and augmented with correction of acidosis. Plasma
electrolytes and pH should be monitored to promote alkaline diuresis of salicylate if renal function
is normal. Infusion of glucose may be required to control hypoglycemia.
Hemodialysisand peritoneal dialysis can be performed to reduce the body drug content. In
patients with renal insufficiency or in cases of life-threatening intoxication, dialysis is usually
required, Exchangetransfusion may be indicated in infants and young children.
Page 7 of 9


EC and Immune Activation, V 12 
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DOSAGE
AND
ADMINISTRATION
Each doseof aspirin should be taken with a full glass of water unless patient is fluid restricted.
Anti-inflammatory and analgesic dosages should be individualized. When aspirin is used in high
doses, the development of tinnitus may be used as a clinical sign of elevated plasma salicylate
levels except in patients with high frequency hearing loss.
Ischemic Stroke and TIA:
50-325 mg once a day. Continue therapy indefinitely.
Suspected Acute MI:
The initial dose of 160-162.5 mg is administered as soon as an MI is suspected. The
maintenance dose of 160-162.5 mg a day is continued for 30 days post-infarction. After 30
days, consider further therapy based on dosage and administration for prevention of
recurrent MI.
Prevention
of Recurrent MI:
75-325 mg once a day. Continue therapy indefinitely.
Unstable Angina Pectoris:
75-325 mg once a day. Continue therapy indefinitely.
Chronic Stable Angina Pectoris:
75-325 mg once a day. Continue therapy indefinitely.
CABG:
325 mg daily starting 6 hours post-procedure. Continue therapy for one year post-
procedure.
PTCA:
The initial dose of 325 mg should be given 2 hours pre-surgery. Maintenance dose is 160-
325 mg daily. Continue therapy indefinitely.
Carotid Endarterectomy:
Doses of 80 mg once daily to 650 mg twice daily, started pre-surgery, are recommended.
Continue therapy indefinitely.
Rheumatoid Arthritis:
The initial dose is 3 g a day in divided doses. Increase as needed for anti-inflammatory
efficacy with target plasma salicylate levels of 150-300 mcg/mL. At high doses (i.e.,
plasma levels of greater than 200 mcg/mL), the incidence of toxicity increases.
Juvenile Rheumatoid Arthritis:
Initial dose is 90-130 mg/kg/day in divided doses. Increase as neededfor
anti-
inflammatory efficacy with target plasma salicylate levels of 150-300 mcg/mL. At high
doses (i.e., plasma levels of greater than 200 mcg/mL), the incidence of toxicity increases.
Spondyloarthropathiea:
Up to 4 g per day in divided doses.
Osteoarth_tis:
Up to 3 g per day in divided doses,
Arthritis and Pleurisy of SLE:
The initial dose is 3 g a day in divided doses. Increase as needed for anti-inflammatory
efficacy with target plasma sallcylate levels of 150-300 mcg/mL. At high doses (i.e.,
plasma levelsof greater than 200 mcg/mL), the incidence of toxicity increases.
Page 8 of 9


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[/
•
HOW SUPPLIED
BAYER®SAFETYCOATEDASPIRINis available in 81 tugtablets and 325 mg caplets. The 81 mg'
tablets are available in bottles of 32, 120, 180 and 240. The 325 mg caplets are available in bottles
ofI00.
Tablet Identification
81 mg tablet: round, yellow, "81" printed on one side
325 mg caplet: capsule shaped tablets, yellow, "Bayer 325" printed on one side
Storage Conditions
Store at room temperature.
Bayer Corporation
PO Box 1910
Morristown, N3 07962-1910 USA
Page 9 of 9

ICF_001.pdf: 
 
 
 
 
 
 
INSTITUTE: 
National institutes of Allergy and infectious Diseases 
 
 
STUDY NUMBER: 
14-I-0039 
PRINCIPAL INVESTIGATOR:   Irini Sereti, MD 
 
 
STUDY TITLE: 
Elite Controller and ART-treated HIV+ Statin versus ASA Treatment Intervention Study 
(ECSTATIN) 
 
 
Continuing Review Approved by the IRB on 04/23/18 
Amendment Approved by the IRB on 09/25/18 (O) 
Date Posted to Web: 10/03/18 
Standard 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary. 
 
