A Phase I Single-arm, Multicenter Pilot Study Aimed at Validating γ-OHPdG as a Biomarker and Testing the Effects of Polyphenon E on Its Levels in Patients With Cirrhosis
Phase: PHASE1
Conditions: Cirrhosis
Sponsor: National Cancer Institute (NCI)

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COVER PAGE 
 
 
 
 
 
DCP Protocol #: NWU2016-08-02 
 
Local Protocol #: NCI 2016-08-02 
 
A phase I single-arm, multicenter pilot study aimed at validating γ-OHPdG as a biomarker 
and testing the effects of Polyphenon E® on its levels in patients with cirrhosis.  
 
Consortium Name*:  
 
Northwestern Cancer Prevention Consortium 
Consortium Principal 
Seema A. Khan, M.D. 
Investigator (PI): 
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:  
 
Georgetown University 
Protocol PI:   
 
 
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 
arh29@georgetown.edu 
 
Organization: 
 
 
Georgetown University 
Investigator:  
 
 
Fung-Lung Chung, Ph.D. 
 
 
 
 
 
Departments of Oncology, Biochemistry, and Molecular & 
Cellular Biology 
E215 New Research Building  
Washington DC, 20007 
 
 
 
 
 
Telephone: 202-687-3021 
 
 
 
 
 
Fax: 202-687-1068 
 
 
 
 
 
flc6@georgetown.edu 
 
*No participant accrual occurs at this site 
 
 

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Organization:  
 
 
MedStar Health Transplant Institute 
 
 
 
 
 
MedStar Georgetown University Hospital 
Investigator:  
 
 
Coleman Smith, M.D. 
 
MedStar Georgetown University Hospital Transplant Institute 
3800 Reservoir Road, NW 
Washington DC, 20007 
 
MedStar Georgetown Transplant Institute in Fairfax 
3301 Woodburn Road, Suite 209 
Annadale, VA 22003 
Telephone: 202-444-1085  
Fax: 202-444-9429 
Coleman.I.Smith@gunet.georgetown.edu  
 
Organization: 
 
 
MedStar Washington Hospital Center 
Investigator:   
 
 
Arul Thomas, M.D.  
 
 
 
 
 
110 Irving St NW 
 
 
 
 
 
Washington DC 20010 
 
 
 
 
 
Telephone: 202-444-3700 
 
 
 
 
 
Arul.M.Thomas@gunet.georgetown.edu 
 
 
 
 
 
 
Organization:  
 
 
MedStar Georgetown University Hospital 
Investigator: 
Bhaskar V.S. Kallakury, MD 
 
Department of Pathology 
3900 Reservoir Road NW Room SW203, Medical Dental 
Building Washington, DC 20007 
Telephone: 202-687-3444  
Fax: 202-687-8935 
kallakub@gunet.georgetown.edu 
 
Organization:  
 
 
MedStar Georgetown University Hospital 
Investigator: 
Amol Rangnekar, M.D. 
Transplant Institute 
3800 Reservoir Rd, NW  
Transplant PHC 2nd Floor 
Washington, DC 20007 
Telephone: 202-444-3700 
Amol.S.Rangnekar@gunet.georgetown.edu  
 
Organization:  
 
 
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 

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Fax: 787-758-2557 
marcia.cruz1@upr.edu 
 
Organization:  
 
 
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.carlo@upr.edu 
 
Organization*:  
Northwestern University 
Statistician:  
 
 
Masha Kocherginsky, PhD 
 
 
 
 
 
Professor of Preventive Medicine 
 
 
 
 
 
The Feinberg School of Medicine 
 
 
 
 
680 North Lake Shore Drive, Suite 1400 
 
 
 
 
Chicago IL 60611 USA  
 
 
 
 
 
Telephone: 312.503.4224 
 
 
 
 
 
Fax: 312.908.9588 
 
 
 
 
 
mkocherg@northwestern.edu   
 
*No participant accrual occurs at this site 
 
Organization:  
 
     Georgetown University 
Statistician:  
 
 
Hongkun Wang, Ph.D. 
Department of Biostatistics, Bioinformatics, and 
Biomathematics 
Building D, Suite 180 
4000 Reservoir Road, NW 
Washington DC, 20057 
Telephone: 202-687-4146 
 
Hongkun.Wang@georgetown.edu  
 
IND Sponsor: 
NCI/Division of Cancer Prevention 
IND#  
 
 
Agent(s)/Supplier: 
Polyphenon E/EGCG (one capsule of Polyphenon E contains 
200mg EGCG) / NCI, Division of Cancer Prevention 
 
NCI Contract # 
HHSN2612201200035I 
Protocol Template: 
Protocol Template Version 8.5 8/31/2016 
 
Protocol Version Date:  
March 6, 2023 
 
 
 
Protocol Revision or  
 
Amendment # 
Version 4.13 
 

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SCHEMA 
A phase I single-arm, multicenter pilot study aimed at validating γ-OHPdG as a biomarker 
and testing the effects of Polyphenon E on its levels in patients with cirrhosis.  
Screen 1: Eligibility (n=4-171) 
Participants with a diagnosis of liver cirrhosis are seen in clinic:  
Informed consent, history/physical/conmed review, CT or MRI, FibroScan
®, clinical labs, Child Pugh score, pregnancy test, questionnaires, 
eligibility review 
Screen 2: Liver Biopsy and Eligibility 
Participants meeting Screen 1 eligibility criteria are seen in clinic:  
Liver biopsy obtained, samples tested for γ-OHPdG level, slides reviewed and scored by a pathologist 
Pre-Screen: Chart Review 
Medical charts are reviewed by a pathologist for eligibility 
Study Visit 1: Week 1 Day 1 (n=2-48) 
Participants with high levels of γ-OHPdG (IHC ≥3) meeting eligibility criteria receive Polyphenon E according to the dose escalation schema 
3+3 design plus expansion cohort to 24 for Maximum Tolerated Dose: 
400 mg EGCG QD 
400 mg EGCG BID 
600 mg EGCG BID 
800 mg EGCG BID 
1000 mg EGCG BID  
Physical, conmed/AE review, clinical labs, dispense agent, urine/blood collection for PK 
Weekly or bi-weekly (depending on assigned dose, clinical stability, and liver biochemical stability of the participant) liver function tests 
Study Visit 2: Week 13 ± 3 Days 
Mid-study clinic visit: 
Physical, conmed/AE review, clinical labs, dispense agent 
Study Visit 3: Week 25 ± 3 Days 
Last day of agent: 
Physical exam, conmen/AE review, clinical labs, Child Pugh score, CT or MRI, FibroScan, liver biopsy testing for γ-OHPdG 
Weekly or bi-weekly (depending on assigned dose, clinical stability, and liver biochemical stability of the participant) liver function tests 
Study Visit 4: Week 28 ± 3 Days 
Follow-up: 
Physical exam, clinical labs 
Primary Objectives: 
•
To establish maximum tolerated dose (MTD) and to collect safety data of Polyphenon E/EGCG treatment in patients with cirrhosis. 
•
To determine the effects of Polyphenon E/EGCG treatment on the suppression of γ-hydroxy-1,N(2)-propanodeoxyguanosine (γ-
OHPdG) levels in cirrhotic liver.  
Secondary Objectives: 
•
To collect Polyphenon E/EGCG pharmacokinetic data in patients with cirrhosis. 
•
To determine the effects of Polyphenon E/EGCG treatment on the suppression of γ-hydroxy-1,N(2)-propanodeoxyguanosine (γ-
OHPdG) levels in cirrhotic liver by LC-MS assay from baseline to post-treatment.  
•
To estimate the fraction of patients with liver cirrhosis that have high levels of γ-OHPdG. 
 
Exploratory Objective: 
•
To assess the effects of Polyphenon E/EGCG on the grade of cirrhosis as measured by FibroScan and FIB-4 score. 
•
To develop an LC-MS and/or ELISA-based method for detecting urinary and blood γ-OHPdG, to correlate with liver ɣ-OHPdG 
levels. 
•
To evaluate any HCC development during the treatment.  
Participant Flow Schema 

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TABLE OF CONTENTS 
 
COVER PAGE.............................................................................................................................................. 1 
SCHEMA ...................................................................................................................................................... 4 
1. 
OBJECTIVES ..................................................................................................................................... 7 
1.1 
Primary Objective ........................................................................................................................................ 7 
1.2 
Secondary Objectives .................................................................................................................................. 7 
1.3 
Exploratory Endpoint ................................................................................................................................... 7 
2. 
BACKGROUND ................................................................................................................................. 7 
2.1 
Hepatocellular carcinoma (HCC) ................................................................................................................ 7 
2.2 
Cirrhosis ....................................................................................................................................................... 7 
2.3 
γ-OHPdG, the biomarker to be tested in this protocol ................................................................................. 9 
2.4 
Polyphenon E ............................................................................................................................................. 16 
2.5 
Rationale .................................................................................................................................................... 17 
3. 
SUMMARY OF STUDY PLAN ...................................................................................................... 20 
4. 
PARTICIPANT SELECTION .......................................................................................................... 22 
4.1 
Inclusion Criteria ....................................................................................................................................... 22 
4.2 
Exclusion Criteria ...................................................................................................................................... 24 
4.3 
Inclusion of Women and Minorities .......................................................................................................... 25 
4.4 
Recruitment and Retention Plan ................................................................................................................ 25 
5. 
AGENT ADMINISTRATION .......................................................................................................... 26 
5.1 
Dose Regimen and Dose Groups ............................................................................................................... 26 
5.2 
Polyphenon E Administration .................................................................................................................... 27 
5.3 
Run-in Procedures ..................................................................................................................................... 27 
5.4 
Contraindications ....................................................................................................................................... 28 
5.5 
Concomitant Medications .......................................................................................................................... 28 
5.6 
Dose Interruption and Modification ........................................................................................................... 28 
5.7 
Adherence/Compliance .............................................................................................................................. 29 
6. 
PHARMACEUTICAL INFORMATION ......................................................................................... 29 
6.1 
Polyphenon E (IND 
, NCI/DCP) .................................................................................................... 29 
6.2 
Reported Adverse Events and Potential Risks ........................................................................................... 30 
6.3  
Availability ................................................................................................................................................ 32 
6.4 
Agent Distribution ..................................................................................................................................... 32 
6.5 
Agent Accountability ................................................................................................................................. 33 
6.6 
Packaging and Labeling ............................................................................................................................. 33 
6.8 
Registration/Randomization ...................................................................................................................... 33 
6.9 
Blinding and Unblinding Methods ............................................................................................................. 34 
6.10 Agent Destruction/Disposal ....................................................................................................................... 34 
7. 
CLINICAL EVALUATIONS AND PROCEDURES ...................................................................... 35 
7.1 
Schedule of Events .................................................................................................................................... 35 
7.2 
Baseline Testing/Prestudy Evaluation ....................................................................................................... 37 
7.3 
Evaluation During Study Intervention ....................................................................................................... 38 
7.4 
Evaluation at Completion of Study Intervention ....................................................................................... 41 
7.5 
Post-intervention Follow-up Period/ Final Evaluations, Off Study ........................................................... 41 
7.6 
Methods for Clinical Procedures ............................................................................................................... 42 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION............................................... 45 
8.1 
Primary Endpoint ....................................................................................................................................... 45 
8.2 
Secondary Endpoints ................................................................................................................................. 46 
8.3 
Off-Agent Criteria ..................................................................................................................................... 47 
8.4 
Off-Study Criteria ...................................................................................................................................... 48 
8.5 
Study Termination ..................................................................................................................................... 48 
9. 
CORRELATIVE/SPECIAL STUDIES ............................................................................................ 49 
9.1 
Rationale for Methodology Selection ........................................................................................................ 49 

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9.2 
Comparable Methods ................................................................................................................................. 50 
10. 
SPECIMEN MANAGEMENT ......................................................................................................... 51 
10.1 Laboratories ............................................................................................................................................... 51 
10.2 Collection and Handling Procedures ......................................................................................................... 51 
10.3 Shipping Instructions ................................................................................................................................. 55 
10.4 Tissue Banking .......................................................................................................................................... 56 
11. 
REPORTING ADVERSE EVENTS ................................................................................................. 56 
11.1 Adverse Events .......................................................................................................................................... 56 
11.2 Serious Adverse Events ............................................................................................................................. 58 
12. 
STUDY MONITORING ................................................................................................................... 59 
12.1 Data Management ...................................................................................................................................... 59 
12.2 Case Report Forms .................................................................................................................................... 60 
12.3 Source Documents ..................................................................................................................................... 60 
12.4 Data and Safety Monitoring Plan ............................................................................................................... 60 
12.5 Sponsor or FDA Monitoring ...................................................................................................................... 60 
12.6 Record Retention ....................................................................................................................................... 60 
12.7 Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement (CTA) ......... 61 
13. 
STATISTICAL CONSIDERATIONS .............................................................................................. 61 
13.1 Study Design/Description .......................................................................................................................... 61 
13.2 Randomization/Stratification ..................................................................................................................... 61 
13.3 Accrual and Feasibility .............................................................................................................................. 62 
13.4 Primary Objective, Endpoint(s), Analysis Plan ......................................................................................... 63 
13.5 Secondary Objectives, Endpoints, Analysis Plans ..................................................................................... 64 
13.6 Reporting and Exclusions .......................................................................................................................... 65 
13.7 Evaluation of Toxicity ............................................................................................................................... 65 
13.8 Evaluation of Response ............................................................................................................................. 66 
13.9 Interim Analysis ......................................................................................................................................... 66 
13.10 Ancillary Studies ....................................................................................................................................... 66 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................ 66 
14.1 Form FDA 1572 ......................................................................................................................................... 66 
14.2 Other Required Documents ....................................................................................................................... 66 
14.3 Institutional Review Board Approval ........................................................................................................ 67 
14.4 Informed Consent ...................................................................................................................................... 67 
14.5 Submission of Regulatory Documents ....................................................................................................... 67 
14.6 Other .......................................................................................................................................................... 68 
15. 
FINANCING, EXPENSES, AND/OR INSURANCE ...................................................................... 68 
REFERENCES ........................................................................................................................................... 69 
Consent Form .............................................................................................................................................. 74 
APPENDIX A ............................................................................................................................................. 88 
APPENDIX B ............................................................................................................................................. 89 
APPENDIX C ............................................................................................................................................. 90 
APPENDIX D ............................................................................................................................................. 91 
APPENDIX E ............................................................................................................................................. 95 
APPENDIX F.............................................................................................................................................. 97 
APPENDIX G ........................................................................................................................................... 100 
APPENDIX H ........................................................................................................................................... 101 
APPENDIX I ............................................................................................................................................ 104 

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1. 
OBJECTIVES 
 
1.1 
Primary Objective 
 
1.1.1 To establish maximum tolerated dose (MTD) and to collect safety data of 
Polyphenon E/EGCG treatment in participants with cirrhosis. 
 
1.1.2    To determine the effects of Polyphenon E/EGCG treatment on the suppression of 
γ-hydroxy-1,N(2)-propanodeoxyguanosine (γ-OHPdG) levels in cirrhotic liver. 
 
