Clinical trial NCT01935674
Conditions: HIV Hypercholesterolaemia
Keywords: Hypercholesterolaemia HIV Rosuvastatin Protease inhibitor switching
Sponsor: Juan A. Arnaiz
Start date: 2013-09-01; Completion date: 2014-09-01
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To compare the effect of rosuvastatin to protease inhibitor switching on fasting total cholesterol over 12 weeks.

Detailed description:
To compare the effects of rosuvastatin to protease inhibitor switching on:

* Total cholesterol through week 12
* Safety parameters (HIV viral load, clinical adverse events, serious adverse events, laboratory adverse events, modifications to antiretroviral therapy)
* Quality of life (SF-12)
* Fasting LDL cholesterol (estimated with Friedewald equation unless triglycerides \>400mg/dL, in which case LDL-C would be measured directly), HDL cholesterol, total : HDL cholesterol ratio, LDL particles sizes, triglycerides
* Fasting glucose and insulin
* Framingham cardiovascular risk score
* D:A:D 5-year estimated risk calculator

Arms: arm 1: Switch their existing ritonavir-boosted PI to another potent ART drug with lesser effects on serum cholesterol selected by the investigator. arm 2: Continue ritonavir-boosted PI-based ART and commence rosuvastatin 10 mg daily (5 mg daily in Asian participants).
Interventions: intervention 1: Switch ritonavir-boosted PI intervention 2: Continue Ritonavir-boosted PI+Rosuvastatin
Intervention descriptions: intervention 1: Switch their existing ritonavir-boosted PI to another potent ART drug with lesser effects on serum cholesterol selected by the investigator. intervention 2: Continue ritonavir-boosted PI-based ART and commence rosuvastatin 10 mg daily (5 mg daily in Asian participants).

Protocol documents:
Prot_SAP_000.pdf: 
Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Rosuvastatin versus Protease 
Inhibitor Switching for 
Hypercholesterolaemia in HIV-
infected Adults 
 
 
INVESTIGATORS (Sydney)  
 
Professor Andrew Carr (Principal investigator) 
 
Dr. Frederick J. Lee 
 
Professor Bruce Brew 
 
Associate Professor Debbie Marriott 
 
Associate Professor Tony Kelleher 
 
Dr. Gail Matthews 
 
Dr. Sarah Pett 
 
Robyn Richardson, RN 
 
Nicola Mackenzie, RN 
  
 
St. Vincent’s Hospital, AMR-CRP 
 
University of New South Wales 
 
 
 
Dr. Mark Bloch 
Holdsworth House Medical Practice 
  
 
Dr. David Baker 
East Sydney Doctors 
 
Dr. Robert Finlayson 
Taylor Square Private Clinic 
 
 
 
INVESTIGATORS (Melbourne)
 
Professor Jennifer Hoy 
 
Alfred Hospital and Monash University  
 
 
 
Dr. Norman Roth 
Prahran Market Clinic 
 
Dr. Richard Moore 
Northside Clinic 
 
Dr. Ban Kiem Tee 
Centre Clinic 
 
 
 
INVESTIGATORS (Spain) 
 
Associate Professor Esteban Martínez 
 
University of Barcelona 
 
 
 
 
Protocol Version:  5.0 
 
Date of Protocol:  October 22, 2012 
 
NCT Number: NCT01935674


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
TABLE OF CONTENTS 
1. 
BACKGROUND 
8 
1.1. 
Management of dyslipidaemia in HIV-infected adults receiving a protease inhibitor 
8 
1.2. 
Rationale for Performing the Study 
10 
1.3. 
Hypothesis 
10 
2. 
STUDY OBJECTIVES 
11 
2.1. 
Primary Objective 
11 
2.2. 
Secondary Objectives 
11 
2.3. 
Key Outcomes Expected 
11 
3. 
STUDY DURATION 
12 
3.1. 
Number of Centres 
12 
4. 
SELECTION CRITERIA 
12 
4.1. 
Total Number of patients 
12 
4.2. 
Inclusion criteria: 
12 
4.3. 
Exclusion criteria: 
12 
5. 
STUDY DESIGN 
13 
5.1. 
Design 
13 
5.2. 
Interventions and Assessments 
15 
6. 
STUDY MEDICATION 
16 
6.1. 
Rosuvastatin 
16 
6.2. 
ART Switch Options 
16 
6.3. 
Provision of Antiretroviral drugs and Rosuvastatin at Study Completion 
16 
7. 
VISIT SCHEDULE 
17 
7.1. 
Screening Visit (days -14 to -1) 
17 
7.2. 
Inclusion criteria: 
17 
7.3. 
Exclusion criteria: 
18 
7.4. 
Eligibility of participants 
19 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
7.5. 
Randomisation 
19 
7.6. 
Baseline Visit (week 0) 
20 
7.7. 
Week 4 
20 
7.8. 
Week 12 
21 
7.9. 
Study Visit Windows 
21 
8. 
UNSCHEDULED VISIT 
21 
9. 
PREGNANCY 
21 
10. PATHOLOGY SPECIMEN MANAGEMENT 
22 
11. ADVERSE EVENTS 
23 
12. SERIOUS ADVERSE EVENTS 
23 
12.1. 
Serious Adverse Event Reporting Requirements 
23 
13. DATA SAFETY AND MONITORING BOARD 
24 
14. SAMPLE SIZE AND STATISTICAL ANALYSIS 
24 
14.1. 
Statistical analysis 
24 
14.2. 
Sample size 
24 
15. RECORDING AND TRANSFER OF STUDY DATA 
25 
15.1. 
Data recording 
25 
15.2. 
Data transfer to Study Sponsor 
26 
16. PUBLICATIONS AND PRESENTATIONS 
26 
17. REFERENCES 
27 
18. APPENDIX 1 – ETHICS REFERENCE 
28 
19. APPENDIX 2 – SF-12 
29 
20. APPENDIX 3 – GIT SYMPTOMS QUESTIONNAIRE 
32 
21. APPENDIX 4 – DRUGS@FDA LINKS FOR INFORMATION RE CONTRA-
INDICATED (ABSOLUTE AND RELATIVE) MEDICATIONS IN PATIENTS RECEIVING: 
ROSUVASTATIN, RALTEGRAVIR, ETRAVIRINE, TENOFOVIR, ATAZANAVIR, 
NEVIRAPINE, LAMIVUDINE AND EMTRICITABINE 
33 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 1 of 33 
Investigator Agreement and Signature Page 
We accept responsibility for the conduct of the research detailed in the proposal including 
all protocol-specific assessments, and we agree to abide by all decisions made by our 
Ethics Committee.  
 
We agree to the above which, in conjunction with the NHMRC Statement on Ethical 
Conduct in Research Involving Humans, will serve as the basis for co-operation in this 
study.  
  