You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not 
lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
You may receive no benefit from taking part. The research may give us knowledge that may help people in the 
future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
 
Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
THE PURPOSE OF THIS STUDY 
You are being asked to take part in this research study because you are infected with the human immunodeficiency virus 
(HIV) and have an HIV viral load (measure of the HIV virus in the blood) below the limit of detection and either: (1) you 
have never had to take anti-HIV medications (ARVs), have stable CD4 counts, and never had an opportunistic infection, 
or (2) you have been taking ARVs for 4 continuous years. 
 
You are invited to participate in a study that will look at changes in the body’s immune and clotting system markers. The 
immune system is made up of cells and substances that protect the body from infection and foreign matter. The activation 
of the immune system (or inflammation) can sometimes be harmful. Similarly, the clotting system is what makes the blood 
clot and protects us from bleeding but can be sometimes harmful if it is inappropriately activated.  
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
RESEARCH STUDY 
• Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent (1) 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
Adult Patient or 
• Parent, for Minor Patient 


CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
MEDICAL RECORD 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
 
 
 
STUDY NUMBER: 
14-I-0039 
CONTINUATION: Page 2 of 8 pages 
 
 
In chronic HIV infection, there is increased inflammation and coagulation (clotting) that may put people at higher risk for 
cardiovascular diseases such as stroke or heart attacks. Our goal is to study how immune and clotting system markers 
may change in people infected with HIV after receiving 9 months of a daily dose of aspirin (a medication that decreases 
clotting and inflammation) or atorvastatin (a medication which lowers blood cholesterol and decreases inflammation). As 
part of the study we will also examine your carotid vessels (the major blood vessels that supply blood to the neck and 
head) by magnetic tomography to look at the thickness of the vessel wall. 
 
A total of 80 people will be enrolled in the study. There will be 40 volunteers in each category. Half of the volunteers in 
each category will be randomized (process similar to the toss of the coin) to either a once daily dose of aspirin or a once 
daily dose of atorvastatin. Each group will receive 9 months of the medication. Volunteers in each group will have a 3 
month observation period before and after treatment. The total duration of the study for each volunteer will be 15 
months. 
 
Study Procedures and Timeline: 
 
 
 
 
 
 
 
 
 
 
STUDY PROCEDURES 
 
Medication Administration 
 
Both aspirin (81 mg tablet daily) and atorvastatin (40 mg tablet daily, dose adjusted for subjects on antiretroviral 
regimens with significant interactions) are 2 FDA approved, well-studied and well-tolerated drugs known to decrease 
immune activation (inflammation) and prevent cardiovascular events (strokes and heart attacks) with minimal side 
effects. Study administration of both aspirin and atorvastatin are at dosages with limited risk for side effects. 


CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
MEDICAL RECORD 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
 
 
 
STUDY NUMBER: 
14-I-0039 
CONTINUATION: Page 3 of 8 pages 
 
 
 
Risks Associated with Aspirin and Atorvastatin 
 
Risks associated with aspirin include increased risk of bleeding, particularly for people who consume 3 or more alcoholic 
drinks a day, clotting abnormalities, stomach pain, heartburn, nausea, vomiting and bleeding of the stomach and 
gastrointestinal track. Aspirin can also cause irritation of the stomach lining. Patients with kidney disease and liver 
insufficiency should avoid the use of aspirin. Aspirin should generally not be used in pregnancy. Aspirin has been known 
to cause birth defects and miscarriages in pregnant women. 
 
Risks associated with atorvastatin include muscle damage and an increase in sugar in your blood. Atorvastatin can 
increase blood levels of liver enzymes, and should not be used in patients with chronic liver disease and in those who 
consume large amounts of alcohol. Fatal liver failure has been reported in patients on atorvastatin. Atorvastatin is not to 
be used in pregnancy due to significant risk of injury to the fetus. 
 
Risk associated with medications in pregnant and breastfeeding women 
 
Due to the risk associated with these medications if taken during pregnancy, you must agree not to become pregnant 
during this study.  Women of childbearing potential will have a pregnancy test before starting the study drugs and at each 
study visit. Because of the risk involved, you and your partner must use 2 methods of birth control, one of which must 
be a barrier method. You must continue to use both methods until the last study visit (Month 15). If you become 
pregnant while taking study drugs, the study drug will be discontinued immediately and you will be referred to a maternal 
fetal medicine specialist. You will be followed by the study team for the remainder of the study period or until you deliver 
the baby, whichever occurs later. You must contact us immediately if you think you might be pregnant. 
 
Due to the potential for risk to a nursing infant if a mother is receiving either of the study drugs, breastfeeding should be 
discontinued while the mother is taking the study drug. 
 