1.2 
Secondary Objectives  
 
1.2.1 To collect Polyphenon E/EGCG pharmacokinetic data in participants with 
cirrhosis. 
 
1.2.2    To determine the effects of Polyphenon E/EGCG treatment on the suppression of 
γ-hydroxy-1,N(2)-propanodeoxyguanosine (γ-OHPdG) levels in cirrhotic liver by LC-MS 
assay from baseline to post-treatment. 
 
1.2.3 To estimate the fraction of participants with liver cirrhosis that have high levels of 
γ-OHPdG. 
 
1.3 
Exploratory Endpoint 
 
 
1.3.1 To assess the effects of Polyphenon E/EGCG on the grade of cirrhosis as measured 
by FibroScan® and FIB-4 score. 
 
1.3.2 To develop an LC-MS and/or ELISA-based method for detecting urinary and blood 
γ-OHPdG, to correlate with liver ɣ-OHPdG levels. 
 
1.3.3 To evaluate any HCC development during the treatment. 
 
2. 
BACKGROUND 
 
2.1 
Hepatocellular carcinoma (HCC) 
 
HCC is the second and sixth leading cause of cancer related mortality in men and women, 
respectively (1). Despite advances in our understanding of the molecular pathways involved in 
HCC, our therapeutic armamentarium remains limited and survival dismal. In early stage disease 
(Barcelona clinic liver cancer [BCLC] stages 0 and A), surgical resection, ablation methods, and 
liver transplantation reportedly extend survival by more than 5 years. However, less than half of 
participants have resectable tumors at initial presentation and, even after successful resection, 
70% will eventually relapse due to micrometastases and de-novo malignant transformation of 
adjacent liver cells (2,3). There is no preventive treatment for this deadly disease at this time. 
 
2.2 
Cirrhosis 
 

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2.2.1 Diagnosis of cirrhosis.  
 
Despite geographical differences, chronic liver diseases are highly prevalent worldwide. It is 
estimated that at least 350 million and 120 million people globally are chronically infected with 
hepatitis B virus (HBV) and hepatitis C virus, respectively. (4,5) Non-alcoholic fatty liver 
disease (NAFLD) affects 15-40% of the general population and is particularly prevalent in 
participants with diabetes and obesity.(6-8) Alcoholic liver disease affects people in both 
developed and developing countries and may account for up to 9.2% of all disability-adjusted 
life years in some regions. (9) Although the etiologies are different, chronic liver disease leads to 
liver injury, progressive liver fibrosis, and finally to the stage of cirrhosis and liver 
decompensation. As a result, cirrhosis remains the twelfth global leading cause of death in 2010. 
(10) 
 
The diagnosis of cirrhosis is not as simple as it seems. It is straightforward when a patient has 
already developed clinical manifestations of portal hypertension such as ascites, varices and 
hypersplenism. However, these signs are absent in participants with early cirrhosis, and the 
radiological features of early cirrhosis are subtle and unreliable. (11) Cirrhosis is usually 
diagnosed by way of liver biopsy, which is an invasive procedure with a small risk of bleeding. 
In recent years, the development and application of non-invasive tests of liver fibrosis have 
revolutionized hepatology practice. Numerous studies have confirmed the accuracy of FibroScan 
in fibrosis staging and the diagnosis of cirrhosis. In general, the tests have high negative 
predictive value for the exclusion of advanced fibrosis and cirrhosis, and have been 
recommended by the European Association for the Study of the Liver as initial assessment in 
participants with various liver diseases. (12)  
 
The Fibrosis-4 (FIB-4) score is an exploratory endpoint which helps to estimate the amount of 
scarring in the liver (see the equation below). Using a lower cutoff value of 1.45, a FIB-4 score < 
1.45 had a negative predictive value of 90% for advanced fibrosis (Ishak fibrosis score 4-6 which 
includes early bridging fibrosis to cirrhosis). In 
contrast, a FIB-4 > 3.25 would have a 97% 
specificity and a positive predictive value of 65% 
for advanced fibrosis. 
 
2.2.2 Compensated vs. Decompensated cirrhosis 
 
Cirrhosis is the end-stage of every chronic liver disease; that is, if participants don’t go on to 
develop HCC. Its natural history is characterized by an asymptomatic phase, termed 
‘compensated’ cirrhosis followed by a rapidly progressive phase marked by the development of 
complications of portal hypertension and/or liver dysfunction, termed ‘decompensated cirrhosis’. 
In the compensated phase, portal pressure may be normal or below the threshold level identified 
for the development of varices or ascites (‘clinically significant portal hypertension’). (13,14) As 
the disease progresses, portal pressure increases and liver function decreases, resulting in the 
development of ascites, portal hypertensive gastrointestinal (GI) bleeding, encephalopathy, and 
jaundice. The development of any of these complications marks the transition from a 
compensated to a decompensated phase. 
 

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2.2.3 Risk of development of HCC. 
 
Participants with liver cirrhosis, independent of their etiology, as well as individuals without 
cirrhosis but with chronic hepatitis B infection or non-alcoholic fatty liver disease (NAFLD) 
have a very high risk for the development of hepatocellular carcinoma (HCC). (15) Worldwide, 
HCC is the fifth most common malignancy. (57) In Europe, North America, and Japan, the HCC 
incidence is lower compared to South-Asian countries and Africa, but not negligible. (58) Thus, 
a challenging task is the early diagnosis of HCC in participants with known risk factors. 
Participants with HCC and tumor symptoms have a survival rate of only 0-10%. (59) In contrast, 
participants with an early diagnosis of HCC can achieve 5-year survival rates of over 50%. (15) 
The surveillance for HCC in participants with cirrhosis by clinic visit, laboratory test, and twice 
per year scan is recommended by AASLD. However, the current best prevention strategy for 
HCC development is to avoid the development of liver disease and the progression to liver 
cirrhosis. Effective HCC preventive interventions in participants with cirrhosis are lacking. 
 
2.3 
γ-OHPdG, the biomarker to be tested in this protocol 
 
2.3.1 γ-OHPdG is a lipid peroxidation (LPO)-derived endogenous cyclic DNA adduct, which 
causes somatic mutations and is a possible surrogate marker for inflammation-associated cancer.  
It is known that chronic inflammation leads to oxidative/nitrosative stress and lipid peroxidation 
(LPO), generating excess reactive oxygen species (ROS) and reactive nitrogen species (RNS) (1-
19). Highly reactive α, β-unsaturated aldehydes (enals) are also generated due to oxidation of 
membrane polyunsaturated fatty acids (PUFAs), which can modify DNA bases, forming 
promutagenic cyclic DNA adducts (20-23). Oxidative stress caused by chronic inflammation has 
emerged as a major player in liver carcinogenesis of different etiologies, including HCV/HBV, 
alcoholism, and obesity (24). Oxidative stress drives genomic damage and genetic instability to 
cause mutations. LPO-derived endogenous cyclic DNA adducts have been investigated as 
potential markers for various types of inflammatory cancer-prone diseases (e.g. chronic 
pancreatitis, Crohn`s disease, ulcerative colitis, alcohol related hepatitis, and H. pylori infection) 
and cancer initiation/promotion (25). Among the LPO-derived DNA adducts, γ-hydroxy-1,N(2)-
propanodeoxyguanosine (γ-OHPdG) is one of the most abundant and well-studied adducts, and 
has been ubiquitously detected in mammalian tissues (26). γ-OHPdG is formed due to modification 
of deoxyguanosine (dG) in DNA by acrolein, an aldehyde that is a major constituent of cigarette 
smoke, as well as being endogenously formed by LPO. The γ-OHPdG adduct is mutagenic and 
induces predominantly G to T and G to A mutations (27-30). One study found that γ-OHPdG 
occurs at sites that coincide with p53 mutation hotspots in lung cancers of smokers (31). These 
results support the role of γ-OHPdG-induced somatic mutations in human cancers.  
 
Epidemiological studies have shown antioxidants to be preventive against various types of cancer 
(32); however, contradicting results have been obtained in intervention trials (33, 34). A possible 
explanation for the contradictory results is bias from unmeasured confounders in the 
epidemiological studies.  Biomarkers are crucial for the selection of participants likely to benefit 
from antioxidant therapy. There is thus an unmet and urgent need for the detection and validation 
of carcinogenesis-related biomarkers in cancer prevention trials. The prevalence of a commonly 
oxidized DNA base—8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxo-dG)—has been found to 
increase during hepatocarcinogenesis (35, 36). However, to date there have been no reports of 

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specific mechanism-based DNA adducts acting successfully as predictive biomarkers for 
hepatocellular carcinoma (HCC).  
 
Ongoing studies in our laboratory are focused on the role of γ-OHPdG in hepatocarcinogenesis, as 
well as elucidation of the mechanism by which Theaphenon® E/Polyphenon E prevent 
accumulation of γ-OHPdG, and thus HCC. 
 
 
2.3.2 γ-OHPdG is a biomarker of hepatocarcinogenesis in animals and correlates with 
high levels of GC to TA and GC to AT mutations 
 
Figure 1 
Primary liver cancer is the third most 
common cause of cancer-related death 
globally; this disease lacks a suitable 
biomarker for early detection, is resistant to 
current chemotherapy, and has molecular 
features that are inadequately understood 
(37). HCC accounts for approximately 85% 
of liver cancer and is an inflammation-
associated 
cancer 
(38, 
39). 
The 
mutagenicity of γ-OHPdG has been well 
studied in vitro (40) but in vivo data is 
lacking. In our laboratory, we first studied 
γ-OHPdG 
as 
a 
biomarker 
of 
hepatocarcinogenesis in vivo in C57/B6 
mice 
(transgenic 
Xpa-/- 
and 
diethylnitrosamine (DEN)-induced HCC 
models) and rats (Long Evans Cinnamon 
[LEC]).  
 
Xpa-/- C57/B6 mice are primarily used as a 
skin-cancer model following exposure to 
ultraviolet (UV)-B irradiation; however, 
these mice also develop spontaneous liver 
tumors (41). As 
repair of γ-OHPdG DNA adducts occurs via 
nucleotide excision repair (NER) (42), and the xeroderma pigmentosum group A correcting (Xpa) 
protein participates in the initial steps of NER, we proposed that an accumulation of γ-OHPdG in 
Xpa-/- mice occurs due to lack of NER activity, and this contributes to the observed 
hepatocarcinogenesis in this model. We back-crossed Xpa-/- C57/B6 mice with C3H/HeNCrl mice 
in order to breed mice with a high rate of spontaneous liver cancer (43). Compared with WT 
controls, these Xpa-/- mice not only had a higher incidence of liver tumors, but also showed 
significantly larger tumor sizes and increased multiplicity (fig. 1). The γ-OHPdG levels increased 
age-dependently in Xpa-/- mice from age 8-week to 32-week (p < 0.05, fig. 1C). We were able to 
detect a statistically significant difference in the hepatic levels of γ-OHPdG and the liver cancer 
development between Xpa-/- and WT mice (fig. 1). 

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Figure 2 
The relationship of γ-
OHPdG in HCC was 
further examined in 
C57/B6 
mice 
involving a single 
injection 
of 
procarcinogen DEN 
(fig 2). In this model, 
mice develop poorly 
differentiated 
HCC 
nodules within 32 to 
36 weeks after DEN 
exposure (44). We 
administered DEN (5 
mg/kg) to male mice 
on postnatal day 14, 
and placed the mice 
on AIN-76A powder 
diet. 
A 
time-
dependent increase of 
steatosis 
was 
observed in the mice 
under the control diet. 
HCCs were observed 
after 6 months. An 
age-dependent increase of γ-OHPdG was seen in the livers, but not in the lungs (a non-target 
tissue). These results are consistent with previous reports that DEN can cause oxidative stress and 
induce LPO (45). LEC rats are inflicted with increased LPO due to abnormal copper accumulation, 
mimicking that of human Wilson’s disease (46). As a result, LEC rats develop acute hepatitis, 
followed by chronic hepatitis, and eventually HCC (39). We found that γ-OHPdG levels in the 
livers of LEC rats were significantly higher than those seen in WT Long Evans (LE) rats (data not 
shown). These results provide additional support for elevated γ-OHPdG levels in the livers of 
animals with an increased risk of HCC. 
 
Studies have shown that γ-OHPdG causes GC to TA and GC to AT mutations (27, 28). We 
reasoned that the increased γ-OHPdG in the livers of Xpa-/- mice can lead to a somatic mutation 
pattern in which GC to TA and GC to AT mutations are the most frequent alterations. We 
compared mutation frequencies in 2 pairs of liver tumor nodules versus adjacent normal liver 
tissues from 2 Xpa-/- mice using whole exome next-generation sequencing (NGS). Whole exome 
sequencing produced a mean yield of 23.8 million reads or 2.5 gigabases of data per sample with 
94.1% > Q30. The samples were sequenced to a mean coverage of 29X, and 99.4% of the reads 
were mapped to the target regions. We found 60 and 100 variants in the 2 liver nodules, with GC 
to TA mutation as the dominant alteration, accounting for 92% and 86% mutations, respectively. 
While examining the Sorting Intolerant from Tolerant (SIFT) prediction scores, we also noted that 

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not shown), which is in agreement with the effects on γ-OHPdG suppression in both genders. The 
potency of LPO inhibition by the antioxidants, obtained by measuring MDA levels in mouse livers, 
is consistent with that of γ-OHPdG (fig. 3E). Although no food consumption differences were 
observed, mice in the Theaphenon E group weighed less (were leaner) and appeared healthier than 
mice in the other groups. This is probably related to thermogenesis, fat oxidation, and the sparing 
of fat free mass effects known to be caused by green tea extract (48).   
 
We tested whether antioxidants can suppress HCC development in the DEN mouse model. Similar 
to Xpa-/- mouse results, Theaphenon E showed remarkable suppression of HCC formation in these 
mice, decreasing incidence from 100% to 40%, tumor size from 10 mm to < 1 mm, and multiplicity 
from 30 to 3 nodules per mouse. Again, Theaphenon E effectively inhibited HCC formation in the 
DEN-induced HCC model. 
 
2.3.4 γ-OHPdG is elevated in human cirrhotic liver compared with normal liver. 
The data described above demonstrates that γ-OHPdG is closely associated with liver 
carcinogenesis in animal models. To investigate the role of γ-OHPdG in human HCC, 40 human 
liver samples were procured with different pathologies/diagnoses, including 2 normal livers, 7 
livers with cirrhosis, 4 with hyperplasia, 3 with cirrhosis and hyperplasia, and 22 with HCC. 
Samples were stained with a γ-OHPdG monoclonal antibody developed in our laboratory (49). 
The association between pathology and expression level of γ-OHPdG was examined using Fisher 
test. A significant association was found between liver disease progression and the immunoscore 
of γ-OHPdG with p = 0.0364. However, the immunoscore of γ-OHPdG was not associated with 
the stages of HCC (p = 0.3259). 
 
