Statin Therapy to Reduce Disease Progression From Liver Cirrhosis to Cancer
Phase: PHASE2
Conditions: Cirrhosis, Hepatocellular Carcinoma
Sponsor: National Cancer Institute (NCI)

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COVER PAGE 
 
 
 
 
 
DCP Protocol #: 
NWU2015-06-03  
 
Local Protocol #: NCI 2015-06-03  
 
Statin Therapy to Reduce Disease Progression from Liver Cirrhosis to Cancer 
 
Consortium Name: 
Northwestern Cancer Prevention Consortium 
Name of Consortium Principal 
Seema A. Khan, M.D. 
Investigator: 
Bluhm Family Professor of Cancer Research 
Professor of Surgery 
Feinberg School of Medicine 
303 E. Superior, Suite 4-111 
Chicago, IL 60611 
Telephone: (312) 503-4236 
Fax: (312) 503-2555 
E-mail address: skhan@nm.org  
 
Organization Name: 
University of California, Davis  
Protocol Co-PI: 
Shehnaz K. Hussain, Ph.D., Sc.M. 
Professor 
Department of Public Health Sciences 
School of Medicine 
University of California, Davis 
4610 X Street 
Sacramento, CA 95817 
Telephone: (310) 429-9859  
E-mail address: skhussain@ucdavis.edu  
 
 
Organization Name: 
Cedars-Sinai Medical Center  
Protocol Principal Investigator: 
Marc T. Goodman, Ph.D., M.P.H. 
Director, Cancer Prevention and Control 
Samuel Oschin Comprehensive Cancer Institute 
Director, Community and Population Health Research Institute 
Department of Biomedical Sciences 
Professor of Medicine 
Cedars-Sinai Medical Center 
8700 Beverly Boulevard, SCCT 1S37 
Los Angeles, CA 90048 
Telephone: (310) 423-6188 
Fax: (310) 423-7182 
E-mail address: marc.goodman@cshs.org  

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Organization Name:  
Cedars-Sinai Medical Center  
Clinical Co-PI: 
Walid S. Ayoub, M.D. 
Assistant Medical Director, Liver Transplantation 
Department of Digestive Diseases 
Liver Disease and Transplant Center 
Cedars-Sinai Medical Center 
8900 Beverly Boulevard, Suite 215 
Los Angeles, CA 90048 
Telephone: (310) 423-1971 
Fax: (310) 423-2356 
E-mail address: Walid.Ayoub@cshs.org  
 
 Organization Name: 
Northwestern University 
Investigator: 
Laura M. Kulik, M.D. 
Associate Professor of Medicine  
Division of Gastroenterology and Hepatology 
Department of Surgery, Division of Organ Transplantation 
Department of Radiology  
Feinberg School of Medicine 
Northwestern Memorial Hospital /Arkes Family Pavilion 
676 N. Saint Clair Street, Suite 1900 
Chicago IL 60611 
Telephone: (312) 695-6110  
Fax: (312) 695-5998 
E-mail address: Laura.Kulik@nm.org 
 
Organization Name: 
Northwestern University 
Investigator: 
Daniel R. Ganger, M.D. 
Associate Professor of Medicine  
Department of Medicine 
Division of Gastroenterology and Hepatology 
Department of Surgery, Division of Organ Transplantation 
Feinberg School of Medicine 
Northwestern Memorial Hospital /Arkes Family Pavilion 
676 N. Saint Clair Street, Suite 19-042 
Chicago IL 60611 
Telephone: (312) 695-4496  
Fax: (312) 695-0042 
E-mail address: dganger@nm.org 
 
Organization Name:   
 
MedStar Health Transplant Institute 
Investigator:  
 
 
Coleman Smith, M.D. 
The Transplant Institute 
MedStar Georgetown University Hospital 
3800 Reservoir Road, NW 
Washington DC, 20007 
Telephone: 202-444-1085  
Fax: 202-444-9429 
E-mail address: Coleman.I.Smith@gunet.georgetown.edu  
 
Organization Name: 
 
 
Georgetown University 

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Investigator:   
 
 
Aiwu Ruth He, M.D., Ph.D. 
 
 
 
 
 
Oncology 
Lombardi Comprehensive Cancer Center 
Georgetown University 
3800 Reservoir Road, NW 
Washington DC, 20007 
Telephone: 202-444-8642 
Fax: 202-444-9429 
E-mail address: arh29@georgetown.edu 
 
Organization Name:   
 
University of Puerto Rico Comprehensive Cancer Center 
Investigator: 
Division of Cancer Biology 
 
Marcia R. Cruz-Correa, M.D., Ph.D., AGAF, FASGE 
 
PO BOX 365067 
 
San Juan, PR 00936 
Telephone: 787-772-8300 
Fax: 787-758-2557 
marcia.cruz1@upr.edu 
 
Organization Name:   
 
University of Puerto Rico Comprehensive Cancer Center 
Investigator: 
Department of Medicine 
 
Victor Carlo, M.D. 
PO BOX 365067 
San Juan, PR 00936 
Telephone: 787-317-3387 
Fax: 787-522-3282 
 
 
 
 
 
victor.carlo2@upr.edu 
 
Organization Name: 
Northwestern University 
Statistician: 
Masha Kocherginsky, Ph.D. 
680 North Lake Shore Drive, Suite 1400 
Chicago, IL 60611 
Telephone: (312) 503-4224 
Fax: (312) 908-9588 
E-mail address: mkocherg@northwestern.edu  
 
IND Sponsor: 
NCI/Division of Cancer Prevention 
IND# 
 (Exempt) 
Agent(s)/Supplier: 
Simvastatin / NCI, DCP 
NCI Contract # 
HHSN261201200035I 
Protocol Version Date: 
February 7, 2023 
Protocol Revision or   
Amendment # 
Version 2.11 
 
Contacting the NCI CIRB. Be sure to specify that you are part of the NCI DCP Consortia. 
For CPC CIRB review and trial-wide questions, send an e-mail to CPCCIRB@emmes.com.  
For other questions, including Local Context Reviews, contact the CIRB Helpdesk. 
E-mail address: ncicirbcontact@emmes.com  
Toll-free telephone: (888) 657-3711 
CIRB website: https://ncicirb.org 
 

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TABLE OF CONTENTS 
 
COVER PAGE.............................................................................................................................................. 1 
SCHEMA ...................................................................................................................................................... 4 
1. 
OBJECTIVES ..................................................................................................................................... 7 
1.1 
Primary Objectives ...................................................................................................................................... 7 
1.2 
Secondary Objectives .................................................................................................................................. 7 
1.3  
Exploratory Objectives ................................................................................................................................ 7 
2. 
BACKGROUND ................................................................................................................................. 7 
2.1 
Study Disease .............................................................................................................................................. 7 
2.2 
Study Agent ................................................................................................................................................. 8 
2.3 
Rationale ...................................................................................................................................................... 8 
3. 
SUMMARY OF STUDY PLAN ...................................................................................................... 13 
4. 
PARTICIPANT SELECTION .......................................................................................................... 16 
4.1 
Inclusion Criteria ....................................................................................................................................... 16 
4.2 
Exclusion Criteria ...................................................................................................................................... 17 
4.3 
Inclusion of Women and Minorities .......................................................................................................... 18 
4.4 
Recruitment and Retention Plan ................................................................................................................ 18 
5. 
AGENT ADMINISTRATION .......................................................................................................... 21 
5.1 
Dose Regimen and Dose Groups ............................................................................................................... 21 
5.2 
Study Agent Administration ...................................................................................................................... 22 
5.3 
Run-in Procedures ..................................................................................................................................... 22 
5.4 
Contraindications ....................................................................................................................................... 22 
5.5 
Concomitant Medications .......................................................................................................................... 22 
5.6 
Dose Modification ..................................................................................................................................... 22 
5.7 
Adherence/Compliance .............................................................................................................................. 23 
6. 
PHARMACEUTICAL INFORMATION ......................................................................................... 23 
6.1 
Study Agent (IND#
 (Exempt), IND Sponsor: NCI/Division of Cancer Prevention) ..................... 23 
6.2 
Reported Adverse Events and Potential Risks ........................................................................................... 24 
6.3  
Availability ................................................................................................................................................ 24 
6.4 
Agent Distribution ..................................................................................................................................... 24 
6.5  
Agent Accountability ................................................................................................................................. 25 
6.6 
Packaging and Labeling ............................................................................................................................. 25 
6.7 
Storage ....................................................................................................................................................... 25 
6.8 
Registration/Randomization ...................................................................................................................... 26 
6.9 
Blinding and Unblinding Methods ............................................................................................................. 26 
6.10 Agent Destruction/Disposal ....................................................................................................................... 27 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ...................................................................... 27 
7.1 
Schedule of Events .................................................................................................................................... 27 
7.2 
Pre-Study Evaluation and Baseline Testing ............................................................................................... 28 
7.3 
Evaluation During the Study Intervention ................................................................................................. 30 
7.4 
Evaluation at Completion of the Study Intervention.................................................................................. 32 
7.5 
Post-intervention Follow-up Procedures .................................................................................................... 33 
7.6 
Methods for Clinical Procedures ............................................................................................................... 33 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION............................................... 34 
8.1 
Primary Endpoint ....................................................................................................................................... 34 
8.2 
Secondary and Exploratory Endpoints ....................................................................................................... 35 
8.3 
Off-Agent Criteria ..................................................................................................................................... 35 
8.4 
Off-Study Criteria ...................................................................................................................................... 36 
8.5 
Study Termination ..................................................................................................................................... 36 
9. 
CORRELATIVE/SPECIAL STUDIES ............................................................................................ 36 
9.1 
Rationale for Methodology Selection ........................................................................................................ 36 
9.2 
Comparable Methods ................................................................................................................................. 37 
10. 
SPECIMEN MANAGEMENT ......................................................................................................... 37 
10.1 Laboratories ............................................................................................................................................... 37 

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10.2 Collection and Handling Procedures ......................................................................................................... 39 
10.3 Shipping Instructions ................................................................................................................................. 39 
10.4 Tissue Banking .......................................................................................................................................... 41 
11. 
REPORTING ADVERSE EVENTS ................................................................................................. 41 
11.1 Adverse Events .......................................................................................................................................... 41 
11.2 Serious Adverse Events ............................................................................................................................. 42 
12. 
STUDY MONITORING ................................................................................................................... 44 
12.1 Data Management ...................................................................................................................................... 44 
12.2 Case Report Forms .................................................................................................................................... 44 
12.3 Source Documents ..................................................................................................................................... 44 
12.4 Data and Safety Monitoring Plan ............................................................................................................... 44 
12.5 Sponsor or FDA Monitoring ...................................................................................................................... 45 
12.6 Record Retention ....................................................................................................................................... 45 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ......... 45 
13. 
STATISTICAL CONSIDERATIONS .............................................................................................. 45 
13.1 Study Design/Description .......................................................................................................................... 45 
13.2 Randomization/Stratification ..................................................................................................................... 45 
13.3 Accrual and Feasibility .............................................................................................................................. 45 
13.4 Primary Objective, Endpoint(s), Analysis Plan ......................................................................................... 46 
13.5 Secondary and Exploratory Objectives, Endpoints, Analysis Plans .......................................................... 46 
13.6 Reporting and Exclusions .......................................................................................................................... 47 
13.7 Evaluation of Toxicity ............................................................................................................................... 47 
13.8 Evaluation of Response ............................................................................................................................. 47 
13.9 Interim Analysis ......................................................................................................................................... 47 
13.10 Ancillary Studies ....................................................................................................................................... 47 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................ 47 
14.1 Form FDA 1572 ......................................................................................................................................... 47 
14.2 Other Required Documents ....................................................................................................................... 48 
14.3 Institutional Review Board Approval ........................................................................................................ 48 
14.4 Informed Consent ...................................................................................................................................... 48 
14.5 Submission of Regulatory Documents ....................................................................................................... 49 
14.6 Other .......................................................................................................................................................... 49 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ...................................................................... 49 
REFERENCES ........................................................................................................................................... 50 
CONSENT FORM ...................................................................................................................................... 56 
APPENDIX A ............................................................................................................................................. 72 
APPENDIX B ............................................................................................................................................. 73 
APPENDIX C ............................................................................................................................................. 74 
APPENDIX D ............................................................................................................................................. 79 
APPENDIX E ............................................................................................................................................. 80 
APPENDIX F.............................................................................................................................................. 81 
APPENDIX G ............................................................................................................................................. 92 
APPENDIX H ............................................................................................................................................. 93 
APPENDIX I .............................................................................................................................................. 94 
APPENDIX J .............................................................................................................................................. 95 
 
 

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1. 
OBJECTIVES 
 
The objective of this randomized double-blinded, placebo-controlled Phase II trial is to examine the 
effects of simvastatin use versus placebo after 6 months of treatment on liver disease progression in 80 
patients with liver cirrhosis who have a current Model for End-6WDJH/LYHU'LVHDVH0(/'DQGQR
evidence of hepatocellular carcinoma (HCC). 
 
1.1 
Primary Objectives 
 
To evaluate the effect of a simvastatin intervention versus placebo on the change in serum AFP-L3% 
from baseline to 6 months following treatment initiation in patients with liver cirrhosis who have a 
current Model for End-6WDJH/LYHU'LVHDVH0(/' 
 
1.2 
Secondary Objectives  
 
To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the 
change in:  
1)  serum AFP;  
2)  serum IL-6;  
3)  serum deoxycholic acid; 
4)  liver stiffness; 
5) FIB-4 score; and 
6) MELD score. 
 
1.3  
Exploratory Objectives 
 
To evaluate the effect of a simvastatin intervention versus placebo at 6 months from baseline on the 
change in other: 
1)   serum bile acid levels; and 
2)   serum immune markers 
 
2. 
BACKGROUND 
 
2.1 
Study Disease 
 
Hepatocellular carcinoma (HCC) is a highly lethal cancer with rising incidence and mortality rates. 
Approximately 33,000 HCC diagnoses were expected in 2014, 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, 3]. 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, 
2]. 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 

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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 cirrhotics 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.
2.2
Study Agent
Simvastatin (butanoic acid, see Figure 1) is a lipid-lowering agent that is 
derived synthetically from a fermentation product of Aspergillus terreus. 
After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed 
WRWKHFRUUHVSRQGLQJȕ-hydroxyacid form. This 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 
simvastatin is C25H38O5 and its molecular weight is 418.57. Simvastatin is a 
white to off-white, nonhygroscopic, crystalline powder that is practically 
insoluble in water, and freely soluble in chloroform, methanol, and ethanol. 
Simvastatin tablets for oral administration contain 5 mg, 10 mg, 20 mg, 40 mg, or 80 mg simvastatin and 
the following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, hypromellose, iron 
oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, and titanium dioxide. 
Butylated hydroxyanisole is added as a preservative.
Simvastatin is the most commonly prescribed HMG-CoA reductase inhibitor, which has a widely 
accepted tolerability profile with few serious side effects [21]. 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 [22]. In a clinical trial database in which 41,413 patients were treated with simvastatin, 60% of 
whom were enrolled in studies with a median follow-up of at least 4 years, the incidence of myopathy 
was approximately 0.03% and 0.08% at 20 and 40 mg/day, respectively. The incidence of myopathy with 
80 mg (0.61%) was disproportionately higher than that observed at the lower doses [23]. 
Simvastatin is prescribed for primary and secondary prevention of cardiovascular disease and thus is 
indicated for long-term use. We propose to administer simvastatin 40 mg daily for 6 months in this trial.
2.3
Rationale
Figure 1. Molecular 
structure of simvastatin

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Hypotheses:   
1)  Participants randomized to simvastatin will experience a decrease from baseline to 6 months in serum 
AFP-L3% compared to the placebo group.  
 
2)  Compared to the placebo group, participants randomized to simvastatin will have: 
a)  lower serum AFP levels; 
b)  lower serum IL-6 levels;   
c)  lower serum deoxycholic acid (DCA) levels; 
d)  less liver stiffness; 
e) lower FIB-4 score; and 
f) lower MELD score. 
 
HCC is amenable to a chemoprevention strategy. Cirrhosis is the penultimate step of the multistage 
pathogenesis of HCC [4, 5]. Currently, the only clinical option for cirrhotics awaiting a transplant is to 
watch and wait for HCC to develop and hope that the tumor is caught early enough so that transplantation 
is still a viable option. In a recent paper, in a convenience sample including Child class B/C patients with 
chronic liver disease attending a hepatology clinic (similar to recruitment methods for this trial), the 3-
year cumulative HCC incidence was 14.8%. Although the data are not presented explicitly, based on the 
Kaplan-Meyer plot, the cumulative incidence over the first 6-months of follow-up appears to be around 
1% [8]. For this current trial, this would amount to less than 1 participant. An intervention that has the 
ability to delay or halt the development of HCC in the high risk setting of cirrhosis would have a major 
clinical impact for individual patients, better utilization of precious donor organs, and an improvement of 
outcomes for this liver disease cohort in aggregate. In spite of this unmet need, chemopreventive 
strategies for HCC have been understudied in clinical trials.  
 
Statins and the prevention of HCC: mechanistic links and human studies. HMG-CoA reductase 
inhibitors, commonly known as statins, are pleiotropic drugs that also have chemopreventive properties 
mediated through diverse pathways [24, 25]. The potential for liver cancer prevention is particularly 
relevant, due to the fact that the liver is the target organ for statins and sequesters the majority of the drug. 
For example, statins inhibit downstream products of the mevalonate pathway including isoprenoid (e.g., 
farnesyl pyrophostate, geranyl pyrophosphate), a necessary post-translational modifier of the RAS 
oncoprotein, which promotes cell cycle progression, growth, and survival of cancer cells [26]. Statins may 
DOVRVXSSUHVVȕ-catenin, the main downstream effector of the canonical WNT signaling pathway which is 
commonly activated in HCC and detected in 30-90% of tumors [27-30]. Statins have also been shown to 
modulate the bile acid pool and reduce levels of putative hepatocarcinogenic bile acids such as 
deoxycholic acid (DCA) in human secretions [31-35], as well as tumor promoting cytokines (such as IL-
6) in human serum. In hepatocellular carcinoma cells, statins can induce autophagy, the selective 
recycling of damaged cellular organelles [36]. Impaired autophagy leads to development of liver tumors 
[37]. Statins are also immunomodulatory, and can decrease TLR4 expression in response to LPS, which 
has been implicated in hepatocarcinogenesis [38]. Furthermore, statins can inhibit HCV-induced 
hepatocarcinogenesis by inhibiting the formation of lipid rafts and host factors necessary for HCV 
replication and epidermal growth factor signaling pathway increasing opportunity for HCV cellular entry 
[39]. 
 
There is accumulating epidemiological data supporting the notion that statins prevent HCC. A recent 
meta-analysis of 11 studies found that statins were associated with a significant reduction in HCC risk 
(HR=0.6, 95%CI=0.5-0.7) [40]. This reduced hazard of HCC has been observed in diverse populations 
with high and low prevalence of underlying liver disease etiologies (e.g., HCV, hepatitis B virus (HBV), 
and diabetes) [41-46]. The most recent and largest study to date of statins and HCC was conducted within 
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[42]. This study found that statins were associated with a significant reduction in HCC risk (OR = 0.55, 
95% CI = 0.45 to 0.69), and that diabetics on a statin had a more pronounced reduction of HCC risk. 
While some contrasting pre-clinical studies suggest that lipophilic statins (such as lovastatin and 
simvastatin) might have greater chemopreventive effects due to their greater lipid solubility and 
membrane permeability, and others suggest that lipophobic statins (such as pravastatin) may have greater 
chemopreventive effects due to the ability to accumulate in cells, the observational data suggest that the 
reduction in HCC risk is a class effect and not specific for particular formulation of statins. Although 
these observational studies support the hypothesis that statins prevent or reduce the risk of HCC, these 
studies cannot prove a causal link. Importantly, they have been criticized for bias due to confounding by 
contraindication (i.e., statin prescribing patterns). Secondary analyses of randomized control trials  
(RCTs) of statins and cardiovascular disease have also examined HCC risk as an outcome, although the 
results are inconclusive [45]. These RCTs are limited in that they often were unable to account for 
important HCC risk factors, and were based in low HCC risk populations with inadequate follow-up time 
and statistical power for HCC as an outcome. An RCT with defined intermediate biomarkers of HCC in a 
high-risk HCC population could shed much needed light on the potential for statins to protect against, or 
delay the progression to, HCC.  
 
HCC Biomarkers and Their Links to Statins  
 
Alpha Fetoprotein (AFP) and AFP-L3%. Serum levels of AFP, a glycoprotein expressed by fetal 
hepatocytes or poorly differentiated HCC cells, is the most frequently used biomarker for HCC 
worldwide. Although the sensitivity and specificity of AFP for detecting HCC, and particularly early 
HCC, vary according to study population, it is clear that AFP is far from a perfect marker for HCC. 
Serum AFP levels may be elevated in patients with chronic liver disease in the absence of HCC or in 
patients with other cancers. Thus, even if one assumes best-case estimates of sensitivity and specificity, 
the case for surveillance by AFP, particularly for early HCC, remains weak [47]. The poor performance 
of AFP in detecting HCC has led to increased interest in identifying tumor markers with greater clinical 
utility.  
 
