Conditions: Hepatocellular Carcinoma Liver Cirrhoses
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
Hepatocellular Carcinoma (HCC) is a major health concern in the United States, particularly among people with liver cirrhosis. Out of every 100 patients with liver cancer, only 18 will survive 5 years or more. While locoregional therapies are utilized in an effort to combat this disease, the recurrence rate of HCC after these therapies are high.

Statins are widely used drugs that lower cholesterol levels. Some studies have suggested that statins lower risk of HCC recurrence, but this possibility has not been studied thoroughly in a clinical trial. This study will examine the effects of pravastatin, a type of statin, on time to HCC recurrence in patients with early stage HCC. It is possible that pravastatin in combination with locoregional therapies may delay or protect against HCC recurrence.

Detailed description:
To date, there has been a scarcity of clinical trials evaluating the effectiveness of adjuvant therapies in patients with early stage HCC, although it is widely considered an area of highly unmet need.

The objective of this randomized double-blinded, placebo-controlled Phase II trial is to examine the effects of pravastatin use versus placebo after 12 months of treatment on hepatocellular cancer (HCC) recurrence in 130 patients with liver cirrhosis, HCC meeting Milan Criteria or OPTN tumor downstaging criteria for tumor burden, and initial locoregional therapy (LRT) with adequate response.

Arms:
arm 1: Daily pravastatin (40mg) arm 2: Placebo

Interventions: intervention 1: Pravastatin Pill intervention 2: Placebo Oral Tablet
Intervention descriptions: intervention 1: statin intervention 2: placebo

Protocol document:
Prot_SAP_000.pdf: 
 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
IIT2017-08-Hussain-StatLv  
 
 
Pravastatin Intervention to Delay Hepatocellular 
Carcinoma Recurrence 
 
 
Principal Investigator:  
Shehnaz K. Hussain, PhD., Sc.M. 
 
 
 
 
Associate Professor 
 
 
 
 
Department of Medicine 
 
 
 
 
Cancer Prevention and Control 
 
 
 
 
Samuel Oschin Comprehensive Cancer Institute 
 
 
 
 
Cedars-Sinai Medical Center 
 
 
 
 
8700 Beverly Boulevard, SCCT 1S31 
 
 
 
 
Los Angeles, CA 90048 
 
 
 
 
Telephone: (424) 345-4373  
 
 
 
 
Fax: (310) 423-7182 
 
 
 
 
E-mail address: shehnaz.hussain@cshs.org 
  
Sub-Investigator(s) 
Institution 
Walid S. Ayoub, M.D. 
CSMC (Site PI) 
Laura M. Kulik, M.D. 
NWU (Site PI) 
Vatche Agopian, M.D. 
UCLA (Site PI) 
Neil Mehta, M.D 
UCSF (Site PI) 
Joel Wedd, M.D. 
EU (Site PI) 
Marc T. Goodman, Ph.D., M.P.H. 
CSMC  
Mazen Noureddin, M.D., MHSc. 
CSMC 
Vinay Sundaram, M.D. 
CSMC 
Marc L Friedman, M.D. 
CSMC 
H. G. Lipshutz, M.D. 
CSMC 
Jonathan Steinberger, M.D. 
CSMC 
Ju Dong Yang, M.D. 
CSMC 
Saeed Sadeghi, M.D. 
UCLA 
Richard Finn, M.D. 
UCLA  
David Lu, M.D. 
UCLA  
Otoniel Martinez-Maza, Ph.D. 
UCLA 
Marty T. Sellers, M.D., M.P.H. 
EU 
Mehmet Akce, M.D. 
EU 
Bassel El-Rayes, M.D. 
EU 
 
Medical Monitor:  
 
Balaji Tamarappoo, MD  
 
 
 
 
Biostatistician: 
Mourad Tighiouart, Ph.D, Catherine Bresee, M.S. 
 
Funding Source:  
National Institute of Health (NIH) 
 
Version: 
 
 
Protocol Version 5.0 dated 07/12/2019 


 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. Do not disclose or use except as authorized in writing by the study sponsor. 
 
 
 
 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name: _____________________________ 
 
 
 
Signature: _____________________________  Date: ____________________ 
 
 


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TABLE OF CONTENTS  
 
LIST OF ABBREVIATIONS ............................................................................................1 
STUDY SCHEMA..............................................................................................................2 
STUDY SUMMARY ..........................................................................................................3 
1.0 
BACKGROUND AND RATIONALE ...................................................................4 
1.1 
Study Disease .................................................................................................................. 4 
1.2 
Study Agent ..................................................................................................................... 5 
1.3 
Rationale .......................................................................................................................... 6 
2.0 
STUDY OBJECTIVES...........................................................................................6 
2.1 
Primary Objectives ........................................................................................................... 6 
2.2 
Secondary Objectives ...................................................................................................... 6 
2.3 
Endpoints ......................................................................................................................... 7 
3.0 
STUDY DESIGN SUMMARY ...............................................................................8 
3.1 
Study Measurements. ...................................................................................................... 9 
4.0 
ELIGIBILITY CRITERIA .....................................................................................11 
4.1 
Inclusion Criteria ............................................................................................................ 11 
4.2 
Exclusion Criteria ........................................................................................................... 12 
4.3 
Inclusion of Women and Minorities ................................................................................ 13 
4.4 
Source Population ......................................................................................................... 13 
4.5 
Recruitment and Feasibility ........................................................................................... 13 
4.6 
Pre-Screen Medical Chart Review - Initial determination of eligibility and recruitment . 14 
4.7 
Consent and Eligibility ................................................................................................... 14 
5.0 
TREATMENT PLAN ............................................................................................15 
5.1 
Treatment Dosage and Administration .......................................................................... 15 
5.2 
Method of Assigning Subjects to Treatment Groups ..................................................... 15 
5.3 
Blinding/Unblinding ........................................................................................................ 15 
5.4 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 16 
5.5 
Concomitant Medications/Treatments ........................................................................... 17 
5.6 
Adherence/Compliance ................................................................................................. 17 
5.7 
Stopping Rules .............................................................................................................. 18 
5.8 
Duration of Therapy ....................................................................................................... 18 
5.9 
Duration of Follow Up .................................................................................................... 18 
5.10 
Removal of Patients from Protocol ................................................................................ 18 
5.11 
Subject Replacement ..................................................................................................... 18 
6.0 
STUDY PROCEDURES ......................................................................................18 
6.1 
Screening/Baseline Procedures .................................................................................... 18 
6.2 
Procedures During Treatment ....................................................................................... 19 
6.3 
Follow-up telephone contact .......................................................................................... 22 
6.4 
Schedule of Events Table .............................................................................................. 22 
6.5 
Clinical Laboratory Minimum Test Requirements .......................................................... 23 
6.6 
Off Agent Criteria ........................................................................................................... 23 
6.7 
Removal of Subjects from Study ................................................................................... 23 
7.0 
ADVERSE EVENTS ............................................................................................24 
7.1 
Risks of participation ...................................................................................................... 24 
7.2 
Adverse Event Monitoring ............................................................................................. 24 
7.3 
DEFINITIONS ................................................................................................................ 25 
7.4 
Severity of Adverse Events ........................................................................................... 26 
7.5 
Procedures for Recording AEs, SAEs, and Ups ........................................................... 26 
7.6 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 27 
7.7 
Reporting Requirements for Adverse Events ................................................................ 27 
8.0 
SPECIMEN MANAGEMENT .............................................................................28 
9.0 
STATISTICAL CONSIDERATIONS .................................................................28 


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9.1 
Randomization/Stratification .......................................................................................... 28 
9.2 
Sample Size and Randomization .................................................................................. 28 
9.3 
Study Endpoints ............................................................................................................. 29 
10.0 
STUDY MANAGEMENT .................................................................................30 
10.1 
Conflict of Interest .......................................................................................................... 30 
10.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 31 
10.3 
Registration Procedures ................................................................................................ 31 
10.4 
Data Management and Quality Control and Reporting ................................................. 32 
10.5 
Data and Safety Monitoring ........................................................................................... 32 
10.6 
Record Retention ........................................................................................................... 33 
10.7 
Obligations of Investigators ........................................................................................... 35 
11.0 
REFERENCES..................................................................................................37 
12.0 
APPENDIX A ....................................................................................................39 
13.0 
APPENDIX B.....................................................................................................40 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AFP 
α-fetoprotein 
AUC 
Area Under the Curve  
BMI 
Body Mass Index 
CPK 
Creatine Phosphokinase 
CSMC 
Cedars Sinai Medical Center  
CTCAE 
Common Terminology Criteria for Adverse Events  
CTMS 
Clinical Trials Management System  
DSMB 
Data Safety Monitoring Board 
EU 
Emory University 
HCC 
Hepatocellular Carcinoma  
HCV 
Hepatitis C Virus  
HR 
Hazard Ratio  
LI-RADS 
Liver Imaging Reporting and Data System  
LRTs 
Locoregional Therapies  
LT 
Liver Transplantation  
MELD 
Model for End Stage Liver Disease 
MRE 
Magnetic Resonance Elastography  
mRECIST 
Modified Response Evaluation Criteria in Solid Tumors 
MRI 
Magnetic Resonance Imaging  
MRI-PDFF 
Proton Density Fat Fraction 
NASH 
Nonalcoholic Steatohepatitis  
NWU 
Northwestern Memorial Hospital  
ORA 
Office of Regulatory Affairs 
OPTN 
Organ Procurement and Transplantation Network 
OS 
Overall survival 
PT/INR 
Prothrombin Time 
QMC 
Quality management core 
RCT 
Randomized Control Trial  
RFA 
Radiofrequency Ablation  
RFS 
Recurrence-Free Survival  
SAE 
Serious Adverse Event  
sCD163/14 
Soluble Cluster Differentiation 163/14 
SOC 
System Organ Class  
sTNFR I/II 
Soluble Tumor Necrosis Factor Receptor I/II 
TAC 
Treatment Assignment Code   
TACE 
Transarterial Chemoembolization  
TGFβ1 
Transforming Growth Factor-β1 
TTR 
Time to Recurrence  
UCLA 
University of California, Los Angeles 
UCSF 
University of California, San Francisco 
UNOS 
Milan/United Network for Organ Sharing  


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STUDY SCHEMA  
Patients with compensated liver cirrhosis with early stage hepatocellular carcinoma (HCC) 
Tumor burden within Milan Criteria or OPTN tumor downstaging criteria at staging scan (CT or MRI) 
Initial locoregional therapy with verification of adequate response 
▼ 
Pre-Screen Chart Review – Initial determination of eligibility (N=162; 33 at CSMC, 32 at UCLA, 32 at NWU, 32 at 
UCSF, and 32 at EU)  
Medical charts of patients with HCC reviewed for cirrhosis diagnosis, prior or current statin use, prohibited concomitant 
medications, medical contraindications, laboratory results, size and number of tumors from staging scan (confirm meeting 
Milan Criteria or OPTN tumor downstaging criteria), first liver directed therapy followed by an MRI or CT to verify HCC 
response.  A study information packet that includes an introductory letter, leaflet, consent and HIPAA forms will be 
mailed to potentially eligible patients. Study coordinator will call all potentially eligible patients to introduce the study and 
answer questions. 
▼ 
Screening Visit – Consent and Final determination of eligibility (N=144; 29 at CSMC, 28 at UCLA, 28 at NWU, 28 
at UCSF, and 28 at EU) 
Patients who are eligible based on pre-screen chart review will be consented into the trial before any research procedures 
are initiated. Study physician will thoroughly review the patient’s medical history and medications and evaluate all 
inclusion/exclusion criteria. Patients will undergo blood tests to confirm eligibility and safety of statin initiation; urine 
pregnancy test for women able to become pregnant. Patients with a MELD score ≥30 or, AST/ALT >5x ULN; and women 
who are pregnant will be excluded. 
▼ 
Eligible, consented patients with HCC randomized to pravastatin or placebo (N=130; 26 per site) 
Pravastatin 40 mg, daily for 12 months  
(N=65)  
 
Placebo identical in color, consistency, and appearance to 
pravastatin 40 mg, daily for 12 months (N=65) 
 
▼ 
▼ 
Study Visit 1 – Baseline / initiation of intervention (0-30 days following Screening Visit) 
Review medical history, medications, and laboratory test results; symptom assessment; ECOG performance status; blood 
draw; MRE with fat fraction or FibroScan for liver stiffness testing review inclusion/exclusion criteria; interviewer-
administered questionnaire; dispense study drug and diary 
▼ 
Study Visit 2 (30 days ± 5 days after initiation of intervention) 
Review medical history, medications, and laboratory test results; symptom assessment; ECOG performance status; blood 
draw; collect study drug and diary; assess compliance (pill count); review study diary; assess adverse events; review 
inclusion/exclusion criteria; dispense study drug and diary 
▼ 
Study Visit 3 (3 months ± 15 days following initiation of intervention) 
Review medical history, medications, and laboratory test results; symptom assessment; ECOG performance status; blood draw; 
MRI or CT for HCC surveillance; collect study drug and diary; assess compliance (pill count); review study diary; assess adverse 
events; review inclusion/exclusion criteria; dispense study drug and diary 
▼ 
Study Visit 4 & 5 (6 and 9 months ± 15 days following initiation of intervention, respectively) 
Review medical history, medications, and laboratory test results; symptom assessment; ECOG performance status; blood 
draw; MRI or CT for HCC surveillance; collect study drug and diary; assess compliance (pill count); review study diary; 
assess adverse events; review inclusion/exclusion criteria; interviewer-administered questionnaire (Visits 4 and 6 only); 
dispense study drug and diary 
▼ 
Study Visit 6 (12 months ± 15 days following initiation of intervention, N=47 in each group) 
Review medical history, medications, and laboratory test results; symptom assessment; ECOG performance status; blood 
draw; MRI or CT for HCC surveillance; MRE with fat fraction or FibroScan for liver stiffness testing collect study drug 
and diary; assess compliance (pill count); interviewer-administered questionnaire; assess adverse events; review study 
diary 
▼ 
Endpoints – Evaluate the effect of pravastatin versus placebo after 12 months of treatment on: 
1) Time to recurrence 
2) Recurrence-free survival 
3) Overall survival 


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4) Waitlist drop-off  
5) Change in liver stiffness 
6) Change in liver fat fraction 
7) Change in serum biomarkers of monocyte/macrophage and stellate cell activation 
8) Levels of liver tissue markers related to HCC 
*Blue box = standard of care clinical visit 
STUDY SUMMARY 
Title 
Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence 
Protocol Number 
IIT2017-Hussain-StatLv 
Phase 
Phase II 
Methodology 
Randomized, double-blinded, placebo-controlled, Phase II trial of statin 
to increase time to recurrence in patients with liver cirrhosis and initial 
hepatocellular carcinoma 
Study Duration 
5 years 
Study Center(s) 
Cedars-Sinai Medical Center (CSMC), Ronald Reagan UCLA Medical 
Center (UCLA), Northwestern Memorial Hospital (NWU), UCSF Medical 
Center (UCSF), Emory University Woodruff Health Sciences Center (EU) 
Objectives 
Primary Objective: To evaluate the effect of a pravastatin intervention 
versus placebo on the change in time to recurrence (TTR) from baseline 
to 12 months following treatment initiation. 
 
Secondary Objective: To evaluate the effect of a pravastatin intervention 
versus placebo at 12 months from baseline on:  
1) 
Recurrence-free survival 
2) 
Overall survival 
3) 
Waitlist drop-off  
4) 
Change in liver stiffness  
5)        Change in liver fat fraction 
6) 
Change in serum biomarkers of monocyte/macrophage and    
             stellate cell activation 
7) 
Levels of liver tissue markers related to HCC 
Number of Subjects 
130 
Diagnosis and Main 
Inclusion Criteria 
Patients with a confirmed diagnosis of liver cirrhosis (Child-Pugh A or B); 
current Model for End-Stage Liver Disease (MELD) < 30; Minimum 18 
years of age; HCCs must fall within the Milan Criteria or OPTN tumor 
downstaging criteria; receipt of LRT with verification of adequate 
response; and patients whose lab results meet the inclusion criteria after 
the Screening visit blood tests. 
Study Product(s), Dose, 
Route, Regimen 
Pravastatin 40 mg and placebo identical in color, consistency, and 
appearance to pravastatin; oral administration daily (N=65 in each 
group) 
Duration of administration 
12 months 
Statistical Methodology 
Statistical analyses for the primary objective will be conducted on 
participants who complete the 12 month MRI or CT and blood specimen 
collection. The distribution of the clinical and demographical covariates, 
including but not limited to; age, race, smoking status, BMI, and 
comorbid conditions, will be summarized and compared between the 
intervention and control groups to assess the adequacy of the 
randomization. Chance differences between groups will be adjusted for 
using multiple regression modeling. 
 