We then further characterized γ-OHPdG adduct levels in participants with cirrhosis (an advanced 
stage of liver disease preceding HCC development). Sixty-eight human liver biopsy samples from 
participants with liver cirrhosis but without HCC at the time of biopsy were stained with a γ-
OHPdG monoclonal antibody. γ-OHPdG levels were scored on a scale of 0-3 for distribution of 
positive stain, and again, 0-3 for intensity of positive stain. Sixty-two percent (n = 42) had an IHC 
score of 2 or less, and 38% (n = 26) had an IHC score of 3 or higher (Table 1). 
 
2.3.5 Stability of γ-OHPdG levels in each patient’s cirrhotic liver over time   
In order to evaluate γ-OHPdG as a biomarker for HCC development in cirrhotic participants, the 
stability of the biomarker was studied in participants with serial liver biopsies. The levels of γ-
OHPdG were compared between the 1st and 2nd biopsies in 20 cirrhotic participants with serial 
liver biopsies (fig 4). Six of the 20 participants were not suitable for analysis: 2 subjects (cases 4 
and 6) had liver transplantation between the 2 biopsies; 2 (cases 13 and 22) did not have cirrhosis 
at the first biopsy, but had developed cirrhosis at the second biopsy; 2 (cases 20 and 23) had 
developed HCC between the first and second liver biopsies. Once these 6 cases had been 
excluded from the study, the remaining 14 subjects were evaluated for the stability of γ-OHPdG 
in their serial biopsies. The median interval between the 2 serial biopsies was 7 months (range: 
1-37 months). The γ-OHPdG levels from all 14 subjects remained in either the low IHC score 
category (2 or less) or the high IHC score category (3 or higher), i.e., there was no crossing over 
from low to high or high to low in the interval between the 2 biopsies.  
 
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suppressed the accumulation of γ-OHPdG and inhibited HCC formation in animal models of HCC. 
We reported that γ-OHPdG is elevated in a portion of human cirrhotic liver, and found that the 
levels of γ-OHPdG remain relatively stable in cirrhotic participants over time. Furthermore, γ-
OHPdG serves as a biomarker of HCC recurrence. The study revealed that higher levels of γ-
OHPdG are strongly associated with low recurrence-free survival (p < 0.007). Collectively, these 
results support the role of γ-OHPdG in HCC development and provide a strong rationale for the 
development of an antioxidant formulation of green tea extract (i.e., Theaphenon E/Polyphenon 
E) for HCC prevention. To date, no chemopreventive agents have been developed for liver cancer. 
Although Polyphenon E has been studied in other cancers, it has never been examined in the 
prevention of HCC. This study will verify the role of γ-OHPdG as a predictive biomarker of HCC; 
provide a novel prevention strategy for liver cancer, the third leading cause of cancer-related death 
globally; and expand knowledge of the antioxidant effects of green tea polyphenols in the 
prevention of liver cancer. 
 
2.3.7 Alcohol and Tobacco Use Questionnaires 
Increasing evidence suggests that tobacco and alcohol use are risk factors in the development of 
intraepithelial neoplasia and cancer. In addition, tobacco and alcohol use may adversely affect 
agent intervention, for example by altering the safety profile or metabolism of a drug. 
Standardized assessments of tobacco and alcohol use during clinical trials will aid in 
understanding the potential relationship between the use of these products and clinical endpoints 
or cancer prevention biomarkers. Therefore, NCI, DCP is including assessment of tobacco and 
alcohol use at baseline and Study Visit 3, to determine the potential impact of tobacco and 
alcohol use on 1) treatment toxicity and symptom burden, and 2) the efficacy of treatment 
intervention. 
 
2.4 
Polyphenon E 
 
Green tea has been shown to exhibit cancer-preventive activities in preclinical studies. Its principal 
active components include epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin 
(EC), and epicatechin gallate (EG), of which EGCG is the most abundant and possesses the most 
potent antioxidant activity. Theaphenon E and Polyphenon E have the same chemical composition. 
Polyphenon E formulation has been granted an IND by the FDA and is produced for human 
studies.  
 
2.4.1 Pharmacokinetics of Polyphenon E 
A Phase I pharmacokinetic study was carried out to determine the systemic availability of green 
tea catechins after single oral dose administration of Polyphenon E (decaffeinated green tea 
catechin mixture) (50). Twenty healthy subjects (5 subjects/ per dose level) were randomly 
assigned to one of the dose levels (200, 400, 600, and 800 mg based on EGCG content). The AUC 
and Cmax of EGCG after the 800- mg dose were significantly higher than those after the 3 lower 
doses. EGC and EC were present in the body after the Polyphenon E administration; however, they 
were present predominantly in their conjugated forms. The effect of food on oral bioavailability 
of Polyphenon E administration was tested in 30 healthy volunteers, and it was found that taking 
the Polyphenon E capsules on an empty stomach resulted in greater oral bioavailability of free 
catechins (51, 52). The pharmacokinetics of the conjugated metabolites of EGC and EC were not 
affected by repeat green tea polyphenol daily treatment for 4 weeks. A limited sampling strategy 

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was developed to predict EGCG pharmacokinetics after green tea administration (53). The median 
sampling times were 0.7, 1.4, and 7.0 hours (fasting conditions) and 1.4, 3.6, and 8.7 hours (fed 
conditions). The sampling schemes were accurate and precise in predicting EGCG oral clearance 
and exposure (area under the curve [AUC]) under both fasting and fed conditions. In our study, 
participants who agree to do the PK tests at Georgetown will be asked to fast on their first study 
visit and blood and urine samples will be collected on day 1 of a 4 week cycle, prior to the first 
dose, and then at 1.5, 3.5, and 8.5 hours (+/- 5 minutes) after the first dose of Polyphenon E. 
Clearance of Polyphenon E will be compared among cirrhotic liver participants in this study and 
results from this population will be compared with non-cirrhotic historical control participants 
(53).  
 
2.4.2 Supply of Polyphenon E for this study 
The Chemopreventive Agent Development Research Group, Division of Cancer Prevention, 
National Cancer Institute, NIH is supporting this clinical study by providing Polyphenon E as 200 
mg capsules. The capsules will provide 200 mg of EGCG each. Participants will take 2 - 5 capsules 
once or twice per day continuously for six months, according to the dose escalation 3 + 3 design. 
Polyphenon E/EGCG capsules will be stored at room temperature, avoiding direct sun exposure. 
 
2.5 
Rationale 
 
2.5.1 
Overall Rationale 
γ-Hydroxy-1, N2-propanodeoxyguanosine (γ-OHPdG) is a lipid peroxidation-derived mutagenic 
DNA adduct, which is repaired by the nucleotide excision repair (NER) pathway. Xeroderma 
pigmentosum group A (Xpa) knockout mice deficient in NER developed a high incidence of 
spontaneous liver tumors with more than 85% of GC to TA somatic mutations. We found that 
levels of γ-OHPdG showed an age-dependent increase in mice, and that they were higher in the 
livers of Xpa-/- mice than WT mice. Theaphenon E, an anti-oxidant, effectively decreased γ-
OHPdG levels in the liver DNA of Xpa-/- mice and reduced HCC incidence to 14% and 65%, 
respectively, from 100% in the untreated controls. γ-OHPdG was also found to be elevated in the 
livers of diethyl nitrosamine (DEN)-treated mice and Long-Evans Cinnamon rats—other models 
with high risk of HCC. Again, Theaphenon E effectively inhibited HCC formation in the DEN-
induced HCC model. We examined whether γ-OHPdG serves as a biomarker of HCC recurrence 
using HCC specimens from 45 participants. The study revealed that higher levels of γ-OHPdG are 
strongly associated with low recurrence-free survival (p < 0.0002). Together, these results suggest 
γ-OHPdG is a potentially biologically relevant biomarker for predicting the risk of HCC.  
 
Three antioxidants known to suppress LPO—Theaphenon E (a similar green tea polyphenol to 
Polyphenon E), α-lipoic acid, and vitamin E—were used (47). We observed a significant decrease 
in liver γ-OHPdG levels in the mice fed all 3 antioxidant diets, although the individual antioxidants 
appeared to have different potencies: Theaphenon E > α-lipoic acid > vitamin E (fig 2 and fig. 3). 
Theaphenon E, α-lipoic acid, and vitamin E decreased the accumulation of γ-OHPdG levels by 
65%, 30%, and 30%, respectively, after 16 weeks of treatment, and 83%, 66% or 50%, 
respectively, after 32 weeks of treatment. We next examined the relationship between γ-OHPdG 
and hepatocarcinogenesis in the 3 treatment groups. Hepatocarcinogenesis was most strongly 
reduced in mice fed Theaphenon E (14% HCC incidence vs. 100% in mice fed the control diet), 
α-Lipoic acid resulted in a decrease of HCC incidence to 65%, whereas vitamin E had no 
significant effect (fig. 3). The potency of tumor inhibition by the antioxidants showed a strong 

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correlation with liver γ-OHPdG levels in treated mice. In our preclinical model, Theaphenon 
E/Polyphenon E appeared to be superior in its suppression of γ-OHPdG accumulation and HCC 
development in comparison to α-lipoic acid or vitamin E. α-Lipoic acid has been mainly tested in 
cardiovascular diseases (CVD), obesity, pain, inflammatory diseases, and aging (54) and was 
found to be a reasonable alternative to Polyphenon E, although α-lipoic acid is not as potent as 
Polyphenon E in the prevention of liver cancer in our preclinical HCC models. 
 
We hypothesize that accumulation of the DNA adduct, γ-OHPdG, predicts the development of 
HCC, and that the dietary antioxidant, Theaphenon E/Polyphenon E, suppresses the formation of 
γ-OHPdG, which may reduce HCC development in participants with cirrhosis.  
 
HYPOTHESES: 1) accumulation of γ-OHPdG predicts the development of HCC in cirrhotic 
participants. 2) Polyphenon E suppresses the formation of γ-OHPdG and reduces HCC 
development in participants with cirrhosis. 
 
2.5.2 Polyphenon E Dose Selection /Modification  
In previous chemoprevention trials, the daily dose of Polyphenon E ranged from 400 to 4000 mg 
EGCG. It is not known whether the maximum tolerated dose (MTD) of Polyphenon E/EGCG is 
actually needed to bring about the greatest possible reduction of γ-OHPdG in cirrhotic liver. To 
ensure the safe use of Polyphenon E in cirrhotic participants, we propose a 3+3 dose escalation 
study with daily EGCG dose levels of 400 mg, 800 mg, 1200 mg, 1600 mg, and 2000 mg, with an 
expansion cohort such that a total of 24 subjects complete the study at the MTD as shown in the 
study scheme on page 4 of the protocol. MTD is defined as the dose at which ≤1 subjects out of 6 
experiences a Grade 3 or higher toxicity based on CTCAE criteria, or requires discontinuation of 
treatment based on the Hepatotoxicity Assessment Algorithm provided in the Appendix (shown in 
Appendix D). Subjects at one dose level will have liver function & coagulation tests repeated every 
2 weeks; if no subject requires discontinuation of treatment during the first 4 weeks of treatment 
based on the Hepatotoxicity Assessment Algorithm, subjects will then be enrolled at the next dose 
level. With consideration of the underlying liver cirrhosis in our study population, we propose a 
dose escalation study with careful safety monitoring for liver toxicities.  
 
The maximum dose of 2000 mg EGCG daily selected for the dose escalation cohort is only 50% 
of the maximum dose used in a previous phase II study [56]. This study design will ensure safety 
of cirrhotic participants, and provide an opportunity to evaluate the effect of EGCG on γ-OHPdG 
at a different (lower) dose level. 
 
EGCG 
One published review assessed 34 clinical trials that evaluated green tea extracts in which EGCG 
was the main component (57). The summary odds ratio, estimated using a meta-analysis method 
for sparse event data, for intervention versus placebo was reported to be 2.1 (95% confidence 
interval: 0.5-9.8). Liver enzyme effects were reported in both placebo and treatment groups and, 
where liver enzyme elevations were observed, effects were mild and no serious liver-related 
adverse events were reported. Results from this review, although not conclusive, suggest that 
liver-related adverse events following intake of green tea extracts are expected to be rare (57). 
The mechanisms of EGCG induced antioxidant activity and hepatotoxicity has been studied in 
animal models. (58). The mechanism of EGCG-triggered hepatotoxicity involves suppression of 

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major antioxidant enzymes and the Nrf2 rescue pathway plays a vital role in the counteraction of 
this EGCG toxicity. It is not clear whether upregulation of the Nrf2 pathway by EGCG 
contributes to the antioxidant property of EGCG in humans. The baseline and post treatment 
liver biopsies to be collected in our proposed clinical study will be used to study the mechanism 
of antioxidant effect of EGCG.  
 
In some reviews, green tea extracts containing EGCG have been shown to improve liver function 
in participants with non-alcoholic fatty liver disease (NAFLD). (ref 59 and 60) The investigators 
concluded that upon ingestion of 700 ml per day of green tea containing > 1 g catechin, 
participants with NAFLD demonstrated improved liver fat content and reduced inflammation. 
Several mechanisms have been proposed to account for this liver protective effect of EGCG, 
including but not limited to reduction in liver oxidative stress, inhibitory activity against lipase, 
decreased mitochondrial β-oxidation, and non-heme iron absorption.  
 
In this study, we are targeting participants with well-compensated cirrhosis (Child Pugh A) who 
have a high risk of developing HCC (annual incidence of 3-5%) and have no proven options for 
preventive treatment. A preventive therapy against HCC development is urgently needed. Given 
the rare liver toxicities and the effective HCC prevention observed in preclinical models, we 
believe that the evaluation of Polyphenon E, green tea extract, in subjects with a high risk of 
HCC development (high γ-OHPdG liver in cirrhotic liver) is worthwhile. 
 
Cirrhotic participants are likely to have a baseline increase in transaminases. We deduce this from 
the fact that most participants are found to have cirrhosis only after having a blood test for an 
unrelated condition (such as chronic viral hepatitis, non-alcoholic steatohepatitis, or alcoholic liver 
disease) that causes elevated transaminases. A mild increase (</= 2.5 x upper normal level (UNL)) 
in transaminase does not reflect the level of liver function impairment in well-compensated 
cirrhosis.  To ensure safety, subjects selected will have normal direct bilirubin, and synthetic 
function including albumin > 3.0 g/dL and INR ≤ 1.3. Following FDA recommendations, weekly 
or bi-weekly (depending on assigned dose, clinical stability, and liver biochemical stability of the 
participant) liver function & coagulation tests will be carried out for safety monitoring. We propose 
to enroll participants with baseline AST/ALT that is less than 2.5 x UNL. Change of transaminase 
levels from baseline will be used to monitor the hepatotoxicity of Polyphenon E. In participants 
who develop changes in transaminases, we will hold treatment until levels recover to baseline OR 
discontinue therapy based on the extent of the increase of AST/ALT from the baseline level, 
according to the detailed dose modification/withholding drug scheme for elevated ALT/AST 
described in Section 5.6.  
 