An AFP glycoform may have greater utility as a biomarker for HCC than AFP. There are three AFP 
glycoforms that can be determined by the degree of fucosylation of the N-acetylglucosamine-linked sugar 
chain, based on their reactivity in lectin affinity electrophoresis (ability to bind the lectin Lens culinaris 
agglutinin, a carbohydrate binding protein isolated from lentil seeds). AFP-L1 is non-LCA binding and 
the major glycoform found in individuals with nonmalignant hepatopathy (e.g., cirrhosis or chronic HBV 
infection). AFP-L2 has an intermediate LCA binding capacity and is primarily produced by yolk sac 
tumors. AFP-L3 is produced by malignant liver cells, binds to LCA with high affinity, and is the major 
glycoform found in individuals with HCC [48, 49]. Because AFP-L3 is produced by malignant 
hepatocytes, its measurement helps distinguish non-malignant hepatic disease from HCC. Results from a 
large multicenter prospective study showed elevated AFP-L3% was the only biomarker that was 
predictive of HCC in multivariate analyses OR=5.2, p=0.0003 [50, 51], when compared against AFP and 
other biomarkers. Even more striking, is that the change in AFP-L3% over time was also a highly 
predictive marker of HCC, OR=7.2, p<0.0001 [50, 51]. The diagnostic sensitivity and specificity ranges 
from 36% to 66% and 77% to 95%, respectively [52, 53]. 
 
In addition to its important use in HCC surveillance and detection, there is reason to believe that AFP-
L3% may also be indicator of biological processes that predispose to HCC, making it a good target for 
chemoprevention. Hepatocytes are normally organized to be polar with the basolateral side facing the 
circulation and the apical side forming the bile canalicular network [54]. Core fucosylated glycoproteins 
produced by hepatocytes in the liver are sorted such that they are directed apically and secreted into the 
bile. Liver-derived fucosylated glycoproteins in the circulation are thought to result from loss of polarity 
and adhesion of hepatocytes, which is also a common feature of cancer cells. Thus, AFP-L3 in circulation 

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may represent this early malignant phenotype. Additionally, fucosylated proteins may be directly related 
WRWKHDFWLYDWLRQRIWKHFDQRQLFDOȕ-catenin signaling pathway, which is often activated in HCC, 
suggesting a direct relationship between the alteration in glycosylation with activation of known cancer 
pathways [55]. The fact that AFP-L3% is widely used as a serum marker for early recognition of HCC, 
coupled with studies illustrating that AFP-L3 reflects biological features of HCCs, opens that possibility 
that AFP-L3% is a marker for biological activity important in the etiology of HCC, and may serve as an 
intermediate marker for chemoprevention studies for HCC.  
 
Although the evidence is lacking with respect to statin influence on AFP-L3%, there is evidence that 
statins can reduce AFP. In a small randomized control trial including ~80 patients with HCC, 6 months of 
pravastatin (40 mg/day) was associated with significantly lower AFP levels (p=0.04) and HCC diameter 
(p=0.03) compared to controls [56]. By extension, statin should also reduce AFP-L3% levels, and given 
that AFP-L3% is a more specific marker for HCC, we feel that AFP-L3% is best suited to serve as a 
primary endpoint for this study. We will examine AFP as a secondary endpoint. 
 
AFP and AFP-L3 will be measured simultaneously by Quest Diagnostics using an immunofluorescent 
liquid-phase binding assay. Ion exchange chromatography will be employed to separate AFP-L3 and non-
AFP-L3 glycoforms. Fluorescence detection of the 2 chromatography fractions will be conducted. The 
analytic sensitivity of the assay is 0.8 ng/mL for AFP and 0.5% for AFP-L3%. The reference ranges for 
AFP are 1.6-4.5 ng/mL, and for AFP-L3% are 0.5-9.9 %. For cirrhotics without HCC, median AFP-L3% 
levels have been reported at 0.5% (25th and 75th quartiles: 0.5,1.7%) [50]. Abnormal is typically defined 
at >10%, and 8.4% of cirrhotics without HCC were abnormal in that prior study. In the same study, 
among cirrhotics who went on to develop HCC, the median for AFP-L3% was 6.1% (25th and 75th 
quartiles: 0.7, 21.3%). Based on a >10% cutoff, 44.1% of those who went on to develop HCC were 
abnormal [50]. 
 
Interleukin 6 (IL-6). It is known that the hepatic inflammatory process plays an important role in liver 
carcinogenesis. There is strong and consistent epidemiological evidence that elevated serum levels of IL-6 
predisposes to HCC development by several years [57-60]. In healthy subjects, 14-day treatment with 
simvastatin (40 mg/day) resulted in a significant reduction in serum IL-6 levels [61]. The reduction of IL-
6 by statin is also observed in disease states including chronic obstructive pulmonary disease and 
hypercholesterolemia [62, 63]. We will explore the secondary hypothesis that statins exert a suppressive 
effect on the key inflammatory cytokine IL-6.  
 
Bile acids. Bile acids are the end products of cholesterol metabolism. Recently, we found that serum 
DCA, a secondary bile acid, was elevated in cirrhotics with HCC compared to cirrhotics without HCC, 
and several other bile acids were reduced in HCC cases (Figure 2). This finding with DCA is interesting 
in the context of a recent study reporting that DCA was necessary for hepatocarcinogenesis in a mouse 
model of NASH cirrhosis [64]. DCA is known to cause DNA damage by inducing mitochondrial 
oxidative stress, reactive oxygen species (ROS) production, and NF-kappaB (NF-kB) activation [65]. 
Furthermore, antioxidants have been shown to ameliorate the DCA-induced carcinogenesis [66]. Three 
recent studies have used global metabolomics profiling of blood to identify small molecule differences 
between cirrhotics with and without HCC, although the bile acid associations with HCC have been 
varied: DCA and taurocholic acid were elevated; lithocholic acid (LCA), glycodeoxycholic acid (GDCA), 
and taurochenodeoxycholic acid (TCDCA) were reduced; and glycochenodeoxycholic acid (GCDCA) 
and glycocholic acid (GCA) were both elevated and reduced (depending on the study) in cirrhotics with 
HCC compared to cirrhotics without HCC [67-69]. Prior studies have shown that statins modulate the 

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composition of the bile acid pool 
[31-35] and can lead to a reduction 
in the putatively 
hepatocarcinogenic bile acid DCA 
[33, 34]. We will explore the 
secondary hypothesis that statins 
modulate serum bile acid levels.  
 
Liver stiffness. Recent studies 
have pointed to the predictive 
power of liver stiffness for HCC in 
patients with chronic hepatitis 
and/or cirrhosis [70-76]. 
Myofibroblasts are a major source 
of the hepatic extracellular matrix 
constituting the fibrous scar. 
Experimental studies have shown 
that statins can attenuate fibrosis by 
inhibiting activation, proliferation, 
and cytokine and collagen 
production of hepatic 
myofibroblasts [77, 78]. 
Furthermore, epidemiological studies have reported significant associations between statin use and 
fibrosis regression in patients with advanced fibrosis [39, 79, 80]. Reducing or reversing fibrosis and 
cirrhosis may create a less favorable environment for tumor development. FibroScan® examination is a 
non-invasive measurement of liver fibrosis. The advantage of FibroScan over biopsy is that it provides a 
look at the state of the liver globally, as opposed to a biopsy where only a very small sample is measured. 
A test result of >20 kPa (kilopascal) is generally associated with an increased HCC risk [81]. Another 
non-invasive measure of liver fibrosis is the Fibrosis 4 index (FIB-4) [82]. The FIB-4 index is calculated 
as follows: FIB-4 = (Age × AST (U/L)) ÷ (PLT (109/î¥$/78/+LJKYDOXHVRI),%-4 are 
associated with increased risk of hepatocellular carcinoma [83, 84]. Although there is limited data 
regarding statin use and liver stiffness, data show that statin use is significantly associated with a reduced 
risk of fibrosis progression among patients with chronic HCV infection [79, 85]. Thus, we will explore 
the secondary hypothesis that a statin intervention reduces liver stiffness as measured by FibroScan and 
the FIB-4 Index.  
 
MELD. As described in Section 2.1, over the last decade the growing crisis of insufficient livers for 
transplantation has led to a near doubling of the transplant wait time. In addition to increasing the risk for 
developing HCC, this increased wait time also increases the risk for waitlist dropout due to mortality. The 
Model for End-Stage Liver Disease (MELD) is a validated predictor of survival among different 
populations of patients with advanced liver disease [86-89]. MELD score is calculated using a patient's 
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 = 9.57 x ln(creatinine [mg/dL]) + 3.78 x ln(total bilirubin [mg/dL]) + 11.2 x ln(INR) + 6.43  
MELD-Na = 1.32 x (137 – sodium [mEq/L]) – [0.033 x MELD x (137 – sodium [mEq/L])]  
If the patient has been dialyzed at least twice within the last 7 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 

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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. 
 
The major use of the MELD score has been in allocation of organs for liver transplantation, a system 
which was implemented in 2002. Although statin use has been associated with lower risk of mortality and 
transplantation in observation studies [90], the effect of a statin intervention on MELD has not been 
examined.  
 
Statin Use in Cirrhosis. Statins have been used clinically for a long time, and in most settings have a 
very favorable toxicity profile [91]. Historically, there has been reluctance to prescribe statins to patients 
with preexisting liver disease due concerns of causing an elevation in liver enzymes and/or inducing 
diabetes [92]. However, in recent years, a benefit of statin use has proven to outweigh the potential for 
adverse events in the liver disease population: statins have been shown to delay liver disease progression, 
improve survival, reverse non-alcoholic steatohepatitis, and ameliorate metabolic syndrome [85, 93, 94]. 
Even so, currently, only 5% of registered liver transplant patients at Cedars-Sinai Medical Center 
(CSMC) are on a statin, according to their medical records. Therefore, given the overall potential benefit 
of statins in patients with liver disease, and the current lack of widespread clinical implementation, we are 
well-positioned to conduct this randomized study of statins in a low-exposure population that has a great 
deal to gain from its use.  
 
3. 
SUMMARY OF STUDY PLAN 
 
Design Overview. We will conduct a randomized double-blinded, placebo-controlled Phase II trial of 
statin to reduce disease progression in 80 patients with liver cirrhosis enrolled at four study sites: Cedars-
Sinai Medical Center (CSMC), Northwestern University Feinberg School of Medicine (NWU), 
Georgetown University/MedStar Georgetown University Hospital (GU), and the University of Puerto 
Rico Comprehensive Cancer Center (UPR). We will focus on patients with a current Model for End-Stage 
/LYHU'LVHDVH0(/'WRLQFUHDVHWKHOLNHOLKRRGWKDWWKH\ZLOOEHKHDOWK\DQGWUDQVSODQW-free for the 
duration of the 6-month intervention and follow-up. Cirrhotics, given their high risk of developing HCC, 
have the potential to derive the maximum benefit from an intervention that could delay the progression to 
HCC.  
 
Eighty patients will be randomized to simvastatin or placebo (40 in the simvastatin arm, 40 in the placebo 
arm). Assuming that ~10% of the study participants drop-out, we expect to have data on a final sample of 
72 men and women (36 simvastatin, 36 control) completing the 6-month follow-up visit (Study Visit 4). 
Clinical and research measurements will be taken at baseline (Study Visit 1), month 1 (Study Visit 2), 
month 3 (Study Visit 3), and month 6 (Study Visit 4). The 6-month intervention duration was chosen 
because it corresponds to 1) mandated interval for clinical follow-up for those who are on the transplant 
waitlist, and 2) widely recommended interval for HCC surveillance in high risk cirrhotic patients based on 
tumor doubling time [95, 96]. In addition, a prior study showed that 6 months of statin intervention led to 
a decrease in serum AFP, which was not the case after only 3 months on statin [56]. 
 
Screening, Recruitment, and Consent. Medical charts of patients who have an upcoming appointment 
with a study hepatologist will be reviewed for age, cirrhosis diagnosis, prior liver transplant, prior statin 
use, prohibited concomitant medications, previous malignancies, medical contraindications, laboratory 
results, and evidence of HCC from last abdominal image (ultrasound, computed tomography (CT), or 
magnetic resonance imaging (MRI)) occurring within the past 18 months. 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 will be done for the Screen 1 visit and reviewed by a study hepatologist. An 
information packet that introduces the study may be mailed to potentially eligible patients approved for 
contact by a study hepatologist. The packet will include the study consent form (ICF), HIPAA 

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authorization, and IRB-approved recruitment materials (e.g., introductory letter, leaflet; each participating 
site will choose what materials to include). One of the study hepatologists or clinical research staff will 
call potentially eligible patients before their scheduled 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 at their next standard of care visit with a study 
hepatologist. 
 
For potentially eligible patients who may not be mailed a recruitment packet in advance of the regular 
clinic visit (e.g., new patients or patients added to the schedule late), a study hepatologist will introduce 
the study to the patient during the standard of care clinic visit. The patient may 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 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 sign informed consent documents with the study hepatologist or a member of the clinical 
research team. 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. 
 
Written consent will be obtained after all clinical options have been presented and before any research 
related procedures are initiated. Consented patients will undergo additional screening and testing at the 
clinic to confirm eligibility and safety of statin initiation. The study hepatologist will thoroughly review 
the patient’s medical history, concomitant medications, and laboratory test results and evaluate all 
inclusion and exclusion criteria. Patients will undergo blood tests to confirm eligibility. If a patient’s lab 
results are current (within the past 30 days) in the medical record and within eligibility range, blood will 
not be drawn for lab testing at the Screen 1 visit. Otherwise, blood will be drawn to confirm eligibility. 
Because statins are known to be teratogenic, women who are able to become pregnant will be required to 
have a urine pregnancy test. :RPHQ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. Patients with a MELD score >20, AST/ALT >5x ULN, or other lab 
results that do not meet the eligibility criteria; and women who are pregnant will be excluded from the 
study. Patients who qualify for the study after the eligibility evaluations will be registered and enrolled in 
the study and randomized to the intervention (simvastatin or placebo). 
 
Study Visits. There will be four study visits: Study Visit 1 (baseline measurements and initiation of the 
intervention) will occur 0-30 days after the eligibility screening visit; Study Visit 2 (30 days after 
initiation of the intervention); Study Visit 3 (3 months after initiation of the intervention); and Study Visit 
4 (6 months after initiation of the intervention). Each study visit will include a medical history and 
medications review; vital signs and symptom assessment; ECOG performance status; and a blood draw. A 
risk questionnaire (interviewer-administered) and food frequency questionnaire (self-administered) will 
be done at baseline (Study Visit 1). A liver elastography (FibroScan) examination will be done at the 
baseline and 6-month visits (Study Visits 1 and 4). An abdominal image (CT, MRI, or ultrasound) will be 
taken at Study Visit 4. 
 
Study Measurements. Following is a brief description of study measurements. 
Medical history, medications, and laboratory test results review. Medical history, concomitant 
medications, and laboratory test results will be reviewed at Study Visits 1, 2, 3, and 4 by one of the study 
hepatologists or the clinical research staff. 

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Vital signs and symptom assessment. Participants will have a vital signs and symptom assessment at 
Screen 1 and Study Visits 1, 2, 3, and 4. Each assessment will include an interval symptom history; 
ECOG performance status; vital signs, including blood pressure, heart rate, and temperature; and 
measurement of weight. Height will be measured at Study Visit 1. A physical assessment, including 
assessment of liver disease sequelae (varices, ascites, and encephalopathy) will be done at Screen 1 and 
Study Visit 4.  
 
Blood specimen. A blood specimen (approximately 15 mL) will be collected from patients at the Screen 
1 eligibility visit for blood tests to confirm eligibility. If a patient’s lab results are current (within the past 
30 days) in the medical record and within eligibility range, their blood will not be drawn at the Screen 1 
visit. Otherwise, the patient’s blood will be drawn to confirm eligibility. A Complete Blood Count and 
Automated Differential (CBDF), a Comprehensive Metabolic Panel (CMPL), and Prothrombin Time 
(PT/INR) will be done to confirm that blood levels are within the eligibility requirements (acceptable 
organ function, AST/ALT [XSSHUOLPLWVRIQRUPDODQG0(/' 
 
A blood specimen (approximately 10-15 mL) will be collected from each participant at Study Visits 1, 2, 
3, and 4 for laboratory blood tests to monitor for potential adverse effects of the intervention. A Lipid 
Panel and hemoglobin A1C will be done at Study Visits 1, 3, and 4. A Complete Blood Count and 
Automated Differential (CBDF) and Comprehensive Metabolic Panel (CMPL) will be done at Study 
Visits 2, 3, and 4. Creatine Phosphokinase (CPK) will be measured at Study Visit 1. Prothrombin Time 
(PT/INR) will be done at Study Visit 4 to calculate the MELD score. Clinical lab results from Screen 1 
and Study Visit 4 will be used to calculate the MELD and FIB-4 scores. 
 
An additional blood specimen (20 mL) will be collected from each participant at Study Visits 1 and 4 for 
research purposes. Ten mL of blood will be drawn for measurement of protocol-specific biomarkers 
(AFP, AFP-L3%, IL-6, and bile acids) and 10 mL of blood will be drawn for DNA extraction and use in 
future studies.  
 
Liver elastography (FibroScan). A FibroScan examination will be conducted at Study Visits 1 and 4. 
Participants will be instructed to refrain from eating for 3 hours before the FibroScan examination. The 
test result provides a look at the state of the liver globally, as opposed to a biopsy where only a very small 
sample is measured. The FibroScan will be used as a non-invasive measurement of liver stiffness. 
 
Abdominal imaging. Abdominal imaging is done every 6 months for HCC surveillance and is standard 
of care in this high-risk study population. Typically, imaging occurs within a few weeks prior to the 
patient’s clinical appointment with hepatology, and we will require that eligible patients for this trial have 
had imaging done (CT, MRI, or ultrasound) within 18 months prior to Study Visit 1 to assure that there is 
no HCC present prior to enrollment. Another abdominal image will be taken for all trial participants at 
Study Visit 4, which will be another standard of care procedure. 
 
Baseline risk factor questionnaire. A structured questionnaire developed for this investigation will be 
administered at Study Visit 1 in either Spanish or English, according to each participant’s preference. The 
interview will elicit information on detailed race/ethnicity; education and marital status; medical and 
medications history; alcoholic beverage consumption; tobacco smoking; and anthropometry including 
weight at different decades of life. Reporting of alcohol use is sensitive for cirrhotics, as it is a factor in 
their transplant eligibility. Nevertheless, prior studies have found that one-third of registered participants 
are active drinkers [97]. We will use a three-item alcohol questionnaire, the Alcohol Use Disorders 
Identification Test for Alcohol Consumption (AUDIT-C), FRPSULVHGRIWKH¿UVWWKUHHTXHVWLRQVIURPWKH
Alcohol Use Disorders Identification Test (AUDIT) proposed by the World Health Organization for the 
assessment of hazardous drinking in primary care, which is 83.5% accurate at identifying active alcohol 

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users from a liver transplant waitlist population [97].  
 
Food frequency questionnaire (FFQ). A food frequency questionnaire (FFQ) will be administered at 
Study Visit 1 to capture usual diet over the last 90 days using VioScreen®, a graphical dietary assessment 
that has been validated against traditional paper-based FFQs, available in English and Spanish [98]. The 
VioScreen® is a self-administered electronic questionnaire that participants will complete online using a 
computer or tablet. Food items and components that are of particular interest include total fat, saturated 
fat, carbohydrate, dietary fiber, coffee, and antioxidants, based on prior publications reporting 
associations with HCC [99-112]. Please see Appendix J for VioScreen® instructions for participants. 
 
4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1  Confirmed diagnosis of liver cirrhosis assessed by the presence of clinical signs, symptoms, body 
imaging (ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI)), or liver biopsy 
 
4.1.2 
$JH\HDUV 
 
4.1.3 
(&2*SHUIRUPDQFHVWDWXV.DUQRIVN\VHH$SSHQGL[$ 
 
4.1.4 
Participants must have acceptable organ, hepatic and renal function as defined below: 
Leukocytes 
PLFUROLWHU 
Absolute neutrophil count 
PLFUROLWHU 
Platelets 
50,000/microliter 
Hemoglobin 
8 g/dL 
Total bilirubin 
3 × institutional upper limit of normal (ULN) 
AST (SGOT)/ALT (SGPT) 
5 × institutional ULN 
Creatinine 
îLQVWLWXWLRQDO8/1 
 
Patients whose lab results meet the inclusion criteria after the Screen 1 blood tests will be included in the 
trial. 
 
4.1.5 
Women who are able to become pregnant must have a confirmed negative pregnancy test result 
prior to enrollment. :RPHQ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. 
 
4.1.6 
The effects of simvastatin on the developing human fetus at the recommended therapeutic dose 
are unknown. For this reason, 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. 
 
4.1.7  Ability to understand and the willingness to sign a written informed consent document and 
medical release 
 
4.1.8  Willing and able to comply with trial protocol and follow-up 
 
4.1.9 
Have had an abdominal imaging test (CT, MRI, or ultrasound) within the past 18 months 
 

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4.2 
Exclusion Criteria 
 
4.2.1 
Prior or current use of statin medication 
 
4.2.2 
Current systemic use of medications known to interact with statins and potentially increase 
toxicity, including gemfibrozil, cyclosporine, danazol, lomitapide, verapamil, diltiazem, dronedarone, 
amiodarone, amlodipine, ranolazine, strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, 
posaconazole, voriconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, 
clarithromycin, telithromycin, nefazodone, or cobicistat-containing products), or strong CYP3A4 inducers 
(e.g., carbamazepine, phenytoin, rifampin, St. John’s wort, bosentan, efavirenz, etravirine, modafinil, 
nafcillin) 
 
4.2.3 
History of adverse effects, intolerance, or allergic reactions attributed to compounds of similar 
chemical or biologic composition to simvastatin (i.e., other statin medications) 
 
4.2.4 
Current use of any other investigational agents 
 
4.2.5 
Women who are pregnant or breastfeeding. Pregnant women are excluded from this study 
because simvastatin is a lipid-lowering agent with the potential for teratogenic or abortifacient effects. It 
is not known whether simvastatin 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 events 
in nursing infants secondary to treatment of the mother with simvastatin, breastfeeding should be 
discontinued if the mother is treated with simvastatin. 
 