 


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1.0 
BACKGROUND AND RATIONALE 
1.1 
Study Disease 
Hepatocellular carcinoma (HCC) is a highly lethal cancer with rising incidence and mortality rates. 
Approximately 33,000 HCC diagnoses were expected in 2016, and the incidence is increasing 
among the most rapidly of any cancer, with an age-adjusted annual increase of 3.7% and 2.9% in 
men and women, respectively (1). HCC burden depends heavily on age and ethnicity. Older 
Hispanic men have the highest HCC incidence rate of any major demographic group, and HCC 
risk overall is nearly 3 times higher in Hispanics compared to non-Hispanic whites (2). Tragically, 
HCC has a dismal 5-year survival rate of 18%, second in lethality only to pancreatic cancer (1). 
Thus, in-line with the incidence trends, HCC mortality is also increasing at the most rapid pace of 
any cancer and is highest in older Hispanic men (1, 3). Targeted studies of HCC in populations 
consisting of a high proportion of Hispanics are needed to identify strategies to curtail the rising 
HCC burden.  
 
Between 70-90% of HCCs develop in people with liver cirrhosis, and cirrhosis is considered a 
pre-cancer lesion (4, 5). For a person with cirrhosis, the 5-year risk of developing HCC varies 
according to several influential characteristics including race/ethnicity, liver disease etiology, and 
severity of complications, with a cumulative HCC risk as high as 30% among patients with 
advanced cirrhosis (6-9). Hispanics have a more rapid progression from cirrhosis to HCC 
compared to other major racial/ethnic groups (10). Liver transplantation is the only curative option 
for cirrhosis and can prevent the development of HCC if patients can be transplanted in time. 
Over the last decade, there has been a growing crisis of insufficient donor livers for 
transplantation due to the convergence of increasing need, decreasing donation, and increasing 
discard of sub-optimal livers, leading to a near doubling of the median transplant wait time (11). 
Long wait times increase the chance for HCC development. Although patients who develop HCC 
are given priority on the waitlist and thus “advantaged” in the current system for liver allocation, 
between 10-15% of patients with cirrhosis who develop an HCC prior to receiving a transplant 
have a fatal recurrence of their cancer post-transplant (12). 
 
The rising HCC burden has been attributed to the changing etiological landscape for HCC 
primarily brought on by the rising obesity pandemic. Obesity and diabetes are currently the 
leading risk factors for HCC, followed by alcohol abuse and hepatitis C virus (HCV) (13). Obesity 
(body mass index (BMI) ≥ 30) affects 34.9% of all adults and 42.5% of Hispanic adults; an overall 
increase of 2.8% from a decade ago (14). Nonalcoholic steatohepatitis (NASH), the hepatic 
manifestation of obesity and diabetes, is twice as common in Hispanics compared to non-
Hispanic whites (15). NASH has more than doubled in incidence over the last decade, and it is 
projected that 25 million Americans will develop NASH by 2025, with 20% progressing to cirrhosis 
and/or HCC and may require liver transplantation (16-20). In summary, there is a rising problem 
of HCC which poses a substantial public health problem. 


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1.2 
Study Agent   
 
Pravastatin (see Figure 1) is a lipid-lowering agent pravastatin is a derivative 
of ML236B (compactin), which was identified in a fungus called Penicillium 
citrinum in the 1970s. It is an inhibitor of 3-hydroxy-3-methylglutaryl-
coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion 
of HMG-CoA to mevalonate, an early and rate-limiting step in the 
biosynthesis of cholesterol. The empirical formula of pravastatin is C23H36O7 
and its molecular weight is 424.534 g/mol. Pravastatin sodium tablets, USP 
are available for oral administration as 10 mg, 20 mg, 40 mg, and 80 mg 
tablets. Inactive ingredients include: croscarmellose sodium, lactose 
monohydrate, magnesium oxide, magnesium stearate, microcrystalline 
cellulose and povidone. The 10 mg tablet also contains ferric oxide red, the 
20 mg and 80 mg tablets also contain ferric oxide yellow, and the 40 mg tablet also contains D & 
C yellow No. 10 aluminum lake & FD & C blue No. l aluminum lake. 
 
Pravastatin a commonly prescribed HMG-CoA reductase inhibitor, which has a widely accepted 
tolerability profile with few serious side effects (21-23). Potential, but uncommon side effects 
include muscle, liver, and kidney problems. Elevated levels of creatine kinase and 
rhabdomyolysis occur in <1% of consumers, and myalgia, or muscle ache or weakness, can 
occur in approximately 5% of consumers (21-23). Historically, there has been reluctance to 
prescribe statins to patients with preexisting liver disease due to concerns regarding additional 
liver injury and diabetes (24) . However, in recent years, the benefits of statin use have proven to 
substantially outweigh the minimal potential for adverse events in patients with liver disease: 
statins delay liver disease progression, improve survival, reverse non-alcoholic steatohepatitis, 
and ameliorate metabolic syndrome (25-28). 
 
Despite the overall excellent hepatic safety profile of statins, underlying liver disease is a label-
defined contraindication. The hepatic safety of high dose pravastatin among 326 hyperlipidemic 
adults with well-compensated chronic liver disease was evaluated using a randomized, double-
blind, placebo-controlled, trial (29). Patients were randomized to daily pravastatin (80 mg) or 
placebo for 36 weeks. The primary safety endpoint was doubling of baseline alanine 
aminotransferase (ALT) values during 36 weeks of therapy. Overall, 8% of patients in the 
pravastatin group and 13% of patients in the placebo group experienced doubling of baseline ALT 
values during 36 weeks of therapy (P>0.05). These results have lessened the concern over an 
increased potential for statin-induced hepatotoxicity in patients with chronic liver disease. 
Furthermore, recommendations from National Lipid Association Statin Safety Task Force state 
that chronic disease and compensated cirrhosis are not contraindications for statin therapy (30) . 
 
Also, throughout the protocol, where we mention evaluation of medical contraindications to 
pravastatin we have included a clause “with the exception of active liver disease”.  
 
Lastly, with regards to liver function monitoring, we will test liver function 30 days after the 
initiation of therapy, then again after 60 days, and then once every 3-months for the duration of 
the trial. Based on data from the RCT in patients with compensated cirrhosis who were on high-
dose pravastatin for 36 weeks, the frequency of our monitoring is adequate (29). Therapy will be 
stopped in any patient whose AST or ALT exceeds 5 times the institutional upper limit of normal 
(ULN).   
 
Pravastatin is prescribed for primary and secondary prevention of cardiovascular disease and 
thus is indicated for long-term use. We will administer pravastatin 40 mg daily for 12 months in 
this trial. 
Figure 1. Molecular 
structure of pravastatin 


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1.3 
Rationale 
Cirrhosis affects nearly 633,000 Americans, and HCC is a leading cause of death in non-
symptomatic patients with cirrhosis (5, 31, 32). Less than 5% of patients with cirrhosis and HCC 
are candidates for liver resection due to the high degree of underlying liver dysfunction, which 
makes liver transplantation (LT) the definitive and curative treatment of choice. In 2015, 15,000 
person-years were spent awaiting LT in the U.S, and only 6,600 patients received LT, 
underscoring the major competition among patients with cirrhosis for LT. Although patients with 
HCC receive priority listing for LT if they meet Milan/United Network for Organ Sharing (UNOS) 
T2 criteria, the wait time often exceeds 1 year. Exacerbating the problem for patients with HCC, 
very recent changes to the national liver allocation policy (October, 2015) delay the assignment of 
Model for End Stage Liver Disease (MELD) exception points for 6 months after listing, and reduce 
the maximum value of exception points to 34 for those with HCC. MELD is a clinical score that is 
a validated predictor of survival among patients with advanced liver disease used to prioritize 
patients for LT, and exception points increase a patients MELD score and therefore chances for 
LT. These changes were intended to create a better balance in transplant opportunities between 
those with and without HCC, and allow observation of tumor behavior to avoid transplanting 
aggressive tumors too quickly. However, for patients with HCC, these policy changes translate to 
longer wait times and growing concern that the tumor biology may shift from less to more 
aggressive over time. “Bridging” locoregional therapies (LRTs) are utilized while a patient is on 
the waitlist for LT, however drop-out from the waitlist remains a problem largely due to tumor 
progression or recurrence to beyond accepted radiological criteria. For example, the cumulative 
recurrence rate 2–3 years after radiofrequency ablation (RFA), the most common LRT in patients 
with cirrhosis eligible for transplant, has been reported at 72%–80%. Novel therapeutics offered in 
conjunction with LRT that could achieve lower rates or delay time to recurrence, could maintain 
transplant candidacy for sufficient time to achieve treatment with LT. 
 
 
Hypothesis: 
1.) Participants randomized to pravastatin will experience an increase from baseline to 12 
months in time to recurrence (TTR) compared to placebo group. 
2.) Compared to placebo group, participants randomized to pravastatin will have: 
a. increase in recurrence-free survival  
b. increase in overall survival 
c. decrease in waitlist drop-off 
d. decrease in liver stiffness 
e. decrease in liver fat fraction 
f. 
greater modulation (increase or decrease, depending on the marker) of 
circulating biomarkers  
g. decrease in liver tissue markers related to HCC 
2.0 STUDY OBJECTIVES 
The objective of this randomized double-blinded, placebo-controlled Phase II trial is to examine 
the effects of pravastatin use versus placebo after 12 months of treatment on hepatocellular 
cancer (HCC) recurrence in 130 patients with liver cirrhosis, HCC meeting Milan Criteria or OPTN 
tumor downstaging criteria for tumor burden, and initial locoregional therapy (LRT) with adequate 
response. 
2.1 
Primary Objectives 
To evaluate the effect of a pravastatin intervention versus placebo on the change in time to 
recurrence (TTR) from baseline to 12 months following treatment initiation. 
2.2 
Secondary Objectives  
To evaluate the effect of a pravastatin intervention versus placebo at 12 months from baseline on:  
1) Recurrence-free survival 
2) Overall survival 


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3) Waitlist drop-off  
4) Change in liver stiffness 
5)   Change in liver fat fraction 
6) Change in serum biomarkers of monocyte/macrophage and stellate cell activation 
7) Levels of liver tissue markers related to HCC 
2.3 
Endpoints 
The overall objective of this trial is to examine the effects of pravastatin use versus placebo at 12 
months from baseline (Study Visit 1) on TTR in high-risk patients with liver cirrhosis. Participants 
will be on the study drug from Study Visit 1 until the last study visit (Study Visit 6 at 12 months). 
Primary and secondary endpoints are measured radiographically and in biological samples. 
 
 
• 
Primary Efficacy Endpoint 
Following the American Association for the Study of Liver Diseases-Journal of the 
National Cancer Institute guidelines for trial design in HCC, we have set our 
primary endpoint as TTR, according to the recommendation for Phase II studies 
that assess adjuvant therapies secondary to liver directed therapy (33) . TTR will 
be defined as the time from randomization to the first occurrence of a documented 
HCC recurrence or HCC death, within the 12-month intervention and assessment 
period.  Participants who experience death attributed to their underlying liver 
cirrhosis, or other cause, will be censored at death date. For participants who do 
not recur or die and are lost to follow-up prior to the 12-month study visit, analysis 
of TTR will be censored at their last date of evaluable scan before drop-out. 
 
In this study, we will rely heavily on the mRECIST outcome guidelines and the 
Liver Imaging Reporting and Data System (LI-RADS) diagnostic algorithm for 
defining hepatic recurrence (34, 35), and central expert independent radiographic 
review by MedQIA.  
 
Pathological Definition: Participants who receive a transplant will become 
ineligible at the time of transplantation. Recurrent HCCs may also be identified at 
time of transplantation during the examination of the explant by a pathologist. 
These “incidental” HCCs represent a sizable proportion, amounting to 22% of 
HCCs among those receiving a liver transplant. Thus, if transplantation occurs 
and a pathologically confirmed HCC is detected, we will examine these 
pathologically defined tumors as a secondary definition of recurrence.  
 
• 
Secondary Efficacy Endpoints 
Secondary endpoints include recurrence-free survival (RFS), overall survival (OS), 
waitlist survival, liver stiffness, liver fat fraction, circulating biomarkers, and liver 
tissue biomarkers. Differences in secondary endpoints will be compared in the 
pravastatin and placebo groups. 
 
1) RFS: We will assess the effect of pravastatin on RFS. RFS will be defined as 
the time from randomization to the first occurrence of a documented HCC 
recurrence, within the 12-month intervention and assessment period.  
 
2) OS: We will examine the effect of pravastatin on OS (defined as the time from 
randomization to death from any cause). 
 
3) Waitlist drop-off: We will evaluate the effect of pravastatin on reducing waitlist 
dropout due to any of the following causes: 1) HCC progression outside of 
Milan/T2 criteria, 2) cirrhosis progression (too sick to transplant), or 3) death. 


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Participants who are delisted for other reasons (such as positive alcohol test) will 
be censored at date of delisting.  
 
4) Change in liver stiffness: We will evaluate the effect of pravastatin on within-
person change in liver stiffness, as measured by magnetic resonance 
elastography (MRE) or FibroScan, between Study Visit 1 (0 month) and Visit 6 (12 
month). Within-patient consistency is required between Study Visits 1 and 6 with 
regards to liver stiffness testing modality (MRE or FibroScan).  
 
5) Change in liver fat fraction: We will evaluate the effect of pravastatin on within-
person change in liver fat fraction, as measured by MRI-proton density fat fraction 
(PDFF), between Study Visit 1 (0 month) and Visit 6 (12 month).   
 
6) Change in serum biomarkers of monocyte/macrophage and stellate cell 
activation: We will examine the effect of pravastatin on change in serum 
biomarkers including cytokines, chemokines, soluble receptors, and proteins 
(specifically, IL6, TNFα, sTNFRII, IL18BP, sCD163, IL10, IL17, IL-8, CCL17, 
TGFβ). 
 
 7) Levels of liver tissue markers related to HCC: We will examine the effect of 
pravastatin on levels of liver tissue markers related to HCC including those in the 
Wnt/β-catenin pathway (specifically, β-catenin and glutamine synthetase). 
3.0 STUDY DESIGN SUMMARY 
This is a Phase II randomized, double-blinded, placebo-controlled clinical trial including 130 
patients with cirrhosis diagnosed with HCC recruited from Cedars-Sinai Medical Center (CSMC), 
Ronald Reagan UCLA Medical Center (UCLA), Northwestern Memorial Hospital (NWU), UCSF 
Medical Center (UCSF), or Emory University Woodruff Health Sciences Center (EU). We will 
randomize study participants 1:1 to daily pravastatin 40 mg or placebo, created to be identical in 
color, consistency, and appearance to pravastatin, for an intervention period of 12 months. We 
expect to have a final sample of 47 study participants on pravastatin and 47 on placebo after 
accounting for the competing risk of transplantation or death due to cirrhosis (Figure 3). 
Evaluations will be taken at baseline and at study visits 1-6. Screening data will be reviewed to 
determine subject eligibility. Subjects who meet all inclusion criteria and none of the exclusion 
criteria will be enrolled in the study.  
The following treatment regimens will be used: 
• 
Experimental treatment: 40 mg pravastatin (N=65). 
• 
Placebo: (N=65). 
Total duration of active participation will be 12 months. Total duration of the study is expected to 
be 5 years. 
 
 
Figure 3. Study profile for the primary endpoint of time to HCC recurrence 
 


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3.1 
Study Measurements.  
Following is a brief description of study measurements. 
3.1.1 Non-laboratory Measurements 
 
Imaging review. Review of medical record by research coordinator to identify imaging 
required for eligibility purposes (see section 4.1.3 and 4.1.4) or all imaging studies 
conducted since eligibility or since the last study visit. Images will be sent to MedQIA (see 
3.1.3) for central imaging review.  
 
Medical history. Detailed medical history, including past medical/surgical interventions, 
disease history, and relevant laboratory results, obtained via patient interview and/or 
review of medical records by a study physician or research coordinator. 
 
Concomitant medications review. Review of all current concomitant medications, 
including start and stop dates, dose, frequency, route, and indication (if 
available/applicable), obtained via review of the medical record or by patient self-report 
by a study physician or research coordinator.  
 
Medication compliance review. Participants will be asked if they missed any doses of 
the study medication, and the dates of all missed doses will be recorded. 
 