2.5.3 Rationale - Study Endpoints 
Our preliminary data shows that γ-OHPdG predicts HCC development. Among the 3 anti-oxidants, 
including Theaphenon E, lipoic acid, and vitamin E, used in the 3 HCC animal models, only 
Theaphenon E effectively suppressed the accumulation of γ-OHPdG and prevented the HCC 
development. Theaphenon E contains the same active components—epigallocatechin gallate 
(EGCG), epigallocatechin (EGC), and epicatechin (EC)—as the dietary antioxidant, Polyphenon 
E whichhas been tested in many cancer prevention clinical trials. We propose that the accumulation 
of the DNA adduct, γ-OHPdG, predicts the development of HCC, and that Polyphenon E 
suppresses the formation of γ-OHPdG, which may reduce HCC development in participants with 

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cirrhosis. In this pilot study, our primary endpoint is to determine the effect of treatment on γ-
OHPdG levels in cirrhotic liver. On enrollment, subjects will have a baseline biopsy taken. Only 
subjects found to have high γ-OHPdG levels in their cirrhotic liver will receive Polyphenon E 
treatment for 24 weeks. A repeat biopsy will be taken 6 months after treatment initiation, and will 
be compared with the baseline biopsy for changes in liver γ-OHPdG levels. 
 
HCC animal model data support the ability of γ-OHPdG levels to predict the development of HCC. 
In addition, γ-OHPdG levels have been shown to correlate with GC to AT mutations, and other 
mutations in oncogene and tumor suppressor genes found in human HCC, which supports the 
mechanistic role of γ-OHPdG in hepatocarcinogenesis. In our preliminary study, we found that 
38% of 68 cirrhotic liver samples expressed high level of γ-OHPdG. In order to test γ-OHPdG as 
a predictive biomarker for HCC development, we first need to collect additional data on the 
prevalence of high γ-OHPdG levels (IHC score of 3 or higher) in liver cirrhosis, the stability of γ-
OHPdG levels during the course of cirrhosis, and the correlation of high γ-OHPdG levels (IHC 
score of 3 or higher) with the development of HCC. In this phase I study, secondary endpoints 
were chosen to estimate the fraction of participants with liver cirrhosis that have high levels of γ-
OHPdG, and the stability of the γ-OHPdG marker over time in each individual.  In addition, we 
will also test the effect of EGCG on the level of liver stiffness as measured by FibroScan® and 
FIB-4 score as an exploratory study endpoint. We will also develop an LC-MS and/or ELISA-
based method for detecting urinary γ-OHPdG as an exploratory study endpoint.  Lastly, it is 
unlikely that a patient will develop HCC during the short time they are on study. However, we will 
measure the incidence of HCC across all dosage levels, and have thus added it as an exploratory 
endpoint.  
 
3. 
SUMMARY OF STUDY PLAN 
 
3.1 
We propose a single arm, multicenter phase I study of subjects with cirrhotic livers 
expressing high levels (score 3 and above) of γ-OHPdG (γ-OHPdG-high) in their baseline biopsy 
(biopsy 1) who will receive Polyphenon E for 24 weeks. This study is a dose escalation design 
(see Dose Escalation Schema below). Participants in each cohort will be monitored for 4 weeks 
for Discontinue Therapy Criteria (DTC) before additional participants will be enrolled for the next 
dose cohort.  
 
The Discontinue Therapy Criteria is defined as:  
a. Grade 3 or higher toxicity based on CTCAE criteria which is possibly, probably, or 
definitely related to the study agent OR 
b. Requires discontinuation of treatment based on the Hepatotoxicity Assessment Algorithm 
(Appendix D) OR 
c. Any hepatic decompensation such as  
1. New onset ascites or worsening of ascites (requiring increase in drug therapy or 
requiring surgical intervention such as paracentesis). 
2. Variceal bleeding documented by endoscopy 
3. Spontaneous bacterial peritonitis documented by positive culture 
4. Hepatic encephalopathy 
5. Hepatorenal syndrome (Type 1 or 2) 
6. Porto-pulmonary hypertension 

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7. Hepato-pulmonary hypertension 
8. Any liver related event that leads to hospitalization or G4 event. 
 
 
 
One month following the end of intervention (i.e. 7 months from study entry), subjects will have 
a post-therapy clinic visit, to be evaluated for the resolution of any side effect from the treatment 
and review of the six-month repeat scan results. All participants will have a repeat liver biopsy 
(exit biopsy) taken at the end of the 24 week intervention (see Participant Flow Schema at the 
beginning of this document). The Participant Flow Schema at the beginning of this document 
summarizes the sequence of events for participants.  Details are not presented in the Schema, but 
can be found under Section 7. 

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In our unpublished data, 68 participants with cirrhosis, 38% (90% confidence interval, range 0.28, 
0.49) of cirrhotic liver biopsies demonstrated high γ-OHPdG levels (IHC score ≥ 3). Therefore, a 
minimum of 4 and maximum of 171 participants with liver cirrhosis will be screened in our current 
study. A minimum of 2 and a maximum of 48 participants whose cirrhotic liver biopsies show a 
γ-OHPdG score ≥ 3 will be enrolled.  If a maximum tolerated dose is established, a total of 24 
participants will receive the maximum tolerated dose.    
 
3.2 
UNL  
 
For the first six subjects who consent for additional PK collections at Georgetown University, 
blood will be collected for pharmacokinetic study on Visit 1 (day 1 of week 1): pre-dose and at 
1.5, 3.5, and 8.5 hours (+/- 5 minutes) after the first dose of Polyphenon E under fed conditions. 
Study subjects will self-collect their urine before dosing and at three intervals during the 24-h 
period after dosing (0–4, 4–8, and 8–24 h).. 
 
All subjects will have a clinic visit at Screen 1, Screen 2, Visit 1 (week 1 day 1), Visit 2 (week 13 
+/- 3 days), Visit 3 (week 25 +/- 3 days, end of treatment), Visit 4 (week 28 +/- 7 days, end of 
study visit), described in detail in Section 7.1. The laboratory tests at Screen 1 and Visits 1-4 
include CBC, chemistry and liver function tests (CMP), and coagulation tests. Following the FDA 
mandate, weekly or bi-weekly (depending on assigned dose, clinical stability, and liver 
biochemical stability of the participant) liver function & coagulation tests will be carried out for 
safety monitoring.  
 
An ultrasound, CT or MRI scan will also be performed after consent and prior to starting agent 
unless it has been done per standard of care within three months from the consenting date and 
showed no evidence of HCC. It will also be performed at the end of intervention (Visit 3 + 3 
weeks) as part of standard of care. The imaging performed at the beginning and end of intervention 
must be the same method (i.e. if an ultrasound was used or performed during screening, then an 
ultrasound must be performed at the end of intervention). These evaluations will detect any HCC 
development during the treatment.  
 
FibroScan will be performed after consent and prior to starting agent as part of standard of care 
unless the scan has been done within three months from the consenting date. It will also be 
performed at the end of intervention (Visit 3 + 3 weeks) as a research procedure. These evaluations 
will evaluate the change of liver stiffness after six months of Polyphenon E treatment. 
 
4. 
PARTICIPANT SELECTION 
 
4.1 
Inclusion Criteria 
 
4.1.1 Participants with a clinical diagnosis of cirrhosis based on the investigators  
evaluation, confirmed by ANY ONE of the three following methods to define cirrhosis: 
• Established cirrhosis on liver biopsy (METAVIR F4); 
• Ultrasound, CT or MRI findings consistent with cirrhosis. Nodular appearing liver with or 
without evidence of portal hypertension 

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• Transient elastography (FibroScan) with a result > 12.5 kPa 
Etiology of cirrhosis will not be considered in determining inclusion in the study. 
 
4.1.2 Participant is able and willing to comply with study procedures, and signed and dated 
informed consent is obtained.  
 
4.1.3 Participant agrees to consume no more than 2 cups of green tea per day and refrain from 
taking supplements or foods labeled as containing green tea.   
 
4.1.4 Participant must be aged ≥ 18 years. Because no dosing or adverse event (AE) data are 
currently available on the use of Polyphenon E in participants < 18 years of age, children are 
excluded from this study but will be eligible for future pediatric trials, if applicable. 
4.1.5 ECOG performance status ≤ 1 (Karnofsky ≥ 70%; see Appendix A). 
 
 
4.1.6 Participants must have adequate organ and marrow function as defined below in Table 2: 
 
Table 2: 
 
System 
Laboratory Value 
Hematological 
 
Platelets 
≥ 75,000 / μL 
Hemoglobin 
≥ 8 g/dL  
Renal function 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
Within normal institutional limits OR 
 
GFR within normal institutional limits as adjusted for age 
and sex. 
Hepatic function 
 
Serum direct bilirubin 
Within normal institutional limits 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X UNL   
Albumin 
> 3.0 g/dL 
Coagulation 
International Normalized Ratio (INR)  ≤ 1.3 
Other 
Ascites 
Absent 
Encephalopathy 
Absent 
 
4.1.7 Only participants found to express high levels (IHC score 3 and above) of γ-OHPdG (γ-
OHPdG-high HCC) in baseline or archival liver biopsy will be registered to receive Polyphenon 
E treatment.  
 
4.1.8 Participant is able to undergo radiographic evaluation with ultrasound, CT or MRI. 
 
4.1.9 The effects of Polyphenon E on the developing human fetus at the recommended 
therapeutic dose are unknown. For this reason, women of child-bearing potential and men must 
agree to use adequate contraception (hormonal or barrier method of birth control; abstinence). 
Contraception must be used prior to study entry and for the duration of study participation. Should 

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a woman become pregnant or suspect she is pregnant while participating in this study, she should 
inform her study physician immediately. Female participants of childbearing potential should have 
a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study 
medication (if a urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required).   
 
4.2 
Exclusion Criteria 
 
4.2.1 Participant has confirmed HCC by ultrasound/CT/MRI. Participants who have previously 
had HCC but have been treated and have been recurrence free for 5 years are eligible. 
 
4.2.2 Participant has or has had other cancer(s) within 3 years of study; however, in situ breast, 
in situ cervical, and basal cell/squamous cell skin cancers are allowed. Participant with active, 
other cancer that requires systemic therapy will be excluded from this study. Participant with early 
stage cancer that requires local therapy, such as cervical ablation for early stage cervical cancer, 
are allowed to be registered in the study and are allowed to receive local therapy.   
 
4.2.3 Inability to swallow capsules. 
 
4.2.4 Participant has a known diagnosis of mental incapacitation that may affect their ability to 
consent and be compliant with the protocol. 
 
4.2.5 Participant has ever experienced one or more hepatic decompensation events or a history 
of decompensated liver disease as listed below:  
• Clinical ascites 
• Variceal bleeding documented by endoscopy 
• Spontaneous bacterial peritonitis documented by positive culture 
• Hepatic encephalopathy 
• Hepatorenal syndrome (Type 1 or 2) 
• Porto-pulmonary hypertension 
• Hepato-pulmonary hypertension 
• Any liver-related event which led to a hospitalization or a grade 4 event 
 
4.2.6 Participant has an underlying predisposition to GI or rectal bleeding are considered 
ineligible for study participation. 
 
4.2.7 History of allergic reactions attributed to compounds of similar chemical composition to 
Polyphenon E (or green tea). Note that participants who are unable to tolerate intravenous contrast 
for CT scans should have MRIs or ultrasounds during the study instead of CT scans.   
 
4.2.8 Participant is receiving any other investigational agents. 
 
4.2.9 Participants have taken supplements or foods that are labelled as containing green tea for 
8 weeks before start of treatment.  
 

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4.2.10 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. HBV and HCV 
infections are allowed. 
 
4.2.11 Green tea has been consumed by humans for thousands of years and teratogenic or 
abortifacient effects have not been reported. However, subjects in this study will take high doses 
of Polyphenon E. The teratogenic or abortifacient effects of high dose Polyphenon E is unknown; 
therefore pregnant women are excluded from this study. Because there is an unknown but potential 
risk for AEs in nursing infants secondary to treatment of the mother with Polyphenon E, 
breastfeeding should be discontinued if the mother is treated with this study agent. 
 
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 
 
The following strategies will be applied to ensure complete enrollment within the first twelve 
months of study initiation: 
 
MedStar Georgetown Transplant Institute is a network of multidisciplinary teams that provides 
medical care to participants with chronic liver disease. This network includes GUH, Washington 
Hospital Center (WHC), Franklin Square Medical Center, and MedStar Georgetown Transplant 
Institutes in Fairfax and Frederick.  The network serves about 2,200 participants with chronic liver 
disease each year. Dr. Coleman Smith has weekly clinics at GUH, Franklin Square Medical Center, 
and MedStar Georgetown Transplant Institutes in Fairfax. Dr. Rangnekar and Dr. Thomas have 
weekly clinics at the GUH, WHC and MedStar Georgetown Transplant Institute in Frederick. 
When they identify potential candidates at any of the sites (pre-screen), eligible and interested 
subjects will be scheduled for a Screen 1 visit at GUH in DC and enrolled if indeed eligible at 
GUH. GUH is the site with the largest patient volume, will provide 70-80% enrollment for this 
study under MedStar Georgetown transplant Institute. The distance between GUH to other sites 
ranges from 5 to 17 miles (travel time 15 min to 40 min). These distances allow participants 
relatively easy travel from other MedStar sites to GUH, although only about 20-30% of enrollment 
under MedStar Georgetown Transplant Institute (GUH) will be referred from other MedStar sites. 
The transplant institute at Frederick is 45 miles from Georgetown (approx 1 hr drive), but due to 
the small patient volume seen the transplant institute at Frederick, and not many participants are 
expected to be referred to GUH. Therefore, the distance between GUH and the transplant institute 
at Frederick will have minimal impact on enrollment.    
 
Among the 2,200 hepatology participants seen under the MedStar Network within one year, 
approximately 20% have compensated cirrhosis without liver cancer. Therefore we have a pool of 
440 participants that meet the eligibility criteria for this study. Based on our small 50-patient 
survey, 90% of participants should be interested in participating in the study, despite having to 
undergo liver biopsy. Thus we have a pool of 400 participants per year from which to draw 
potential study candidates.  

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At the University of Puerto Rico, over 1000 participants are seen annually over the hepatology 
clinical enterprise. It is estimated that approximately 50% of these participants have underlying 
cirrhosis at different stages, including pre-transplant participants. Dr. Cruz estimates that 10% of 
cirrhotic individuals may be eligible for the study translating to approximately 50-100 participants 
providing adequate numbers for screening into the study. 
 
Monthly teleconferences will be arranged for Drs. Coleman Smith, Marcia Cruz, Victor Carlo, 
Rafael Pastrana, Ruth He, and the study coordinators to discuss enrollment and study related 
issues. 
 
Our strategies are to prescreen most participants by medical record review after the protocol is 
approved, obtain consent, and, if needed, obtain a baseline biopsy from most participants within 
the first few months of study initiation so that candidates for intervention are identified quickly. 
From the pool of study candidates, we plan to screen 6 participants per month if possible. With 
this plan, even if there are delays for any reason, we will be able to complete the study within two 
years. We estimate 60% enrollment will occur at MedStar and 40% enrollment will occur at UPR. 
 
We plan to allow up to three weeks from the day of biopsy to obtain the liver γ-OHPdG score. The 
liver samples will be batched and tested at least twice per month. If the rate of cirrhotic liver 
biopsies with a γ-OHPdG score ≥ 3 is lower than expected, we will increase the number of subjects 
that are pre-screened per month. 
 