4.2.6 
Prior liver transplant 
 
4.2.7 
Prior known or suspected hepatocellular carcinoma  
 
4.2.8 
Prior cholangiocarcinoma  
 
4.2.9 
Model for End-Stage Liver Disease (MELD) >20 
 
4.2.10 Any lab results that do not meet inclusion criteria 4.1.4 after the Screen 1 blood tests   
 
4.2.11 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric 
illness/social situations that would limit compliance with study requirements  
 
4.2.12 History of chronic myopathy 
 
4.2.13 Prior germ cell cancer  
 
4.2.14 History of active malignancy within the past 5 years (excluding basal/squamous cell skin cancer 
or prostate cancer with a Gleason score 6 or less) 
 
4.2.15 Known active infection with HIV 
 
4.2.16 Medical contraindications to blood draw (e.g., hemophilia) 
 
4.2.17 Concurrent illness which in the opinion of the investigators would compromise either the patient 
or the integrity of the data 

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4.2.18 Current 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 ethnic groups are eligible for this trial.  
 
4.4 
Recruitment and Retention Plan 
 
Source Population. Participants will be recruited from all eligible patients who have a confirmed 
diagnosis of cirrhosis assessed by the presence of clinical signs, symptoms, body imaging (ultrasound, 
computed tomography (CT), or magnetic resonance imaging (MRI)), or liver biopsy. Patients will not be 
restricted on the basis of their cirrhosis severity, but Child Pugh classification will be captured and 
considered in statistical analysis. We will recruit patients from hepatology clinics and will target patients 
who are currently waitlisted, or under evaluation, for a liver transplant. However, patients who are 
inactive on the waitlist, or ineligible for a transplant, will still be eligible for this trial, since many attend 
hepatology clinics on the same 6 month schedule as those who are waitlisted. Compared to other 
transplant centers in the region, patients awaiting a liver transplant at CSMC tend to be lower acuity (94% 
KDYHD0(/'FRPSDUHGWR80% regionally and 85% nationally), providing the study team access to 
a large number of patients who are likely to remain listed and healthy for the 6 month trial duration [113]. 
At NWU, GU, and UPR, a smaller proportion (79%, 78%, 69% respectively) of patients listed are 
H[SHFWHGWRKDYHD0(/'. However, among the four institutions, we will have a substantial pool of 
patients to select from for this trial (see Figure 3) . CSMC and NWU liver transplant waitlist candidates 
DUHDOODGXOWV\HDUVROG; 95% of GU’s and 98% of UPR’s candidates are adults. Among the four 
institutions, about 65% are male, and about 81% are between 18 and 65 years old [113]. A large 
proportion (40%) of the CSMC liver transplant candidates are Hispanic/Latino, more than twice the 
national average of liver transplant candidates (18%). Coupled with a majority Hispanic/Latino liver 
transplant population at UPR, this provides a unique opportunity to test an intervention for a cancer that is 
the most burdensome to this large, growing, and understudied demographic group [113]. We will make 
every attempt to enroll and retain Hispanic participants, particularly Spanish monolingual participants, by 
using interpreters and study materials (e.g., ICFs, study information sheets, questionnaires) translated into 
Spanish). In 2015, 12% of patients listed for a liver transplant at CSMC indicated that Spanish was their 
preferred language. 
 
Recruitment and Feasibility. Recruitment will occur over 12 months and will target patients who are 
attending a usual care appointment at the transplant hepatology clinics at CSMC, NWU, GU, and UPR. 
Most of these patients are on the waiting list for a liver transplant. Based on the most recent Scientific 
Registry of Transplant Recipients (SRTR) report and data on patients registered for a liver transplant 
during July, 2016-June, 2017, we expect that there will be approximately 187 (CSMC), 77 (NWU), 269 
(GU), and 15 at UPR patients actively registered for a liver transplant at the start of the study, and that 
over the course of 12 months, 110 new patients will be added at CSMC, 140 at NWU, 224 at GU, and 55 
at UPR [113].  Thus, over the 12-month recruitment period for this study, we will have access to 1077 
patients awaiting liver transplant. Major exclusion criteria include MELD aSULRU+&&RU
cholangiocarcinoma (~5%), prior or current use of statins (~10%), and prior liver transplant (~5%). We 
estimate that 15% of patients not excluded for the previously stated reasons, will be excluded for other 
less common reasons. Thus, we are anticipating that 65% of the source population will be ineligible for 
the study, leaving 377 or 35% of the source population eligible. Based on prior experiences recruiting 
similar patients into trials, our expectation is that we will obtain consent from ~24% of eligible patients 
(target n=90), and that 80 patients (21% of eligible patients) will pass the Screen 1 evaluations and be 
randomized to the study intervention.  

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considered for participation. The packet will include the study consent form (ICF), HIPAA authorization, 
and IRB-approved recruitment materials (e.g., introductory letter, leaflet; each participating site will 
choose what materials to include). One of the study hepatologists or clinical research staff will call 
potentially eligible patients before their scheduled 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 at their next standard of care visit with a study 
hepatologist. 
 
For potentially eligible patients who may not be mailed a recruitment packet in advance of the regular 
clinic visit (e.g., new patients or patients added to the schedule late), a study hepatologist will introduce 
the study to the patient during the standard of care clinic visit. The patient may 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 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 sign informed consent documents with the study hepatologist or a member of the clinical 
research team. 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. 
 
We estimate that 377 of the patients registered for a liver transplant during the 12-month recruitment 
period will be potentially eligible. Cirrhotics who are eligible and not listed for transplant may also be 
recruited.  
 
Screen 1 Consent and Final determination of eligibility. The study hepatologist will review the study 
details and answer any questions regarding the proposed trial after all clinical options have been presented 
to the patient. After the patient's questions have been answered, the study hepatologist will obtain 
signatures on the consent documents from patients who are eligible based on the pre-screen chart review 
and wish to volunteer for the study. Patients for whom Spanish is their preferred language will be 
consented using a version of ICF translated into Spanish, administered by an interpreter. The patient will 
carefully review and sign the study consent form and HIPAA authorization. Copies of each form will be 
given to the patient and placed in the medical record. Participants who sign consent will be provided a 
copy of Appendix D (Food and Medications to Avoid During Your Participation in the Study). We 
anticipate that we will obtain consent from 90 patients. Written consent will be obtained before any 
research related procedures are initiated. After consent has been obtained, a final assessment of eligibility 
will be conducted. Consented patients will undergo additional screening and testing to confirm eligibility 
and safety of statin initiation.  
 
The study hepatologist will thoroughly review the patient’s medical history, concomitant medications, 
and laboratory test results and evaluate all inclusion and exclusion criteria. A blood specimen will be 
collected from patients for blood tests to confirm eligibility. If a patient’s lab results are current (within 
the past 30 days) in the medical record and within eligibility range, their blood will not be drawn at the 
Screen 1 visit. Otherwise, the patient’s blood will be drawn to confirm eligibility. A Complete Blood 
Count and Automated Differential (CBDF) (for leukocytes, neutrophils, platelets, and hemoglobin), a 
Comprehensive Metabolic Panel (CMPL) (for liver enzymes (AST/ALT) and for total bilirubin, 
creatinine, and sodium (required for calculation of the MELD score)), and Prothrombin Time (PT/INR) 
(required for calculation of MELD) will be done to confirm that blood levels are within the eligibility 
requirements (acceptable organ function, AST/ALT 3x upper limits of noUPDODQG0(/'
Because statins are known to be teratogenic, women who are able to become pregnant will be required to 

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have a urine pregnancy test. :RPHQ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. Patients with a MELD score >20, AST/ALT >5x ULN, or other lab 
results that do not meet the eligibility criteria; and women who are pregnant will be excluded from the 
study. Following eligibility screening, and prior to Study Visit 1, consented patients who qualify for the 
study after the eligibility evaluations will be registered and enrolled in the study and randomized to the 
intervention (simvastatin or placebo). 
 
There will be four study visits. Study Visit 1 (baseline measurements and initiation of the intervention) 
will occur 0-30 days after the Screen 1 eligibility visit. Follow-up visits will be scheduled at 1 month (± 
14 days), 3 months (± 14 days), and 6 months (± 30 days) after initiation of the intervention to avoid 
protocol violations. Study visits will coincide whenever practicable with usual care appointments to 
reduce travel time and to increase compliance with the study protocol. Participants will receive $50 when 
they complete the Screen 1 testing and $100 at the completion of each study visit for their time, 
transportation, parking, and other expenses related to the study. Participants who complete the entire 
study – the Screen 1 eligibility testing and four study visits – will receive $450. 
 
Compensation schedule  
Screen 1 
Study Visit 1 
Study Visit 2 
Study Visit 3 
Study Visit 4 
$50 
$100 
$100 
$100 
$100 
 
The participant will be contacted by telephone 5-7 days prior to the scheduled study visit to confirm or 
reschedule his/her visit. If a study participant misses his/her visit study visit, s/he will be called promptly 
to reschedule. The study coordinator will have a database which tracks active participants who do not 
have a scheduled visit or who have missed their targeted visit date. Study visits will be rescheduled for up 
to 2 months until the participant is considered lost to follow-up.  
 
5. 
AGENT ADMINISTRATION 
 
Intervention will be administered on an outpatient basis. Reported adverse events (AEs) and potential 
risks are described in Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
Eighty participants with liver cirrhosis will be randomized into one of 2 groups: 40 participants will 
receive 40 mg simvastatin per day and 40 participants will receive a placebo identical in color, 
consistency, and appearance to simvastatin 40 mg. Simvastatin and placebo will be provided as over-
encapsulated tablets. Dosing will extend for 6 months. 
 
x 
Agent(s): Simvastatin and placebo 
x 
Daily dose(s) and regimen(s) for each agent: One 40 mg capsule per day 
x 
Duration for each agent: Daily treatment for 6 months 
 
The usual recommended dose of simvastatin is 10-40 mg/day, and the toxicity and tolerability are 
comparable for 20 mg and 40 mg [23]. In a prior published trial of patients with chronic hepatitis or 
cirrhosis, statin dosing began at 20 mg and was titrated up to 40 mg, and no serious side effects or 
discontinuation of therapy were noted [56]. Thus, we feel that a 40 mg dose will be well-tolerated by the 
participants in this trial. 
 
 

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5.2 
Study Agent Administration 
 
Patients will self-administer the 40 mg capsule of simvastatin 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/shipped 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).  
 
5.3 
Run-in Procedures  
 
None. 
 
5.4 
Contraindications 
 
Patients are advised not to consume any form of grapefruit (e.g., juice, fruit, grapefruit seed extract, 
dietary supplements containing grapefruit) while on simvastatin as grapefruit may increase the blood 
levels of simvastatin [114]. Participants enrolled in the study will be instructed to avoid all forms of 
grapefruit. 
 
The combined use of simvastatin with systemic formulations of gemfibrozil, cyclosporine, danazol, 
lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, ranolazine, or strong CYP3A4 
inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors, 
boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and cobicistat-containing 
products) is contraindicated due to an increased risk for myopathy. Patients will be screened for 
contraindications to simvastatin 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. 
 
5.5 
Concomitant Medications 
 
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, dose and route of administration, and indication. Medications taken for a procedure (e.g., 
biopsy) should also be included. 
 
5.6 
Dose Modification 
 
1RGRVHPRGLILFDWLRQVDUHSODQQHG7KHVWXG\DJHQWZLOOEHVWRSSHGLQWKHHYHQWRIDQ$(JUDGH
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 hepatotoxicity (ALT or AST > 5 times 

NWU2015-06-03 
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–23– 
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 
simvastatin below 40 mg: lomitapide, verapamil, diltiazem, dronedarone, amiodarone, amlodipine, or 
ranolazine. 
 
5.7 
Adherence/Compliance 
 
Compliance will be measured by pill counts and patient diaries. For telehealth visits, we will ask 
participants to photograph unused pills for remote pill counts and patient pill diaries and compliance will 
be assessed remotely. Compliance is defined as 85% of the total dose over the entire study period. A 
participant diary will be used to monitor daily compliance (Appendix C). 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 2-4. 
 
Phone calls will be made to study participants every four weeks (± 7 days) to monitor compliance. 
Participants will be asked if they missed any doses of medication, and the dates of all missed doses will 
be recorded. The study agent diary will be reviewed with participants at every visit. Participants who 
report having taken < 85% of the study drug doses between phone calls, or whose pill count at a study 
visit reveals < 85% compliance, will be called every two weeks (± 3 days) to monitor compliance. 
 
The participant will be asked at registration if they would like to receive reminder emails or text messages 
regarding the study medication. Messages will be sent daily for the first week; in following weeks, 
messaging will be targeted to participants having difficulty remembering their dose. In addition, phone 
calls will be made to all study participants during the week before their final visit (Visit 4) to remind them 
to take the study drug every day until the last study visit. Participants will also be reminded to bring any 
leftover study drugs and the study diary with them to each visit. 
 
Capsule counts will be performed at Study Visits 2, 3, and 4 to assess compliance. If less than 85% of the 
dose has been consumed during the study period, the subject will be considered non-compliant. All 
participants that receive a study agent for any period of time will be evaluable for toxicity. 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
Study Agent (IND#
 (Exempt), IND Sponsor: NCI/Division of Cancer Prevention)   
 
Simvastatin (Zocor) 40 mg and simvastatin placebo will be supplied by NCI, DCP. Simvastatin is a lipid-
lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral 
ingestion, simvastatin, which is an inactive ODFWRQHLVK\GURO\]HGWRWKHFRUUHVSRQGLQJȕ-hydroxyacid 
form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, and 
catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the 
biosynthesis of cholesterol. 
 
The empirical formula of simvastatin is C25H38O5 and its molecular weight is 418.57. It is a white to off-
white, nonhygroscopic, crystalline powder that is practically insoluble in water, and freely soluble in 
chloroform, methanol, and ethanol. Simvastatin tablets for oral administration contain 40 mg of 
simvastatin and the following inactive ingredients: ascorbic acid, citric acid, hydroxypropyl cellulose, 

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–24– 
hypromellose, iron oxides, lactose, magnesium stearate, microcrystalline cellulose, starch, talc, and 
titanium dioxide. Butylated hydroxyanisole is added as a preservative.  
 
Information on the placebo will be provided when available. 
 
6.2 
Reported Adverse Events and Potential Risks 
  
The most common reported adverse events (incideQFHDUHXSSHUUHVSLUDWRU\LQIHFWLRQKHDGDFKH
abdominal pain, constipation, and nausea. Other adverse events reported in clinical trials (<5%) were 
diarrhea, rash, dyspepsia, flatulence, and asthenia. 
 
Persistent increases in serum transaminases (to more than 3× the ULN) have occurred in approximately 
1% of patients who received simvastatin 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. 
 
Simvastatin 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 
LQFOXGHDGYDQFHGDJH\HDUVIHPDOHJHQGHUXQFRQWUROOHGK\SRWK\URLGLVPDQGUHQDOLPSDLUPHQW
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. Simvastatin is metabolized by the 
cytochrome P450 isoform 3A4 (CYP3A4). Certain drugs which inhibit this metabolic pathway can raise 
the plasma levels of simvastatin and may increase the risk of myopathy. These include itraconazole, 
ketoconazole, posaconazole, voriconazole, the macrolide antibiotics erythromycin and clarithromycin, the 
ketolide antibiotic telithromycin, HIV protease inhibitors, boceprevir, telaprevir, the antidepressant 
nefazodone, cobicistat-containing products, or grapefruit-containing products. Combination of these drugs 
with simvastatin is contraindicated. If short-term treatment with strong CYP3A4 inhibitors is 
unavoidable, therapy with simvastatin 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 simvastatin. 
 
6.3  
Availability 
 
Simvastatin and matching placebo are investigational agents supplied to investigators by DCP, NCI. 
Simvastatin 40 mg and matching placebo will be supplied as over-encapsulated tablets for oral 
administration. Simvastatin and matching placebo will be packaged with 120-count 40 mg capsules per 
bottle. Each participant will be given/shipped one bottle at Study Visit 1 and one bottle at Study Visit 3 
(Month 3). Please see the NWU2015-06-03 pharmacy manual for shipping procedures.  
 
6.4 
Agent Distribution 
 
Agents will only be released by NCI, DCP after documentation of NCI Central IRB (CIRB) approval of 
the DCP-approved protocol and consent is provided to DCP and the collection of all Essential Documents 
is complete (see DCP website for description of Essential Documents).  
 
NCI, DCP-supplied agents may be requested by the Investigator (or their authorized designees) at each 

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–25– 
Organization. DCP guidelines require that the agent be shipped directly to the institution or site where the 
agent will be prepared and administered. DCP does not permit the transfer of agents between institutions 
(unless prior approval from DCP is obtained). DCP does not automatically ship agents; the site must 
make a request. Agents are requested by completing the DCP Clinical Drug Request form (NIH-986) (to 
include complete shipping contact information) and faxing or mailing the form to the DCP agent 
repository contractor: 
 
John Cookinham 
MRIGlobal 
DCP Repository 
1222 Ozark Street 
North Kansas City, MO 64116   
Phone: (816) 360-3805 
FAX: (816) 753-5359 
Emergency Telephone: (816) 360-3800 
 
6.5  
Agent Accountability 
 
The Investigator, or a responsible party designated by the Investigator, must maintain a careful record of 
the inventory and disposition of all agents received from DCP using the NCI Drug Accountability Record 
Form (DARF). The Investigator is required to maintain adequate records of receipt, dispensing, and final 
disposition of study agent. This responsibility has been delegated to the study pharmacists: Annie Yi, 
Pharm.D., Investigational Drug Pharmacist at Cedars-Sinai Medical Center; Jane Regalado, Pharm. D., 
Investigational Drug Pharmacist at Northwestern Memorial Hospital; Khang Ho, Pharm.D. at 
Georgetown University, and Elsa Pedro, Pharm.D. at the University of Puerto Rico. Include on receipt 
record from whom the agent was received and to whom study agent was shipped, date, quantity and batch 
or lot number. On dispensing record, note quantities and dates study agent was dispensed to and returned 
by each participant.  
 
6.6 
Packaging and Labeling 
 
Simvastatin and placebo will be packaged by NCI, DCP. 
 
Each bottle will be labeled with a one-part label identifying study specific information, such as study title, 
DCP protocol number, dosing instructions, recommended storage conditions, the name and address of the 
distributor, randomization number, and a caution statement indicating that the agent is limited by United 
States law to investigational use only and the agent should be kept out of reach of children. 
 
6.7 
Storage 
 
The DCP Drug Repository, MRIGlobal, will distribute the study agent directly to each participating site. 
Study agents will be stored in a safe, secure, temperature monitored limited access drug storage area 
specifically for research medication at the Research Pharmacy at each site. Study agents shall be 
maintained at a controlled room temperature [between 15-30°C] by the Research Pharmacy at each site 
and once dispensed, the subjects will be instructed to store the drug in their homes protected from light, 
heat, and moisture. MRIGlobal will be notified in the event of a temperature excursion below 15°C or 
above 30°C for 24 hours continuously. MRIGlobal will evaluate the temperature excursions on a case-by-
case basis. 
 
 
 

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6.8 
Registration/Randomization 
 
1. A study coordinator must upload into the Northwestern Clinical Trials Management System, a 
signed and complete informed consent along with HIPAA authorization and a completed 
eligibility form for each participant identified as eligible to be entered into the study.   
2. All participants must be registered in the Northwestern University Robert H. Lurie 
Comprehensive Cancer Center Clinical Trials Management System (CTMS).  Participants must 
not start protocol treatment prior to registration in the Lurie Cancer Center CTMS. 
3. After registration in the CTMS, participants will be assigned a participant identification number 
and a randomization number when applicable.  
4. An NCPC Quality Assurance Monitor will submit the following into the REDCap Randomization 
Information Form: (1) Study Number, (2) Site, (3) Pharmacist Email(s), (4) Participant ID, (5) 
Participant Initials, and (6) Randomization Date.  
5. An Automatic Treatment Assignment Notification email will be sent to the research pharmacist(s) 
containing: (1) Study Number, (2) Site, (3) Participant ID, (4) Participant Initials, (5) 
Randomization Date, and (6) Treatment Assignment. 
6. The clinical research coordinator(s) will receive a Confirmation of Registration containing the 
PID via email. 
7. The following people will have a copy of the un-blinded randomization log: the study statistician 
at NU, the Quality Assurance Team at NU, and the Investigational Pharmacists at each site.  The 
following people will have access to the REDCap study project containing randomization 
information: the study statistician at NU and the Quality Assurance Team at NU. The study 
statistician will set up randomization blocks.  
 
When possible, the study coordinator will notify an NCPC Quality Assurance Monitor and/or send an 
email to ncpc@northwestern.edu prior to registering a participant. Prior notification is required for 
participant randomizations outside the normal business hours of Monday-Friday 9:00am-5:00pm CT.   
 
6.9 
Blinding and Unblinding Methods 
 
The research pharmacist will manage the investigational agent. The blind will be maintained through the 
effort of the research pharmacist, and the pharmacy. Unblinding will only occur when it is deemed 
medically necessary, and will only take place after consultation with the NCI, DCP Task Order Monitor. 
If the NCI Task Order Monitor cannot be reached and the participant requires emergency care, the Study 
Chairman may authorize the site PI to break the blind. The date and reason for breaking the blind must be 
submitted by the site PI to the Study Chairman and the NCI Task Order Monitor as soon as possible. 
 
The NCI Medical Monitor must be notified that the blind has been broken. The NCI CIRB and the IRB at 
the site where the blind is broken will also be notified. 
 