Responsible Investigator 
Professor Andrew Carr 
(signature and date) 
 
 
 
Co-Investigators  
Dr. Sarah Pett 
(signature and date) 
 
 
 
Professor Bruce Brew 
(signature and date) 
 
 
 
A/Professor Debbie Marriott 
(signature and date) 
 
 
 
A/Professor Tony Kelleher 
(signature and date) 
 
 
 
Dr. Gail Matthews 
(signature and date) 
 
 
 
Dr. Frederick J. Lee 
(signature and date) 
 
 
 
Robyn Richardson, RN 
(signature and date) 
 
 
 
Nicola Mackenzie, RN 
(signature and date) 
 
 
 
Dr. Mark Bloch 
(signature and date) 
 
 
 
Dr. David Baker 
(signature and date) 
 
 
 
Dr. Robert Finlayson 
(signature and date) 
 
 
 
Professor Jenny Hoy 
(signature and date) 
 
 
 
Dr. Norman Roth 
(signature and date) 
 
 
 
Dr. Richard Moore 
(signature and date) 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 2 of 33 
 
Dr. Ban Kiem Tee 
(signature and date) 
 
 
 
A/Professor Esteban Martínez 
(signature and date) 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 3 of 33 
CONTACT DETAILS 
 
 
Sponsor Project Team 
 
Co-ordinating Investigator 
 
 
Professor Andrew Carr 
 
Project Manager/Co-investigator 
 
Dr. Frederick J. Lee 
 
Co-investigator 
 
 
 
Robyn Richardson, RN 
 
Study Co-ordinator/Co-investigator  
Nicola Mackenzie, RN 
 
 
Address: 
Centre for Applied Medical Research 
Clinical Research Program and 
HIV, Immunology and Infectious Diseases Unit 
Level 4 Xavier Building 
St Vincent’s Hospital 
390 Victoria Street 
Darlinghurst NSW 2010 
 
 
External Site Principal Investigators 
 
Professor Jenny Hoy 
Infectious Diseases Unit 
Level 2, Burnet Institute 
The Alfred Hospital  
85 Commercial Road 
Melbourne VIC 3004 
 
Dr. Mark Bloch 
Holdsworth House Medical Practice 
32a Oxford Street 
Darlinghurst NSW 2010 
 
Dr. David Baker 
East Sydney Doctors 
102 Burton St 
East Sydney NSW 2010  
 
Dr. Robert Finlayson 
Taylor Square Private Clinic 
393 Bourke St 
Darlinghurst NSW 2010 
 
Dr. Norman Roth 
Prahran Market Clinic 
Prahran Central, Mezzanine Level 
Corner Commercial Road & Chapel Street 
Prahran VIC 3181 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 4 of 33 
Dr. Richard Moore 
 
Northside Clinic 
370 St Georges Rd 
Fitzroy North VIC 3068  
 
Dr. Ban Kiem Tee 
Centre Clinic 
The rear 77 Fitzroy St 
St Kilda, VIC 3182 
 
A/Professor Esteban Martínez 
Infectious Diseases Unit 
Hospital Clinic 
University of Barcelona 
08036 Barcelona 
Spain European Union 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 5 of 33 
PROTOCOL SYNOPSIS 
 
Protocol title:  Rosuvastatin versus Protease Inhibitor Switching for 
Hypercholesterolaemia in HIV-infected Adults. 
 
Primary Objective: To compare the effect of rosuvastatin to protease inhibitor switching 
on fasting total cholesterol over 12 weeks. 
 
Study design: The study is an open-label, randomised, 12-week trial. Sixty (60) eligible 
participants will be randomly allocated 1:1 to: 
a. switch their existing ritonavir-boosted protease inhibitor to another potent antiretroviral 
therapy (ART) drug with lesser effects on serum cholesterol selected by the 
investigator. Potential switch drugs include: 
• for patients receiving a ritonavir-boosted protease inhibitor (PI) with 2 nucleoside 
analogue reverse transcriptase inhibitors (NRTIs): raltegravir, nevirapine, 
rilpivirine and unboosted atazanavir  
• for patients receiving a ritonavir-boosted PI plus 1 or more other drugs (e.g. 
raltegravir, efavirenz) but not a NRTI - additional switch options include 
tenofovir, lamivudine and emtricitabine, such that the patient is receiving at least 
3 potent drugs after the switch)  
OR 
b. continue ritonavir-boosted PI-based ART and commence rosuvastatin 10 mg daily (5 
mg daily in Asian participants). 
Planned sample size: Sixty (60) eligible participants 
 
Inclusion criteria: 
1. 
HIV-positive status  
2. 
Adults (≥18 years of age) 
3. 
Stable and well-tolerated combination ART including a ritonavir-boosted PI for the 
previous 6 months 
4. 
HIV RNA <50 copies/mL for at least the preceding 3 months 
5. 
Fasting total cholesterol ≥5.5 mmol/L (>213 mg/dL) 
6. 
Framingham risk score ≥8% at 10 years OR diabetes mellitus OR a family history of 
premature coronary artery disease in a first-degree relative  
7. 
Provision of written, informed consent 
 
Exclusion criteria: 
8. 
Any statin in the previous 12 weeks 
9. 
Previous statin-induced myopathy or hepatitis  
10. History of coronary artery disease, stroke or any other indication for the use of statin 
therapy (hyperlipidaemia: genetic, secondary or idiopathic) 
11. Concurrent use of: 
• oral corticosteroids use other than for replacement therapy (ie. prednisolone 5-
7.5 mg, hydrocortisone 20-30 mg, cortisone acetate 25-37.5 mg daily) 
• other immunosuppressive or immunomodulating drugs 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 6 of 33 
12. Contra-indication to rosuvastatin therapy: 
• liver transaminases >5 times the upper normal limit 
• creatinine clearance <30 mL/min 
• known myopathy 
• current fibrate therapy 
• known resistance to one or more “backbone” ART drugs 
13. No potent switch ART drug available to replace the current ritonavir-boosted PI 
14. Known intolerance to rosuvastatin or the proposed switch ART drug 
15. Women attempting or likely to become pregnant, or who are pregnant or breast-
feeding  
16. A patient with a history or current evidence of any condition, therapy, or laboratory 
abnormality, or other circumstance that might confound the results of the study, or 
interfere with the patient’s participation for the full duration of the study 
17. Unable to complete study procedures 
 
Study procedures: 
There will be 4 study visits over the 14-week study period. Procedures will include 
assessments of safety, HIV viral load, and fasting lipid and glycaemic levels.  
All participants will receive standardised dietary and exercise education at each visit. 
Patients and physicians will be blinded to lipid results until week 12. 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 7 of 33 
Flow chart of assessments 
 
Time of Visit 
Screen 
Baseline 
Week 
-2 
0 
4 
12 
Clinical 
 
 
 
 
Informed consent 
x 
 
 
 
Inclusion / exclusion criteria 
x 
 
 
 
Demographic data 
x 
 
 
 
Full physical examination / history 
x 
 
 
 
Targeted physical examination  
 
x 
x 
x 
Concomitant medication  
x 
x 
x 
x 
Adverse events 
 
x 
x 
x 
Select drug to replace current boosted PI 
x 
 
 
 
Randomization* 
x 
 
 
 
Framingham and DAD scores  
x  
 
 
x 
Vital signs (pulse, blood pressure, temperature) 
x 
x 
x 
x 
Height  
 
x 
 
 
Weight 
x 
x 
x 
x 
SF-12 QOL & GIT symptoms questionnaires 
 
x 
x 
x 
Dispense rosuvastatin or change PI  
 
x  
x 
 
Dietary and exercise education 
 
x 
x  
x 
Pathology 
 
 
 
 
Pregnancy test 
x^ 
 
 
 
HIV RNA viral load  
x^  
 
x^ 
x^ 
Biochemistry1 
x^ 
x^ 
x^ 
x^ 
Full blood count 
 
x^ 
x^ 
x^ 
CD4+ lymphocyte count and percentage 
 
x^ 
x^ 
x^ 
Fasting total cholesterol 
x^ 
 
 
 
