High Intensity Lipid Lowering Following Acute Coronary Syndromes for Persons Living With Human Immunodeficiency Virus (HILLCLIMBER)
Phase: PHASE2
Conditions: HIV Infection, Coronary Heart Disease
Sponsor: Matthew Feinstein

 
 
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CSC01: High Intensity Lipid Lowering for Coronary Artery Disease Prevention for Persons 
Living with Human Immunodeficiency Virus (HILLCLIMBER)  
 
 
 
 
 
 
 
IND Investigator Sponsor: 
Donald M. Lloyd-Jones, M.D.   
Northwestern University  
IND Pending  
 
 
 
 
 
Financial Support Provided by: 
 
Northwestern University  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HILLCLIMBER  
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CONTENTS 
 
 
 
Page 
 
Site Participating in the Study ......................................................................................................... 4 
 
Protocol Team Roster ...................................................................................................................... 4 
Abbreviations………………………………………………………………………………………………6 
 
SCHEMA .......................................................................................................................................... 7 
1.0 STUDY OBJECTIVES............................................................................................................. 7 
 
   1.1       Primary Objective..................................................................................................... 7 
1.2 
Secondary  Objective............................................................................................... 8 
1 
2.0 BACKGROUND....................................................................................................................... 8 
2.1 
Rationale .................................................................................................................. 8 
3.0 STUDY DESIGN ..................................................................................................................... 9 
4.0 SELECTION AND ENROLLMENT OF SUBJECTS ............................................................. 10 
4.1 
Inclusion Criteria .................................................................................................... 10 
4.2 
Exclusion Criteria ................................................................................................... 10 
4.3 
Study Enrollment Procedures .............................................................................. 121 
5.0 STUDY TREATMENT ........................................................................................................... 12 
5.1 
Regimens, Administration, and Duration............................................................... 12 
5.2 
Study Product Formulation and Preparation ......................................................... 13 
5.3 
Pharmacy: Product Supply, Distribution, and Accountability ................................ 13 
5.4 
Concomitant Medications ...................................................................................... 13 
5.5 
Adherence Assessment ......................................................................................... 16 
6.0 CLINICAL AND LABORATORY EVALUATIONS ................................................................. 16 
6.1 
Schedule of Events ................................................................................................ 16 
6.2 
Timing of Evaluations ............................................................................................ 17 
6.3 
Instructions for Evaluations ................................................................................... 17 
7.0 CLINICAL MANAGEMENT ISSUES..................................................................................... 21 
7.1 
Toxicity Management (Grades 1, 2, 3, 4) .............................................................. 21 
7.2 
General Reactions ................................................................................................. 21 
7.3 
ALT Elevations ....................................................................................................... 22 
7.4 
Myalgias and Myopathy ......................................................................................... 23 
7.5 
Rhabdomyolysis  ................................................................................................... 23 
7.6 
Requirement for Precautionary Medications ......................................................... 24 
7.7 
Pregnancy  ............................................................................................................. 24 
8.0 CRITERIA FOR DISCONTINUATION .................................................................................. 24 
8.1 
Permanent Treatment Discontinuation .................................................................. 24 
8.2 
Premature Study Discontinuation .......................................................................... 25 

 
 
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9.0 STATISTICAL CONSIDERATIONS...................................................................................... 25 
9.1 
General Design Issues .......................................................................................... 25 
9.2 
Endpoints ............................................................................................................... 25 
9.3 
Randomization and Stratification ........................................................................... 26 
9.4       Sample size and Accrual ....................................................................................... 26 
9.5 
Monitoring - Data Safety Monitoring Committee ................................................... 26 
            9.6       Analyses………………………………………………………………………………..27 
10.0 DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING .......... 27 
10.1 
Records to Be Kept................................................................................................ 27 
10.2 
Role of Data Management..................................................................................... 27 
10.3 
Clinical Site Monitoring and Record Availability .................................................... 28 
10.4 
Expedited Adverse Event Reporting ..................................................................... 28 
11.0 HUMAN SUBJECTS ........................................................................................................... 29 
11.1 
Institutional Review Board (IRB) Review and Informed Consent ......................... 29 
11.2 
Subject Confidentiality ........................................................................................... 29 
11.3 
Study Discontinuation ............................................................................................ 29 
12.0 PUBLICATION OF RESEARCH FINDINGS ...................................................................... 29 
13.0 BIOHAZARD CONTAINMENT ............................................................................................ 29 
 
14.0   REFERENCES…………………………………………………………………………………..30                   
 APPENDIX I: SAMPLE INFORMED CONSENT……………………………………………………32 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Site and Investigator Participating in the Study  
 
Northwestern University, Chicago, IL (Matthew J. Feinstein, M.D.)  
 
Protocol Team Roster 
 
IND Investigator-Sponsor  
Donald Lloyd-Jones, MD, ScM 
Department of Preventive Medicine 
Northwestern University 
680 N. Lake Shore Drive, Suite 1400  
Chicago, IL 60611 
Telephone: 312-908-1718 
FAX: 312-908-9588 
Email: dlj@northwestern.edu 
 
Principal Investigator  
Matthew J. Feinstein, MD 
Division of Cardiovascular Diseases  
Northwestern University 
680 N. Lake Shore Drive, Suite 1400  
Chicago, IL 60611 
Telephone: 312-503-0027 
Fax: 312-695-0063 
Email: matthewjfeinstein@northwestern.edu 
 
Investigators 
Chad Achenbach, MD 
Division of Infectious Diseases  
Northwestern University  
645 N. Michigan Avenue, Suite 900  
Chicago, IL  60611 
Phone: (312) 695- 
FAX: (312) 695-5088 
E-Mail: c-achenbach@northwestern.edu 
 
Babafemi Taiwo, MBBS  
Division of Infectious Diseases  
Northwestern University  
645 N. Michigan Avenue, Suite 900  
Chicago, IL  60611 
Phone: (312) 695-5012 
FAX: (312) 695-5088 
E-Mail:b-taiwo@northwestern.edu 
 
Neil Stone, MD 
Division of Cardiovascular Diseases  
Northwester University  
NMH/Galter 19th floor, Ste 10 
675 N Saint Clair 
Chicago IL 60611 
Phone: (312) 695-4965 

 
 
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E-mail: n-stone@northwestern.edu 
 
Research Manager 
Baiba Berzins, M.P.H. 
Division of Infectious Diseases  
Northwestern University  
645 N. Michigan Avenue, Suite 900  
Chicago, IL  60611 
Phone: (312) 695-5012 
FAX: (312) 695-5088 
E-Mail: baiba@northwestern.edu 

 
 
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ABBREVIATIONS 
ACS 
AE 
Acute coronary syndrome 
adverse event 
ALT 
alanine aminotransferase 
ART 
Antiretroviral Therapy 
AST 
aspartate aminotransferase 
BUN 
blood urea nitrogen 
CHD 
CK 
CKD 
CRF 
Coronary Heart Disease 
Creatine Kinase 
Chronic Kidney Disease 
case report form 
CRP 
C-reactive protein 
CVD 
CYP 
DMC 
Cardiovascular Disease 
Cytochrome P450 
Data Monitoring Committee 
GCP 
Good Clinical Practice 
HDL-c 
High-density lipoprotine cholesterol 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
ICF 
Human immunodeficiency virus 
Informed consent form 
ICH 
International Conference on Harmonisation 
INR 
IRB 
International Normalized Ratio 
Institutional Review Board 
IV 
Intravenous 
LDL-C 
LFTs 
Lp-PLA2 
LVEF 
mEq 
Low-density lipoprotein cholesterol 
Liver Function Tests 
Lipoprotein-associated phospholipase A2 
Left Ventricular Ejection Fraction 
Milliequivalents 
MI 
PAI-1 
PCR 
PI 
Myocardial Infarction 
Plasminogen Activator Inhibitor-1 
Polymerase Chain Reaction 
Principal Investigator 
PT 
SAE 
TSH 
Prothrombin time 
serious adverse experience 
Thyroid-stimulating hormone 
 
 
 
 
 
 
 
 

 
 
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SCHEMA 
 
DESIGN 
 
HILLCLIMBER is a randomized, controlled, open-label phase II trial of moderate 
dose statin therapy versus high-dose statin therapy in HIV-infected persons taking 
antiretroviral therapy (ART) who have coronary heart disease (CHD) or are at high 
risk for atherosclerotic cardiovascular disease.  All subjects will have an initial two-
week run-in period with pravastatin 40mg daily. Subjects not demonstrating 
significant toxicity at week 2 will then be randomized to rosuvastatin 20mg versus 
continuing pravastatin 40mg daily. At week 6; those in the rosuvastatin arm who do 
not demonstrate significant clinical or laboratory safety/toxicity issues will then have 
doses increased to rosuvastatin 40mg (high intensity dose group). The group 
randomized to pravastatin 40mg daily at week 2 will not have their dose increased 
at the end of week 6 (moderate intensity group).  
• 
The primary endpoint is percent change in low-density lipoprotein cholesterol 
(LDL-c) from Week 2 to 14 of high versus moderate intensity lipid-lowering 
statin therapy  
 
DURATION 
Total duration of the study is 14 weeks: 2 weeks for the initial run-in, 12 weeks 
on therapy as per randomization (weeks 6-14 with possible dose increase).  
 