DCP Medical/Task Order Monitor 
Luz Maria Rodriguez, MD, FACS 
NCI/Division of Cancer Prevention 
9609 Medical Center Dr. 
Rm 5E-228 
Bethesda, MD 20892 
Telephone (240) 276-7039 
Fax (240) 276-7848 
Email: rodrigul@mail.nih.gov 
 
 

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–27– 
6.10 
Agent Destruction/Disposal 
 
At the completion of investigation, all unused study agent will be destroyed according to local 
institutional procedures. Destruction records must be provided to MRIGlobal at the end of the study.  
 
7. 
CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events 
 
Procedure 
Pre-
Screen1 
Screen 
12ޔ 
Study 
Visit 13 
Study 
Visit 24 
Study 
Visit 35 
Study 
Visit 46ޔ  
Follow-
Up 
Assess eligibility (review inclusion/exclusion 
criteria) and recruitment 
X 
X 
 
 
 
 
 
Informed Consent and HIPAA authorization 
 
X 
 
 
  
  
 
Abdominal imaging (CT, MRI, ultrasound)7 
X 
 
 
 
 
X 
 
Review study requirements 
X 
X 
X 
X 
X 
 
 
Review medical history, medications, and 
laboratory test results 
X 
X 
X 
X 
X 
X 
 
Blood hematology: Complete Blood Count 
and Automated Differential (CBDF) 
 
X 
X 
X 
X 
X 
 
Blood chemistry: Comprehensive Metabolic 
Panel (CMPL) 
 
X 
X 
X 
X 
X 
 
Blood test: Prothrombin Time (PT/INR) 
 
X 
 
 
 
X 
 
Urine pregnancy test8 
 
X 
 
 
 
 
 
Registration and randomization to 
simvastatin or placebo 
 
X 
 
 
 
 
Demographics (race, ethnicity, education) 
 
 
X 
 
  
  
 
Assess symptoms and ECOG performance 
status 
 
X 
X 
X 
X 
X 
 
Physical assessment, assess liver disease 
sequelae 
 
X 
 
 
 
X 
 
Vital signs assessment, measure weight 
 
X 
X 
X 
X 
X 
 
Blood test: Lipid Panel 
 
 
X 
 
X 
X 
 
Blood test: Hemoglobin A1C (HbA1C) 
 
 
X 
 
X 
X 
 
Blood test: Creatine Phosphokinase (CPK) 
 
 
X 
 
 
 
 
Collect blood specimen for research9 
 
 
X 
 
 
X 
 
Conduct liver elastography (FibroScan) 
 
 
X 
 
 
X 
 
Interviewer-administered risk questionnaire 
 
 
X 
 
 
 
 
Self-administered VioScreen® food 
frequency questionnaire11 
 
 
X 
 
 
 
 
Dispense study agent and diary 
 
 
X 
X 
X 
 
 
Collect study agent and diary 
 
 
 
X 
X 
X 
 
Review study diary 
 
 
 
X 
X 
X 
 
Assess compliance (pill count) 
 
 
 
X 
X 
X 
 
Assess adverse events 
 
 
 
X 
X 
X 
X 
Telephone contact10 
X 
X 
X 
X 
X 
X 
X 
 ޔ Screen 1 and Study Visit 4 are concurrent with standard of care visit. 

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–28– 
Procedure 
Pre-
Screen1 
Screen 
12ޔ 
Study 
Visit 13 
Study 
Visit 24 
Study 
Visit 35 
Study 
Visit 46ޔ  
Follow-
Up 
1 Medical chart review for patients who are liver transplant candidates and have an upcoming appointment with a study 
hepatologist to determine initial eligibility; recruitment of potentially eligible patients 
2 Obtain consent of potentially eligible patients; thorough review of patient’s medical history, concomitant medications, 
and laboratory test results; evaluation of inclusion and exclusion criteria; and assessments for final determination of 
eligibility. Screen 1 eligible/consented patients will be registered and randomized to the intervention (simvastatin or 
placebo). 
3 Study Visit 1 (baseline measurements/initiation of the intervention) will occur 0-30 days after Screen 1. 
4 Study Visit 2 will occur 1 month (± 14 days after initiation of the intervention. 
5 Study Visit 3 will occur 3 months (± 14 days) after initiation of the intervention. 
6 Study Visit 4 (last day of study intervention) will occur 6 months (± 30 days) after initiation of the intervention. 
7 Abdominal imaging results will be reviewed during pre-screen medical chart review to determine initial eligibility. An 
abdominal image (CT, MRI, or ultrasound), which is a standard of care procedure for the study population, will be taken 
at Study Visit 4. The abdominal imaging may be done up to the end of follow-up for the study (3 months after completion 
of Study Visit 4 [Visit 4 ± 3 months]). 
8 Because statins are known to be teratogenic, women able to become pregnant will be required to have a urine pregnancy 
test. :RPHQ\HDUVRIDJHZKRKDYHQRWKDGDPHQVWUXDOSHULRGLQWKHSDVW\HDUDQGZRPHQZKRKDYHKDGD
hysterectomy, both ovaries removed, or a tubal ligation; will not be required to have a pregnancy test. Women who are 
pregnant will be excluded from the study. 
9 Blood collection for research: A 20 mL blood specimen will be collected from each participant at Study Visits 1 and 4 
for research purposes. Ten mL of blood will be drawn for measurement of protocol-specific biomarkers (AFP, AFP-L3%, 
IL-6, and bile acids) and 10 mL of blood will be drawn for DNA extraction and use in future studies. 
10 Telephone contact with patients during the screening period to assess eligibility, introduce the study, and answer 
questions. Telephone contact every four weeks (± 7 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 4 to assess adverse events. 
11 Please see Appendix J for VioScreen® instructions for participants. 
 
7.2 
Pre-Study Evaluation and Baseline Testing 
 
7.2.1  Pre-Screen Medical Chart Review – Initial determination of eligibility and recruitment 
 
Patients who have an upcoming usual care appointment with a study hepatologist will be identified and 
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, prior liver transplant, prior statin use, prohibited concomitant medications, previous 
malignancies, medical contraindications, laboratory results, and evidence of HCC from last abdominal 
image (ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI)) occurring within 
the past 18 months. 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 will be done at the Screen 1 visit. 
The research staff will notify the study hepatologist that a patient is potentially eligible for the trial based 
on the pre-screen evaluation. The hepatologist will review the eligibility information and notify research 
staff whether the patient may be considered for participation. An information packet that introduces the 
study may be mailed to potentially eligible patients who may be considered for participation. The packet 
will include the study consent form (ICF), HIPAA authorization, and IRB-approved recruitment materials 
(e.g., introductory letter, leaflet; each participating site will choose what materials to include). One of the 
study hepatologists or clinical research staff will call potentially eligible patients before their scheduled 
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 

NWU2015-06-03 
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–29– 
withdraw from the study at any time. Patients who wish to participate will be consented into the trial at 
their next standard of care visit with a study hepatologist. 
 
For potentially eligible patients who may not be mailed a recruitment packet in advance of the regular 
clinic visit (e.g., new patients or patients added to the schedule late), a study hepatologist will introduce 
the study to the patient during the standard of care clinic visit. The patient may 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 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 sign informed consent documents with the study hepatologist or a member of the clinical 
research team. 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. 
 
7.2.2  Screen 1 – Consent, Final determination of eligibility, Registration, and Randomization  
 
The study hepatologist will review the study details and answer any questions regarding the proposed trial 
after all clinical options have been presented to the patient. After the patient's questions have been 
answered, the study hepatologist will obtain signatures on the consent documents from patients who are 
eligible based on the pre-screen chart review and wish to volunteer for the study. Patients for whom 
Spanish is their preferred language will be consented using a version of ICF translated into Spanish, 
administered by an interpreter. The patient will carefully review and sign the study consent form and 
HIPAA authorization. Copies of each form will be given to the patient and placed in the medical record. 
Written consent will be obtained before any research related procedures are initiated. Participants who 
sign consent will be provided a copy of Appendix D (Food and Medications to Avoid During Your 
Participation in the Study).  
 
After consent has been obtained, a final assessment of eligibility will be conducted. Consented patients 
will undergo additional screening and testing to confirm eligibility and safety of statin initiation. 
1. The study hepatologist will thoroughly review the patient’s medical history, concomitant 
medications, and laboratory test results. 
2. All inclusion and exclusion criteria will be evaluated for the patient. 
3. Symptom assessment and ECOG performance status  
4. Physical assessment including vital signs, measurement of weight, and assessment of liver disease 
sequelae (varices, ascites, and encephalopathy) 
5. A blood specimen (approximately 15 mL) will be collected from patients for blood tests to 
confirm eligibility. If a patient’s lab results are current (within the past 30 days) in the medical 
record and within eligibility range, their blood will not be drawn at the Screen 1 visit. Otherwise, 
the patient’s blood will be drawn to confirm eligibility. A Complete Blood Count and Automated 
Differential (CBDF) (for leukocytes, neutrophils, platelets, and hemoglobin), a Comprehensive 
Metabolic Panel (CMPL) (for liver enzymes (AST/ALT) and for total bilirubin, creatinine, and 
sodium (required for calculation of the MELD score)), and Prothrombin Time (PT/INR) (required 
for calculation of MELD) will be done to confirm that blood levels are within the eligibility 
requirements (acceptable organ function, AST/ALT [XSSHUOLPLWVRIQRUPDODQG0(/'
20). See Appendix E for Clinical Laboratory Minimum Test Requirements. 
6. Women who are able to become pregnant will be required to have a pregnancy test because 
statins are known to be teratogenic. :RPHQ50 years of age who have not had a menstrual 

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–30– 
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. 
 
Patients with a MELD score >20, AST/ALT >5x ULN, or other lab results that do not meet the eligibility 
criteria; and women who are pregnant will be excluded from the study. Following eligibility screening, 
and prior to Study Visit 1, consented patients who qualify for the study after the eligibility evaluations 
will be registered and enrolled in the study and randomized to the intervention (simvastatin or placebo). 
The Screen 1 MELD calculation will be used as the baseline MELD score, and Screen 1 lab values for 
AST, ALT, and platelets (PLT) will be used to calculate the baseline FIB-4 score.  
 
7.2.3  Study Visit 1 – Baseline Testing and Initiation of the intervention  
 
Study Visit 1 (Baseline measurements) will occur 0-30 days after the Screen 1 eligibility visit. The 
following procedures will be performed during this visit: 
1) Review of medical history, medications, and laboratory test results  
2) Symptom assessment and ECOG performance status 
3) Vital signs assessment, including blood pressure, heart rate, and temperature; and measurement of 
height and weight 
4) Blood collection for clinical labs (approximately 10 mL). Laboratory blood tests will be done for 
a Lipid Panel, hemoglobin A1C, and Creatine Phosphokinase (CPK) to establish baseline levels 
prior to initiating the study agent. CBDF and CMPL lab results from the Screen 1 eligibility visit 
will be used to establish patient-specific references prior to initiation of therapy. If blood tests 
were not done at the Screen 1 visit for a CBDF and CMPL; and lab results within 30 days prior to 
this visit for these tests are not available in the medical record, a CBDF and CMPL will be done 
at this visit. See Appendix E for Clinical Laboratory Minimum Test Requirements. 
5) Blood collection for research (20 mL). Ten mL of blood will be collected for measurement of 
protocol-specific biomarkers (AFP, AFP-L3%, IL-6, and bile acids) and 10 mL of blood will be 
drawn for DNA extraction and use in future studies. 
6) Liver elastography (FibroScan). A FibroScan examination will be conducted. Participants will be 
instructed to refrain from eating for 3 hours before the FibroScan examination. The FibroScan 
will be used as a non-invasive measurement of liver stiffness. 
7) Interviewer-administered baseline questionnaire to obtain demographic information (detailed race 
and ethnicity, education); medical and medications history; alcoholic beverage consumption; 
tobacco smoking; and anthropometry (Appendix F) 
8) Food frequency questionnaire (FFQ). The VioScreen® graphical dietary assessment will be self-
administered to capture usual diet over the last 30 days. 
9) Review of study requirements 
10) Dispense the study agent (one bottle of 120 capsules) and review instructions for how to take it 
11) Dispense and review the study diary 
 
7.3 
Evaluation During the Study Intervention 
 
7.3.1  Study Visit 2 
 
Study Visit 2 will occur 1 month (± 14 days) after initiation of the intervention. The following procedures 
will be performed during this visit: 
1) Review of medical history, medications, and laboratory test results  
2) Symptom assessment and ECOG performance status 

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3) Vital signs assessment, including blood pressure, heart rate, and temperature; and measurement of 
weight 
4) Blood collection for clinical labs (approximately 10 mL). Laboratory blood tests will be done for 
a CBDF and CMPL to monitor for potential adverse effects of the intervention. If lab results 
within 30 days prior to this visit for CBDF or CMPL are available in the medical record, the 
blood test(s) will not be repeated. See Appendix E for Clinical Laboratory Minimum Test 
Requirements.  
5) Review of study requirements 
6) Collect study agent and diary 
7) Assess compliance (pill count) 
8) Review study diary 
9) Assess adverse events 
10) Dispense study agent (same bottle that was brought to the visit/collected for pill count) and diary 
 
7.3.2  Study Visit 3 
 
Study Visit 3 will occur 3 months (±14 days) after initiation of the intervention. The following procedures 
will be performed during this visit: 
1) Review of medical history, medications, and laboratory test results  
2) Symptom assessment and ECOG performance status 
3) Vital signs assessment including blood pressure, heart rate, and temperature; and measurement of 
weight 
4) Blood collection for clinical labs (approximately 10 mL). Laboratory blood tests will be done for 
a CBDF, CMPL, Lipid Panel, and hemoglobin A1C to monitor for potential adverse effects of the 
intervention. If lab results within 30 days prior to this visit for any of these tests are available in 
the medical record, the blood test(s) will not be repeated. See Appendix E for Clinical Laboratory 
Minimum Test Requirements. 
5) Review of study requirements 
6) Collect study agent and diary 
7) Assess compliance (pill count) 
8) Review study diary 
9) Assess adverse events 
10) Dispense study agent (one new bottle of 120 capsules) and diary 
 
7.3.3 
Telephone Calls and Email/Text Messages 
 
Study participants will be followed during the intervention via telephone calls every four weeks (± 7 
days) by the clinical research staff to assess compliance and adverse events. Participants who report 
having taken < 85% of the study drug doses between phone calls, or whose pill count at a study visit 
reveals < 85% compliance, will be called every two weeks (± 3 days) to monitor compliance. 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 if it occurs in person. For remote visits 
patients will be reminded to photograph their study diary and any unused study agent. Study participants 
will also be called during the week before their final visit (Visit 4) to remind them to take the study drug 
every day until the visit appointment. 
 

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Participants who opt to receive reminders for study medication intake via email or text messages will be 
contacted by the study staff during the first week of study and further as needed. The study staff will send 
emails or text messages on cellular phone; participants will be encouraged to respond to these messages 
indicating if the study drug has been taken. These responses will be used to assess compliance and will be 
reviewed during phone contacts. For participants who miss more than one dose of the study drug in a 
week, the email/text reminders will continue further into dosing period. Since agent compliance is very 
important during the final week of the intervention, text/email messages will be sent to all study 
participants who opt to receive these reminders.  
 
The following information with be collected during the telephone calls: 
x 
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. 
x 
Concomitant medications review 
x 
Adverse events: participants will be asked if they have experienced any of the following 
symptoms to assess adverse events:  
o Upper respiratory infection 
o Headache 
o Abdominal pain 
o Constipation 
o Nausea 
o Vomiting 
o Mild muscle aches 
x 
Additional symptoms experienced by participants will be recorded to assess adverse events  
 
7.4 
Evaluation at Completion of the Study Intervention 
 
7.4.1  Study Visit 4 
 
The final study visit will occur 6 months (± 30 days) after initiation of the intervention. Study Visit 4 is 
concurrent with a standard of care visit. The following procedures will be performed during this visit: 
1) Review of medical history, medications, and laboratory test results  
2) Symptom assessment and ECOG performance status 
3) Physical assessment including vital signs, measurement of weight, and assessment of liver disease 
sequelae (varices, ascites, and encephalopathy) 
4) Blood collection for clinical labs (approximately 15 mL). Laboratory blood tests will be done for 
a CBDF, CMPL, Lipid Panel, and hemoglobin A1C to monitor for potential adverse effects of the 
intervention; and for measurement of Prothrombin Time (PT/INR) to calculate the MELD score. 
Clinical lab results (AST, ALT, and platelets (PLT)) will also be used to calculate the FIB-4 
score. If lab results within 30 days prior to this visit for any of these tests are available in the 
medical record, the blood test(s) will not be repeated. See Appendix E for Clinical Laboratory 
Minimum Test Requirements. 
5) Blood collection for research (20 mL). Ten mL of blood will be collected for measurement of 
protocol-specific biomarkers (AFP, AFP-L3%, IL-6, and bile acids) and 10 mL of blood will be 
drawn for DNA extraction and use in future studies. 
6) Liver elastography (FibroScan). A FibroScan examination will be conducted. Participants will be 
instructed to refrain from eating for 3 hours before the FibroScan examination. The FibroScan 
will be used as a non-invasive measurement of liver stiffness. 

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7) Abdominal imaging. An abdominal image (CT, MRI, or ultrasound) will be taken for standard of 
care HCC surveillance. The abdominal imaging may be done up to the end of follow-up for the 
study (3 months after completion of Study Visit 4 [Visit 4 ± 3 months]). 
8) Collect study agent and diary 
9) Assess compliance (pill count) 
10) Review study diary 
11) Assess adverse events 
 
7.5 
Post-intervention Follow-up Procedures 
 
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 4 to assess symptoms and adverse events.  
 
7.6 
Methods for Clinical Procedures 
 
Blood specimen. A blood specimen (approximately 15 mL) will be collected from each participant at the 
Screen 1 eligibility visit for blood tests to confirm eligibility. If a patient’s lab results are current (within 
the past 30 days) in the medical record and within eligibility range, their blood will not be drawn at the 
Screen 1 visit. Otherwise, the patient’s blood will be drawn to confirm eligibility. Clinical labs will be 
done for a Complete Blood Count and Automated Differential (CBDF), a Comprehensive Metabolic 
Panel (CMPL), and Prothrombin Time (PT/INR). The CBDF includes tests for leukocytes, neutrophils, 
platelets, and hemoglobin; test results will be used to establish acceptable organ function necessary for 
trial eligibility. The CMPL includes tests for liver enzymes (AST/ALT); and for total bilirubin, creatinine, 
and sodium for calculation of the MELD score. Prothrombin Time is required for calculation of MELD. 
The CMPL and PT/INR test results will be used to confirm that blood levels are within the eligibility 
requirements (acceptable organ function, AST/ALT [XSSHUOLPLWVRIQRUPDODQG0(/' 
 
A blood specimen (approximately 10-15 mL) will be collected from each participant at Study Visits 1, 2, 
3, and 4 for blood tests to monitor for potential adverse effects of the intervention. The date and time of 
the blood draw and the participant’s last meal will be recorded. A Lipid Panel and hemoglobin A1C will 
be done at Study Visits 1, 3, and 4. A CBDF and CMPL will be done at Study Visits 2, 3, and 4. Creatine 
Phosphokinase (CPK) will be measured at Study Visit 1. Prothrombin Time (PT/INR) will be done at 
Study Visit 4 to calculate the MELD score. See Appendix E for Clinical Laboratory Minimum Test 
Requirements.  
 
The CMPL and CBDF test results will be utilized to screen for any issues that could be related to an 
adverse event or affect eligibility for continuation in the trial. It is the consensus of the liver expert panel 
that obtaining baseline liver enzymes (AST/ALT) and monitoring them is optimal in the care of statin-
treated patients [115]. CBDF and CMPL lab results from the Screen 1 eligibility visit (blood collected at 
most 30 days prior to Study Visit 1) will be used to establish patient-specific references prior to initiation 
of therapy. If blood tests were not done at the Screen 1 visit for a CBDF and CMPL; and lab results 
within 30 days prior to Study Visit 1 for these tests are not available in the medical record, a CBDF and 
CMPL will be done at Study Visit 1. The Lipid Panel includes tests for cholesterol, high density 
lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides. Since the study agent is a 
cholesterol lowering agent, we feel that it is important to establish baseline lipid levels prior to initiating 
the study agent (Study Visit 1) and monitor lipids at Study Visits 3 and 4 (3- and 6-month visits). 
Hemoglobin A1C is used to assess glucose control in insulin-dependent diabetics whose glucose levels 
are very labile and in whom single blood glucose measurements may not accurately reflect the level of 
control present over the preceding few weeks. Glucose and hemoglobin A1C will be used for monitoring 
adverse events (incident diabetes) during the trial. CPK will be tested to establish a baseline for 

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monitoring myopathy, a rare complication associated with the study agent (<1%). We will measure levels 
of CPK at Study Visit 1 to establish a patient-specific reference for this indicator of muscle toxicity. If the 
participant reports unexplained muscle pain or weakness during the trial, CPK will be tested again to 
check for elevation. 
 
An additional blood specimen (20 mL) will be collected from each participant at Study Visits 1 and 4 for 
research purposes. The blood will be drawn into one 10 mL red top serum vacutainer tube for 
measurement of protocol-specific biomarkers (AFP, AFP-L3%, IL-6, deoxycholic acid, and other serum 
bile acids and immune markers), and one 10 mL lavender top EDTA tube for DNA extraction and use in 
future studies.  
 
Liver elastography (FibroScan). A FibroScan examination will be conducted at Study Visits 1 and 4. 
Participants will be instructed to refrain from eating for 3 hours before the FibroScan examination. The 
FibroScan will be used as a non-invasive measurement of liver stiffness. Patients will be placed in a 
supine position with the right hand at the most abducted position for right intercostal scanning. The probe 
will be placed over a small amount of water based gel with slight pressure, and ten effective 
measurements will be made at the same location such that the interquartile range is less than 30%. The 
median measurement will be employed as the result of the test, provided as a number between 1.5 and 75 
kPa (the stiffer the liver, the higher the number). The test result provides a look at the state of the liver 
globally, as opposed to a biopsy where only a very small sample is measured. The test takes about 10 
minutes, and the result is delivered immediately at the end. 
 