Complete fasting lipid profile2  
x^ 
x 
x 
x 
LDL particle size (fasting)  
 
x 
x 
x 
Glucose / insulin (fasting) 
 
x^ 
 
x^ 
D-dimer3 
 
x 
x 
x 
Plasma and serum storage4 
 
x 
x 
x 
*  
Randomization to take place at Day -2 or -1, after all eligibility criteria confirmed 
 
1  
Biochemistry: urea, electrolytes (including calcium, magnesium and phosphate), creatinine, liver function tests 
(alanine aminotransferase [ALT], aspartate aminotransferase [AST], albumin, total protein, alkaline phosphatase 
[ALP], gamma glutamyltransferase [GGT], bilirubin), creatine kinase 
^ 
Requested as standard-of-care pathology 
2 
Complete fasting lipid profile: Triglycerides, total cholesterol, HDL and LDL cholesterol, and calculated VLDL 
cholesterol. Measured VLDL cholesterol, if required, is available for participants from Sydney sites only. Blood 
samples collected after a 9- to 12-hour overnight fast (usual intake of water recommended) 
3 
Collected as plasma storage samples; D-dimer will be analysed at the end of study from stored samples 
4 
4 x 1 mL plasma and 3 x 1 mL serum aliquots to be stored 
 
Unscheduled visits would include: targeted medical review, safety bloods, and study co-ordinator assessment 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 8 of 33 
1. BACKGROUND 
1.1. 
Management of dyslipidaemia in HIV-infected adults receiving a protease 
inhibitor 
Dyslipidaemia, and in particular elevated plasma levels of total and low-density lipoprotein 
(LDL) cholesterol, is common in HIV-infected adults. Dyslipidaemia is associated with 
protease inhibitor (PI) -based anti-retroviral therapy (ART) and an increased risk of 
myocardial infarction (1). 
 
Dyslipidaemia has proven to be a common reason for switching from PI-based therapy, 
particularly from lopinavir-ritonavir, initially to atazanavir, and more recently to raltegravir. 
The effects of ritonavir-boosted darunavir and fosamprenavir are very similar to those of 
lopinavir-ritonavir – switching from ritonavir-boosted darunavir as likely to become more 
common as more patients commence darunavir as first-line ART. 
 
The two proven strategies to lower total and LDL cholesterol levels in HIV-infected adults 
receiving a PI and who have hypercholesterolaemia are statin therapy and PI-switching to 
an alternative ART (2-6). The preferred strategy is unknown. 
 
The preferred statin in this population may be rosuvastatin 10 mg daily, as it had greater 
lipid-lowering activity than and similar tolerability to pravastatin 40 mg daily (6).  
 
Potential switch drugs for patients receiving a ritonavir-boosted PI with 2 nucleoside 
analogues are raltegravir, nevirapine, rilpivirine and unboosted atazanavir, all of which 
have little if any effect on lipid metabolism (although not all drugs may be suitable for 
virological or other reasons). For patients receiving a ritonavir-boosted PI plus other drugs 
(e.g. raltegravir, efavirenz) but not a nucleoside analogue, additional switch options without 
lipid effects are include tenofovir, abacavir, lamivudine and emtricitabine. Statin therapy 
and PI switching both have potential advantages and disadvantages: 
 
• 
Statin therapy - potential advantages 
o 
proven efficacy in reducing cardiovascular risk in the general population both as 
primary and secondary prevention 
o 
generally well-tolerated. Indeed, simvastatin is available over-the-counter in 
some countries without a prescription  
o 
several statins (pravastatin, atorvastatin or rosuvastatin) can be used safely 
with PI therapy, although smaller than usual doses of atorvastatin and 
rosuvastatin are often used as both drugs can attain higher levels in patients 
receiving a PI because of pharmacokinetic interactions  
o 
statins may have anti-inflammatory effects independent of their lipid-lowering 
effects (7) that have been hypothesised to incur additional cardiovascular benefit 
o 
minimal risk of virological failure 
• 
Statin therapy - potential disadvantages 
o 
potential side effects (hepatitis and myopathy/rhabdomyolysis) 
o 
means using a drug to treat another drug toxicity  
o 
increases pill burden and treatment costs, both undesirable in a disease in 
which pill burden associates with ART efficacy and in a disease that is lifelong  


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 9 of 33 
 
• 
PI switching - potential advantages 
o 
removes cause of the hypercholesterolaemia  
o 
less likely to increase pill burden or costs 
• 
PI switching - potential disadvantages 
o 
PI therapy may not be the cause of dyslipidaemia in many patients - other 
causes include genetics, diet and obesity 
o 
virological failure; e.g. in the SWITCHMRK study, switching from a protease 
inhibitor to raltegravir resulted in significantly greater virological failure, which 
was evident within 12 weeks of switching (8) 
o 
drug toxicity from the new antiretroviral drug 
o 
reduces available ART choices, which is increasingly important given the 
greatly diminishing HIV drug pipeline 
Only one study has compared the statin and switch strategies (2). In this trial, statin therapy 
appeared similar to PI switching at lowering total and LDL cholesterol over 24 weeks. 
However, this study has numerous limitations and uncertainties: 
• one of the switch drugs was efavirenz, which is also known to occasionally induce 
very similar lipid changes as protease inhibitor therapy 
• the PI drugs evaluated are now rarely prescribed (indinavir, saquinavir, nelfinavir) 
• the maximum effect on cholesterol levels was observed at 24 weeks, which is 
substantially later than the 4 to 6 weeks stated in statin product labels (9,10) 
• the statin used was pravastatin 40 mg nocte, which has subsequently been found to 
be less potent than rosuvastatin 10 mg daily (6). 
Intervening for hypercholesterolaemia will only be clinically meaningful if patients have 
elevated underlying cardiovascular risk that, for the purposes of this study, is defined as a 
Framingham score of at least 8% at 10 years (a score of at least 10% would be 
reasonable in HIV-negative patients, but HIV-infected adults appear to have a rate of 
myocardial infarction higher than expected for any given Framingham score), or a 
diagnosis of diabetes mellitus, or a family history of premature coronary artery disease. 
We propose a randomised, open-label, 12-week trial in which eligible participants will be 
randomised 1:1 to either:  
A.  Switch of existing ritonavir-boosted protease inhibitor to another potent antiretroviral 
drug without effects on serum cholesterol selected by the investigator. Potential switch 
drugs: 
• for patients receiving a ritonavir-boosted PI with 2 nucleoside analogues - 
raltegravir, nevirapine, rilpivirine, and unboosted atazanavir. 
• for patients receiving a ritonavir-boosted PI plus 1 or more other drugs (e.g. 
raltegravir, efavirenz) but not a nucleoside analogue - additional switch options 
include tenofovir, abacavir, lamivudine and emtricitabine, such that the patient is 
receiving at least 3 potent drugs after the switch.  
OR 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 10 of 33 
B. Continue ritonavir-boosted protease inhibitor-based ART and commence rosuvastatin 
10 mg daily (5 mg daily in Asian participants). 
1.2. 
Rationale for Performing the Study 
Intervening for hypercholesterolaemia will only be of clinical significance if patients have 
an elevated underlying cardiovascular risk profile. For the purposes of this study, this is 
defined as any of the following: a Framingham score of ≥8% at 10 years in an HIV-infected 
person OR a diagnosis of diabetes mellitus OR a family history of premature coronary 
artery disease in a first-degree relative. In persons who are HIV-negative, a Framingham 
score of 10% would be not unreasonable, but HIV-infected adults have a trend of higher 
rates of myocardial infarction for any given Framingham score. 
Presently, the two proven and accepted strategies for lowering total and LDL cholesterol 
levels in HIV-infected adults receiving a ritonavir-boosted PI with hypercholesterolaemia 
are either:  
(1) statin therapy; or  
(2) switching the ritonavir-boosted PI to an alternative ART (2-6).  
The optimal strategy however, is not known. Therefore, we propose a randomised, open-
label, 12-week prospective trial to compare the effect of rosuvastatin to protease inhibitor 
switching on fasting total serum cholesterol.   
1.3. 
Hypothesis  
That rosuvastatin will be more effective than protease inhibitor switching for 
hypercholesterolaemia in HIV-infected adults receiving a ritonavir-boosted protease 
inhibitor. 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 11 of 33 
2. STUDY OBJECTIVES 
2.1. 
Primary Objective 
To compare the effect of rosuvastatin to protease inhibitor switching on fasting total 
cholesterol over 12 weeks 
2.2. 
Secondary Objectives 
To compare the effects of rosuvastatin to protease inhibitor switching on: 
• Total cholesterol through week 12 
• Safety parameters (HIV viral load, clinical adverse events, serious adverse events, 
laboratory adverse events, modifications to antiretroviral therapy) 
• Quality of life (SF-12) 
• Fasting LDL cholesterol (estimated with Friedwald equation unless triglycerides 
>400mg/dL, in which case LDL-C would be measured directly), HDL cholesterol, 
total : HDL cholesterol ratio, LDL particles sizes, triglycerides 
• Fasting glucose and insulin 
• Framingham cardiovascular risk score (available at:  
http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof) 
• D:A:D 5-year estimated risk calculator (available at: 
http://www.cphiv.dk/TOOLS/DADRiskEquations/tabid/437/Default.aspx) 
2.3. 
Key Outcomes Expected 
That rosuvastatin therapy will lead to greater reduction in total cholesterol than protease 
inhibitor switching, with similar safety and no adverse effect on HIV virological control.  