Physical assessment. Physician-directed physical assessment. Each assessment will 
include an interval symptom history; ECOG performance status assessment; vital signs, 
including blood pressure, heart rate, respiratory rate, and temperature; weight; and 
assessment of liver disease sequelae (varices, ascites and encephalopathy). 
 
Health assessment. RN-directed assessment, consisting of ECOG performance status 
assessment and vital signs (including blood pressure, heart rate, temperature; and 
weight) 
 
Baseline symptom assessment. Assessment of symptoms presenting prior to start of 
study intervention (Study Visit 1), obtained via review of the medical record or by patient 
self-report, by a study physician or research coordinator. NCI Common Terminology 
Criteria for Adverse Events version 5.0 (CTCAE v5.0) term, start and stop dates, grade, 
and treatment will be recorded on the Baseline Symptom Log. Grade should be 
determined by a study physician. Symptom assessment includes:  
o 
Upper respiratory infection 
o 
Headache 
o 
Abdominal pain 
o 
Constipation 
o 
Nausea 
o 
Vomiting 
o 
Mild muscle aches 
o 
Any other symptoms  
 
Symptom/adverse event assessment. Assessment of symptoms presenting after the 
start of study intervention (Study visit 1), obtained via review of the medical record or by 
patient self-report, by a study physician or research coordinator. CTCAE v5.0 term, start 
and stop dates, grade, treatment, attribution, action taken, outcome, and expectedness 
will be recorded on the Adverse Event Log. Grade, attribution, and expectedness should 
be determined by a study physician. Symptom assessment includes:  
o 
Upper respiratory infection 
o 
Headache 
o 
Abdominal pain 


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o 
Constipation 
o 
Nausea 
o 
Vomiting 
o 
Mild muscle aches 
o 
Any other symptoms 
 
Baseline risk factor questionnaire. A structured questionnaire will be administered by 
the research coordinator via patient interview of approximately 45 minutes’ duration. The 
interview will elicit information on detailed race/ethnicity; acculturation, quality of life; 
medical and medications history; alcohol and tobacco use; and anthropometry including 
weight at different decades of life. 
 
Follow-up risk factor questionnaire.  A shorter questionnaire will be administered by 
the research coordinator via patient interview to assess changes in exposures and 
behaviors between visits. The interview will elicit information on quality of life, medical 
and medications history, and alcohol and tobacco use. 
 
3.1.2 Laboratory Measurements 
MELD-Na score. MELD-Na score is calculated using a patient's laboratory values for 
serum bilirubin, serum creatinine, serum sodium, and the international normalized ratio 
for prothrombin time (INR). This version of the MELD calculation (MELD-Na) is the United 
Network for Organ Sharing (UNOS) 2016 modification of the original model to include 
serum sodium as a factor. The score is calculated as: 
MELD-Na = 1.32 x (137 – sodium [mEq/L]) – [0.033 x MELD x (137 – sodium [mEq/L])] 
 
If the patient has undergone dialysis at least twice within the last seven days, then the 
factor used for serum creatinine should be 4.0. Any value less than one is given a value 
of 1 (i.e., if bilirubin is 0.8 a value of 1.0 is used) to prevent the occurrence of scores 
below 0 (because any positive value below 1 the natural logarithm would yield a negative 
result). The upper limit of serum creatinine is capped at 4.0. The lower limit of serum 
sodium (Na) is capped at 125, and the upper limit is capped at 137.  
 
MELD-Na score may be computed using the following online calculator: 
https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/ 
 
Physiological Model for End-Stage Liver Disease (MELD) must be less than 30 at the 
time of screening. After enrollment, if a patient’s MELD increases to 30 or greater, they 
can still be eligible. 
 
Research blood specimen.  A blood specimen of approximately 20 mL will be collected 
from each participant for research purposes for measurement of protocol-specific 
biomarkers and biobanking. See Laboratory Manual for research blood collection and 
processing details.  
 
Eligibility blood specimen. A blood specimen of approximately 15 mL will be collected 
from each participant at the Screening eligibility visit to confirm eligibility, including AFP, a 
blood chemistry and prothrombin time (PT/INR). If a patient’s lab results are current 
(within the past 30 days) in the medical record and within eligibility range, labs will not be 
re-tested at the Screening visit. See section 6.5 for lab details.  
 
Clinical blood specimen. A blood specimen of approximately 10-15 mL will be collected 
from each participant for blood tests to establish baseline levels and monitor for potential 
adverse effects of the intervention. Clinical labs include blood chemistry, lipid panel, 
hemoglobin A1C, creatine phosphokinase (CPK), and prothrombin time. If a patient’s lab 


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results are current (within the past 30 days) in the medical record, labs will not be re-
tested. See section 6.5 for clinical lab details.  
 
Pregnancy test. Women who are able to become pregnant must have a confirmed 
negative pregnancy test result prior to enrollment. Women ≥ 50 years of age who have 
not had a menstrual period in the past year; and women who have had a hysterectomy, 
both ovaries removed, or a tubal ligation, will not be required to have a pregnancy test. 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her study physician immediately. Women who are able to 
become pregnant must agree to use adequate contraception (hormonal or barrier method 
of birth control; abstinence) prior to study entry and for the duration of study participation. 
Should a woman become pregnant or suspect she is pregnant while participating in this 
study, she should inform her study physician immediately. 
 
Liver stiffness.  MRE will be utilized to measure liver stiffness. If the subject has a 
contraindication to MRE, a FibroScan can be used instead. Subject must use the same 
modality of either MRE or FibroScan throughout their participation in the study in order to 
assess intra-individual change using the same procedure.   
 
Liver fat fraction.  MRI-PDFF will be utilized to measure fat fraction.  
 
Transplant tissue specimen.  For all patients who enter the trial and receive a liver 
transplant before the end of this study, we will collect explant tissue (from the native 
liver), that would otherwise be discarded, to examine biomarkers in liver tissue that are 
putatively related to HCC risk, progression, or statin intervention. See Laboratory Manual 
for tissue collection and processing details.  
 
3.1.3 
Central Imaging Review (MedQIA) 
Imaging will be conducted throughout the duration of the study as standard clinical care 
for HCC surveillance (recurrence or metastasis) and will be no cost to the study. All 
standard of care imaging scans (MRIs, CTs, or ultrasounds) will be sent to the central 
imaging core laboratory (MedQIA) and reviewed per the Imaging Charter. Assessment of 
eligibility and HCC recurrence will be made by an independent team of reviewers outside 
of the patient’s care team, coordinated by our imaging core laboratory (MedQIA), per the 
Imaging Charter. Image procedures, acquisition, and transfer guidelines will be 
harmonized across the clinical sites by MedQIA and the study team. MedQIA uses 
proprietary computer-aided technologies for image analysis to maximize accuracy and 
reproducibility and reduce adjudication rates. Tumor measurements will be computed 
from radiologist-approved volumetric contours, providing data on diameter, volume, 
density, and heterogeneity. MedQIA was chosen for this study given their past 
performance, including serving as the imaging core for oncology clinical trial submissions 
to the FDA with imaging as the primary endpoint. 
 
4.0 
ELIGIBILITY CRITERIA 
4.1 
Inclusion Criteria  
4.1.1 Age ≥ 18 years 
4.1.2 Confirmed diagnosis of liver cirrhosis (Child-Pugh A or B) assessed by the             
presence of clinical signs, symptoms, body imaging, or liver biopsy 
4.1.3 Diagnosis of HCC falling within one of the following criteria prior to LRT. 


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a. One lesion ≤ 5 cm or two to three lesions, each ≤ 3 cm.  
b. One lesion > 5 cm and ≤ 8 cm. 
c. Two or three lesions, of which at least one is > 3 cm and all are ≤ 5 cm each. 
The sum of all diameters must be ≤ 8 cm. 
d. Four or five lesions, each < 3 cm. The sum of all diameters must be ≤ 8 cm. 
Criteria fulfillment will be confirmed by the Imaging Charter and MedQIA. 
4.1.4 Initiation of LRT (according to clinical judgement) within 24 months prior to 
Screening Visit, with adequate response as determined by Imaging Charter and 
MedQIA.   
4.1.5 ECOG performance status ≤ 1 (or Karnofsky ≥ 70%; see Appendix A) 
4.1.6 AST (SGOT) & ALT (SGPT) ≤ 5x institutional ULN 
4.1.7 AFP < 400 ng/mL 
4.1.8 Ability to understand and the willingness to sign a written informed consent 
document and medical release 
4.1.9 Agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry and for the duration of study participation; for 
women who are able to become pregnant. 
4.1.10 Willing and able to comply with trial protocol and follow-up 
4.2 
Exclusion Criteria 
4.2.1 Current use of statin medication or statin use within 12 months of Screening visit. 
4.2.2 Current systemic use of medications known to interact with statins and potentially 
increase toxicity, including (e.g., gemfibrozil, cyclosporine, clarithromycin, 
colchicine, niacin and fibrates).  
4.2.3 History of adverse effects, intolerance, or allergic reactions attributed to 
compounds of similar chemical or biologic composition to pravastatin (i.e., other 
statin medications) 
4.2.4 Current use of any other investigational agents 
4.2.5 Women who are pregnant. Women who are able to become pregnant must have a 
confirmed negative pregnancy test prior to enrollment. 
4.2.6 Women who are breastfeeding. It is not known whether pravastatin is excreted 
into human milk; however, a small amount of another drug in this class does pass 
into breast milk. Because there is an unknown but potential risk for adverse 


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events in nursing infants secondary to treatment of the mother with pravastatin, 
breastfeeding should be discontinued if the mother is treated with pravastatin. 
4.2.7 Prior liver transplant 
4.2.8 MELD score ≥ 30.     
4.2.9 History of chronic myopathy 
4.2.10 Active malignancy within the past 5 years (excluding HCC, basal/squamous cell 
skin cancer, or prostate cancer with a Gleason score 6 or less) 
4.2.11 Known HIV infection 
4.2.12 Hemophilia 
4.2.13 Concurrent illness which in the opinion of the investigators would compromise 
either the patient or the integrity of the data 
4.2.14 Concurrent excessive alcohol consumption (average alcohol consumption of more 
than 5 drinks per day) 
4.3 
Inclusion of Women and Minorities  
Both men and women and members of all races and ethnicity groups are eligible for this 
trial.  
4.4 
Source Population  
Participants will be recruited from all eligible patients who have liver cirrhosis and a first 
HCC meeting Milan criteria or OPTN tumor downstaging criteria (described in eligibility). 
We will recruit patients from liver transplant hepatology clinics and will target patients who 
are currently waitlisted, or under evaluation, for a liver transplant. Patients who are inactive 
on the waitlist, or ineligible for a transplant (for reason other than HCC) may still be 
recruited if they meet all eligibility criteria. 
4.5 
Recruitment and Feasibility  
Recruitment will occur over 3 years. We will identify patients via the physician’s upcoming 
appointments and reviewing their medical records for eligibility. The research staff will 
notify the study physician that a patient is potentially eligible for the trial based on the pre-
screen evaluation. The physician will review the eligibility information and notify research 
staff whether the patient may be considered for participation. A study information packet 
may be mailed to potential participants. Clinical research staff will call all potentially 
eligible patients before their scheduled standard of care clinical appointment to introduce 
the study and answer questions. Patients will be encouraged to review the consent 
documents with family, friends, and/or other physicians. The patient will be told that the 
decision to join or not join the study will not affect the medical treatment that s/he 
receives, and that s/he can withdraw from the study at any time. Patients who wish to 
participate will be consented into the trial by a study physician.  
 
For potentially eligible patients who may not be mailed a recruitment packet in advance of 
the regular clinic visit (e.g., new patients who do not already have an established 
relationship with the physician or patients added to the clinical schedule late), a study 
physician will introduce the study to the patient during the standard of care clinic visit. 
The patient will be given a study information packet to take home for review. Clinical 
research staff will be present at the clinic during this visit and will be available to review 
the materials in the information packet with the patient and answer questions about the 


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study. Clinical research staff will follow-up with a phone call to the patient a few days later 
to evaluate interest in study participation and answer additional questions. Interested 
patients will be scheduled to come to the clinic to sign informed consent documents with 
the study physician. Patients who have had all their questions about the study answered 
on the day they first learn about the study, and who wish to participate, may be 
consented the same day they are first informed of the research. Patients who do not 
speak English may be consented according to the policies at their local institutions. In an 
effort to minimize participant burden and increase the likelihood of enrollment and follow-
up, we will coordinate study visits with usual care appointments and tests to the extent 
practical. 
 
There will be six study visits. Study Visit 1 (baseline measurements and initiation of the 
intervention) will occur 0-30 days after the Screening eligibility visit. Follow-up visits will 
be scheduled at 1 month (± 15 days), 3 months (± 15 days), 6 months (± 15 days), 9 
months (± 15 days), and 12 months (± 15 days) after initiation of the intervention to avoid 
protocol deviations. Participants will receive $75 when they complete Study Visits 1, 2, 3, 
and 5 (which do not coincide with usual care visits or require significant time/burden in 
addition to the usual care visit) and $25 when they complete Screening, Study Visits 4 
and 6 for their time, transportation, parking, and other expenses related to the study. 
Participants who complete the entire study will receive $375. 
 
 
         Compensation schedule  
Screening 
Visit 
Study Visit 1 Study Visit 2 Study Visit 3 Study Visit 4 Study Visit 5 Study Visit 6 
       $25 
       $75 
        $75 
        $75 
        $25 
        $75 
        $25 
 
The participant will be contacted prior to the scheduled study visit to confirm or 
reschedule his/her visit, for example a telephone call 5-7 days prior to the scheduled 
study visit. If a study participant misses his/her study visit, s/he will be called promptly to 
reschedule. Study visits will be rescheduled for up to 2 months, at which point the 
participant is considered lost to follow-up.  
4.6 
Pre-Screen Medical Chart Review - Initial determination of eligibility and 
recruitment  
Patients who were identified as a potential participant will be pre-screened for eligibility 
based on the most updated information in their medical charts, prior to their visit. The 
medical records will be reviewed by the clinical research staff to determine initial eligibility 
as specified in the inclusion and exclusion criteria. Medical charts will be reviewed for 
age, cirrhosis diagnosis, HCC diagnosis, HCC treatment history, prior liver transplant, 
prior statin use, prohibited concomitant medications, previous malignancies, medical 
contraindications, laboratory results, and HCC characteristics (size and number of 
tumors).  
4.7 
Consent and Eligibility  
The study physician will review the consent document with the patient and will answer 
any questions regarding the trial. After the patient's questions have been answered, the 
study physician will obtain signatures on the consent documents from patients who wish 
to volunteer for the study. The patient will review and sign the study consent form and 
HIPAA authorization. Copies of each document will be given to patients who agree and 
consent into the study, the original signed consent will be placed in the research binder, 
and copies will be distributed/maintained per local institutional policy. Written consent will 
be obtained before any research related procedures are initiated. After consent has been 
obtained, the screening visit and procedures will be completed. Final determination of 
eligibility will be conducted using an eligibility checklist that requires double signoff (by 


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the study physician and study team member) and also central eligibility verification by the 
Quality management core (QMC) at Cedars-Sinai.  
 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
One hundred and thirty participants with liver cirrhosis and an initial HCC diagnosis will 
be randomized into one of 2 groups: 65 participants will be randomized to receive 40 mg 
pravastatin per day and 65 participants will be randomized to receive a placebo identical 
in color, consistency, and appearance to pravastatin 40 mg. Pravastatin and placebo will 
be provided as over-encapsulated tablets. Dosing will extend for 12 months 
 
• 
Agent(s): Pravastatin and placebo 
• 
Daily dose(s) and regimen(s) for each agent: One capsule per day 
• 
Duration for each agent: Daily treatment for 12 months 
 
The usual recommended dose of pravastatin is 10-40 mg/day, and the toxicity and 
tolerability are comparable for 20 mg and 40 mg (21-23). In a prior published trial of 
patients with chronic hepatitis or cirrhosis and HCC, pravastatin dosing began at 20 mg 
and was titrated up to 40 mg, and no serious side effects or discontinuation of therapy 
were noted (37). Thus, we feel that a 40 mg dose will be well-tolerated by the participants 
in this trial. 
 
Patients will self-administer the 40 mg capsule of pravastatin or placebo daily in the 
evening. Patients will be instructed to take the study agent at bedtime or with an evening 
meal. Each participant will be given one bottle of 120 capsules at Study Visit 1 (90-day 
supply + buffer) and one bottle of 120 capsules (90-day supply + buffer) at Study Visit 3 
(Month 3), Study Visit 4 (Month 6), and Study Visit 5 (Month 9). 
 
