Clinical trial NCT01813357
Conditions: HIV Cardiovascular Disease
Keywords: HIV Cardiovascular disease Inflammation Statin
Sponsor: Bayside Health
Start date: 2013-07-02; Completion date: 2018-11-01
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a randomised double blind placebo controlled trial comparing Rosuvastatin with placebo in HIV positive people who are at intermediate cardiovascular risk.

It is possible that HIV positive people will receive a greater benefit from statins because of their higher baseline levels of inflammation. Current Australian guidelines recommend initiation of statin therapy on the basis of cholesterol level and the presence of other risk factors for heart disease (such as diabetes) but do not take into account whether a patient is infected with HIV. This study aims to determine what benefit HIV infected people will receive from starting statin therapy earlier then currently recommended.

Detailed description:
Participants will be randomised to receive either the active agent (Rosuvastatin) or a placebo once daily for 96 weeks.

Participants will undergo blood tests and ultrasounds of the arteries of the neck (carotid intima media thickness) prior to starting Rosuvastatin and then after 1 and 2 years on the drug to determine what effect it has on markers of inflammation, cholesterol levels and thickness of blood vessels.

Arms: arm 1: sugar pill that is encapsulated so as to appear identical to the active agent arm 2: Rosuvastatin 20mg daily
Interventions: intervention 1: Rosuvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: encapsulated tablet 20mg daily intervention 2: Placebo arm included to maintain blinding

Protocol documents:
Prot_SAP_ICF_000.pdf: 
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Project 
Title 
Does rosuvastatin delay progression of atherosclerosis in people 
with HIV infection at moderate cardiovascular risk? 
 
A multicentre, randomized, double blind, placebo-controlled trial 
 
Version Date: 14/02/2014 
Version Number: 2.2 
 
 
INVESTIGATORS 
 
Professor Jennifer Hoy (PI) 
Dr Janine Trevillyan 
Professor Suzanne Crowe 
 
 
Dr Julian Elliott 
A. Professor Anthony Jaworowski 
Dr James Shaw  
Professor Anthony Dart 
The Alfred Hospital 
Monash University 
Melbourne Australia 
 
Contact: 
 
Infectious Diseases Department 
Alfred Hospital 
55 Commercial Road 
Melbourne VIC 3004 
PO Box 315 Prahran 
Victoria 3181 Australia 
Telephone: 03 90762000 
Fax: 03 90766557 
 
INVESTIGATORS SWITZERLAND 
 
Dr Alexandra Calmy (PI and person responsible according to art. 7 Oclin for 
the study conduct in Switzerland) 
Prof François Mach (Cardiology) 
Dr Baris Gencer (Cardiology) 
Dr Roman Sztajzel (Neurology) 


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Employees: 
Rachel Spycher Elbes (Coordinator) 
Cecile Delhumeau (Statistician) 
 
Contact of PI:  
 
Infectious Diseases Department / HIV Unit (coordinating centre for Swiss sites) 
Hôpitaux Universitaires de Genève  
4, rue Gabrielle Perret Gentil 
CH-1211 Genève 14 
Switzerland  
Telephone: +41 (0)22 372 98 12 
Fax: +41 (0)22 372 98 20 
 
 


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Table of Contents 
1 
Signature Form................................................................................................................... 6 
2 
List of abbreviations .......................................................................................................... 7 
3 
Definition of Terms............................................................................................................ 8 
4 
Protocol Synopsis............................................................................................................... 9 
5 
Flow Chart ....................................................................................................................... 11 
6 
Background ...................................................................................................................... 12 
6.1 
Relationship between HIV infection and CVD ......................................................... 12 
6.2 
Surrogate markers of cardiovascular outcomes ........................................................ 13 
6.3 
Statin therapy............................................................................................................. 13 
6.4 
Selection of doses ...................................................................................................... 14 
6.5 
Rationale for performing study ................................................................................. 14 
6.6 
Sample size ................................................................................................................ 14 
6.7 
Hypothesis ................................................................................................................. 15 
7 
Study objectives ............................................................................................................... 15 
7.1 
Primary Objective ..................................................................................................... 15 
7.2 
Secondary Objectives ................................................................................................ 15 
8 
Study Design .................................................................................................................... 16 
8.1 
Design........................................................................................................................ 16 
8.2 
Duration ..................................................................................................................... 17 
8.3 
Study centres ............................................................................................................. 17 
9 
Study Population .............................................................................................................. 17 
9.1 
Inclusion Criteria ....................................................................................................... 17 
9.2 
Exclusion criteria....................................................................................................... 17 
9.3 
Prohibitions ............................................................................................................... 18 
9.4 
Removal of participants from therapy/assessment .................................................... 18 
9.5 
Pregnancy .................................................................................................................. 19 
10 
Study Medication .......................................................................................................... 19 
10.1 
Rosuvastatin........................................................................................................... 19 
10.2 
Placebo................................................................................................................... 19 
10.3 
Packaging and Labelling ....................................................................................... 19 
10.4 
Timing of dosing ................................................................................................... 20 
10.5 
Storage ................................................................................................................... 20 
10.6 
Drug Accountability .............................................................................................. 20 
10.7 
Compliance assessment ......................................................................................... 20 
10.8 
Warnings and precautions ..................................................................................... 20 


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10.9 
Concomitant medications ...................................................................................... 21 
10.9.1 
Contraindications ........................................................................................... 21 
10.9.2 
Warfarin ......................................................................................................... 21 
10.9.3 
Antiretrovirals ................................................................................................ 21 
10.10 
Drug interactions list ............................................................................................. 22 
10.11 
Blinding and Emergency Unblinding .................................................................... 23 
11 
Assessments .................................................................................................................. 23 
11.1 
Calculations ........................................................................................................... 24 
11.2 
Laboratory Assessments ........................................................................................ 25 
11.3 
Carotid IMT ........................................................................................................... 26 
11.4 
Pulse Wave Velocity ............................................................................................. 27 
12 
Visit Schedule ............................................................................................................... 27 
12.1 
Screening ............................................................................................................... 27 
12.1.1 
Eligibility ........................................................................................................ 28 
12.2 
Inclusion Criteria ................................................................................................... 28 
12.3 
Exclusion criteria ................................................................................................... 28 
12.4 
Randomisation ....................................................................................................... 29 
12.5 
Baseline visit.......................................................................................................... 29 
12.6 
Week 12 visit ......................................................................................................... 30 
12.7 
Week 24 visit ......................................................................................................... 30 
12.8 
Week 48 visit ......................................................................................................... 30 
12.9 
Week 72 visit ......................................................................................................... 31 
12.10 
Week 96 visit ......................................................................................................... 31 
12.11 
Unscheduled visits ................................................................................................. 32 
12.1 
Withdrawal visit .................................................................................................... 32 
12.2 
Time windows ....................................................................................................... 32 
13 
Adverse Events ............................................................................................................. 32 
14 
Serious Adverse Events ................................................................................................ 33 
14.1 
Serious Adverse Event Reporting Requirements .................................................. 33 
15 
Data safety and monitoring board ................................................................................. 34 
16 
Trial or site discontinuation .......................................................................................... 35 
17 
Statistical Analysis ........................................................................................................ 35 
18 
Insurance and Finances ................................................................................................. 36 
19 
Quality Control and quality assurance .......................................................................... 36 
19.1 
Source documents .................................................................................................. 36 
19.2 
Retention of essential documents .......................................................................... 36 


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19.3 
Data protection ...................................................................................................... 37 
19.4 
Monitoring, audits and inspections ........................................................................ 37 
20 
Publications and presentations ...................................................................................... 37 
21 
References ..................................................................................................................... 38 
22 
Appendix ....................................................................................................................... 41 
22.1 
Case Record Forms ................................................................................................ 41 
22.1.1 
Screening Visit ............................................................................................... 41 
22.1.2 
Baseline Visit ................................................................................................. 47 
22.1.3 
Week 12 Visit ................................................................................................. 48 
22.1.4 
Week 24 Visit ................................................................................................. 49 
22.1.5 
Week 48 Visit ................................................................................................. 50 
22.1.6 
Week 72 Visit ................................................................................................. 52 
22.1.7 
Week 96 Visit ................................................................................................. 53 
22.1.8 
Unscheduled Visits ......................................................................................... 55 
22.2 
Serious Adverse Event (SAE) Form ...................................................................... 56 
22.3 
Units of measurement and reference ranges .......................................................... 57 
22.4 
Units of measurement and reference ranges for Swiss sites .................................. 59 
22.5 
Patient Informed Consent Form ............................................................................ 61 
22.6 
Severity Grading of Adverse Events ..................................................................... 74 
 
 
 


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1 Signature Form 
 
I, the undersigned, have reviewed this Protocol, including Appendices. I will conduct the 
clinical study as described and I will adhere to GCP/ICH and all the local ethical and regulatory 
requirements. 
 
 
 
Principal Investigator Melbourne (AUS)  
Signature 
 
 
Date 
 
 
Title 
 
 
Institution and address 
 
 
Phone 
 
 
Principal Investigator Geneva (CH)  
 
Signature 
 
 
Date 
Dre Alexandra Calmy 
 
Title 
MD, PD médecin adjoint agrégé 
 
Institution and address 
Consultation des maladies infectieuses / unité VIH 
Hôpitaux Universitaires de Genève. 4, rue Gabrielle Perret-Gentil, 1211 Genève 14 
 
Phone  
+41 22 372 98 12 
 
 
For additional Swiss sites:  
 
Site Name:  
 
 
Site main investigator 
 
 
Signature 
 
 
Date 
 
 
Title 
 
 
Institution and address 
 
 
Phone 


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2 List of abbreviations 
 
 
ACCF  
 
American College of Cardiology Federation 
AE 
 
 
Adverse Events 
AHA  
 
American Heart Association 
AIDS  
 
Acquired immunodeficiency syndrome 
Alb 
 
 
Albumin 
ALP 
 
 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AMI 
 
 
Acute Myocardial Infarction 
ART  
 
Antiretroviral Therapy 
ARV  
 
Antiretroviral 
BMI 
 
 
Body Mass Index 
Ca 
 
 
Calcium 
cART  
 
Combination Antiretroviral Therapy 
CD4+ cells 
 
CD4+ T-cell count  
CHD  
 
Coronary Heart Disease 
cIMT  
 
Carotid artery Intima Media Thickness 
Cl 
 
 
Chloride 
CMV  
 
Cytomegalovirus 
CPK 
 
 
Creatinine phosphokinase 
cPWV  
 
Carotid-femoral pulse wave velocity 
Cr 
 
 
Creatinine 
CrCl 
 
 
Creatinine Clearance 
CRF 
 
 
Case Report Form 
CVA  
 
Cerebrovascular accident 
CVD   
 
Cardiovascular disease 
CVE  
 
Cardiovascular events 
D.A.D –RS 
 
D.A.D risk score 
D.A.D. 
 
Data collection on Adverse events of anti-HIV Drugs 
DBP 
 
 
Diastolic Blood Pressure 
DSMB  
 
Data Safety and Monitoring Board 
ECG  
 
Electrocardiograph 
eGFR  
 
estimated glomerular filtration rate 
ESC 
 
 
European Society of Cardiology 
FBE 
 
 
Full Blood Examination 
FRS 
 
 
Framingham Risk Score 
GGT  
 
Gamma- glutamyl transpeptidase 
HaCH  
 
HIV and Cardiovascular Health 
Hb 
 
 
Haemoglobin 
HCO3  
 
Bicarbonate 
HDL-C 
 
High-density lipoprotein cholesterol 
HIV 
 
 
Human Immunodeficiency Virus 
HMG Co-A 
3-hydroxy-3-methylglutaryl coenzyme A  
 
HUG  
 
Geneva University Hospitals 
hsCRP  
 
High sensitivity C-reactive protein 
K+ 
 
 
Potassium 
LDL-C 
 
Low-density lipoprotein cholesterol 
LFT 
 
 
Liver Function Tests 


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LPS 
 
 
Lipopolysaccharide 
Lymp  
 
Lymphocyte Count 
MAC  
 
Mycobacterium avian complex 
MDRD 
 
Modification of Diet in Renal Disease 
Na 
 
 
Sodium 
Neut 
 
 
Neutrophil Count 
PBMC  
 
Peripheral blood mononuclear cells 
PBS 
 
 
Pharmaceutical Benefits Scheme 
PCP 
 
 
Pneumocystis jirovecii pneumonia 
Plt 
 
 
Platelets 
PML  
 
Progressive multifocal leucoencephalopathy 
PO4 
 
 
Phosphate 
PVD  
 
Peripheral vascular disease 
RNA  
 
Ribonucleic acid 
SAE 
 
 
Serious Adverse Events 
SBP 
 
 
Systolic Blood Pressure 
SHCS  
 
Swiss HIV Cohort Study 
SLE 
 
 
Systemic Lupus Erythematosus 
Statin  
 
HMG Co-A reductase inhibitor 
TC 
 
 
Total Cholesterol 
 
TG 
 
 
Triglycerides 
TIA 
 
 
Transient ischaemic attack 
TP 
 
 
Total Protein 
UEC  
 
Urea, Electrolytes and Creatinine 
ULN  
 
Upper limit of normal 
Ur 
 
 
Urea 
VAS  
 
Visual Analogue Scale 
VIDRL 
 
Victorian Infectious Diseases Reference Laboratory 
WCC  
 
Total White Cell Count 
WHF  
 
World Health Federation 
β-HCG 
 
Beta-human chorionic gonadotropin 
3 Definition of Terms 
 
Study medication 
the medication under investigation (rosuvastatin) or the corresponding 
placebo product administered for blinding 
 
 
 


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4 Protocol Synopsis 
 
Protocol title: Does rosuvastatin delay progression of atherosclerosis in people with HIV 
infection at moderate cardiovascular risk? A randomized, placebo-controlled trial 
 
Primary Objective: The primary objective is to determine the effect of rosuvastatin on 
atherosclerosis progression in individuals with HIV infection who are at moderate 
cardiovascular risk. 
 
Study Design: This study will be a randomized, double blinded, placebo controlled, 
multicentre trial comparing the effect of rosuvastatin 20mg daily versus placebo over 96 
weeks in people with HIV infection who are at moderate cardiovascular risk (as estimated by 
a Framingham Risk Score (FRS) between 10 – 15%).Participants will be randomised 1:1 to 
active rosuvastatin 20mg once daily or matching placebo. Participants on a protease inhibitor 
will receive dose reduced rosuvastatin (10 mg).  
 
Planned sample size: 102 HIV positive participants (72 participants in Melbourne and 30 in 
Switzerland)  
 
Inclusion Criteria 
1. Provision of written, informed consent 
2. Age >30 years 
3. Moderate coronary heart Disease (CHD)  risk, defined as FRS of 10-15%1 
4. HIV positive 
5. Stable ARV regimen > 3 months (i.e. no recent drug change [changes in dosages are 
accepted]) 
6. Plasma HIV viral load <200copies/ml for ≥ 6 months 
 
Exclusion criteria 
1. Recommended use of lipid lowering drug therapy according to Australian Guidelines 
(National heart foundation 2012)2 
2. Family History of myocardial infarction or stroke  
3. Type 2 Diabetes 
4. Familial hypercholesterolemia 
5. Aboriginal or Torres Strait Islander people with LDL-C >2.5 mmol/L 
6. Blood pressure ≥ 180/110 
7. Documented history of:  
a. Ischemic stroke or transient ischemic attack (TIA) 
b. Peripheral arterial disease  
c. Congestive heart failure 
d. Coronary artery disease or ECG findings consistent with prior MI 
8. Carotid artery stenosis or >50% occlusion of the carotid artery  
9. Total Cholesterol  > 7.5 mmol/L 
10. Triglyceride level >4.0 mmol/L 
11. HDL-c <1 and Total cholesterol > 6.5 mmol/L 
12. Current or prior (last 6 months) statin, ezetimibe, fibrate or niacin therapy  


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13. Contraindication to statin use  
a. Pregnancy or lactation 
b. Hypersensitivity to statins 
c. Known myopathy or baseline CK > 3x ULN 
d. Contraindicated concurrent medication 
e. Current cyclosporine, fusidic acid  or oral corticosteroid use 
14. Concomitant antiplatelet drug  
15. Unable to complete study procedures  
16. Any active, clinically significant disease  
17. Concomitant renal or hepatic disease, defined as the presence of the following: 
a. Creatinine Clearance <50ml/min 
b. Transaminase (ALT, AST) above 3 times upper normal limit 
c. Acute hepatic failure 
d. Compensated cirrhosis Child Class B or C 
 
Study procedures 
Carotid intima media thickness (cIMT), carotid-femoral pulse wave velocity (cPWV) and 
biomarkers of immune activation and inflammation will be measured at baseline and 
compared to values obtained after 48 and 96 weeks of treatment with the study medication. 
Other procedures will include assessments of safety, fasting lipid and glucose analysis and 
storage of plasma and peripheral blood mononuclear cells (PBMCs) for future research. 
 
 


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5 Flow Chart 
 
 
 
 
a Demographic data, medical history and medication questionnaire (will be performed with a trained interpreter 
if required) 
b Includes blood pressure measurement, cardiovascular examination; electrocardiogram (ECG) at screening visit 
only 
c See appendix17.2: Compliance self-assessment questionnaire and visual analogue scale 
d Height will only be measured at screening visit. Body Mass Index (BMI) will be calculated at screening and 12 
and 24 month post randomisation 
e Unscheduled visits may be performed for safety/tolerability concerns 
f Framingham (FRS) and Data Collection on Adverse Events of Anti-HIV Drugs (D.A.D) risk scores calculated 
g Full Blood Examination: Haemoglobin, White cell count, Lymphocyte count, Neutrophil count, Platelet count 
h Including sodium, potassium, bicarbonate, chloride, calcium, phosphate, urea, creatinine; Liver function tests 
(LFTs): alanine aminotransferase (ALT), alkaline phosphatase (ALP), total protein, albumin; creatinine 
phosphokinase (CPK), pregnancy screen in women with child bearing potential  
i Participants will fast overnight and have bloods taken in the morning for total cholesterol (TC), low-density 
lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), triglycerides (TG) and glucose 
j Blood for markers of innate immunity and inflammation; see Section11.2 for full description of testing to be 
performed and stored bloods for future projects 
k Carotid intima media thickness (cIMT) will be performed on the left and right common carotid arteries, 12 
consecutive measurements will be made 1-3cm proximal to the carotid bulb in areas identified as being without 
plague.  
l Carotid-femoral Pulse Wave Velocity (cPWV) will be determined by using simultaneous applanation 
tonometry of the carotid and femoral arteries. Only for Australian site.  
Assessment 
Screen  Baseline 
Post randomization 
Week 
-4 
0 
12 
24 
48 
72 
96 
Written Informed consent 
X 
 
 
 
 
 
 
Inclusion / exclusion criteria 
X 
 
 
 
 
 
 
Demographic questionnairea 
X 
 
 
 
 
 
 
Physical examination b 
X 
X 
 
 
X 
 
X 
Compliance assessmentc 
 
 
 
 
X 
 
X 
Weight & Height measurementd 
X 
 
 
 
X 
 
X 
Adverse event assessmente 
 
X 
X 
X 
X 
X 
X 
Risk Score Calculationf 
X 
 
 
 
 
 
 
Laboratory Assessments 
T Cells 
X 
 
X 
X 
X 
X 
X 
HIV RNA viral load 
X 
 
X 
X 
X 
X 
X 
FBEg 
X 
X 
X 
X 
X 
X 
X 
Biochemistryh 
X 
X 
X 
X 
X 
X 
X 
Fasting Lipids/glucosei 
X 
X 
 
X 
X 
 
X 
hsCRP 
 
X 
X 
 
 
 
X 
Research Blood samples j 
 
X 
X 
 
X 
 
X 
Structural assessments 
Carotid IMTk 
X 
 
 
 
X 
 
X 
Pulse Wave Velocityl 
X 
 
 
 
X 
 
X 


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6 Background 
6.1 Relationship between HIV infection and CVD 
 
HIV positive patients have a two-fold increased risk of CVD 
cART has dramatically reduced HIV-related morbidity and mortality resulting in a rapidly 
growing population of older patients living with HIV3,4. The major burden of illness, health 
care utilization and premature death in people with HIV is now due to diseases of ageing, 
particularly CVD, which occurs not only at higher rates (2 fold increased relative risk)5 but 
also at a younger age than in the general population6. In a case-control study performed at the 
Alfred Hospital (AH) in 2010, the incidence of cardiovascular events (CVE) in HIV positive 
people was 8.5 cases per 1000 person years7, twice the rate reported rates in HIV negative 
males of similar age (3.9 per 1000 person years)8. HIV may promote atherogenesis by a 
reduction in high-density lipoprotein cholesterol (HDL-C) and reverse cholesterol transport9, 
immune activation and inflammation, increases in thrombosis and fibrinolysis and endothelial 
dysfunction10,11.  
 