Participants will also be able to find trial details and sites through the Lombardi Cancer Center and 
Northwestern Cancer Prevention Consortium websites. In addition, the study investigators will 
work with advocacy groups across the country to improve awareness. 
 
5. 
AGENT ADMINISTRATION 
 
Polyphenon E will be administered on an outpatient basis. Reported AEs and potential risks are 
described in Section 6.2.  
 
5.1 
Dose Regimen and Dose Groups 
 
The treatment to be used in this trial is outlined below in Table 3: 
 
Table 3: Trial Treatment 
Drug 
Dose/ 
Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ 
Treatment 
Period 
Use 
Polyphenon E 
400 mg EGCG 
daily 
oral 
Continuously 
for 24 weeks 
Experimental 
400mg EGCG 
bid 
600mg EGCG 
bid 
800mg EGCG 
bid 
1000mg EGCG 
bid 
 
On an outpatient basis, Polyphenon E will be administered orally according the dose level of 

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EGCG assigned for each cohort on a continuous dosing schedule for 24 weeks.  
 
The medication will be released on Visit 1 (week 1, day 1); and Visit 2 (week 13 +/-3 days).  A 
participant diary will be provided to participants and collected from them by the study coordinator 
approximately every 12 weeks during clinic visits for the 24 weeks of treatment. Thus participants 
will have their diary reviewed and a pill count performed at their Visit 2 (week 13 +/- 3 days) and 
at Visit 3 (end of intervention, 25 +/- 3 days).  
 
5.2 
Polyphenon E Administration 
 
The study agent will be self-administered by the subject.  Participants will be instructed to take 
each dose of Polyphenon E after a light meal.   
 
The medication will be released by the research pharmacies at GUH or UPR every 12 weeks; thus 
on Visit 1 (week 1, day 1), and Visit 2 (week 13 +/- 3 days). A participant diary will be provided. 
In order to give participants some flexibility for Visit 2 (week 13+/- 3 days), patient will be 
provided one extra week of medication, so they will not run out of medication before they receive 
the medication on Visit 2 (week 13 +/- 3 days).  Participants will have their diary reviewed and a 
pill count performed at their Visit 2 (week 13 +/- 3 days) and Visit 3 (end of intervention, week 
25 +/- 3 days). 
 
Polyphenon E/EGCG will be administered orally at a doses of 400 mg qd, 400 mg bid, 600 mg 
bid, 800 mg bid, 1000 mg bid on a continuous dosing schedule for a total of 24 weeks, according 
to the dose escalation 3 + 3 design. Participants are instructed to take their medication after a light 
meal.  The meal should not include either milk or juice during the meal. If a dose is missed, the 
participant should not make up the missing dose the next day, as this would result in an extra dose 
for that day. Participants should not make up vomited doses. The missing dose or vomited dose 
should be recorded in the medication diary. 
 
Pharmacokinetics study: 
The day before the pharmacokinetic study (Visit 1), study participants at Georgetown University 
are instructed to fast after midnight except for drinking water. On the pharmacokinetic study day, 
study subjects at Georgetown University skip breakfast and take no over the counter medications, 
vitamins, or health food products. Study participants at Georgetown University come to the clinic 
in the early morning (6–8 a.m.) and are provided with food for breakfast. Immediately after or 
during breakfast, study subjects swallow their Polyphenon E capsules with a glass of water. Study 
subjects are allowed unlimited water intake throughout the study day. Other drinks are not allowed. 
Blood samples (5–7 ml each) are collected before the administration of the Polyphenon E and then 
at time points 1.5, 3.5, and 8.5 hours (+/- 5 minutes) after drug administration. Study subjects self-
collect urine before dosing and at each PK blood draw. After the 3.5 h blood collection, food for 
lunch is provided to the study subjects.  
 
5.3 
Run-in Procedures  
 
Not applicable 
 

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5.4 
Contraindications 
 
Participants who consume 3 or more cups of green tea per day, or take vitamins or health food 
products that are labelled as containing green tea components. 
 
5.5 
Concomitant Medications 
 
Medications specifically prohibited in the exclusion criteria are not allowed during the ongoing 
trial.  
 
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, 
over-the-counter (OTC), vitamin and mineral supplements, herbal supplements, and IV 
medications and fluids. CRF reporting will include: 1) start and stop date, dose and route of 
administration, and indication. Medications taken for study procedures (e.g. biopsy) will not be 
included. If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date should also be included on the CRF.  
 
All concomitant medications received starting at Screen 1 or within 28 days of the first dose of 
trial treatment (whichever is earlier) and at every clinic visit should be recorded.   
 
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Investigational agents other than Polyphenon E 
• 
Medications listed as prohibited in the trial Exclusion Criteria (Section 4.2). 
Participants must be willing to refrain from drinking > 3 cups of green tea daily, or take 
supplements or foods that are labelled as containing green tea during the screening, intervention, 
and follow-up periods  
 
There are no restrictions on other caffeine-containing beverages or over-the-counter medications. 
 
5.6 
Dose Interruption and Modification 
 
Guidelines for Dose Interruption of Polyphenon E provided below are based on the National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE Version 4.0) 
and the Hepatotoxicity Assessment Algorithm. 
 
For any non-liver related toxicities, Polyphenon E can be continued for grade 1 adverse events 
attributed by an investigators to be possibly, probably, or definitely related to treatment. 
Polyphenon E will be held for grade 2 adverse events attributed by an investigator to be possibly, 
probably, or definitely related to the treatment.  In this case, Polyphenon E will be held until the 
adverse reaction resolves or improves to baseline, at which time Polyphenon E can be re-initiated 
at the same dose level. If the adverse reaction re-occurs at grade 2, Polyphenon E should be 

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permanently discontinued. Polyphenon E will be discontinued for grade 3 or 4 adverse events 
attributed by an investigator to be possibly, probably, or definitely related to the treatment.  
 
Polyphenon E will be held for any elevation in liver function tests and investigators will 
determine the course of action according to Hepatotoxicity Assessment Algorithm (Appendix D) 
for details. 
 
Hepatotoxicity Assessment Algorithm (Appendix D) is being used for hepatotoxicity safety 
monitoring, in conjunction with NCI CTCAE which is used for grading of adverse events. We will 
monitor participants’ laboratory parameters every 1-2 weeks as recommended. Participants who 
do experience toxicity should be reassessed within 3-4 days of the toxicity for resolution. 
Regarding hepatotoxicity, the procedures for laboratory monitoring, treatment interruption, 
preinitiation, or permanent discontinuation are described in detail in Appendix D.   
 
There is no plan for dose modification after patient has started Polyphenon E treatment.  
 
5.7 
Adherence/Compliance 
 
5.7.1 All toxicity and samples from all subjects who receive drug will be evaluated and included 
in the primary analysis, which will be based on intent to treat principle. 
 
5.7.2 The unused pill count and/or participant diary will be provided to and collected from 
participants by the study coordinator every 3 months during clinic visits for the 6 months of 
Polyphenon E treatment. 
 
5.7.3 Additionally, an adequate record of receipt, distribution, and return of all study drugs must 
be kept in a pill count form for the pharmacist to complete. 
 
5.7.4 Measuring the three major metabolites (EGCG, EGC, and EC) of green tea catechins in 
urine will provide additional evidence of compliance.  Pill count and diary are usually used for 
compliance, however these parameters could be misreported or tampered by participants. For this 
purpose, urine samples will be collected at Visit 2 and Visit 3. 
 
Subject compliance with the treatment and protocol includes willingness to comply with all aspects 
of the protocol, and to have blood collected for all safety evaluations.  At the discretion of the 
principal investigator, a subject may be discontinued from the trial for non-compliance with 
follow-up visits or study drug. 
 
6. 
PHARMACEUTICAL INFORMATION 
 
6.1 
Polyphenon E (IND 
, NCI/DCP)    
 
Polyphenon E (Mitsui Norin Co., Ltd., Shizuoka, Japan) is a botanical drug substance containing 
a mixture of catechins originating from the leaves of green tea (Camellia sinensis). The active 
pharmaceutical ingredient is a purified tea fraction containing 80–98% total catechins by weight; 
the main component is epigallocatechin gallate (EGCG), which comprises 50–75% of the material. 

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Other catechins are present at levels of 12% or below each, including epicatechin (EC), 
epigallocatechin (EGC), epicatechin gallate (ECG), and gallocatechin gallate (GCG). Polyphenon 
E may also contain caffeine (<1.0%), theobromine (<1.0%), and gallic acid (<0.5%). 
 
The investigational product to be used in the proposed clinical investigation is a Swedish orange, 
opaque, size 00 hard gelatin capsule containing enough Polyphenon E to deliver 200 mg 
EGCG/capsule. Inactive excipients in capsules include microcrystalline cellulose national 
formulary (NF), croscarmellose sodium NF, colloidal silicon dioxide NF, and magnesium stearate 
NF.  
 
Clinical studies investigating the safety and chemopreventive efficacy of Polyphenon E are being 
conducted under NCI, DCP-sponsored IND 
, filed in FDA’s Division of Oncology 
Products.  
 
6.2 
Reported Adverse Events and Potential Risks 
 
Safety data are available from multiple NCI, DCP-sponsored clinical studies with Polyphenon E. 
In two completed single-dose phase 1 studies, a total of 50 subjects received Polyphenon E in dose 
levels from 200–1200 mg EGCG, in both fed and fasted conditions [64,65]. The most severe 
treatment-emergent adverse event (TEAE) was one grade 3 event of atrial fibrillation that was 
considered unlikely to be related to study medication. Frequently reported TEAEs included grade 
1 and 2 headache, nausea, and abdominal pain, which in some cases were considered possibly or 
probably related to study drug. Reports of nausea and abdominal pain appeared to increase in 
frequency with increasing dose, especially under fasting conditions. Other TEAEs possibly or 
probably related to Polyphenon E administration did not have a clear dose-response relationship. 
Gastrointestinal (GI) AEs were usually mild, and seen most often in the fasting condition and at 
the highest dose level (1200 mg EGCG). Onset of GI events typically occurred within two to three 
hours of dosing and resolved within two hours. Headaches and fatigue were not dose-related and 
may have been related to abstinence from caffeine or other procedure-related stresses. 
 
Two NCI, DCP-sponsored multi-dose studies with Polyphenon E were conducted in healthy 
subjects, who were administered study drug at 400 mg EGCG twice daily (bid) (16 subjects) or 
800 mg EGCG once daily (qd) (58 subjects) [64, 66]. All TEAEs were grade 1 or 2, with headache 
and nausea reported in >20% of subjects, abdominal pain in approximately 15% of subjects, and 
diarrhea, dizziness, and rhinitis in approximately 10% of subjects. 
 
Five NCI, DCP-sponsored placebo-controlled multi-dose studies with Polyphenon E have been 
conducted, with dose levels ranging from 800–1200 mg EGCG qd to 200–800 mg EGCG bid; dose 
durations ranged from two weeks to six months [61-63]. Of the TEAEs that were reported, 98% 
were grade 1 or 2. The majority of subjects were given 800 mg EGCG qd (n=85), and the most 
commonly reported TEAEs at that dose were nausea (24% of subjects) and headache (18%). 
Headache and GI-related TEAEs, including diarrhea, nausea, and dyspepsia, were common across 
dose levels. These TEAEs tended to increase from 400 mg EGCG/day to 800 and 1200 mg 
EGCG/day; they were not reported at 1600 mg EGCG/day, perhaps due to the low number of 
subjects (n=3) at that dose level. These events were generally observed at a higher incidence in 
Polyphenon E-treated subjects compared with placebo subjects. Additional TEAEs that were 

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frequently reported included grade 1 laboratory abnormalities in a Barrett’s esophagus study, with 
23 subjects given 200, 400, or 600 mg EGCG bid.  
 
In NCI, DCP-sponsored trials, as well as investigator-sponsored studies with Polyphenon E, grade 
3 TEAEs considered probably or possibly related to study drug included abdominal pain, 
dyspepsia, diarrhea, fatigue, and rectal hemorrhage. The grade 3 rectal bleeding was unexpected; 
it is therefore recommended that participants with an underlying predisposition to GI or rectal 
bleeding be considered ineligible for study participation. These grade 3 TEAEs occurred in 
subjects administered 400–2000 mg EGCG bid. There were also three grade 3 incidences of 
increased alanine aminotransferase (ALT) considered probably or possibly related to study drug. 
These events occurred in a phase 2 chronic lymphocytic leukemia (CLL) study at 2000 mg EGCG 
bid [56], in a cervical cancer study at 800 mg EGCG qd [62], and in a breast cancer study at 800 
mg EGCG bid [62]. 
 
The safety of tea and tea compounds is supported by centuries of human consumption. However, 
in recent years, oral use of green tea extracts (GTEs) has been associated with several instances of 
hepatotoxicity [67, 68]. Most affected participants were women, and many were consuming GTEs 
for the purpose of weight loss. Although hepatotoxicity in most cases resolved within four months 
of stopping GTE, there have been cases of positive rechallenge and liver failure requiring liver 
transplantation. A written safety report submitted to NCI, DCP-sponsored IND 
 in 
December 2005 described a case of acute liver failure in a woman consuming Green Lite® 
capsules distributed by Origin Biomedicinals, Inc., Halifax, Canada. Green Lite capsules contain 
Polyphenon 70A, a GTE manufactured by Mitsui Norin, and similar in composition to Polyphenon 
E. In addition, the sale of Exolise (an ethanolic GTE sold as a weight reduction aid) was suspended 
in Spain in 2003 after reports of hepatotoxicity (four cases in Spain and nine in France) associated 
with its use [69]. Time to onset of hepatotoxicity following ingestion of GTEs ranged from several 
days to several months. Increased oral bioavailability occurs when GTEs are administered on an 
empty stomach after an overnight fast. These severe adverse reactions appear to be rare and have 
never been reported in any subject administered Polyphenon E. However, increased toxicity, 
including hepatotoxicity, is observed when Polyphenon E or EGCG is administered to fasted dogs. 
Therefore, the FDA Division of Oncology Products has recommended that Polyphenon E be taken 
with food by subjects participating in clinical studies. In addition, subjects should have liver 
function tests performed at baseline and repeated every four weeks while on treatment. Following 
any elevation in ALT, study drug should be withheld (grade 1) or discontinued (grade ≥2), and 
liver function monitored until recovery to normal. 
 