5.2 
Method of Assigning Subjects to Treatment Groups  
A designee of the QMC at Cedars-Sinai will conduct a final eligibility check prior to 
registration. Randomization will be carried out by the Research Pharmacy at each site 
among consented subjects who meet all eligibility criteria after the eligibility evaluations.      
5.3 
Blinding/Unblinding   
Due to the objectives of the study, the identity of test and control treatments will not be 
known to investigators, research staff, or subjects. The following study procedures will be 
in place to ensure double-blind administration of study treatments.   
• 
The study biostatisticians will set up randomization blocks.  
• 
After registration, participants will be randomized to treatment with the study 
agent or placebo 
• 
Investigators and participants will be blinded as to the result of randomization. 
The following people will be unblinded: the study biostatisticians at Cedars-Sinai 
and the investigational pharmacists at each participating site. 
• 
The investigational pharmacist will manage the study agent and placebo.  
• 
Unblinding will only occur when it is deemed medically necessary.  
5.3.1 
Emergency Unblinding  
o 
Emergency unblindings are left up to the discretion of the accrual site 
clinical PI.   


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o 
Prior to unblinding, the accrual site should attempt to notify the protocol 
PI that an unblinding will occur, and why.   
o 
The accrual site should work with their pharmacy in the event of an 
emergency that requires an immediate unblinding. 
o 
In case of medical emergency, the participant may discontinue the study 
agent under the advice of a doctor, and if unblinding is deemed medically 
necessary by the accrual site clinical investigator, this can be addressed 
during the next business hours. 
5.3.2 
Non-Emergency Unblinding  
o 
The pharmacy may unblind in a non-emergency only upon approval of 
the protocol PI.   
o 
In the event of a non-emergency unblinding, the pharmacy will receive 
an Unblinding Request Note to File indicating: 
▪ 
The PID(s) to be unblinded 
▪ 
The reason for unblinding 
▪ 
Study staff responsible for unblinding 
▪ 
Signed or emailed approval by the protocol PI 
o 
Upon receipt, the pharmacy will compose a Pharmacy Note to File based 
on their dispensing records, indicating: 
▪ 
The requested PID(s) 
▪ 
The corresponding unblinded treatment assignments 
▪ 
A pharmacist signature 
o 
The Pharmacy Note to File should be sent to the accrual site clinical 
investigator. 
• 
Once a participant is unblinded, they will be taken off treatment but may remain 
on study as long as no off study criteria are met.  
5.4 
Toxicities and Dosing Delays/Dose Modifications  
Toxicities  
All participants will be evaluable for toxicity from the time of their first dose of pravastatin. 
Dosing Delays/Dose Modifications  
No dose modifications are planned. The study agent will be temporarily stopped in the 
event of an AE ≥ grade 3 considered possibly, probably, or definitely related to the study 
agent. The study agent will be restarted after resolution. One of the common side effects 
of statin medication is myalgia (muscle pain with normal Creatine Phosphokinase (CPK) 
level), and rarely this is associated with statin myopathy (muscle weakness or other 
muscle injury with or without elevation in CPK level). In randomized controlled trials of 
standard dose statin therapy, the risk is very low (<1%). We will measure levels of CPK in 
the blood drawn at the first study visit to establish a patient-specific reference for this 
indicator of muscle toxicity. During the trial, if the participant reports unexplained muscle 
pain or weakness, CPK will be tested again to check for elevation. 
 
The study agent will be permanently discontinued in subjects experiencing grade 3 or 
greater myopathy (unexplained muscle symptoms and CPK > 5 times ULN) or 


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hepatotoxicity (ALT or AST > 5 times ULN) that is considered possibly, probably, or 
definitely related to the study agent. 
 
The study agent will be permanently discontinued in subjects experiencing the following 
grade 2 hepatotoxicities considered possibly, probably, or definitely related to the study 
agent: (1) hemorrhage requiring medical attention, and (2) symptomatic fistulas. All other 
grade 2 hepatotoxicities can be restarted after resolution. 
 
Because dose modification could lead to lack of dose homogeneity that may impair the 
research objectives, we will stop the intervention in patients who initiate drugs that 
require dose modifications of pravastatin below 40 mg (e.g. cyclosporine). 
5.5 
Concomitant Medications/Treatments 
All medications (prescription and over-the-counter), vitamin and mineral supplements, 
and/or herbs taken by the participant will be documented on the concomitant medication 
CRF and will include: 1) start and stop date, 2) dose, 3) frequency, 4) route of 
administration, and 5) indication. Medications taken for a procedure (e.g., biopsy) should 
also be included. 
 
Patients are advised not to consume any form of grapefruit (e.g., juice, fruit, grapefruit 
seed extract, dietary supplements containing grapefruit) while on pravastatin as grapefruit 
may increase the blood levels of pravastatin. Participants enrolled in the study will be 
instructed to avoid all forms of grapefruit. 
 
The combined use of pravastatin with systemic formulations of gemfibrozil, cyclosporine, 
clarithromycin, erythromycin, azithromycin, colchicine, fibrates, and niacins 
contraindicated due to an increased risk for myopathy. Additionally, other drug-drug 
interactions exist with pravastatin such as; boceprevir, cimetidine, cholestyramine, 
colestipol, darunavir, digoxin, diltiazem, fluconazole, itraconazole, probucol, ritonavir, 
verapamil, and warfarin. These medications should be avoided if possible or used with 
caution per investigator discretion.  
 
Pravastatin must be administered either 1 hour or more before or at least 4 hours after 
bile acid resins (e.g., cholestyramine, colestipol).  Patients will be screened for 
contraindications to pravastatin prior to enrollment in the study. Patients with known 
active infection with HIV will be excluded from the study. Patients will be advised not to 
use contraindicated medications during the study and will be excluded if systemic use of 
any contraindicated medication is unavoidable. Concomitant medications will be reviewed 
at study visits and during follow-up telephone calls. Participants will be closely monitored 
for symptoms and side effects to the study drug and will be instructed to call the study 
doctor immediately if they have a serious adverse reaction. 
5.6 
Adherence/Compliance 
Compliance will be measured by pill counts and patient diaries. Compliance is defined as 
85% of the total dose of the study agent. A participant diary will be used to monitor daily 
compliance. Participants will be instructed to record the time the study drug was taken 
each day in the diary, as well as any potential side effects. Diaries will be reviewed and 
compliance will be assessed at Study Visits 2-6. Compliance will be reinforced 
throughout the study with regular telephone calls and text/email messages as detailed in 
Section 6.2.1. 
 
Patients will return the unused capsules to the study coordinator at Visits 3 through 6. 
Study agent should be received and accounted for according to local institutional policy. 
See Pharmacy Manual for further details on study agent accountability and compliance. 
 


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All participants that receive a study agent for any period of time will be evaluable for 
toxicity. 
5.7 
Stopping Rules  
Continuous assessment of the 40 mg dose of pravastatin will be ongoing to ensure safety 
and toxicity monitoring at this dose. Accrual will be stopped if 30% or more of study 
participants come off the study agent due to serious adverse events probably or definitely 
related to the agent, after at least 15 patients have been registered. Toxicity will be 
reviewed to determine whether accrual to the study should be permanently stopped.  
5.8 
Duration of Therapy 
 
Participants will be on study agent pravastatin or placebo for a duration of 12 months. 
5.9 
Duration of Follow Up 
Clinical research staff will make follow-up telephone calls to study participants on days 30 
± 7, 60 ± 7, and 90 ± 7 after completion of Study Visit 6 to assess symptoms and adverse 
events. For all patients who enter the trial and receive a liver transplant before the end of 
this 5-year study (within or beyond the 12-month intervention period), we will obtain 
specimens at the time of transplantation. 
5.10 
Removal of Patients from Protocol  
Patients will be removed from the study when any of the criteria listed in Section 6.7 
apply. Notify the Principal Investigator, and document the reason for study removal and 
the date the patient was removed in the Case Report Form. The patient should be 
followed-up per protocol (Section 6.3).  
5.11 
Subject Replacement 
Subjects who withdraw from the study treatment will not be replaced.   
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. If a patient’s lab results in the 
medical record do not meet the eligibility criteria, the patient may still be considered 
potentially eligible because blood tests may be done at the Screening visit. The study 
coordinator will collect a urine sample to test for pregnancy (for women of child bearing 
potential, defined in 3.1.2), and blood tests will be conducted for confirmation of eligibility 
(see section 4.0 for details). MedQIA will review the patient’s scans to confirm eligibility 
per the Imaging Charter (see 4.1.3 and 4.1.4).    
 
All screening procedures must be performed within 60 days prior to registration with the 
exception of imaging. Historical (standard of care) images taken greater than 30 days 
prior to registration will be required to verify eligibility per the Imaging Charter. The 
screening procedures are detailed below. 
6.1.1 Screening Visit- Consent, Final determination of eligibility, registration, and 
randomization  
 
After consent has been obtained, a final assessment of eligibility will be 
conducted. Consented patients will undergo additional screening and testing at 
the clinic to confirm eligibility and safety of study drug initiation. 


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For definition of any procedures, please see section 3.1 Study Measurements. 
The following procedures will be performed during the Screening Visit: 
 
• 
Physical assessment  
• 
Pregnancy test 
• 
Imaging review  
• 
Eligibility blood specimen 
o 
AFP 
o 
Blood chemistry 
o 
PT/INR  
• 
Review Subject Eligibility Criteria 
o 
All inclusion and exclusion criteria will be evaluated for the patient 
• 
Registration and randomization 
o 
Eligible participants will be registered and randomized to 
pravastatin or placebo 
 
6.2 
Procedures During Treatment  
There will be six study visits along with telephone calls during treatment. A packet of 
material, including an appointment letter, a map, and parking instructions will be sent to 
the study participant prior to each scheduled study visit. For definition of any items please 
see section 3.1 Study Measurements.  
 
6.2.1 
Telephone Calls and Email/Text Messages.  
Study participants will be followed during the intervention via telephone calls 
once a month (± 3 days) by the clinical research staff to assess compliance and 
adverse events. In addition, participants will receive a phone call the day before 
each scheduled study visit to remind them to bring any leftover study drugs and 
the study diary with them to the visit.  
 
 
The following information with be collected during the telephone calls: 
• 
Medication compliance review  
• 
Concomitant medications review 
• 
Symptom/adverse event assessment 
 
6.2.2 
Study Visit 1- Baseline Testing and Initiation of the Intervention  
Study Visit 1 (Baseline measurements) will occur 0-30 days after the Screening 
Visit. The following procedures will be performed during this visit: 
• 
Medical history 
• 
Concomitant medication review 
• 
Health assessment 
• 
Clinical blood specimen 
o 
Blood chemistry 
o 
Lipid 
o 
HbA1C 
o 
CPK 
• 
Research blood specimen 
• 
Liver stiffness 
• 
Liver fat fraction 
• 
Baseline risk factor questionnaire 


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• 
Baseline symptom assessment  
• 
Study agent  
o 
Dispense the study agent (one bottle of 120 capsules) and 
review instructions for how to take it 
o 
Dispense and review the study diary 
6.2.3 
Study Visit 2 
 
 
Study Visit 2 will occur 1 month (± 15 days) after initiation of the  
 
 
Intervention. The following procedures will be performed during this visit: 
• 
Symptom/adverse events assessment  
• 
Medical history  
• 
Concomitant medications review  
• 
Health assessment  
• 
Clinical blood specimen 
o 
Blood chemistry 
o 
Lipid 
• 
Imaging review  
• 
Study agent 
o 
Collect study agent and diary 
o 
Assess compliance (pill count) 
o 
Review study diary 
o 
Dispense study agent (same bottle that was brought to the 
visit/collected for pill count)  
6.2.4 
Study Visit 3 
Study Visit 3 will occur 3 months (± 15 days) after initiation of the intervention 
(study drug initiation).  
 
 
The following procedures will be performed during this visit: 
• 
Symptom/adverse events assessment 
• 
Medical history  
• 
Concomitant medications review 
• 
Health assessment  
• 
Imaging review 
• 
Study agent  
o 
Collect study agent and diary 
o 
Assess compliance (pill count) 
o 
Review study diary 
o 
Dispense study agent (one new bottle of 120 capsules) and diary 
 
6.2.5 
Study Visit 4 
Study Visit 4 will occur 6 months (± 15 days) after initiation of the Intervention 
(study drug initiation). The following procedures will be performed during this 
visit: 
• 
Symptom/adverse events assessment 
• 
Medical history  
• 
Concomitant medications review 
• 
Physical assessment 
• 
Clinical blood specimen 
o 
Blood chemistry 
o 
Hba1c 
o 
AFP 
• 
Research blood specimen 
• 
Follow-up risk factor questionnaire 


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• 
Imaging review  
• 
Study agent 
o 
Collect study agent and diary 
o 
Assess compliance (pill count) 
o 
Review study diary 
o 
Dispense study agent (one bottle of 120 capsules) and diary 
 
6.2.6 
Study Visit 5 
Study Visit 5 will occur 9 months (± 15 days) after initiation of the intervention 
(study drug initiation). The following procedures will be performed during this 
visit: 
• 
Symptom/adverse events assessment 
• 
Medical history  
• 
Concomitant medications review  
• 
Health assessment 
• 
Imaging review  
• 
Study Agent  
o 
Collect study agent and diary 
o 
Assess compliance (pill count) 
o 
Review study diary 
o 
Dispense study agent (one new bottle of 120 capsules) and diary 
6.2.7 
Study Visit 6 
Study Visit 6 will occur 12 months (± 15 days) after initiation of the intervention 
(study drug initiation). The following procedures will be performed during this 
visit: 
• 
Symptom/adverse events assessment 
• 
Medical history  
• 
Concomitant medication review 
• 
Physical assessment 
• 
Clinical blood specimen 
o 
Blood Chemistry 
o 
Lipid 
o 
Hba1c 
o 
PT/INR 
o 
AFP 
• 
Research blood specimen 
• 
Imaging review  
• 
Liver stiffness 
• 
Liver fat fraction 
• 
Follow-up risk factor questionnaire 
• 
Study agent 
o 
Collect study agent and diary 
o 
Assess compliance (pill count) 
o 
Review study diary 
 
6.2.8 
Unscheduled Visit (Transplant Specimen Collection). For all patients who 
enter the trial and receive a liver transplant before the end of this study, we will obtain 
specimens at the time of transplantation. The research blood specimen will be collected 
prior to transplant (while the patient is being prepped for surgery).  
• 
Research blood specimen 
• 
Transplant tissue specimen 


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6.3 
Follow-up telephone contact 
 
Clinical research staff will make follow-up telephone calls to study participants on days 30  
± 7, 60 ± 7, and 90 ± 7 after completion of Study Visit 6 (or earlier if study agent 
discontinued prior to completion) to assess symptoms and adverse events. 
 
6.4 
Schedule of Events Table 
 
 
 
Month 0 Month 1 Month 3 Month 6 Month 9 Month 12 30, 60, 90 
days 
Unscheduled 
Study Activity/Measurement Screen 1 
Study 
Visit 1 
Study 
Visit 2 
Study 
Visit 3 
Study 
Visit 4  
Study 
Visit 5  
Study 
Visit 6  
Follow-up 
Calls^ 
Liver 
Transplant% 
Review subject eligibility 
criteria  
X 
 
 
 
 
 
 
 
 
Obtain informed consent and 
HIPPA authorization 
X 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
Imaging review 
X 
 
X 
X 
X 
X 
X 
 
 
Registration/randomization 
X 
 
 
 
 
 
 
 
 
Medical history 
 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medication 
review  
 
X 
X 
X 
X 
X 
X 
 
 
Physical assessment 
X 
 
 
 
X 
 
X 
 
 
Health assessment 
 
X 
X 
X 
 
X 
 
 
 
Baseline symptom assessment 
 
X 
 
 
 
 
 
 
 
Blood chemistry 
X 
X 
X 
 
X 
 
X 
 
 
Prothrombin time  
X 
 
 
 
 
 
X 
 
 
Creatine kinase 
 
X 
 
 
 
 
 
 
 
Hemoglobin A1c (glycated 
hemoglobin) 
 
X 
 
 
X 
 
X 
 
 
Lipid panel 
 
X 
X 
 
 
 
X 
 
 
Serum AFP test 
X 
 
 
 
X 
 
X 
 
 
Liver stiffness 
 
X 
 
 
 
 
X 
 
 
Liver fat fraction 
 
X 
 
 
 
 
X 
 
 
Research blood specimen  
 
X 
 
 
X 
 
X 
 
X 
Baseline risk factor 
questionnaire 
 
X 
 
 
 
 
 
 
 
Follow-up risk factor 
questionnaire 
 
 
 
 
X 
 
X 
 
 
Dispense study drug and diary 
with instructions 
 
X 
X 
X 
X 
X 
 
 
 
Symptom/adverse event 
assessment 
 
 
X 
X 
X 
X 
X 
X 
 
Collection and review agent 
and diary, assess medication 
compliance 
 
 
X 
X 
X 
X 
X 
 
 
Telephone contact# 
X 
Once a Month 
X 
X 
Transplant tissue specimen  
 
 
 
 
 
 
 
 
X 
+ Abdominal imaging results will be reviewed during pre-screen medical chart review to determine initial eligibility. At study visits 3-6, all 
standard of care images occurring since screening or the last study visit will be reviewed.  
 #Telephone contact once a month (± 3 days) during the intervention to assess compliance and adverse events.  
^Follow-up telephone contact on days 30 ± 7, 60 ± 7, and 90 ± 7 after completion of Study Visit 6 to assess adverse events. 
% Unscheduled liver transplant may occur at any time post-intervention depending on the date of the transplant.  