Cardiovascular risk is likely to be underestimated in people with HIV. The contributing effect 
of HIV-associated immune activation and cART on CVD risk in HIV positive people is not 
considered in traditional CVD risk scores (such as the FRS1). In a cohort study conducted by 
our group at the AH, the FRS correlated only moderately with carotid intima media thickness 
(cIMT), a well validated surrogate marker of CVE. 11% of HIV positive patients with low 
(<10%) FRS had a cIMT >0.7 mm (HIV and cardiovascular health (HaCH) study pilot data). 
Whilst others have also shown the true CVD risk is likely to be underestimated by FRS in 
people with HIV12, correlation between FRS and risk of CVD in HIV patients remains 
uncertain. 
 
CVD is associated with immune activation and inflammation in people with HIV. 
The increased risk of CVD in HIV positive people is thought to be due to a combination of 
the effects of HIV infection, toxicity from ART and conventional CVD risk factors. The Data 
collection on Adverse Effects of Anti-HIV Drugs (D:A:D) study, (including data from the 
AH HIV cohort) provided the first evidence of increased incidence of myocardial infarction 
with longer duration of cART (26% increased rate of AMI per year of ART use)13, in 
addition to different relative risks according to class of ART used and specific ART 
drugs14,15. HIV infection is associated with chronic immune activation and inflammation that 
persists despite virologic suppression16. The increased risk of CVD decreases with successful 
ART, but does not return to that of the general population17.  It is also known that increased 
levels of T cell activation in HIV positive participants predicts subclinical carotid artery 
disease18.  
 
The pathogenesis of atherosclerosis is complex but inflammation is a key driving force. 
Inflammation drives oxidation of plasma low-density lipoprotein (LDL-C) and activates 
endothelial cells allowing monocytes to attach to them via their CD11b receptor and then 
migrate into the forming atherosclerotic plaque within the vessel wall. Bacterial endotoxin or 
lipopolysaccharide (LPS) is a potent inducer of inflammation; chronic endotoxemia and high 
plasma soluble CD14 (sCD14, released from monocytes and macrophages) are found in most 
HIV positive people. This is secondary to HIV-induced CD4+ T-cell depletion in the gut and 
loss of mucosal integrity allowing translocation of microbial products (e.g. LPS) across the 
gut19. LPS binds to monocytes via CD14, signalling cellular activation and pro-inflammatory 


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cytokine (e.g. IL-6) production that is critical for the initiation of CVD. Production of CRP in 
the liver is primarily driven by IL-6, which activates further IL-6 production by monocytes20. 
6.2 Surrogate markers of cardiovascular outcomes 
Given the large number of patients that have been required to perform clinical outcome 
studies in CVD it is neither feasible nor practical to design such a study in the HIV 
population. . Thus surrogate markers of CVD endpoints are necessary to allow to effects of 
therapeutic interventions on CVD risk to be assessed in this population. In this study we will 
be utilising two well validated surrogate markers of CVD; cIMT and cPWV. 
 
Carotid intima media thickness  
cIMT has been validated as an independent predictor of CVD outcomes in the general 
population after adjustment for other risk factors21. cIMT has been used as an endpoint in 
clinical trials evaluating the effect of statins on CVD outcomes with a correlation between 
treatment induced reductions in cIMT and AMI22. Several cross-sectional studies have shown 
HIV+ people have greater cIMT than age and sex matched controls23-25, and significantly 
higher progression rates than historical reports in HIV negative populations.  
 
Pulse Wave Velocity  
cPWV is a surrogate measure of arterial stiffness and is considered a marker of 
atherosclerosis. It has been shown to be an independent predictor of CVD events in 
prospective studies26. Increased arterial stiffness has been reported in HIV infection 
compared with HIV negative controls25,27,28. Rosuvastatin has been shown to improve aortic 
arterial stiffness with changes strongly correlated with reduction in LDL29. cPWV will not be 
performed at Swiss sites.  
6.3 Statin therapy 
Statins are HMG-CoA reductase inhibitors that lower total cholesterol, improve endothelial 
function, and halt progression of atherosclerosis30. Randomized trials of rosuvastatin in the 
general population have shown a reduction in major CVD events and in the inflammatory 
biomarker high sensitivity C-reactive protein (hsCRP) in healthy adults with normal LDL 
levels (the JUPITER trial)31. High levels of baseline hsCRP were an independent predictor of 
CVD in this cohort32. The absolute CVD event reduction with rosuvastatin was greatest in 
those with highest baseline hsCRP levels and in those who achieve low hsCRP levels 
regardless of LDL level achieved33,34. The cIMT effect size seen with statin therapy correlates 
with reduction in LDL and baseline cIMT30. As previously shown HIV positive people have, 
on average, greater cIMT and faster cIMT progression rates, thus it is likely that the 
magnitude of effect seen with statin therapy may be greater. 
 
Furthermore, statins are immune modulators, and inhibit inflammation in part by reducing 
chemokine and pro-inflammatory cytokine synthesis by monocytes, inhibiting monocyte 
adhesion to the blood vessel wall as well as improving the function of other cells involved in 
atherogenesis (smooth muscle cells, platelets, endothelial cells)35-37. Rosuvastatin is predicted 
to alter the plasma levels of inflammatory markers and monocyte phenotype by week 12. 
Atorvastatin decreased CRP, IL-6 and CCL2 levels in 4 -6 weeks in HIV negative 
participants38,39. Rosuvastatin has been shown to induce a 16% reduction in hsCRP in stable 
ART-treated HIV positive participants over 45 days40. High dose atorvastatin over 8 weeks in 
ART naive HIV positive participants resulted in significant decreases in immune activation 
(CD4+ HLA-DR+, CD8+ HLA-DR+ and CD8+ CD38+ T cells)41. These effects may provide 


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additional benefit in HIV positive participants given high baseline levels of immune 
activation and inflammation and the association between these markers and CVD outcomes.  
6.4 Selection of doses 
The Jupiter study, using a rosuvastatin dose of 20 mg daily, demonstrated reductions in LDL 
cholesterol by 50% and hsCRP by 37%; resulting in a 50% reduction in vascular events31. 
The METEOR study reported a significant reduction in cIMT progression after 12 months of 
rosuvastatin therapy with the divergence continuing to increase with further follow-up out to 
24 months22. Most rosuvastatin (90%) is excreted unchanged, while 10% undergoes limited 
metabolism by cytochrome P450 2C9. Pharmacokinetic studies of drug-drug interactions in 
healthy volunteers have shown that protease inhibitors (PI) in current use caused a 2.4-4.7 
fold increase in Cmax and 1.5-3 fold increase in AUC for rosuvastatin42,43. For the 
participants receiving a non-PI based cART regimen, a dose of 20 mg rosuvastatin (1 x20 mg 
tablet) will be used. Participants on any PI-based cART regimen will receive 1 X 10 mg 
rosuvastatin (effective exposure 20 mg daily). 
6.5 Rationale for performing study 
The key questions regarding CVD in HIV positive people is the extent to which the 
pathogenesis of CVD differs between HIV positive people and the general population, and 
whether treatment thresholds established in the general population for the initiation of 
conventional CVD interventions (such as statin therapy) apply to HIV positive people. Given 
the role of inflammation in atherosclerosis, strong evidence of higher cIMT and greater 
progression rates of cIMT in HIV infection it is plausible that HIV positive people may 
experience a clinical benefit from the earlier initiation of statin therapy.  
 
This study will prospectively collect validated surrogate CVD endpoint data and extensive 
biomarker investigations in HIV positive participants, enabling controlled comparisons of 
these endpoints between the two treatment arms. It is likely that HIV positive patients at 
moderate FRS (who would not normally qualify for stain therapy on current guidelines) will 
experience quantifiable benefits from administration of rosuvastatin due either to higher 
baseline levels of atherosclerosis not reflected in FRS or due to differential immunological 
effects in the unique milieu of immune activation seen in HIV positive people. 
6.6 Sample size 
The METEOR study of rosuvastatin in HIV negative participants with low to intermediate 
CVD risk  found a mean Common Carotid Artery cIMT progression rate of 0.0088 mm/2 
years in the placebo arm and 0.0004mm/2 years in the rosuvastatin arm22, giving an effect 
size of 0.0084 mm/2 years (95% relative reduction) with a standard deviation (SD) of 0.033 
mm/year. A pilot study in HIV positive patients at the AH (n=10) found that in participants 
treated with non-nucleoside reverse transcriptase inhibitors (the most common cART 
regimen), the mean cIMT progression rate was 0.04 mm/year with a SD of 0.0782 mm 
(personal communication Dmitri Sviridov, Baker IDI), similar to estimated values proposed 
for cIMT progression in HIV positive participants at low to intermediate CVD risk (mean 
0.045 mm/year, SD 0.08 mm; 62).  
 
Conservatively assuming a cIMT progression rate of 0.080 mm with a SD of 0.09 mm over 2 
years and near stabilisation of cIMT (95% relative reduction) with rosuvastatin, we can 
assume an effect size of 0.076 mm with a SD of 0.09 mm. Sample size was calculated using 
an independent groups t-test with an alpha threshold of 1% and a power of 90%. Based on 
these hypotheses, with 44 participants in each group this study will be able to detect an effect 


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size of 0.076 mm with a SD of 0.09 mm over 2 years between the 2 groups. With an 
estimated 15% total drop-out rate over 96 weeks, we estimate that a total study population of 
102 will be required. 
6.7 Hypothesis 
That treatment with rosuvastatin 20mg daily will delay progression of atherosclerosis and 
reduce biomarkers of activation and inflammation in HIV positive people with intermediate 
FRS.  
7 Study objectives 
7.1 Primary Objective 
The primary objective is to determine the effect of rosuvastatin on atherosclerosis progression 
in individuals with HIV infection who are at moderate cardiovascular risk. 
 
The primary outcome measure will be the difference in cIMT progression (measured as a 
change from baseline) between the rosuvastatin and placebo arms.  
7.2 Secondary Objectives 
Secondary objectives are to determine in HIV positive patients: 
1. The safety profile of rosuvastatin  
2. The effect of rosuvastatin on vessel wall function and biomarkers of atherosclerosis 
and innate immune activation 
3. The effect of rosuvastatin on fasting lipids and glucose 
4. Whether baseline measures of immune activation and inflammation predicts cIMT or 
progression of cIMT 
5. Whether a change in measures of immune activation and inflammation from baseline 
after three months of rosuvastatin therapy predicts progression of cIMT 
 
 
Secondary outcome measures include: 
1. The rate of adverse effects (symptomatic and biochemical) between the two treatment 
arms 
2. The effect of rosuvastatin on cIMT and cPWV  
3. The effect of rosuvastatin on immunological and inflammatory markers (including 
sCD14, sCD163, neopterin, S-VCAM-1, adiponectin, CCL2, inflammatory (CD16+) 
monocyte expression of CD38, CX3CR1 and CD11b)  
4. The effect of rosuvastatin on fasting total cholesterol, LDL, HDL, TG and glucose 
levels after 6, 12 and 24 months of therapy 
5. The relationship between baseline measures ofsCD14, sCD163, and neopterin and 
baseline cIMT 
6. The relationship between baseline measures of sCD14, sCD163, and neopterin and 
rate of progression of cIMT 
7. The relationship between change from baseline to 3 months in markers of immune 
activation and inflammation (sCD14, CCL2, and inflammatory (CD16+) monocyte 
phenotypic expression of CD38, CD11b) and progression of cIMT at 12 and 24 
months. 


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8 Study Design 
8.1 Design 
The study will be a randomized, double blinded, placebo controlled, multicentre trial 
comparing the effect of rosuvastatin 20 mg daily versus placebo over 96 weeks in people 
with HIV infection at moderate cardiovascular risk. 
  
Individuals (n=102) with moderate CVD 
risk, as estimated by the FRS (10-15% 10 
year risk of CVD), who do not qualify for 
statin therapy under Australian 
guidelines2, will be randomized 1:1 to 
active rosuvastatin 20mg once daily or 
matching placebo.  
 
Placebo and rosuvastatin capsules identical 
in shape and colour will be used to help 
preserve blinding. Participants on a 
protease inhibitor based cART regimen 
will receive 10 mg rosuvastatin or 
matching placebo.  
 
Randomisation 
A computerized random number generator 
will be used to assign treatment arms. 
Block Randomisation will be stratified by 
country.  
 
There will be seven study visits over the 
96 week duration of the study. 
 
 cIMT, cPWV and biomarkers of immune 
activation and inflammation will be 
measured at screening visit and compared to values obtained after 48 and 96 weeks of 
treatment with the study medication. 
 
cIMT and cPWV measurements will be performed in duplicate, by the same operator at the 
AH Heart Centre or the Swiss site, who will remain blinded to participant randomization, 
throughout the study.  
 
All samples will be processed on site at the AH or the Swiss site. Standard laboratory 
assessments (i.e. biochemistry, full blood examination (FBE), fasting lipids, hsCRP) will be 
processed by AH pathology department or the Swiss sites’ local laboratories. Markers of 
innate immunity and inflammation will be performed in the Burnet laboratories. Plasma and 
PBMCs will be separated from research bloods samples, frozen to -1400C and stored onsite in 
the Burnet laboratory for possible further analysis in the future.  
For Switzerland: Plasma samples for testing of inflammation markers will be stored on site 
at minus 80°  and shipped to central biobank (sérothèque) HUG for analysis at the HUG 
cardiology laboratory. 
HIV Positive Patients 
with Framingham risk 
score of 10 – 15% 
Randomisation 
Week 0 
Placebo 
n=51 
Rosuvastatin 
n=51 
Followed to 96 weeks 
1:1 
n = 102 


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8.2 Duration 
Ninety-six (96) weeks per patient 
Expected duration for entire project – 5 years 
8.3 Study centres 
Patients will be recruited and followed at the Alfred Hospital (Victorian HIV service) 
Infectious Diseases Clinic.  
Switzerland: Patients will be recruited within the HIV Cohort Network, at the following 
hospitals following regulatory approval: University Hospitals in Geneva, Lausanne, Berne, 
Zurich and Basel and the Cantonal Hospitals of St Gallen and Lugano, providing that these 
centers and affiliated Ethics Committee do accept to enrol patients in the present study. The 
patients will be recruited during their routine visits to the sites by the local investigators. The 
use of recruitment advertisements or flyers is not intended.   
9 Study Population 
9.1 Inclusion Criteria 
1. Provision of written, informed consent 
2. Age >30 years 
3. Moderate coronary heart Disease (CHD)  risk, defined as FRS of 10-15%1 
4. HIV positive 
5. Stable ARV regimen > 3 months (i.e. no recent drug change [changes in dosages are 
accepted]) 
6. Plasma HIV viral load <200copies/ml for ≥ 6 months 
9.2 Exclusion criteria 
1. Recommended use of lipid lowering drug therapy according to Australian Guidelines 
(National heart foundation 2012)2 
2. Family History of myocardial infarction or stroke in a male first degree relative before 
55 years of age, or a female first degree relative before 65 years of age  
3. Type 2 Diabetes 
4. Familial hypercholesterolemia 
5. Aboriginal or Torres Strait Islander people with LDL-C >2.5 mmol/L 
6. Blood pressure ≥ 180/110 
7. Documented history of:  
a. Ischemic stroke or transient ischemic attack (TIA) 
b. Peripheral arterial disease (regardless of severity) 
c. Congestive heart failure 
d. Coronary artery disease or ECG findings consistent with prior MI 
8. Carotid artery stenosis or >50% occlusion of the carotid artery known previously or 
discovered during screening procedures 
9. Total Cholesterol  > 7.5 mmol/L 
10. Triglyceride level >4.0 mmol/L 
11. HDL-c <1 and Total cholesterol > 6.5mmol/L 
12. Current or prior (last 6 months) statin therapy  


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13. Current or prior (last 6 months) use of ezetimibe 
14. Current or prior (last 6 months) use of fibrates or niacin 
15. Contraindication to statin use 
a. Pregnancy or lactation 
b. Hypersensitivity to statins 
c. Known myopathy or baseline CK > 3x ULN 
d. Contraindicated concurrent medication 
e. Current cyclosporine, fusidic acid  or oral corticosteroid use 
16. Concomitant antiplatelet drug (Aspirin, Abciximab, Anagrelide, Cilostazol, Clopidogrel, 
Dipyridamole, Eptifibatide, Ticagrelor, Ticlopidine, Tirofiban, Terutroban) 
17. Unable to complete study procedures (i.e. attendance at AH for cIMT and cPWV testing 
or cIMT images not accepted for analysis despite redo examination)  
18. Any active, clinically significant disease (including but not limited to; pancreatitis, 
significant psychiatric disorders, acquired immunodeficiency syndrome (AIDS) defining 
illnesses) which may impact on the results of the study, increase the risk of serious 
adverse events (SAE) or limit participants life expectancy to < 24 months 
19. Concomitant renal or hepatic disease, defined as the presence of the following: 
a. Creatinine clearance <50 ml/min (calculated using the Cockroft-Gault 
equation)45 
b. Transaminase (ALT, AST) above 3 times upper normal limit 
c. Acute hepatic failure 
d. Compensated cirrhosis Child Class B or C 
9.3 Prohibitions 
Concurrent participation in non-related clinical trials is allowed as long as there is no impact 
on the objectives of this trial. 
9.4 Removal of participants from therapy/assessment 
Participants will be withdrawn from the trial if: 
1. A SAE occurs which is thought to be related to involvement in the study 
2. The subject withdraws consent 
3. The subject becomes pregnant 
4. The subject is diagnosed with clinical cardiovascular disease 
a. Cardiovascular 
i. Acute myocardial infarction (AMI) 
ii. Development of angina 
iii. New ECG changes consistent with cardiovascular disease 
b. Cerebrovascular 
i. Stroke or Transient Ischaemic Attack (TIA) 
c. Peripheral vascular disease 
i. Symptomatic claudication 
5. The subject is diagnosed with an acute serious medical illness that would be a 
contraindication to statin therapy i.e. 
a. Acute viral hepatitis ( A, B or C) 
6. CK or transaminase elevation (> 3 times) 


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7. Subject is judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol so as to cause harm to self or seriously interfere with the 
validity of the study result.  
9.5 Pregnancy 
Women of child-bearing potential will be screened for pregnancy on admission to the study. 
Due to a lack of study data relating to the effects of statins on pregnant woman and/or the 
foetus those who are found to be pregnant will be excluded from study participation and 
referred to an appropriate medical service46. 
Female participants will be advised to avoid pregnancy while participating in the study. 
Women who become pregnant after randomisation will be withdrawn from the trial but will 
continue to be monitored for the development of adverse events (AE) or serious adverse 
events (SAE). 
For Switzerland: Women of childbearing potential must use two reliable contraceptive 
methods during the entire trial, from day 1 to one month after the end of the trial. Accepted 
methods are hormonal methods such as the birth control pill associated with a barrier 
method such as the preservative.  
10 Study Medication 
Participants will be randomly assigned in a 1:1 ratio to receive rosuvastatin or matched 
placebo.  
10.1 Rosuvastatin 
Rosuvastatin is a hypolipidaemic agent and member of the drug class of statins used to treat 
high cholesterol and related conditions. Rosuvastatin is licensed by the Australian 
Therapeutic Goods Administration (TGA) for the prevention of major cardiovascular events 
and in patients with hypercholesterolemia (including familial hypercholesterolemia). 
Rosuvastatin should be used as an adjunct to dietary modification. 
 
Rosuvastatin capsules of 10mg and 20mg dosages will be purchased from the manufacturer - 
Astra Zeneca. 
10.2 Placebo 
A placebo identical in appearance to rosuvastatin will be produced by Pharmaceutical 
Packaging Professionals (PPP)in Thebarton South Australia. Stability tests will be performed 
by PPP and lot numbers and expiry dates provided to the sites.  
10.3 Packaging and Labelling 
Packaging and labelling will be in accordance with the applicable local regulatory 
requirements.  
 
The study medication will be packed into bottles by Pharmaceutical Packaging Professionals 
(PPP) and shipped to the sites.  
 
Labels will contain the following information: “for clinical trial use only”; study name and 
number; lot number, expiry date or re-testing date; patient ID or randomization number; 
“keep out of reach of children”; storage condition; name of PI and Institution.  
 


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The study medication will be distributed to the patient by the local research investigator or 
study nurse.  
10.4 Timing of dosing 
Rosuvastatin is taken once daily and can be taken with or without food. Participants will be 
encouraged to take it at the same time every day with a glass of water. Catch up doses should 
NOT be taken in the setting of a missed/forgotten dose. 
10.5 Storage 
The study medication should be stored in its provided packaging at room temperature 
(<30°C) away from heat and moisture. 
10.6 Drug Accountability 
The Investigator is responsible for ensuring accountability for the study medication, including 
reconciliation of drugs and maintenance of drug records.  
 
Drug accountability documentation will be performed according to the local regulatory 
requirements and will include confirmation of the study medication received at the site; the 
study medication distributed to the patient and returned by the patient; lost or destroyed study 
medication; corresponding dates, quantities, batch numbers, expiry dates, as well as subject 
identification numbers.  
 
The investigator should maintain records that adequately document:  
- That the subjects were provided the doses specified by the protocol/amendment(s) 
- That all study medication provided to the site was fully reconciled.  
10.7 Compliance assessment 
Compliance to the study medication (rosuvastatin and placebo) will be assessed by self-
reported questionnaire using a modified Medication Adherence Self-Report Inventory and 
visual analogue scale (VAS) 47.  
 