In nearly 30 completed multidose studies with Polyphenon E, including NCI, DCP- and 
investigator-sponsored, there have been >200 reports of elevated ALT or aspartate 
aminotransferase (AST), in approximately 5% of subjects. Of these events, 90% were grade 1, 
with 19 grade 2 events and four grade 3 events. Of the grade 2 events, nine occurred at 2000 mg 
EGCG bid, one at 1200 mg EGCG bid, three at 800 mg EGCG bid, four at 800 mg EGCG qd, and 
two at 400 mg EGCG bid. The grade 3 events occurred at 2000 mg EGCG bid, 1200 mg EGCG 
bid, 800 mg EGCG bid, and 800 mg EGCG qd. The majority of elevated ALT and AST events 
were reported in two open label Polyphenon E studies conducted in subjects with CLL [66, 70]. 
The phase 1 study evaluated the safety and preliminary efficacy of Polyphenon E at doses from 
400 mg to 2000 mg EGCG bid for six months; subjects benefiting from treatment who had not 

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experienced unacceptable toxicity were offered up to one additional year of supplementation with 
either Polyphenon E or the GTE Polyphenon 100 (Mitsui Norin) at the same dose. Polyphenon 
100 contains 120 mg GTE, and provides 100 mg catechins/capsule (65% EGCG). During this 
continuation portion of the trial, subjects had liver enzyme testing (ALT and AST) once each 
month. A phase 2 open-label study in the same cohort at 2000 mg EGCG bid for six months was 
also completed. The incidence of increased ALT and AST events (number of events/number of 
treated subjects) was approximately similar at doses of 400 and 800 mg EGCG bid (1.4–1.7 and 
0.8–1.2 for ALT and AST, respectively); subjects at these dose levels were instructed to take the 
study medication on an empty stomach. At doses of 1000 mg EGCG bid and above, subjects were 
instructed to take the study medication within one hour of eating a substantial meal. The incidence 
of elevated ALT events at doses ≥1000 mg EGCG was 0.3–1.4 and 0.3–1.7 for ALT and AST, 
respectively. There was no obvious dose relationship at Polyphenon E doses of 1000−2000 mg 
EGCG bid taken with food. The incidence of events was generally higher at doses of 400 EGCG 
bid and 800 mg EGCG bid, taken on an empty stomach, compared with higher doses taken with 
food. Thus, there may be a decrease in frequency of ALT and AST elevations when study drug is 
administered on a full stomach; however, the subject numbers are small. 
 
6.3  
Availability 
 
Polyphenon E is investigational agents supplied to investigators by NCI, DCP. 
Table 5 describes supplies to be provided by DCP, NCI. 
 
Table 5 
Product Name & Potency 
Dosage Form 
Polyphenon E 
Capsule (200 mg EGCG) 
 
6.4 
Agent Distribution 
 
Agents will only be released by NCI, DCP after documentation of IRB 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 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 

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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 GUH research pharmacy, UPR research pharmacy, and the principal investigator. The receipt 
record must include from whom the agent was received and to who study agent was shipped, as 
well as the date, quantity and batch or lot number. The dispensing record must note quantities and 
dates that the study agent was dispensed to and returned by each participant.  
 
6.6 
Packaging and Labeling 
 
Polphenon E will be labeled and packaged by NCI, DCP. 
 
Clinical supplies (Polyphenon E) will be affixed with a clinical label in accordance with 
regulatory requirements. 
 
6.7 
Storage 
 
Study drug will be stored in a secure room temperature location, between 15–30°C.  
 
An authorized person at the trial site must record receipt and dispensing of trial medication. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
6.8 
Registration/Randomization 
 
1. Laboratory tests for screening or study entry should be performed within 60 days prior to 
registration.  
2. A study coordinator must upload into the Northwestern Clinical Trials Management 
System, a signed and complete informed consent and a completed eligibility form for each 
participant identified as eligible to be entered into the study.   
3. 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 approval by the NCPC.   
4. An eligibility checklist must be signed by a physician and uploaded into the CTMS.  The 
pathology source documentation will be submitted and reviewed by NCPC quality 
checkers prior to registration approval (evidence of cirrhosis and y-OHPdG score). 
5. 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. 

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6. After registration approval, participants will be assigned a participant identification 
number.  
7. The clinical research coordinator and the research pharmacist will receive a participant 
identification number code for the patient via email. 
 
6.9 
Blinding and Unblinding Methods 
 
This trial is a single-arm, open-label study.  
 
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 
 
6.10 
Agent Destruction/Disposal 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
DCP, NCI, the amount dispensed to and returned by the subjects, and the amount remaining at the 
conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed according to local institutional procedures. Destruction records must be 
provided to MRIGlobal at the end of the study. 
 
 

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7. CLINICAL EVALUATIONS AND PROCEDURES 
 
7.1 
Schedule of Events 
 
 
Pre-
Screen 
Screen 1a 
(0-60 
days 
prior to 
registra-
tion) 
Screen 2a 
(0-60 
days 
prior to 
registra-
tion) 
Visit 1: 
Week1 
Day 1 (0-
14 days 
after 
registra-
tion) 
Between 
Visits 1 
and Visit 
2 
Visit 2: 
Week 13 
+/- 3 
days) 
Between 
Visits 2 
and 3 
Visit 3: 
End of 
Treat-
ment 
(week 25 
+/- 3 
days) 
Visit 4: 
End of 
Study 
(week 
28+/- 7 
days) 
Pre Screen Eligibility performed by 
investigatorb 
x 
 
 
 
 
 
 
 
 
Informed consent 
 
x 
 
 
 
 
 
 
 
Medical History 
 
x 
 
 
 
 
 
 
 
Concomitant Medications Collection 
 
x 
 
x 
 
x 
 
x 
 
Adverse Events Assessments 
 
 
 
x 
 
x 
 
x 
 
Physical Examinationc 
 
x 
 
x 
 
x 
 
x 
x 
Vital Signs (temperature, pulse, 
respiratory rate, and blood pressure)c 
 
x 
 
x 
 
x 
 
x 
x 
Pregnancy test 
 
x 
 
xd 
 
 
 
 
 
Ultrasound, CT or MRI Scan Abdomene 
 
x 
 
 
 
x 
 
FibroScanf 
 
x 
 
 
 
x 
 
Venipuncture for clinical labs 
 
x 
 
x 
 
x 
 
x 
x 
Hematology (CBC w/ diff and platelets) 
 
x 
 
x 
 
x 
 
x 
x 
Coagulation: INR 
 
x 
 
x 
x 
x 
x 
x 
x 
Comprehensive Metabolic Panel 
(CMP)g 
 
x 
 
x 
 
x 
 
x 
x 
Liver function testsh 
 
x 
 
x 
x 
x 
x 
x 
x 
Child Pugh Scorei 
 
x 
 
 
 
 
 
x 
 
AFP (alpha-fetoprotein) and AFP-L3 
 
x 
 
x 
 
x 
 
x 
x 
Biopsy  
 
 
Xj 
 
 
 
 
x 
 
Pathologist Review 
x 
 
x 
 
 
 
 
x 
 
Research Urine collectionk 
 
 
x 
 
x 
 
x 
 
Research Blood collectionl 
 
 
 
x 
 
x 
 
x 
 
Research Blood PKsm 
 
 
 
x 
 
 
 
 
 
Research Urine PKsm 
 
 
 
x 
 
 
 
 
 
Alcohol and Tobacco Use Assessmentsn 
 
 
 
x 
 
 
 
x 
 
Dispensation of study drugo 
 
 
 
x 
 
x 
 
 
 
 
 
a. All subjects will be consented for study, have clinical visit, physical examination/vital signs, and 
laboratory test. Screen 1 and Screen 2 visit procedures may be combined or split into multiple visits, 

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as long as they occur within the window specified. Participants should not have liver biopsy until 
after confirmation of Screen 1 clinical blood lab results.  
b. All subjects will first receive pre-screen for the diagnosis of cirrhosis and eligibility criteria by 
medical chart review.  
c. All subjects will have a clinic visit and laboratory test at Screen 1, Visit 1 (week 1 day 1), Visit 2 
(week 13 +/- 3 days), Visit 3 (week 25 +/- 3 days, end of treatment), Visit 4 (week 28 +/- 7 days, 
end of study visit). The laboratory tests at each visit include CBC with differential and platelets, 
CMP including BUN, creatinine, sodium, potassium, chloride, calcium, bicarbonate, glucose, 
chemistry and liver function tests including AST, ALT, alkaline phosphatase, total protein, 
albumin, direct bilirubin, indirect bilirubin, total bilirubin, magnesium, GGT, and phosphorus, 
coagulation tests INR, and AFP, AFP-L3.  
d. If the participant is pre-menopausal and of child-bearing potential, and has not had a negative 
pregnancy test within 72 hours prior to starting study agent, another pregnancy test will be 
performed at this visit.  If a test is performed, the result must be negative in order to start study 
agent.   
e. All subjects will have undergone imaging (ultrasound, CT or MRI) to exclude HCC, performed as 
part of standard of care after consent and before starting agent unless the imaging has been done 
within three months from the consenting date.  Imaging will be performed at the end of the 
intervention period (Visit 3 + 3 weeks) as part of standard of care. When one type of scan is 
selected, the scans chosen thereafter should be the same type during the period of time that the 
participant is treated or followed on the study.  
f. Fibroscan is performed as part of standard of care after consent and before starting agent unless it 
has been done within three months from the consenting date.  It is performed at the end of 
intervention (Visit 3 + 3 weeks) as a research procedure. 
g. The CMP includes BUN, creatinine, sodium, potassium, chloride, calcium, bicarbonate, and 
glucose. 
h. In between Visits 1 and 2, and between Visits 2 and 3, liver function & coagulation tests including 
AST, ALT, alkaline phosphatase, total protein, albumin, direct bilirubin, indirect bilirubin, total 
bilirubin, magnesium, GGT, calcium, phosphorus, and INR will be performed according to the 
schedule below.  These tests will be performed at the central lab, or, if the participant prefers, at a 
local clinic lab.  Participants who experience hepatotoxicity according to Appendix D will be re-
evaluated every 3-4 days until resolution.   
a. For participants assigned to 400 mg EGCG QD or 400 mg EGCG BID: bi-weekly liver 
function & coagulation testing (every 14 +/- 3 days).    
b. For participant assigned to ≥600 mg EGCG BID: weekly liver function & coagulation 
testing (every 7 +/-3 days) for the first 2 weeks on agent, or until the participant 
demonstrates stability of clinical condition and liver biochemical enzymes* for at least 2 
weeks, whichever is longer.  Thereafter, the participant will receive bi-weekly liver 
function & coagulation testing (every 14 +/- 3 days).   
*Stability of clinical condition and liver biochemical enzymes is defined as meeting all of 
the following, as listed in Appendix D:  
a. No symptoms of clinical hepatitis (vomiting, nausea, right upper quadrant pain) 
b. No ALT or AST increases to ≥5x upper limit of normal  
c. No ALT or AST increases to ≥3x baseline levels 
d. No elevations in direct bilirubin > 1.5 ULN 
e. No elevation of direct bilirubin > ULN, regardless of ALT or AST levels, with 
indicators of immunological reaction (i.e., rash or >5% eosinophilia). 
i. 
For details on the Child-Pugh score, see https://www.qxmd.com/calculate/calculator_43/child-
pugh-score. 
j. 
Only the subjects with γ-OHPdG-high in the base-line liver biopsy will be registered for treatment. 
The treatment is to start within 14 days from registration. The subjects with γ-OHPdG-low liver 

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will have one follow up visit to discuss the test result and surveillance plan. Liver biopsy is required 
for participants who have no archival liver biopsy tissue adequate for γ-OHPdG testing collected 
and stored within 12 months prior to consent. Participants with archival liver biopsy tissue adequate 
for γ-OHPdG testing, and collected and stored within 12 months prior to consent, may optionally 
have the liver biopsy at Screen 2. If the participant has archival liver biopsy tissue collected within 
the last 12 months prior to consent, the archival tissue can be tested (or sent for testing) for γ-
OHPdG at either Screen 1 or Screen 2. 
k. Urine samples for compliance will be collected at Visit 2 and Visit 3. Urine sample for biomarker 
analysis will be collected at Screen 2 or Visit 1 if participant has archival biopsy. 
l. 
Two green and two purple top tubes are collected.  At Visit 1, the Research Blood should be 
collected prior to agent administration. 
m. First six participantsparticipants who consented for PK sample collection at Georgetown: 
Participants will be asked to fast after midnight except for drinking water prior to coming into the 
clinic.  Blood and Urine samples for pharmacokinetic analysis will be obtained on Visit 1 (week 1 
day 1) in clinic prior to Polyphenon E treatment, and at 1.5 hour, 3.5 hour, and 8.5 hours (+/-5 
minutes for blood PKs, and +/- 15 minutes for urine collection) for participantspartcipants receiving 
Polyphenon E treatment after a light breakfast.  Urine samples are self-collected as indicated in 
section 10.2.   
n. The Alcohol and Tobacco Assessments are found in Appendices E-H.  The Baseline questionnaires 
(Appendices E & F) should be administered at Visit 1.  The Follow-up Questionnaires (Appendices 
G & H) should be administered at Visit 3 or at the end of study treatment.  Appendix I should be 
given to each participant upon completing the Alcohol and Tobacco Use Assessment the first time.  
o. Polyphenon E will be dispensed at Visit 1 (week 1 day 1) (3 month supply) and Visit 2 (week 13 
+/- 3 days) (3 month supply). Participant diary will be collected when the drug is dispensed. Unused 
pills will be counted at Visit 2 (week 13 +/- 3 days) visit and Visit 3 (week 25 +/- 3 days). 
 
 
7.2 
Baseline Testing/Prestudy Evaluation 
 
Pre-Screening Evaluation 
The medical charts for the proposed study eligibility (pre-screen) will be reviewed.  
 
Screen 1 Visit 
Participants who wish to be considered for registration will undergo a screening evaluation. A 
complete history and physical exam will be obtained at the screening visit. Additionally, labs 
will be ordered/reviewed to assess eligibility, and imaging will be reviewed to assess cirrhosis.  
• Informed Consent 
• Medical History  
• Record Concomitant Medications 
• Physical Exam & Vital Signs 
• Ultrasound, CT or MRI of the abdomen will be performed at Screen 1, Screen 2, or at 
Visit 1 prior to starting agent, if not performed within 3 months prior to consent 
• FibroScan will be performed at Screen 1, Screen 2, or at Visit 1 prior to starting agent, if 
not performed within 3 months prior to consent 
• Clinical Labs – including CBC with differential and platelets, comprehensive metabolic 
panel including BUN, creatinine, sodium, potassium, chloride, calcium, bicarbonate, 
glucose, liver function tests including AST, ALT alkaline phosphatase, total protein, 
albumin, direct bilirubin, indirect bilirubin, and total bilirubin, magnesium, GGT, and 
phosphorous, coagulation test (INR), AFP and AFP-L3.   

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• Calculate Child Pugh score 
• Pregnancy Test (only offered for premenopausal women with child-bearing potential). 
 
• If the participant has archival liver biopsy tissue collected within the last 12 months prior 
to consent, the archival tissue can be tested (or sent for testing) for γ-OHPdG at either 
Screen 1 or Screen 2. 
Screen 1 Visit will be performed 0-60 days prior to registration. Screen 1 and Screen 2 visit 
procedures may be combined or split into multiple visits, as long as they occur within the 
window specified. Participants should not have liver biopsy until after confirmation of Screen 1 
clinical blood lab results. 
 