SAMPLE SIZE 
40 subjects 
 
POPULATION 
HIV-infected subjects not already on high dose statin therapy who have 
coronary heart disease (CHD) or are at high risk for atherosclerotic 
cardiovascular disease (ASCVD, which includes myocardial infarction and 
stroke) as evidenced by 10-year ASCVD risk of 15.0% or greater.  
 
 
REGIMEN  
 
The following treatment regimens will be used: 
Stage One (Run-in): Pravastatin 40mg daily (Weeks 0-2),  
Stage Two (Randomization in 1:1 ratio):   
• 
Moderate intensity group: Pravastatin 40mg daily (Weeks 2-14)   
OR 
• 
High intensity group: Rosuvastatin 20mg daily (Weeks 2-6), titrated to 
Rosuvastatin 40mg daily (Weeks 6-14). 
 
  
 
1.0 
STUDY OBJECTIVES 
1.1 
Primary Objectives 
 
• 
To evaluate the lipid-lowering efficacy, as measured by percent change in low-density 
lipoprotein cholesterol (LDL-c) from Week 2 to 14 of high versus moderate intensity 
lipid-lowering statin therapy in HIV-infected persons taking antiretroviral therapy (ART) 

 
 
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who have coronary heart disease (CHD) or are at high risk for atherosclerotic 
cardiovascular disease (ASCVD).  
 
 
1.2 
Secondary Objectives  
 
To determine mean changes from week 2 to week 14 for patients randomized to high 
versus moderate intensity statins in the following: 
 
• 
Lipid parameters (HDL-c, triglycerides, and total cholesterol) 
• 
Inflammatory biomarkers (soluble CD163, ST2, high sensitivity troponin I, and high-
sensitivity C-reactive protein) 
• 
Immunologic markers (T cell reactivity) and viral reservoir persistence   
 
To evaluate safety, as measured by treatment-emergent clinical and laboratory 
adverse events, of high versus moderate intensity statin therapy in HIV-infected 
persons taking ART who have coronary heart disease (CHD) or are at high risk for 
ASCVD.  
 
2.0 
Background 
This study is a phase II investigation of the efficacy of high intensity versus moderate intensity 
lipid lowering statin therapy for HIV-infected persons with coronary heart disease (CHD) and/or 
high risk for atherosclerotic cardiovascular disease (ASCVD) not already on high intensity lipid 
lowering therapy. This is a pilot study for potential future studies that would be adequately 
powered to evaluate the safety – in addition to efficacy – of high-intensity versus moderate-
intensity statin regimens for HIV-infected persons with CHD and/or high risk for ASCVD. The 
study drugs (rosuvastatin and pravastatin) are approved and in regular clinical use, but 
rosuvastatin is being repurposed in this study for a new population in which there are no data 
for the higher intensity therapy under study. 
 
2.1 
Rationale 
Over the past two decades, antiretroviral therapy (ART) has dramatically improved longevity 
among persons living with human immunodeficiency virus (HIV), who are increasingly at risk 
for non-communicable comorbidities such as cardiovascular disease (CVD). (1-5) Compared 
with uninfected persons, persons living with HIV are at 50% or greater risk for myocardial 
infarction (MI), even after adjustment for CVD risk factors, and over fourfold greater risk for 
sudden cardiac death. (6-13) Standard care for persons with coronary heart disease (CHD), 
which includes previous acute coronary syndromes (ACS) and MI, in the general population 
includes intensive lipid lowering with high dose statin therapy, such as rosuvastatin 20-40mg 
daily or atorvastatin 40-80mg daily, due to high-quality clinical trial data demonstrating 
significant net clinical benefits of intensive lipid lowering with high dose statins compared with 
less intensive lipid lowering with lower dose statins. (14-16) The importance of intensive lipid 
lowering following coronary events has been re-affirmed by a recent trial in which patients 
hospitalized for ACS randomized to a statin plus ezetimibe versus a statin alone achieved 
lower LDL-c levels (median LDL-c 53.7 mg/dl versus 69.5 mg/dl) and experienced improved 
cardiovascular outcomes without excess adverse events. (17) Furthermore, the most recent 
American College of Cardiology (ACC)/American Heart Association (AHA) evidence-based 
guidelines recommend that persons with predicted 10-year ASCVD risks of 7.5% or greater be 
prescribed moderate-to-high-intensity statins; the absolute net benefit of intensifying statin 

 
 
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therapy becomes even greater and thus favors high intensity statin therapy at higher ASCVD 
risk levels. (18) 
 
Despite these convincing data in the general population, it remains unknown whether intensive 
lipid lowering with high dose statins for HIV-infected persons with known CHD and/or high risk 
for ASCVD confers clinical benefit. Trials of lipid-lowering therapy among persons living with 
HIV on ART have generally tested lower dose statins due to safety concerns related to 
theoretical and observed drug-drug interactions between ARTs, particularly protease inhibitors 
(PIs), and statins. Some of this is warranted; simvastatin is contraindicated with concomitant 
PI use and should generally be avoided in patients on ART, as simvastatin levels increase 
more than fivefold with concomitant PI use. (18) However, most other statins have proven safe 
and efficacious in numerous small trials of HIV-infected persons on ART, albeit at relatively 
low doses. (19) The most potent statin doses tested in these trials have generally been 
rosuvastatin 10mg daily or atorvastatin 10mg daily (20-24); a lone exception is a recent trial in 
which 19 HIV-infected persons were started on atorvastatin 20mg daily and titrated up to 40mg 
daily, which revealed similar safety profiles of atorvastatin 40mg daily and placebo. (25) No 
trials of any size have evaluated HIV-infected persons on ART taking atorvastatin 80mg daily 
or rosuvastatin 20-40mg daily, which are the standard of care for persons with CHD, 
particularly previous ACS, as well as persons with high ASCVD risk, in the general population. 
 
In this study, we intend to evaluate high intensity rosuvastatin (20mg daily uptitrated to 40mg 
daily) rather than atorvastatin 80mg daily because rosuvastatin 40mg daily has somewhat 
greater LDL-lowering efficacy and fewer pharmacological interactions with common HIV 
medications, particularly protease inhibitors. Rosuvastatin is not lipophilic, absorbed rapidly, 
and minimally (<10%) metabolized by the CYP450 system, resulting in negligible 
pharmacokinetic interactions with protease inhibitors or other CYP450-metabolized 
medications; meanwhile, atorvastatin is more lipophilic and metabolized extensively by the 
CYP450 system, resulting in potential toxicity due to accumulation in the setting of co-
administration with protease inhibitors and other CYP450-metabolized medications. (26) Thus, 
although rosuvastatin and atorvastatin both appear to be safe based on limited data in HIV-
infected persons taking ART, we anticipated that the safety margin would be greater for high-
dose rosuvastatin compared with atorvastatin in this population. This a randomized, controlled, 
open-label Phase II study of a known approved drug re-purposed for a unique population. 
 
Full prescribing information for rosuvastatin, which is an approved drug with tablets of doses 
5mg, 10mg, 20mg, and 40mg, may be found at: http://www1.astrazeneca-
us.com/pi/crestor.pdf.  Full information for pravastatin, which is an approved drug with tablets 
of doses 10mg, 20mg, 40mg, and 80mg, may be found at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/019898s062lbl.pdf.  
 