Apheresis 
As part of this study, apheresis will be performed at Month 3 and Month 15 in those subjects deemed eligible for the 
procedure. In automated apheresis, blood is removed through a needle in the vein of one arm, spun in a machine which 
allows separation of the blood parts (usually white blood cells and plasma) needed for research, and then the remainder 
is given back to the patient through a needle in a vein in the other arm. A blood thinner is usually added to the blood 
while in the machine to prevent it from clotting during this processing. 
 
The goal of these procedures is to allow the investigator to get a larger number of white blood cells than by simple blood 
drawing for study in the laboratory. Similar procedures are used in the Blood Bank of the Clinical Center to obtain blood 
products from healthy, non-study donors and as a form of therapy for certain diseases. The procedure will take 
approximately 60 to 90 minutes depending upon the amount of blood that is being collected and will be done at the 
beginning of the study and approximately at 9 months after starting the study drug (aspirin or atorvastatin). You have the 
right to refuse any apheresis procedures at any time. 
 
Risks Associated with Apheresis Procedure 
 
The risks associated with these procedures are mostly those of putting an intravenous line (a catheter placed into a vein) 
and are discomfort or pain at the site, occasionally bruising under the skin where the needle was placed, a lump at the 


CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
MEDICAL RECORD 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
 
 
 
STUDY NUMBER: 
14-I-0039 
CONTINUATION: Page 4 of 8 pages 
 
 
needle insertion site (hematoma), a tingling sensation during the procedure that can usually be relieved by chewing a 
calcium-containing tablet (such as Tums®), and rarely infection, and possible fainting. The intravenous line with flowing 
saline solution will be kept in place during the manual apheresis procedure. Other uncommon side effects of the procedure 
include anxiety, chills, pain, and lightheadedness. There may also be a slightly increased bleeding tendency for a few hours 
after the procedure due to the use of the anticoagulant (blood thinner). In addition, there are potential risks from re-
infusion (giving back) of the blood after processing by the machine such as infection or a bad reaction to the blood parts. 
Very rarely, there can be blood vessel or nerve damage at the needle injection site, Finally, if the machine malfunctions, 
you may not have the blood returned to you, so it will be as if you had a large amount of blood drawn. In that event, the 
research blood draws of the protocol will be appropriately adjusted and you may have an additional blood count checked 
for your own safety. However, these risks are rare at our facility, since they have not been seen in many thousands of 
volunteers who have undergone this or similar procedures to date. 
 
Rarely the performance of frequent apheresis procedures over a short period of time can result in a drop in total 
lymphocyte counts (white blood cells), including the absolute CD4+ T cell count, or a drop in the platelet count (platelets 
are the blood cells that help your blood to clot). The extent or duration of the drop in these counts may be unpredictable 
and vary from person to person, although we plan to monitor your counts during participation so that this is less likely to 
occur. The short or long-term risks associated with these drops are also unknown, although they could possibly be more 
serious in those individuals whose starting counts are already below the normal range as a result of HIV-1 infection or 
other medical conditions. We may limit the number of times that you are eligible to undergo apheresis over a set period 
of time, and may require that these or other safety blood studies be performed and checked periodically during the time 
that you are enrolled on this protocol. The time and volume of blood drawn each time you undergo this procedure will be 
determined by the study team and will strictly follow the clinical center guidelines for this procedure. 
 
Magnetic Resonance Imaging (MRI) of Carotids 
Magnetic Resonance Imaging (MRI) is a way to visualize the vascular walls of the major blood vessels to the neck and the 
head. It can detect build up of plaques and narrowing of vessel walls. It can potentially monitor worsening of vascular 
diseases. For this procedure, you will lay flat in a long metal cylinder as the machine makes images of the vessels. 
If you are found to have abnormalities on the MRI, the findings will be reviewed with you in detail by the study team. 
This will include any clinical recommendations for future care or follow-up testing, and this information will also be 
provided to your doctor(s) when indicated. 
 
Risks Associated With MRI 
 
For most volunteers, the risk of the MRI will be discomfort. You will be asked to lie still for a long period of time. The 
machine makes a clicking sound, which many people find disturbing. The technician can give you special ear phones to 
quiet the nose. Volunteers with pacemakers, aneurysm clips, metallic prostheses, shrapnel fragments, welders and metal 
workers are at risk for injury and will be excluded from having the MRI performed. 
 
Rectal swab and dietary questionnaire 
We will be collecting a small sample of stool from your rectum. This will be done by inserting a small cotton swab (Q-tip) 
into the rectum. We will also be collecting information about foods and beverages that you have consumed. 
 