If it appears that a participant is not taking the study medication according to protocol they 
will be counselled by the investigator in an attempt to improve compliance. 
10.8 Warnings and precautions 
Musculoskeletal reported side effects 
HMG-CoA reductase inhibitors (statins) have been associated with rare cases of severe 
myopathy and rhabdomyolysis, accompanied by increases in creatine kinase (>10x upper 
normal limit), myoglobinuria, proteinuria, and renal failure, mainly observed in 40mg daily 
dosage.  Concomitant use with gemfibrozil (fibric acid derivatives), niacin, cyclosporine, 
erythromycin (macrolides) or azole antifungals may increase the incidence and severity of 
musculoskeletal side effects. Milder forms of myotoxicity (i.e., myalgia) are commonly 
reported and occur in approximately 5% to 7% of patients taking a statin drug. 
 
Other reported side effects 
frequent (≥1/100, <1/10):  
- 
Myalgia 
- 
Diabetes (JUPITER study 2,8% in the rosuvastatin arm versus 2,3% in the placebo 
arm) 
- 
Headache, dizziniess 


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- 
Abdominal pain, constipation, nausea 
- 
Asthenia 
Occasional (≥100/10, <1/10):  
- 
Pruritis, rash 
Rare (≥1/10’000, <1/1000) side effets include:  
- 
Myopathy, arthralgia 
- 
Hepatic transaminases elevations 
- 
Hypersensitivity reactions 
- 
Pancreatitis 
Very rare (<1/10’000) side effects: 
- 
Jaundice, hepatitis 
- 
Hematuria 
- 
Polyneuropathy 
Frequency unknown: 
- 
Cough, dyspnea  
- 
Diarrhea 
- 
Steven-Johnson syndrome 
- 
Necrotic myopathy 
- 
Gynecomastia  
- 
Oedema 
10.9 Concomitant medications 
Participants are not to commence any new medication without notifying the study 
coordinators to allow an assessment for potential interactions with the study medication. 
10.9.1 Contraindications 
The use of rosuvastatin is contraindicated in combination with the following medications. A 
patient requiring commencement of these medications following enrolment will be 
withdrawn from the study. 
- 
Cyclosporine  
o Combined uses significantly increases rosuvastatin exposure. 
- 
Gemfibrozil and other fibrates 
o Combined use increases the risk of adverse skeletal muscle effects and should 
only be used with caution 
- 
Niacin 
o Combined use increases the risk of adverse skeletal muscle effects and should 
only be used with caution 
- 
Fusidic acid 
o Combined use increased rosuvastatin levels and the risk of adverse skeletal 
muscle effects 
10.9.2 Warfarin 
Combined use of coumarin anticoagulants with rosuvastatin is not contraindicated but will 
lead to prolonged INR. Patients should have a stable INR prior to starting rosuvastatin. INR 
monitoring should occur at increased frequency upon initiation or alteration of rosuvastatin 
dose. 
10.9.3 Antiretrovirals 
Participants must be on a stable ARV regimen for > 3 months (with HIV viral load <200 for 
>6 months) to be eligible for acceptance into the study.  ARV regimens will remain at the 


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discretion of the patients treating physician who will be blinded to study medication but not 
involvement in the study. 
 
Participants on any PI-based cART regimen will receive 1 x 10 mg rosuvastatin (effective 
exposure 20 mg daily). 
 
Participants who require a change in antiretroviral regimen following randomisation on the 
basis of treatment failure or intolerability (that could not be attributed to the study 
medication) may remain within the study. 
- 
Patients who switch from a PI containing regimen to a non-PI containing regimen will 
have the dose of rosuvastatin (or placebo) increased to 20mg daily 
- 
Patients who switch from a non-PI containing regimen to a PI containing regimen will 
have the dose of rosuvastatin (or placebo) reduced to 10mg daily 
- 
Switches within classes of ARV require no change in study medication dose 
10.10 Drug interactions listm 
 
Table below: Influence of concomitantly administered drugs on exposure to rosuvastatin (AUC, Cmax in 
descending order of effect size) based on published clinical trials. Source: Swiss Compendium 
(www.compendium.ch)   
 
Interacting Drug, dosage and 
treatment period 
Rosuvastatin-dosage and 
treatment period 
Effect on   
rosuvastatin AUC 
Effect on   
rosuvastatin-Cmax 
Ciclosporin 75 mg b.i.d. up to 
200 mg b.i.d., 6 Months 
10 mg q.d., 10 days 
7,1 fold ↑ 
11 fold ↑ 
Atazanavir 300 mg/Ritonavir  
100 mg q.d., 8 days 
10 mg, single dose 
3,1 fold ↑ 
7 fold ↑ 
Lopinavir 400 mg/Ritonavir  
100 mg B.I.D., 17 days 
20 mg q.d., 7 days 
2,1 fold ↑ 
5 fold ↑ 
Gemfibrozil 600 mg b.i.d., 7 
days 
80 mg, single dose 
1,9 fold ↑ 
2,2 fold ↑ 
Eltromobopag 75 mg q.d. , 
10 days 
10 mg, single dose 
1,6 fold ↑ 
2 fold ↑ 
Darunavir 600 mg/Ritonavir  
100 mg b.i.d., 7 days 
10 mg q.d., 7 days 
1,5 fold ↑ 
2,4 fold ↑ 
Tipranavir 500 mg/Ritonavir  
200 mg b.i.d., 11 days 
10 mg, single dose 
1,4 fold ↑ 
2,2 fold ↑ 
Dronedaron 400 mg b.i.d. 
No data 
1,4 fold ↑ 
No data 
Itraconazol 200 mg q.d. , 5 days 10 mg or 80 mg,  
single dose 
1,4 fold ↑ 
1,4 fold ↑ 
Ezetimibe 10 mg q.d. , 14 days 10 mg q.d. , 14 days 
1,2 fold ↑ 
1,2 fold ↑ 
Fosamprenavir 700 mg/ 
Ritonavir  
100 mg b.i.d., 8 days 
10 mg, single dose 
↑ 8% 
1,5 fold ↑ 
Aleglitazar 0,3 mg, 7 days 
40 mg, 7 Days 
↔ 
1,1 fold ↑ 
Silymarin 140 mg t.i.d., 5 days 10 mg, single dose 
↔ 
↔ 
Fenofibrat 67 mg t.i.d., 7 days 
10 mg, 7 Days 
↑ 7% 
1,2 fold ↑ 
Rifampicin 450 mg q.d. , 7 days 20 mg, single dose 
↔ 
↔ 
 
m Source:  Swiss Compendium and translated into the English by the Swiss site : www.compendium .ch 


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Interacting Drug, dosage and 
treatment period 
Rosuvastatin-dosage and 
treatment period 
Effect on   
rosuvastatin AUC 
Effect on   
rosuvastatin-Cmax 
Ketoconazol 200 mg b.i.d., 7 
days 
80 mg, single dose 
↑ 2% 
↔ 
Fluconazol 200 mg q.d. , 11 
days 
80 mg, single dose 
↑ 14% 
↔ 
Erythromycin 500 mg q.i.d., 7 
days 
80 mg, single dose 
28% ↓ 
31% ↓ 
Baicalin 50 mg t.i.d., 14 Days 
20 mg, Single dose 
47% ↓ 
19% ↓ 
«↑»: Increase. 
«↔»: No change (defined as <20% change of rosuvastatin -AUC, C-max). 
«↓»: Decrease. 
 
10.11 Blinding and Emergency Unblinding 
The personnel involved in the conduct of the trial as well as the study participants will remain 
blinded to the assigned study medication, throughout the trial.  
 
Unblinding: The study physician may decide to break the randomization code of the 
participant for security reasons only. Emergency code breaking instructions will be provided 
to the sites. In Switzerland: the coordinating centre must be informed immediately if a code 
has been broken.  
11 Assessments 
All assessments including screening and unplanned study visits will be recorded on the case 
report form (CRF) – See Appendix 22.1 
 
Demographic data, medical history and medication questionnaire  
Patients will be questioned on details necessary for determining eligibility for entry into the 
trial and important study variables. Topics to be covered include, age, gender, race, presence 
of CVD risk factors (smoking status, family history of CVD etc.), past medical history, 
current medications and the presence of any allergies.  
The questionnaire will be completed by a study investigator at the screening visit. At all 
subsequent visits patients will be asked: 
1. If they  have developed or been diagnosed with any new medical illnesses since the 
last review 
2. If they have started or stopped any non-study medications 
3. Their current smoking status. 
 
Compliance assessment 
1. Compliance with the study medication will be performed at two time points (Weeks 
48 and 96) to estimate compliance throughout the study. A self-assessment question 
sheet and VAS will be used asking participants to estimate compliance over the last 
fortnight and month. (See appendix 22.2) 
 
Physical examination 
Consists of: 
1. Complete physical examination 
2. Blood pressure measurement with patient sitting 


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3. Recording presence of bilateral lower limb peripheral pulses of the posterior tibial and 
the dorsalis pedis arteries 
4. Anthropometry 
a. Weight will be measured in kilograms (kg) with patient clothed; footwear 
removed 
b. Height will be measured in metres (m) with footwear removed 
c. Waist circumference (adapted from the International Diabetes Federation 
guidelines on the diagnosis and management of the metabolic syndrome)48  
i. Subject should be standing erect dressed in underwear; all outer 
clothing should be removed. 
ii. Make sure the tape does not compress the tissues during the 
measurement. 
iii. Record the measurement after the subject has exhaled with the tape 
measure in a horizontal plane, midway between the inferior margin of 
the ribs and the superior border of the iliac crest. 
 
Electrocardiogram (ECG) 
ECG will be performed by trained study investigators at screening visit. 
All ECGs will be read by a blinded study doctor; all important abnormalities on the ECG will 
be reported. Specifically the presence of findings consistent with prior myocardial infarction 
(as defined by the 2007 Joint European Society of Cardiology/American College of 
Cardiology Federation/American Heart Association/World Health Federation 
(ESC/ACCF/AHA/WHF) Task Force49; 
- 
Any Q-wave in leads V2-V3 ≥ 0.02s or QS complex in leads V2 and V3 
- 
Q-wave ≥ 0.03s and ≥ 0.1mV deep or QS complex in leads I, II, aVL, aVF or V4-V6, 
in any two leads of a contiguous lead grouping (I, aVL, V6; V4-V6; II, III, aVF) 
- 
R-wave ≥ 0.04s in V1-V2 and R/S ≥ 1 with a concordant positive T-wave in the 
absence of a conduction defect 
 
Adverse event assessment 
See sections 13 and 14 for details on AE and SAE reporting and assessment 
At each study visit patients will be asked to report any untoward medical occurrences and 
will also be specifically questioned regarding the presence of: 
- 
Myopathic symptoms (weakness, muscle pain) 
- 
Gastrointestinal disturbance (diarrhoea, nausea, vomiting, abdominal pain) 
- 
Jaundice 
11.1 Calculations 
 
Framingham Risk Score 
Ten-year risk of developing “hard” coronary heart disease endpoints (myocardial infarction 
and coronary death) will be calculated based on the Framingham Risk Score using an online 
calculator available at www.old.mdcalc.com/framingham-coronary-heart-disease-risk-score-
si-units/ 
 
D.A.D Risk Score 
The D.A.D equation is a cardiovascular risk assessment model that is tailored for use in HIV 
positive participants, taking into account exposure to specific PIs, family history of CHD and 
previous, as well as current smoking status50. A D.A.D. risk score will be calculated on all 


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participants at baseline to allow for a comparison with the FRS and to compare each measure 
with cIMT. The calculation will be performed using an online tool available at: 
http://www.cphiv.dk/tools/dadriskequations/tabid/437/default.aspx 
 
Body Mass Index (BMI) 
A BMI will be calculated at screening visit and at the forty-eight (48) and ninety-six (96) 
week visits. Height will only be measured at screening and assumed to remain stable through 
the study period 
BMI = Weight (kg) / height2 (m)  
 
Creatinine clearance 
An estimated creatinine clearance will be calculated at screening visit to determine eligibility 
for entry into the trial using the Cockroft-Gault equation45 
 
For men 𝐶𝑙=
1.23 × weight (kg) ×(140−𝑎𝑔𝑒(𝑦𝑒𝑎𝑟𝑠))
Creatinine (µmol/L)
 
 
For women 𝐶𝑙=
1.03 × weight (kg) ×(140−𝑎𝑔𝑒(𝑦𝑒𝑎𝑟𝑠))
Creatinine (µmol/L)
 
11.2 Laboratory Assessments 
 
Handling of Biological samples 
All biological samples (excluding those for storage and testing of innate immunity) will be 
processed at the Alfred Hospital laboratory or the Swiss site; local laboratory reference 
ranges will apply (see appendix 22.3 and 22.4). 
 
Biological samples for testing of innate immunity will be handled at the Burnet Institute. 
Plasma will be separated and frozen (-80ºC). Plasma markers will be analysed on batched 
frozen samples by ELISA. 
Swiss sites will store plasma samples (6mls per visit) at -80°C and ship to the HUG 
cardiology laboratory for testing of plasma markers. Innate immunity markers (PBMC) will 
not be performed at Swiss sites.  
A separate laboratory SOP will be provided to all the Swiss sites.  
 
HIV specific testing 
HIV monitoring (CD4+ T-cell count and HIV viral load) will be performed at screening, 
baseline and weeks 12, 48, 72 and 96 
 
Laboratory assessments for safety 
Routine laboratory assessments for safety and tolerability will be performed including: 
- 
Full Blood Examination (FBE) 
o Consisting of; Haemoglobin (Hb), total White Cell Count (WCC), 
Lymphocyte Count (Lymp), Neutrophil Count (Neut) and Platelet count (Plt) 
- 
Biochemistry 
o Consisting of; Sodium (Na), Potassium (K+), Chloride (Cl), Bicarbonate 
(HCO3), Calcium (Ca), Phosphate (PO4), Urea (Ur), Creatinine (Cr) and 
creatinine phosphokinase (CPK) 


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o An estimated glomerular filtration rate (eGFR) based on the Modification of 
Diet in Renal Disease (MDRD)51 equation is calculated electronically by the 
AH laboratory and will be recorded 
o Liver Function Tests: Total Protein (TP), Albumin (Alb), Bilirubin (Bil), 
Alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and Gamma-
glutamyl transpeptidase (GGT) 
o Pregnancy screen in women with child bearing potential (at screening visit); 
Beta Human chorionic gonadotrophin (β-HCG) 
 
Fasting metabolic parameters  
Patients will be requested to attend the study visit having fasted overnight (for 12 hours).  
Definition of fasting: no food, caffeine or caloric drinks; free water is allowed and 
encouraged. Samples will be sent for TC, HDL, LDL, TG and glucose. 
Study participants and site investigators will be blinded to the results of metabolic testing 
until the completion of the study. This is to prevent self-modification of lifestyle or diet in an 
attempt to normalise out-of-range results 
 
Markers of Innate immunity and inflammation 
Markers of Innate immunity and inflammation will be measured at baseline, and weeks 12, 
48, and 96.  
For participants recruited in Melbourne only: A panel of innate immune markers selected 
from HaCH including monocyte markers (CD14, CD16) of activation (CD38), of expression 
linked to migration, adhesion and progression of atherosclerotic plaque (CD11b, CX3CR1) 
will be performed.  
In participants from both sites in plasma, markers of inflammation (IL6, sCD163) and 
monocyte activation / chemokine ligands (sCD14, neopterin, CCL2), S-VCAM-1 and 
adinopectin will be measured. 
 
High sensitivity C-reactive protein (hsCRP) will be performed by the AH laboratory 
according to standard protocols 
 
Stored Samples 
4ml of plasma will be stored indefinitely for possible future testing and research for 
participants that give their consent. Storage samples will be collected at baseline and weeks 
12, 48 and 96. 
Samples will be stored at -800C in the Burnet research laboratory and -80°C at the Swiss 
sites. Swiss sites will transfer the samples to the HUG central “sérothèque” for storage.  
Participants recruited from the Alfred Hospital will also have PBMC’s stored at -140 in the 
Burnet research laboratory. 
11.3 Carotid IMT  
The bilateral carotid artery will be assessed for cIMT by B Mode ultrasound using a Philips 
iE33 with 11 MHz linear transducer (Melbourne). The Swiss sites will be using the 
ultrasound machine tested and accepted by the core lab in Montréal following the Standard 
Operating Procedures for cIMT. The cIMT measurement is a painless and harmless non-
invasive ultrasound procedure performed on patients’ left and right common carotid arteries. 
The procedure takes 20 minutes to perform. The cIMT defined as the distance between 
lumen-intima interface and media-adventia interface is measured from the 2D high resolution 
digital images obtained using an automated border-detection algorithm. cIMT will be 


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determined on areas identified as without plaque by 12 consecutive measurements made 1-3 
cm proximal to the carotid bulb, but the presence of plaques will be noted. All measurements 
will be performed in duplicate, by the same operator at the AH Heart Centre or the Swiss site, 
who will remain blinded to participant randomization, throughout the study.  
 
Investigators and patients will not receive results from cIMT (or cPWV – see below) until the 
end of the study, unless a significant carotid plaque warranting further investigation and 
management is identified. Patients who are identified as having a significant plaque will be 
withdrawn from the study and referred to a cardiologist at the AH or the Swiss site for further 
assessment and management as necessary. 
11.4 Pulse Wave Velocity 
Australian site only: cPWV will be determined using simultaneous applanation tonometry of 
the carotid and femoral arteries. PWV will be calculated as manubrium sternum-to-femoral 
artery distance minus carotid artery-to-manubrium sternum distance divided by the time 
interval between the carotid and femoral pulses calculated from the upstroke of the systolic 
waveform (maximum of the second derivative). The cPWV will be reported as the average of 
pulse waves recorded over a 10 second period. It is a painless and harmless procedure that 
takes 20 min to perform by trained operators. The co-efficient of variation for this 
measurement is 5%. 
12 Visit Schedule 
12.1 Screening 
The screening procedures will be completed in one visit at the study site. 
Participants will present to the study site, having fasted from overnight for at least 12 hours 
(no food, caffeine or caloric drink; free water is encouraged). 
 
Written informed consent will be obtained at screening visit by trained research staff (see 
Appendix 22.5 and 22.6). Participants will be informed in written and orally prior to the 
screening visit and given sufficient time for reflexion before signing the consent form.  
 
 Assessments 
1. Demographic data, medical history and medication questionnaire to be completed 
2. Full physical examination including: 
a. Height and weight  
b. Assessment of peripheral pulses 
c. Blood pressure 
d. ECG 
3. Laboratory assessments 
a. FBE and biochemistry 
b. Beta HCG for all women of child bearing potential 
c. Fasting metabolic assessment 
d. HIV viral load and CD4+ T cell count (and percentage) 
4. Structural assessments 
a. cIMT 
b. cPWV (*Melbourne Participants only) 
5. Calculations 
a. BMI  


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b. Creatinine clearance 
c. FRS 
d. D.A.D. risk score 
12.1.1 Eligibility 
Clinical eligibility will be recorded based on the inclusion (1-6) and exclusion criteria (7-26) 
listed below. 
12.2 Inclusion Criteria 
1. Provision of written, informed consent 
2. Age >30 years 
3. Moderate coronary heart Disease (CHD)  risk, defined as FRS of 10-15%1 
4. HIV positive 
5. Stable ARV regimen > 3 months (i.e. no recent drug change [changes in dosages are 
accepted]) 
6. Plasma HIV viral load <200copies/ml for ≥ 6 months 
12.3 Exclusion criteria 
7. Recommended use of lipid lowering drug therapy according to Australian Guidelines 
(National heart foundation 2012)2 
8. Family History of myocardial infarction or stroke in a male first degree relative before 
55 years of age, or a female first degree relative before 65 years of age  
9. Type 2 Diabetes 
10. Familial hypercholesterolemia 
11. Aboriginal or Torres Strait Islander people with LDL-C >2.5 mmol/L 
12. Blood pressure ≥ 180/110 
13. Documented history of:  
a) Ischemic stroke or transient ischemic attack (TIA) 
b) Peripheral arterial disease (regardless of severity) 
c) Congestive heart failure 
d) Coronary artery disease or ECG findings consistent with prior MI 
14. Carotid artery stenosis or >50% occlusion of the carotid artery known previously or 
discovered during screening procedures 
15. Total Cholesterol  > 7.5 mmol/L 
16. Triglyceride level >4.0 mmol/L 
17. HDL-c <1 and Total cholesterol > 6.5mmol/L 
18. Current or prior (last 6 months) statin therapy  
19. Current or prior (last 6 months) use of ezetimibe 
20. Current or prior (last 6 months) use of fibrates or niacin 
21. Contraindication to statin use 
f. Pregnancy or lactation 
g. Hypersensitivity to statins 
h. Known myopathy or baseline CK > 3x ULN 
i. Contraindicated concurrent medication 
j. Current cyclosporine, fusidic acid  or oral corticosteroid use 


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22. Concomitant antiplatelet drug (Aspirin, Abciximab, Anagrelide, Cilostazol, Clopidogrel, 
Dipyridamole, Eptifibatide, Ticagrelor, Ticlopidine, Tirofiban, Terutroban) 
23. Unable to complete study procedures (i.e. attendance at AH for cIMT and cPWV testing 
or cIMT images not accepted for analysis despite redo examination)  
24. Any active, clinically significant disease (including but not limited to; pancreatitis, 
significant psychiatric disorders, acquired immunodeficiency syndrome (AIDS) defining 
illnesses) which may impact on the results of the study, increase the risk of serious 
adverse events (SAE) or limit participants life expectancy to < 24 months,  
25. Any active, clinically significant disease (including but not limited to; pancreatitis, 
significant psychiatric disorders, acquired immunodeficiency syndrome (AIDS) defining 
illnesses) which may impact on the results of the study, increase the risk of serious 
adverse events (SAE) or limit participants life expectancy to < 24 months 
26. Concomitant renal or hepatic disease, defined as the presence of the following: 
a. Creatinine clearance <50 ml/min (calculated using the Cockroft-Gault 
equation)45 
b. Transaminase (ALT, AST) above 3 times upper normal limit 
c. Acute hepatic failure 
d. Compensated cirrhosis Child Class B or C 
 
If the patient fulfils all eligibility criteria (1-26 above) then a baseline visit will be booked. 
CRFs from participants assessed but found to be ineligible for inclusion in the study will be 
entered into the database recording the reason for ineligibility. 
12.4 Randomisation 
Patients will be block randomised in a 1:1 ratio to receive rosuvastatin or placebo. 
Randomisation will be stratified by centre.  
12.5 Baseline visit 
Participants will be required to present to the study site having fasted overnight for at least 12 
hours (no food, caffeine or caloric drinks; free water is encouraged) 
 
Assessments performed: 
1. Targeted physical examination and updated history, assessment for new concomitant 
medications  
2. Adverse event assessment 
3. Laboratory assessments 
a. Biochemistry 
b. Fasting metabolic assessment 
c. hsCRP 
d. Markers of innate immunity and inflammation 
e. Storage of plasma and PBMCs (*Melbourne participants only) for possible 
further analysis in the future 
 
Patients will be provided with a three (3) month supply of the study medication and educated 
regarding possible clinical signs of potential adverse events (muscle ache, fever, abdominal 
pain, jaundice, rash); regardless of randomisation.  Patients will also be provided with contact 
details for study co-ordinators in case of adverse event.  