3.0 
STUDY DESIGN 
 
This is a single center, randomized, controlled, open-label phase II trial. Up to 40 subjects not already 
on high dose statin therapy who have documented CHD and/or calculated 10-year ASCVD risk >15% 
will be included and started on moderate dose statin therapy (pravastatin 40mg daily) for an initial 
two-week run-in period. Subjects not demonstrating significant toxicity at week 2 will then be 
randomized to rosuvastatin 20mg versus continuing pravastatin 40mg daily. Subjects will return at 
week 6; those in the rosuvastatin arm who do not demonstrate significant safety or toxicity concerns 
will then have doses increased to rosuvastatin 40mg (high dose group). The group randomized to 
pravastatin 40mg daily at week 2 will not have their dose increased at the end of week 6.  

 
 
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The following treatment regimens will be used: 
 
Stage One (Run-in): Pravastatin 40mg daily (Weeks 0-2),  
Stage Two (Randomization in 1:1 ratio):   
▪ 
Moderate intensity group: Pravastatin 40mg daily (Weeks 2-14)   
OR 
▪ 
High intensity group: Rosuvastatin 20mg daily (Weeks 2-6), potentially titrated 
to Rosuvastatin 40mg daily (Weeks 6-14). 
Total duration of the study is 14 weeks: 2 weeks for the initial run-in, 6 weeks following randomization, 
and 6 weeks following dose increase.  
 
 
4.0 SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 Inclusion Criteria 
 
4.1.1 HIV-1 infection, documented by: any licensed rapid HIV test or HIV enzyme or 
chemoiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and 
confirmed by a licensed Western blot or a second antibody test by a method other than 
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA viral load. 
OR HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating >1000 RNA 
copies/mL 
 
 
 
4.1.2. HIV RNA below the lower limit of assay detection within 12 months of study entry  
 
 
 
 
NOTE: one detectable HIV RNA (<400 copies/ml) is allowed.   
 
     4.1.3 (1) Documented coronary heart disease (CHD): nonfatal MI, unrecognized MI, unstable 
angina pectoris, and/or stable angina pectoris, as defined by the American Heart 
Association Case Definitions for Acute Coronary Heart Disease in Epidemiology and 
Clinical Research Studies (Luepker R et al., Circulation 2003. 108(20):2543-9. URL:  
http://circ.ahajournals.org/content/108/20/2543).  
 
 
Or (2) Documented 10-year ASCVD risk of 15% or greater based on the ACC/AHA 
ASCVD Risk Estimator (http://tools.acc.org/ASCVD-Risk-estimator/). 
4.1.4 Negative serum or urine pregnancy test within 48 hours of study entry for women with 
reproductive potential (defined as women who have not been postmenopausal for at 
least 24 consecutive months, i.e., who have had menses within the preceding 24 
months, or have not undergone surgical sterilization [e.g., hysterectomy, bilateral 
oophorectomy, or salpingectomy]) .The urine test must have a sensitivity of ≤50 
mIU/mL. 
 
4.1.5 If participating in sexual activity that could lead to pregnancy, female subjects with 
reproductive potential must use one form of contraceptive as listed below while 
receiving protocol-specified medications.  At least one of the following methods MUST 
be used appropriately: 
• 
Condoms (male or female) with or without a spermicidal agent. Condoms are 
recommended because their appropriate use is the only contraception method 
effective for preventing HIV transmission. 
• 
Diaphragm or cervical cap with spermicide 

 
 
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• 
IUD (intrauterine device) 
• 
Hormone-based contraceptive. Subject-reported history is acceptable 
documentation of sterilization, other contraception methods, menopause, and 
reproductive potential. 
 
         4.1.6 
Men and women age 18 to 75 years of age  
 
         4.1.7 
Ability and willingness of subject to provide informed consent 
4.2. Exclusion Criteria 
 
4.2.1 Serious illness or AIDS-related complication within 21 days of screening requiring 
systemic treatment and/or hospitalization until candidate either completes therapy or is 
clinically stable on therapy, in the opinion of the site investigator, for at least 7 days 
prior to study entry.  Need for systemic therapy for malignancy currently or anticipated 
during the study period.  
 
4.2.2 No coronary heart disease (CHD) and 10-year ASCVD risk <15.0%. 
 
4.2.3 Not currently receiving antiretroviral therapy or taking any of the following antiretroviral 
agents: atazanavir/ritonavir, lopinavir/ritonavir, or simeprevir.   
4.2.4 Not currently receiving any of the following agents: cyclosporine or rifampin.  
4.2.5    History of statin intolerance leading to discontinuation, dose decrease, or change to 
less potent dose equivalent 
4.2.6 Statin absolute contraindication 
4.2.7 Current use of atorvastatin 20mg daily or greater or rosuvastatin 10mg daily or greater  
4.2.8 Chronic kidney disease stage 4 or greater (including dialysis) 
4.2.9 Systolic heart failure with last documented LVEF <35%  
4.2.10. Pregnant or breastfeeding 
4.2.11. Laboratory values obtained within 45 days prior to study entry:  
LDL-c <80 mg/dl while not on statin or LDL-c <60 mg/dl while on statin 
ALT > 3 x Upper Limit of Normal (ULN) 
AST > 3 x ULN 
Creatinine kinase (CK) > 10 x ULN 
Calculated creatinine clearance (CrCl) <50 mL/min, as estimated by the Cockcroft-
Gault equation 
4.2.12. Life expectancy <12 months 
4.2.13. Prior organ transplant 
4.2.14. Active malignancy 
4.2.15. Inflammatory muscle disease 
 

 
 
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4.3 Study Enrollment Procedures 
 
4.3.1 Prior to implementation of this protocol, sites must have the protocol and the protocol 
consent form approved by their local institutional review board (IRB). 
Once a candidate for study entry has been identified, details will be carefully discussed 
with the subject. The subject will be asked to read and sign the approved protocol 
consent form.  
Candidates for study entry will be identified using an existing IRB-approved data 
repository of HIV-infected persons in the Northwestern Medicine Enterprise Data 
Warehouse (NMEDW). These candidates will be identified by querying this NMEDW 
data repository for any living HIV-infected persons aged 18 to 75 who have no HIV viral 
RNA values of 400 copies/ml or greater anytime in the previous 12 months from the 
time of screening and who have any diagnosis of coronary heart disease (CHD) based 
on any documented ICD-9-CM codes 410-414 and/or ICD-10-CM codes I21-I25. 
Candidates will also be identified by calculating the 10-year ASCVD risk of patients 
referred by primary care providers.  Once these candidates are identified, participants 
will be excluded if they are noted to be prescribed atorvastatin 20mg daily or greater, 
rosuvastatin 10mg daily greater, atazanavir/ritonavir (at any dose), lopinavir/ritonavir 
(at any dose), simeprevir.(at any dose), or are not currently taking antiretroviral 
therapy. Of the remaining candidates, persons with an active primary care provider 
and/or infectious disease provider at Northwestern Medicine will be eligible to be 
contacted for enrollment via telephone. The order of contacting patients will be by 
those with the most recent new diagnoses of CHD first, with the plan to continue 
contacting patients (those with the earlier CHD diagnosis dates would be contacted 
later, then patients with no known CHD but with 10-year ASCVD risk of 15% or greater) 
until the target enrollment is achieved. 
 
4.3.2 Randomization 
Subjects who meet enrollment criteria will be randomized at Week 2 (the end of the 
pravastatin 40ml daily run-in period) in a 1:1 ratio according to the study treatment that 
has been randomly assigned to the Patient Number on the Randomization List held by 
the local site pharmacist.    
Randomization will be stratified by type of ART: patients taking any booster (ritonavir or 
cobicistat) as part of their ART regimen and patients not taking a booster. 
 
 
 
5.0 
STUDY TREATMENT 
5.1 Regimens, Administration, and Duration 
 
After a 2-week pravastatin 40mg daily run-in period, subjects will be randomly assigned to 
rosuvastatin 20mg daily or pravastatin 40mg daily at week 2 in a 1:1 ratio.   At week 6, subjects on the 
Rosuvastatin arm may have their dose escalated to 40mg daily.    
 