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6.5 
Clinical Laboratory Minimum Test Requirements 
Blood Chemistry 
Lipid Panel 
Other Blood Tests 
Alanine aminotransferase 
(ALT (SGPT)) 
Aspartate aminotransferase 
(AST (SGOT)) 
Alkaline phosphatase (ALP) 
Bilirubin, total 
Creatinine 
Glucose 
Sodium 
Total cholesterol 
High density lipoprotein (HDL) 
cholesterol 
Low density lipoprotein (LDL) 
cholesterol 
Triglycerides 
Hemoglobin A1C (HbA1C) 
Creatine phosphokinase 
(CPK) 
Prothrombin Time (PT/INR) 
Alpha-fetoprotein (AFP) 
 
6.6 
Off Agent Criteria 
Participants may stop taking study agent for the following reasons:  
• 
Completed the protocol-prescribed intervention  
• 
Adverse event or serious adverse event 
• 
Inadequate agent supply 
• 
Noncompliance/refusal due to non-medical reasons 
• 
Concomitant medications 
• 
Medical contraindication 
• 
Receive a liver transplant prior to completion of the intervention  
 
Participants will continue to be followed, if possible, for safety reasons and in order to 
collect endpoint data according to the schedule of events. As described in section 
6.3, clinical research staff will follow participants by telephone on days 30 ± 7, 60 ± 7, 
and 90 ± 7 after the participant discontinues the study agent to assess symptoms and 
adverse events. Standard of care data (medical history, laboratory test results, 
concomitant medications, HCC surveillance data) will continue to be collected via 
review of the participant’s electronic medical record at the time points specified in the 
Schedule of Time and Events.  
 
6.7 
Removal of Subjects from Study 
Patients can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The reason(s) for discontinuation will be 
documented and may include: 
• 
Patient voluntarily withdraws (follow-up permitted);  
• 
Patient withdraws consent (termination of treatment and follow-up); 
• 
Patient is unable to comply with protocol requirements; 
• 
Patient demonstrates recurrence of HCC (unless continued treatment with study 
drug is deemed appropriate at the discretion of the investigator); 
• 
Patient experiences toxicity that makes continuation in the protocol unsafe; 


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• 
Treating physician judges continuation on the study would not be in the patient’s 
best interest; 
• 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
• 
Development of second primary malignancy (basal/squamous cell skin cancer, or 
prostate cancer with a Gleason score 6 or less) that requires treatment, which 
would interfere with this study; 
• 
Lost to follow-up. If a research subject cannot be located to document survival 
after a period of 2 years, the subject may be considered “lost to follow-up.” All 
attempts to contact the subject during the two years must be documented and 
approved by the Data Monitoring Committee. 
7.0 
ADVERSE EVENTS 
7.1 
Risks of participation 
The most common reported adverse events (incidence ≥4.0%) associated with 
pravastatin are upper respiratory infection (stuffy or runny nose, sneezing, sore throat, or 
cough), diarrhea, and musculoskeletal pain (aching or stiffness of the body, twitching 
muscles, etc.). Other adverse events reported in clinical trials (<4%) were angina 
pectoris, rash, nausea, muscle myalgia, pharyngitis, rhinitis, fatigue, headache, 
dyspepsia, flatulence, confusion, abdominal distension, influenza, dizziness, allergic 
reaction, liver failure, and rhabdomyolysis. 
 
Persistent increases in serum transaminases (to more than 3× the ULN) have occurred in 
approximately 1% of patients who received pravastatin in clinical studies. When drug 
treatment was interrupted or discontinued in these patients, the transaminase levels 
usually fell slowly to pretreatment levels. The increases were not associated with 
jaundice or other clinical signs or symptoms. It is recommended that liver function tests 
be performed before the initiation of treatment, and thereafter when clinically indicated. 
 
Pravastatin occasionally causes myopathy manifested as muscle pain, tenderness, or 
weakness with creatine kinase above ten times the ULN. Myopathy sometimes takes the 
form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, 
and rare fatalities have occurred. The risk of myopathy is increased by high levels of 
statin activity in plasma. Predisposing factors for myopathy include advanced age (≥65 
years), female gender, uncontrolled hypothyroidism, and renal impairment. The risk of 
myopathy, including rhabdomyolysis, is dose related. The risk of myopathy and 
rhabdomyolysis is increased by high levels of statin activity in plasma. Pravastatin is 
metabolized by the cytochrome P450 isoform 3A4 (CYP3A4). Certain drugs which inhibit 
this metabolic pathway can raise the plasma levels of pravastatin and may increase the 
risk of myopathy. These include gemfibrozil, cyclosporine, clarithromycin, erythromycin, 
azithromycin, colchicine, fibrates, niacin, or grapefruit-containing products. Combination 
of these drugs with pravastatin is contraindicated. If short-term treatment with strong 
CYP3A4 inhibitors is unavoidable, therapy with pravastatin must be suspended during 
the course of treatment. 
 
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA 
reductase inhibitors, including pravastatin. 
7.2 
Adverse Event Monitoring  
Adverse events will be reported in a routine manner at scheduled times during the trial 
using CTCAE Version 5.0. Certain adverse events must be reported in an expedited 
manner to allow for optimal monitoring of patient safety and care.  


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All patients experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
• 
The adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline 
• 
Any abnormal laboratory values have returned to baseline 
• 
There is a satisfactory explanation other than the study drug for the changes 
observed 
• 
Death 
7.3 
DEFINITIONS 
7.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an experimental intervention, whether or not related to 
the intervention.  
7.3.2 Serious Adverse Events 
A “serious” adverse event is defined in regulatory terminology as any untoward 
medical occurrence that: 
7.3.2.1 
Results in death. 
If death results from (progression of) the disease, the disease should 
be reported as event (SAE) itself. 
7.3.2.2 
Is life-threatening. 
The patient was at risk of death at the time of the event; it does not 
refer to an event that hypothetically might have caused death if it were 
more severe. 
7.3.2.3 
Requires in-patient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours. 
7.3.2.4 
Results in persistent or significant disability or incapacity. 
7.3.2.5 
Is a congenital anomaly/birth defect 
7.3.2.6 
Is an important medical event 
Any event that does not meet the above criteria, but that in the 
judgment of the investigator jeopardizes the patient, may be 
considered for reporting as a serious adverse event. The event may 
require medical or surgical intervention to prevent one of the 
outcomes listed in the definition of “Serious Adverse Event”.  
For example: allergic bronchospasm requiring intensive treatment in 
an emergency room or at home; convulsions that may not result in 
hospitalization; development of drug abuse or drug dependency. 
 
 
 


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7.3.3 Unanticipated Problem (UP) 
Unanticipated problems include any incident, experience, or outcome that meets all of 
the following criteria: 
• 
Unexpected (in terms of nature, severity, frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; 
• 
Related or possibly related to participation in the research (possibly related 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research); and 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was originally 
anticipated. 
7.4 
Severity of Adverse Events 
All non-hematologic adverse events will be graded according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE v5 is 
available at http://ctep.cancer.gov/reporting/ctc.html 
 
 
If no CTCAE grading is available, the severity of an AE is graded as follows:  
•  Mild (grade 1): the event causes discomfort without disruption of normal daily 
activities. 
• 
Moderate (grade 2): the event causes discomfort that affects normal daily 
activities. 
• 
Severe (grade 3): the event makes the patient unable to perform normal daily 
activities or significantly affects his/her clinical status. 
• 
Life-threatening (grade 4): the patient was at risk of death at the time of the 
event. 
• 
Fatal (grade 5): the event caused death. 
7.5 
Procedures for Recording AEs, SAEs, and Ups 
The PI is ultimately responsible for the required reporting of all adverse events. 
All AEs that occur after the informed consent is signed and baseline measurements (Visit 
1) are completed must be recorded on the AE CRF (paper and/or electronic) whether or 
not related to study agent.  
The following data elements are required for AE reporting. 
• 
AE verbatim term 
• 
NCI Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) 
AE term (MedDRA lowest level term) 
• 
CTCAE (MedDRA) System Organ Class (SOC) 
• 
Event onset date and event ended date 
• 
Treatment assignment code (TAC) at time of AE onset 
• 
Severity grade 
• 
Attribution to study agent (relatedness) 
• 
Whether or not the event was reported as a SAE 
• 
Whether or not the participant dropped due to the event 
• 
Outcome of the event 


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7.6 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v5).  
 
Step 2: Grade the adverse event using the NCI CTCAE v5. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely related – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4:  Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
• 
The current known adverse events listed in the Agent Information Section of this 
protocol 
• 
The drug package insert 
• 
The current Investigator’s Brochure 
7.7 
Reporting Requirements for Adverse Events 
7.7.1 Expedited Reporting 
• 
The site PI, CSMC protocol PI (Dr. Shehnaz Hussain, CSMC) and medical 
monitor must be notified by phone within 24 hours of learning of any fatal or 
serious adverse events, regardless of attribution, occurring during the study 
or within 30 days of the last administration of the study drug. Include the 
following information when calling: 
o 
Date and Time of SAE 
o 
Date and time of the SAE report 
o 
Name of reporter 
o 
Call back phone number 
o 
Affiliation/Institution conducting study 
o 
Protocol Number  
o 
Title of Protocol 
o 
Description of the SAE, including attribution 
• 
A Serious Adverse Event deemed to be related to the protocol and on-study 
deaths, including death of a research subject unless the death is expected 
(e.g. due to disease progression), must be reported to the DSMC within 24 
hours for medical monitor ad hoc review between meetings to determine if 
immediate action is required. Reports may be emailed to the DSMC Admin at 
GroupSOCCICCTODSMCAdmin@cshs.org. 
• 
Within 48 hours, research study staff must document the SAE using the NCI 
DCP Serious Adverse Event Form (https://prevention.cancer.gov/clinical-


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trials/clinical-trials-management/protocol-information-office/pio-instructions-
and-tools/2012-consortia) and email the following people: 
o 
Site PI 
o 
Protocol PI 
Shehnaz Hussain, PhD. 
Phone: (310) 423-6401 
Email: Shehnaz.hussain@cshs.org 
o 
Medical Monitor 
BJ Rimel, MD 
Phone: 310-423-1126 
Email: bobbie.rimel@cshs.org 
 
   
An unanticipated problem is considered reportable to the Reviewing (CSMC) 
Institutional Review Board (IRB) and possibly local IRB depending on the 
institutional/local IRB policies. Research study staff must notify the Site PI, 
Protocol PI, and the Medical Monitor within 48 hours of learning of any 
unanticipated problems. Reviewing Institutional Review Board will be notified 
as soon as possible but no later than 10 calendar days after the Protocol PI 
becomes aware of any internal or external reportable event. Prompt follow-up 
reports of the clinical outcome will be sent to the Site PI, Protocol PI, and 
Medical Monitor.   
7.7.2 Routine Reporting 
All other adverse events- such as those that are expected, or are unlikely or 
definitely not related to the study participation are to be reported annually as part 
of regular data submission.  
8.0 SPECIMEN MANAGEMENT  
• 
Clinical lab testing for blood chemistry, prothrombin time, a lipid panel, hemoglobin A1C, 
creatine phosphokinase, and AFP will be conducted or coordinated by the clinical 
laboratories at each institution. 
• 
Research blood specimens and transplant tissue specimens will be collected, processed, 
and tested as described in the Laboratory Manual.   
9.0 STATISTICAL CONSIDERATIONS 
This is a randomized double-blinded, placebo-controlled Phase II trial of statin to evaluate the 
impact of statin treatment on HCC progression in 130 patients. The primary objective of this study 
will be to demonstrate that statins will increase TTR. Secondary outcomes will include RFS, 
overall survival, waitlist drop-off, liver stiffness, liver fat fraction, serum biomarkers, and liver 
tissue biomarkers. 
9.1 
Randomization/Stratification  
Patients will be randomized by the Research Pharmacy at each site. Randomization will 
be carried out among consented patients meeting the Screening Visit eligibility criteria at 
each site with a 1:1 ratio for pravastatin and placebo assignment, by blocks based on 
clinical site and initial HCC treatment type. 
9.2 
Sample Size and Randomization 
Sample size: Intervention = 130 (65 statin: 65 placebo) randomized sample; Analytic 
sample = 94 (47:47) after 28% drop-out. The expected accrual rate is 5 participants per 
month across three sites (1.6 participants per site), and the planned recruitment duration 


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is 3 years. We anticipate that all evaluable participants will have completed all study 
procedures within 4 years. Power and precision arguments are provided below. 
 
9.3 
Study Endpoints 
We have set our primary endpoint as TTR. Secondary endpoints include RFS, OS, 
waitlist survival, liver stiffness, and circulating biomarkers. Differences in secondary 
endpoints from baseline to 12-month follow-up will be compared in the pravastatin and 
placebo groups using a similar approach to the main endpoint. 
9.3.1 
Analysis of Primary Endpoint: TTR  
The log-rank test will be carried out to compare the distributions of TTR between placebo 
and pravastatin groups and the Kaplan-Meier estimators will be presented graphically. 
Cox proportional hazards model will be fitted to the data where the explanatory variable 
of interest is the indicator of treatment allocation adjusting for clinical and demographic 
baseline covariates, including sex. Patients who did not experience HCC recurrence, or 
receive a liver transplant and are still alive at the end of the study will be right censored. 
Patients who are transplanted or die before HCC recurrence will be treated as a 
competing risk. A competing risk model for TTR will be used to estimate the cumulative 
incidence of TTR using time to transplant or death as a competing risk. The proportional 
hazards assumption will be tested graphically and analytically, and model diagnostics 
such as martingale and Schoenfeld residuals will be conducted to assess model 
adequacy. Violation of the proportional hazards assumption will be addressed by use of 
time-dependent covariates or extended Cox models. The possibility of collinearity among 
the explanatory variables will be reduced after careful assessment of the correlation 
matrix and condition index. Automatic variable selection methods in a multivariable Cox 
proportional hazards model such as stepwise, backward, and forward will be used as a 
guideline to identify sets of important predictors and a more rigorous approach based on 
a 4-step procedure outlined in Collett (2003) will be employed (55). Power. Preliminary 
data indicate that the 12-month RFS is between 57% and 78% in patients with: 1) Child 
Pugh A or B cirrhosis, 2) small HCCs (typically meeting Milan criteria) 3) liver directed 
therapy (typically RFA or resection), and 4) no other interventions (27, 56-59). Therefore, 
we will assume that the 12-month RFS in the control group is 65%. Assuming a common 
cumulative incidence of the competing risk events at 12 months of 20% (10% due to liver 
transplant and 10% due to death), a 42-month accrual time and 15-month follow up time, 
and 10% drop out, data from 47 patients per group achieve 80% power to detect a 
hazard ratio of 0.45 using a two-sided log-rank test with a 0.1 level of significance. This is 
equivalent to detecting a decrease in the 12-month cumulative incidence of disease 
recurrence from 35% in the control group to 18% in the treatment group, which is 
clinically meaningful. The choice of a type I error rate of 0.1 is appropriate for a 
randomized phase II trial since this can serve as a randomized screening design for a 
nondefinitive comparison of statin vs placebo (reference: Mandrekar and Sargent (2010)).  
We further assumed that TTR and time to death or transplant are independent and 
exponentially distributed. Statistical power was based on the formulas in Machin et al. 
(2008) and Pintilie (2006) and were carried out using PASS version 13 (60, 61).  
 