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12.6 Week 12 visit 
Participants will be required to present to the study site having fasted overnight for at least 12 
hours (no food, caffeine or caloric drinks; free water is encouraged) 
 
Assessments performed: 
1. Assessment for adverse events 
2. Laboratory assessment for: 
a. FBE 
b. Biochemistry 
c. hsCRP 
d. Markers of innate immunity and inflammation 
e. HIV Viral load and CD4+ T-cell count (and percentage)  
3. Storage of plasma and PBMCs (*Melbourne participants only) for possible future 
analysis 
 
Patients provided with a further three (3) month supply of the study medication. 
12.7 Week 24 visit 
Participants will be required to present having fasted overnight for at least 12 hours (no food, 
caffeine or caloric drinks; free water is encouraged) 
 
Assessments performed: 
1. Assessment for adverse events 
2. Laboratory assessment for: 
a. Biochemistry 
b. Fasting metabolic assessment 
c. HIV Viral load and CD4+ T-cell count (and percentage) 
 
Patients will be provided with a six (6) month supply of the study medication 
12.8 Week 48 visit 
Participants will be required to present having fasted overnight for at least 12 hours (no food, 
caffeine or caloric drinks; free water is encouraged). 
 
Assessments performed: 
1. Targeted physical examination and updated history, assessment for new concomitant 
medications  
2. Weight recorded 
3. Compliance assessment 
a. Self-assessment questionnaire and VAS 
4. Adverse event assessment 
5. Laboratory assessments 
a. Biochemistry 
b. Fasting metabolic assessment 
c. HIV Viral load and CD4+ T-cell count (and percentage)  
d. Markers of innate immunity and inflammation 
e. Storage of plasma and PBMCs (*Melbourne participants only) for possible 
further analysis in the future 
6. Calculations 


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a. Creatinine clearance 
b. BMI 
7. Structural assessments 
a. cIMT 
b. cPWV (*Melbourne participants only) 
 
Patients will be provided with a six (6) month supply of the study medication 
12.9 Week 72 visit 
Fasting NOT required for this visit 
 
Assessments performed: 
1. Assessment for adverse events 
2. Laboratory assessment for: 
a. Biochemistry 
b. HIV Viral load and CD4+ T-cell count (and percentage) 
 
Patients will be provided with a six (6) month supply of the study medication 
12.10 
Week 96 visit 
Participants will be required to present to the AH having fasted overnight for at least 12 hours 
(no food, caffeine or caloric drinks; free water is encouraged). 
 
Assessments performed: 
1. Targeted physical examination and updated history, assessment for new concomitant 
medications  
2. Weight recorded 
3. Compliance assessment 
a. Self-assessment questionnaire and VAS 
4. Adverse event assessment 
5. Laboratory assessments 
a. FBE 
b. Biochemistry 
c. Fasting metabolic assessment 
d. hsCRP 
e. HIV Viral load and CD4+ T-cell count (and percentage) 
f. Markers of innate immunity and inflammation 
g. Storage of plasma and PBMCs (*Melbourne participants only) for possible 
further analysis in the future 
6. Calculations 
a. Creatinine clearance 
b. BMI 
7. Structural assessments 
a. cIMT 
b. cPWV (*Melbourne participants only) 
 
Patients will be advised to cease study medication. Statin will be prescribed according to 
phycisian’s assessment. 


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12.11 
Unscheduled visits 
Unscheduled visits may be initiated by study co-ordinators and doctors, participants or 
treating physicians. All assessments made during unscheduled visits will be recorded on the 
CRF. 
This visit may involve, but is not limited to, the following assessments; targeted medical 
review and physical examination, additional laboratory examination for safety reasons. SAE 
or AE visits may occur as unscheduled visits. 
12.1 Withdrawal visit  
For participants that fulfil any of the withdrawal criteria above a withdrawal visit is 
performed if the participant agrees. All assessments made during the withdrawal visit can be 
recorded on the CRF (unscheduled visit). This visit will include, but is not limited to, a 
targeted medical review and physical examination, laboratory examination for safety reasons 
(chemistry and haematology), pregnancy test for women and study drug return. Tests 
performed can vary according to the judgement of the study physician.  
 
Clinical or biological abnormalities perceived at the withdrawal visit will be followed at an 
interval decided by the study physician, until they are resolved or baseline values obtained. 
 
Participants that withdraw from the study may be contacted by telephone at study end for 
vital status, unless they refuse and this is documented.  
 
In Australia: In the event of withdrawal of consent by the participant, the Form for 
withdrawal of participants is completed.  
 
12.2 Time windows 
The baseline visit will occur within four (4) weeks of screening to allow for laboratory 
assessments to be completed and FRS to be calculated confirming eligibility 
Study visits at weeks 12 and 24 have a visit window of +/- 14 days (to allow for scheduling 
of structural assessments and subject convenience). Study visits at weeks 48, 72 and 96 have 
a visit window of +/- 6 weeks. 
13 Adverse Events 
 
An AE is defined as follows: 
Any untoward medical occurrence in a clinical investigation subject administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavourable and unintended sign, symptom, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
Pre-existing or recurrent conditions that occur during the study should not be considered as 
AEs unless they change in frequency or severity. 
All AEs that occur from the time the subject consents to participate in the study and 
throughout the duration of the study shall be recorded as an AE in the individuals CRF. 
At the final study visit (week 96) any ongoing adverse events deemed related to study drug 
will be followed up for a minimum of 30 days and until resolution. 
 


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In case a treatment interruption is needed during the treatment period in the event of a 
suspected toxicity, the subject will not automatically be withdrawn from the trial, as long as 
treatment interruption does not exceed 4 weeks. 
 
AEs and SAEs will be categorised and recorded as per the modified Division of AIDS table 
for grading the Severity of Adverse Events (see Appendix 22.6). Causal relationship of AEs 
and SAEs to the trial and the study medication will also be assessed. 
14 Serious Adverse Events 
 
A serious adverse event (SAE) is defined as follows: 
Any adverse drug experience occurring at any dose that results in any of the following 
outcomes: 
- 
Death 
- 
Life-threatening situation (subject is at immediate risk of death) 
- 
In-patient hospitalisation or prolongation of existing hospitalisation 
- 
Persistent or significant disability/incapacity 
- 
Congenital anomaly/birth defect in the offspring of a subject who received the study 
drug 
- 
Other medically significant events that may not be immediately life-threatening or 
result in death or hospitalization, but based upon appropriate medical and scientific 
judgement, may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the outcomes listed above. 
14.1 Serious Adverse Event Reporting Requirements 
The Principal Investigator and/or the project coordinator (coordinating center for Swiss sites) 
must be notified immediately (within 24 hrs of awareness of the event) regarding the 
occurrence of any SAEs. 
The Principal Investigator and/or the study monitor (coordinating center for Switzerland) will 
report any SAE that fulfils the criteria for expedited reporting (unexpected and drug related 
events) to the appropriate regulatory authorities within the required reporting time frame. 
SAEs must also be reported to the approving ethics committee(s) as required by the ethics 
committee reporting procedures. 
SAEs must be reported during a subject’s participation in the study (whether receiving study 
medication or not) or within 30 days of receiving the last dose of study agent, whichever is 
longer.  
 
Any SAE that is ongoing at the final study visit (week 96) will be followed until resolution or 
stabilisation (for those events that will not resolve). 
 
For Switzerland: Safety reporting will be performed according to regulatory requirements 
detailed in the Overview of safety reporting procedures that is published on the Swissethics 
(Swiss association of Ethics Committees for clinical trials) website: 
http://www.swissethics.ch/doc/templates/Overview_safety_AGEK_dec11_final.pdf.  
The coordinating centre Geneva must be reported to immediately by the study site in case of 
an SAE or SUSAR. The coordinating centre Geneva will report all drug related events 
(Adverse Drug Reactions) to Swissmedic in an annual update safety report. All 
SUSARS/SUSADRs (Suspected, unexpected Serious Adverse Drug Reaction) will be reported 


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to Swissmedic within 7 days for fatal and/or life threatening ADRs, 15 days for all other 
reportable ADRs.  
15 Data safety and monitoring board 
 
An independent Data safety and monitoring board (DSMB) will be set up to monitor the 
safety of and efficacy in the participants enrolled in the trial. The DSMB will be chaired by 
A. Carr. Members will include one cardiologist from Switzerland (Proposition: R Lerch), one 
methodologist (Proposition: Prof  Perneger), and one statistician from Australia (Proposition: 
T Spelman). 
 
Data will be sent to the DSMB every 24 weeks. A summary of SAEs, grade 3/4 AEs and 
laboratory toxicities, and AEs leading to discontinuation will be provided on a monthly basis.  
 
There will be a single, un-blinded, interim safety and efficacy analysis and review meeting 
after the last participants has completed 48 weeks of follow-up. The following data will be 
reviewed:  
 
Safety data:  
• Participant recruitment, accrual, retention, and withdrawal information 
• Adverse events (AEs) and serious adverse events (SAEs)  
• Clinical test results and laboratory values  
• Vital signs and physical exam outcomes 
• Participant questionnaires  
• Study drug dose information 
• Any other safety-supporting data requested by the DSMB 
 
Efficacy data 
• cIMT data (primary endpoint measure) 
 
Primary outcome measures (cIMT) and the first secondary outcome measure (adverse effects) 
will be analysed. Based on these analyses, the DSMB will make recommendations regarding 
the continuation, modification or termination of the trial.  
 
Stopping rules:  
The DSMB may recommend stopping of the trial for the following reasons:  
• The data show a significantly increased risk of serious adverse effects in one of the 
treatment groups.   
• On the basis of a positive efficacy result only when the data are truly compelling and 
the risk of a false positive conclusion is acceptably low. The trial will only be stopped 
for positive efficacy if a strong statistically and clinically significant difference in 
cIMT is seen between treatment arms.  
• If interim data suggest that the product under study is of no benefit (no trend 
indicating superiority of the product), or that accrual rates are too low and/or that 
noncompliance is too great to provide adequate power for identifying the specified 
benefit, the DSMB may consider whether continuation of the study is futile and may 
recommend termination on this basis. 


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• It becomes clear that successful completion of the study is not feasible (e.g. there is an 
excess of patient dropout, missing data, lack of recruitment etc). 
 
The DSMB may recommend modifications to individual stopping rules if additional safety 
concerns arise during from their continuing reviews of the study data.   
16 Trial or site discontinuation 
The trial leaders (Principal Investigator in Melbourne and Geneva) reserve the right to 
discontinue the trial at any time for the following reasons:  
• Emergence of safety of other information that could significantly affect the 
continuation of the trial; 
• Failure to meet expected enrolment goals overall or at a particular trial site; 
• Violation of GCP or the agreement of the investigator to conduct the trial 
appropriately.  
17 Statistical Analysis 
Baseline characteristics will be summarized using median (interquartile range) for quantitative 
variables and frequency and percentage for qualitative variables. 
 
1. Analysis of the primary endpoint: 
To study rosuvastatin effect from baseline to week 96 on mean and / or of left and right maximal 
IMT progression, multi-levels, repeated measures, linear mixed-effects models adjusted for 
demographics and/or traditional CVD risk factors and centre (Melbourne, Geneva, Lausanne, 
Berne, Zurich, Basel, St. Gallen, Lugano) will be used. Levels used for the data will be patient 
and carotid artery locations (CCA, ICA, BIF and ECA) within patients; the repeated measure 
will be time (baseline, week 48 and week 96). 
 
A comparison across arms (placebo/rosuvastatin) of missing IMT measurements (0, 1, 2 or 3 
missing per IMT location) will be performed using a Chi-Square Test with a threshold of 1%. 
 
2. Analysis of the secondary endpoints: 
To study rosuvastatin effect from baseline to week 48 on mean and / or of left and right maximal 
IMT progression, multi-levels, repeated measures, linear mixed-effects models adjusted for 
demographics and/or traditional CVD risk factors and centre will be used. Levels used for the 
data will be patient and carotid artery locations (CCA, ICA, BIF and ECA) within patients; the 
repeated measure will be time (baseline and week 48). 
 
Repeated measures linear mixed-effects models adjusted for demographics and/or traditional 
CVD risk factors and centre will be used to assess the association between the arms 
(placebo/rosuvastatin) and each of the following parameters at week 0, 12, 24, 48, 72 and 96. 
We will test the interaction term between the arms and time (Month 0, 6, 12 and 24) to 
determine whether the rate of progression of the following parameters differed between arms 
(rosuvastatin versus placebo): Fasting Total Cholesterol, low-density lipoprotein (LDL)-
cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides and glucose. 
 
Biomarkers of inflammatory process (sCD14, sCD163, neopterin, S-VCAM-1, adiponectin, 
CCL2, inflammatory (CD16+) monocyte expression of CD38, CX3CR1 and CD11b) will be 


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analysed using the same kind of regression with the same adjustments as described above 
including (LDL)-cholesterol and (HDL)-cholesterol. 
 
The rate of adverse effects (symptomatic and biochemical) from the safety report will be 
summarized using frequency and percentage. 
 
All efficacy analyses will compare the randomised treatment groups on an intention to treat 
basis regardless of treatments received during the study, including all patients with data at 
randomisation and at least one follow-up visit. Primary endpoint analyses will use a last value-
carried forward approach for any patients permanently lost to follow-up. Secondary endpoints 
analyses will only include available data. 
 
Statistical analysis will be performed using STATA Release 12.0 or updated version (Stata 
Statistical Software: Release 12.0, Stata Corporation, and College Station, USA). 
 
We plan to recruit 102 patients. Drop outs will not be replaced unless the number surpasses the 
attrition rate of 15%. 
 
An interim analysis will be performed at 48 weeks. The final analysis at 96 weeks will be 
conducted when all patients will have completed the follow-up visits or have been 
permanently lost to follow-up, and the study database is signed off as checked and complete. 
18 Insurance and Finances 
Insurance for the Melbourne site is set up by AH and applies only to the one site.  
Insurance for Swiss sites is set up by the University Hospitals of Geneva (HUG) to cover the 
damages that may occur within this trial. The insurance applies to all Swiss participating 
study sites.  
 
Swiss sites: Costs for the local laboratory tests (haematology, biochemistry, virology) that 
are not included in the routine HIV patient care will be covered by the patient care payments 
made to the sites by the leading site, Geneva.   
19 Quality Control and quality assurance 
19.1 Source documents 
Considered source documents are the patient’s medical records including, but not limited to 
written electronic, magnetic and optical records and scans, x-rays, IMT images and 
electrocardiograms.  
 
The following data will be considered source data:  
• CRF: Compliance assessment, physical examination including measurements, 
smoking status, self-reported pregnancy or breast-feeding status 
• Study medication distribution and return details.  
19.2 Retention of essential documents 
Essential documents as defined by ICH GCP include the signed protocol and any 
amendment(s), copies of the completed CRFs, signed Informed Consent Forms from all 
subjects who consented, hospital records, diary cards and other source documents, IRB/IEC 


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approvals and all related correspondence including approved documents, drug accountability 
records, trial correspondence and a list of the subject’s names and addresses.  
 
The Investigator must maintain all essential study documentation, and take measures to 
prevent accidental or premature destruction of these documents. The Investigator must retain 
the study documentation until at least ten years after completion or discontinuation of the 
study. After that period of time, the documents may be destroyed according local regulations. 
19.3 Data protection 
Intima carotid ultrasound images will be coded with the subject’s ID numbers and transferred 
for analysis to the cIMT Core Facility, Department of Medicine, Montreal Heart Institute, 
Université de Montréal, Montreal, Quebec, Canada Responsible: Pr Jean-Claude Tardif. 
Transfer of this data will be performed strictly anonymously (without personal identifiers), 
maintaining confidentiality and in line with both the Australian Privacy Law and the Swiss 
Federal Law on data protection that correspond to applicable laws of the province of Quebec, 
Canada.  
 
Plasma samples will be coded with the subject’s ID number and stored at the Burnet Institute 
85 Commercial Rd, Melbourne, Victoria 3004 Australia or at the “sérothèque” (biobank) 
HUG in Switzerland. Swiss sites will ship the plasma samples to the central biobank 
(“sérothèque”) of the HUG, 4, rue Gabrielle-Perret-Gentil 4, Geneva University Hospitals, 
Switzerland.  
 
Samples may need to be transferred from Melbourne to Geneva or vice versa for analysis 
purposes. Shipment of plasma samples between the AH between AH (Burnet Institute, 85 
Commercial Rd, Melbourne, Victoria 3004 Australia) and the HUG (Cardiology Laboratory, 
Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1211 Geneva, 
Switzerland) for storage and testing of inflammatory markers will be performed strictly 
anonymously and in compliance with the Swiss Federal Law on data protection, which 
corresponds to applicable privacy laws of Australia and the state of Victoria, Melbourne.   
19.4 Monitoring, audits and inspections 
Independent monitoring of the Swiss sites will be performed to ensure the strict 
implementation of the protocol and guidelines as well as to check consistency between the 
source data and the CRF in at least 50 percent of the number of enrolled subjects.  
 
In case of audits or inspections by regulatory authorities or the ethics committee, the 
investigator will provide direct access to the original data, study documents and the sites 
facilities as well as to the site’s personnel involved directly or indirectly in the trial.  
20 Publications and presentations 
 
The final data will be presented at one or more scientific meetings. No patient data will be 
presented that could permit identification of any individual study participant. Publication of 
data derived from this protocol will be supervised by the Principal Investigator in Melbourne 
and Geneva in conjunction with all study investigators. No other publication will be made 
before the primary manuscript has been agreed upon and accepted for publication and 
without prior approval of the principal investigator in Melbourne. 
 