Run-in:  
Pravastatin 40mg daily for 2 weeks (Weeks 0-2)  

 
 
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Randomization (1:1 ratio) at Week 2:   
o Moderate intensity strategy: Pravastatin 40mg once daily for 12 weeks (Weeks 2-14)   
OR 
o High-intensity strategy: Rosuvastatin 20mg once daily for 4 weeks (Weeks 2 to 6)  
o Continue Rosuvastatin 20 mg once daily (Weeks 6 to 14) if:  
▪ 
AST or ALT between 1.5x and 3x ULN 
OR 
▪ 
CK between 3x and 10x ULN 
OR 
▪ 
Grade 1 or 2 toxicity attributable to rosuvastatin is present 
o Escalation of Rosuvastatin to 40 mg daily (Weeks 6 to 14) if:  
 
▪ 
AST, ALT, and CK < 1.5x ULN at week 6  
AND 
▪ 
CK ≤3x ULN at week 6 
AND 
▪ 
No grade 1 or greater toxicity attributable to rosuvastatin is present 
5.1.1 Regimen 
 
Subjects should begin study treatment within 72 hours after entry and continue on 
study treatment for 14 weeks. 
Study drugs will be supplied in bottles for this open-label study. The pharmacist will 
dispense 2 weeks (15 tablets) of pravastatin 40 mg at week 0 to all participants.  At 
week 2, subjects will be randomized to receive either 12 weeks (3 bottles, 90  tablets) 
of rosuvastatin 20 mg tablets or 12 weeks (85 tablets) of pravastatin 40 mg tablets.   
Based on LFTs, CK, and safety/toxicity assessments at Week 6, participants in the 
rosuvastatin arm will be notified within 5 days whether or not they are to escalate to 
two 20mg tablets daily or continue taking one tablet daily.  If the dose is escalated, 
participants will need to return to the pharmacy within the next 4 weeks to receive an 
additional supply of 30 tablets (1 bottle) of rosuvastatin 20mg.  
At the Week 14 visit, subjects should return any remaining study-provided study 
products. 
 
5.1.2 Administration 
 
Pravastatin will be administered orally as one 40 mg tablet once daily with or without 
food.  
 
Rosuvastatin will be administered orally as one or two (high-dose) 20 mg tablet(s) once 
daily with or without food.    
 

 
 
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5.2 Study Product Formulation and Preparation 
 
5.2.1    Pravastatin sodium 40 mg tablets. Store at 25°C (77°F); excursions permitted 
to 15°C - 30°C (59°-86°F).  Each bottle contains 100 tablets.   
 
Rosuvastatin 20 mg tablets. Store at 25C (77F); excursions permitted to 15 to 30C (59 
to 86F).  Each bottle contains 30 tablets.   
 
The study drug will be stored by the study site at controlled room temperature, 15 to 
30ºC (59 to 86ºF). Subjects will be instructed to store the medication in original 
packaging at room temperature according to the instructions outlined on the Drug 
Administration Instructions. 
 
 
5.3 Pharmacy: Product Supply, Distribution, and Accountability 
 
5.3.1 Study Product Supply/Distribution 
The drug products used will be rosuvastatin 20 mg oral tablets (AstraZeneca: London, 
UK) and pravastatin 40 mg oral tablets (Bristol-Meyers Squibb: New York, NY, USA).  
 
These are approved drugs in regular clinical use at the doses proposed in this study 
and will be purchased through the Northwestern Memorial Hospital Investigational 
Pharmacy.   
 
5.3.2 Study Product Accountability 
The site pharmacist is required to maintain complete records of all study products 
received. All unused study products must be returned to the site (or as otherwise 
directed by the sponsor) after the study is completed or terminated.  
5.4 Concomitant Medications 
 
Below are lists of selected concomitant medications. These lists are only current as of 
the date of this protocol. Therefore, whenever a concomitant medication or study agent 
is initiated or a dose changed, investigators must review the concomitant medications’ 
and study agents' most recent package inserts, and Investigator’s Brochures to obtain 
the most current information on drug interactions, contraindications, and precautions. 
5.4.1 Required Medications:  
All subjects should be maintained on the same antiretroviral medications throughout 
the entire study period, as medically feasible, with no introduction of new chronic 
therapies. 
Standard therapy for HIV and care in the setting of CHD and/or high risk for ASCVD is 
allowed except for treatments noted in the exclusion criteria described above and as 
noted in the prohibited medications section below.   
 
5.4.2 Prohibited Medications  

 
 
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The following medications are prohibited during the study and administration will be 
considered a protocol violation. 
 
- 
Atazanavir/ritonavir 
- 
Lopinavir/ritonavir (Kaletra) 
- 
Cyclosporine 
- 
Rifampin 
- 
Simeprevir 
- 
Cholestyramine / aspartame 
- 
Cholestyramine / sucrose 
- 
Colesevelam 
- 
Colestipol 
- 
Prevalite 
- 
Questran 
- 
Questran Light 
- 
Welchol 
- 
Colestid 
- 
Ezetimibe 
- 
Zetia 
- 
Liptruzet 
- 
Vytorin 
- 
Fenofibrate 
- 
Fenofibric acid 
- 
Gemfibrozil 
- 
Antara 
- 
Lipofen 
- 
Lofibra 
- 
Tricor 
- 
Fenoglide 
- 
Triglide 
- 
Trilipix 
- 
Fibricor 
- 
Lopid 
- 
Icosapent ethyl 
- 
Lomitapide 
- 
Mipomersen 
- 
Vascepa 
- 
Juxtapid 
- 
Kynamro 
- 
Niacin 
- 
Niaspan 
- 
Simcor 
- 
Niacinamide 
- 
Simvastatin 

 
 
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- 
Fluvastatin 
- 
Lovastatin 
- 
Cerivastatin 
- 
Atorvastatin 
- 
Pitavastatin 
- 
Advicor 
- 
Altocor 
- 
Altoprev 
- 
Atorlip 
- 
Baycol 
- 
Caduet 
- 
Canef 
- 
Inegy 
- 
Lescol 
- 
Lipex 
- 
Lipitor 
- 
Lipobay 
- 
Lipostat 
- 
Lipvas 
- 
Mevacor 
- 
Pitava 
- 
Selektine 
- 
Simcard 
- 
Simcor 
- 
Simlup 
- 
Sortis 
- 
Torvacard 
- 
Torvast 
- 
Totalip 
- 
Tulip 
- 
Vytorin 
- 
Zocor 
 
 
5.4.3 Precautionary Medications 
Whenever a concomitant medication or study agent is initiated or a dose changed, 
investigators must review the concomitant medications’ and study agents' most recent 
package inserts, Investigator’s Brochures to obtain the most current information on 
drug interactions, contraindications, and precautions. 
 
     
5.5 Adherence Assessment 
 
Adherence to all study drugs will be monitored by self-report.  
 

 
 
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Subjects will be asked to keep a patient diary noting the day and date they take their study 
drug and any adverse events. They will be asked to bring their patient diary to each study visit 
along with all used and unused study drug containers. 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
6.1 Schedule of Events 
 
 
 
SCREEN-
ING  
WEEK 
0a 
WEEK 
2a 
WEEK 
6a 
WEEK 
10 
Week 14/ or 
discontinuation 
Informed Consent 
X 
X 
 
 
 
 
Medical and Medication 
History (including 
cardiovascular risk; HIV RNA 
and CD4, lipids) 
X 
 
 
 
 
 
Complete Physical Exam 
X 
 
 
 
 
 
Targeted Physical Exam 
 
X 
X 
X 
X 
X 
Height , Weight 
X 
 
 
 
X 
 
Vital Signs  
X 
X 
X 
X 
X 
X 
Chemistry Panel, Liver 
Function Tests 
X 
X 
X 
X 
X 
X 
Creatine Kinase  
X 
X 
X 
X 
X 
X 
Fasting Lipid Panel 
X 
X 
X 
X 
X 
X 
Pregnancy Test   
X 
X 
 
 
 
X 
Hematology, Hemoglobin A1c 
 
X 
 
 
 
X 
Stored Plasma/Serum/PBMCs  
 
X 
X 
 
 
X 
Pharmacokinetics/dynamics 
 
 
X 
X 
 
X 
Randomization 
 
 
X 
 
 
 