Risk of rectal swab 
You may experience pressure as the swab is inserted into the rectum, but the test is usually not painful. 


CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
MEDICAL RECORD 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
 
 
 
STUDY NUMBER: 
14-I-0039 
CONTINUATION: Page 5 of 8 pages 
 
 
 
 
GENETICTESTING 
 
Some of the blood drawn from you as part of this study may be used for a test of genes that code for the immune system. 
Genes are pieces of DNA. DNA serves as nature’s code (instructions) for protein production in the body. We will 
also check you for HLA type, which is a genetic test of markers of the immune system. It is usually used in matching for 
bone marrow or organ transplants. For research, HLA testing will be used to try to identify factors associated with the rate 
of progression of HIV disease or related conditions. Some HLA types have been associated with an increased risk of certain 
diseases like arthritis and other rheumatologic problems. However, simply having those HLA types doesn’t mean you will 
develop these diseases. 
 
In general, genetic testing may tell researchers something about how health or illness is passed on to you by your parents 
or from you to your children. When thinking about whether or not to participate in genetic studies, you should 
consider the possible effects on your emotional well-being. In other words, how might you feel about yourself and your 
life if you learn information about risks that could affect your own health or that of your children? In some cases, there 
may be no treatment. This could cause stress, anxiety, or depression. Additional genetics counseling and advice is 
available from NIH to help you understand the nature and implications of findings about you and your family. Also, 
relationships with other family members may be affected by finding out risks they have but did not want to know. An 
example would be if your children, brothers or sisters find out they have risks for health problems because of information 
found out about you. 
 
Any genetic information collected or discovered about you or your family will be confidential. Results of HLA testing will 
become a part of your medical record at NIH. Medical records containing this information are maintained in a secured 
manner. Genetic information about you will not be revealed to others, including your relatives, without your permission. 
We will not release any information about you or your family to any insurance company or employer unless you sign a 
document allowing release of information. There may be a risk that genetic information obtained as a result of 
participation in research could be misused for discriminatory purposes. However, state and federal laws provide some 
protections against genetic discrimination. Researchers who will have access to genetic information about you will take 
measures to maintain the confidentiality of your genetic information. 
 
Phlebotomy 
Possible complications from drawing blood (venipuncture) include pain or bruising at the site of the blood draw, feeling 
lightheaded, a lump at the needle insertion site (hematoma), fainting, and rarely, infection. During each venipuncture, 
approximately 3 to 10 tablespoons of blood will be obtained (15 to 150 mL of blood). The amount of blood drawn will not 
exceed 37 tablespoons (550 mL) in an 8-week period, which is within the safety guidelines set by the Clinical Center of 
the NIH. 
 
 
SCHEDULE OF VISITS AND PROCEDURES 
Screening Visit 
! 
Medical history that will include a review of your medical record and questions about current and past 
medications and illnesses 
! 
Complete physical examination 
! 
Blood and urine test to assess the function of your liver, kidneys and your HIV infection status 


CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
MEDICAL RECORD 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
 
 
 
STUDY NUMBER: 
14-I-0039 
CONTINUATION: Page 6 of 8 pages 
 
 
! 
Additional testing for HIV viral load, blood clotting, inflammation, hepatitis viruses, and lipid problems 
! 
Women will undergo urine or blood testing for pregnancy 
 
Baseline Visit and Months 3, 6, 9, 12, and 15 
! 
Physical exam, medical history and medication history 
! 
HIV Viral load and CD4+T cell count 
! 
Blood and urine test for liver and kidney function, pregnancy testing, diabetes and lipid profile 
! 
Additional testing for HIV viral load, blood clotting, inflammation, hepatitis viruses, and lipid problems 
 
Baseline Visit and Month 12 Visit Only 
! 
MRI of carotids 
! 
Rectal swab and dietary history questionnaire. Dietary questionnaire at Baseline Visit only. 
 
Months 3 through Month 9 Visits Only 
! 
Daily aspirin or atorvastatin administration 
 
Month 3 and Month 12 Visit only 
! 
1 liter apheresis or 30 mL blood collection 
STORED SAMPLES AND FUTURE RESEARCH 
Stored Samples and Future Research 
If you agree to participate in this study, you also agree to let us store your samples for future research. These stored 
samples may help us learn more about HIV or other health problems. We will label your stored samples with information 
with a code that only the study team can link to you. We will keep any information that can be traced back to you as 
private as possible. If you change your mind and decide you do not want us to store your samples, please contact us. We 
will do our best to comply with your request, but cannot guarantee that we will always be able to destroy all your 
samples. 
 