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21 References 
 
1. D'Agostino RB, Sr., Vasan RS, Pencina MJ, et al. General cardiovascular risk profile for 
use in primary care: the Framingham Heart Study. Circulation 2008;117:743-53. 
2. National Vascular Disease Prevention Alliance. Guidelines for the management of absolute 
cardiovascular disease risk. 2012. Accessed at www.heartfoundation.com.au 
3. d'Arminio Monforte A, Sabin CA, Phillips A, et al. The changing incidence of AIDS 
events in patients receiving highly active antiretroviral therapy. Arch Intern Med 
2005;165:416-23. 
4. Palella FJ, Jr., Delaney KM, Moorman AC, et al. Declining morbidity and mortality among 
patients with advanced human immunodeficiency virus infection. HIV Outpatient Study 
Investigators. N Engl J Med 1998;338:853-60. 
5. Obel N, Thomsen HF, Kronborg G, et al. Ischemic heart disease in HIV-infected and HIV-
uninfected individuals: a population-based cohort study. Clin Infect Dis 2007;44:1625-31. 
6. Lohse N, Hansen AB, Pedersen G, et al. Survival of persons with and without HIV 
infection in Denmark, 1995-2005. Ann Intern Med 2007;146:87-95. 
7. Trevillyan J CA, Hoy J. Predictors of Coronary Heart Disease in HIV Positive Patients. 
22nd Annual Conference of the Australasian Society for HIV Medicine 2010. 
8. Bradshaw PJ, Alfonso HS, Finn J, Owen J, Thompson PL. A comparison of coronary heart 
disease event rates among urban Australian Aboriginal people and a matched non-Aboriginal 
population. J Epidemiol Community Health 2011;65:315-9. 
9. Rose H, Hoy J, Woolley I, et al. HIV infection and high density lipoprotein metabolism. 
Atherosclerosis 2008;199:79-86. 
10. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and 
mortality in patients with HIV infection. PLoS Med 2008;5:e203. 
11. Solages A, Vita JA, Thornton DJ, et al. Endothelial function in HIV-infected persons. 
Clin Infect Dis 2006;42:1325-32. 
12. Parra S, Coll B, Aragones G, et al. Nonconcordance between subclinical atherosclerosis 
and the calculated Framingham risk score in HIV-infected patients: relationships with serum 
markers of oxidation and inflammation. HIV Med 2010;11:225-31. 
13. Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk 
of myocardial infarction. N Engl J Med 2003;349:1993-2003. 
14. Friis-Moller N, Reiss P, Sabin CA, et al. Class of antiretroviral drugs and the risk of 
myocardial infarction. N Engl J Med 2007;356:1723-35. 
15. Worm SW, Sabin C, Weber R, et al. Risk of myocardial infarction in patients with HIV 
infection exposed to specific individual antiretroviral drugs from the 3 major drug classes: the 
data collection on adverse events of anti-HIV drugs (D:A:D) study. J Infect Dis 
2010;201:318-30. 
16. Neuhaus J, Jacobs DR, Jr., Baker JV, et al. Markers of inflammation, coagulation, and 
renal function are elevated in adults with HIV infection. J Infect Dis 2010;201:1788-95. 
17. Emery S, Neuhaus JA, Phillips AN, et al. Major clinical outcomes in antiretroviral 
therapy (ART)-naive participants and in those not receiving ART at baseline in the SMART 
study. J Infect Dis 2008;197:1133-44. 
18. Kaplan RC, Sinclair E, Landay AL, et al. T cell activation and senescence predict 
subclinical carotid artery disease in HIV-infected women. J Infect Dis 2011;203:452-63. 
19. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of 
systemic immune activation in chronic HIV infection. Nat Med 2006;12:1365-71. 
20. Ballou SP, Lozanski G. Induction of inflammatory cytokine release from cultured human 
monocytes by C-reactive protein. Cytokine 1992;4:361-8. 


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21. Chambless LE, Heiss G, Folsom AR, et al. Association of coronary heart disease 
incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk 
in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997;146:483-94. 
22. Bots ML, Palmer MK, Dogan S, et al. Intensive lipid lowering may reduce progression of 
carotid atherosclerosis within 12 months of treatment: the METEOR study. Journal of 
Internal Medicine 2009;265:698-707. 
23. Hsue PY, Giri K, Erickson S, et al. Clinical features of acute coronary syndromes in 
patients with human immunodeficiency virus infection. Circulation 2004;109:316-9. 
24. van Vonderen MGA, Hassink EAM, van Agtmael MA, et al. Increase in carotid artery 
intima-media thickness and arterial stiffness but improvement in several markers of 
endothelial function after initiation of antiretroviral therapy. Journal of Infectious Diseases 
2009;199:1186-94. 
25. van Vonderen MGA, Smulders YM, Stehouwer CDA, et al. Carotid intima-media 
thickness and arterial stiffness in HIV-infected patients: the role of HIV, antiretroviral 
therapy, and lipodystrophy. Journal of Acquired Immune Deficiency Syndromes: JAIDS 
2009;50:153-61. 
26. Duprez DA, Cohn JN. Arterial stiffness as a risk factor for coronary atherosclerosis. Curr 
Atheroscler Rep 2007;9:139-44. 
27. Schillaci G, De Socio GVL, Pucci G, et al. Aortic stiffness in untreated adult patients 
with human immunodeficiency virus infection. Hypertension 2008;52:308-13. 
28. van Wijk JPH, de Koning EJP, Cabezas MC, et al. Functional and structural markers of 
atherosclerosis in human immunodeficiency virus-infected patients. Journal of the American 
College of Cardiology 2006;47:1117-23. 
29. Pirro M, Schillaci G, Mannarino MR, et al. Effects of rosuvastatin on 3-nitrotyrosine and 
aortic stiffness in hypercholesterolemia. Nutr Metab Cardiovasc Dis 2007;17:436-41. 
30. Amarenco P, Labreuche J, Lavallee P, Touboul PJ. Statins in stroke prevention and 
carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 
2004;35:2902-9. 
31. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in 
men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207. 
32. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and 
low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N 
Engl J Med 2002;347:1557-65. 
33. Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after 
statin therapy. N Engl J Med 2005;352:20-8. 
34. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-
reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use 
of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). American 
Journal of Cardiology 2010;106:204-9. 
35. Jain MK, Ridker PM. Anti-inflammatory effects of statins: clinical evidence and basic 
mechanisms. Nat Rev Drug Discov 2005;4:977-87. 
36. Mira E, Leon B, Barber DF, et al. Statins induce regulatory T cell recruitment via a CCL1 
dependent pathway. J Immunol 2008;181:3524-34. 
37. Montecucco F, Mach F. Update on statin-mediated anti-inflammatory activities in 
atherosclerosis. Semin Immunopathol 2009;31:127-42. 
38. Dimitrow PP, Jawien M. Anti-inflammatory effect of atorvastatin in patients with aortic 
sclerosis or mild aortic stenosis independent of hypercholesterolemia. Pharmacol Rep 
2010;62:1250-4. 


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39. Lewandowski M, Kornacewicz-Jach Z, Millo B, et al. The influence of low dose 
atorvastatin on inflammatory marker levels in patients with acute coronary syndrome and its 
potential clinical value. Cardiol J 2008;15:357-64. 
40. Aslangul E, Fellahi S, Assoumou LK, Bastard JP, Capeau J, Costagliola D. High-
sensitivity C-reactive protein levels fall during statin therapy in HIV-infected patients 
receiving ritonavir-boosted protease inhibitors. Aids 2011;25:1128-31. 
41. Ganesan A, Crum-Cianflone NF, Higgins J, et al. High dose atorvastatindecreases cellular 
markers of immune activation: Results of a double-blind randomized controlled clinical trial. 
Journal of Infectious Diseases 2011;203:756-64. 
42. Busti AJ, Bain AM, Hall RG, 2nd, et al. Effects of atazanavir/ritonavir or 
fosamprenavir/ritonavir on the pharmacokinetics of rosuvastatin. Journal of Cardiovascular 
Pharmacology 2008;51:605-10. 
43. Kiser JJ, Gerber JG, Predhomme JA, Wolfe P, Flynn DM, Hoody DW. Drug/Drug 
interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers. J Acquir 
Immune Defic Syndr 2008;47:570-8. 
44. Ageing AG-DoHa. General statement for lipid-lowering drugs prescribed as 
pharmaceutical benefits. In. 
45. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:31-41. 
46. Kazmin A, Garcia-Bournissen F, Koren G. Risks of statin use during pregnancy: a 
systematic review. J Obstet Gynaecol Can 2007;29:906-8. 
47. Walsh JC, Mandalia S, Gazzard BG. Responses to a 1 month self-report on adherence to 
antiretroviral therapy are consistent with electronic data and virological treatment outcome. 
Aids 2002;16:269-77. 
48. The IDF consensus worldwide definition of the metabolic syndrome. (Accessed 20th 
April, 2012, at http//www.idf.org/webdata/doc/IDF_Meta_def_final.pdf.) 
49. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. Eur 
Heart J 2007;28:2525-38. 
50. Friis-Moller N, Thiebaut R, Reiss P, et al. Predicting the risk of cardiovascular disease in 
HIV-infected patients: the data collection on adverse effects of anti-HIV drugs study. Eur J 
Cardiovasc Prev Rehabil 2010;17:491-501. 
51. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. 
Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-70. 
 
 
 
 


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22 Appendix 
22.1 Case Record Forms 
22.1.1 Screening Visit 
 
Screening Visit – Rosuvastatin Trial 
Screening Number 
 
Date 
_____/______/______ 
Informed Consent Signed  
☐   Yes         ☐   No 
Age (years – round number) 
 
Gender  
☐   Male       ☐   Female 
Ethnicity 
 
☐   Caucasian 
☐   Asian 
☐   African 
☐   Aboriginal/Torres Strait Islander 
Date first diagnosed with HIV  
_____/______/______ 
Prior AIDS defining illnesses  
☐   Yes         ☐   No 
List any previous  AIDS defining illness 
1. 
2.  
3.  
4.  
5.  
6. 
7. 
Currently taking antiretrovirals 
☐   Yes         ☐   No 
Change in antiretroviral in last six (6) 
☐   Yes         ☐   No 
Total cumulative years on Indinavir 
 
Total cumulative years on lopinavir 
 
HIV Viral load been <200 copies/ml for 
☐   Yes         ☐   No 
CD4+ T-cell Nadir  
 
List all past medical history 
(Tick box if currently active/being treated) 
1.  
☐ 
2.  
☐ 
3.  
☐ 
4.  
☐ 
5.  
☐ 
6.  
☐ 
7. 
☐ 
8. 
☐ 
9. 
☐ 


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10. 
☐ 
11. 
☐ 
12. 
☐ 
Specifically ever diagnosed with: 
a. Coronary Heart Disease/AMI 
☐   Yes         ☐   No 
b. Angina 
☐   Yes         ☐   No 
c. Diabetes  
☐   Yes         ☐   No 
d. Stroke 
☐   Yes         ☐   No 
e. Transient Ischaemic attack 
☐   Yes         ☐   No 
f. Peripheral vascular disease 
☐   Yes         ☐   No 
g. Hypertension 
☐   Yes         ☐   No 
h. Hypercholesterolemia 
☐   Yes         ☐   No 
i. Familial Hypercholesterolemia 
☐   Yes         ☐   No 
j. Myopathy 
☐   Yes         ☐   No 
Exposure to the following drugs in last 
 
a. Statins 
☐   Yes         ☐   No 
b. Ezetimibe 
☐   Yes         ☐   No 
c. Fibrates 
☐   Yes         ☐   No 
d. Niacin 
☐   Yes         ☐   No 
e. Anti-hypertensives 
☐   Yes         ☐   No 
f. Anti-platelets 
☐   Yes         ☐   No 
Pregnant? 
☐   Yes         ☐   No 
Breast Feeding? 
☐   Yes         ☐   No 
Smoking status 
☐   Never Smoked 
☐   Ex-smoker 
☐   Current smoker 
IF ex-smoker: 
Time since quitting 
 
Estimated quantity/day when was smoking 
 
Duration of smoking history  (years) 
 
IF current smoker 
Estimated quantity/day 
 
Duration of smoking history (years) 
 
Family history of heart disease 
☐   Yes         ☐   No 
Age of Diagnosis in male 1st degree relative 
 
Age of Diagnosis in female 1st degree 
 
 
 
 
 
 


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Current Antiretroviral Medications 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2.  
 
 
 
3.  
 
 
 
4.  
 
 
 
5.  
 
 
 
6.  
 
 
 
 
 
 
 
Concomitant Medications / Supplements 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
4. 
 
 
 
5. 
 
 
 
6. 
 
 
 
7. 
 
 
 
8. 
 
 
 
9. 
 
 
 
10. 
 
 
 
11. 
 
 
 
12. 
 
 
 
13. 
 
 
 
14. 
 
 
 
15. 
 
 
 
16. 
 
 
 
Medication Allergies 
Name of Medication 
Description of allergy 
1. 
 
2. 
 
3. 
 
4. 
 
5. 
 
 
 


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Examination 
Height (m) 
 
Weight  (kg) 
 
Waist circumference (cm) 
 
Peripheral pulses  
☐   present             ☐   absent 
Systolic Blood Pressure 
 
Diastolic Blood Pressure 
 
Physical examination  
(Document any relevant abnormalities) 
 
 
 
 
 
 
 
 
 
 
 
Date ECG performed 
 
Date cIMT performed 
 
Date cPWV performed 
 
Date bloods taken 
 
Once Results available: 
Creatinine clearance 
 
Framingham Risk score 
 
Is patient eligible for enrolment 
☐   Yes         ☐   No 
If No, please document why 
 
If yes, Randomisation number 
 
 
 
 
 
 
 


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Inclusion /Exclusion Checklist 
 
INCLUSION CRITERIA 
 
 
 
Signed consent form 
 
 YES 
 NO 
Age ≥ 30 years 
 
 YES 
 NO 
Framingham Risk Score of 10-15%  [FRS =________ ] 
 
 YES 
 NO 
HIV positive 
 
 YES 
 NO 
Stable cART regimen for ≥ 6 months 
 
 YES 
 NO 
HIV viral load <200copies/ml for ≥ 6 months 
 
 YES 
 NO 
 
 
 
 
EXCLUSION CRITERIA 
 
 
 
Coronary heart disease (CHD), stroke or PVD 
 
 YES 
 NO 
Family history of CHD < 55 in a male first degree relative 
 
 YES 
 NO 
Family history of CHD <65 in a female first degree 
relative 
 
 YES 
 NO 
Type 2 Diabetes         
 
 YES 
 NO 
Familial hypercholesterolaemia 
 
 YES 
 NO 
Aboriginal or Torres Strait Islander people with LDL-C 
>2.5 mmol/L 
 
 YES 
 NO 
Blood pressure ≥ 180/110 
 
 YES 
 NO 
HDL-C < 1 mmol/L and total cholesterol > 6.5 mmol/L 
 
 YES 
 NO 
Documented history of: 
 
 
 
Ischemic stroke or transient ischemic attack (TIA) 
 
 YES 
 NO 
Peripheral arterial disease (regardless of severity) 
 
 YES 
 NO 
Congestive heart failure 
 
 YES 
 NO 
Coronary artery disease or ECG findings consistent with 
prior MI 
 
 YES 
 NO 
Carotid artery stenosis or >50% occlusion of carotid 
artery known previously or discovered during screening 
procedures 
 
 YES 
 NO 
Total cholesterol >7.5 mmol/L 
 
 YES 
 NO 


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Triglyceride level > 4 mmol/L 
 
 YES 
 NO 
HDL-c <1mmol/l and total cholesterol >6.5mmol/l 
 
 YES 
 NO 
Current or prior (last 6 months) statin therapy 
 
 YES 
 NO 
Current or prior (last 6 months) use of ezetimibe 
 
 YES 
 NO 
Current or prior (last 6 months) use of fibrates or niacin 
 
 YES 
 NO 
Pregnancy or lactation 
 
 YES 
 NO 
Hypersensitivity to statins 
 
 YES 
 NO 
Known myopathy or baseline CK > 3x ULN 
 
 YES 
 NO 
Contraindicated concurrent medication (to statin use) 
 
 YES 
 NO 
Current cyclosporine, fusidic acid  or oral corticosteroid 
use 
 
 YES 
 NO 
Concomitant antiplatelet drug  
 
 YES 
 NO 
Unable to complete study procedures (i.e. attendance at AH 
for cIMT and cPWV testing or cIMT images not accepted for 
analysis despite redo examination)  
 
 YES 
 NO 
Conocmitant renal or hepatic disease, defind as the 
presence of the following:  
 
 YES 
 NO 
Creatinine clearance <30 ml/min  [CCL = ________ ] 
 
 YES 
 NO 
Transaminases (ALT, AST) >3x the upper limit of 
normal 
 
 YES 
 NO 
Acute hepatic failure 
 
 YES 
 NO 
Compensated cirrhosis Child Class B or C 
 
 YES 
 NO 
Other active significant disease 
 
 YES 
 NO 
- Describe  
_______________________________ 
 
  
  
Eligible for Trial?   
 
 YES 
 NO 
 
Completed by: _____________________________ 
 
Signed ____________________________________         Date      /      / 
 
 


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22.1.2 Baseline Visit 
 
Study number 
 
Date of Visit 
_____/______/______ 
Any new medical diagnosis since 
screening? 
If yes, list: 
☐   Yes         ☐   No 
1. 
2. 
3. 
4. 
Any new medications since last visit? 
If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Any medications ceased since last 
visit? If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Stop Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Smoking status 
 
☐   Non-smoker 
☐   Ex- Smoker 
☐   Current smoker 
Has an adverse event occurred? 
☐   Yes         ☐   No 
If yes please complete adverse event 
 
Any new abnormalities on 
☐   Yes         ☐   No  
If yes list: 
1. 
 
2. 
 
3. 
Weight (kg) 
 
Blood Pressure 
 
Provided with 3/12 supply of 
☐   Yes         ☐   No 
Bloods taken?  
☐   Yes         ☐   No 
 
 
Completed by: __________________________Signed _____________________________        
 
 


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22.1.3 Week 12 Visit 
 
Study number 
 
Date of Visit 
_____/______/______ 
Any new medical diagnosis since 
screening? 
If yes, list: 
☐   Yes         ☐   No 
1. 
2. 
3. 
4. 
Any new medications since last visit? 
If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Any medications ceased since last 
visit? If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Stop Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Smoking status 
 
☐   Non-smoker 
☐   Ex- Smoker 
☐   Current smoker 
Has an adverse event occurred? 
☐   Yes         ☐   No  
Myopathic symptoms 
☐   Yes         ☐   No 
Gastrointestinal disturbance 
☐   Yes         ☐   No 
Jaundice 
☐   Yes         ☐   No 
If yes please complete adverse event 
 
Any new abnormalities on 
☐   Yes         ☐   No  
If yes list: 
1. 
 
2. 
 
3. 
Weight (kg) 
 
Blood Pressure 
 
Bloods taken?  
☐   Yes         ☐   No 
 
Completed by: __________________________Signed _____________________________        
 
 


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22.1.4 
Week 24 Visit 
Study number 
 
Date of Visit 
_____/______/______ 
Any new medical diagnosis since 
screening? 
If yes, list: 
☐   Yes         ☐   No 
1. 
2. 
3. 
4. 
Any new medications since last visit? 
If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Any medications ceased since last 
visit? If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Stop Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Smoking status 
 
☐   Non-smoker 
☐   Ex- Smoker 
☐   Current smoker 
Has an adverse event occurred? 
☐   Yes         ☐   No  
Myopathic symptoms 
☐   Yes         ☐   No 
Gastrointestinal disturbance 
☐   Yes         ☐   No 
Jaundice 
☐   Yes         ☐   No 
If yes please complete adverse event 
 
Any new abnormalities on 
☐   Yes         ☐   No  
If yes list: 
1. 
 
2. 
 
3. 
Weight (kg) 
 
Blood Pressure 
 
Bloods taken?  
☐   Yes         ☐   No 
 
 
Completed by: __________________________Signed _____________________________        
 
 


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22.1.5 Week 48 Visit 
Study number 
 
Date of Visit 
_____/______/______ 
Any new medical diagnosis since 
screening? 
If yes, list: 
☐   Yes         ☐   No 
1. 
2. 
3. 
4. 
Any new medications since last visit? 
If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Any medications ceased since last 
visit?  If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Stop Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Smoking status 
 
☐   Non-smoker 
☐   Ex- Smoker 
☐   Current smoker 
Has an adverse event occurred? 
☐   Yes         ☐   No  
Myopathic symptoms 
☐   Yes         ☐   No 
Gastrointestinal disturbance 
☐   Yes         ☐   No 
Jaundice 
☐   Yes         ☐   No 
If yes please complete adverse event 
 
Any new abnormalities on 
☐   Yes         ☐   No  
If yes list: 
1. 
 
2. 
 
3. 
Weight (kg) 
 
Blood Pressure 
 
Compliance assessment performed  
☐   Yes         ☐   No 
Bloods taken? 
 
Date cIMT/PWV performed /booked 
 
 
Completed by: __________________________Signed _____________________________   
 
 


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Compliance Assessment Week 48 study Visit 
 
Study Number_____________________ 
Date _____/______/________ 
 
 
We understand that many people on medications find it very difficult to 
take them regularly, and often miss doses. It is important for us to know 
how many doses of the study medication you’ve missed. 
 
This questionnaire is completely confidential. Your answers will not be 
shown to your doctor or others involved in your care 
 
How many doses (tablets) have you missed in the last 
seven (7) days? 
 
How many doses (tablets) have you missed in the last 
twenty-eight (28) days? 
 
 
Put an X on the line below at the point showing your best guess about how 
much of the study medication you have taken during the past 28 days. 
 