Dispensing of Study Drug 
 
X 
X 
X  
(X)* 
 
Adherence Assessment 
 
 
X 
X 
X 
X 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
X 
AE Determination 
 
X 
X 
X 
X 
X 
Phone Call 
 
 
 
 
(X)* 
 
Statin Intolerance Survey 
 
 
X 
X 
X 
X 
*(X) if on escalated rosuvastatin dose (40mg daily)  
 
 
 
 
 
 
 
6.2 
Timing of Evaluations 
 
6.2.1 Screening Evaluations  
 

 
 
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Screening evaluations must occur prior to the subject starting any study medications, 
treatments, or interventions. 
Screening 
Screening evaluations to determine eligibility must be completed within 45 days prior to 
study entry, unless otherwise specified.  
In addition to data being collected on subjects who enroll into the study, reason(s) for  
screening failures will be captured on a Screening Failure form  and will not be entered 
directly in REDCap.   
6.2.2 Entry Evaluations 
Entry evaluations must occur at least 24 hours after screening evaluation and be 
completed prior to the initiation of study medications.  
6.2.3 Post-Entry Evaluations 
On-Treatment Evaluations 
Evaluations should occur +/- 2 days of the scheduled visit.    
 
6.2.4 Discontinuation Evaluations 
 
Evaluations for Registered Subjects Who Do Not Start Study Treatment 
Subjects who do not begin study treatment should have screening and entry forms 
completed and entered in the database. Beyond the entry visit, no further evaluations 
are required. These subjects will be replaced. 
 
Premature Treatment Discontinuation Evaluations  
Subjects who discontinue the study medications before the end of the study (Week 14) 
should have the Premature Treatment Discontinuation evaluations done within 7 days 
after stopping study drugs. They will be encouraged to continue to attend all study 
visits and receive study evaluations as per section 6.1 through Week 14.   
 
Premature Study Discontinuation Evaluations  
All subjects who prematurely discontinue participation in the study should have the 
Premature Study Discontinuation evaluations done. 
 
6.3 Instructions for Evaluations 
 
All clinical and laboratory information required by this protocol must be present in the source 
documents. 
All stated evaluations are to be recorded on the CRF and keyed into the REDCap database 
unless otherwise specified. 
 
6.3.1 Documentation of HIV-1 

 
 
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Section 4.1.1 specifies assay requirements for HIV-1 documentation. HIV-1 
documentation is not recorded on the CRF.  
 
6.3.2 Medical History 
The medical history must include all diagnoses identified by the ACTG criteria for 
clinical events and other diagnoses within 30 days. In addition, the following diagnoses 
should be reported regardless of when the diagnosis was made: 
• 
AIDS-defining conditions 
• 
Coronary heart disease 
o Previous ACS, which includes myocardial infarction and unstable angina 
o Angina 
• 
Cerebrovascular disease 
• 
Cancer (exclusive of basal/squamous cell skin cancer) 
• 
Diabetes 
 
Any allergies to any medications and their formulations must also be documented.  
 
 
 
Cardiovascular risk:  An assessment of general cardiovascular risk factors, smoking, 
alcohol use, substance use, family history of premature CVD, hormonal history will be 
assessed at screen.  ASCVD risk will be calculated using the ACC/AHA ASCVD Risk 
Estimator (http://tools.acc.org/ASCVD-Risk-estimator/). 
 
 
         6.3.3 
Medication History 
A medication history must be present in the history and recorded in the source 
documents:  
Medication History Table 
Medication Category 
Complete History or 
Timeframe 
Record in 
CRFs 
Antiretroviral therapy 
Start date of initial ART 
regimen, current ART regimen  Yes 
Statin and other lipid-lowering 
therapy (prescription and non-
prescription) 
 
Complete history 
Yes 
Prescription drugs  
Within 30 days prior to entry  
Yes 
Non-prescription drugs  
Within 30 days prior to entry 
No 
Complementary and alternative 
medicines 
Within 30 days prior to entry 
No 
 
 
 
6.3.4 Clinical Assessments 
 
Complete Physical Exam 
A complete physical examination performed at any time between screening and the 
entry evaluation is to include at a minimum an examination of the skin, head, mouth, 
and neck; auscultation of the chest; cardiac exam; abdominal exam; and examination 
of the lower extremities for edema. The complete physical exam will also include signs 

 
 
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and symptoms, diagnoses, height, weight, and vital signs (temperature, pulse, 
respiration rate, and blood pressure). 
Targeted Physical Exam 
A targeted physical examination is to be performed after screening and will be driven 
by any previously identified or new signs or symptoms including diagnoses that the 
subject has experienced since the last visit. This examination includes vital signs 
(temperature, pulse, respiration rate, and blood pressure). 
Signs and Symptoms  
At entry, record on the CRFs all signs/symptoms occurring within 30 days prior to 
entry. 
 
After entry, record all Grade ≥1 signs/symptoms, any signs/symptoms regardless of 
grade that lead to a change in treatment, or that meet EAE, SAE, or ICH guidelines.   
 
Diagnoses 
At screening, record diagnoses in the medical history per section 6.3.2. At study entry 
and thereafter, record all new diagnoses since the last study visit identified by the 
ACTG criteria for clinical events and other diseases.  
 
Concomitant Medications 
Record any prescription medications taken since the last study visit, including actual or 
estimated start dates and stop dates in the CRF. Current non-prescription, alternative 
and traditional medications are recorded in the source documents and CRFs.  
 
Study Treatment  
Record all study treatment modifications, including initial doses, subject-initiated and/or 
protocol-mandated modifications, and inadvertent and deliberate interruptions of more 
than 1 day  since last visit. Record any permanent discontinuation of treatment. 
 
6.3.5 Laboratory Evaluations 
Sites must refer to the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table), Version 2.0, November 2014, which can 
be found at http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx.   
Record all protocol-required laboratory values, regardless of grade, obtained at 
screening and entry on the CRFs.  
After entry, record all laboratory values Grade ≥2. Record all lipid values (Total, HDL, 
and LDL cholesterol, triglycerides) regardless of grade on the CRF. All laboratory 
values that lead to a change in study treatment, and all serum creatinine and liver 
function tests (AST, ALT, alkaline phosphatase, total  bilirubin) regardless of grade, 
must be recorded.  
 
Hematology 
Hemoglobin, hematocrit, white blood cell count (WBC), with differential, absolute 
neutrophil count (ANC), and platelet count.   
 
Liver Function Tests 
AST (SGOT), ALT (SGPT), alkaline phosphatase, total and direct bilirubin  
 

 
 
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Blood Chemistries 
sodium, potassium, chloride, bicarbonate, random glucose, BUN, creatinine, aspartate 
aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT), alkaline 
phosphatase, total bilirubin, direct bilirubin, total protein, and albumin. 
 
Fasting Lipids 
Total, HDL, and LDL cholesterol, triglycerides. 
If triglycerides are >400 at screening and/or high enough that LDL can’t be calculated, 
then come back for direct LDL.  Subsequent LDL should be direct in those patients.   
 
Subjects should be instructed to fast for 8 hours prior to this test. Fasting is defined as 
no food or drink, except for sips of water with medications. If the subject has not been 
fasting, the visit must be rescheduled. Record the non-fasting status on the CRF.    
 
 
Pregnancy Test 
All women with reproductive potential must have a negative serum or urine beta-
human chorionic gonadotropin (-HCG) pregnancy test result at screening and within 
48 hours prior to initiating protocol-specified medications and any time thereafter when 
pregnancy is suspected. (The urine test must have a sensitivity ≤50 mIU/mL).  
 
6.3.6 Laboratory Results from Clinical Care  
CD4 count and HIV-1 RNA results will be obtained from routine clinical care and 
available in the EMR.   
 
   
6.3. 7 Adherence Assessment  
 
 
 
Adherence to all study medications will be assessed by self-report.   Sites will provide 
adherence reinforcement, according to local standard practice throughout the study. 
Subjects with poor adherence will be provided counseling by the site.   
 