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 12 of 33 
3. STUDY DURATION 
Twelve (12) weeks 
3.1. 
Number of Centres 
This study will be performed at nine sites: 
1. St Vincent’s Centre for Applied Medical Research (AMR), Clinical Research 
Program (CRP) St Vincent’s Hospital, Sydney 
2. Holdsworth House Medical Practice, Sydney 
3. East Sydney Doctors, Sydney 
4. Taylor Square Private Clinic, Sydney 
5. Infectious Diseases Unit, Alfred Hospital, Melbourne 
6. Prahran Market Clinic, Melbourne 
7. Northside Clinic, Melbourne 
8. Centre Clinic, Melbourne 
9. Infectious Diseases Department, Hospital Clinic, University of Barcelona  
 
4. SELECTION CRITERIA 
4.1. 
Total Number of patients 
Sixty (60) eligible participants 
4.2. 
Inclusion criteria: 
1. HIV-positive status  
2. Adults (≥18 years of age) 
3. Stable and well-tolerated combination ART including a ritonavir-boosted 
protease inhibitor for the previous 6 months 
4. HIV RNA <50 copies/mL for at least the preceding 3 months 
5. Fasting total cholesterol ≥5.5 mmol/L (>213 mg/dL) 
6. Framingham risk score ≥8% at 10 years OR diabetes mellitus OR a family 
history of premature coronary artery disease in a first-degree relative 
7. Provision of written, informed consent 
4.3. 
Exclusion criteria: 
8. Any statin in the previous 12 weeks 
9. Previous statin-induced myopathy or hepatitis  
10. History of coronary artery disease, stroke or any other indication for the use of 
statin therapy (hyperlipidaemia: genetic, secondary or idiopathic) 
11. Concurrent use of: 
• oral corticosteroids use other than for replacement therapy (i.e. prednisolone 
5-7.5 mg, hydrocortisone 20-30 mg, cortisone acetate 25-37.5 mg daily) 
• other immunosuppressive or immunodulating drugs 
12. Contraindication to rosuvastatin therapy: 
• liver transaminases >5 times the upper normal limit 
• creatinine clearance <30 mL/min 
• known myopathy 
• current fibrate therapy 
• known resistance to one or more “backbone” ART drugs 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 13 of 33 
13. No potent switch ART drug available to replace the current ritonavir-boosted 
protease inhibitor 
14. Known intolerance to rosuvastatin or the proposed switch ART drug 
15. Women attempting or likely to become pregnant, or who are pregnant or breast-
feeding  
16. A patient with a history or current evidence of any condition, therapy, or 
laboratory abnormality, or other circumstance that might confound the results of 
the study, or interfere with the patient’s participation for the full duration of the 
study 
17. Unable to complete study procedures 
 
5. STUDY DESIGN 
5.1. 
Design 
This is a randomized, open-label, 12-week prospective trial. Sixty (60) eligible subjects will 
be randomly allocated 1:1 to either: 
(A) switch their existing ritonavir-boosted PI to another potent ART drug with lesser effects 
on serum cholesterol selected by the investigator; OR  
(B) continue ritonavir-boosted PI-based ART and commence rosuvastatin 10 mg daily (5 
mg daily in Asian participants).      
For patients in the switch arm, potential switch drugs that are recommended are shown in 
the table below: 
 
Lipid switch or statin study – Switch options 
 
Current 
regimen 
Switch options for 
rPI (per DHHS 
guidelines)1 
New regimen 
Considerations 
(apart from prior 
resistance) 
TDF-FTC-rPI 
NNRTI 
TDF-FTC-
NNRTI 
• Nevirapine and 
rilpivirine preferred3 
Raltegravir 
TDF-FTC-RAL 
•  
 
 
 
 
ABC-3TC-rPI 
NNRTI 
ABC-3TC-
NNRTI 
• Nevirapine and 
rilpivirine preferred3 
Raltegravir 
ABC-3TC-RAL •  
 
 
 
 
 
Unboosted 
atazanavir2 
ABC-3TC-AZV • 
 
NNRTI-rPI 
TDF-FTC 
TDF-FTC-
NNRTI 
•  
ABC-3TC 
ABC-3TC-
NNRTI 
•  
RAL-rPI 
TDF-FTC 
RAL-TDF-FTC 
•  
ABC-3TC 
RAL-ABC-3TC •  
 
Footnotes:  
1. rPI switch to etravirine is not permitted until etravirine switching is approved by the Therapeutic Good 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 14 of 33 
Administration and ASHM (Australia) or by the European Medicines Agency and EACS (Spain). rPI 
switch to maraviroc is not permitted until maraviroc switching using the DNA tropism assay is 
approved by the Therapeutic Good Administration and ASHM (Australia) or by the European 
Medicines Agency and EACS (Spain). 
2. Unboosted atazanavir should NOT be used with tenofovir. 
3. Efavirenz as a switch NNRTI is acceptable, but not preferred. 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 15 of 33 
Randomisation will be stratified by baseline protease inhibitor type and by baseline 
total cholesterol (>7.0 mmol/L or ≤7.0 mmol/L [275 mg/dL]). Randomisation (blocks of 
six) within each stratum will be performed by Centre for Applied Medical Research 
(CAMR) staff otherwise not involved in the study. A computerized random number 
generator with a blocking factor of 3 will be used to produce a random number list. 
There will be 4 study visits over the 14-week study period. Procedures will include 
assessments of safety, HIV viral load, and fasting lipid and glycaemic levels.  
All participants will receive standardised dietary and exercise education at each visit. 
LDL particle size testing will be performed at one central laboratory (LipoScience 
Global Research Services, North Carolina, USA). All other study pathology will be 
performed locally for each of the participating study sites.  
New interventions (new pharmacological or antiretroviral drug change, depending on 
randomised study arm) will be discouraged. Patients and physicians will be blinded to 
lipid results until week 12. However, if the total cholesterol rises during the study by 
≥2.0 mmol/L from Baseline (Week 0), then this result will be unblended and notified to 
the respective principal investigators at the corresponding sites for review, follow-up 
and monitoring. Crossover between study arms will not be permitted. Modifications 
after week 12 will be based on local practice.  
5.2. 
Interventions and Assessments 
All study procedures will be performed at the individual study sites over 12 weeks. 
 