For example, 0% means you haven’t taken any dose of the medication above, 
50% means you have taken half of the prescribed doses of the medication 
above and 100% means you have taken every single dose of the medication 
above 
 
 
 
 
 
 
 
 
 
0% 
40
% 
50
% 
60
% 
70
% 
80
% 
90% 
100
% 
30
% 
20
% 
10
% 


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22.1.6 Week 72 Visit 
Study number 
 
Date of Visit 
_____/______/______ 
Any new medical diagnosis since 
screening? 
If yes, list: 
☐   Yes         ☐   No 
1. 
2. 
3. 
4. 
Any new medications since last visit? 
If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Any medications ceased since last 
visit? If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Stop Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Smoking status 
 
☐   Non-smoker 
☐   Ex- Smoker 
☐   Current smoker 
Has an adverse event occurred? 
☐   Yes         ☐   No  
Myopathic symptoms 
☐   Yes         ☐   No 
Gastrointestinal disturbance 
☐   Yes         ☐   No 
Jaundice 
☐   Yes         ☐   No 
If yes please complete adverse event 
 
Any new abnormalities on 
☐   Yes         ☐   No  
If yes list: 
1. 
 
2. 
 
3. 
Weight (kg) 
 
Blood Pressure 
 
Bloods taken?  
☐   Yes         ☐   No 
 
Completed by: __________________________Signed _____________________________ 
 
 
 
 


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22.1.7 Week 96 Visit 
Study number 
 
Date of Visit 
_____/______/______ 
Any new medical diagnosis since 
screening? 
If yes, list: 
☐   Yes         ☐   No 
1. 
2. 
3. 
4. 
Any new medications since last visit? 
If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Start Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Any medications ceased since last 
visit? If yes please detail below 
☐   Yes         ☐   No 
 
Trade Name 
Generic Name 
Daily Dose 
Stop Date 
1. 
 
 
 
2. 
 
 
 
3. 
 
 
 
Smoking status 
(circle whichever is appropriate) 
Non-smoker 
Ex- Smoker 
Current smoker 
Has an adverse event occurred? 
☐   Yes         ☐   No  
Myopathic symptoms 
☐   Yes         ☐   No 
Gastrointestinal disturbance 
☐   Yes         ☐   No 
Jaundice 
☐   Yes         ☐   No 
If yes please complete adverse event 
 
Any new abnormalities on 
☐   Yes         ☐   No  
If yes list: 
1. 
 
2. 
 
3. 
Weight (kg) 
 
Blood Pressure 
 
Compliance assessment performed  
☐   Yes         ☐   No 
Bloods taken? 
 
Date cIMT/PWV performed /booked 
 
 
Completed by: __________________________Signed _____________________________ 
 
 


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Compliance Assessment Week 96 study Visit 
 
Study Number _______________________________________ 
Date______/______/_______ 
 
 
We understand that many people on medications find it very difficult to 
take them regularly, and often miss doses. It is important for us to know 
how many doses of the study medication you’ve missed. 
 
This questionnaire is completely confidential. Your answers will not be 
shown to your doctor or others involved in your care 
 
How many doses (tablets) have you missed in the last 
seven (7) days? 
 
How many doses (tablets) have you missed in the last 
twenty-eight (28) days? 
 
 
Put an X on the line below at the point showing your best guess about how 
much of the study medication you have taken during the past 28 days. 
 
For example, 0% means you haven’t taken any dose of the medication above, 
50% means you have taken half of the prescribed doses of the medication 
above and 100% means you have taken every single dose of the medication 
above 
 
 
 
 
 
 
 
 
 
 
 
0% 
40
% 
50
% 
60
% 
70
% 
80
% 
90% 
100
% 
30
% 
20
% 
10
% 


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22.1.8 Unscheduled Visits 
Study Number 
 
Date of Visit 
_____/______/_______ Time: ____:_____hr 
Person initiating unscheduled 
 
Reason for unscheduled visit 
 
Adverse Event Assessment 
Onset date of Adverse Event 
 
Time of Onset (if Known) 
 
Description of Adverse event: 
 
 
 
 
 
Adverse Event Severity Grade 
(refer to Division of AIDS Table 
for grading of severity) 
☐   Mild (Grade 1)              
☐   Moderate (Grade 2)    
☐   Severe (grade 3-4)       
Is this a Serious Adverse Event 
☐   Yes         ☐   No      (If YES, please fill in the 
Treatment for AE required? 
(If yes describe in detail) 
☐   Yes         ☐   No 
 
 
 
 
 
Related to the study drug? 
☐   Confirmed 
 
☐   Probable 
 
☐   Possible 
 
☐   Excluded 
 
☐   Non -assessable 
Study medication stopped 
☐   Yes         ☐   No 
Withdrawn from the study 
☐   Yes         ☐   No 
Outcome of Adverse Event 
☐   Ongoing              
 
☐   Resolved             
 
☐   Unknown            
Date of resolution of adverse 
_____/______/_______ 
 (If not ongoing) 
 
Date subject will be next 
 
 
Completed by: __________________________Signed _____________________________ 
 
 
 


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22.2 Serious Adverse Event (SAE) Form 
Study Number 
 
Date of Awareness 
_____/______/_______ TIME: _____:______h 
Onset Date of Event 
_____/______/_______ TIME: _____:______h 
Stop Date of Event 
_____/______/_______ TIME: _____:______h 
Type of Report 
☐   Initial             ☐  Follow-up           ☐  Final 
Description of SAE: 
 
 
 
 
 
Category of SAE 
☐   Death   Date of Death _____/______/_____ 
☐   Life Threatening 
☐   Caused or prolonged hospitalization 
☐   Resulted in significant disability or 
☐   Other important medical condition 
Related to the study drug? 
☐   Confirmed 
 
☐   Probable 
 
☐   Possible 
 
☐   Excluded 
 
☐   Non -assessable 
If Adverse Drug reaction please 
 
- 
Generic name 
 
- 
Lot Number 
 
- 
Dosage  
 
- 
Route of administration 
 
- 
Start date 
_____/______/_____ 
- 
Indication 
 
Study medication stopped? 
☐   Yes         ☐   No 
If yes did the AE resolve after 
☐   Yes         ☐   No 
Was the code broken? 
☐   Yes         ☐   No 
If YES, what was the allocation? 
 
Treatment for SAE required? 
(If yes describe in detail) 
☐   Yes         ☐   No 
 
 
 
 
 
Completed by: _______________Signed ____________ Date _____/______/_______  
 
 


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22.3 Units of measurement and reference ranges 
 
Investigation 
Abbreviation 
Units 
Reference Range 
HIV specific tests 
CD4+ T-cell count 
- 
cells/µL 
410 - 1,545 
HIV Viral Load 
- 
copies/ml 
< 20 
Full Blood Examination (FBE) 
Haemoglobin 
Hb 
g/L 
128 - 175 
Total White Cell count 
WCC 
cells x109/L 
3.9 – 12.70  
Lymphocytes 
Lymp 
cells x109/L 
0.9 – 3.30 
Neutrophils 
Neut 
cells x109/L 
1.9 – 8.0 
Platelets 
Plt 
cells x109/L 
150 - 396 
Biochemistry 
Sodium 
Na 
mmol/L 
135 – 143 
Potassium 
K+ 
mmol/L 
3.5 – 5.0 
Chloride 
Cl 
mmol/L 
99 - 107 
Bicarbonate 
HCO3 
mmol/L 
20 - 32 
Calcium 
Ca 
mmol/L 
2.14 – 2.50 
Phosphate 
PO4 
mmol/L 
0.6 – 1.30 
Urea 
Ur 
mmol/L 
4.0 – 9.0 
Creatinine 
Cr 
µmol/L 
60 - 105 
Estimated glomerular filtration rate 
eGFR 
ml/min 
> 90 
Beta Human chorionic gonadotrophin 
β HCG 
U/L 
< 3 
High sensitivity C- reactive protein 
hsCRP 
mg/L 
< 5.0 
Creatinine phosphokinase 
CPK 
U/L 
60 - 285 
Liver Function Tests (LFT) 
Total Protein 
TP 
g/L 
60 - 80 


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Albumin 
Alb 
g/L 
33 - 46 
Bilirubin 
Bil 
µmol/L 
< 23 
Alanine Aminotransferase 
ALT 
U/L 
12-52 
Alkaline Phosphatase 
ALP 
U/L 
42 - 125 
Gamma- glutamyl transpeptidase 
GGT 
U/L 
< 62 
Fasting Metabolic Assessments 
Total Cholesterol 
TC 
mmol/L 
< 5.5 
High Density Lipoprotein Cholesterol 
HDL-C 
mmol/L 
>  1.0 
Low Density Lipoprotein Cholesterol 
LDL-C 
mmol/L 
< 3.5 
Triglycerides 
TG 
mmol/L 
< 2.0 
Glucose 
 - 
mmol/L 
3.8 – 7.7 
Structural / Physical Assessments 
Carotid intima media thickness 
cIMT 
mm 
n/a 
Carotid-femoral pulse wave velocity 
cPWV 
m/s 
n/a 
Height 
 - 
Meters (m) 
n/a 
Weight 
- 
Kilograms 
(Kg)  
n/a 
Calculations 
Body Mass Index 
BMI 
kg/m2 
< 18.5          Underweight 
18.5 – 24.9   Healthy 
25.0 – 29.9   Overweight 
30.0 – 34.9   Obesity I 
35.0 – 39.9   Obesity II 
> 40              Obesity III 
Framingham Risk Score 
FRS 
% 10 year 
risk 
< 10 %     Low Risk 
10 -15 %  Moderate Risk 
> 15 %      High risk 
D.A.D. Risk Score 
DRS 
% 5 year risk 
< 1%       Low Risk 
1 – 5%    Moderate Risk 
5 – 10%  High Risk 
> 10%     Very High Risk 
Estimated creatinine clearance 
CrCl 
ml/min 
> 90 


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22.4 Units of measurement and reference ranges for Swiss sites 
 
Investigation 
Abbreviation 
Units 
Reference Range 
HIV specific tests 
CD4+ T-cell count 
- 
cells/µl 
600 – 1’950 
HIV Viral Load 
- 
copies/ml 
< 20 
Full Blood Examination (FBE) 
Haemoglobin 
Hb 
g/L 
M: 140-180 F: 120-160 
Total White Cell count 
WCC 
G/L 
4.0 – 11.0  
Lymphocytes 
Lymp 
G/L 
1.00 - 4.50 
Neutrophils 
Neut 
G/L 
1.50-8.00 
Platelets 
Plt 
G/L 
150-350 
Biochemistry 
Sodium 
Na 
mmol/L 
136-144 
Potassium 
K+ 
mmol/L 
3.6 – 4.6 
Chloride 
Cl 
mmol/L 
96 - 107 
Bicarbonate 
HCO3 
mmol/L 
23.0-30.0 
Calcium 
Ca 
mmol/L 
2.20– 2.52 
Phosphate 
PO4 
mmol/L 
0.8-1.5 
Urea 
Ur 
mmol/L 
2.8-7.1 
Creatinine 
Cr 
µmol/L 
M: 62-106 F: 35-88 
Estimated glomerular filtration rate 
eGFR 
ml/min 
> 90 
Beta Human chorionic gonadotrophin 
β HCG 
U/L 
 
Creatinine phosphokinase 
CPK 
U/L 
M: 47-222 F:33-187 
Liver Function Tests (LFT) 
Total Protein 
TP 
g/L 
61-79 
Albumin 
Alb 
g/L 
35-48 


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Bilirubin 
Bil 
µmol/L 
6.8-25 
Alanine Aminotransferase 
ALT 
U/L 
M: 12 - 50  F: 9 - 42 
Alkaline Phosphatase 
ALP 
U/L 
30 - 125 
Gamma- glutamyl transpeptidase 
GGT 
U/L 
M: 9 - 40 F: 9 - 35 
Fasting Metabolic Assessments 
Total Cholesterol 
TC 
mmol/L 
< 6.5 
High Density Lipoprotein Cholesterol 
HDL-C 
mmol/L 
M: >0.90  F: >  1.00 
Low Density Lipoprotein Cholesterol 
LDL-C 
mmol/L 
< 4.0 
Triglycerides 
TG 
mmol/L 
< 2.00 
Glucose 
 - 
mmol/L 
4.1 – 6.0 
 
 


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22.5 Patient Informed Consent Form 
 
 
 
 
 
 
Participant Information Sheet/Consent Form 
Interventional Study - Adult providing own consent 
 
The Alfred Hospital 
 
Title 
Does Rosuvastatin delay progression of 
atherosclerosis in people with HIV infection? A 
multicentre randomized, double blind placebo-
controlled trial 
Coordinating Principal Investigator/ 
Principal Investigator 
Dr Janine Trevillyan 
Prof Jennifer Hoy 
Associate Investigator(s) 
 
Professor Suzanne Crowe 
Dr Julian Elliott 
A. Professor Anthony Jaworowski 
Dr James Shaw  
Professor Anthony Dart 
Location  
The Alfred Hospital 
 
 
Part 1 What does my participation involve? 
 
1 
Introduction 
 
You are invited to take part in this research project. This is because you have human 
immunodeficiency virus (HIV) infection, are currently on anti-HIV medications and are 
thought to have a moderate risk of developing heart disease. The research project is testing 
a new treatment to prevent heart disease in HIV positive people. The new treatment is called 
Rosuvastatin, a cholesterol lowering medication. 
 
This Participant Information Sheet/Consent Form tells you about the research project. It 
explains the tests and treatments involved. Knowing what is involved will help you decide if 
you want to take part in the research. 
 
Please read this information carefully. Ask questions about anything that you don’t 
understand or want to know more about. Before deciding whether or not to take part, you 
might want to talk about it with a relative, friend or your local doctor. 
 
Participation in this research is voluntary. If you don’t wish to take part, you don’t have to. 
You will receive the best possible care whether or not you take part. 
 
If you decide you want to take part in the research project, you will be asked to sign the 
consent section. By signing it you are telling us that you: 
• Understand what you have read 
• Consent to take part in the research project 


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• Consent to have the tests and treatments that are described 
 
• Consent to the use of your personal and health information as described. 
 
You will be given a copy of this Participant Information and Consent Form to keep. 
 
2  
What is the purpose of this research? 
 
Since people started taking anti-HIV medications, illness from AIDS has decreased, but 
other serious diseases like heart disease (heart attacks) and other diseases of blood vessels 
(such as strokes) have increased.  HIV causes inflammation (irritation) inside the body that 
cannot be felt but can be measured by certain blood tests. Inflammation may contribute to 
diseases (such as heart attacks) by damaging blood vessels. HIV therapy can partially lower 
inflammation, however the levels of inflammation in people who have HIV may remain high 
even when they are on anti-HIV medications compared with those found in people who do 
not have HIV.   
 
The main goal of this study is to see if taking rosuvastatin (a cholesterol lowering medication 
that also decreases inflammation) will slow down the development of blood vessel damage 
(a sign of future heart attacks) in people infected with HIV who are at moderate risk of heart 
disease and so are not currently eligible for rosuvastatin. 
 
In addition to observing the effects of rosuvastatin on the level of inflammation measured in 
the blood, this study will see if rosuvastatin is safe for people with HIV who are also taking 
medication for HIV. 
 
Medications, drugs and devices have to be approved for use by the Australian Federal 
Government. Rosuvastatin is approved in Australia to treat high cholesterol levels in the 
blood and to prevent heart attacks in people at high risk or who have already had a heart 
attack. However it has not been approved for use in patients who are at moderate risk. 
Therefore, it is an experimental treatment. This means that it must be tested to see if it is an 
effective therapy to prevent heart disease in people at moderate risk. Rosuvastatin has been 
able to lower the level of inflammation in certain other diseases but has not been studied for 
this purpose in people who have HIV.  
 
The results of this research will be used by the study doctor, Dr Janine Trevillyan to obtain a 
PhD degree. 
 
This research has been initiated by the study doctor, Professor Jennifer Hoy and is funded 
through Monash University. 
 
3 
What does participation in this research involve? 
 
If you choose to participate in this project you will be asked to sign this consent form prior to 
any study assessments being performed. If you would like an interpreter to be present at any 
time we will arrange one for you. 
 
You will be participating in a randomised controlled research project. Sometimes we do not 
know whether a medication is going to prevent a particular condition. To find out we need to 
compare the treatment to having no treatment at all. We do this by putting people into 
groups and giving one group the treatment (Rosuvastatin) and one group a placebo. The 
results from each group are compared to see if one is better. A placebo is a medication with 
no active ingredients or any medical benefit. It looks like the real thing but is not. To try to 
make sure the groups are the same, each participant is put into a group by chance 
(random). You will have a 50/50 (equal) chance of being in either group. 


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You will need to take one capsule a day which will contain either the placebo or 20mg of 
rosuvastatin. Some HIV medications (in particular those from the group of drugs known as 
protease inhibitors) can cause the level of rosuvastatin to rise. If you are on one of these 
medications you will be given 10mg of rosuvastatin (or placebo) instead. 
 
You will be participating in a double-blind study. This means that neither you nor your study 
doctor will know which treatment you are receiving. However, in certain circumstances your 
study doctor can find out which treatment you are receiving. 
 
This research project has been designed to make sure the researchers interpret the results 
in a fair and appropriate way and avoids study doctors or participants jumping to 
conclusions.   
 
Evaluations performed during the study 
 
If you decide to take part in the research project you will be asked some questions about 
your medical history, the medications you take and any risk factors you have that might 
predispose you to developing heart disease. We will check how well your liver is functioning 
and your cholesterol levels. This will let us know if you are eligible to take part. Completing 
the screening visit will take approximately 15- 30 minutes. 
 
The study visits will occur at the same time as your routine HIV visits with your primary care 
doctor as far as is possible, and will take between 30 – 45 minutes depending on how many 
tests need to be performed. At the first visit and four times during the study you will be asked 
not to eat or drink anything (other than your required medications and normal amounts of 
plain water) for at least 8 hours (preferably 12 hours) before you come in for blood tests. 
 
At the study visits you will be asked about your health and any medicines you have taken. 
You will be weighed and have your blood pressure checked and will be asked how often you 
have taken your medications over the few days and weeks prior to the visit. 
 
At each study visit you will have blood tests taken to check for side effects of the medication 
and to monitor your liver function. Every six months there will also be blood taken to test for 
signs of inflammation, cholesterol levels, CD4 (T cell) counts and HIV viral loads.  
 
Prior to starting the rosuvastatin or placebo and at 12 months and 24 months, (the end of the 
study), you will have an ultrasound of your carotid arteries (the large arteries in your neck) to 
measure the thickness of the artery wall (which allows us to estimate your chance of 
developing heart disease). This is a painless procedure that takes about 20 minutes. On the 
same day we will also measure the speed your blood flows to the carotid artery (in your 
neck) and the femoral artery (at the top of your thigh). This is done with a machine very 
similar to an ultrasound and is also painless.  It takes about 10 minutes. Both of these tests 
are performed onsite at the Alfred Hospital. 
 
If at any time during the study you develop a side effect from the medication you may need 
to come in for an extra visit to check on your safety. You will be assessed by the study 
doctor and advised whether you should stop the study medication and whether you require 
any other treatment or investigation. 
 
You will be involved in this study for ninety-six (96) weeks, approximately 2 years. The study 
will run for five years in total and will be monitored by an independent review board. 
  


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There are no additional costs associated with participating in this research project, nor will 
you be paid. All medication, tests and medical care required as part of the research project 
will be provided to you free of charge. 
 
You will have to pay for your usual medicines (including HIV medications) like you normally 
would. 
 
4 
What do I have to do? 
 
You do not need to change your diet or level of exercise to participate in this study.  
 
You should keep taking your usual medications (including your HIV medications) throughout 
the study which will be guided by your usual HIV doctor. If you are taking warfarin your INR 
level will need to be monitored more often than usual when you first start taking the study 
drug. 
 
You should not start any of the medications listed below while you’re in this study because 
they may increase your chance of developing a side effect.  
- 
Cholesterol lowering medications including niacin, fibrates  or ‘statins’ 
- 
Fusidic acid (an antibiotic) 
- 
Cyclosporine 
Please tell the study team if you need to start any new medications so that they can check if 
it will be safe to take while taking rosuvastatin. 
 
You can still donate blood while in this study if you wish. 
 
People who have had side effects from cholesterol lowering medications before or have 
significant problems with their liver or muscles cannot take part in this study. If you are 
pregnant or planning on becoming pregnant in the next two years you cannot take part in 
this study. 
 
To be part of the study you need to commit to taking the study medication every day. 
 
5 
Other relevant information about the research project 
 
102 people will be taking part in the project. Half (51 participants) will receive rosuvastatin 
(the cholesterol lowering medication) and the other half (51 participants) will receive a 
placebo capsule. Participants will be recruited into the trial from two sites; here at the Alfred 
Hospital in Melbourne Australia and also from the University Hospital of Geneva in 
Switzerland. It is anticipated that 72 participants will be from Melbourne with the remaining 
30 participants from Switzerland. 
 
 
This project is a collaboration between the Infectious Diseases and Cardiology departments 
of the Alfred Hospital and the Infectious Diseases Department of the University Hospital of 
Geneva 
 
6 
Do I have to take part in this research project? 
 
Participation in any research project is voluntary. If you do not wish to take part, you do not 
have to. If you decide to take part and later change your mind, you are free to withdraw from 
the project at any stage. 
 


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Your decision whether to take part or not to take part, or to take part and then withdraw, will 
not affect your routine treatment, your relationship with those treating you or your 
relationship with the Alfred 
 
 
7 
What are the alternatives to participation?  
 
 
The use of rosuvastatin in people with normal cholesterol levels who are not at high risk for 
heart disease is experimental, and there is no standard clinical treatment which is similar or 
equal to this. Your alternative is to not join the study and continue to receive standard HIV 
care from your doctor. 
 