 
6.3.8   Storage of PBMCs, Plasma and Serum for l future studies 
 
Virologic and Immunologic Studies:  
40 mL of blood will be collected in EDTA tubes.  Peripheral blood mononuclear cells 
(viable PBMCs ) and plasma will be processed or stored for possible later analyses of 
cell-associated HIV RNA and DNA and T cell subsets, soluble and cellular markers of 
immune activation.    
5 mL of blood will be collected in SST tubes and 3 mL in sodium citrate tubes and  
stored for later analyses of inflammatory biomarkers. 
 
Pharmacology:  
5 mL of blood for determination of plasma concentrations of pravastatin and 
rosuvastatin will be collected approximately 12 hours after dosing at weeks 2, 6, and 
14.  Participants will be instructed to take their study medications in the evening, about 
12 hours before their clinic visit.  Time of last dose and blood draw will be collected.   
The samples will be processed and cryopreserved at the study repository at the Lurie 
Special Infectious Diseases (SID) Laboratory 
 

 
 
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7.0 
CLINICAL MANAGEMENT ISSUES 
7.1 
Toxicity Management 
 
Criteria for subject management, dose interruptions, modifications, and discontinuation of 
study treatment will be mandated only for toxicities attributable to study-provided drugs 
(pravastatin and rosuvastatin).  
 
The grading system for drug toxicities is the DAIDS Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Version 2.0, November 2014, located at                              
http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx.  
 
The lone difference between the grading system for drug toxicities used in this trial and the 
DAIDS Table is that our protocol has a lower threshold for grading transaminase (AST and 
ALT) elevations; based on the current ACC/AHA and National Lipid Association Guidelines, 
we consider elevation of AST or ALT ≥3x ULN as grounds for holding the study drug (and a 
grade 3 adverse event in this protocol), and CK ≥10x ULN as a grade 3 adverse event and 
grounds for holding the study drug.  
 
NOTE: The HILLCLIMBER protocol chair must be notified by e-mail regarding toxicities that 
result in regimen interruption or discontinuation. Email: matthewjfeinstein@northwestern.edu. 
General guidelines presented in sections 7.1.1 to 7.1.3 apply to toxicities that are not 
specifically discussed further below.  
 
7.1 
Toxicity Management 
 
7.1.1 General Reactions 
 
Grade 1 or 2 
Subjects who develop a Grade 1 or 2 toxicity may continue study treatment. 
 
Grade 3 
Subjects who develop a Grade 3 toxicity that is judged by the site investigator to be 
study drug-related should have the study drug held and the study team should be 
consulted. The subject should be followed closely and if the toxicity does not return to 
Grade 2 within 2 weeks, the study drug must be permanently discontinued with subject 
evaluations as per section 6.2.4. 
 
If the study drug is resumed and the same Grade 3 toxicity recurs within 4 weeks of 
reintroduction, and the site investigator considers this AE related to the study drug, the 
drug must be permanently discontinued. 
 
With a Grade 3 toxicity that is judged not related to the study drug by the site 
investigator, the study drug may be continued at the discretion of the site investigator in 
consultation with the study team. 
 
Grade 4 
Subjects who develop a Grade 4 toxicity will have the study drug permanently 
discontinued, with clinical assessments and laboratory testing as described for Grade 3 
toxicity. If the investigator feels that the toxicity is clearly related to another cause and 
that the toxicity is not caused by the study drug, and after consultation with the study 
team, dosing may continue when the toxicity has resolved to Grade 2 or less. 

 
 
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Subjects experiencing Grade 4 toxicities should be followed closely with additional 
clinical assessments and laboratory testing as clinically indicated in consultation with 
the study team. 
 
NOTE:  Direct and indirect bilirubin elevations that reach Grade 4 elevations according 
to the DAIDS toxicity schema and are related to atazanavir are excluded from 
reporting. 
 
7.1.2 ALT and AST elevations  
 
ALT and AST levels will be routinely evaluated at screening, week 0, 2, 6, 10, and 14 
visits. All other evaluations of ALT and AST will be performed at the discretion of the 
site investigator based on subject symptoms.  
 
Grade 3 
Subjects who develop asymptomatic >3 x ULN ALT or AST elevations (Grade 3), study 
drug should be held for 2 weeks and the individual should be re-evaluated 3 week after 
drug discontinuation. If at that time the ALT or AST elevation is 3 x ULN and subjects 
remain asymptomatic, the subjects are eligible to continue on study treatment at the 
discretion of the site investigator. If the ALT and AST are not ≤3 x ULN within the 2 
week period, the study drug must be permanently discontinued unless the ALT and 
AST elevations are deemed not related to study drug upon further assessment as per 
the discretion of the care provider (ie, acute hepatitis A or other clear causation). 
 
For any symptomatic (eg, fatigue, nausea and vomiting, right upper quadrant pain, rash 
or eosinophilia) ALT or AST >3 x ULN (Grade 3), study drug should be held. Subjects 
should be asked to return to the research site for repeat testing 2 weeks later. If repeat 
ALT and AST is ≤3 x ULN and the subject is no longer symptomatic, study drug can be 
resumed. 
 
Grade 4 
For any ALT or AST >6 x ULN (Grade 4), the study drug should be discontinued. The 
subject should be brought back for repeat testing every 1 week until the ALT and AST 
≤3 x ULN. Even if ALT and AST are ≤3 x ULN upon repeat testing for these patients, 
the study drug will not be restarted at that time. 
 
NOTE:  If the Grade 3 or 4 elevation is clearly related to another cause and not related 
to study drug (eg, acute hepatitis A infection), the subject should be brought back for 
repeat testing every 2 weeks for Grade 3 or every 1 week for Grade 4 until the ALT or 
AST ≤3 x ULN. The local site investigators should contact the study team for approval 
before resuming study drug. Subjects who permanently discontinue study drug will be 
followed on study, off treatment through the study termination visit with subject 
evaluations as per section 6.2.4. 
 
NOTE:  For those subjects with ALT or AST >3 x ULN upon repeat testing, whether 
symptomatic or not, INR should also be performed (in addition to bilirubin and alkaline 
phosphatase, which will be evaluated with ALT and AST routinely) as part of the study 
to help determine etiology of increased LFTs. Other labs including hepatitis serologies 
may also be indicated and performed in the context of clinical care by PCP.  
 

 
 
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NOTE:  If the subject has recurrent elevations of ALT or AST >3 x ULN but the site 
investigator deems the elevation not related to study drug, the site investigator must 
contact the study team to discuss continuation of study drug.  
 
Abnormal ALT or AST determinations occurring in the course of clinical care should be 
repeated by the treating clinician. Persistently abnormal values which would trigger the 
toxicity guidelines above should be reported to the protocol team. If the ALT or AST 
abnormality is not due to another cause, eg, acute hepatitis, follow the toxicity 
algorithm above. 
 
7.1.3 Myalgias and Myopathy 
 
Persons who present with significant myalgias (Grade ≥3, ie, muscle pain causing 
inability to perform usual social and functional activities) should be evaluated with a 
clinical assessment that includes an evaluation of CK, serum creatinine, potassium, 
and urinalysis. Myopathy is defined as muscle aches, soreness, tenderness, or 
weakness with creatinine kinase (CK) >10 x ULN not related to exercise or other 
causes, including trauma. If the symptoms are associated with Grade 3 elevation in 
CK (10 x ULN) (see table below) that is not related to exercise or other cause, study 
medications should be permanently discontinued. Subjects will be followed on study, 
off treatment through the study termination visit with subject evaluations as per section 
6.2.4.  
 
NOTE:  Mitochondrial toxicity related to nucleoside therapy and not related to study 
medication is a possibility, and evaluations for lactic acidosis should be considered by 
the subject’s primary care provider. 
 
Serum CK Toxicity Grading* 
 
Toxicity Grade 
Value 
Grade 1 
3 – <6 x ULN 
Grade 2 
6 – <10 x ULN 
Grade 3 
10 – <20 x ULN 
Grade 4 
≥20 x ULN 
* Not related to exercise or other cause 
 
7.1.4 Rhabdomyolysis 
 
Rhabdomyolysis is defined as the presence of myopathy as per section 7.1.3 plus one 
or more of the following: 
• 
Hematuria on urine dipstick in the absence of microscopic 
hematuria (myoglobinuria) 
• 
Grade 2 hyperkalemia 
• 
Grade 2 creatinine elevation 
 
If rhabdomyolysis occurs, study medications should be permanently discontinued. The 
team should be consulted. Subjects will be followed on study, off treatment through the 
study termination visit with subject evaluations as per section 6.2.4. In addition, CK will 
be added to the laboratory evaluations performed until it has declined to ≤1 x ULN. 
 