Abdominal imaging. Abdominal imaging is done every 6 months for HCC surveillance and is standard 
of care in this high-risk study population. At CSMC and UPR, computed tomography (CT) with contrast 
and ultrasound are alternated every 6 months. At NWU and GU, magnetic resonance imaging (MRI) is 
done every 6 months. Typically, imaging occurs within a few weeks prior to the patient’s clinical 
appointment with hepatology, when the Screen 1 eligibility assessments will be conducted. Another 
standard of care abdominal image will be taken for all trial participants at Study Visit 4. The abdominal 
imaging may be done up to the end of follow-up for the study (3 months after completion of Study Visit 4 
[Visit 4 ± 3 months]). 
 
Biomarkers. AFP and AFP-L3% will be assessed for each participant by Quest Diagnostics using a 
liquid-phase binding assay system. Serum IL-6 expression and other serum immune markers will be 
assessed by Olink Explore Proximity Extension Assay (PEA) (Waltham, MA). All samples will be run in 
a single batch after all participants have completed their 6-month study visit. Deoxycholic acid and other 
serum bile acids will be measured using liquid chromatography coupled with mass spectrometry (LC-
MS/MS) utilizing Agilent 1290 UHPLC/Sciex QTRAP 6500+, triple quadrupole linear ion trap mass 
spectrometer by Metabolon® (Durham, NC) in a single batch at the end of the study. 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
The overall objective of this trial is to examine the effects of simvastatin use versus placebo at 6 months 
from baseline (Study Visit 1) on liver function in high-risk patients with liver cirrhosis who have a current 
Model for End-6WDJH/LYHU'LVHDVH0(/'DQGQRHYLGHQFHRIKHSDWRFHOOXODUFDUFLQRPD+&&
Participants will be on the study drug from Study Visit 1 until the last study visit (Study Visit 4 at 6 
months). Primary and secondary endpoints are measured in blood samples. 
 
8.1 
Primary Endpoint 
 
The primary endpoint is change in serum AFP-L3% from baseline to 6 months following treatment 
initiation. We hypothesize that participants randomized to simvastatin will experience a decrease from 

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baseline to 6 months in serum AFP L3% compared to the placebo group. In the treatment group, we 
expect change of 2.8%, with standard deviation=5.3% in both groups (or smaller). A 2.8% decline is 
clinically relevant given that prior studies report higher differences (7.9%) in AFP-L3% between 
cirrhotics without HCC and cirrhotics who progress to HCC [50]. 
 
8.2 
Secondary and Exploratory Endpoints 
 
Secondary endpoints include additional measures of liver function and disease progression. Changes in 
secondary endpoints from baseline to 6 months follow-up will be compared between the simvastatin and 
placebo groups using a similar approach to the main endpoint. 
 
8.2.1  Change in serum AFP. We hypothesize that participants randomized to simvastatin will 
experience a decrease from baseline in serum AFP levels compared to the placebo group. 
 
8.2.2 
Change in serum IL-6. We hypothesize that participants randomized to simvastatin will 
experience a decrease from baseline in serum IL-6 compared to the placebo group. 
 
8.2.3  Change in serum deoxycholic acid (DCA)  levels. We hypothesize that participants randomized to 
simvastatin will experience a decrease from baseline in serum DCA (deoxycholic acid) levels compared 
to the placebo group. 
 
8.2.4  Change in liver stiffness. We hypothesize that participants randomized to simvastatin will 
experience a decrease from baseline in liver stiffness compared to the placebo group. 
 
8.2.5  Change in FIB-4 score. We hypothesize that participants randomized to simvastatin will 
experience a decrease from baseline in FIB-4 score compared to the placebo group. 
 
8.2.6  Change in MELD score. We hypothesize that participants randomized to simvastatin will 
experience a decrease from baseline in MELD score compared to the placebo group. 
 
Exploratory endpoints include additional measures of other serum bile acids and immune markers. 
Differences in exploratory endpoints from baseline to 6 months follow-up will be compared in the 
simvastatin and placebo groups using a similar approach to the main endpoint. 
 
8.2.7 
Change in serum bile acids.  
 
8.2.8 
Change in serum immune markers. 
  
8.3 
Off-Agent Criteria  
 
Participants may stop taking study agent for the following reasons: completed the protocol-prescribed 
intervention, AE or serious adverse event (SAE), inadequate agent supply, noncompliance, concomitant 
medications, or medical contraindication. See Section 5.6. Dose Modification for additional off-agent 
criteria. 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 7.5, clinical research staff will make follow-up telephone calls to the participant 
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, concomitant medications, laboratory test 
results, imaging results) will continue to be collected via review of the participant’s electronic medical 
record at the time points specified in the Schedule of Events. If feasible, we will conduct a research visit 

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to collect final measurements for participants who permanently discontinue the study agent early. An end-
of-study research visit will be conducted 6 months (± 30 days) after initiation of the statin intervention 
(Study Visit 4). The procedures that will be performed during the end-of-study visit are described in 
section 7.4.1 Study Visit 4. 
 
8.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons:  
x 
Adverse Event 
x 
Death  
x 
Disease Progression 
x 
Lost to follow-up/Participant Withdrawal 
x 
Participant Refused Follow-up 
x 
Physician Decision 
x 
Protocol Defined Follow-up Completed 
x 
Protocol Violation   
x 
Study Complete  
x 
Ineligible 
x 
Other  
 
8.5 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
Continuous assessment of the 40 mg dose of simvastatin 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. 
 
9. 
CORRELATIVE/SPECIAL STUDIES 
 
9.1 
Rationale for Methodology Selection 
 
AFP and AFP-L3% will be measured by Quest Diagnostics on two specimen-visits per participant using 
a liquid-phase binding assay system. Samples will be sent to Quest from serum samples collected at Study 
Visits 1 and 4. All samples will be run in a single batch after all participants have completed their 6-
month study visit. Ion exchange chromatography will be employed to separate AFP-L3 and non-APR-L3 
glycoforms. The analytic sensitivity of the assay are 0.8 ng/mL for AFP, and 0.5% for AFP-L3. The 
reference ranges for AFP are 0-15 ng/mL, and for AFP-L3 are 0-9.9%.  
 
Serum IL-6 and other serum immune marker expression will be assessed by Olink (Waltham MA) on 
two specimen-visits per participant. Samples will be run in  Olink Explore, a biomarker platform that uses 
Proximity Extension Assay (PEA) technology combined with an innovative new readout methodology 
based on Next Generation Sequencing (NGS). This will be completed in a single batch once all 
participants have completed their 6-month study visit, and both samples from the same participant will be 
batched onto the same analytic plate.  
 
Serum deoxycholic acid and other serum bile acids will be measured using Metabolon® (Durham, NC) 
Bile Acid targeted panel and assays. Metabolon® applies a specific combination of liquid chromatography 

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coupled with mass spectrometry technology (LC-MS/MS) utilizing Agilent 1290 UHPLC/Sciex QTRAP 
6500+, triple quadrupole linear ion trap mass spectrometer in a single batch. Metabolon’s® Bile Acid 
Panel was chosen for bile acid testing given Metabolon’s® significant experience [118-120]. The Liquid 
Chromatograph Mass Spectrometer is an analytical chemistry technique that combines the physical 
separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry. 
Scheduled multiple reaction monitoring (MRM) is performed with optimized collision energies, de-
clustering potentials, and collision cell exit potentials for the individual analytes. All analytes are 
quantified against 6-point calibration curves using internal standards. 
 
Liver Stiffness will be assessed by liver elastography (FibroScan®) examination at Study Visits 1 and 4. 
Participants will be instructed to refrain from eating for 3 hours before the FibroScan examination. 
FibroScan examination is a non-invasive measurement of liver fibrosis that uses a patented technique 
called Vibration Controlled Transient Elastography (VCTE™) to measure the elasticity of the liver. 
VCTE allows non-invasive measurement of liver shear wave speed in m/s which is correlated with the 
elasticity of the liver tissue (stiffness) in kPa. As the shear wave passes through the liver, it is affected by 
the amount of scarring (fibrosis), and this is interpreted to give an accurate global assessment of the stage 
of fibrosis (fibrosis staging). FibroScan uses a button shaped probe with an ultrasound transducer that is 
placed at the skin surface. The probe generates a series of mechanical pulses (shear waves) that travel 
through the liver. The FibroScan measures the velocity of the shock wave, which correlates with the 
stiffness of the liver. Patients will be placed in a supine position with the right hand at the most abducted 
position for right intercostal scanning. The probe will be placed over a small amount of water based gel 
with slight pressure, and ten effective measurements will be made at the same location such that the 
interquartile range is less than 30%. This data is automatically processed by the on-board computer and 
the liver stiffness is displayed on the computer screen. The median measurement will be employed as the 
result of the test, provided as a number between 1.5 and 75 kPa (the stiffer the liver, the higher the 
number). A test result of >20 kPa is generally associated with an increased HCC risk [81]. The advantage 
of FibroScan over biopsy is that it provides a look at the state of the liver globally, as opposed to a biopsy 
where only a very small sample is measured. The test takes about 10 minutes, and the result is delivered 
immediately at the end. 
 
9.2 
Comparable Methods 
 
Proposed methods represent standard technology for measuring the study biomarkers. 
 
10. 
SPECIMEN MANAGEMENT  
 
10.1 
Laboratories 
 
1) Study blood tests will be done for a Complete Blood Count and Automated Differential 
(CBDF), a Comprehensive Metabolic Panel (CMPL), Prothrombin Time (PT/INR), a Lipid 
Panel, hemoglobin A1C, and Creatine Phosphokinase (CPK) at the clinical or local 
laboratories at each study site; or the blood tests will be done at an external CLIA-certified 
clinical laboratory as required by the participant’s health insurance carrier.  
 
2) At CSMC, specimen processing and aliquoting of blood samples collected for protocol-
specific biomarker testing and for use in future studies will be performed by the CSMC 
Biobank & Translational Research Core Laboratory. Along with general supplies, the 
laboratory is fully equipped with the following instrumentation: Refrigerated Centrifuge, 
Ambient Centrifuge, -20ºC Freezer, -80ºC Freezer, 32ºF Refrigerator, laboratory hood, water 
bath, Vortex Machine, calibrated pipettes, dry ice, and supplies. Freezers and refrigerators are 
on daily temperature monitoring and records are meticulously kept and stored for 

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documentation. These main instruments are also on red outlet plugs such that they trigger 
backup generator electricity in case of a black out. All instrumentation is calibrated prior to 
use and maintained yearly by the Biomedical Engineering Services department.  
 
3)  At NWU, specimen processing, aliquoting, and shipping of blood samples collected for 
protocol-specific biomarker testing and for use in future studies will be performed by 
Northwestern University Clinical and Translational Sciences Institute Clinical Research Unit 
and Core Lab. The lab is IATA, CAP and CLIA certified and has 570 square feet of space for 
both clinical and research specimen processing and analytical work (RIA; ELISA). The Core 
lab also has a 65 square-foot walk-in cold room for assay incubation and freezer storage at -
30°C and -70ºC. It accepts specimen submission 24 hours a day, 365 days a year, utilizes the 
“Freezerworks” bar code and inventory system and provides shipment of ambient and frozen 
research samples. 
 
4) At GU, specimen processing, aliquoting, and shipping of blood samples collected for 
protocol-specific biomarker testing and for use in future studies will be performed by the 
Georgetown Clinical Research Unit (GU-CRU) located on 7th floor East Wing of the Main 
Building, Georgetown University Hospital. This location is central to the medical center, and 
is convenient for investigators, clinicians, staff, patients and families. The GU-CRU is 
equipped to provide around-the-clock support for research studies, seven days a week. The 
GU-CRU provides 10 patient-care rooms and occupies approximately 5411 square feet of 
space. It has the flexibility to support inpatient or outpatient services, thereby maximizing use 
of all rooms (2 are dedicated for cognitive testing; 4 are dedicated for outpatient testing; 4 are 
for mixed inpatient/outpatient use). The CRU is equipped with freezer storage at -30°C and -
70ºC. It accepts specimen submission 24 hours a day, 365 days a year, utilizes the 
“Freezerworks” bar code and inventory system and provides shipment of ambient and frozen 
research samples. 
 
5)  At the UPR, specimen processing, aliquoting, and shipping of blood samples collected for 
protocol-specific biomarker testing and for use in future studies will be performed by the 
NIH-funded Biomedical Laboratory of the PR Clinical & Translational Research Consortia 
(Medical Sciences Campus). The lab is IATA, CAP and CLIA certified and has 500 square 
feet of space for both clinical and research specimen processing and analytical work (RIA; 
ELISA). The Core lab also has a freezer storage at -70ºC, -20C and refrigerators. It accepts 
specimen submission during business hours Monday to Friday from 7 am to 5 pm.  After hour 
services are available upon request. 
 
6)  Measurement of serum AFP and AFP-L3% will be performed by Quest Diagnostics Nichols 
Institute. Quest is the world’s leading provider of diagnostic testing services, serving about 
half of the physicians and hospitals in the U.S., with a medical and scientific staff of more 
than 700 M.D.s and Ph.D.s. Quest has strong logistics capabilities, including approximately 
3,000 courier vehicles and 20 aircraft that collectively make tens of thousands of stops daily. 
Quest Diagnostics Nichols Institute focuses on specialized and highly complex laboratory 
testing and plays a key role in Quest Diagnostics research and development efforts, 
performing tests rarely done in most routine or hospital laboratories.  
 
7)   Measurement of serum IL-6 and other immune marker expression will be performed by   
Olink Proteomics, Inc. in Waltham, MA.    
 
8)    Measurement of serum deoxycholic acid and other bile acids will be performed at 
Metabolon®.  

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10.2 
Collection and Handling Procedures 
 
Research study staff at CSMC, NWU, GU, and UPR will receive specific instructions for collection, 
processing, and shipment of specimens.  
 
Blood specimen. A blood specimen (approximately 15 mL) will be collected from each participant at the 
Screen 1 eligibility visit for blood tests to confirm eligibility. If a patient’s lab results are current (within 
the past 30 days) in the medical record and within eligibility range, their blood will not be drawn at the 
Screen 1 visit. Otherwise, the patient’s blood will be drawn to confirm eligibility. Clinical labs will be 
done for a Complete Blood Count and Automated Differential (CBDF), a Comprehensive Metabolic 
Panel (CMPL), and Prothrombin Time (PT/INR). The CBDF includes tests for leukocytes, neutrophils, 
platelets, and hemoglobin; test results will be used to establish acceptable organ function necessary for 
trial eligibility. The CMPL includes tests for liver enzymes (AST/ALT); and for total bilirubin, creatinine, 
and sodium for calculation of the MELD score. Prothrombin Time is required for calculation of MELD. 
The CMPL and PT/INR test results will be used to confirm that blood levels are within the eligibility 
requirements (acceptable organ function, AST/ALT [XSSHUOLPLWVRIQRUPDODQG0(/' 
 
A blood specimen (approximately 10-15 mL) will be collected from each participant at Study Visits 1, 2, 
3, and 4 for blood tests to monitor for potential adverse effects of the intervention. The date and time of 
the blood draw and the participant’s last meal will be recorded. A Lipid Panel and hemoglobin A1C will 
be done at Study Visits 1, 3, and 4. A CBDF and CMPL will be done at Study Visits 2, 3, and 4. If blood 
tests were not done at the Screen 1 visit for a CBDF and CMPL; and lab results within 30 days prior to 
Study Visit 1 for these tests are not available in the medical record, a CBDF and CMPL will also be done 
at Study Visit 1. Creatine Phosphokinase (CPK) will be measured at Study Visit 1. Prothrombin Time 
(PT/INR) will be done at Study Visit 4 to calculate the MELD score. See Appendix E for Clinical 
Laboratory Minimum Test Requirements.  
 
An additional blood specimen (20 mL) will be collected from each participant at Study Visits 1 and 4 for 
research purposes. The blood will be drawn into one 10 mL red top serum vacutainer tube for 
measurement of protocol-specific biomarkers (AFP, AFP-L3%, IL-6, and bile acids), and one 10 mL 
lavender top EDTA tube for DNA extraction and use in future studies. The blood will be transported to 
the research laboratories at CSMC, NWU, GU, and UPR, and processed within two hours of collection. 
The vacutainer tubes will be centrifuged as specified in the Laboratory Manual. After centrifugation, vials 
will be prepared from the blood specimens for research testing. Specimen aliquots from NWU, GU, and 
UPR will be packaged and shipped overnight on dry ice to CSMC. Aliquots will be stored at -80oC until 
analyses, DNA extraction, and use in future studies. 
 
10.3 
Shipping Instructions 
 
Blood samples collected for laboratory blood tests (Complete Blood Count and Automated Differential 
(CBDF), Comprehensive Metabolic Panel (CMPL), Prothrombin Time (PT/INR), Lipid Panel, 
hemoglobin A1C, and Creatine Phosphokinase (CPK)) will be transported to the clinical laboratories at 
each study site for processing and testing; or the blood will be drawn and tested at an external CLIA-
certified clinical laboratory as required by the participant’s health insurance carrier. 
 
Blood samples collected for research will be transported to the designated research laboratories at CSMC, 
NWU, GU, and UPR for processing. 
 

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At CSMC, research study staff will transport the blood samples to the Biobank & Translational Research 
Core Laboratory for processing: 
Cedars-Sinai Biobank & Translational Research Core Laboratory 
Steven Spielberg Building, Room 110 
8723 W. Alden Drive 
Los Angeles, CA 90048  
Telephone: (310) 423-9379 
 
At Northwestern, research study staff will transport the blood samples to the NWU Clinical and 
Translational Sciences Institute Clinical Research Unit and Core Lab: 
Clinical Research Unit Core Lab 
251 E. Huron, Feinberg Pavilion 
Suite 10-754  
Chicago, IL  60611 
Telephone: (312) 227-4083 
 
At Georgetown University, blood will be drawn and processed at the Clinical Research Unit: 
Clinical Research Unit  
Georgetown University Medical Center 
7 East, Main Bldg., M7309 
3800 Reservoir Road, NW  
Washington DC 20007 
Telephone: 202-444-2639 
Fax: 202-444-1505 
 
At the University of Puerto Rico, research study staff will transport the blood samples to the Puerto Rico 
Clinical and Translational Research Consortium: 
 
Puerto Rico Clinical and Translational Research Consortium        
1st Floor University Hospital Medical Sciences Campus                 
PO Box 365067                                                                                 
San Juan PR 00936-5067     
 
Processed blood samples collected for research at NWU, GU, and UPR (blood specimen aliquots) will be 
shipped to the CSMC specimen manager. Please see the study’s Laboratory Manual for the shipping 
address. 
 
The CSMC specimen manager will package and ship serum samples for measurement of AFP and AFP-
L3% to Quest Diagnostics. Shipping address for Quest Diagnostics:  
Quest Diagnostics  
Nichols Institute 
33608 Ortega Highway 
San Juan Capistrano, CA 92675-2042 
Telephone: (949) 728-4000 
 
The CSMC specimen manager will package and ship serum samples for measurement of bile acids to 
Metabolon®. Shipping address Metabolon®:  
Metabolon Sample Acceptance 
617 Davis Drive, Suite 400 
Morrisville, NC 27560 
Telephone: (919) 572-1711 
 

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The CSMC specimen manager will transport serum samples for measurement of serum immune markers 
to Olink Proteomics, Inc. Shipping address for Olink:  
Olink Proteomics, Inc.  
130 Turner St.  
Building 2, Suite 230 
Waltham, MA 02453 
Telephone: (617) 393-3933 
 
All processed blood samples will be shipped overnight in dry ice. All samples will be shipped on Monday 
or Tuesday in compliance with the International Air Transport Association (IATA) Dangerous Goods 
Regulations.  
 
10.4 
Tissue Banking 
 
Biologic specimens collected during the conduct of each clinical trial that are not used during the course 
of the study will be considered deliverables under the contract and thus the property of the NCI. At study 
completion, NCI reserves the option to either retain or relinquish ownership of the unused biologic 
specimens. If NCI retains ownership of specimens, the Contractor shall collect, verify, and transfer the 
requested biologic specimens from the site to a NCI-specified repository or laboratory at NCI’s expense.  
 
11. 
REPORTING ADVERSE EVENTS  
 
DEFINITION: AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE can therefore be any unfavorable and unintended sign), 
symptom, or disease temporally associated with participation in a study, whether or not related to that 
participation. This includes all deaths that occur while a participant is on a study. 
 
Please note that all abnormal clinical laboratory values that are determined to be of clinical significance 
based on a physician’s assessment are to be reported as AEs. Those labs determined to be of no clinical 
significance or of unknown clinical significance (per the physician’s assessment) should not be reported 
as AEs. Any lab value of unknown clinical significance should continue to be investigated/followed-up 
further for a final determination, if possible. 
 
A list of AEs that have occurred or might occur can be found in §6.2 Reported Adverse Events and 
Potential Risks, as well as the Investigator Brochure or package insert.  
 
11.1 
Adverse Events 
 
11.1.1 Reportable AEs 
 
All AEs that occur after the informed consent is signed and baseline assessments are completed 
(including run-in) must be recorded on the AE CRF (paper and/or electronic) whether or not related to 
study agent. 
 