Mandrekar SJ, Sargent DJ. Randomized Phase II Trials. Thorac Oncol. 2010 July ; 5(7): 
932–934 
9.3.2 
Analysis of Secondary Endpoints 
RFS and OS 
For the secondary objective, comparison of overall survival and recurrence free survival 
between the pravastatin and placebo groups will be achieved by fitting a Cox proportional 
hazards model as described above for TTR. In this analysis, a competing risk model will 


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be fitted to the data using time to transplant only as a competing risk since overall 
survival includes death from any cause. 
Waitlist drop-off. Fischer’s exact test will be used to compare the proportions of patients 
on the waitlist who drop off between the pravastatin and placebo group. We expect about 
35% of patients in the placebo group to drop off due to various causes such as death and 
HCC progression beyond Milan. Data from 47 patients per group achieve 80% power to 
detect a decrease in drop-off rates from 35% in the control group to 14% in the treatment 
group using a one-sided Fisher’s exact test at the 0.1 level of significance. 
Liver stiffness and Liver fat fraction. The two-sample t-test will be used to compare the 
change in liver stiffness/fat fraction from 3 to 12 months between pravastatin and placebo 
groups. If the distribution of the change in liver stiffness/fat fraction is highly skewed so 
that the sample mean based on 47 measurements is not approximately normally 
distributed, the Mann-Whitney test will be used instead. Measurements of liver stiffness 
vary between 1.5 and 75 kPa. Therefore, we conservatively estimate the standard 
deviation of liver stiffness at 3 months as (75-1.5)/4 = 18.4. If X and Y denote the random 
variables of liver stiffness at 3 and 12 months, respectively, the Var(Y-X) = Var(X)+Var(Y) 
-2ρ Var(X) Var(Y), where ρ is the correlation coefficient between X and Y. Assuming a 
non-negative correlation between the measurements at 3 and 12 months and the same 
variance at 12 months σ2, then a conservative estimate for the standard deviation of the 
change in liver stiffness is 1.4 σ. Therefore, data from 47 patients per group achieve 80% 
power to detect an effect size of 0.5 using a two-sided two-sample t-test with 0.1 level of 
significance. We therefore have enough patients to detect clinically meaningful 
differences in mean liver stiffness. Here, the effect size is the ratio of the difference in the 
mean change between the two groups relative to the baseline standard deviation σ 
assumed to be the same for the treatment and control groups. Linear regression analysis 
will be carried out to estimate the adjusted pravastatin effect if there is evidence of 
imbalance between the two groups with respect to one or more baseline clinical and 
demographic covariates. 
Change in biomarkers. Two-sample t-test will be carried out to compare the change in 
biomarkers from baseline to each of the two follow-up time points, 6 and 12 months, 
between treatment and placebo groups. The Man-Whitney test will be used in the 
presence of highly skewed distributions and Fisher exact test will be used for 
dichotomous stratifications (high versus low). Assuming a common standard deviation of 
the change in biomarker from baseline to each time point between the two groups 
SD(diff), data from 47 patients per group achieve 80% power to detect an effect size of 
0.72 using a two-sided two-sample t-test with a Bonferroni corrected 0.01 level of 
significance since we plan to test 10 biomarkers (0.1 / 10). Here, the effect size is the 
ratio between the difference in change of biomarkers between the two groups over 
SD(diff). Linear or logistic regression analysis will be carried out if there is evidence of 
imbalance between the two groups with respect to one or more baseline clinical and 
demographic covariates at each time point as in Aim 3. 
 
9.3.3 
Interim Analysis 
 
 
There are no planned interim analyses. 
10.0 
STUDY MANAGEMENT 
10.1 
Conflict of Interest 
Any reportable conflict of interest will be disclosed to the local IRB and will be outlined in 
the Informed Consent Form. 


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10.2 
Institutional Review Board (IRB) Approval and Consent  
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB should approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the patient and the investigator is assured that the patient understands the 
implications of participating in the study, the patient will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the patient and by the person who conducted the 
informed consent discussion. 
10.3 Registration Procedures 
All subjects that sign informed consent will be assigned a screening identification number 
by the study coordinator sequentially by their date of consent, please refer to MOP. 
Those subjects that do not pass the screening phase will be listed as screen failures on 
the master list of consented subjects. Eligible subjects, as determined by screening 
procedures and verified by a treating investigator, will be registered on study by the Study 
Coordinator. 
 
Issues that would cause treatment delays after registration should be discussed with the 
site PI and CSMC protocol PI. If a patient does not receive protocol therapy following 
registration, the patient’s registration on the study may be canceled. The Study 
Coordinator should be notified of cancellations as soon as possible. 
 
The study team will track all subjects who sign consent on a subject screening/enrollment 
log using a unique screening ID. Subjects found to be ineligible will be recorded as 
screen failures. Subjects found to be eligible will be registered. 
10.3.1 Eligibility Verification 
 
Prior to registration, all subjects must undergo eligibility verification by the QMC at 
Cedars-Sinai. The following documents will be completed and provided for review: 
 
• 
Registration form (or equivalent) 
• 
Copy of required MedQIA CRF 
• 
Full Eligibility Checklist (signed by a consenting investigator) with source 
• 
Signed patient consent form and Subject’s Bill of Rights 
• 
HIPAA authorization form 
 
 
Please see MOP for Eligibility Verification details.  
10.3.2 Randomization  
 


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After eligibility is verified, study coordinator assigns the participant ID (PID) and 
registration is completed as follows: 
 
• 
The study coordinator at each site will send an email to the research 
pharmacist. 
• 
Site investigational pharmacist enters patient data into RANDI3 software 
(housed on CSMC server) for randomization, and assigns patient to 
pravastatin or placebo, and emails the study coordinator that 
randomization has been completed. 
• 
Study coordinator enters the patient in OnCore to complete registration 
Only the research pharmacists and the study biostatistician are unblinded; all other study 
team members are blinded and should not have access to the subject’s treatment arm. 
See Pharmacy Manual for more details.  
Research pharmacists can only view subjects they have randomized at their site. The 
study biostatistician maintains the master randomization list and is responsible for the 
predetermined randomization scheme prior to the start of study. Of note, the inform and 
participant eligibility form must be completed prior to randomization 
 
Oversight by the site PI and CSMC protocol PI are required throughout the entire 
registration process. 
 
10.3.3 Registration 
OnCore (https://eoncore.csmc.edu) is the clinical research management system that will 
be used for this study. Refer to the OnCore Instructions for Patient Registration for 
detailed instructions.  
 
10.4 Data Management and Quality Control and Reporting 
The data will be entered into a validated database. Data and/or completed case report 
forms must be uploaded to the study database within two weeks following the study visit.   
 
A data system compliant with the Code of Federal Regulations (CFR) Title 21 and the 
Health Insurance Portability and Accountability Act (HIPAA) must be in place prior to 
enrollment of the first patent. The data system must be provided to each participating site 
and managed by the site research coordinator. 
 
The Study Staff will be responsible for data processing, in accordance with procedural 
documentation. Database lock will occur once quality assurance procedures have been 
completed. 
 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
10.5 Data and Safety Monitoring 
 
 
10.5.1 Data Monitoring and Quality Assurance 
 
 
Adherence to the protocol, recruitment and retention, participant accrual, safety of 
subjects, regulatory compliance, data management, Good Clinical Practices (GCP) and 


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institutional policy will be monitored by the Protocol PI and the Site PIs during the course 
of the study through routine study team meetings (Steering Committee or equivalent). In 
addition, the CSMC QMC and the UCLA CTSI Office of Regulatory Affairs (ORA) 
Services will conduct the following:  
• Central Eligibility Pro00048985 Checklist Review and Eligibility Verification, for all 
subjects enrolled as described in the protocol   
• Monitoring, 100 percent of data will be monitored for the first 5 subjects enrolled at 
each site. If there are no data quality issues, the monitoring of subjects will be 
reduced to every 3rd subject. Should the data quality continue to be acceptable after 
20 enrolled subjects, the monitoring frequency will reduce to every 5 subjects.  This 
reduction in monitoring frequency will be implemented on a per site basis. 
• Auditing, is a review of historic performance of the research effort and is performed 
on case report forms, regulatory files and source documents to measure the quality 
of the research effort in a retrospective manner. During the audit, the auditor will 
review specific data related to the protocol and regulatory requirements. Source 
documents are used to independently verify study data. Source documents may 
include, but are not limited to, inpatient and outpatient medical records, study flow 
sheets and other research records that are signed and dated, protocol or study 
road maps, appointment books, enrollment tracking sheets, subject 
diaries/calendars, and Drug Accountability Record Forms (DARFs). 
 
The auditing visit consists of reviewing and evaluating (1) conformance to IRB and 
informed consent requirements, (2) individual patient records and (3) the pharmacy 
and use of DARFs. The first audit will occur within 2-3 months after the first subject 
is enrolled at each site and will include a thorough review of subject charts, subject 
drug accountability, pharmacy records, and regulatory files. Subsequent audits will 
occur annually and will include review of select subject cases (3 subjects or 10% of 
subjects enrolled since last audit), pharmacy records and regulatory documents. 
The Auditor has the authority to request more frequent reviews or closer data 
auditing if it is deemed appropriate for any reason. 
 
10.5.2 Safety Monitoring 
A Data Safety Monitoring Committee (DSMC) will be convened and will meet at least 
once per year to review data relating to safety and efficacy, to conduct and review interim 
analyses, and to ensure the continued scientific validity and merit of the study, according 
to the SOCCI DSMC Charter. There will be interim reviews conducted by the DSMC for 
the purpose of monitoring study conduct and assessing subject safety. The interim 
reviews will include review of all monitoring and audit reports; serious adverse events 
(SAEs) that occur; and protocol deviations and exceptions. The DSMC findings and any 
concerns and recommendations will be reported in writing to the Principal Investigator. A 
summary report will be forwarded by the Principal Investigator or his/her designee to the 
IRB.   
10.6 Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, monitoring/auditing logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent 
forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. Government agency regulations and directives require that the study 
investigator must retain all study documentation pertaining to the conduct of a clinical 
trial. Study documents should be kept on file per institutional guidelines. 


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10.6.1 Adherence to Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study patient requires alternative treatment, or a protocol exception 
request approved by the SOCCI Medical Director and CSMC IRB, the study shall be 
conducted exactly as described in the approved protocol. 
10.6.2 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to eliminate 
an immediate hazard(s) to trial subjects without prior IRB approval. For any such 
emergency modification implemented, the IRB must be notified as soon as possible, but 
no more than 10 days from the investigator’s awareness of the event. 
 
10.6.3 Protocol Exceptions and Eligibility Waivers  
An exception is an anticipated or planned deviation from the IRB-approved research 
protocol, as described in the IRB Policy, Reporting Possible Unanticipated Problems 
Involving Risks to Subject or Others (UPIRSO) Policy: Institutional Review 
Board/Research Compliance and Quality Improvement.  
 
A protocol exception most often involves a single subject and is not a permanent revision 
to the research protocol. Protocol exceptions that extend beyond a single subject should 
result in a protocol amendment to avoid serial violations.  
All exception requests, except logistical protocol deviations as defined below, must be 
reviewed by the SOCCI Medical Director and the Institutional Review Board prior to 
implementation. The PI or her/his designee is responsible for submitting a protocol 
exception and its supporting documents to the SOCCI Medical Director for review. 
Planned exceptions to the protocol that are more than logistical and/or have the potential 
to affect the subject’s safety and/or study integrity may not be implemented without prior 
approval from the SOCCI Medical Director and IRB. 
Study team should refer to the IRB Reporting Possible Unanticipated Problems Involving 
Risks to Subject or Others (UPIRSO) Policy: Institutional Review Board/Research 
Compliance and Quality Improvement guidelines to determine which deviations and 
exception requests require prior approval from the SOCCI CCTO Medical Director. Once 
approved, the deviation or exception request must be submitted to the IRB for review and 
approval prior to implementation. 
 
Special considerations for Eligibility Waivers (EW) 
In general, subjects who do not meet the eligibility requirements should not be enrolled. 
In the rare event that it is appropriate for subject inclusion, the rationale/justification and 
subject case history should be forwarded to the SOCCI CCTO Medical Director for 
assessment prior to submission to the IRB for approval.  
 
The CCTO Medical Director will review the case and contact the investigator if additional 
information is needed or further discussion is warranted. The CCTO Medical Director will 
provide a written assessment/recommended course of action. The CCTO Medical 
Director’s assessment must be uploaded into CS-IRB with the waiver request for IRB 
review and consideration. The CCTO Medical Director may recommend future protocol 
changes.  
 
Eligibility Waiver Submission Process 
The PI and/or treating physician should provide written request for waiver which includes 
case history and justification for prospective deviation from the study design to the 
SOCCI CCTO Medical Director. “IIT Monitoring – Eligibility Waivers and Exception 


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Requests (EW/ER) Form” must be completed, along with any applicable supporting 
documents, must be emailed to QMC (GroupSOCCICROQMC@cshs.org) to request an 
eligibility exception request from the CCTO Medical Director. This is only a requirement 
for studies with DSM classification of moderate or high. An assessment from the CCTO 
Medical Director or designee must be done prior to submission to the IRB for review. 
10.6.4 Other Protocol Deviations/Violations 
Unintentional deviations from the protocol that might affect subject safety or study 
integrity should be reported to the IRB within 10 days from when the investigator 
becomes aware that such a deviation has occurred, as outlined in the SOCCI Clinical 
Research Office’s Working Instruction 11: Deviation and Noncompliance Reporting. In 
this case, a Protocol Deviation report must be submitted to the IRB, per IRB policy, 
Reporting Possible Unanticipated Problems Involving Risks to Subject or Others 
(UPIRSO) Policy: Institutional Review Board/Research Compliance and Quality 
Improvement. All submissions should include a description of the plan to avoid similar 
deviations or exceptions in the future. 
10.6.5 
Amendments to the Protocol  
Should amendments to the protocol be required, the amendments will be originated and 
documented by the CSMC protocol PI. It should also be noted that when an amendment 
to the protocol substantially alters the study design or the potential risk to the patient, a 
revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation. Repeat exceptions or deviations to the protocol 
may suggest a protocol amendment is needed. 
10.7 
Obligations of Investigators 
The Site PIs are responsible for the conduct of the clinical trial at the site in accordance 
with Title 21 of the Code of Federal Regulations and/or the Declaration of Helsinki. The 
site PI is responsible for personally overseeing the treatment of all study patients. The 
site PI must assure that all study site personnel, including sub-investigators and other 
study staff members, adhere to the study protocol and all FDA/GCP/NCI regulations and 
guidelines regarding clinical trials both during and after study completion. 
 
 The site PI will be responsible for assuring that all the required data will be collected and 
entered onto the Case Report Forms and/or into a HIPAA-compliant study database. 
Periodically, monitoring visits will be conducted and the site PI will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the site PI and will require his/her final 
signature to verify the accuracy of the data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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12.0 
APPENDIX A 
PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
 
Grade Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair. 
5 
Dead. 
 
Karnofsky Performance Scale 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance, but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated. Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead. 
 