7.2 
Requirement for Precautionary or Prohibited Medications (see PSWP) 
 

 
 
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Subjects who need to initiate therapy with erythromycin, colchicine, cyclosporine, or rifampin 
should be asked to hold study drug. If use of one of these precautionary medications is 
anticipated to be short-term, the site investigator may consider restarting study drug after use 
of prohibited medication is discontinued. 
 
Subjects who begin a statin medication provided through clinical care should discontinue study 
drug. Taking two statins can increase the risk of toxicity.  
 
Subjects who temporarily or permanently discontinue study treatment will be followed on 
study, off treatment through the study termination visit with subject evaluations as per section 
6.2.4. 
 
7.3 
Pregnancy  
 
If the pregnancy test is positive at entry, then the subject should not start study treatment. No 
further evaluations are necessary, provided that the subject did not initiate study drug. 
 
Subjects who become pregnant after study entry must discontinue study treatment 
immediately. These subjects should be seen for a premature treatment discontinuation 
evaluation within 7 days. The core team must be notified of any pregnancies that occur in 
subjects on study.  
 
All pregnancies should be followed until the final outcome can be determined. Pregnancies 
that occur on study should be reported prospectively to The Antiretroviral Pregnancy Registry. 
More information is available at www.apregistry.com. Phone: 800-258-4263; Fax: 800-800-
1052 (Non-US sites: Fax: 44-1628-789-666 or 910-246-0637; phone: 910-679-1598.) 
 
 
8.0 
CRITERIA FOR DISCONTINUATION 
8.1 Permanent Study Treatment Discontinuation 
 
• 
Drug-related toxicity requiring permanent study treatment discontinuation (see section 7.0) 
• 
Requirement for prohibited concomitant medications (see section 5.4) 
• 
Pregnancy 
• 
Breast-feeding  
• 
Completion of treatment as defined in the protocol 
• 
Request by subject to terminate treatment 
• 
Clinical reasons believed life threatening by the physician, even if not addressed in the 
toxicity section of the protocol 
• 
Failure by the subject to attend 2 consecutive clinic visits 
 
 
8.2 Premature Study Discontinuation 
 
• 
Request by the subject to withdraw 
• 
Request of the primary care provider or investigator if s/he thinks the study is no longer in 
the best interest of the subject 
• 
Subject judged by the investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of 
the study results 
• 
At the discretion of the IRB, FDA, IND sponsor,  or pharmaceutical supporters  

 
 
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9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 General Design Issues 
HILLCLIMBER is a randomized, controlled, open-label phase II trial. 40 subjects not already on 
high dose statin therapy who have CHD and/or calculated 10-year ASCVD risk >15% will be 
included and started on moderate dose statin therapy (pravastatin 40mg daily) for an initial two-
week run-in period. Subjects not demonstrating significant toxicity at week 2 will then be 
randomized to high intensity statin therapy (rosuvastatin 20mg) versus continuing moderate 
intensity statin therapy (pravastatin 40mg daily). At week 6, subjects in the rosuvastatin arm who 
do not demonstrate significant toxicity and whose LDL-c is >60mg/dl and decreased by less than 
25% compared with week 2 will then have doses increased to rosuvastatin 40mg (high dose 
group).  Efficacy and safety will be evaluated at Week 14.   
 
 
9.2 Endpoints 
 
9.2.1 Primary Endpoints:  
 
Efficacy: The primary efficacy endpoint is mean percent change in fasting LDL-c 
(mg/dl) from week 2 (end of run-in period) to week 14   
 
▪ 
The mean percent change in fasting LDL-c from week 2 to week 14 will be 
compared for the high dose group (rosuvastatin 20mg daily uptitrated to 40mg 
daily) and the moderate dose group (pravastatin 40mg daily). 
 
Safety:   
▪ 
All treatment-emergent adverse events, including but not limited to:  
• 
Incidence of adverse event-related study drug discontinuation (following 
initial 2 week wash-in) or hospitalizations  
• 
Grade 3 or greater adverse events;  
• 
Study drug-related symptoms  
• 
CK elevation > 3x upper limit of normal;  
• 
AST or ALT elevation >3x upper limit of normal;  
 
9.2.2 Secondary Endpoints 
 
Secondary endpoints include mean percent changes in the following from week 2 to 
week 14:  
• 
Lipid parameters (HDL-c, triglycerides, and total cholesterol),  
• 
Inflammatory biomarkers (soluble CD163, ST2, high sensitivity troponin 
I, high-sensitivity CRP, PAI-1, Lp-PLA2) 
• 
Viral and immunologic markers derived from PBMCs (such as T cell 
reactivity and viral reservoir persistence).  
• 
Statin drug levels >400% expected steady-state dose level 
• 
Hemoglobin A1c level  
 
An additional secondary endpoint will evaluate safety, as measured by treatment-

 
 
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emergent clinical and laboratory adverse events, of high versus moderate intensity 
statin therapy in HIV-infected persons taking ART who have coronary heart disease 
(CHD) and/or 15% or greater risk for ASCVD.  
 
 
9.3 
Randomization and Stratification  
 
Subjects who meet enrollment criteria will be randomized at Week 2 in a 1:1 ratio according to 
the study treatment that has been randomly assigned to the Patient Number on the 
Randomization List held by the local site pharmacist.   Randomization will be stratified by: (1) 
type of ART: patients taking any booster (ritonavir or cobicistat) as part of their ART regimen 
and patients not taking a booster; and (2) known CHD or not. 
 
9.4  
Sample size and Accrual 
 
The predicted percent reduction in LDL-c by rosuvastatin dose is as follows: 20mg (55-60%), 
and 40mg (60-63%). The predicted percent reduction in LDL-c by pravastatin 40mg is 30%. 
The expected difference in LDL-c for subjects receiving high (rosuvastatin 20-40mg daily) 
versus moderate (pravastatin 40mg daily) intensity statin doses in this study is therefore 
approximately 25-30% compared with moderate. In a landmark study of patients with CHD 
comparing high intensity statin (atorvastatin 80mg, which is similar in intensity of expected lipid 
lowering to rosuvastatin 20-40mg) versus pravastatin 40mg, mean LDL cholesterol levels 
during treatment were 62mg/dl and 95mg/dl for high intensity and pravastatin groups (with 
standard deviations of approximately 20mg/dl), respectively.  
 
Given potentially lower baseline LDL cholesterol levels in this study (we expect mean LDL of 
participants  will be approximately 105, including patients off statin therapy and those on low 
intensity therapy), realistic expected mean LDL cholesterol levels are 75mg/dl for the 
pravastatin group and 50mg/dl for the high-intensity/rosuvastatin group. These expected LDL 
cholesterol levels are similar to those seen in the high intensity versus lower intensity 
treatment groups in a more recent trial of lipid-lowering strategies in high-risk patients, in which 
there was no excess of adverse events in the higher-intensity group which achieved a mean 
LDL of 53.7mg. In order to have a power of 0.80 with a two-sided alpha of 0.05 to detect a 
25mg/dl difference in LDL-c lowering with a standard deviation of LDL-c of 20, the desired 
sample size would be at least 11 cases and 11 controls. Given the potential for study drug 
discontinuation in an expected 8 or fewer patients (based on on-treatment symptoms being 
present in 5-20% of patients on statins), the goal subject enrollment for this study is 30 with a 
possible enrollment of up to 50 participants in order to ensure adequate power. 
 
9.5 
Monitoring 
 
When approximately 50% of patients have completed the study through week 6, an interim 
analysis for safety will be conducted by an independent data monitoring committee. Patients 
with levels of CK, AST, ALT at weeks 2, 6, or 10 that are 3 times the upper limit of normal or 
greater will have the study drug discontinued at that time. If >25% of study enrollees are 
required to have the study drug discontinued at the interim analysis, the trial will be stopped. 
Serious adverse events will be monitored by the committee on an ongoing basis throughout 
the study. If a study patient has CK, AST, or ALT levels of 3 times the upper limit of normal or 
greater any time prior to the interim safety analysis, the study coordinator will alert the medical 
safety officer (Kunal N. Karmali, MD), who will contact the patient and instruct the patient to 
immediately discontinue the study drug. Such patients who discontinue the study drug at the 

 
 
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medical safety officer’s request will continue to be followed in the study and included in 
intention-to-treat analyses. 
 