Dietary and exercise education: Standardised dietary and exercise education will be 
provided to study patients at baseline, and followed up at week 4 and week 12 visits.  
 
Anthropometry: Weight (at all visits) and height (at baseline only) will be measured. Body 
Mass Index (BMI) will be calculated by dividing weight by height squared (kg/m2).  
 
Fasting metabolic parameters: After arrival and a 10 minute rest, fasting samples will be 
taken for triglycerides, total cholesterol, HDL and LDL cholesterol. LDL particle size, 
glucose and insulin. VLDL cholesterol will be calculated, but if a measured value is 
required, this is only available for participants from Sydney sites. D-dimer will be measured 
at the end of study from a sodium citrate tube (light blue top) collected as part of plasma 
storage. 
Study participants and study staff will be blinded to the results of these tests until 
completion of the study at week 12. This is to prevent self-modification of lifestyle or diet in 
an attempt to normalise out-of-range results.  
 
Quality of Life Questionnaire SF-12: Study participants will be asked to complete the 
SF-12 (standard, 4 week) quality of life questionnaire at baseline, weeks 4 and 12. (see 
appendix 2). 
 
GIT symptoms questionnaire: At baseline, week 4 and week 12, specific questions will 
be asked regarding presence of nausea and diarrhoea and severity if applicable (see 
appendix 3). 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 16 of 33 
 
Blood for storage: Some plasma will be stored for possible subsequent testing of as-yet 
undecided plasma proteins. These proteins might include one or more lipid, glycaemic, 
cardiovascular or inflammatory plasma proteins that are potentially related to 
cardiovascular disease in HIV-infected adults and/or in the general population. Storage 
samples will be collected at visits baseline, week 4 and week 12. 
 
6. STUDY MEDICATION 
Participants will be randomly allocated 1:1 to switch their existing ritonavir-boosted 
protease inhibitor to another potent antiretroviral or continue ritonavir-boosted protease 
inhibitor-based ART and commence rosuvastatin 10mg daily (5 mg daily in Asian 
participants). 
6.1. 
Rosuvastatin 
Rosuvastatin is a hypolipidaemic agent and member of the drug class of statins (HMG-
CoA reductase inhibitors) 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 hypercholesterolaemia 
(including familial hypercholesterolaemia). Rosuvastatin should be used as an adjunct to 
dietary modification.  
In the ROSUVASTATIN (6) study, treatment with rosuvastatin 10 mg daily resulted in a 
28% reduction in total cholesterol (SD=18%) and 35% reduction in LDL cholesterol 
(SD=17%). Rosuvastatin 10mg daily had similar tolerability and greater lipid-lowering 
effect in that study than pravastatin 40 mg daily. Therefore, rosuvastatin is the statin to be 
used in the present study. 
Patients randomised to the rosuvastatin treatment arm will continue their ritonavir-boosted 
protease inhibitor-based ART and commence rosuvastatin 10 mg daily (5 mg daily for 
Asian participants, as the risk of myopathy during rosuvastatin therapy may be increased 
in Asians). Please refer to the rosuvastatin product label and prescribing information for 
further information on the side-effect profile. 
6.2. 
ART Switch Options 
The switch drug will be selected by the site investigator at the screening visit and prior to 
randomisation.  
 
Potential preferred switch drugs for patients receiving a ritonavir-boosted PI with 2 
nucleoside analogues include: raltegravir, nevirapine, rilpivirine, and unboosted atazanavir. 
 
Potential switch drugs for patients receiving a ritonavir-boosted PI plus 1 or more other 
drugs (e.g. raltegravir, efavirenz) but not a nucleoside analogue include: tenofovir, 
lamivudine, abacavir and emtricitabine, such that the patient is receiving at least 3 potent 
drugs after the switch. 
6.3. 
Provision of Antiretroviral drugs and Rosuvastatin at Study Completion 
Once the final study visit has occurred (week 12 visit) all ART will be obtained by 
prescription from the study participant’s treating doctor. If at the end of the study 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 17 of 33 
rosuvastatin is shown to be safe and effective, the study participant’s treating doctor will 
continue to prescribe rosuvastatin. 
 
7. VISIT SCHEDULE 
 
Eligibility Screening Form 
An eligibility screening form should be completed at the screening visit. Participant details 
will be entered on the study participant identification log including whether or not the 
participant was included, and if excluded, the reason why. 
 
Eligibility of participants 
Prior to screening, participants must be on stable and well-tolerated ART including a 
ritonavir-boosted protease inhibitor for at least 6 months prior to randomisation.   
 
Informed consent should be obtained and forms signed and dated by the participant prior 
to any study-related procedures being performed. 
7.1. 
Screening Visit (days -14 to -1) 
The screening procedures will be completed in one visit.  
Participants will present to the study site, having fasted from overnight for the previous 9 to 
12 hours (no food, caffeine or caloric drink; free water intake encouraged to maintain 
adequate hydration) for at least 12 hours.  
 
Assessments (results to be recorded in the CRF) 
Clinical eligibility will be measured by inclusion criteria numbers 1-7 and exclusion criteria 
numbers 8-17 as listed below.  
 
7.2. 
Inclusion criteria: 
1. HIV-positive status  
2. Adults (≥18 years of age) 
3. Stable and well-tolerated combination ART including a ritonavir-boosted PI for the 
previous 6 months 
4. HIV RNA <50 copies/mL for at least the preceding 3 months 
5. Fasting total cholesterol ≥5.5 mmol/L (>213 mg/dL) 
6. Framingham risk score ≥8% at 10 years OR diabetes mellitus OR a family history 
of premature coronary artery disease in a first-degree relative  
7. Provision of written, informed consent 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 18 of 33 
7.3. 
Exclusion criteria: 
8. Any statin in the previous 12 weeks 
9. Previous statin-induced myopathy or hepatitis  
10. History of coronary artery disease, stroke or any other indication for the use of 
statin therapy (hyperlipidaemia: genetic, secondary or idiopathic) 
11. Concurrent use of: 
• oral corticosteroids use other than for replacement therapy (ie. prednisolone 
5-7.5 mg, hydrocortisone 20-30 mg, cortisone acetate 25-37.5 mg daily) 
• other immunosuppressive or immunomodulating drugs 
12. Contra-indication to rosuvastatin therapy: 
• liver transaminases >5 times the upper normal limit 
• creatinine clearance <30mL/min 
• known myopathy 
• current fibrate therapy 
• known resistance to one or more “backbone” ART drugs 
13. No potent switch ART drug available to replace the current ritonavir-boosted 
protease inhibitor 
14. Known intolerance to rosuvastatin or the proposed switch ART drug 
15. Women attempting or likely to become pregnant, or who are pregnant or breast-
feeding  
16. A patient with a history or current evidence of any condition, therapy, or 
laboratory abnormality, or other circumstance that might confound the results of 
the study, or interfere with the patient’s participation for the full duration of the 
study 
17. Unable to complete study procedures 
 