8 
What are the possible benefits of taking part? 
 
We cannot guarantee or promise that you will receive any benefits from your participation in 
this research. However the results from this research may help improve the management of 
people who are infected with HIV. 
 
By participating in this study the health of your arteries and risk for heart problems will be 
assessed very thoroughly, in some instances this may allow us to detect serious treatable 
health issues before you have symptoms. 
 
 
9 
What are the possible risks and disadvantages of taking part? 
 
Medical treatments often cause side effects. You may have none, some or all of the effects 
listed below, and they may be mild, moderate or severe. If you have any of these side 
effects, or are worried about them, talk with your study doctor. Your study doctor will also be 
looking out for side effects. 
 
There may be side effects that the researchers do not expect or do not know about and that 
may be serious. Tell your study doctor immediately about any new or unusual symptoms that 
you get. 
 
Many side effects go away shortly after treatment ends. However, sometimes side effects 
can be serious, long lasting or permanent. If a severe side effect or reaction occurs, your 
study doctor may need to stop your treatment. Your study doctor will discuss the best way of 
managing any side effects with you. 
 
Rosuvastatin is in general a safe medication that has been taken by many patients 
worldwide. Some side effects that can be caused by rosuvastatin include 
 
• 
Muscle problems. Rosuvastatin can very occasionally (less than 1 per 1000 patients) 
cause serious muscle problems that can lead to kidney problems, including kidney 
failure and rarely, death. 
• 
Liver problems. Rosuvastatin can occasionally cause liver problems that may rarely 
be serious or cause death. Your study nurse or doctor will do blood tests to check 
your liver before you start taking rosuvastatin, and while you take it.   
 
Be sure to let your doctor or study nurse know immediately if you have possible signs of one 
of these problems, including:  
o Muscle problems like weakness, tenderness, or pain that happen without a 
good reason, especially if you also have a fever or feel more tired than usual. 
o Nausea and vomiting. 


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o Passing brown or dark-colored urine. 
o Feeling more tired than usual. 
o Noticing the skin and whites of your eyes become yellow.  
o Having stomach pain. 
 
Other problems that have been caused by rosuvastatin include headaches, rash, severe 
allergic reaction or swelling, constipation, gas, diarrhea, tendon rupture, dizziness, memory 
impairment, and depression. All these problems are uncommon to rare (occurring in less 
than 1 in 100 people who take rosuvastatin). 
 
Having a blood sample taken may cause some discomfort, bruising, minor infection or 
bleeding.  If this happens, it can be easily treated. 
 
If, during the course of the study we uncover a medical condition that you did not know about 
the study doctor will explain the condition and arrange for you to have any further 
investigations or treatment that is necessary.  
 
If you develop any condition (such as high cholesterol) which means that you should be 
taking rosuvastatin you will not be able to continue in the study and will be advised to stop 
taking the study medication and to take treatment as recommended by your usual doctor.  
 
Study information that is not critical to your health care will not be given to you or others. 
This means that no one (not you, your family, your GP, your insurance company or your 
employer) will have access to this information during the study. At the end of the study you 
and your GP will be provided with a summary of the results of the study and your personal 
results including cholesterol levels and estimated risk of developing heart disease in the 
future. 
 
 
 
Risks related to conception, pregnancy and breast feeding 
 
Rosuvastatin is unsafe for unborn babies. Because of this, it is important that research 
project participants are not pregnant or breast-feeding and do not become pregnant during 
the course of the research project. You must not participate in the research if you are 
pregnant or trying to become pregnant, or breast-feeding. If you are female and child-
bearing is a possibility, you will be required to undergo a pregnancy test prior to commencing 
the research project.  If you are male, you should not father a child or donate sperm for at 
least one month after the last dose of study medication. 
 
Both male and female participants are strongly advised to use effective contraception during 
the course of the research and for one month after completion of the research project. You 
should discuss methods of effective contraception with your study doctor. 
 
If you do become pregnant whilst participating in the research project, you should advise 
your study doctor immediately. Your study doctor will withdraw you from the research project 
and advise on further medical attention should this be necessary. You must not continue in 
the research if you become pregnant. 
 
You should advise your study doctor if you father a child while participating in the research 
project. Your study doctor will advise on medical attention for your partner should this be 
necessary. 
 
If you become upset or distressed as a result of your participation in the research, the study 
doctor will be able to arrange for counselling or other appropriate support. Any counselling or 


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support will be provided by qualified staff who are not members of the research project team. 
This counselling will be provided free of charge.  
 
10 
What will happen to my test samples? 
 
By signing the consent form you are consenting to the collection of your blood for the 
research project.  
 
The samples that you provide will not be used for any purpose other than what has been 
described in this document. Samples that are part of routine care will be tested at the Alfred 
Hospital and are destroyed as per hospital policy. 
 
If you consent a small sample of blood will be stored for possible use in other research into 
the causes and prevention of heart disease in HIV and the actions of “statins”. This may 
include (but is not limited to) testing for newly discovered markers of inflammation or 
performing special cholesterol studies. These samples would only be used for future 
research that has been approved by The Alfred Hospital Ethics Committee.  
 
Your stored blood samples and the information collected about you during the study will be 
assigned a unique identifying code (that is not your name or birth date). This code will mean 
that results will be able to be re-identified and linked to individual study participants if 
needed. A small portion of your sample may be sent to Geneva for specialised testing. This 
sample will not have your name or date of birth on it and will be labelled only with the study 
code described above. There will be no need to take any extra blood samples and only 
samples from participants who have consented to having blood stored for future research 
will be included. If this does occur any blood remaining after testing is complete in Geneva 
will be destroyed. 
 
The images taken with the ultrasound machine of the arteries in your neck will be stored on 
a CD and sent to Montreal, Canada where a specialist will review them, This CD will be 
labelled with the study code assigned to you and, as with your blood samples, will not 
contain your name or date of birth. At the completion of the trial the CD will be destroyed and 
your images will only be retained on file at the Alfred Hospital. 
 
 
11 
What if new information arises during this research project? 
 
Sometimes during the course of a research project, new information becomes available 
about the treatment that is being studied. If this happens, your study doctor will tell you about 
it and discuss with you whether you want to continue in the research project. If you decide to 
withdraw, your study doctor will make arrangements for your regular health care to continue. 
If you decide to continue in the research project you will be asked to sign an updated 
consent form. 
 
Also, on receiving new information, your study doctor might consider it to be in your best 
interests to withdraw you from the research project. If this happens, he/ she will explain the 
reasons and arrange for your regular health care to continue. 
 
12 
Can I have other treatments during this research project? 
 
It is important to tell your study doctor and the study staff about any treatments or 
medications you may be taking, including over-the-counter medications, vitamins or herbal 
remedies, acupuncture or other alternative treatments. You should also tell your study doctor 
about any changes to these during your participation in the research project. 


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13 
What if I withdraw from this research project? 
 
If you decide to withdraw from the project, please notify a member of the research team 
before you withdraw. This notice will allow that person or the research supervisor to discuss 
any health risks or special requirements linked to withdrawing. 
 
If you do withdraw your consent during the research project, the study doctor and relevant 
study staff will not collect additional personal information from you, although personal 
information already collected will be retained to ensure that the results of the research 
project can be measured properly and to comply with law. You should be aware that data 
collected up to the time you withdraw will form part of the research project results, unless 
you specifically request otherwise. 
 
14 
Could this research project be stopped unexpectedly? 
  
It is not anticipated that this project will be stopped unexpectedly. However, this research 
project may be stopped early if unacceptable side effects were detected. 
 
15 
What happens when the research project ends? 
 
 
After you have completed all the study visits you will stop taking the study medication.  
 
You and your GP will be sent a letter summarising your personal results including 
cholesterol levels and estimated risk of developing heart disease in the future. Once the 
whole study is finished you will receive a short report summarising the main findings of the 
study. 
  
Part 2 How is the research project being conducted? 
 
 
16 
What will happen to information about me? 
 
By signing the consent form you consent to the study doctor and relevant research staff 
collecting and using personal information about you for the research project. Any information 
obtained in connection with this research project that can identify you will remain 
confidential. Information and samples will not be labelled with your name but will instead be 
assigned a code that will enable them to be re-identified and linked to individual study 
participants. This will be essential to perform the required study analyses and to monitor for 
potential side effects. Your information will only be used for the purpose of this research 
project and it will only be disclosed with your permission, except as required by law. 
 
Information about you may be obtained from your health records held at The Alfred Hospital 
for the purpose of this research. By signing the consent form you agree to the study team 
accessing health records if they are relevant to your participation in this research project. 
 
All research records will be kept in locked files located within locked rooms to which only 
study staff have access. Computer files will be stored on secure password protected 
computers 
 
Only study staff, members of The Alfred Hospital Ethics Committee and regulatory 
authorities will have access to study data and participant information. The data and samples 
will not be used for commercial purposes. Written information will be retained indefinitely 
according to Alfred Health policy unless you ask for data to be destroyed. 


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It is anticipated that the results of this research project will be published and presented in a 
variety of forums. In any publication or presentation, information will be provided in such a 
way that you cannot be identified, except with your permission.  
 
Information about your participation in this research project may be recorded in your health 
records. 
 
In accordance with relevant Australian and Victorian privacy and other relevant laws, you 
have the right to request access to your information collected and stored by the research 
team. You also have the right to request that any information with which you disagree be 
corrected. Please contact the study team member named at the end of this document if you 
would like to access your information. 
 
 
 
17 
Complaints and compensation 
 
If you suffer any injuries or complications as a result of this research project, you should 
contact the study team as soon as possible and you will be assisted with arranging 
appropriate medical treatment. If you are eligible for Medicare, you can receive any medical 
treatment required to treat the injury or complication, free of charge, as a public patient in 
any Australian public hospital. 
 
18 
Who is organising and funding the research? 
 
This research project is being conducted by Professor Jennifer Hoy 
 
You will not benefit financially from your involvement in this research project even if, for 
example, your samples (or knowledge acquired from analysis of your samples) prove to be 
of commercial value to The Alfred Hospital. 
 
No member of the research team will receive a personal financial benefit from your 
involvement in this research project (other than their ordinary wages). 
 
19 
Who has reviewed the research project? 
 
 
 
All research in Australia involving humans is reviewed by an independent group of people 
called a Human Research Ethics Committee (HREC).  The ethical aspects of this research 
project have been approved by the HREC of The Alfred Hospital Ethics Committee and the 
ethics committee the University Hospital of Geneva 
 
This project will be carried out according to the National Statement on Ethical Conduct in 
Human Research (2007). This statement has been developed to protect the interests of 
people who agree to participate in human research studies. 
 
20 
Further information and who to contact 
 
The person you may need to contact will depend on the nature of your query.  
 
If you want any further information concerning this project or if you have any medical 
problems which may be related to your involvement in the project (for example, any side 
effects), you can contact the principal study doctor on 90762000 or any of the following 
people: 


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Clinical contact person 
 
 
 
 
 
If you have any complaints about any aspect of the project, the way it is being conducted or 
any questions about being a research participant in general, then you may contact: 
 
Complaints contact person 
 
 
 
Name 
Dr Janine Trevillyan 
Position 
Study co-ordinator and principal researcher 
Telephone 
03 90762000 via Alfred Switchboard (24 hours a day) 
Email 
j.trevillyan@alfred.org.au 
Name 
Sally Price 
Position 
Study co-ordinator 
Telephone 
03  9076 6908 
Email 
clinresearch@alfred.org.au 
Name 
Ms Rowan Frew 
Position 
Ethics Manager 
Telephone 
90763848 
Email 
r.frew@alfred.org.au 


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Consent Form  
Title 
Does Rosuvastatin delay progression of atherosclerosis 
in people with HIV infection? A multicentre randomized, 
double blind placebo-controlled trial 
Coordinating Principal 
Investigator/ Principal Investigator 
Dr Janine Trevillyan 
Prof Jennifer Hoy 
Associate Investigator(s) 
 
Professor Suzanne Crowe 
Dr Julian Elliott 
A. Professor Anthony Jaworowski 
Dr James Shaw  
Professor Anthony Dart 
Location  
The Alfred Hospital 
 
Declaration by Participant 
 
I have read the Participant Information Sheet or someone has read it to me in a language 
that I understand. 
 
I understand the purposes, procedures and risks of the research described in the project. 
 
I give permission for my doctors, other health professionals, hospitals or laboratories outside 
this hospital to release information to The Alfred Hospital concerning my disease and 
treatment for the purposes of this project. I understand that such information will remain 
confidential.  
 
I have had an opportunity to ask questions and I am satisfied with the answers I have 
received. 
 
I freely agree to participate in this research project as described and understand that I am 
free to withdraw at any time during the study without affecting my future health care.  
 
I understand that I will be given a signed copy of this document to keep. 
 
Name of Participant (please 
 
 
 
 
 
Signature  
 
Date  
 
 
 
Name of Witness* to 
Participant’s Signature (please 
print) 
 
 
 
Signature  
 
Date  
 
* Witness is not to be the investigator, a member of the study team or their delegate.  In the 
event that an interpreter is used, the interpreter may not act as a witness to the consent 
process.  Witness must be 18 years or older. 
 
Declaration by Study Doctor/Senior Researcher† 
I have given a verbal explanation of the research project, its procedures and risks and I 
believe that the participant has understood that explanation. 


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Name of Study Doctor/ 
Senior Researcher† (please 
print) 
 
 
 
Signature  
 
Date
 
 
† A senior member of the research team must provide the explanation of, and information 
concerning, the research project.  
 
Note: All parties signing the consent section must date their own signature. 
 
Consent for storage and use of blood samples 
 
Please indicate your choice by checking (ticking) ONE of the options below: 
□ 
I consent to the use of my blood samples for tests related to this research 
project and for a sample to be stored for future research as described in the 
relevant section of the Participant information sheet  
OR 
□ 
I consent to the use of blood samples taken from me for use in this project as 
described in the relevant section of the Participant Information Sheet but do 
not authorize their future use in any other research. 
 
 
Name of Participant (please 
 
 
 
Signature  
 
Date  
 
 
 
Name of Witness* to 
Participant’s Signature (please 
print) 
 
 
 
Signature  
 
Date  
 
* Witness is not to be the investigator, a member of the study team or their delegate.  In the 
event that an interpreter is used, the interpreter may not act as a witness to the consent 
process.  Witness must be 18 years or older. 
 
Name of Study Doctor/ 
Senior Researcher† (please 
print) 
 
 
 
Signature  
 
Date  
 
† A senior member of the research team must provide the explanation of and information 
concerning the research project.  
Note: All parties signing the consent section must date their own signature 
 
 


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Form for Withdrawal of Participation - Adult providing own consent 
 
Title 
Does Rosuvastatin delay progression of atherosclerosis 
in people with HIV infection? A multicentre randomized, 
double blind placebo-controlled trial 
Coordinating Principal 
Investigator/ Principal Investigator 
Dr Janine Trevillyan 
Prof Jennifer Hoy 
Associate Investigator(s) 
 
Professor Suzanne Crowe 
Dr Julian Elliott 
A. Professor Anthony Jaworowski 
Dr James Shaw  
Professor Anthony Dart 
Location  
The Alfred Hospital 
 
Declaration by Participant 
 
I wish to withdraw from participation in the above research project and understand that such 
withdrawal will not affect my routine treatment, my relationship with those treating me or my 
relationship with The Alfred Hospital 
 
 
Name of Participant (please 
 
 
 
 
 
Signature  
 
Date  
 
 
In the event that the participant’s decision to withdraw is communicated verbally, the Study 
Doctor/Senior Researcher will need to provide a description of the circumstances below. 
 
 
 
 
Declaration by Study Doctor/Senior Researcher† 
 
I have given a verbal explanation of the implications of withdrawal from the research project 
and I believe that the participant has understood that explanation. 
 
 
Name of Study Doctor/ 
Senior Researcher† (please 
print) 
 
 
 
Signature  
 
Date
 
 
† A senior member of the research team must provide the explanation of and information 
concerning withdrawal from the research project. Note: All parties signing the consent 
section must date their own signature. 
 


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22.6 Severity Grading of Adverse Events 
 
Modified DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF    
ADULT ADVERSE EVENTS  
 
VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009  
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(“DAIDS AE Grading Table”) is a descriptive terminology which can be utilized for Adverse 
Event (AE) reporting. A grading (severity) scale is provided for each AE term. 
 
Instructions and Clarifications 
In the classification of adverse events, the term “severe” is not the same as “serious.” 
Severity is an indication of the intensity of a specific event (as in mild, moderate, or severe 
chest pain). The term “serious” relates to a participant/event outcome or action criteria, 
usually associated with events that pose a threat to a participant’s life or functioning. 
 
For any AE where the outcome is death, the severity of the AE is classified as Grade 5.    
 
Determining Severity Grade for Parameters “Between Grades” 
If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of 
an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the AE. If a 
laboratory value that is graded as a multiple of the ULN or LLN falls between two grades, 
select the higher of the two grades for the AE. For example, Grade 1 is 2.5 x ULN and Grade 
2 is 2.6 x ULN for a parameter. If the lab value is 
2.53 x ULN (which is between the two grades), the severity of this AE would be Grade 2, the 
higher of the two grades. 
 
Values Below Grade 1: Any laboratory value that is between either the LLN or ULN and 
Grade 1 should not be graded.  
 
Definitions of terms used in the Table: 
 
Basic Self-care Functions 
 Activities such as bathing, dressing, toileting, 
transfer/movement, continence, and feeding 
 
LLN 
 
 
 
 
Lower limit of normal 
 
Medical Intervention 
Use of pharmacologic or biologic agent(s) for treatment 
of an AE. 
 
NA 
 
 
 
 
Not Applicable 
 
Operative Intervention 
 
Surgical OR other invasive mechanical procedures 
 
ULN  
 
 
 
Upper limit of normal 
 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
ESTIMATING SEVERITY GRADE 
Clinical adverse event 
NOT identified 
elsewhere in this 
DAIDS AE Grading 
Table 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing 
inability to perform basic 
self-care functions OR 
Medical or operative 
intervention indicated to 
prevent permanent 
impairment, persistent 
disability, or death 
SYSTEMIC 
Acute systemic 
Localized urticaria 
Localized urticaria with 
Generalized urticaria 
Acute anaphylaxis OR 
allergic reaction 
(wheals) with no 
medical intervention 
indicated 
medical intervention 
indicated OR Mild 
angioedema with no 
medical intervention 
indicated 
OR Angioedema with 
medical intervention 
indicated OR 
Symptomatic mild 
bronchospasm 
Life-threatening 
bronchospasm OR 
laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
NA 
Fatigue 
Symptoms causing no 
Symptoms causing 
Symptoms causing 
Incapacitating fatigue/ 
Malaise 
or minimal 
interference with 
usual social & 
functional activities 
greater than minimal 
interference with usual 
social & functional 
activities 
inability to perform usual 
social & functional 
activities 
malaise symptoms 
causing inability to 
perform basic self-care 
functions 
Fever (nonaxillary) 
37.7 – 38.6C 
38.7 – 39.3C 
39.4 – 40.5C 
> 40.5C 
Pain (indicate body 
site) 
DO NOT use for pain 
due to injection (See 
Injection Site 
Reactions: Injection 
site pain) 
See also Headache, 
Arthralgia, and 
Myalgia 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Pain causing inability to 
perform usual social & 
functional activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization (other 
than emergency room 
visit) indicated 
Unintentional 
weight loss 
NA 
5 – 9% loss in body 
weight from baseline 
10 – 19% loss in body 
weight from baseline 
20% loss in body weight 
from baseline OR 
Aggressive intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
 
 
 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
INFECTION 
Infection (any other 
than HIV infection) 
Localized, no 
systemic antimicrobial 
treatment indicated 
AND Symptoms 
causing no or minimal 
interference with 
usual social & 
functional activities 
Systemic antimicrobial 
treatment indicated 
OR Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Systemic antimicrobial 
treatment indicated 
AND Symptoms causing 
inability to perform usual 
social & functional 
activities OR Operative 
intervention (other than 
simple incision and 
drainage) indicated 
Life-threatening 
consequences (e.g., 
septic shock) 
INJECTION SITE REACTIONS 
Injection site pain 
(pain without touching) 
Or 
Tenderness (pain 
when area is touched) 
Pain/tenderness 
causing no or minimal 
limitation of use of 
limb 
Pain/tenderness 
limiting use of limb OR 
Pain/tenderness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Pain/tenderness 
causing inability to 
perform usual social & 
functional activities 
Pain/tenderness causing 
inability to perform basic 
self-care function OR 
Hospitalization (other 
than emergency room 
visit) indicated for 
management of 
pain/tenderness 
Injection site reaction 
(localized) 
Erythema OR 
Induration 
of 5x5 cm – 9x9 cm 
(or 25 cm
2 – 81cm2) 
Erythema OR 
Induration OR Edema 
> 9 cm any diameter 
(or > 81 cm2) 
Ulceration OR 
Secondary infection OR 
Phlebitis OR Sterile 
abscess OR Drainage 
Necrosis (involving 
dermis and deeper 
tissue) 
Pruritis associated with 
injection 
See also Skin: Pruritis 
(itching - no skin 
lesions) 
Itching localized to         
injection site AND 
Relieved spontaneously 
or with 
< 48 hours treatment 
 