11.1.2 AE Data Elements 
 
The following data elements are required for AE reporting. 
x 
AE verbatim term 
x 
NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term) 
x 
CTCAE (MedDRA) System Organ Class (SOC) 

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x 
Event onset date and event ended date 
x 
Treatment assignment code (TAC) at time of AE onset 
x 
Severity grade 
x 
Attribution to study agent (relatedness) 
x 
Whether or not the event was reported as a SAE 
x 
Whether or not the participant dropped due to the event 
x 
Outcome of the event 
 
11.1.3  Severity of AEs 
 
11.1.3.1 Identify the AE using the CTCAE version 4.0. The CTCAE provides descriptive terminology 
(MedDRA lowest level term) and a grading scale for each AE listed. A copy of the CTCAE can be found 
at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
AEs will be assessed according to the grade associated with the CTCAE term. AEs that do not have a 
corresponding CTCAE term will be assessed according to the general guidelines for grading used in the 
CTCAE v4.0 as stated below.  
 
CTCAE v4.0 general severity guidelines:  
Grade 
Severity 
Description  
1 
Mild 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2 
Moderate 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living 
(ADL)*. 
3 
Severe 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL**. 
4 
Life-threatening 
Life-threatening consequences; urgent intervention indicated. 
5 
Fatal 
Death related to AE. 
   
ADL 
*Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
**Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
11.1.4 Assessment of relationship of AE to treatment 
 
 
The possibility that the AE is related to study agent will be classified as one of the following: not related, 
unlikely, possible, probable, definite. 
  
11.1.5 Follow-up of AEs 
 
All AEs, including lab abnormalities that in the opinion of the investigator are clinically significant, will 
be followed according to good medical practices and documented as such.  
 
11.2 
Serious Adverse Events  

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11.2.1 DEFINITION: Regulations at 21 CFR §312.32 (revised April 1, 2014) defines an SAE as any 
untoward medical occurrence that at any dose has one or more of the following outcomes: 
 
• 
Death 
• 
A life-threatening AE 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to perform normal life 
functions 
• 
A congenital anomaly or birth defect 
• 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization should also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require intervention to 
prevent one of the other outcomes. 
 
11.2.2 Reporting SAEs to DCP 
 
11.2.2.1 The Lead Organization and all Participating Organizations will report SAEs on the DCP SAE 
Report Form found at http://prevention.cancer.gov/clinical-trials/clinical-trials-management/protocol-
information-office/pio-instructions-and-tools/2012-consortia. 
 
11.2.2.2 Contact the DCP Medical Monitor by phone within 24 hours of knowledge of the event.  
 
DCP Medical/Task Order Monitor  
Luz Maria Rodriguez, MD, FACS  
NCI/Division of Cancer Prevention  
9609 Medical Center Dr.  
Rm 5E-228  
Bethesda, MD 20892 
Telephone (240) 276-7039  
Fax (240) 276-7848  
Email: rodrigul@mail.nih.gov 
 
Include the following information when calling the Medical Monitor: 
x 
Date and time of the SAE 
x 
Date and time of the SAE report 
x 
Name of reporter 
x 
Call back phone number 
x 
Affiliation/Institution conducting the study 
x 
DCP protocol number 
x 
Title of protocol 
x 
Description of the SAE, including attribution to drug 
 
11.2.2.3 The Lead Organization and all Participating Organizations will email written SAE reports to 
the following within 48 hours of learning of the event using the fillable PDF SAE Report Form.  
x 
DCP’s Regulatory Contractor CCS Associates, Inc. (CCSA; phone: 650-691-4400) at 
safety@ccsainc.com 
x 
DCP Medical Monitor, Dr. Luz Rodriguez (rodrigul@mail.nih.gov) 
x 
Northwestern Cancer Prevention Consortium (ncpc@northwestern.edu) 
 

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11.2.2.4 The DCP Medical Monitor and CCSA regulatory and safety staff will determine which SAEs 
require FDA submission as IND safety reports. 
 
11.2.2.5 The Lead Organization and all Participating Organizations will comply with applicable 
regulatory requirements related to reporting SAEs to the CIRB/IEC.  
 
11.2.3 Follow-up of SAE 
 
Site staff should send follow-up reports as requested when additional information is available. Additional 
information should be entered on the DCP SAE Report Form in the appropriate format. Follow-up 
information should be sent to DCP as soon as available. All SAEs will be followed according to standard 
of care. SAEs possibly, probably, or definitely related to the study agent will be followed until resolved.  
  
12. 
STUDY MONITORING 
 
12.1 
Data Management 
 
Data will be managed by the study statistician, Dr. Kocherginsky according to standard operating 
procedures, which meet the guidelines of DCP Requirements for Data Management and which follow the 
Data Management Plan that Northwestern University has on file with the Division of Cancer Prevention, 
NCI. Source data verification will be performed by the Northwestern Cancer Prevention Consortium. The 
Consortia 2012 Data Management Plan, submitted as part of a contract agreement with the NCI 
(HHSN261201200035I), was approved.  
 
Clinical data will be reported to Northwestern University through the Lurie Cancer Center Clinical Trials 
Management System (CTMS), which will be the database of record.  
 
12.2 
Case Report Forms 
 
Participant data will be collected using protocol-specific case report forms (CRFs) developed from the 
standard set of DCP Chemoprevention CRF Templates and utilizing NCI-approved Common Data 
Elements (CDEs). The approved CRFs will be used by Northwestern University to create the electronic 
CRFs (e-CRFs) screens in the CTMS-RDC application. Site staff will enter data into the e-CRFs for 
transmission to DCP according to DCP standards and procedures. 
 
All specimen results that are batch analyzed will be collected and stored on excel spreadsheets. The excel 
spreadsheets will constitute the database of record.  
 
12.3 
Source Documents 
 
All source documents will be collected and stored by the research staff at the site of accrual. Any data 
recorded directly in CTMS that constitute no prior written or electronic record of data, will be specifically 
identified as source data. Questionnaires completed in person may be completed on the paper and entered 
into CTMS.  
 
12.4 
Data and Safety Monitoring Plan 
 
A comprehensive Data Safety and Monitoring Plan has been submitted by Northwestern University, 
approved by the DCP, and is on file there. Any future changes will be forwarded for review.  
 
This trial is subject to review by the Lurie Cancer Center Data Monitoring Committee (DMC). Semi-

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Annual reports, SAEs, and protocol deviations will be reviewed by the DMC at bi-weekly meetings. This 
trial is also subject to possible annual audits by the Lurie Cancer Center Clinical Trials Audit Committee 
(CTAC).  
 
12.5 
Sponsor or FDA Monitoring 
 
The NCI, DCP (or their designee), pharmaceutical collaborator (or their designee), or FDA may 
monitor/audit various aspects of the study. These monitors will be given access to facilities, databases, 
supplies, and records to review and verify data pertinent to the study.  
 
12.6 
Record Retention 
 
Clinical records for all participants, including CRFs, all source documentation (containing evidence to 
study eligibility, history and physical findings, laboratory data, results of consultations, etc.), as well as 
IRB records and other regulatory documentation will be retained by the Investigator in a secure storage 
facility in compliance with Health Insurance Portability and Accountability Act (HIPAA), Office of 
Human Research Protections (OHRP), Food and Drug Administration (FDA) regulations and guidances, 
and NCI/DCP requirements, unless the standard at the site is more stringent. The records for all studies 
performed under an IND will be maintained, at a minimum, for two years after the approval of a New 
Drug Application (NDA). For NCI/DCP, records will be retained for at least three years after the 
completion of the research. NCI will be notified prior to the planned destruction of any materials. The 
records should be accessible for inspection and copying by authorized persons of the Food and Drug 
Administration. If the study is done outside of the United States, applicable regulatory requirements for 
the specific country participating in the study also apply. 
 
12.7 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA) 
 
Not applicable. 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description 
 
This is a randomized double-blinded, placebo-controlled Phase II trial of statin to evaluate the impact of 
statin treatment on disease progression in 80 patients with liver cirrhosis who have a current Model for 
End-6WDJH/LYHU'LVHDVH0(/'DQGQRHYLGHQFHRIKHSDWRFHOOXODUFDUFLQRPD+&&7KHSULPDU\
objective of this study will be to demonstrate that statins will improve liver function in high-risk patients. 
The primary outcome is change from baseline (Study Visit 1) at 6 months in AFP-L3%. Secondary 
outcomes will include additional measures of liver function (serum AFP, IL-6 and DCA levels, liver 
stiffness, FIB-4 score, and MELD score). 
 
13.2 
Randomization/Stratification  
 
Patients will be randomized by the study statistician at Northwestern University. Randomization will be 
carried out among consented patients meeting the Screen 1 eligibility criteria at each site (CSMC, NWU, 
GU, and UPR) with a 1:1 ratio for simvastatin and placebo assignment. 
 
13.3 
Accrual and Feasibility 
 
Sample size: Intervention = 80 (40 statin: 40 placebo) randomized sample; Analytic sample = 72 (36:36) 

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after 10% drop-out. The expected accrual rate is 6-7 participants per month across four study sites, and 
the planned recruitment duration is 12 months. We anticipate that all evaluable participants will have 
completed all study procedures within 24 months. Power and precision arguments are provided below. 
 
Accrual was calculated based on the number of liver transplant candidates actively registered at CSMC, 
NWU, GU, and UPR at a given time in addition to the number of new candidates expected to be 
registered over a 12-month period. Cirrhotics who are eligible and not listed for transplant may also be 
recruited. 
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary outcome for this study is change from baseline to 6 months in AFP-L3%. Power calculations 
are presented in Table 2. In the treatment group, we expect change of 2.8 over 6 months, and in the 
placebo group we expect 
a change of 0, with 
standard deviation=5.3 in 
both groups (or smaller). 
For a Phase II study we 
have an acceptable alpha of 10%. For the primary endpoint, AFP-L3%, we will consider changes D(T) 
and D(P) for D=After-Before, for simvastatin (T) and placebo (P) groups, respectively. We will use a 
nonparametric two-sample Wilcoxon-Mann-Whitney test to address the hypothesis H0: mean [D(T)] 
=mean [D(P)] versus H1: means[D(T)] > mean [D(P)] and report a defined one-sided p-value. If p<0.1 we 
will consider this to be evidence of an effect of simvastatin on AFP-L3%. If p>0.1 we will report the 
actual means and the corresponding confidence intervals observed and declare the trial had failed. If we 
observe: mean[(D(P)] > mean[D(T)] which would be unexpected, we will declare the trial failed and 
discuss possible explanations for the observed situation, which would suggest possibly adverse effect of 
the treatment. We are expecting less than 1 participant to progress to HCC in either the placebo or 
treatment arms during the course of the study [8].  
 
13.5 
Secondary and Exploratory Objectives, Endpoints, Analysis Plans 
 
For the continuous secondary endpoints (serum AFP, IL-6, serum DCA, liver stiffness, FIB-4 score, and 
MELD score) and exploratory endpoints, we will consider D(T) and D(P) as well as percent change 
relative to baseline, namely, D(T)/B(T) and D(P)/B(P). Biomarker levels at baseline and 6 months, as 
well as changes from baseline to 6 months, will be summarized using descriptive statistics and graphical 
methods. ANCOVA models with post-treatment value as the outcome, and treatment group and baseline 
value as predictors will be used to examine treatment differences. In these models, the estimated 
coefficient for treatment is the difference between the mean change scores of each arm [116]. Model fit 
will be assessed using standard model diagnostics including residual plots, influence statistics, and model 
assumptions such as normality and equivariance, will be verified. Potential outliers will be identified and 
reasons for extreme values will be investigated. Biomarker values may be transformed, e.g. 
logarithmically, to satisfy the normality assumption. Interaction between treatment group and baseline 
will be tested. Additional models that further adjust for other baseline characteristics, including routine 
clinical tests that have been shown to be strongly predictive of HCC diagnosis in prospective cohorts of 
cirrhosis such as higher alkaline phosphatase [6], lower platelets [6, 71, 73, 117], lower albumin [73, 
118], and lower prothrombin activity [119]. We will also consider clinical variables representing 
important HCC risk factors captured through the epidemiological questionnaire (Appendix F), including 
body mass index, current alcohol use, and current dietary fat, carbohydrate, fiber, coffee, and antioxidants 
[99-112]. The change in variable criterion will be used to identify confounders for our final models. 
Model selection will be performed using the purposeful model selection approach [120], resulting in a 
parsimonious model that includes adequate control for confounding. Adjusted treatment effects will be 
Table 2. Numeric Results for Mann-Whitney Test  
Power 
N1 
N2 
Ratio 
Alpha 
Beta 
Mean1 
Mean2 
S1 
S2 
0.81 
36 
36 
1 
0.1 
0.19 
2.8 
0 
5.3 
5.3 
Null Hypothesis: Mean1=Mean2. Alternative Hypothesis: Mean1>Mean2.  
The standard deviations were assumed to be unknown and unequal. 

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reported.  
 
Analyses will be performed with R statistical software. All analyses will be conducted on an intention to 
treat basis (all randomized participants will be included in the assigned group) and will begin with 
univariate cross-sectional statistics for profiling the study population and bivariate tabulations as a 
preliminary step to possible model building. We will not control for overall Type I error due to small 
number of observations and the preliminary nature of the study. 
 
13.6 
Reporting and Exclusions 
 
We are anticipating a small proportion (10%) of drop-outs due to health deterioration, transplantation, or 
death. We are proposing to exclude patients with high MELDs to reduce this possibility. The median time 
to transplantation from waitlist registration nationally is approximately 16 months, thus we feel that the 
risk of transplantation in the newly registered patient population with low MELDs is very low [113].  
Among patients who are already on the waitlist, there is certainly a risk for drop-out due to transplantation 
over a 6-month period, but we do not anticipate that this will be greater than 10%. We also anticipate 
some contamination from the simvastatin intervention to placebo due to non-compliance and this will be 
monitored and managed through blood tests. We do not expect cross-over from the placebo to the 
intervention group as participants will be aware that they might be on statins already and would not want 
to jeopardize their safety and care. However, the 2013 ACC/AHA clinical guidelines for prescription of 
statins may also influence drop-outs among participants who wish to reduce the risk of cardiovascular 
disease [121]. These guidelines recommend targeting men and women with cardiovascular disease, LDL 
FKROHVWHUROPJG/DQGSHUVRQV-75 years with diabetes or a 10-\HDUFDUGLRYDVFXODUGLVHDVHULVN
7.5%. Most of these people would not meet the eligibility criteria for study participation. The drop-out 
rate is expected to be 10% from baseline to 6 months follow-up. 
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose of simvastatin. Presence or 
absence of toxicity will be registered as a binary variable. Comparison of assumed underlying rates 
between groups will be performed using Fisher's exact test, and exact confidence intervals will follow the 
Clopper-Pearson method. 
 
13.8 
Evaluation of Response 
 
Changes in AFP-L3% will be evaluated for all randomized participants. 
 
13.9 
Interim Analysis 
 
There will be no planned interim analyses.  
 
13.10 Ancillary Studies 
 
Not applicable. 
 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
14.1 
Form FDA 1572 
 
Prior to initiating this study, the Protocol Lead Investigator at the Lead or Participating Organization(s) 
will provide a signed Form FDA 1572 stating that the study will be conducted in compliance with 

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regulations for clinical investigations and listing the investigators, at each site that will participate in the 
protocol. All personnel directly involved in the performance of procedures required by the protocol and 
the collection of data should be listed on Form FDA 1572. 
 
14.2 
Other Required Documents 
 
14.2.1 Current (within two years) CV or biosketch for all study personnel listed on the Form FDA 1572 
and Delegation of Tasks form for the Lead Organization and all Participating Organizations.  
 
14.2.2 Current medical licenses (where applicable) for all study personnel listed on Form FDA 1572 and 
Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.3 Lab certification (e.g., CLIA, CAP) and lab normal ranges for all labs listed on Form FDA 1572 
for the Lead Organization and all Participating Organizations. 
 
14.2.4 Documentation of training in Good Clinical Practice for all study personnel listed on the FDA 
Form 1572 and Delegation of Tasks form for the Lead Organization and all Participating Organizations. 
 
14.2.5 Documentation of Federalwide Assurance (FWA) number for the Lead Organization and all 
Participating Organizations. 
 
14.2.6 Signed Investigator’s Brochure/Package Insert acknowledgement form 
 
14.2.7 Delegation of Tasks form for the Lead Organization and all Participating Organizations signed by 
the Principal Investigator for each site and initialed by all study personnel listed on the form 
 
14.2.8 Signed and dated NCI, DCP Financial Disclosure Form for all study personnel listed on Form 
FDA 1572 for the Lead Organization and all Participating Organizations 
 
14.3 
Institutional Review Board Approval 
 
Prior to initiating the study and receiving agent, the Investigators at the Lead Organization and the 
Participating Organization(s) must obtain written approval to conduct the study from the NCI Central IRB 
(CIRB). Should changes to the study become necessary, protocol amendments will be submitted to the 
DCP PIO according to DCP Amendment Guidelines. The DCP-approved amended protocol must be 
approved by the CIRB prior to implementation. 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the CIRB-approved Informed Consent to review. 
The investigator will explain all aspects of the study in lay language and answer all questions regarding 
the study. If the participant decides to participate in the study, he/she will be asked to sign and date the 
Informed Consent document. The study agent(s) will not be released to a participant who has not signed 
the Informed Consent document. Subjects who refuse to participate or who withdraw from the study will 
be treated without prejudice. 
 
Participants must be provided the option to allow the use of blood samples, other body fluids, and tissues 
obtained during testing, operative procedures, or other standard medical practices for further research 
purposes. If applicable, statement of this option may be included within the informed consent document 
or may be provided as an addendum to the consent. A Model Consent Form for Use of Tissue for 
Research is available through a link in the DCP website.  

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Prior to study initiation, the informed consent document must be reviewed and approved by NCI, DCP, 
the Consortium Lead Organization, CIRB, and the IRB at each Organization at which the protocol will be 
implemented. Any subsequent changes to the informed consent must be approved by NCI, DCP, the 
Consortium Lead Organization’s IRB, CIRB, and then submitted to each organization’s IRB for approval 
prior to initiation. 
 
14.5 
Submission of Regulatory Documents 
 
All regulatory documents are collected by the Consortia Lead Organization and reviewed for 
completeness and accuracy. Once the Consortia Lead Organization has received complete and accurate 
documents from a participating organization, the Consortium Lead Organization will forward the 
regulatory documents to DCP’s Regulatory Contractor: 
 
 
Paper Document/CD-ROM Submissions: 
 
Regulatory Affairs Department 
 
CCS Associates, Inc. 
 
2001 Gateway Place, Suite 350 West 
 
San Jose, CA 95110 
 
Phone: 650-691-4400 
 
Fax: 650-691-4410 
 
 
E-mail Submissions: 
 
regulatory@ccsainc.com 
 
Regulatory documents that do not require an original signature may be sent electronically to the 
Consortium Lead Organization for review, which will then be electronically forwarded to DCP’s 
Regulatory Contractor. 
 
14.6 
Other 
 
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE 
 
All research related costs associated with participating in this study will be paid for, and will not be the 
responsibility of the participant. Participants will receive $50 when they complete the Screen 1 testing and 
$100 at the completion of each study visit for their time, transportation, parking, and other expenses 
related to the study. Participants who complete the entire study – the Screen 1 eligibility testing and four 
study visits – will receive $450. 
 
It is possible that a research injury or illness may result from participating in this study. Any expenses 
incurred as a result of research related injury will be the responsibility of the study participant and/or their 
insurance carrier.  
 

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REFERENCES 
 
1. 
Siegel, R., et al., Cancer Statistics, 2014. CA Cancer J Clin, 2014. 64(1): p. 9-29. 
2. 
Altekruse, S.F., et al., Changing hepatocellular carcinoma incidence and liver cancer mortality 
rates in the United States. Am J Gastroenterol, 2014. 109(4): p. 542-553. 
3. 
Setiawan, V.W., et al., Diabetes and racial/ethnic differences in hepatocellular carcinoma risk: 
the multiethnic cohort. J Natl Cancer Inst, 2014. 106(12). 
4. 
Yu, J., et al., Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer 
Biol, 2013. 23(6 Pt B): p. 483-91. 
5. 
El-Serag, H.B. and K.L. Rudolph, Hepatocellular carcinoma: epidemiology and molecular 
carcinogenesis. Gastroenterology, 2007. 132(7): p. 2557-2576. 
6. 
Lok, A.S., et al., Incidence of hepatocellular carcinoma and associated risk factors in hepatitis 
C-related advanced liver disease. Gastroenterology, 2009. 136(1): p. 138-48. 
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CONSENT FORM 
 
Consent Form 
Study Title for Study Participants: A Study Testing Simvastatin to Prevent Liver Cancer 
in People with Liver Cirrhosis 
Protocol Title: NWU2015-06-03, Statin Therapy to Reduce Disease Progression from Liver 
Cirrhosis to Cancer 
Principal Investigator: Marc T. Goodman, Ph.D., M.P.H. 
Sponsored By: National Cancer Institute (NCI) 
 
Introduction 
This is a clinical trial, a type of research study. Your study doctor will explain the clinical trial to 
you. Clinical trials include only people who choose to take part in the research. This document 
has important information about the reason for the study, what you will do if you choose to be in 
this research study, and the way we would like to use information about you and your health. 
 
Please take your time to make your decision about volunteering. You may discuss your decision 
with your friends and family. You can also discuss this study with your health care team. If you 
have any questions, you can ask your study doctor for more of an explanation. You should only 
agree to participate in this study when you are comfortable enough with the information so that 
you can make an informed decision about joining. 
 