 


IIT2017-08-Hussain-StatLv 
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Page 40 of 39 
13.0 
APPENDIX B 
Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence  
STUDY DIARY 
Please bring your completed diary and your study drug supply, including empty bottles, to 
every study visit. This will help us keep track of your study drug and how well you are 
tolerating it. 
Protocol Number:                                                      Site:  
Participant Study ID:   
Participant Name:  
 
Date Study Drug Dispensed:  
 Participant Signature:  
 
Instructions 
Complete one line in the table for each day you take the study drug.  
Please contact the clinical research coordinator at <<phone number>> if you have any 
questions. 
• Take your study drug once per day at bedtime or with an evening meal. Take the capsule at the same 
time every day. Please swallow the capsule whole and do not chew, crush, or open it.  
• Record the date and time of day you took the study drug.  
• If you notice any side effects (such as headache, abdominal pain, constipation, nausea or vomiting, 
respiratory infection, mild skin rash) or if you have any other symptoms or comments, please record 
them in the Side Effects/Comments column and tell the study staff when they call you.  
• If you miss a dose of the study drug, take it as soon as you remember. Do not take the drug if it has 
been more than 12 hours since you missed your last dose. Wait and take the next dose at your regular 
time. Do not take two doses of the study drug at the same time. Please write the reason for missing a 
dose in the Side Effects/Comments column.  
Day 
Date 
Time Study Drug Taken 
Side Effects/Comments 
(Please include reason for missed dose) 
1 
 
____:____  
 a.m. / 
 p.m.  
2 
 
____:____  
 a.m. / 
 p.m.  
3 
 
____:____  
 a.m. / 
 p.m.  
4 
 
____:____  
 a.m. / 
 p.m.  
5 
 
____:____  
 a.m. / 
 p.m.  
6 
 
____:____  
 a.m. / 
 p.m.  
7 
 
____:____  
 a.m. / 
 p.m.  
8 
 
____:____  
 a.m. / 
 p.m.  
9 
 
____:____  
 a.m. / 
 p.m.  
10 
 
____:____  
 a.m. / 
 p.m.  
11 
 
____:____  
 a.m. / 
 p.m.  
12 
 
____:____  
 a.m. / 
 p.m.  
13 
 
____:____  
 a.m. / 
 p.m.  
14 
 
____:____  
 a.m. / 
 p.m.  
 

ICF_001.pdf: 
STOP HCC Recurrence Main Consent
Version Date: 07/12/2019
Page 1 of 18
CONSENT FORM FOR RESEARCH
TITLE: Pravastatin Intervention to Delay Hepatocellular Carcinoma Recurrence
SPONSOR: NATIONAL INSTITUTE OF HEALTH (NIH)
PRINCIPAL INVESTIGATOR: Shehnaz K. Hussain, PhD, ScM
STUDY CONTACT PHONE NUMBER:   Shehnaz K. Hussain, PhD, ScM         310-423-6401
AFTER HOURS CONTACT (24 HOURS):  Walid S. Ayoub, MD               310-384-1242
This research study is sponsored by the National Institute of Health (NIH).  NIH only reimburses 
Cedars-Sinai Medical Center (CSMC), Northwestern University (NWU), University of California, Los 
Angeles (UCLA), Universify of California, San Francisco (UCSF), and Emory University (EU) for the 
costs associated with running the study; NIH is not providing additional compensation to these 
institutions or the Investigators for their participation in the study.
1.
WHAT IS THE PURPOSE OF THIS RESEARCH STUDY?
Hepatocellular Carcinoma (HCC) is a major health concern in the United States, particularly among 
people with liver cirrhosis. Out of every 100 patients with liver cancer, only 18 will survive 5 years or 
more. While therapies targeting the liver are used in an effort to combat this disease, there is a high 
chance of HCC occurring again after these therapies.
Statins are widely used drugs that lower cholesterol levels. Some studies have suggested that statins 
lower risk of HCC, but this possibility has not been studied thoroughly in a clinical trial.  
We are doing this study to examine the effects that pravastatin, a type of statin, has on the time it takes 
for HCC to occur again in patients with early stage HCC.  We think that pravastatin in combination 
with therapies targeting the liver may delay or protect against HCC occurring again.  
You are being asked to take part in this research study because you have been diagnosed with an early 
stage HCC and have been treated with therapies targeting the liver. 
This research study is designed to study the investigational use of pravastatin. Pravastatin is approved 
by the U.S. Food and Drug Administration (FDA) to lower cholesterol and reduce the risk for heart 
attack, stroke, and chest pain in patients who have heart disease or at risk for heart disease. However, 
pravastatin is not approved by the FDA to delay or protect against HCC occurring again.
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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The study will enroll up to 130 people in total.  This study will be conducted and enroll patients at five 
different sites: CSMC (lead site and data and specimen coordinating center), NWU, UCLA, UCSF, 
and EU.  
2.
WHAT WILL HAPPEN DURING THE STUDY?
This section provides a general overview of what will happen during your participation in this study.  
Information included below should be considered along with the flowchart of procedures attached as 
Appendix A.  
The flowchart shows a timeline for research-related or standard of care procedures that are involved in 
your participation in this study.  Research-related procedures are those performed solely for the 
research.  They would not be performed if you did not take part in the study. Standard of care 
(routine) procedures would be performed both as part of this study and if you do not participate in this 
study.   
    
A table describing common medical procedures done solely for the purposes of monitoring and 
assessing your condition during this study is attached as Appendix B to the end of this consent form.  
Standard of care procedures that will be repeated or done at greater frequency are listed in the flow 
chart, attached Appendix A. 
Overview of study:
Patients at all three sites will undergo the same research procedures as noted below. 
This is a randomized, double-blind research study. 

“Randomized” means that you will be assigned to a study group by chance, like flipping a 
coin.  You will be randomized into one of 2 study groups, and will have an equal chance of 
being placed in one of the groups described above. 

“Double-blind” means neither you nor the researchers will know what group you are assigned 
to. 
This is a placebo-controlled study.  It will compare the effects (good or bad) of pravastatin against the 
effects of a placebo (an inactive substance, such as, a sugar pill) on the condition being studied in this 
research.  
Research participants in this study will be treated with the study drug, either pravastatin or a placebo.  
You will not get both.  This study has two study groups:

Group 1, the statin group, will receive 40 mg of pravastatin per day in a capsule.

Group 2, the placebo group, will receive a capsule that is identical in color, consistency, and 
appearance to pravastatin but it will not contain any medication. 
A computer will randomly assign you to a study group.  This is done because no one knows if the 
results experienced by the participants in one study group are better, the same, or worse than the 
results experienced by participants in the other.  Once you are put in one group, you cannot switch to 
another group.  Neither you nor your doctor can choose the group in which you will be placed.  
Another way to understand what will happen to you during the study is to read the chart below.  Start 
reading at the left side and read across to the right, following the lines and arrows. 
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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Page 3 of 18
O
Data and specimens collected for this study will be stored at the central data and biospecimen 
repository at CSMC. CSMC will be responsible for storing and maintaining specimens and data from 
CSMC, UCLA, NWU, UCSF, and EU patients.  Specimens collected from patients at UCLA will be 
packaged in batches and transported via courier on dry ice to CSMC. Specimens collected from NWU, 
UCSF, and EU will be packaged in batches and shipped overnight on dry ice to CSMC. Data collected 
from UCLA, NWU, UCSF, and EU will be maintained on a secure CSMC Enterprise Information 
Systems (EIS) server. Appropriate administrative, physical, and technical safeguards are in place to 
ensure the confidentiality, integrity, and security of electronic protected health information (EPHI). 
Security measures for the databases include password management, transmission security, and data 
encryption to guard against unauthorized access to EPHI while it is being transmitted over the 
network.   Specimens and data will be labeled with a unique code, so identifying information will not 
be linked to the specimens or data. Only the PIs and study staff from UCLA, NWU, UCSF, and EU 
will have access to the key code for participants at their institutions. 
Coded specimens will be maintained at the central biospecimen repository at CSMC for use in this 
study. “Coded” means your name and other identifying information will be removed from the 
specimens, and instead a unique study ID will be linked to the specimen. Your unique study ID and 
identifying information will be protected and stored separately, so researchers will not be able to easily 
identify you.  Data provided through the questionnaires and medical record review will be maintained 
in a coded manner on a secured database at CSMC, for the purposes of this research study. Records for 
patients will only be viewable to research staff from same institution, or members of the Central 
Quality Office at CSMC for the purposes of eligibility confirmation and monitoring.
Optional Sub-study
You are also invited to participate in a related biological specimen repository in which your specimens 
and data collected under this study may be used for future research. Details of this repository are 
described in a separate consent form. You are not required to participate in the repository study in 
order to take part in this research study.  
How long will you be in the study
We think you will be actively participating in this study for about 12 months. The total time includes 6 
study visits over 12 months. You will start the study drug (pravastatin or placebo) at the first study 
visit and will be required to take it daily over these 12 months. Study Visits will take between 1-3 
hours to complete. We will make follow-up telephone calls to you 30, 60, and 90 days after 
completion of Study Visit 6 to assess symptoms and adverse events. If you receive a liver transplant 
before the end of this study (within or beyond the 12-month intervention period), we will obtain blood 
You agree to 
take part in the 
study 
and sign this 
consent form 
Your medical 
records will be 
reviewed and 
tests will be 
performed to 
confirm that you 
are eligible for 
the study
Randomization
(The computer 
will randomly 
assign you to a 
study group)
Group 1
Pravastatin
Group 2
Placebo
Both Groups receive 
the study drug for 12 
months and do six 
research study visits. 
Blood and liver 
tissue specimens will 
be collected from 
transplant recipients
OR
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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and liver tissue specimens from the liver that is removed at the time of transplantation. No additional 
visit will be required for these collections. 
Regardless of whether or not you receive a liver transplant, we would like to keep track of your 
medical condition for ten years and review your medical records periodically to see how you are 
doing. Checking on your condition every so often helps us look at long-term effects of the 
intervention.
3.
WHAT ARE THE POSSIBLE RISKS?
Risks of common medical procedures performed solely for research purposes are described in a table 
attached to the end of this consent form as Appendix B.  Side effects and risks of standard of care 
procedures are not described in this consent form. 
This section describes the possible risks and/or discomforts we anticipate you could experience that 
are related to the study procedures. 
The study drug capsules (pravastatin and placebo) contain a small amount of lactose powder that is 
much less than the amount of lactose contained in a glass of milk.  Mild abdominal issues (cramping, 
bloating, flatulence, diarrhea, nausea) are possible, but very rare with this small amount of lactose.
Risks of Pravastatin 
Pravastatin may affect how different parts of your body work, such as your liver and kidneys. You will 
have blood tests before and during the study to monitor your organ function. Your study doctor will let 
you know if changes occur that may affect your health.  Women who are pregnant or may become 
pregnant should not use pravastatin.  When taken during pregnancy, pravastatin may cause harm to a 
developing baby.  If you are able to become pregnant, you will have a pregnancy test before the study 
start.  Let your study doctor know immediately if you believe you might be pregnant.
Other possible side effects of pravastatin are summarized in the table below.  You will be asked to 
keep a diary during the study to record any side effects and symptoms you may be experiencing.
Occasional, 
some may be serious 
(occurs in 4-20% of people)
Possible, 
some may be serious 
(occurs in 1-3% of people)
Rare, 
and serious 
(occurs in less than 1% of people)
Diarrhea
Musculoskeletal pain 
(Symptoms: Aching or 
stiffness of the entire body, 
twitching muscles, 
sensation of “burning” in 
your muscles, localized or 
widespread pain)
Upper Respiratory Infection 
(stuffy or runny nose, 
sneezing, sore throat, or 
cough)
Angina Pectoris 
(uncomfortable pressure, 
fullness, squeezing or pain 
in the center of the chest)
Rash
Nausea/vomiting
Muscle Myalgia (pain)
Pharyngitis (Sore throat)
Rhinitis (Stuffy nose)
Cough
Flatulence (gas)
Fatigue
Confusion, forgetfulness, or 
memory problems 