Itching beyond the 
injection site but not 
generalized OR 
Itching localized to 
injection site requiring 
48 hours treatment 
Generalized itching 
causing inability to 
perform usual social & 
functional activities 
 
N/A 
SKIN – DERMATOLOGICAL 
Alopecia 
Thinning detectable by 
study participant (or by 
caregiver for young 
children and disabled 
adults) 
Alopecia 
Thinning detectable by 
study participant (or by 
caregiver for young children
and disabled adults) 
Alopecia 
Cutaneous reaction 
(Rash) 
Localized macular rash 
Diffuse macular, 
maculopapular, or 
morbilliform rash OR 
Target lesions 
Diffuse macular, 
maculopapular, or 
morbilliform rash with 
vesicles or limited 
number of bullae OR 
Superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Stevens-Johnson 
syndrome OR Ulceration 
of mucous membrane 
involving two or more 
distinct mucosal sites 
OR Toxic epidermal 
necrolysis (TEN) 
Pruritis (itching – no 
skin lesions) 
(See also Injection Site 
Reactions: Pruritis 
associated with 
injection) 
Itching causing no or 
minimal interference with 
usual social & functional 
activities 
Itching causing greater 
than minimal interference 
with usual social & 
functional activities 
 
Itching causing inability 
 
to perform usual social 
& functional activities 
 
NA 


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Vasovagal episode 
(associated with a 
procedure of any kind) 
Present without loss of 
consciousness 
Present with transient loss 
of consciousness 
NA 
NA 
Ventricular dysfunction 
(congestive heart failure) 
NA 
Asymptomatic diagnostic 
finding AND intervention 
indicated 
New onset with 
symptoms OR 
Worsening 
symptomatic 
congestive heart 
failure 
Life-threatening 
congestive heart failure
GASTROINTESTINAL 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive 
intervention 
indicated [e.g., tube 
feeding or total 
parenteral nutrition 
(TPN)] 
Ascites 
Asymptomatic 
Symptomatic AND 
Intervention indicated 
(e.g., diuretics or 
therapeutic 
paracentesis) 
Symptomatic despite 
intervention 
Life-
threatening 
consequence
s 
Cholecystitis 
NA 
Symptomatic AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic,or operative 
intervention indicated 
Life-threatening 
consequences 
(e.g., sepsis or 
perforation) 
Constipation 
NA 
Persistent constipation 
requiring regular use 
of dietary 
modifications, 
laxatives, or enemas 
Obstipation with manual 
evacuation indicated 
Life-threatening 
consequences 
(e.g., obstruction) 
 Diarrhea 
Transient or intermittent 
episodes of unformed 
stools OR Increase of ≤ 
3 stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 – 6 stools over 
baseline per 24-hour 
period 
Bloody diarrhea OR 
Increase of ≥ 7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated 
Life-threatening 
consequences 
(e.g., hypotensive 
shock) 
Dysphagia- 
Odynophagia 
Symptomatic but able to 
eat usual diet 
Symptoms causing 
altered dietary intake 
without medical 
intervention indicated 
Symptoms causing 
severely altered dietary 
intake with medical 
intervention indicated 
Life-threatening 
reduction in oral 
intake 


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Mucositis/stomatitis 
(clinical exam) 
Indicate site (e.g., 
larynx, oral) 
See Genitourinary for 
Vulvovaginitis 
Erythema of the 
mucosa 
Patchy 
pseudomembranes or 
ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR Mucosal 
bleeding with minor 
trauma 
Tissue necrosis 
OR Diffuse 
spontaneous 
mucosal bleeding 
OR Life-
threatening 
consequences
Nausea 
Transient (< 24 
hours) or 
intermittent nausea 
with no or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 – 48 
hours 
Persistent nausea 
resulting in minimal oral 
intake for > 48 hours 
OR Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences 
(e.g., hypotensive 
shock) 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Pancreatitis 
NA 
Symptomatic AND 
Hospitalization not 
indicated (other than 
emergency room visit) 
Symptomatic AND 
Hospitalization indicated 
(other than emergency 
room visit) 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Proctitis (functional- 
Rectal discomfort 
Symptoms causing 
Symptoms causing 
Life-threatening 
symptomatic) 
AND No intervention 
greater than minimal 
inability to perform usual 
consequences (e.g., 
Also see 
indicated 
interference with usual 
social & functional 
perforation) 
Mucositis/stomatitis 
social & functional 
activities OR Operative 
for clinical exam 
activities OR Medical 
intervention indicated 
intervention indicated 
Vomiting 
Transient or 
intermittent vomiting 
with no or minimal 
interference with oral 
intake 
Frequent episodes of 
vomiting with no or 
mild dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive rehydration 
indicated (e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
NEUROLOGIC 
Alteration in 
Alteration causing no 
Alteration causing 
Alteration causing 
Behavior potentially 
personality-behavior 
or minimal 
greater than minimal 
inability to perform usual 
harmful to self or others 
or in mood (e.g., 
interference with 
interference with usual 
social & functional 
(e.g., suicidal and 
agitation, anxiety, 
usual social & 
social & functional 
activities 
homicidal ideation or 
depression, mania, 
functional activities 
activities 
attempt, acute 
psychosis) 
psychosis) OR Causing 
inability to perform basic 
self-care functions 
Altered Mental Status 
For Dementia, see 
Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit 
disorder) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Confusion, memory 
impairment, lethargy, or 
somnolence causing 
inability to perform usual 
social & functional 
activities 
Delirium OR 
obtundation, OR coma 


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Cognitive and 
behavioral/attentional 
disturbance (including 
dementia and 
attention deficit disorder) 
Disability causing no or 
minimal interference with 
usual social & functional 
activities OR Specialized 
resources not indicated 
Disability causing greater 
than minimal interference 
with usual social & 
functional activities OR 
Specialized resources on 
part-time basis indicated 
Disability causing inability 
to perform usual social & 
functional activities OR 
Specialized resources on 
a full-time basis indicated 
Disability causing inability to 
perform basic self-care 
functions OR 
Institutionalization indicated 
CNS ischemia 
(acute) 
NA 
NA 
Transient ischemic attack Cerebral vascular accident 
(CVA, stroke) with 
neurological deficit 
Headache 
Symptoms causing no or 
minimal 
interference with usual 
social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
inability to perform usual 
social & functional 
activities 
Symptoms causing inability 
to perform basic self-care 
functions OR 
Hospitalization indicated 
(other than emergency 
room visit) OR Headache 
with significant impairment 
of alertness or other 
neurologic function 
Insomnia 
NA 
Difficulty sleeping causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Difficulty sleeping causing 
inability to perform usual 
social & functional 
activities 
Disabling insomnia causing 
inability to perform basic 
self-care functions 
Neuromuscular 
weakness 
(including myopathy & 
neuropathy) 
Asymptomatic with 
decreased strength on 
exam OR Minimal muscle 
weakness 
causing no or minimal 
interference with 
usual social & 
functional activities 
Muscle weakness causing 
greater than minimal 
interference with usual 
social & functional 
activities 
Muscle weakness causing 
inability to perform usual 
social & functional 
activities 
Disabling muscle weakness 
causing inability to perform 
basic self-care functions OR 
Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory 
Asymptomatic with 
Sensory alteration or 
Sensory alteration or 
Disabling sensory 
alteration (including 
sensory alteration on 
paresthesia causing 
paresthesia causing 
alteration or paresthesia 
paresthesia and 
exam or minimal 
greater than minimal 
inability to perform usual causing inability to 
painful neuropathy) 
paresthesia causing 
no or minimal 
interference with 
usual social & 
functional activities 
interference with usual 
social & functional 
activities 
social & functional 
activities 
perform basic self-care 
functions 
Seizure: (new onset) 
NA 
1 seizure 
2 – 4 seizures 
Seizures of any kind 
– Adult ≥ 18 years 
which are prolonged, 
See also Seizure: 
repetitive (e.g., status 
(known pre-existing 
epilepticus), or difficult 
seizure disorder) 
to control (e.g., 
refractory epilepsy) 
Ataxia 
Asymptomatic ataxia 
detectable on exam 
OR Minimal ataxia 
causing no or minimal 
interference with 
usual social & 
functional activities 
Symptomatic ataxia 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Symptomatic ataxia 
causing inability to 
perform usual social & 
functional activities 
Disabling ataxia causing 
inability to perform basic 
self-care functions 


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Seizure: (known pre- 
existing seizure 
disorder) 
 
NA 
Increased frequency of 
pre-existing seizures 
(non-repetitive) without 
change in seizure 
character OR Infrequent 
break- through seizures 
while on stable 
medication 
in a previously 
controlled seizure 
disorder 
Change in seizure 
character from baseline 
either in duration or 
quality (e.g., severity or 
focality) 
Seizures of any kind 
which are prolonged, 
repetitive (e.g., status 
epilepticus), or difficult 
to control (e.g., 
refractory epilepsy) 
Vertigo 
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities 
Vertigo causing greater 
than minimal 
interference with usual 
social & functional 
activities 
Vertigo causing inability 
to perform usual social 
& functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
RESPIRATORY 
Bronchospasm (acute) FEV1 or peak flow 
reduced to 
70 – 80% 
FEV1 or peak flow 
50 – 69% 
FEV1 or peak flow 
25 – 49% 
Cyanosis OR FEV1 or 
peak flow < 25% OR 
Intubation 
Dyspnea or respiratory 
distress 
Dyspnea on exertion 
with no or minimal 
interference with usual 
social & functional 
activities 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Dyspnea at rest causing 
inability to perform usual 
social & functional 
activities 
Respiratory failure with 
ventilatory support 
indicated 
MUSCULOSKELETAL 
Arthralgia 
See also Arthritis 
Joint pain causing no or 
minimal interference with 
usual social & functional 
activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform usual 
social & functional 
activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
See also Arthralgia 
Stiffness or joint swelling 
causing no or minimal 
interference with usual 
social & functional 
activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform usual 
social & functional 
activities 
Disabling joint stiffness or 
swelling causing inability 
to perform basic self-care 
functions 
Bone Mineral Loss 
BMD t-score 
-2.5 to -1.0 
BMD t-score < -2.5 
Pathological fracture 
(including loss of 
vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
Myalgia 
(non-injection site) 
Muscle pain causing no 
or minimal interference 
with usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform usual 
social & functional 
activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA 
Asymptomatic with 
radiographic findings 
AND No operative 
intervention indicated 
Symptomatic bone pain 
with radiographic 
findings OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 


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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
GENITOURINARY 
Cervicitis 
Symptoms causing 
Symptoms causing 
Symptoms causing 
Symptoms causing 
(symptoms) 
or minimal 
greater than minimal 
inability to perform usual 
inability to perform basic 
(For use in studies 
interference with 
interference with usual 
social & functional 
self-care functions 
evaluating topical 
usual social & 
social & functional 
activities 
study agents) 
functional activities 
activities 
Cervicitis 
Minimal cervical 
Moderate cervical 
Severe cervical 
Epithelial disruption 
(clinical exam) 
abnormalities on 
abnormalities on 
abnormalities on 
> 75% total surface 
(For use in studies 
examination 
examination 
examination (erythema, 
evaluating topical 
(erythema, 
(erythema, 
mucopurulent 
study agents) 
mucopurulent 
mucopurulent 
discharge, or friability) 
For other cervicitis see 
Infection: Infection 
(any other than HIV 
infection) 
discharge, or 
friability) 
OR 
Epithelial 
disruption 
25%
f t t l
discharge, or friability) 
OR Epithelial 
disruption of 25 – 49% 
total surface 
OR Epithelial disruption 
50 – 75% total surface 
Inter-menstrual 
Spotting observed 
Inter-menstrual 
Inter-menstrual bleeding 
Hemorrhage with life- 
bleeding (IMB) 
participant OR 
bleeding not greater in 
greater in duration or 
threatening hypotension 
Minimal blood 
duration or amount 
amount than usual 
OR Operative 
observed during 
than usual menstrual 
menstrual cycle 
intervention indicated 
clinical or 
colposcopic 
examination 
cycle 
Urinary tract 
N
Signs or symptoms of 
Signs or symptoms of 
Obstruction causing life- 
obstruction (e.g., 
urinary tract 
urinary tract obstruction 
threatening 
stone) 
obstruction without 
hydronephrosis or 
renal dysfunction 
with hydronephrosis or 
renal dysfunction 
consequences 
OCULAR/VISUAL 
Uveitis 
Asymptomatic but 
detectable on exam 
Symptomatic 
anterior uveitis OR 
Medical 
intervention 
indicated
Posterior or pan-uveitis 
OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Visual changes (from 
Visual changes 
Visual changes 
Visual changes causing 
Disabling visual loss in 
baseline) 
causing no or minimal 
interference with 
usual social & 
functional activities 
causing greater than 
minimal 
interference with 
usual social & 
functional 
activities 
inability to perform usual 
social & functional 
activities 
affected eye(s) 
ENDOCRINE/METABOLIC 
Abnormal fat 
Detectable by study 
Detectable on physical Disfiguring OR Obvious 
NA 
accumulation 
participant (or by 
exam by health care 
changes on casual 
(e.g., back of neck, 
caregiver for young 
provider 
visual inspection 
breasts, abdomen) 
children and disabled 
adults) 


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Diabetes mellitus 
NA 
New onset without 
need to initiate 
medication OR 
Modification of 
current medications 
to regain glucose 
control
New onset with initiation 
of medication indicated 
OR Diabetes 
uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non- 
ketotic coma) 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Gynecomastia 
Detectable by study 
participant or 
caregiver (for young 
children and disabled 
adults) 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
Hyperthyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
Asymptomatic 
Symptomatic causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform usual 
social & functional 
activities OR 
Uncontrolled despite 
treatment modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy 
(e.g., fat loss from 
the face, 
extremities, 
buttocks) 
Detectable by study 
participant (or by 
caregiver for young 
children and disabled 
adults) 
Detectable on 
physical exam by 
health care provider 
Disfiguring OR Obvious 
on casual visual 
inspection 
NA 
 
 
LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
HEMATOLOGY 
Standard International Units are listed in italics 
Absolute neutrophil count 
(ANC) 
1.000 x 109 – 
1.300 x 109/L 
0.750  x 109 – 
0.999 x 109/L 
0.500  x 109 – 
0.749 x 109/L 
< 0.500 x 109/L 
Fibrinogen, decreased 
1.00 – 2.00 g/L 
OR 
0.75 – 0.99 x LLN 
0.75 – 0.99 g/L 
OR 
0.50 – 0.74 x LLN 
 
0.50 – 0.74 g/L 
OR 
0.25 – 0.49 x LLN 
< 0.50 g/L 
OR 
< 0.25 x LLN 
OR 
Associated with gross 
bleeding 
 


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LABORATORY 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Hemoglobin (Hgb) 
HIV POSITIVE ONLY 
8.5 – 10.0 g/dL 
 
7.5 – 8.4 g/dL 
 
6.50 – 7.4 g/dL 
 
< 6.5 g/dL 
 
HIV NEGATIVE 
ONLY 
10.0 – 10.9 g/dL 
OR 
Any decrease 
2.5 – 3.4 g/dL 
 
9.0 – 9.9 g/dL 
OR 
Any decrease 
3.5 – 4.4 g/dL 
 
7.0 – 8.9 g/dL 
OR 
Any decrease 
 4.5 g/dL 
 
< 7.0 g/dL 
 
Comment:  The decrease is a decrease from baseline 
International Normalized 
Ratio of prothrombin time 
(INR) 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 3.0 x ULN 
> 3.0 x ULN 
Methemoglobin 
5.0 – 10.0% 
10.1 – 15.0% 
15.1 – 20.0% 
> 20.0% 
Prothrombin Time (PT) 
1.1 – 1.25 x ULN 
1.26 – 1.50 x ULN 
1.51 – 3.00 x ULN 
> 3.00 x ULN 
Partial Thromboplastin 
Time (PTT) 
1.1 – 1.66 x ULN 
1.67 – 2.33 x ULN 
2.34 – 3.00 x ULN 
> 3.00 x ULN 
Platelets, decreased 
100.000 x 109 – 
124.999 x 109/L 
50.000 x 109 – 
99.999 x 109/L 
25.000 x 109 – 
49.999 x 109/L 
< 25.000 x 109/L 
WBC, decreased 
2.000 x 109 – 
2.500 x 109/L 
1.500 x 109 – 
1.999 x 109/L 
1.000 x 109 – 
1.499 x 109/L 
< 1.000 x 109/L 
CHEMISTRIES 
 
Acidosis 
NA 
pH < normal, but  7.3 
pH < 7.3 without life- 
threatening 
consequences 
pH < 7.3 with life- 
threatening 
consequences 
Albumin, serum, low 
30 g/L – < LLN 
20 – 29 g/L 
< 20 g/L 
NA 
Alkaline Phosphatase 
1.25 – 2.5 x ULN† 
2.6 – 5.0 x ULN† 
5.1 – 10.0 x ULN† 
> 10.0 x ULN† 
Alkalosis 
NA 
pH > normal, but  7.5 
pH > 7.5 without life- 
threatening 
consequences 
pH > 7.5 with life- 
threatening 
consequences 
ALT (SGPT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
AST (SGOT) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10.0 x ULN 
> 10.0 x ULN 
Bicarbonate, serum, low 
16.0 mmol/L – < LLN 
11.0 – 15.9 mmol/L 
8.0 – 10.9 mmol/L 
< 8.0 mmol/L 
Bilirubin (Total) 
1.1 – 1.5 x ULN 
1.6 – 2.5 x ULN 
2.6 – 5.0 x ULN 
> 5.0 x ULN 
Calcium, serum, high 
2.65 – 2.88 mmol/L 
2.89 – 3.13 mmol/L 
3.14 – 3.38 mmol/L 
> 3.38 mmol/L 
Calcium, serum, low 
 
1.95 – 2.10 mmol/L 
1.75 – 1.94 mmol/L 
1.53 – 1.74 mmol/L 
< 1.53 mmol/L 


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Cardiac troponin I (cTnI) 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the 
manufacturer 
Creatine Kinase 
3.0 – 5.9 x ULN† 
6.0 – 9.9 x ULN† 
10.0 – 19.9 x ULN† 
≥20.0 x ULN† 
Creatinine 
1.1 – 1.3 x ULN† 
1.4 – 1.8 x ULN† 
1.9 – 3.4 x ULN† 
≥3.5 x ULN† 
 
 
 
Lipase 
1.1 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 5.0 x ULN 
> 5.0 x ULN 
Lactate 
ULN - < 2.0 x ULN 
without acidosis 
 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life- 
Increased lactate with 
pH < 7.3 with life- 
Magnesium, serum, low 
0.60 – 0.70 mmol/L 
0.45 – 0.59 mmol/L 
0.30 – 0.44 mmol/L 
< 0.30 mmol/L 
Pancreatic amylase 
1.1 – 1.5 x ULN 
1.6 – 2.0 x ULN 
2.1 – 5.0 x ULN 
> 5.0 x ULN 
 Phosphate, serum, low 
0.81 mmol/L – < LLN 
0.65 – 0.80 mmol/L 
0.32 – 0.64 mmol/L 
< 0.32 mmol/L 
Potassium, serum, high 
5.6 – 6.0 mmol/L 
6.1 – 6.5 mmol/L 
6.6 – 7.0 mmol/L 
> 7.0 mmol/L 
Potassium, serum, low 
3.0 – 3.4 mmol/L 
2.5 – 2.9 mmol/L 
2.0 – 2.4 mmol/L 
< 2.0 mmol/L 
Sodium, serum, high 
146 – 150 mmol/L 
151 – 154 mmol/L 
155 – 159 mmol/L 
 160 mmol/L 
Sodium, serum, low 
130 – 135 mmol/L 
125 – 129 mmol/L 
121 – 124 mmol/L 
 120 mmol/L 
URINALYSIS 
Standard International Units are listed in italics 
Hematuria (microscopic) 
6 – 10 RBC/HPF 
> 10 RBC/HPF 
Gross, with or without 
clots OR with RBC 
casts 
Transfusion indicated 
Proteinuria, random 
collection 
1 + 
2 – 3 + 
4 + 
NA 
Proteinuria, 24 hour collection 
 Adult 
0.200 – 0.999 g/d 
1.000 – 1.999 g/d 
2.000 – 3.500 g/d 
> 3.500 g/d 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Glucose, serum, high 
Nonfasting 
6.44 – 8.88 mmol/L 
8.89 – 13.88 mmol/L 
13.89 – 27.75 mmol/L 
> 27.75 mmol/L 
Fasting 
6.11 – 6.94 mmol/L 
6.95 – 13.88 mmol/L 
13.89 – 27.75 mmol/L 
> 27.75 mmol/L 
Glucose, serum, low 
3.05 – 3.55 mmol/L 
2.22 – 3.06 mmol/L 
1.67 – 2.23 mmol/L 
< 1.67 mmol/L