We might send your samples to other investigators for their research, without any information that can identify you. We 
might also share information such as your sex, age, health history, or ethnicity. We will not sell your samples and you will 
not be paid for any products that result from the research. Some future studies may need health information (such as 
smoking history or present health status) that we don’t already have. If so, our study team will contact you. Future 
research that uses your samples will probably not help you, but it may help us learn more about how to treat or prevent 
HIV and other health problems. In general, the research tests we perform are not like routine medical tests, and may not 
relate directly to your medical care. 
 
Risks Associated with Stored Samples 
 
The greatest risk associated with storing samples is that someone may take information from your medical records without 
your permission. The chances of this happening are very low. If this information becomes available, you may face 
discrimination when you apply for insurance or a job. You may also have similar problems if you share the information 
yourself or let us release your medical records. 


CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
MEDICAL RECORD 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (10-84) 
NIH-2514-2 (10-84) 
P.A.: 09-25-0099 
 
 
 
STUDY NUMBER: 
14-I-0039 
CONTINUATION: Page 7 of 8 pages 
 
 
BENEFITS 
 
Participation in this study provides no direct benefit to you. You will receive information about your health from the 
screening tests and physical exam. The results of the imaging of the carotids will not be provided until the end of the 
study. In the future, it is possible that information learned from this study may help HIV-infected persons at risk for heart 
disease. 
 
ALTERNATIVES 
 
Participation in this protocol is voluntary. You can choose not to participate in this study, and you can choose not to allow 
HIV, hepatitis or genetic testing or storage of blood, in which case you would not be eligible for further participation in the 
protocol. 
 
COSTS TO YOU FOR YOUR PARTICIPATION 
 
There will be no charge to you or your health insurance company for any of the costs that are directly related to this 
study. 
 
COMPENSATION 
 
You will receive $150 for each attempted or completed 1 liter apheresis procedure. If you are ineligible for the apheresis 
procedure, you will be compensated $40 for an additional blood draw of 30 mL (2 tablespoons). You will also receive 
$150 for each MRI; $70 for the dietary questionnaire and $30 for the rectal swab; $60 for each clinic visit with blood 
draw. At the End of Study Visit, volunteers will receive and additional $200 if all protocol study visits have been 
completed. You will be compensated for travel according to the NIAID/NIH travel policy. 
 
CONFLICT OF INTEREST 
 
The National Institutes of Health reviews NIH staff researchers at least yearly for conflicts of interest. The following link 
contains details on this process http://ethics.od.nih.gov/forms/Protocol-Review-Guide.pdf. You may ask your research 
team for additional information or a copy of the Protocol Review Guide. This protocol may have investigators who are not 
NIH employees. Non-NIH investigators are expected to adhere to the principles of the Protocol Review Guide but are not 
required to report their personal financial holdings to the NIH. 
 
POLICY REGARDING HIV TESTING 
 
As part of this study, we will test you for infection with the human immunodeficiency virus (HIV), the virus that causes 
AIDS, in order to confirm your diagnosis for participation in the study. We will tell you what the results mean, how to find 
care, how to avoid infecting others, how we report HIV infection, and the importance of informing your partners at 
possible risk because of your HIV infection. 


 
 
 
STUDY NUMBER: 
14-I-0039 
 
CONTINUATION: Page 8 of 8 pages 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality. When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified. In most cases, the NIH will not release any information about 
your research involvement without your written permission. However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record. This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records. However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. Policy Regarding Research-Related Injuries. The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here. In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
3. Payments. The amount of payment to research volunteers is guided by the National Institutes of Health policies. In 
general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
4. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Irini Sereti, MD, Building 10, Telephone 
301-496-5533 or the Study Coordinator, Dorinda Metzger, RN at 240-669-2962. 
You may also call the Clinical Center Patient Representative at (301) 496-2626. 
5. Consent Document.   Please keep a copy of this document in case you want to read it again. 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A.   Adult Patient’s Consent 
B.   Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study. 
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
Signature of Adult Patient/Legal Representative 
Date 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
C.   Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE 
FROM APRIL 23, 2018 THROUGH APRIL 22, 2019. 
Signature of Investigator 
Date 
 
Print Name 
Signature of Witness 
Date 
 
Print Name 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• Adult Patient or 
•  Parent, for Minor Patient 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
• Adult Patient or  • Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.: 09-25-0099 
File in Section 4: Protocol Consent