Other screening assessments 
• Demographic data: date of birth, age, gender, race, smoking status (nil ever, years 
since stopped, current per day), alcohol intake (drinks per week) 
• Framingham and D:A:D score and components 
o 
number of years on indinavir, lopinavir 
o 
myocardial infarction or stroke in a first degree relative (mother, father or 
sibling) and age of relative at time of incident 
o 
use of medication to treat blood pressure  
o 
has the patient been diagnosed with diabetes 
• Full physical examination, medical history concomitant medications information and 
selection of drug to replace current boosted PI will be obtained by the study doctor  
• Pulse and blood pressure will be recorded with the patient sitting for at least 10 
minutes 
• Weight 
• Quality of life and GIT symptoms questionnaires  
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 19 of 33 
After 10 minutes of rest, blood samples will be taken for Pathology 
 
Safety 
• For potentially child-bearing female participants a blood test will be done to exclude 
pregnancy.  
• HIV antibodies/Western blot/proviral DNA (if report not available prior to study entry) 
• HIV RNA viral load 
• Biochemistry – urea, electrolytes (sodium, potassium, chloride, bicarbonate, 
calcium, magnesium and phosphate), creatinine, liver function tests (alanine 
aminotransferase [ALT], aspartate aminotransferase [AST], albumin, total protein, 
alkaline phosphatase [ALP], gamma glutamyltransferase [GGT], bilirubin, creatine 
kinase 
 
Fasting metabolic parameters 
• total cholesterol, triglycerides, HDL/LDL cholesterol and calculated VLDL 
cholesterol. Measured VLDL cholesterol is available for subjects from Sydney sites 
only. 
• D-dimer will be measured at the end of study from a sodium citrate tube (light blue 
top) collected as part of the plasma storage sample. 
 
Pathology results are to be attached behind the pathology collection page of the 
screening CRF. 
7.4. 
Eligibility of participants 
Screened participants will have their switch ART (to replace current boosted PI) by an 
investigator during the screening visit, prior to randomisation. If the participant meets all 
the eligibility criteria (1 to 17) then a Baseline (Week 0) Visit will be booked. 
 
7.5. 
Randomisation 
Eligible subjects will be randomly allocated 1:1 to switch their existing ritonavir-boosted PI 
to another potent antiretroviral drug without effects on serum cholesterol selected by the 
investigator OR continue ritonavir-boosted PI-based ART and commence rosuvastatin  
10 mg daily (5 mg daily in Asian participants).  
 
Participant randomisation to one of the two arms should occur as soon as screening 
pathology results are available, but in any case not less than one (1) working day prior to 
baseline visit to allow for medication arrangement and coordination of Baseline Visit. 
 
Central randomisation will be performed by a staff member of the Clinical Research 
Program, St Vincent’s Hospital, NSW, Australia who is uninvolved in the conduct of the 
trial. A computerized random number generator with a blocking factor of 3 will be used to 
produce a random number list. 
 
Following randomisation, a prescription for the switch ART or rosuvastatin will be written 
by the study doctor. The hospital pharmacy will prepare the script prior to the Baseline 
Visit in preparation for the participants scheduled Baseline Visit. 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 20 of 33 
7.6. 
Baseline Visit (week 0)  
Participants will present to the study site having fasted from overnight for the previous 9 to 
12 hours (no food or drink with calories; but free water intake encouraged to maintain 
adequate hydration).  
 
Baseline assessments will be recorded in the CRF: vital signs (blood pressure and pulse 
rate), height and weight, targeted physical examination, new concomitant medications, and 
adverse events and SF-12 quality of life and GIT Symptoms questionnaires. 
 
After 10 minutes of rest, blood samples will be taken for full blood count, biochemistry – 
urea, electrolytes (sodium, potassium, chloride, bicarbonate, calcium, magnesium and 
phosphate), creatinine, liver function tests (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], albumin, total protein, alkaline phosphatase [ALP], gamma 
glutamyltransferase [GGT], bilirubin), creatine kinase, CD4+ lymphocyte count,  total 
cholesterol, triglycerides, HDL and LDL cholesterol, LDL particle size, glucose, insulin and 
plasma and serum for storage. VLDL cholesterol will be calculated, but if a measured 
value is required, this is only available for participants from Sydney sites. D-dimer will be 
measured at the end of study from a sodium citrate tube (light blue top) collected as part of 
the plasma storage sample. 
 
Dietary and exercise advice will be provided (Dietary and exercise advice for HIV-positive 
persons with high cholesterol, Master Version 1.0, June 30, 2012). 
 
Study participants will be provided with one (1) month’s supply of study medication, 
sufficient to cover 4 weeks, including the allowable study window (±2 days). 
7.7. 
Week 4  
Participants will present to the study site having fasted from overnight for the previous 9 to 
12 hours (no food or drink with calories; but free water intake encouraged maintain 
adequate hydration).  
 
Week 4 assessments will be recorded in the CRF: vital signs (blood pressure and pulse 
rate), weight, targeted physical examination, new concomitant medications, and adverse 
events and SF-12 quality of life and GIT Symptoms questionnaires. 
 
After 10 minutes of rest, blood samples will be taken for full blood count, biochemistry – 
urea, electrolytes (sodium, potassium, chloride, bicarbonate, calcium, magnesium and 
phosphate), creatinine, liver function tests (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], albumin, total protein, alkaline phosphatase [ALP], gamma 
glutamyltransferase [GGT], bilirubin), creatine kinase, CD4+ lymphocyte count, total 
cholesterol, triglycerides, HDL and LDL cholesterol, LDL particle size, glucose, insulin and 
plasma and serum for storage. VLDL cholesterol will be calculated, but if a measured 
value is required, this is only available for participants from Sydney sites. D-dimer will be 
measured at the end of study from a sodium citrate tube (light blue top) collected as part of 
the plasma storage sample. 
 
Dietary and exercise advice will be provided (Dietary and exercise advice for HIV-positive 
persons with high cholesterol, Master Version 1.0, June 30, 2012). 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 21 of 33 
At Week 4, study participants will be provided with study medication for two (2) months 
plus an additional two (2) weeks supply to allow for the allowable study window (±7 days). 
The additional supply is dispensed at this visit, and not baseline, to ensure tolerability. 
7.8. 
Week 12 
Participants will present to the study site having fasted from overnight for the previous 9 to 
12 hours (no food or drink with calories; but free water intake encouraged to maintain 
adequate hydration).  
 
Week 12 assessments will be recorded in the CRF: vital signs (blood pressure and pulse 
rate), weight, targeted physical examination, new concomitant medications, and adverse 
events and SF-12 quality of life and GIT Symptoms questionnaires. 
 