What is the usual approach to managing my liver cirrhosis? 
You are being asked to take part in this research study because you have liver cirrhosis (scarring 
of the liver which results in abnormal liver function). People who have liver cirrhosis may be 
treated for the underlying cause of their cirrhosis, such as treatment for viral hepatitis B or C 
infections, weight loss, or alcohol dependency. Also, people who have liver cirrhosis may be 
treated for complications due to their cirrhosis including drainage of excess body fluids and 
medications to treat infections and other health problems associated with cirrhosis. When 
cirrhosis is advanced and liver function is very poor, a liver transplant may be the only treatment 
option. People who have liver cirrhosis are at increased risk for liver cancer. People who are at 
increased risk for liver cancer and choose not to participate in a study are followed closely by 
their doctor to watch for the development of cancer. 
 
What are my other choices if I do not take part in this study? 
x You may choose to have the usual approach described above; 
x You may choose to take part in a different study, if one is available; or 
x You may choose to do nothing. 
 
Why is this study being done? 
The purpose of this study is to compare the safety and effects of simvastatin in people with liver 
cirrhosis who are at an increased risk for liver cancer. In this study, you will get either 

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simvastatin 40 mg daily or placebo daily, a pill that looks like simvastatin 40 mg but contains no 
medication. Simvastatin is approved by the U.S. Food and Drug Administration (FDA) to reduce 
the risk for heart attack, stroke, and chest pain in patients who have heart disease or risk factors 
for heart disease such as smoking, high blood pressure, low high-density lipoprotein (HDL), or 
family history of early heart disease. It is also approved to lower the risk for heart attack or 
stroke in patients with type 2 diabetes and risk factors such as diabetic eye or kidney problems, 
smoking, or high blood pressure. However, simvastatin is not approved by the FDA to decrease 
the risk of liver cancer. Simvastatin is considered “investigational” (a study drug) in this study. 
Studies show that simvastatin lowers the risk of heart disease not only by decreasing cholesterol, 
but also by decreasing inflammation. We believe that this anti-inflammatory effect of simvastatin 
may help patients with liver cirrhosis. There will be about 80 people taking part in this study at 
Cedars-Sinai Medical Center, Northwestern University Feinberg School of Medicine, 
Georgetown University/MedStar Georgetown University Hospital, and the University of Puerto 
Rico. 
What are the study groups?
This study has two study groups. Group 1 will receive simvastatin 40 mg daily, and Group 2 will 
receive a placebo daily. There will be 40 people in Group 1 and 40 people in Group 2. 
A computer will randomly put you in a study group—like a coin toss—to decide what group you 
get placed into. This is done because no one knows if one study group is better, the same, or 
worse than the other group. Once you are put in a group, you cannot switch to the other group. 
Neither you nor your doctor will know if you are receiving simvastatin or placebo. Your doctor 
cannot choose which group you will be in.
How long will I be in this study?
Your participation in the study will last 9 months. You will receive the study drug (either 
simvastatin 40 mg or placebo) daily for 6 months, and your doctor will continue to watch you for 
side effects and follow your condition for three months after you stop taking the study drug. If 
you stop taking the study drug early, your doctor will continue to watch you for side effects for 3 
months. 
What extra tests and procedures will I have if I take part in this study?
If you agree to participate in this study, you will be required to sign this consent form before you 
have any tests or procedures that are done only for this study.  Most of the tests and procedures 
you will have are part of the usual approach for your condition. However, there are some extra 
tests and procedures that you will need to have if you take part in this study, including review of 
your medical history and medications, blood tests, non-invasive scans and images of your liver, 
Randomize 
A computer 
will randomly 
put you in a 
study group.
You agree to 
take part in 
the study and 
sign this 
consent form.
Both Groups 
receive the study 
drug daily for 6 
months and 
come to four 
study visits.
You will have 
some tests to 
confirm that 
you qualify 
for the study.
Group 1
Simvastatin 40 mg
(40 people)
Group 2
Placebo
(40 people)

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completion of questionnaires, and pregnancy tests (only for women who are able to become 
pregnant). These extra tests and procedures are described in further detail below. 
 
There are 3 main parts to this study: Screening, Intervention, and Follow-up after Completion of 
Study Intervention. 
 
Screening 
Screening is a period during which tests and procedures will be done to determine if you are 
eligible to participate in the study. After you sign the consent form, the following will be done to 
determine if you are eligible for the study: 
x Your study doctor will review your medical history, medications, and laboratory test 
results, and evaluate the study inclusion and exclusion criteria as they apply to you 
x A physical assessment including your vital signs and measurement of your weight 
x Review of your symptoms and current activity level and limitations 
x Blood tests (approximately 15 mL of your blood will be collected, which is about the 
same as 3 teaspoons) to check for a low blood count or clotting problems and to check 
your organ function 
x Pregnancy test (for women who are able to become pregnant) 
If the clinical laboratory results within the past 30 days are available in your medical record and 
are within the eligibility requirements for the study, and indicate that your organ function is 
acceptable, you may not need to have the blood tests during screening. If you are pregnant or if 
your blood tests show you have advanced liver disease, you will not be eligible for the study. 
 
Intervention (Study Visits 1, 2, 3, and 4) 
If the Screening exams and tests show that you can take part in the study, and you choose to, 
then you will be enrolled in the study and you will be randomized to a study group. During the 
Intervention portion of this study, you will be asked to take the study drug every day for 6 
months and participate in 4 study visits. Research staff will contact you approximately every four 
weeks by phone to check on your progress and answer any questions regarding the study. You 
will also be asked questions about potential side effects of the study drug. These phone calls will 
last approximately 10 minutes.  
Reminders to take your study drug: You will have the option of receiving email or text messages 
from research staff to remind you to take the study drug during the first week of the intervention 
period. We encourage you to respond to indicate if the dose has been taken. If you are having 
trouble remembering, these reminders can be extended beyond the first week. It is important that 
you stay on the study drug until the last study visit 6 months after you start intervention with the 
study drug. You will receive a phone call from research staff to remind you to stay on the study 
drug during the last week of the study intervention, as it is very important that you not miss any 
dose during this week so that we are able to fully use all data collected. Reminder messages to 
take the study drug will also be sent to you. 
 
¾ Study Visit 1 
The first study visit will take place 0-30 days after the Screening tests. The following 
procedures will be done during this visit: 
x Review of your medical history, medications, and laboratory test results  

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x A vital signs assessment including your blood pressure, heart rate, and 
temperature, and measurement of your height and weight 
x Review of your symptoms and current activity level and limitations 
x Collection of a blood sample (approximately 30 mL will be collected, which is 
about the same as 6 teaspoons) for blood tests to check your organ function, for 
research measurements of molecular markers in the blood that are related to liver 
function, and for use in future research studies 
x A FibroScan examination of your liver. You will be asked to refrain from eating 
for 3 hours before the FibroScan examination. 
x Completion of a questionnaire that asks about your background (race, education, 
marital status), health habits, tobacco and alcohol use, and quality of life. The 
questionnaire will be administered by a research staff person, who will ask you 
the questions and record the answers. 
x Completion of a diet questionnaire that asks about the types and quantities of food 
you eat. This is a self-administered electronic questionnaire that you will 
complete online using a computer or tablet. 
 
This study visit will last approximately 3 hours. The blood sample is required in order for 
you to take part in this study because the research on the samples is an important part of 
the study. 
 
The FibroScan is a non-invasive, pain-free examination of your liver. It is a scan similar 
to an ultrasound used during pregnancy. During the exam, you will be asked to lie on 
your back with your right arm raised and tucked behind your head. You may wish to 
wear a loose-fitting shirt as the skin covering your right rib cage area will need to be 
exposed in order to complete the exam. A staff member will place a probe, similar to an 
ultrasound probe, on your side near where your liver is. The probe sends a painless 
vibration through your body and into your liver, and measures how fast it takes the 
vibration to travel through the liver. The examination takes about 10 minutes. 
 
The study drug (either simvastatin or placebo) will be provided to you at this visit or 
shipped to your home.  Study staff will review instructions for how and when to take the 
study drug. You will be given a study diary to fill out and record each dose of study drug 
that you take. You should mark any missed or skipped doses in this diary, as well as any 
side effects that you are experiencing.  
 
¾ Study Visit 2 
The second study visit will take place 1 month after you start taking the study drug. The 
following procedures will be done during this visit: 
x Review of your medical history, medications, and laboratory test results  
x A vital signs assessment including your blood pressure, heart rate, temperature, 
and measurement of your weight 
x Review of your symptoms and current activity level and limitations 
x Collection of a blood sample (approximately 10 mL will be collected, which is 
about the same as 2 teaspoons) for blood tests to monitor you for side effects of 
the study drug 

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This study visit will last about 1 hour. You will receive a phone call the day before the 
visit to remind you to bring your study diary and any leftover study drugs to the visit. The 
bottle of study drug pills will be given back to you at this visit after we confirm that there 
are enough pills to last until your next study visit. 
 
¾ Study Visit 3 
 The third study visit will take place 3 months after you start taking the study drug. The 
following procedures will be done during this visit: 
x Review of your medical history, medications, and laboratory test results  
x A vital signs assessment including your blood pressure, heart rate, and 
temperature, and measurement of your weight 
x Review of your symptoms and current activity level and limitations 
x Collection of a blood sample (approximately 10 mL will be collected, which is 
about the same as 2 teaspoons) for blood tests to monitor you for side effects of 
the study drug 
 
This study visit will last about 1 hour. You will receive a phone call the day before the 
visit to remind you to bring your study diary and any leftover study drugs to the visit. 
You will be given another bottle of the study drug at this visit. 
 
¾ Study Visit 4 
The final study visit will take place 6 months after you start taking the study drug. The 
following procedures will be done during this visit: 
x Review of your medical history, medications, and laboratory test results  
x A physical assessment including your vital signs and measurement of your weight 
x Review of your symptoms and current activity level and limitations 
x Collection of a blood sample (approximately 35 mL will be collected, which is 
about the same as 7 teaspoons) for blood tests to check your organ function, for 
research measurements of molecular markers in the blood that are related to liver 
function, and for use in future research studies 
x A FibroScan examination of your liver. This is the same test performed during 
Study Visit 1. You will be asked to refrain from eating for 3 hours before the 
FibroScan examination. 
x An imaging scan of your abdominal area. The procedure used may be ultrasound, 
computed tomography (CT), or magnetic resonance imaging (MRI). 
 
This study visit will last approximately 3 hours. You will receive a phone call the day 
before the visit to remind you to bring your study diary and any leftover study drugs to 
the visit.  
 
An abdominal ultrasound is a safe and painless procedure that uses sound waves to create 
pictures of the organs and other structures in your upper belly. During the procedure, you 
will lie flat on your back on a padded exam table. The technologist will spread warm gel 
to the skin of your abdomen to help the sound waves work best. A transducer, a small, 
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waves will bounce off organs and tissue in your body, which creates echoes. The echoes 
are sent to the transducer, which converts them to electronic signals. A computer 
processes the signals into images and shows them on a screen. The ultrasound procedure 
usually takes 30 to 45 minutes. 
 
An abdominal CT scan is an imaging method that uses x-rays to create cross-sectional 
pictures of the belly area. You will be given a special dye, called contrast, which helps 
certain areas show up better on the x-rays. Contrast can be given through a vein in your 
hand or forearm. Sometimes you may have to drink the contrast before the exam, and in 
other cases it may be placed by using an enema. During the procedure, you will lie on 
your back on a narrow exam table with your arms raised above your head. The table will 
slide into the center of the CT scanner. The scanner is open at the back and the front, 
allowing you to see out. The technologist will always be able to see and hear you during 
your exam. Once you are inside the scanner, the machine's x-ray beam rotates around you 
and a computer creates separate images of the belly area. You will be asked to hold very 
still during the exam because movement causes blurred images. You may be told to hold 
your breath for short periods of time. The CT procedure usually takes 15 and 30 minutes. 
 
An abdominal MRI is a non-invasive procedure that uses a magnetic field and pulses of 
radio wave energy to create detailed images of organs and other internal body structures. 
The MRI does not use radiation (x-rays). You may be asked to wear a hospital gown or 
clothing without metal zippers or snaps (such as sweatpants and a t-shirt) because certain 
types of metal can cause blurry images. In some cases, a contrast agent (dye) may be 
injected into a vein in your hand or arm to improve the quality of the images. During the 
procedure, you will lie on the scanning table headfirst with arms at your side. Coils 
(special devices to improve image quality) may be placed on or around your abdomen. 
The table slides into a large tube-shaped magnet. As pictures are taken you must hold 
very still, and in some cases, you must hold your breath up to 25 seconds. Moving too 
much can blur MRI images and cause errors. During the MRI, the technologist who 
operates the machine monitors you from another room and will always be able to see and 
hear you during your exam. The MRI procedure usually takes 45 to 60 minutes. 
 
Follow-up after Completion of Study Intervention 
We will continue to follow your condition for 3 months after you stop taking the study drug. 
Research staff will contact you by phone to check on potential symptoms and side effects you 
may be experiencing, and to answer any questions you may have. These phone calls will last 
approximately 10 minutes. You will be contacted approximately 30 days, 60 days, and 90 days 
after you complete the study. 
 
What possible risks can I expect from taking part in this study?  
Your involvement in this study may involve the following risks: 
 
Risks Associated with Simvastatin 
The study drug simvastatin 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.  

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There may be pain, swelling, or bruising around the vein where your blood is collected. You may 
feel faint. There is a small risk of infection at the place on your body from which the blood is 
collected. The blood will be drawn by a person trained to collect blood using sterile (clean) 
equipment, and a very small needle will be used for drawing your blood to minimize discomfort.  
 
Questionnaires 
You may feel uncomfortable answering some of the questions you will be asked. If you feel 
uncomfortable answering any question, you can choose not to answer it.  
 
Scans and Imaging Procedures 
FibroScan 
There are no known risks associated with a FibroScan examination. 
Abdominal ultrasound 
There are no known risks from having an abdominal ultrasound. 
Abdominal computed tomography (CT)  
An abdominal CT is a relatively safe procedure, but there are risks. CT scans expose you to more 
ionizing radiation than regular x-rays. CT scans have not been shown to cause long-term harm, 
although many x-rays or CT scans over time may increase your risk for cancer. However, the 
risk from any one scan is extremely small. If you have contrast through a vein (IV), you may 
have a warm, flushed sensation during the injection of the contrast materials and a metallic taste 
in your mouth that lasts for a few minutes. These feelings are normal and go away within a few 
seconds. Although rare, the contrast dye can cause medical problems or allergic reactions. Most 
reactions are mild and result in a rash or itchiness. In rare instances, an allergic reaction can be 
serious, even life-threatening. Tell your doctor about any allergies you may have, and tell the 
scanner operator right away if you have any trouble breathing during the procedure. Scanners 
come with an intercom and speakers, so the operator can hear you at all times. 
Abdominal magnetic resonance imaging (MRI) 
An abdominal MRI exam causes no pain. No side effects from the magnetic fields and radio 
waves have been reported. You may experience some discomfort as you will be asked to remain 
relatively motionless for a long period of time (about 1 hour). You may feel anxiety from the 
confinement in a tight space (claustrophobia). If you become anxious, you can stop the procedure 
at any time. At times, you may hear very loud noises as the MRI machine is taking pictures of 
your body. During the scan, earplugs will be provided to help mask the noise (intermittent 
humming, thumping, clicking, and knocking). You will be able to communicate with the 
technologist during the MRI and you may ask to stop the procedure at any time. The presence of 
metal in your body may be a safety hazard or affect a portion of the MRI image. Before 
receiving an MRI, tell the technologist if you have any metal or electronic devices in your body. 
The contrast agent used for MRIs is less likely to cause an allergic reaction than the contrast 
material used for CT scans. 
 
What possible benefits can I expect from taking part in this study? 
You should not expect to benefit from taking part in this research study. The results from this 
study will provide information that will help scientists to learn whether simvastatin will improve 
liver function in individuals with liver cirrhosis. This knowledge could help prevent liver cancer 
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Can I stop taking part in this study? 
Your participation in this research study is voluntary so you may decline to participate or to stop 
being in this study at any time. If you decide to stop for any reason, it is important to let your 
study doctor know as soon as possible so you can stop safely. If you choose not to participate in 
this study or decide to stop participating, you will not suffer any loss of benefits to which you 
would be entitled outside of the study. Choosing not to participate will not negatively affect the 
care you receive or any present or future medical treatment.  
 
You will be told about any new information or changes in the study that could affect your health 
or your willingness to continue in the study. 
 
Your participation in this study may be ended without your consent by the Principal Investigator 
or your study doctor for the following reasons: 
x If you develop a dangerous side effect; 
x If you become pregnant; 
x If your health changes;  
x If the study is no longer in your best interest; 
x If you do not follow the study rules; 
x If the study is stopped early for any reason by the sponsor (NCI), the NCI Central IRB 
(CIRB), or FDA. 
 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. If you choose to be in this study, you have the right to be treated with respect, including 
respect for your decision whether or not you wish to continue or stop being in the study.  
 
If you want to speak with someone who is not directly involved in this research, or have 
questions about your rights as a research subject, please contact the (Insert institution name and 
Institutional Review Board or other site specific entity). You can call them at (insert phone 
number) or contact them by email at (insert email address). The (site specific entity) has been 
established to protect the rights and welfare of research participants. You may also contact the 
(site specific entity) if you want to offer input or obtain information regarding the study. 
 
What are the costs of taking part in this study? 
The simvastatin and placebo will be supplied at no charge while you take part in this study. The 
cost of study-specific exams, tests, and any other procedures performed for research purposes 
will be paid for by the study. 
 
The study may include some tests and procedures that may be considered part of your standard 
of care (routine medical care), and will be billed to you or your insurance company. You will 
have to pay for any costs (including deductibles and co-payments) not covered by your health 
insurer. Before you decide to be in the study, you should check with your health plan or 
insurance company to find out what they will pay for. 
 

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Will I receive payment for taking part in this study? 
You will receive $50 after completing Screening and $100 at the completion of each study visit 
to reimburse you for your time, transportation, parking, and other expenses related to the study, 
as summarized in the table below. The total amount you will receive after you complete the 
entire study – Screening and all four study visits – is $450. If you do not complete the entire 
research study, you will only be reimbursed for those visits you do complete. 
Research 
Visit 
Covered by the study (done for 
research purposes at no cost to you) 
Not covered by the 
study (routine medical 
care, billed to you or 
your insurance) 
Reimbursement 
to you when 
you finish the 
visit 
Screening  
Medical history, medications, and 
laboratory test results review, vital 
signs and symptom assessment, blood 
tests, pregnancy test (for women who 
are able to become pregnant) 
Physical assessment 
$50  
Study Visit 1 Medical history, medications, and 
laboratory test results review, vital 
signs and symptom assessment, blood 
tests, FibroScan exam, questionnaires 
 
$100 
Study Visit 2 Medical history, medications, and 
laboratory test results review, vital 
signs and symptom assessment, blood 
tests 
 
$100 
Study Visit 3 Medical history, medications, and 
laboratory test results review, vital 
signs and symptom assessment, blood 
tests 
 
$100 
Study Visit 4 Medical history, medications, and 
laboratory test results review, vital 
signs and symptom assessment, blood 
tests, FibroScan exam 
Physical assessment; 
imaging scan of your 
abdominal area 
(ultrasound, 
computed 
tomography (CT), or 
magnetic resonance 
imaging (MRI)) 
$100 
 
(If W-9 information is not applicable to your institution then please remove the below 
paragraph) 
You may be required to complete a W-9 Form in order to receive payment. The W-9 Form will 
be maintained by the accounting department at (Insert institution name). Although any amount of 
payment may be reportable (check with a tax professional if you have questions about your 
obligations), if total payment by (Insert institution name) 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 (Insert 
institution name) employee, you should provide your employee identification number to the 

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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 (Insert institution name). 
 
What happens if I am injured or hurt because I took part in this study? 
It is possible a research injury or illness may result from participating in this study.  Any 
expenses incurred as a result of research related injury will be the responsibility of the study 
participant and/or their insurance carrier. If you feel you have been injured or hurt as a result of 
taking part in the study, it is important that you contact your study doctor immediately: (Insert 
site specific investigator's name and contact number). If it is a medical emergency, call 911 or go 
to an emergency room. You will get medical treatment if you are injured or hurt as a result of 
taking part in this research study. 
 
Who will see my medical information? 
Your privacy is very important to us and we will make every effort to protect it. The study 
doctors have a privacy permit to help protect your records if there is a court case. Your 
information may be given out if required by law. For example, certain states require doctors to 
report to health boards if they find a disease like tuberculosis. However, we will do our best to 
make sure that any information that is released will not be able to identify you. Some of your 
health information, and information about your specimens, from this study will be kept in a 
central database for research. Your name or contact information will not be put in the database. 
 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private. Some of these organizations are:  
x The study sponsor, the National Cancer Institute (NCI)  
x The Institutional Review Board, IRB, is a group of people who review the research with 
the goal of protecting the people who take part in the study. 
x The Food and Drug Administration and the National Cancer Institute in the US. 
x The National Cancer Institute will obtain information for this clinical trial under data 
collection authority Title 42 U.S.C. 285. 
 
Where can I get more information? 
You may visit the NCI website at http://cancer.gov/ for more information about studies or 
general information about cancer. You may also call the NCI Cancer Information Service to 
get the same information at: 1-800-4-CANCER (1-800-422-6237).  
 
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. 
 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor (insert name of site-specific study 
doctor(s) at (insert telephone number). 

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This section is about optional studies you can choose to take part in. 
 
Optional Sample Collections for Biobanking for Possible Future Studies 
 
Researchers are trying to learn more about cancer and other health problems. Much of this 
research is done using samples from your biopsies, blood, or other fluids. Through these studies, 
researchers hope to find new ways to prevent, detect, treat, or cure health problems. Some of 
these studies may be about genes. Genes carry information about features that are found in you 
and in people who are related to you. Researchers are interested in the way that genes affect how 
your body responds to treatment. 
 