Screen 2 Visit 
Participants who meet the Screen 1 eligibility criteria, will return for the Screen 2 Visit. 
• Ultrasound, CT or MRI of the abdomen will be performed at Screen 1, Screen 2, or at 
Visit 1 prior to starting agent, if not performed within 3 months prior to consent 
• FibroScan will be performed at Screen 1, Screen 2, or at Visit 1 prior to starting agent, if 
not performed within 3 months prior to consent 
• Liver biopsy is required for participants who have no archival liver biopsy tissue 
adequate for γ-OHPdG testing collected and stored within 12 months prior to consent. 
Participants with archival liver biopsy tissue adequate for γ-OHPdG testing and collected 
and stored within 12 months prior to consent, may optionally have the liver biopsy at 
Screen 2.  
• If the participant has archival liver biopsy tissue collected within 12 months prior to 
consent, the archival tissue can be tested (or sent for testing) for γ-OHPdG at either 
Screen 1 or Screen 2. 
• Research Urine for γ-OHPdG level 
• The liver biopsy samples will be tested for γ-OHPdG level, if this was not done 
previously 
• The pathology slides will be reviewed and scored for the γ-OHPdG level by pathologists. 
Screen 2 Visit will be performed 0-60 days prior to registration. Screen 1 and Screen 2 visit 
procedures may be combined or split into multiple visits, as long as they occur within the 
window specified. Participants should not have liver biopsy until after confirmation of Screen 1 
clinical blood lab results. 
 
Registration and Randomization 
Participants will be registered between Screen 2 and Visit 1 (week 1 day 1).  For more 
information, see protocol section 6.8 Registration. There is no randomization in this study. 
 
7.3 
Evaluation During Study Intervention 
 
Study Visit 1 (Week 1 Day 1) 
Participants will come to the clinic to receive study procedures and their first dose of study 
agent.  Participants who volunteer for the PK tests at Georgetown will be asked to fast after 
midnight except for drinking water prior to coming into the clinic.   
• 
Ultrasound, CT or MRI of the abdomen will be performed at Screen 1, Screen 2, or at 
Visit 1 prior to starting agent, if not performed within 3 months prior to consent 
• 
FibroScan will be performed at Screen 1, Screen 2, or at Visit 1 prior to starting agent, if 

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not performed within 3 months prior to consent 
• 
If the participant is pre-menopausal and of child-bearing potential, and has not had a 
negative pregnancy test within 72 hours prior to starting study agent, another pregnancy 
test will be performed at this visit.  If a test is performed, the result must be negative in 
order to start agent.   
• 
Record Concomitant Medications 
• 
Physical Exam & Vital Signs 
• 
Adverse Events Assessments. 
• 
Venipuncture for clinical labs 
• 
Clinical Labs – including CBC with differential and platelets, comprehensive  metabolic 
panel including BUN, creatinine, sodium, potassium, chloride, calcium, bicarbonate, 
glucose, liver function tests including AST, ALT alkaline phosphatase, total protein, 
albumin, direct bilirubin, indirect bilirubin, and total bilirubin, magnesium, GGT, and 
phosphorous, coagulation test (INR), AFP and AFP-L3.   
• 
Administer the Alcohol and Tobacco Baseline Assessments (Appendices E & F) 
• 
Provide participant with the participant diary (Appendix C), agent study drug instructions 
(Appendix B), and the resources handout (Appendix I).   
• 
Research Blood (for γ-OHPdG level) 
• 
Research Blood PKs (for the first six participants at Georgetown University who agree) 
• 
Research Urine PKs (for the first six participants at Georgetown University who agree) 
• 
Research Urine for γ-OHPdG level if participant had archival biopsy 
• 
Dispensation of study drug 
Study Visit 1 will be performed 0-14 days after registration.  
 
Between Visits 1 and 2  
Participants will complete weekly or bi-weekly liver function & coagulation tests according to 
the chart below. These tests can be done with local lab or MD, for convenience; LabCorp or 
Quest are preferred, as the results will be reported directly to hospital electronic medical chart. If 
another lab is used, the report can be requested to be faxed to the investigator and/or study 
coordinator.  
• 
Venipuncture for clinical labs 
• 
Liver function tests, including ALT, AST, direct bilirubin, indirect bilirubin, and total 
bilirubin, alkaline phosphatase, total protein, albumin, GGT, calcium, phosphorous, 
and magnesium 
• 
Coagulation test (INR) 
Assigned Dose 
Schedule of liver function & coagulation tests 
400 mg EGCG QD or 
400 mg EGCG BID 
Bi-weekly liver function & coagulation testing (every 14 +/- 3 days) 
≥600 mg EGCG BID 
Weekly liver function & coagulation testing (every 7 +/-3 days) for 
the first 2 weeks on agent, or until the participant demonstrates 
stability of clinical condition and liver biochemical enzymes* for at 
least 2 weeks, whichever is longer.  Thereafter, the participant will 
receive bi-weekly liver function & coagulation testing (every 14 +/- 3 
days). 
* Stability of clinical condition and liver biochemical enzymes is defined as meeting all of the 
following, as listed in Appendix D:  

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     a. No symptoms of clinical hepatitis (vomiting, nausea, right upper quadrant pain) 
     b. No ALT or AST increases to ≥5x upper limit of normal  
     c. No ALT or AST increases to ≥3x baseline levels 
     d. No elevations in direct bilirubin > 1.5 x ULN. 
     e. No elevation of direct bilirubin > ULN, regardless of ALT or AST levels, with indicators 
of immunological reaction (i.e., rash or >5% eosinophilia). 
 
Study Visit 2 (Week 13 +/-3 days) 
After taking the study medication for 12 weeks +/-3 days, participants will return to the clinic. 
• 
Record Concomitant Medications 
• 
Physical Exam & Vital Signs 
• 
Adverse Events Assessments. 
• 
Venipuncture for clinical labs 
• 
Clinical Labs – including CBC with differential and platelets, comprehensive 
metabolic panel including BUN, creatinine, sodium, potassium, chloride, calcium, 
bicarbonate, glucose, liver function tests including AST, ALT alkaline phosphatase, 
total protein, albumin, direct bilirubin, indirect bilirubin, total bilirubin, magnesium, 
GGT, and phosphorous, coagulation test (INR), AFP and AFP-L3. 
• 
Research Urine collection (compliance) 
• 
Research Blood collection (for γ-OHPdG level) 
• 
Dispensation of study drug 
• 
Participant diary review and unused pill count 
• 
Give participant blank participant diary 
 
Between Visits 2 and 3  
Participants will complete weekly or bi-weekly liver function & coagulation tests according to 
the chart below. These tests can be done with local lab or MD, for convenience; LabCorp or 
Quest are preferred, as the results will be reported directly to hospital electronic medical chart. If 
another lab is used, the report can be requested to be faxed to the investigator and/or study 
coordinator.  
• 
Venipuncture for clinical labs 
• 
Liver function tests, including ALT, AST, direct bilirubin, indirect bilirubin, total 
bilirubin, alkaline phosphatase, total protein, albumin, GGT, calcium, phosphorous, 
and magnesium 
• 
Coagulation test (INR) 
Assigned Dose 
Schedule of liver function & coagulation tests 
400 mg EGCG QD or 
400 mg EGCG BID 
Bi-weekly liver function & coagulation testing (every 14 +/- 3 days) 
≥600 mg EGCG BID 
If the participant has previously demonstrated stability of clinical 
condition and liver biochemical enzymes* for at least 2 weeks, the 
participant will receive bi-weekly liver function & coagulation 
testing (every 14 +/- 3 days). 
 
If the participant has not already demonstrated stability of clinical 
condition and liver biochemical enzymes* for at least 2 weeks, the 
participant will receive weekly liver function & coagulation testing 

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(every 7 +/-3 days) until the participant demonstrates stability* for at 
least 2 weeks. Thereafter, the participant will receive bi-weekly liver 
function & coagulation testing (every 14 +/- 3 days). 
* Stability of clinical condition and liver biochemical enzymes is defined as meeting all of the 
following, as listed in Appendix D:  
     a. No symptoms of clinical hepatitis (vomiting, nausea, right upper quadrant pain) 
     b. No ALT or AST increases to ≥5x upper limit of normal  
     c. No ALT or AST increases to ≥3x baseline levels 
     d. No elevations in direct bilirubin > 1.5 x ULN. 
     e. No elevation of direct bilirubin > ULN, regardless of ALT or AST levels, with indicators 
of immunological reaction (i.e., rash or >5% eosinophilia). 
 
7.4 
Evaluation at Completion of Study Intervention 
 
Study Visit 3 (Week 25 +/- 3 days) 
After their last day of taking the study agent, the participant will come in for a clinic visit. 
• 
Record Concomitant Medications 
• 
Physical Exam & Vital Signs 
• 
Adverse Events Assessments. 
• 
Administer the Alcohol and Tobacco Follow-up Questionnaire (Appendices G & H) 
• 
Venipuncture for clinical labs 
• 
Clinical Labs – including CBC with differential and platelets, comprehensive metabolic 
panel including BUN, creatinine, sodium, potassium, chloride, calcium, bicarbonate, 
glucose, liver function tests including AST, ALT alkaline phosphatase, total protein, 
albumin, direct bilirubin, indirect bilirubin, total bilirubin, magnesium, GGT, and 
phosphorous, coagulation test (INR), AFP and AFP-L3. 
• 
Research Urine Collection (compliance) 
• 
Research Blood collection (for γ-OHPdG level) 
• 
Calculate Child Pugh score 
• 
Participant diary review and unused pill count 
• 
Ultrasound, CT or MRI of the abdomen (this procedure can be performed at a separate 
visit + 3 weeks from the Visit 3 date). The same imaging performed during screening 
should be performed at Study Visit 3.  
• 
FibroScan (this procedure can be performed at a separate visit + 3 weeks from the Visit 3 
date). 
• 
Liver biopsy 
 
7.5 
Post-intervention Follow-up Period/ Final Evaluations, Off Study 
 
Study Visit 4 (Week 28 +/- 3 days) 
After a 3 week follow-up, participants will return to the clinic. 
• 
Physical Exam & Vital Signs 
• 
Venipuncture for clinical labs 
• 
Clinical Labs – including CBC with differential and platelets, comprehensive metabolic 
panel including BUN, creatinine, sodium, potassium, chloride, calcium, bicarbonate, 
glucose, liver function tests including AST, ALT alkaline phosphatase, total protein, 

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albumin, direct bilirubin, indirect bilirubin, and total bilirubin, magnesium, GGT, and 
phosphorous, coagulation test (INR), AFP and AFP-L3. 
 
7.6 
Methods for Clinical Procedures 
 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in this clinical trial.  Consent must be documented by the subject’s dated signature 
or by the subject’s legally acceptable representative’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion.  A copy of the signed 
and dated consent form should be given to the subject before participation in the trial.  The initial 
informed consent form, any subsequent revised written informed consent form, and any written 
information provided to the subject must receive the IRB/ERC’s approval/favorable opinion in 
advance of use. The subject or his/her legally acceptable representative should be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this information will be 
provided and documented via a revised consent form or addendum to the original consent form 
that captures the subject’s dated signature or by the subject’s legally acceptable representative’s 
dated signature.  Specifics about the trial and trial population will be added to the consent form 
template at the protocol level.  The informed consent will adhere to IRB/ERC requirements, 
applicable laws and regulations, and Sponsor requirements. 
 
Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by a study physician to ensure that the 
subject qualifies for the trial.  See protocol section 6.8 Registration/Randomization for more 
information. 
 
Medical History and physical exam (H&P) 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that are 
considered to be clinically significant by the Investigator.   
Information collected in the H&P is as follows: 
1. All prescription, herbal medications, vitamins, and supplements taken, starting at Screen 
1 or 28 days prior to starting study agent, whichever is earlier. Any medication or vaccine 
(including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at Screen 1 up to the Final Visit must be 
recorded in source documents and the case report forms (CRFs). The reason for use, 
date(s) of administration (including start and end dates), and dosage information 
(including dose and frequency) must be recorded. Any change in concomitant therapy 
during the study period must be similarly recorded. Questions regarding prior or 
concomitant therapy should be directed to one of the investigators.  
2. Vital signs including history of weight change. 
3. Complete physical exam. 
4. Laboratory study results must be obtained within 60 days prior to registration include the 
following: 
• Complete blood count (CBC) with differential and platelets. 

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• Serum chemistries:  
o Complete Metabolic Panel including BUN, creatinine, sodium, potassium, 
chloride, calcium, bicarbonate, glucose 
o Liver function tests including AST, ALT, alkaline phosphatase, total protein, 
albumin, direct bilirubin, indirect bilirubin, total bilirubin, magnesium, GGT, 
calcium, and phosphorus.  
o Coagulation test (INR) 
o Tumor marker- AFP, AFP-L3. 
• For women of child bearing potential, a serum β-HCG pregnancy test. This is for 
premenopausal women are those who have had the last menstrual period (LMP) within 
the last 12 months OR those who have had a hysterectomy, but have at least one intact 
ovary and are under age 55. Premenopausal women with child-bearing potential are those 
with at least one ovary, an intact uterus, and LMP less than 12 months previously 
• Radiographic evaluation of cirrhosis or development of HCC with FibroScan and either 
ultrasound, CT or MRI. 
 
Prior Medications Review 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject starting at 
Screen 1 or within 28 days before starting study agent, whichever is earlier. Treatment for the 
disease for which the subject has registered in this study will be recorded separately and not 
listed as a prior medication.  
 
Concomitant Medications Review 
The investigator or qualified designee will record medication, if any, that will be taken by the 
subject during the trial. All medications related to reportable SAEs and ECIs should be recorded 
as defined. 
 
Disease Details and Treatments 
The investigator or qualified designee will obtain prior and current details regarding disease 
status, and review all prior treatments including those for HBV and HCV. 
 
Assignment of Screening Number 
All participant records and tissue specimens will be de-identified using a letter and number 
assigned to their case at the time of screening.  Screening ID blocks will be provided by 
Northwestern, and assigned to the participant by the accrual site at the time of screening.  No 
record or specimen will contain information that could identify the participant.  The key that 
connects participant identifiable information with this assigned number will be held by the 
Principal investigator.  For computer records, the key will be protected by a double password 
protection system.  Any paper records will be contained in a locked cabinet within a locked 
office to ensure participants’ privacy is protected. 
 
Biopsies 
Of note, participants who are on chronic anticoagulation will be required to hold anticoagulation 
prior to the biopsies being performed. Participants on warfarin must hold treatment for 5 days, but 
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will continue until the evening prior to the biopsy. LMWH will be held in the morning of the 
procedure, but the patient will receive LMWH the evening of the day of biopsy. Participant may 
then resume warfarin the day of biopsy.   
 
Preferred biopsy is core biopsy; 14 -18 gauge (G), 2.11-1.27 mm outer diameter (OD), 1.6-0.84 
mm inner diameter (ID), 0.254-0.216 mm wall thickness, hypodermic needles can be used to 
perform the core biopsies based on the sites standard of care procedures. The use of a 16G needle 
is highly recommended as it is the most appropriate size to use for percutaneous liver biopsies 
(70,71). Twenty (20) unstained liver biopsy sections, cut 4-microns-thick must be submitted to the 
Dr. Chung’s laboratory at Georgetown University/Lombardi for assessment of γ-OHPdG levels in 
liver samples. Subjects with high levels of γ-OHPdG (IHC stain =/> 3) who meet all other 
eligibility criteria will then be receive Polyphenon E treatment. A random liver biopsy will be 
performed at 24 weeks (+/- 7 days) prior to end of treatment. The liver tissue will be evaluated by 
Dr. Chung’s laboratory at Georgetown University/Lombardi to assess for γ-OHPdG levels 
(Section 10.2). Liver biopsy samples will be stored in the lab of Dr. Fung-Lung Chung. γ-OHPdG 
testing of the liver biopsy will be carried out at least twice each month at Dr. Chung’s lab. The 
liver biopsy samples will be shipped Monday-Thursday, after communication with the receiving site.  
 