After 10 minutes of rest, blood samples will be taken for full blood count, biochemistry – 
urea, electrolytes (sodium, potassium, chloride, bicarbonate, calcium, magnesium and 
phosphate), creatinine, liver function tests (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], albumin, total protein, alkaline phosphatase [ALP], gamma 
glutamyltransferase [GGT], bilirubin, creatine kinase, CD4+ lymphocyte count, total 
cholesterol, triglycerides, HDL and LDL cholesterol, LDL particle size, glucose, insulin and 
plasma and serum for storage. VLDL cholesterol will be calculated, but if a measured 
value is required, this is only available for participants from Sydney sites. D-dimer will be 
measured at the end of study from a sodium citrate tube (light blue top) collected as part of 
plasma storage. 
 
Dietary and exercise advice will be provided (Dietary and exercise advice for HIV-positive 
persons with high cholesterol, Master Version 1.0, June 30, 2012). 
 
Calculation of the Framingham and D:A:D Risk Scores. Lipid results for all study visits will 
be made available (unblinded) at this time point.  
7.9. 
Study Visit Windows 
• 
Baseline and Week 4 visits have a visit window of ±2 days. 
• 
Week 12 visit has a visit window of ±7 days. 
 
8. UNSCHEDULED VISIT 
Unscheduled visit assessments will be recorded in the CRF including the reason(s) for the 
visit. This visit would include, but is not limited to, the following study assessments: 
targeted medical review, blood pressure, pulse rate, physical examination, safety bloods 
and study doctor and or study coordinator assessment. 
 
This visit could also include Serious Adverse Event (SAE) or Adverse Event (AE) 
assessment/follow up.  
 
9.  PREGNANCY 
Because of the unknown effects of the study drugs, women should avoid becoming 
pregnant during the course of this trial.  If a participant becomes pregnant, she will be 
required to withdraw from the trial but will continue to be monitored. These precautions are 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 22 of 33 
necessary because the information on the effects on the unborn or newborn baby of both 
study drugs is still very limited. 
 
10. 
PATHOLOGY SPECIMEN MANAGEMENT  
Safety parameters will be assessed by the local laboratory at each site.  Local laboratory 
pathology reference ranges will apply. Safety parameter blood samples will be transported 
according to the local laboratory requirements for measurement of: urea, electrolytes 
(including calcium, magnesium and phosphate), creatinine, liver function tests - alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), albumin, total protein, alkaline 
phosphatase (ALP), gamma glutamyltransferase (GGT), bilirubin and creatine kinase.  
 
Fasting metabolic parameters will be assessed by the local laboratory at each site and 
LDL particle size testing will be performed at a central laboratory LipoScience Global 
Research Services, North Carolina, USA).  Local laboratory and LipoScience Global 
Research Services laboratory reference ranges will apply. Fasting metabolic blood 
samples will be transported according to the local laboratory and LipoScience Global 
Research Services laboratory requirements for measurement of: triglycerides, total 
cholesterol, HDL, LDL, VLDL cholesterol, glucose, insulin, and LDL particle size. 
 
HIV parameters will be assessed by the central laboratories for each area (Sydney, 
Melbourne and Barcelona). Local laboratory pathology reference ranges will apply. HIV 
parameter blood samples will be transported to according to the local laboratory 
requirements for measurement of: full blood count, CD4+ lymphocyte count and 
percentage and HIV viral load.  
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 23 of 33 
11. 
ADVERSE EVENTS 
An adverse event (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 should be recorded as an AE in the individuals CRF. 
 
At the final study visit (week 12) any ongoing adverse events deemed related to study drug 
will be followed up for 30 days and until resolution. Phone contact with the patient is 
acceptable unless pathology tests are required.  
 
12. 
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. 
12.1. 
Serious Adverse Event Reporting Requirements 
 
The Co-ordinating Principal Investigator and/or the project coordinator must be notified 
immediately regarding the occurrence of any serious adverse events (SAEs).   
 
The Coordinating Principal Investigator and/or the study monitor 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. The study monitor will be responsible for reporting all 
SAEs to pharmaceutical companies as/if necessary. 
 
Any SAE that is ongoing at the final study visit (week 12) must be followed until resolution 
or until the event stabilises (for those events that will not resolve). 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 24 of 33 
 
13. 
Data Safety and Monitoring Board 
The independent Data Safety and Monitoring Board (DSMB) will be composed of 
members with expertise in HIV management, cardiovascular risk and statistical and trial 
design. Members will elect a chairperson. The first meeting will occur after 20 patients 
have been enrolled, at which time terms of reference will be ratified and frequency of 
meetings decided upon. 
 
All reported SAEs and adverse events that are unexpected and drug related events will be 
summarised (by the project coordinator) on a regular basis and reviewed by the study 
team at weekly project meetings. HIV RNA data on each participant will be included.  
All SAEs and any patterns of repeated adverse events will be communicated to the DSMB 
Chairperson and may lead to consideration by other DSMB members and/or full interim 
safety data review as is thought appropriate. Based on formal review of data the DSMB 
may recommend one of the following courses of action:  
 
i) 
continue the study without modification, 
ii) 
continue the study with modifications to the protocol 
iii) 
suspend enrolment pending either resolution of specific issues or 
amendment of the protocol as specified  
iv) 
terminate the study 
 
The DSMB Chairperson will be responsible for providing a written report of findings and 
recommendations to the coordinating investigator in a timely manner. The coordinating 
investigator and project coordinator will be responsible for informing the HREC, study sites 
and appropriate regulatory authorities of any DSMB recommendation relating to conduct of 
the study. 
 
14. 
Sample size and Statistical analysis 
14.1. 
Statistical analysis 
All analyses will be performed after all participants have completed the study, permanently 
withdrawn or been lost to follow-up. The primary outcome is percentage change from 
baseline in total cholesterol at 12 weeks by intent-to-treat analysis.  
 
Descriptive statistics will be used for continuous and ordinal variables. For continuous 
data, mean change from baseline to weeks 4, and 12 will be calculated for participants 
with baseline and at least 1 follow-up visit. We will conduct intention-to-treat and on-
treatment analyses and use T tests to compare groups (Wilcoxon’s test if data are not 
normally distributed). To assess differences in proportions, we will use Fisher’s exact test 
and calculate exact CIs. Hazard ratios for comparison of event rates, adjusted for duration 
of randomized therapy, will be assessed using Cox regression. All analyses will use a 2-
sided α of 0.05. No adjustment will be made for multiple comparisons. Analyses will be 
primarily by intent-to-treat. As this study is designed to evaluate the biological effects of an 
intervention, a per-protocol analysis will also be performed. 
14.2. 
Sample size 
In published cholesterol-lowering treatment studies in HIV-infected adults, the following 
reductions in total or LDL cholesterol were reported:  


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 25 of 33 
• ROSUVASTATIN (6): Rosuvastatin 10mg daily, caused a 28% reduction in total 
cholesterol (SD 18%), 35% reduction in LDL cholesterol (SD 17%)  
• SWITCHMRK (8): Switching lopinavir/ritonavir to raltegravir caused a 12% relative 
reduction (13% absolute; SD not reported) in total cholesterol, 4% reduction in LDL 
cholesterol (SD not reported)  
• SPIRAL (11): Switching one of various ritonavir-boosted protease inhibitors to 
raltegravir caused a 14% relative reduction (6% absolute; SD not reported) in total 
cholesterol, 17% for those switching from lopinavir/ritonavir, 3% for those switching 
from atazanavir/ritonavir, 9% relative reduction (6% absolute; SD not reported) in 
LDL cholesterol. 
 
These data suggest a difference in total cholesterol between rosuvastatin and lopinavir/r 
switching of about 15%.  
 