The researchers, insert names of site specific investigators, would like to ask your permission to 
store left over samples and health information obtained during your participation in this study for 
future medical research. Storing samples for future studies is called biobanking. The Biobank is 
being run by Cedars-Sinai Medical Center and supported by the National Cancer Institute.  
 
The research that may be done is unknown at this time. Future research may include: 1) studies 
to identify genes and/or biomarkers and proteins that influence a risk of cancer in people with 
liver disease; 2) studies to identify specific pathways and mechanisms that promote cancer. A 
biomarker is a biological molecule found in blood, other body fluids, or tissues that may be a 
sign of a condition or disease. 
 
What is involved? 
If you agree to take part, your samples and related information will be stored at Cedars-Sinai 
Medical Center until the end of the study, when they may be transferred to the NCI Biobank, 
along with samples and information from other people who take part. These are not additional 
samples that will be collected, but will consist of any material (blood samples) that remains after 
the tests described for this study have been conducted.  
 
Qualified researchers can submit a request to use the materials stored in the NCI Biobank. A 
research committee will review each request. There will also be an ethics review to ensure that 
the request is necessary and proper. You will not be notified if/when research is conducted using 
your samples. 
 
What are the possible risks? 
1) There is a risk that an unauthorized person could obtain the personal information in your 
medical records or other information we have stored about you. 
2) There is a potential risk someone could trace the genetic information about you. Even 
without your name or other identifiers, your genetic information is unique to you. The 
researchers believe the chance that someone will identify you is very small, but the risk 
may change in the future as people come up with new ways of tracing information. There 
are laws against the misuse of genetic information, but they may not give full protection. 
New health information about inherited traits that might affect you or your blood 
relatives could be found during a study. The researchers believe the chance these things 
will happen is very small, but cannot promise that they will not occur. 
 

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A new Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. This law generally will protect you 
in the following ways: 
x Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 
x Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums. 
 
Employers with 15 or more employees may not use your genetic information that we get from 
this research when making a decision to hire, promote, or fire you or when setting the terms of 
your employment. All health insurance companies and group health plans must follow this law 
by May 21, 2010. All employers with 15 or more employees must follow this law as of 
November 21, 2009. 
 
Be aware that this new Federal law does not protect you against genetic discrimination by 
companies that sell life insurance, disability insurance, or long-term care insurance. 
 
How will information about me be kept private? 
Your privacy is very important to the researchers and they will make every effort to protect it. 
Here are just a few of the steps they will take: 
1) When your sample(s) is sent to the researchers, no information identifying you (such as 
your name or birth date) will be sent. Samples will be identified by a unique study code 
only.  
2) The list that links the unique code to your name will be kept separate from your sample 
and health information. Any NCI Biobank and Cedars-Sinai Medical Center staff with 
access to the list must sign an agreement to keep your identity confidential. 
3) Researchers to whom Cedars-Sinai Medical Center sends your samples and information 
will not know who you are. They must also sign an agreement that they will not try to 
find out who you are. 
4) Information that identifies you will not be given to anyone, unless required by law. 
5) The results from research on your samples will not be put in your medical record. 
6) If research results are published, your name and other personal information will not be 
used. 
 
What are the possible benefits? 
You will not benefit from taking part. We hope that studying your samples and data may, in the 
future, help to decrease or prevent liver cancer in people who have liver disease.  
 
Are there any costs or payments?  
There will be no cost to you or your insurance company for storage of your samples. Your blood 
samples will be used only for research and will not be sold. You will not be paid for allowing 
your leftover samples to be used in research. If any of the research leads to new tests, drugs, or 
other commercial products, you will not share in any profits. 
 
What if I change my mind?  

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If you decide you no longer want your samples to be used, you can call Dr. Marc T. Goodman at 
(310) 423-6188, who will let the researchers know. Then, any samples that remain in the bank 
will be destroyed. Samples or related information that have already been given to or used by 
researchers will not be returned. 
 
What if I have more questions?  
If you have questions about the use of your samples for research, contact the Principal 
Investigator, Dr. Marc T. Goodman, at (310) 423-6188. 
 
Samples for future research studies 
Please circle your answer to show whether or not you would like to take part in each option. 
 
My blood samples and related information may be kept in the NCI Biobank for use in future 
health research. These are blood samples left over from the main study. 
Please circle one: 
YES 
NO 
 
I agree that the researchers, insert names of site specific investigators, or their representative, 
insert names of site specific research staff, may contact me or my physician to see if I wish to 
participate in other research in the future. 
Please circle one: 
YES 
NO 
 
Access to unused samples 
The researchers, insert names of site specific investigators, would like your permission to access 
unused samples collected for clinical purposes as part of your usual care, such as leftover tissue 
from biopsies, pathology slides, and tissue blocks. These unused samples would be tissue 
samples routinely collected as part of your clinical care including surgical procedures, endoscopy 
procedures, and outpatient procedures. The samples would be obtained from the pathology 
laboratory and routine doctor’s visits. Please circle your answer to show whether or not you give 
permission. 
 
I agree that the researchers, or their representative, may have to access to my unused samples. 
Please circle one: 
YES 
NO 
 
Medical records access and future contact  
There may be other important questions about you that have not been answered during the course 
of this research study. In order to answer these questions, we may need to contact you or review 
your medical records in the future. We request access to your medical records for 10 years. 
 
Please circle your answer to show whether or not you give permission for each of the following. 
 
I agree that the researchers, insert names of site specific investigators, or their representative, insert 
names of site specific research staff, may review my medical records in the future. 
Please circle one: 
YES 
NO 
 

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I agree that the researchers, insert names of site specific investigators, or their representative, insert 
names of site specific research staff, may contact me in the future if they have additional questions. 
Please circle one: 
YES 
NO 
 
I agree that the researchers, insert names of site specific investigators, or their representative, insert 
names of site specific research staff, may contact me in the future to see if I wish to learn about 
results from the study. 
Please circle one: 
YES 
NO 
 
 
This is the end of the section about optional studies. 
 
Consent Summary 
I have read this consent form and the research study has been explained to me. I have been given 
time to ask questions, and have been told whom to contact if I have more questions. I agree to be 
in the research study described above. I will be given a signed copy of this form. I agree to take 
part in the main study and any additional studies where I circled ‘yes’.    
 
 
 
 
 
 
Name (printed) and Signature of Research Participant 
Date of Signature 
 
 
 
 
 
 
Name (printed) and Signature of Person Obtaining Consent 
Date of Signature 
 
 
 

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Protocol Version 2.11, February 7, 2023 
 
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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. 
 
 
 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
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HIV protease inhibitors (atazanavir, 
darunavir, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, 
tipranavir) 
Aptivus, Crixivan, Invirase, Kaletra, Lexiva, 
Norvir, Prezista, Reyataz, Viracept  
APPENDIX E 
 
Clinical Laboratory Minimum Test Requirements 
 
Clinical labs will be done at Screen 1 to confirm eligibility for the trial; and at Study Visits 1, 2, 3, and 4 
to monitor for potential adverse effects of the intervention. Labs must include at least the following tests. 
It is acceptable to do additional tests if they are included in the blood panels at your institution. 
 
Blood Hematology: 
Complete Blood Count 
and Differential 
Blood Chemistry: 
Comprehensive Metabolic 
Panel 
Lipid Panel * 
Other Blood Tests 
Hemoglobin 
Platelet count 
Leukocytes (White blood 
cell count, total) 
Neutrophil count, absolute 
Alanine aminotransferase 
(ALT (SGPT)) 
Aspartate aminotransferase 
(AST (SGOT)) 
Alkaline phosphatase (ALP) 
Bilirubin, total 
Creatinine 
Sodium 
Glucose 
Potassium 
Total Protein 
Total cholesterol 
High density lipoprotein 
(HDL) cholesterol 
Low density lipoprotein 
(LDL) cholesterol 
Triglycerides 
Hemoglobin A1C 
(HbA1C) * 
Prothrombin Time 
(PT/INR) † 
Creatine phosphokinase 
(CPK) § 
* Lipid panel and hemoglobin A1C will be done at Study Visits 1, 3, and 4. 
† Prothrombin Time will be done at Screen 1 and Study Visit 4 to calculate the MELD score. 
§ Creatine phosphokinase (CPK) will be measured at Study Visit 1 to establish a patient-specific reference 
for this indicator of muscle toxicity. If the patient reports unexplained muscle pain or weakness during the 
trial, CPK will be tested again to check for elevation. 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
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APPENDIX F 
 
Participant ID:        
 
Date:       
 
 
 
 
 
 
 
 
 
Statin Therapy to Reduce Disease Progression 
from Liver Cirrhosis to Cancer 
 
 
Risk Questionnaire 
 
 
 
We appreciate the time you are taking to complete this interview. We will be 
asking you questions about factors and behaviors that we believe may be 
related to the development of liver cancer. Please try to answer each 
question as completely as you can, even if you are unsure about the answer. 
All answers will be kept confidential. 
 
 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–83– 
6. What is the highest grade or level of schooling you have completed? Check one box only. 
1 
 No formal education 
5 
 Technical or vocational school 
 
 
2 
 8th grade or less 
6 
 Associate degree or some college 
 
3 
 Some high school (9th -11th grade) 
7 
 Bachelor’s degree 
4 
 High school graduate or GED 
8 
 Advanced degree (Master’s or Doctoral degree) 
 
7. 
Are you currently employed (including self-employed)? 
1 
 Yes 
 
0 
 No 
a. On average, how many hours do you work each week? Check one box only. 
1 
 1-29 hours 
2 
 30-44 hours 
3 
 45-54 hours 
4 
 55+ hours 
 
8. What is your current marital status? Check one box only. 
1 
 Single (never married) 
2 
 Married 
3 
 Living with partner 
 
4 
 Separated 
5 
 Divorced 
6 
 Widowed 
 
 
 
9. With whom do you currently live? Check all boxes that apply. 
1 
 Spouse/partner 
2 
 Children  
3 
 Parent(s) 
4 
 Parent(s)-in-law 
5 
 Other relative(s) 
6 
 Friend(s) 
7 
 I live alone 
8 
 Other (please describe)       
 
 
 
10. Excluding you, how many people live in your home who are age… If none enter 0. 
over 18 years old 
between 12–18 years old 
between 6–11 years old 
under 6 years old 
      
      
      
      
 
11. Are you covered by health insurance or a health care plan? 
1 
 Yes 
 
0 
 No ї If NO skip to next section – SLEEP 
a. What type of health insurance or health care plan are you enrolled in? Check all boxes that apply. 
1 
 Employer group insurance through my job or my partner’s job 
2 
 Self-employed health plan 
 
3 
 Medicaid/Medi-Cal or other government program 
4 
 Medicare 
 
5 
 Private health insurance that I pay for myself 
6 
 Military health care 
7 
 I have health insurance, but I don’t know what type  
8 
 Other health insurance plan (please describe)       
 
 
 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–85– 
DISEASE SPECIFIC QUALITY OF LIFE 
CHRONIC LIVER DISEASE QUESTIONNAIRE (CLDQ) 
 
These questions are designed to find out how you have been feeling during the last two weeks. You will be 
asked about your symptoms related to your liver disease, how you have been affected in doing activities, and 
how your mood has been. Please select only one response for each question. 
 
All of 
the 
time 
Most 
of the 
time 
A good 
bit of 
the time 
Some 
of the 
time 
A little 
of the 
time 
Hardly 
any of 
the time 
None 
of the 
time 
1.  How much of the time during the last two 
weeks have you been troubled by a feeling of 
abdominal bloating? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
2.  How much of the time have you been tired or 
fatigued during the last two weeks? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
3.  How much of the time during the last two 
weeks have you experienced bodily pain? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
4.  How often during the last two weeks have 
you felt sleepy during the day? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
5.  How much of the time during the last two 
weeks have you experienced abdominal 
pain? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
6.  How much of the time during the last two 
weeks has shortness of breath been a 
problem for you in your daily activities? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
7.  How much of the time during the last two 
weeks have you not been able to eat as much 
as you would like? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8.  How much of the time in the last two weeks 
have you been bothered by having decreased 
strength? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
9.  How often during the last two weeks have 
you had trouble lifting or carrying heavy 
objects? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
10.  How often during the last two weeks have 
you felt anxious? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
11.  How often during the last two weeks have 
you felt a decreased level of energy? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
12.  How much of the time during the last two 
weeks have you felt unhappy? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
13.  How often during the last two weeks have 
you felt drowsy? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
14.  How much of the time during the last two 
weeks have you been bothered by a 
limitation of your diet? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
15.  How often during the last two weeks have 
you been irritable? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–86– 
 
All of 
the 
time 
Most 
of the 
time 
A good 
bit of 
the time 
Some 
of the 
time 
A little 
of the 
time 
Hardly 
any of 
the time 
None 
of the 
time 
16.  How much of the time during the last two 
weeks have you had difficulty sleeping at 
night? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
17.  How much of the time during the last two 
weeks have you been troubled by a feeling of 
abdominal discomfort? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
18.  How much of the time during the last two 
weeks have you been worried about the 
impact your liver disease has on your family? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
19.  How much of the time during the last two 
weeks have you had mood swings? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
20.  How much of the time during the last two 
weeks have you been unable to fall asleep at 
night? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
21.  How often during the last two weeks have 
you had muscle cramps? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
22.  How much of the time during the last two 
weeks have you been worried that your 
symptoms will develop into major problems? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
23.  How much of the time during the last two 
weeks have you had a dry mouth? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
24.  How much of the time during the last two 
weeks have you felt depressed? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
25.  How much of the time during the last two 
weeks have you been worried about your 
condition getting worse? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
26.  How much of the time during the last two 
weeks have you had problems concentrating? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
27.  How much of the time have you been 
troubled by itching during the last two 
weeks? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
28.  How much of the time during the last two 
weeks have you been worried about never 
feeling any better? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
29.  How much of the time during the last two 
weeks have you been concerned about the 
availability of a liver if you need a liver 
transplant? 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
 
 
 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–88– 
5.  Have you ever taken Celebrex at least 4 days per week for 3 months or longer?  
1 
 Yes 
 
0 
 No ї If NO skip to question # 6 
a. How old were you when you started taking Celebrex at least 4 days per week?       years old  
b. Do you take Celebrex at least 4 days per week now? 1 
 Yes 
0 
 No  
<<IF NO>> c. When did you stop taking Celebrex at least 4 days per week?       years old 
 
6.  Have you ever taken other anti-inflammatory pain relievers (examples: Aleve, naproxen, mobic, 
nabumetone, meloxicam, diclofenac, indomethacin) at least 4 days per week for 3 months or longer?  
1 
 Yes 
 
0 
 No ї If NO skip to question # 7 
a. How old were you when you started taking other anti-inflammatory pain relievers at least 4 days per 
week?       years old  
b. Do you take other anti-inflammatory pain relievers at least 4 days per week now? 1 
 Yes 
0 
 No  
<<IF NO>> c. When did you stop taking other anti-inflammatory pain relievers at least 4 days per 
 
week?       years old 
 
7.  Have you ever taken beta blockers (examples: Sectral, Tenormin, Zebeta, Lopressor, Corgard, Bystolic, 
Inderal LA, InnoPran XL) at least 4 days per week for 3 months or longer?  
1 
 Yes 
 
0 
 No ї If NO skip to question # 8 
a. How old were you when you started taking beta blockers at least 4 days per week?       years old  
b. Do you take beta blockers at least 4 days per week now? 1 
 Yes 
0 
 No 
<<IF NO>> c. When did you stop taking beta blockers at least 4 days per week?       years old 
 
8. Current Medications << Review Current Medication list with participant to verify what has been extracted 
from the medical chart with respect to drug name, drug dosage, and age started. >> 
 
9. Has a doctor or health care provider ever told you that you had diabetes? 
1 
 Yes 
 
0 
 No ї If NO skip to question # 10 
a. How old were you when a doctor first told you that you had diabetes?       years old  
b. Did you do any of the following to monitor or treat your diabetes?  
Check Yes or No for each item. 
Yes 
No 
a. Use a home glucose test to monitor your insulin level? 
1 
 
0 
 
b. Change your diet? 
1 
 
0 
 
c. Take medication by mouth? 
1 
 
0 
 
d. Take insulin by injection? 
1 
 
0 
 
 
10. Have you ever had surgery to remove your [type 
of tissue]? Repeat for each type of tissue. If Yes, 
ask question about age when had surgery. 
Yes 
No 
How old were 
you when you 
had this surgery? 
a. Appendix 
1 
 
0 
 
      
b. Gall Bladder 
1 
 
0 
 
      
c. Gall Stones 
1 
 
0 
 
      
d. Stomach or part of your stomach 
1 
 
0 
 
      
e.  Colon or rectum 
1 
 
0 
 
      
WOMEN ONLY: 
 
 
 
f. Breast (mastectomy) 
1 
 
0 
 
      
g. Uterus (hysterectomy) 
1 
 
0 
 
      
h. Ovaries (oophorectomy) 
1 
 
0 
 
      
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–91– 
INTERVIEWER'S REMARKS 
 
1. Participant ID       
 
 
2. Interviewer 
        (Initials) 
 
3. Participant’s sex 
1 
 Male 
2 
 Female 
 
4. Participant’s date of birth 
Month       Day       Year        
(Current Age:      ) 
 
5. Date of Interview 
Month       Day       Year        
 
6. Interview Start Time 
        :          (Hour: Minutes [24-hour time]) 
 
7. Interview End Time 
        :          (Hour: Minutes [24-hour time]) 
 
8. The interview included: (Check all boxes that apply.) 
1 
 The participant only 
2 
 A spouse or partner 
3 
 Another family member 
4 
 Another person (please specify)       
  
 
9. The participant's cooperation was: (Check one box only.) 
1 
 Excellent 
2 
 Very Good 
3 
 Good 
4 
 Fair 
5 
 Poor 
 
10. The quality of the interview is: (Check one box only.) 
1 
 Excellent 
2 
 Generally reliable 
3 
 Questionable 
4 
 Unreliable 
 
 
 
 
  
_ 
 
 
Signature of Clinical Research Staff who administered questionnaire 
Date 
 
 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–92– 
APPENDIX G 
Medication Reminder to be sent via Text Message and Email 
 
 
Text Message:  
This is a reminder to take your medication for the Statin Therapy to Reduce Disease Progression from Liver 
Cirrhosis to Cancer research study this evening. Please swallow the capsule whole, and please remember to fill 
out your study diary. Thank you! 
 
 
Email:  
This is just a friendly reminder to take your medication for the Statin Therapy to Reduce Disease Progression 
from Liver Cirrhosis to Cancer research study at bedtime or with your evening meal. Please swallow the capsule 
whole and do not chew, crush, or open it. Please also remember to fill out your study diary, noting the date and 
time when you took the medication. Let us know if you have any questions or concerns. Thank you very much! 
 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–93– 
APPENDIX H 
Patient Appointment Letter – No FibroScan 
[Insert Clinical Site Logo or Name] 
 
Date» 
 
«Name» 
«Address» 
«City, state, zip code» 
 
Dear «Name» 
 
Thank you very much for participating in our research study, Statin Therapy to Reduce Disease Progression from 
Liver Cirrhosis to Cancer. Your participation is vital to the success of this study. 
 
Following are the date, time, and location of your research study visit. Please see the attached map. The visit 
appointment will take about one hour.  
 
Date: 
________________________________ 
Time: 
________________________________ 
Place: 
 
 
 
 
 
 
  
 
We look forward to meeting with you. This research could not be conducted without your participation, and we 
are grateful for your time and interest. If you have any questions or if you need to change the date or time of the 
appointment, please call me at «clinical research staff phone number». 
 
Sincerely, 
 
 
 
«Clinical research staff name» 
«Clinical research staff job title» 
 
 
[Insert directions to clinic and map on next page] 
 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023 
 
–94– 
APPENDIX I 
Patient Appointment Letter – FibroScan 
 
[Insert Clinical Site Logo or Name] 
 
«Date» 
 
«Name» 
«Address» 
«City, state, zip code» 
 
Dear «Name» 
 
Thank you very much for participating in our research study, Statin Therapy to Reduce Disease Progression from 
Liver Cirrhosis to Cancer. Your participation is vital to the success of this study. 
 
Following are the date, time, and location of your research study visit. Please see the attached map. The visit 
appointment will take about three hours.  
 
Date: 
________________________________ 
Time: 
________________________________ 
Place: 
 
 
 
 
  
 
Please do not eat or snack during the 3 hours before your study appointment. Since your appointment is at 
________, please do not eat any food or chew any gum after ________ on the day of your appointment. You 
may drink water and take medications with water according to your normal schedule.  
 
We look forward to meeting with you. This research could not be conducted without your participation, and we 
are grateful for your time and interest. If you have any questions or if you need to change the date or time of the 
appointment, please call me at «clinical research staff phone number». 
 
Sincerely, 
 
 
 
«Clinical research staff name» 
«Clinical research staff job title» 
 
 
 
 
 
 
 
 
[Insert directions to clinic and map on next page] 
 

NWU2015-06-03 
Protocol Version 2.11, February 7, 2023
–95– 
APPENDIX J
VioScreen Instructions 
Instructions to Complete the VioScreen Dietary Assessment
9
For best results reserve 20 minutes of quiet time to complete the assessment.  
9
If for some reason you need to exit the questionnaire prior to completion your answers will be remembered 
and you may resume where you left off on next login.
9
Take the assessment from a tablet or computer not a mobile phone. 
9
Use one of these browsers: IE, Fire Fox, Chrome, Opera, Safari
9
The new password you create is important to keep, you will use it throughout the study. 
9
If you have questions or concerns please contact << Coordinator Name and Number>>
My Subject ID:
My Username:
Password: 
1.
Go to https://vioscreen.com.  Select 
the Login button.
2.
Enter the username and 
password above to log in.