Dyspepsia/Heartburn 
Abdominal Distension 
(swelling of the abdomen either 
caused by gas or fluid 
collection)
Influenza
Dizziness
Allergic reaction including 
swelling of the face, lips, 
tongue, and/or throat that may 
cause difficulty in breathing or 
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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Page 5 of 18
Headache
swallowing
Liver failure (symptoms: 
weakness, fatigue, weight loss, 
yellowing of the skin or eyes)
Rhabdomyolysis (a breakdown 
of muscle tissue), a rare 
condition that may cause 
kidney damage (symptoms: 
muscle pain, tenderness, or 
weakness; dark colored urine)
Food and Medication Interactions
Grapefruit and grapefruit juice may interact with pravastatin and lead to potentially dangerous effects. 
Do not consume grapefruit products (grapefruit, grapefruit juice, grapefruit seed extract, or dietary 
supplements containing grapefruit) during the intervention portion of this study. 
Pravastatin interacts with many other medications in ways that can increase or decrease the amount of 
medication in your blood. The interactions could result in increased levels that can be dangerous, or 
decreased levels so that drugs don’t work. Please refer to the attached list of drugs (Appendix C) that 
must be avoided while you are participating in this study.
Unknown Risks
There also may be other side effects or risks that we cannot predict.  Many side effects may go away 
shortly after the study medication or procedure is stopped.  However, in some cases they may be 
serious, long-lasting, permanent, and/or fatal.  Tell your study doctor if you notice or feel anything 
different so they can check if you may be having a side effect.
Alcohol consumption
Pravastatin should be used with caution in patients who consume more than 5 drinks per day of 
alcohol as pravastatin may cause liver injury. We will monitor your liver function closely.
Reproductive and Lactation Risks 
Taking part in this research study can affect an unborn baby.  Therefore, you should not become 
pregnant while on this study.  Women who are able to become pregnant will be required to have a 
pregnancy test before the study, and must agree to use adequate birth control (hormonal or barrier 
method of birth control; abstinence) prior to study entry and for the duration of study participation. Let 
your study doctor know immediately if you believe you might be pregnant.
Women should not breastfeed a baby while on this study.  
Unknown Risks to the Developing Embryo or Fetus (an unborn baby)
If you are pregnant, or become pregnant during participation in this research, the study drug might 
involve risks to an embryo or fetus, which are currently unknown.  It is important that you contact the 
researcher immediately if you believe you might be pregnant.
Participation in Double-Blinded Studies 
Participation in a double-blind study means that you may not be able to participate in other, similar 
trials since unblinding would generally only occur for emergent, life-threatening situations. We might 
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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Page 6 of 18
not be able to tell you if you received the study drug or placebo in a situation where you would like to 
qualify for another research study.  Because you may not know the study group to which you were 
assigned, in the future should you wish to participate in a different study that requires knowing what 
drug you received in this study, you may not be eligible to participate in the different study. 
Unblinding will only occur when it is deemed medically necessary, and will only take place after 
consultation with the PI.
Follow-up Visit for Discontinuing Participants
While you are free to discontinue your participation at any time, we encourage you to complete a Final 
Study Visit.  During this visit, we will conduct tests to collect safety data, and discuss any information 
that may be important to share with your treating physician.
Incidental Findings and Duplicate Tests
It is possible that the research procedures could uncover information related to your health that you did 
not know about before and that is unrelated to the Study. Some of these findings may be too 
preliminary to share.  We will carefully consider the research findings and determine if they should be 
shared with you.  Research findings would only be shared with you if such sharing is approved by the 
CSMC IRB and is permitted by applicable law. In some cases, additional clinical testing may be 
required. The cost of any additional testing and any related treatment will be your responsibility.  
4.
ARE THERE BENEFITS IN TAKING PART IN THE STUDY?
If you agree to take part in this research study, there may or may not be direct medical benefit to you.  
If you are randomized to receive pravastatin, the possible benefit of taking part in the research study is 
that the study drug may delay or prevent HCC recurrence. However, no benefit is guaranteed. If you 
are randomized to receive placebo, you should not expect to benefit from taking part in this research 
study. In either case, it’s possible that your condition may remain unchanged or even get worse.
We hope the information learned from this research study will benefit other individuals with HCC and 
cirrhosis in the future by helping us to learn whether pravastatin may delay or prevent HCC 
recurrence.  
5.
WHY WOULD MY PARTICIPATION BE STOPPED?
Your participation in this study may be stopped at any time by the researcher or the sponsor without 
your consent for any reason, including:
•    The study is stopped or suspended;
• 
Funding for the study is reduced, stopped or withdrawn;
•
If treating physician judges that discontinuation in the study is in your best interest;
•
You do not consent to continue in the study after being told of changes in the research that may 
affect you;
•
You do not follow the study procedures;
•
You demonstrate recurrence of HCC (unless continued treatment with study drug is deemed 
appropriate at the discretion of the investigator);
•
You experience toxicity that makes continuation of the drug unsafe;
•
You become pregnant;
•
You develop a second malignancy (except for basal cell carcinoma or squamous cell carcinoma of 
the skin) that requires treatment, which would interfere with this study;
CSMC IRB No: Pro00048985 / MOD00000224
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You may choose (or you may be required) to withdraw from certain parts of the study, but invited to 
continue with other parts.  For example, you might stop taking a study drug, but continue with follow-
up visits or allow us to continue to collect data from your medical records.  Separate written consent 
will be requested if your continued participation will involve procedures not described in this consent 
form. 
6.
ARE THERE ANY OTHER OPTIONS?
Your participation is voluntary so you have the right to decline to participate or to withdraw from this 
research study at any time without any penalty or loss of benefits to which you would be entitled 
outside of the study.  Choosing not to participate will not affect the care you receive. 
If you decide not to take part in this study, you have other choices. For example:
•
you may choose to be treated following the usual clinical approach 
•
you may choose to take part in a different study, if one is available
•
you could decide not to be treated.
The researcher will discuss these options and their risks and benefits with you. 
7.
WILL MY INFORMATION BE KEPT CONFIDENTIAL?
We will do our best to make sure that the personal information collected as part of this study is kept 
private.  However, we cannot guarantee total privacy.  A copy of your research consent and 
authorization forms may be filed in your electronic medical record.  Your personal information may be 
given out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other identifiable personal information will not be used. Organizations that 
may look at and/or copy your medical records for research, quality assurance, and data analysis 
include: accrediting agencies, government and regulatory groups (such as Food and Drug 
Administration (FDA), Office for Human Research Protections (OHRP), etc.), safety monitors, 
companies that sponsor the study, CSMC coordinating center Staff for safety and quality monitoring, 
and authorized representatives of the sponsor. 
UCLA, NWU, UCSF, and EU participant data and specimens will be sent to CSMC in a coded 
manner.  CSMC personnel will not have access to the key code; only the PIs and study staff from 
UCLA, NWU, UCSF, and EU will have access to the key code for participants at their institutions. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law.  This Website will not include information that can identify you.  At most, the Website will 
include a summary of the results.  You can search this Website at any time.
As part of this research, it is necessary to restrict your right to access copies of health information 
created during your participation in your research while the research study is in progress.  This 
restriction is necessary to maintain the blinding, in other words, it is important to the study outcomes 
that you not know into which treatment group you were assigned.  Your right to access this 
information will be restored upon completion of the entire study if requested.
8.
WHAT IF I BECOME ILL OR INJURED BECAUSE OF TAKING PART IN THIS 
STUDY?
CSMC IRB No: Pro00048985 / MOD00000224
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Contact your researcher at once if you feel that you are ill or have been injured because of taking part 
in this study.  If it is a medical emergency, call 911 or go to an emergency room.  Promptly notify your 
researcher of your situation at the phone number listed on page 1 of this consent form.
Who pays for my research related illness or injury?
Cedars-Sinai has no plans to pay for costs associated with the treatment of research-related injury or 
illness.  We will make every effort to seek reimbursement from your health plan.  However, you will 
be responsible for any deductibles and co-payments required under your health plan and for any claims 
ultimately denied by your health plan.  Financial assistance may be available under Cedars-Sinai’s 
Charity Care Policy and Procedure.  If you feel that you have had a research-related injury and need 
financial assistance, please contact the IRB Office at 310-423-3783.
9.
FINANCIAL CONSIDERATIONS
Costs of Participation
Please review the attached Appendix A flowchart for a listing of items, drugs and services that will be 
billed to you and/or your insurance and those that will be covered by the study sponsor.
Only items, drugs and services that are reasonable and necessary for your medical care throughout the 
study will be billed to your insurance.  You remain responsible for all deductibles, co-pays, and 
balances under your health benefit plan. If your insurance company does not pay, you will be billed for 
those charges.  You should check with your health benefit plan if you have questions or concerns 
about your insurance coverage.
Compensation for Participating
You will be paid for each study visit. Visits 1, 2, 3 and 5 will have a $75 compensation each. 
Screening, Visits 4 and 6 will have a $25 compensation. The total amount you will receive if you 
complete the whole study is $375. Payment will be issued after each visit date. If you do not complete 
the entire research study, you will only be paid for those visits and procedures you do complete. You 
may be required to complete a W-9 Form in order to receive payment. Although any amount of 
payment may be reportable (check with a tax professional if you have questions about your 
obligations), if total payment is $600 or more in a calendar year, a 1099 Form will be filed with the 
IRS in accordance with federal tax law.
If you are a Cedars-Sinai employee, you should provide your employee identification number to the 
research team so that your payment can be appropriately processed through Payroll.  For your own 
protection and to comply with tax laws, your payment for participation will be reported to the IRS 
together with other compensation you receive from Cedars-Sinai.
Compensation will be managed by a private company contracted to issue a specially designed debit 
card onto which your compensation for research participation will be loaded. When a visit is 
completed, funds will be approved and loaded onto your card. The funds will generally be available 
within 5 business days, however, should you identify any concerns with an expected deposit, please 
contact the study team. You will be issued one card for the duration of your participation. If your card 
is lost or stolen, you will need to request a replacement. 
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To be able to issue you a debit card, we will need to share your name, address, social security number, 
and date of birth with the private company contracted to issue and manage the debit card.   All 
information is stored in a secure fashion and is deleted from the debit card system once the study has 
been completed and the funds on the card have been exhausted.  The private company will not share 
your information with any other third parties.
For patients who complete the Screening visit but are found to be ineligible for the study, the $25 
compensation may be in the form of a check or other form of payment issued by Cedars-Sinai.
Financial Interest in the Research
The Principal Investigator and institution have no potential financial conflict of interest with respect to 
this study.
10.
WHAT IF I HAVE QUESTIONS OR PROBLEMS?
Please contact one of the investigators listed on the first page of this form for questions or concerns 
about the research.  
If you have questions, problems, or concerns that you want to discuss with someone who is not 
associated with this study, or want to offer suggestions or feedback, please contact:
Cedars-Sinai Human Research Protection Program (HRPP) Phone: (310) 423-3783
Email: ResearchConcerns@cshs.org
The Cedars-Sinai HRPP has been established to protect the rights and welfare of research participants.  
You may also contact the Cedars-Sinai HRPP if you want to offer input or obtain information 
regarding the study.
11.
CONSENT PROVISIONS 
If you sign this form below, it means that:  
(1) You have taken the time to carefully read and understand the information presented in this 
informed consent form; you should discuss it with others, and if appropriate seek a second opinion to 
make an informed decision;
(2) The information concerning the research study and its involved procedures has been fully 
explained to you and your questions have been answered to your satisfaction; 
(3) You have received and understand all of the information you desire regarding your participation 
in the research study; 
(4) You have considered the potential risks, any anticipated benefits and alternatives (and their 
relative risks and benefits) of participation;
(5) You are voluntarily agreeing to participate in this research study;
(6) You understand that by consenting to participate in the research, you are not giving up any of your 
legal rights (other than the postponement of your access to certain health information as described in 
this informed consent form); 
(7) You understand that you have the right to be informed of significant new findings related to this 
research study which may affect your willingness to continue participating in this study; and
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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(8) You have been provided with a copy of the “Experimental Subject’s Bill of Rights”, if applicable 
to this research study, and have been provided with an opportunity to ask questions regarding the Bill 
of Rights.
We will give you a copy of this signed and dated consent form and a signed copy of the Experimental 
Subject’s Bill of Rights.
SIGNATURE BY THE PARTICIPANT:
Name of Participant (Print)
Signature of Participant
Date of Signature
SIGNATURE BY THE INVESTIGATOR:
I have personally explained the research to the participant in non-technical terms, answered all 
questions, and attest that he/she freely consents to participate. The participant has been provided with 
the Experimental Subject’s Bill of Rights.
Signature of the Investigator Who Obtained Consent
Date of Signature
SIGNATURE BY THE INTERPRETER/WITNESS
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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(Signature of an interpreter is only required when a non-English speaking subject is consented with 
the assistance of an interpreter and an IRB-approved ‘short form.’  The witness may be any person 
who is conversant in both English and the language of the Non-English speaking subject, such as the 
interpreter (the certified hospital interpreter), study staff, a family member, or other person.  The 
witness signs the consent forms to confirm that the oral interpretation occurred.)
Signature of Interpreter/Witness
Date of Signature
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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EXPERIMENTAL SUBJECT’S BILL OF RIGHTS
In accordance with California Health and Safety Code 24172, any person who is required to consent to 
participate as a subject in a research study involving a medical experiment or who is requested to 
consent on behalf of another has the right to:
1.
Be informed of the nature and purpose of the experiment.
2.
Be given an explanation of the procedures to be followed in the medical experiment, and any 
drug or device to be utilized.
3.
Be given a description of any attendant discomforts and risks to the subject reasonably to be 
expected from the experiment.
4.
Be given an explanation of any benefits to the subject reasonably to be expected from the 
experiment, if applicable.
5.
Be given a disclosure of any appropriate alternative procedures, drugs or devices that might be 
advantageous to the subject, and their relative risks and benefits.
6.
Be informed of the avenues of medical treatment, if any, available to the subject after the 
experiment if complications should arise.
7.
Be given an opportunity to ask any questions concerning the experiment or the procedure 
involved.
8.
Be instructed that consent to participate in the medical experiment may be withdrawn at any 
time and the subject may discontinue participation in the medical experiment without 
prejudice.
9.
Be given a copy of any signed and dated written consent form used in relation to the 
experiment.
10.
Be given the opportunity to decide to consent or not to consent to a medical experiment 
without the intervention of any element of force, fraud, deceit, duress, coercion, or undue 
influence on the subject’s decision.
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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Distribution instruction for researchers:
The signed (i) Consent form, (ii) Authorization for Use and Disclosure of Identifiable Health 
Information and (iii) "Experimental Subject’s Bill of Rights" (the latter required if the research study 
involves medical interventions)* should be distributed to:
1) Medical Chart
2) Research Participant
3) Pharmacy (if a drug study)
4) Principal Investigator’s research records (original).
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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APPENDIX A:   FLOWCHART OF PROCEDURES – Medicare Coverage Analysis (MCA) Review
FLOWCHART OF PROCEDURES – Medicare Coverage Analysis (MCA) Review
Procedures
Screen
ing 
Visit 
Study 
Visit 1
(0-30 days 
from 
screening) 
Study 
Visit 2
(1 
month 
after 
starting 
study 
drug)
Study 
Visit 3
(3 
months 
after 
starting 
study 
drug)
Study 
Visit 4
(6 
months 
after 
starting 
study 
drug)
Study 
Visit 5
(9 
months 
after 
starting 
study 
drug)
Study 
Visit 6
(12 
months 
after 
starting 
study 
drug)
Follow-Up
(Day 30, 60, 
and 90 
following 
study 
completion)
Standard of Care Procedures: Items and services that are part of regular care and would be done even if you did not take part in 
this research study.  These will be billed to you and/or your insurance company.
Physical Assessment (Including vital 
sings, height, and weight)
X
X
X
Review medical history & 
medications
X
X
X
X
Blood chemistry1 
X
X
X
Serum: α-fetoprotein (AFP)
X
X
X
Imaging for HCC surveillance 
(Magnetic resonance imaging [MRI] 
with contrast, computed tomography 
[CT] scan, or ultrasound)
X
X
X
X
X
Research Related Procedures: Items and services done for research purposes only. These will NOT be billed to your insurance 
company.
Review eligibility criteria 
X
Review medical history & 
medications
X
X
Obtain informed consent
X
Imaging review (any SOC imaging)
X
X
X
X
X
X
Registration & randomization to 
pravastatin or placebo
X
Health assessment (Vital signs, 
weight, and ECOG)
X
X
X
X
Blood chemistry 
X
X
Laboratory Blood Test: Lipid Panel 
X
X
X


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Laboratory Blood Test: Hemoglobin 
A1c (glycated hemoglobin)
X
X
X
Laboratory Blood Test: Prothrombin 
Time
X
X
Laboratory Blood Test: Creatine 
Kinase2
X
Urine Pregnancy Test for women able 
to become pregnant
X
Liver stiffness (Magnetic resonance 
elastography or FibroScan) 
X
X
Liver fat fraction (Magnetic resonance 
elastography or Fibroscan)
X
X
Conduct interviewer-administered 
questionnaire
X
X
X
Dispense study drug and diary with 
instructions
X
X
X
X
X
Research blood specimen 
X
X
X
Collect and complete compliance 
assessment of study drug diary and 
medication 
X
X
X
X
X
Assess Baseline symptoms 
X
Assess symptoms and adverse events
X
X
X
X
X
X
Telephone contact
X
Once a Month  
X 
If patient undergoes liver transplant 
before the end of this study end, liver 
tissue specimen and research blood 
will be collected at time of transplant. 
When it becomes available  

1 Any SOC labs that need to be repeated for research purposes will be billed to research.
2 If the participant reports unexplained muscle pain or weakness, CPK will be tested again to check for elevation and will be billed to research.


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APPENDIX B:  Detailed Description of Common Medical Procedures Performed for Research Purposes 
and Associated Risks
The procedures listed below are often performed as part of routine care for a person with your condition.  
They are being repeated, or performed more frequently as part of this research.  However, the risks 
associated with each procedure should be comparable to what you would experience even if you were 
undergoing the procedure outside this research study.
Study Procedure
Related Risks
Blood draw: A needle is placed in the vein in 
your arm to draw blood
Blood drawing may cause some pain and has a small 
risk of bleeding, bruising, or infection at the 
puncture site.  There is also a small risk of fainting.
Abdominal magnetic resonance 
elastography (MRE): An MRE is a test that 
uses low-frequency vibrations that pass 
through your liver to make pictures of organs 
and structures inside the body. The MRE is 
incorporated into your MRI scan which you 
will be having as standard of care. At the end 
of the MRI session a small pad is placed on the 
surface of your body. The procedure is 
painless. You will hear a knocking sound as 
images are being taken and feel vibration 
around the liver area only during elastography 
series, the MRI technologist will notify you 
when the MRE series will begin.  You will be 
able to communicate with the MRI 
technologist all the time and you will have a 
panic button to use if you want to stop the 
procedure at any time. The MRE will last 
about 5 minutes.
You may feel slightly anxious inside the scanner due 
to a fear of small enclosed spaces (claustrophobia).  
Also, at times, you may hear a knocking sound as 
images are being taken during the MRE session.  
You may be given headphones and may request ear 
plugs if you feel the noise is too loud.  At any time, 
you may ask the technician to stop the exam if you 
are unable to complete the exam.
Liver elastography (FibroScan): A 
FibroScan is a test that uses mechanical pulse 
at the surface of the skin used as a non-
invasive measurement of the liver. You will be 
asked to lie on your back with your right arm 
raised behind your head.  The probe will be 
placed over a small amount of water based gel 
with slight pressure over your rib area. The 
Fibroscan takes about 10 minutes. 
You may feel slight pressure of the probe that might 
make you uncomfortable. 
Tissue Specimen Collection: A specimen 
collection is the removal of a sample of body 
tissue for examination under a microscope, by 
the doctor or scientist, to determine the state of 
health or disease in the tissue.  
There are no risks associated with these procedures. 
The specimen collection will be from the native liver 
after it has been removed during the transplantation 
procedure (prior to discarding it). 
Physical Exam: Includes height, weight, vital 
signs (heart rate and blood pressure)
There are no physical risks associated with these 
procedures.
Concomitant Medications: You will be asked 
about your previous and current medications 
There are no physical risks associated with these 
procedures.
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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that you take. 
Medical History Review: You will be asked 
about your medical and surgical history with 
attention to your cirrhosis, HCC and your 
physical activity.
There are no physical risks associated with this 
procedure.
Pregnancy Test: If you are a woman who is 
able to become pregnant, urine samples will 
also be used to do a pregnancy test
If your test is positive, you will be told and at that 
point you should discuss options available with your 
primary physician.  
Questionnaires: You will be asked to 
complete a questionnaire.  We will ask you 
questions to evaluate things such as 
acculturation, quality of life; medical and 
medications history; alcohol and tobacco 
smoking. We think it should take about 45 
minutes to complete the questionnaire.  
Questionnaires will ask you to respond to 
questions about your current alcohol 
consumption, eating habits, and birth and early 
life.  
If you feel uncomfortable or embarrassed answering 
any question, you may skip it. The questionnaire will 
be labeled with a unique study number that will link 
your identity so that only the research team can 
recognize you.
Demographic Information: You will be 
asked about your age, gender, race, ethnicity
There are no physical risks associated with these 
procedures.
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019


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APPENDIX C: 
Food and Medications to Avoid During Your Participation in the Study
Do not consume grapefruit products (grapefruit, grapefruit juice, grapefruit seed extract, or dietary 
supplements containing grapefruit) while you are participating in the study. Medications including, but 
not limited to, the following medications listed may interact with your study medication.  Please do 
not use any of the following medications while you are participating in the study. Tell your study 
doctor immediately if you use any of these medications, or if any of these medications or any new 
medications, herbal medications, or supplements are prescribed for you during the study.
Generic name
Brand name(s)
azithromyocin 
Zithromax, Zmax, 
clarithromycin 
Biaxin, Prevpac
colchicine
Colcrys
cyclosporine
Gengraf, Neoral, Sandimmune
erythromycin
EES, Erythrocin, Ery-Tab, E-Mycin
fibrates
Lipofen, Lopid, TriCor, Lofibra, Trilipix, 
Fenoglide, Antara, Fibricor, Triglide, 
gemfibrozil
Lopid
niacin 
Advicor, Niaspan, Niacor, Simcor, Slo-Niacin
CSMC IRB No: Pro00048985 / MOD00000224
CSMC Date Effective: 7/22/2019