With a 1:1 randomisation, to be able to reject the null hypothesis that the population 
means of the experimental and control groups are equal with a Type-1 error probability of 
0.05, 80% power and assuming a 10% drop-out, the sample size is: 
If all participants are on lopinavir/r at baseline (estimated 15% difference for total 
cholesterol), the sample size is 27 per group if the SD is 18%. If 50% of participants are on 
lopinavir/r and 50% on atazanavir/r at baseline, the between-group difference for total 
cholesterol would be expected to be larger (about 20%), the sample size is 16 per group if 
the SD is 20%. 
 
The effects of ritonavir-boosted darunavir and ritonavir-boosted fosamprenavir on 
cholesterol levels are similar to those of ritonavir-boosted lopinavir, so the sample size is 
similar if any of these drugs is being used. Therefore, we propose to recruit 30 patients per 
group. 
 
Patient retention on assigned therapy >90% is highly likely. Loss to follow-up in previous 
trials led by the investigators was <5% per year. Rosuvastatin was well tolerated in the 
one trial in HIV+ adults. Failure or intolerance of new antiretroviral therapy over 12 weeks 
is likely to be no more than 5%. With a sample size of 30 per arm, the study would also 
have 99.7% power to demonstrate an anticipated 24% difference in LDL cholesterol 
between groups, assuming 18% SD, with a Type-1 error of 0.05. 
 
15. 
Recording and transfer of study data 
 
15.1. 
Data recording 
Each study site will be provided with CRF folders for the input of study data. These should 
be completed according to the printed set of instructions accompanying these folders. 
Participants will not be identified by name on any CRFs, but rather by a site-specific ‘Study 
Identifier’ and ‘Name Code’. 
 
Details of the Study Identifier and Name Code are included in the ‘SoS Study Manual of 
Operations’ (Version 1, July 16, 2012) to be supplied to each of the sites. 
 
It is a requirement of the study protocol that all forms must be fully completed prior to their 
returning to the Study Sponsor (St. Vincent’s Clinical Research Program). 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 26 of 33 
 
15.2. 
Data transfer to Study Sponsor 
The completed study CRFs should be transferred to the Study Sponsor via fax, and 
addressed to the Project Manager (Dr. Frederick Lee). 
 
Any standard-of-care pathology results being transferred, also by fax, to the Study 
Sponsor should be de-identified of participants’ full names. Only the site-specific Study 
Identifier and Name Code should be used on pathology reports. 
 
All CRF pages and relevant standard-of-care pathology reports should be sent to the 
Project Manager as soon as scheduled visits are completed and pathology results are 
available. This should happen no later than seven (7) working days after the final study 
visit at Week 12. 
 
Any data queries generated will be addressed in consultation with site study co-ordinators 
and study monitors. 
 
 
16. 
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 study participant. Publication of data 
derived from this protocol will be supervised by Co-ordinating Investigator, Professor 
Andrew Carr 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. 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 27 of 33 
 
17. 
REFERENCES 
 
1. DAD Study Group. Class of antiretroviral drug and the risk of myocardial infarction. N 
Engl J Med 2007; 356: 1723-35. 
2. Calza L, Manfredi R, Colangeli V, et al.  Substitution of nevirapine or efavirenz for 
protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. 
AIDS 2005; 19: 1051-58. 
3. Mallon PWG, Miller J, Kovacic JC, et al. Effects of pravastatin on body composition 
and markers of cardiovascular disease in HIV-infected men: a randomised, placebo-
controlled study. AIDS 2006; 20: 1003-10. 
4. Martínez E, Arnaiz JA, Podzamczer D, et al. Substitution of nevirapine, efavirenz, or 
abacavir for protease inhibitors in patients with human immunodeficiency virus 
infection. N Engl J Med 2003; 349: 1036-46. 
5. Carr A, Hudson J, Chuah J, et al. HIV protease inhibitor substitution in patients with 
lipodystrophy: a randomised, multicentre, open-label study. AIDS 2001; 15: 1811-22. 
6. Aslangul E, Assoumou L, Bittar R, et al. Rosuvastatin versus pravastatin in 
dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial. 
AIDS 2010; 24: 77-83. 
7. Ganesan A, Crum-Cianflone N, Higgins J, et al. High dose atorvastatin decreases 
cellular markers of immune activation without affecting HIV-1 RNA levels: results of a 
double-blind randomized placebo controlled clinical trial. J Infect Dis 2011; 203: 756-
64.  
8. Eron JJ, Young B, Cooper DA, et al. Switch to a raltegravir-based regimen versus 
continuation of a lopinavir-ritonavir-based regimen in stable HIV-infected patients with 
suppressed viraemia (SWITCHMRK 1 and 2): two multicentre, double-blind, 
randomised controlled trials. Lancet 2010; 375: 396-407. 
9. Food 
and 
Drug 
Administration. 
Rosuvastatin 
product 
label. 
Available 
at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021366s021lbl.pdf 
(Accessed May 21, 2011). 
10. Food 
and 
Drug 
Administration. 
Pravastatin 
product 
label. 
Available 
at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/019898s060lbl.pdf 
(Accessed May 21, 2011). 
11. Martínez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-
boosted protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS 2010; 
24: 1697-707.. 
 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 28 of 33 
18. 
Appendix 1 – Ethics Reference 
 
• The 2007 revised National Statement on Ethical Conduct in Human Research was 
tabled in parliament on the 28th of March 2007. 
 
• Australian Code for the Responsible Conduct of Research. Guides institutions and 
researchers in responsible research practices. 
 
• World Medical Association Declaration of Helsinki: Recommendations Guiding Medical 
Doctors in Biomedical Research Involving Human Subjects, October, 2000 version. 
 
• The International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 29 of 33 
19. 
Appendix 2 – SF-12 
 
 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 30 of 33 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 31 of 33 
 
 
 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 32 of 33 
20. 
Appendix 3 – GIT symptoms questionnaire 
 
 
 
1. Have you experienced any nausea since the last study visit? 
 
Yes 
 
 
 
 
No 
 
 
 
 
 
 
If ‘Yes’, how would you grade it? 
 
Mild 
 
 
 
 
Moderate 
 
 
 
Severe 
 
 
 
 
2. Have you experienced any diarrhea since the last study visit? 
 
Yes 
 
 
 
 
No 
 
 
 
 
 
 
If ‘Yes’, how would you grade it? 
 
Mild 
 
 
 
 
Moderate 
 
 
 
Severe  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Rosuvastatin versus Protease Inhibitor Switching for Hypercholesterolaemia in HIV-infected Adults 
 
Version 5.0 
October 22, 2012 
Page 33 of 33 
21. 
Appendix 4 – drugs@FDA links for information re contra-indicated 
(absolute and relative) medications in patients receiving: 
rosuvastatin, raltegravir, etravirine, tenofovir, atazanavir, nevirapine, 
lamivudine and emtricitabine 
 
 
 
Rosuvastatin 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021366s021lbl.pdf 
 
Raltegravir 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022145s018lbl.pdf 
 
Etravirine 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/022187s008lbl.pdf 
 
Tenofovir 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021356s037lbl.pdf 
 
Atazanavir 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021567s026lbl.pdf 
 
Nevirapine 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020933s028,020636s037lbl.pdf 
 
Lamivudine 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/020564s028lbl.pdf 
 
Emtricitabine 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021500s010,021896s004lbl.pdf