9.6 
Analyses 
 
9.6.1  Primary Anaysis 
Lipid measurements from week 2 and week 14 will be used for analyses of the primary 
endpoints. We will use intention-to-treat analyses for evaluation of the primary endpoint and 
logistic regressions to compare percent change in LDL-c from week 2 to week 14 for the high-
intensity statin group versus the lower intensity statin group.   
 
The primary analysis will evaluate percent changes in LDL-c at week 14 compared with week 
2 (following wash-in with pravastatin 40mg daily) for patients randomized to a high intensity 
versus lower intensity strategy. Two-sample t-tests will be performed using STATA version 14 
(Stata Statistical Software: Release 14; College Station, TX: StataCorp LP). 
 
9.6.2 Secondary Analyses  
 
Safety and tolerability data will be summarized by treatment group.   
Adverse events (signs, symptoms, and diagnoses) will be analyzed and reported using the 
AIDS Clinical Trials Group (ACTG) medical dictionary and standardized coding for Signs, 
Symptoms, and Diagnoses for Clinical and Adverse Events. Adverse events will be tabulated 
by treatment group and will include the number of patients for whom the event occurred, the 
rate of occurrence, and the severity and relationship to study drug.   
 
Incidence of clinical and/or laboratory toxicities. The safety and tolerability measures will 
include: 
-  
Time to discontinuation of any study medication due to adverse events (AEs), -- 
Proportion of Grade 3 or Grade 4 clinical AEs,  
-  
Proportion of Grade 3 or Grade 4 laboratory abnormalities,  
  
Summaries of all treatment-related AEs 
 
Possible future analyses 
- Measures of the HIV reservoir size  
- Soluble and cellular markers of immune activation and inflammation 
 
 
 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EVENT REPORTING 
10.1 
Records to Be Kept 
 
CRFs will be provided for each subject. Subjects must not be identified by name on 
any CRFs. Subjects will be identified by the Patient Number and Screening Number 
provided upon registration. 
10.2 Role of Data Management 
 
10.2.1 Instructions concerning the recording of study data on CRFs will be provided by the 
central data management team at Northwestern University. The Research Electronic  
Data Capture (REDCap)  data management system will be used.   

 
 
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10.2.2 It is the responsibility of the data management team to assure the quality of 
computerized data for the study. This role extends from protocol development to 
generation of the final study databases.  The REDCap data management system will 
be used for data entry, data queries, and data reports.   
10.3 Clinical Site Monitoring and Record Availability 
 
10.3.1 Site monitors will  review the individual subject records, including consent forms, CRFs, 
supporting data, laboratory specimen records, and medical records (physicians’ 
progress notes, nurses’ notes, individuals’ hospital charts), to ensure protection of 
study subjects, compliance with the protocol, and accuracy and completeness of 
records. The monitors also will inspect sites’ regulatory files to ensure that regulatory 
requirements are being followed and sites’ pharmacies, and to review product storage 
and management. 
10.3.2  The site investigator will make study documents (e.g., consent forms, drug distribution 
forms, CRFs) and pertinent hospital or clinic records readily available for inspection by the 
local IRB, the site monitors, the FDA, the OHRP, and the pharmaceutical supporter(s) or 
designee for confirmation of the study data.  
10.4 Expedited Adverse Event Reporting  
 
The adverse events (AEs) that must be reported in an expedited fashion to the IND Sponsor 
(Dr. Donald Lloyd-Jones at Northwestern University)  are all serious adverse events (SAEs) as 
defined by International Conference on Harmonization (ICH) guidelines regardless of 
relationship to the study agent(s). The protocol for reporting AEs will be as follows: 
o We will report any unexpected fatal or life-threatening suspected adverse reactions to 
the Division of Metabolism and Endocrinology Products no later than 7 calendar days 
after initial receipt of the information [21 CFR 312.31(c)(2)]. 
o We will submit 7-day reports by rapid means of communication (facsimile or email) and 
will address each submission to the Regulatory Product Manager and/or to the Chief, 
Project Management Staff;  
o We will report any (1) serious, unexpected suspected adverse reactions, (2) findings 
from other clinical, animal, or in-vitro studies that suggest significant human risk, and 
(3) a clinically important increase in the rate of a serious suspected adverse reaction to 
the Division of Metabolism and Endocrinology Products and to all investigators no later 
than 15 calendar days after determining that the information qualifies for reporting.  
 
SAEs as defined by ICH guidelines are: deaths, life-threatening events, events that require 
hospitalization or prolongation of hospitalization, events that result in persistent or significant 
disability or incapacity, and congenital anomalies or birth defects. Important medical events as 
assessed by medical and scientific judgment may also be considered SAEs by the investigator 
and should be reported in an expedited fashion.  Possible drug-induced liver injury is also 
considered an SAE in this study and requires expedited reporting. 
 
The study agents that must be considered in determining relationships of AEs requiring 
expedited reporting to the IND Sponsor are pravastatin and rosuvastatin.    
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 2.0, November 2014, must be used and is available at http://rsc.tech-
res.com/safetyandpharmacovigilance/gradingtables.aspx.    
 
Any SAE occurring during the study and up to 28 days post the last dose of study drug must 

 
 
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be documented on the Serious Adverse Events Form and faxed to the IND Sponsor, Dr. 
Donald Lloyd-Jones at 1-312-980-9588 within 24 hours of awareness.  The IND Sponsor and 
the HILLCLIMBER Principle Investigator and Research Manager should be alerted about the 
faxed form by sending an email to matthewjfeinstein@northwestern.edu and 
baiba@northwestern.edu with the title: HILLCLIMBER  SAE REPORT.  
   
The FDA also requires sponsors to submit a written Safety Report of all serious and 
unexpected AEs. The study investigators in this study have the responsibility of promptly 
reporting all SAEs so that IND Sponsor can comply with these regulations. A non-blinded 
safety officer (Kunal N. Karmali, MD) will be available to review SAEs and determine the 
potential relation of the study drug to SAEs. 
 
The protocol-defined expedited event reporting period for this protocol is the entire study 
duration for an individual subject (from study enrollment until study completion or 
discontinuation of the subject from study participation for any reason). 
 
After the end of the protocol-defined reporting period stated above, sites must report serious, 
unexpected, suspected adverse drug reactions if the study site staff becomes aware of the 
event on a passive basis, i.e., from publicly available information.  
 
11.0 
HUMAN SUBJECTS 
11.1 
Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix II) and any subsequent 
modifications will be reviewed and approved by each local IRB or ethics committee 
responsible for oversight of the study. A signed consent form will be obtained from the subject 
(or legal guardian or person with power of attorney for subjects who cannot consent for 
themselves). The consent form will describe the purpose of the study, the procedures to be 
followed, and the risks and benefits of participation. A copy of the consent form will be given to 
the subject or legal guardian, and this fact will be documented in the subject’s record. 
 
11.2 
Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site will 
be identified by coded number only to maintain subject confidentiality. All records will be kept 
locked. All REDCap entry will be done with coded numbers only. Clinical information will not 
be released without written permission of the subject, except as necessary for monitoring by 
the IRB, the FDA, or the IND sponsor.  
11.3 
Study Discontinuation 
 
The study may be discontinued at any time by the IRB, the IND Sponsor, pharmaceutical 
supporters, the FDA, or other government agencies as part of their duties to ensure that 
research subjects are protected.  
12.0 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by Northwestern University policies. Any 
presentation, abstract, or manuscript will be made available for review by the pharmaceutical 
supporters prior to submission.  

 
 
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13.0 
BIOHAZARD CONTAINMENT 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for Disease 
Control and Prevention and the NIH. 
All dangerous goods materials, including diagnostic specimens and infectious substances, 
must be transported using packaging mandated by CFR 42 Part 72. Please refer to 
instructions detailed in the International Air Transport Association (IATA) Dangerous Goods 
Regulations.  
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