Lastly, all liver biopsies taken during the course of the study, regardless of the indication (i.e., 
both protocol-defined and those performed for other clinical indications) must be assessed by the 
PIs and the pathologists at Georgetown University Hospital.  
 
Research Blood (for γ-OHPdG level) 
At visits 1, 2, and 3, two green top tubes of blood will be drawn.  The Research Blood at Visit 1 
should be collected prior to agent administration. These samples will be uses exclusively for 
developing non-invasive methods for testing biomarker detection. 
 
Research Urine (for γ-OHPdG level and compliance) 
At Screen 2 and visits 2 and 3, one 100mL Urine sample will be collected.  The Research Urine 
at Screen 2 will be used for γ-OHPdG levels and at visit 2 and 3 will be used for compliance to 
measure catechin levels. 
 
Research Blood and Urine PKs 
Six participants at Georgetown University will be given the option of participating in extra 
Research Blood and Urine PKs at Visit 1.  The day before the pharmacokinetic study (Visit 1), 
Georgetown University study participants are instructed to fast after midnight except for drinking 
water. On the pharmacokinetic study day, study subjects skip breakfast and take no over the 
counter medications, vitamins, or health food products. Study participants come to the clinic in the 
early morning (6–8 a.m.) and are provided with food for breakfast. Immediately after or during 
breakfast, study subjects swallow their Polyphenon E capsules with a glass of water. Georgetown 
University study subjects are allowed unlimited water intake throughout the study day. Other 
drinks are not allowed. Two green top tubes of blood are collected before the administration of the 
Polyphenon E and then at time points 1.5, 3.5, and 8.5 hours (+/- 5 minutes) after drug 
administration. Study subjects self-collect urine before dosing and at each PK blood draw.  After the 3.5 
h blood collection, food for lunch is provided to the study subjects.  
 

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Study Agent 
Participants will receive Polyphenon E on Visit 1 (week 1 day 1) and Visit 2 (week 13 ± 3 days) 
for a twelve week supply of 840 pills.  To give some flexibility to participants for Visit 2 (week 
13), on Visit 1 (week 1 day 1), participants will be given one extra week drug supply of 
additional 70 pills, therefore on Visit 1 (week 1 day 1) participants will be given a supply of 
study agent of 910 pills, while on Visit 2 (week 13+/- 3 days), participant will be given a supply 
of study agent of 840 pills.  
 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate potential new or 
worsening AEs as specified in 7.1 SCHEDULE OF EVENTS, and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.0 (see Section 11.2).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment.  
 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam and vital signs 
assessment during the screening period.  Clinically significant abnormal findings should be 
recorded as medical history.   
 
Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration 
of each dose of trial treatment and at treatment discontinuation as specified in the protocol section 
7.1 Schedule of Events.  Vital signs should include temperature, pulse, respiratory rate, weight and 
blood pressure.  Height will be measured at screening only. 
 
Liver and Abdominal MRI/CT scans, and Other Imaging 
A comprehensive liver and abdominal ultrasound, MRI or CT scan will be performed at the Screen 
1 or Screen 2 Visit if not performed within 3 months prior to consent, and at the end of intervention 
(+ 3 weeks from Visit 3) as specified in section 7.1 Schedule of Events. Image evidence of cirrhosis 
and HCC will be recorded and followed. These are standard-of-care tests which are usually 
performed at 6-month intervals in participants with cirrhosis. 
 
Standard Laboratory Tests 
Standard laboratory samples for this study will be assessed using the certified laboratories at the 
investigators’ institutions, or at a clinical laboratory such as Quest or LabCorp. The PI or sub-
investigator will review, initial, and date all laboratory results. Any laboratory value outside the 
reference range that is considered clinically significant by the investigator will be followed as 
appropriate. Clinically significant laboratory values will be recorded as adverse events if they meet 
the criteria as specified in Adverse Events (NCI-CTCAE) version 4.0). 
 
8.  
CRITERIA FOR EVALUATION AND ENDPOINT DEFINITION 
 
8.1 
Primary Endpoint 
 

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8.1.1 To establish maximum tolerated dose (MTD) and to collect safety data of Polyphenon 
E/EGCG treatment in participants with cirrhosis 
 
The safety data of Polyphenon E treatment in participants with liver cirrhosis will be collected at 
the monthly visit for the first 3 cycles, then at the end of treatment visit for 4th to 6th cycle of 
treatment). Safety data on hepatotoxicity will be obtained by weekly or bi-weekly (depending on 
assigned dose, clinical stability, and liver biochemical stability of the participant) liver function 
tests. Participants who experience hepatotoxicity according to Appendix D will be re-evaluated 
every 3-4 days until resolution.   
 
Safety and adverse event data will be summarized using descriptive (frequency, %) statistics by 
dose cohort. The primary endpoint of MTD cannot be established because the study was closed 
early, and, based on the observed safety profile with a single DTC occurring in dose cohort 4 (1/4 
patients), future studies can consider dose level 3 as the starting dose. 
 
8.1.2  To determine the effects of Polyphenon E/EGCG treatment on the suppression of γ-
hydroxy-1,N(2)-propanodeoxyguanosine (γ-OHPdG) levels in cirrhotic liver. 
 
Our preliminary data shows that γ-OHPdG predicts HCC development. Among the 3 anti-
oxidants—Theaphenon E, lipoic acid, and vitamin E—used in 3 HCC animal models, only 
Theaphenon E effectively suppressed the accumulation of γ-OHPdG and prevented HCC 
development. Theaphenon E contains the same active components—epigallocatechin gallate 
(EGCG), epigallocatechin (EGC), and epicatechin (EC)—as the dietary antioxidant, Polyphenon 
E. EGCG has been tested in many clinical cancer prevention trials. We propose that the 
accumulation of the DNA adduct, γ-OHPdG, predicts the development of HCC, and that 
Polyphenon E suppresses the formation of γ-OHPdG, which may reduce HCC development in 
participants with cirrhosis. In this pilot study, our primary endpoint is to determine the effect of 
EGCG treatment on γ-OHPdG levels in cirrhotic liver. During screening, subjects will have a 
baseline biopsy taken. Only subjects found to have high γ-OHPdG levels (IHC score equal or 
higher than 3) in their cirrhotic liver will receive EGCG treatment for 24 weeks. An exit liver 
biopsy will be taken at the end of intervention and will be compared with the baseline biopsy for 
changes in liver γ-OHPdG levels. All liver tissue slides from the biopsy will be processed and 
stained with an anti- γ-OHPdG antibody in the lab of Dr. Fung-lung Chung. Two pathologists: Dr 
Bhaskar Kallakury from GU and Dr. Carmen Gonzalez Keelan from UPR will review the slides 
and score the level of γ-OHPdG in the participant liver biopsy samples. 
 
 
8.2 
Secondary Endpoints 
 
8.2.1 To collect Polyphenon E/EGCG pharmacokinetic data in participants with cirrhosis.  
 
In previous preclinical studies, the pharmacokinetics of the conjugated metabolites of EGC and 
EC were not affected by repeat green tea polyphenol daily treatment for 4 weeks. A limited 
sampling strategy was developed to predict EGCG pharmacokinetics after green tea administration 
(38). The median sampling times were 0.7, 1.4, and 7.0 hours (fasting conditions) and 1.4, 3.6, and 
8.7 hours (fed conditions). The sampling schemes were accurate and precise in predicting EGCG 

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oral clearance and exposure (area under the curve [AUC]) under both fasting and fed conditions. 
In this current study, blood and urine samples will be collected in six subjects on day 1 of a 4 week 
cycle, prior to the first dose of Polyphenon E, and then at 1.5, 3.5, and 8.5 hours (+/- 5 minutes) 
after the first dose of Polyphenon E, taken while fed. Clearance of Polyphenon E will be compared 
among cirrhotic liver participants in this study and results from this population will be compared 
with non-cirrhotic historical control participants (38). 
 
8.2.2 LC-MS assay will be used to determine gamma-OHPdG changes from baseline to post-
treatment. This will generate a continuous variable for values of gamma-OHPdG. Descriptive 
statistics (mean, range) will be used to summarize this continuous outcome by dose level.  A 
nonparametric trend test will be used to examine whether there is a trend for greater reduction in 
gamma-OHPdG as the dose level increases.  
 
8.2.3 To estimate the fraction of participants with liver cirrhosis that have high levels of γ-
OHPdG. 
 
The fraction of participants with liver cirrhosis that have high levels of γ-OHPdG is calculated 
based on the number of subjects enrolled over the number of subjects screened based on the levels 
of γ-OHPdG in their first liver biopsy. 
 
8.2.4 Exploratory Endpoint: To assess the effects of Polyphenon E on the grade of cirrhosis as 
measured by FibroScan and FIB-4 score. 
 
Whether Polyphenon E treatment affects the level of cirrhosis will be evaluated by comparing the 
reading of FibroScan at baseline and 6 months of EGCG treatment in the subjects participating the 
intervention study.  
 
8.2.5 Exploratory Endpoint: To develop an LC-MS and/or ELISA-based method for detecting γ-
OHPdG. 
 
The research urine samples at Screen 2 and research blood samples collected at Visit 1, Visit 2, 
and Visit 3 will be used to develop a non-invasive LC-MS and/or ELISA-based method to quantify 
γ-OHPdG in urine and blood samples of collected from trial participants. 
 
8.2.6  Exploratory Endpoint: To evaluate any HCC development during the treatment 
 
The potential incidence of HCC for participants receiving Polyphenon will be evaluated using 
ultrasound/CT/MRI performed before and after study intervention.  
 
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) (see section 5.6, Appendix D), 
inadequate agent supply, noncompliance, concomitant medications, or medical contraindication. 
Participants will continue to be followed, if possible, for safety reasons and in order to collect 
endpoint data according to the 7.1 SCHEDULE OF EVENTS.  

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For any non-liver related toxicities, Polyphenon E will be held for grade 2 adverse events 
attributed by the treatment until the adverse reaction resolves or improves to baseline, at which 
time Polyphenon E can be re-initiated at the same dose level. If the adverse reaction re-occurs at 
grade 2, Polyphenon E should be permanently discontinued.   
 
Hepatotoxicity Assessment Algorithm (Appendix D) is being used for hepatotoxicity safety 
monitoring, in conjunction with NCI CTCAE which is used for grading of adverse events. We will 
monitor participants’ laboratory parameters every 1-2 weeks as recommended, according to 
protocol section 7. Regarding hepatotoxicity, the procedures for laboratory monitoring, treatment 
interruption, preinitiation, or permanent discontinuation are described in detail in Appendix D.   
 
If the participant meets at least one criterion of Appendix D, but close monitoring of a participant 
is not possible, the participant will be taken off agent. 
 
If the participant meets any Discontinue Therapy Criteria, the participant will be taken off agent.  
DTC is defined as: 
a. Grade 3 or higher toxicity based on CTCAE criteria which is possibly, probably, or 
definitely related to the study agent OR 
b. Requires discontinuation of treatment based on the Hepatotoxicity Assessment Algorithm 
(Appendix D) OR 
c. Any hepatic decompensation such as  
1. New onset ascites or worsening of ascites (requiring increase in drug therapy or 
requiring surgical intervention such as paracentesis). 
2. Variceal bleeding documented by endoscopy 
3. Spontaneous bacterial peritonitis documented by positive culture 
4. Hepatic encephalopathy 
5. Hepatorenal syndrome (Type 1 or 2) 
6. Porto-pulmonary hypertension 
7. Hepato-pulmonary hypertension 
8. Any liver related event that leads to hospitalization or G4 event. 
 
Participants taken off-agent due to adverse event will be followed until resolution of the adverse 
event or until stabilization of labs and the participant’s clinical picture.   
 
8.4 
Off-Study Criteria 
 
Participants may go ‘off-study’ for the following reasons: the protocol intervention and any 
protocol-required follow-up period is completed, AE/SAE, lost to follow-up, non-compliance, 
concomitant medication, medical contraindication, withdrawal of consent, death, determination of 
ineligibility (including screen failure), or pregnancy.  
 
8.5 
Study Termination 
 
NCI, DCP as the study sponsor has the right to discontinue the study at any time.  
 
The study will be placed on hold if at any time one of the following occurs: 

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• One fatality deemed to be possibly, probably, or definitely related to treatment 
• ≥ 2 participants meet the criteria for hepatic decompensation, defined as any of the 
following: 
o New onset ascites or worsening of ascites (requiring increase in drug therapy or 
requiring surgical intervention such as paracentesis) 
o Variceal bleeding documented by endoscopy 
o Spontaneous bacterial peritonitis documented by positive culture 
o Hepatic encephalopathy 
o Hepatorenal syndrome (Type 1 or 2) 
o Porto-pulmonary hypertension 
o Hepato-pulmonary hypertension 
o Any liver-related event that leads to hospitalization or a grade 4 event 
• ≥ 4 participants meet at least one criterion in the algorithm for hepatoxicity (Appendix D) 
 
While the study is on hold, the occurrence will be reviewed and investigated by NCI, DCP and 
Protocol PI and discussed with the FDA to determine whether the study will be terminated. In the 
dose escalation cohorts, we plan to follow the 3+3 design to avoid unnecessary exposure of 
participants to EGCG at doses that may cause hepatotoxicity.  
 
9. 
CORRELATIVE/SPECIAL STUDIES  
 
9.1 
Rationale for Methodology Selection 
 
Our proposed study will assess whether our preclinical finding that Polyphenon E decreases the 
levels of γ-OHPdG holds true in the clinical setting. Our long term goal is to evaluate the role of 
γ-OHPdG as a predictive biomarker of HCC, and provide a novel prevention strategy for liver 
cancer, the third leading cause of cancer-related death globally, while expanding knowledge of the 
antioxidant effects of green tea polyphenols in the prevention of liver cancer.  
 
To evaluate the change of γ-OHPdG in subjects treated with Polyphenon E, two methods will be 
used to measure the level of γ-OHPdG in liver tissue. First, γ-OHPdG levels in liver specimens 
will be determined by IHC, as previously described (34). Second, portions of the liver sample will 
be used for DNA isolation and further assay using LC/tandem MS methodology (for confirmation 
of γ-OHPdG antibody staining results by IHC) (34). The first method will provide rapid and semi-
quantitative measurement of the γ-OHPdG level. The second method will provide quantitative and 
important confirmatory measurements of γ-OHPdG.  IHC analysis is applicable in large-scale 
analysis of clinical samples, while LC/tandem MS methodology is costly and time consuming, but 
needed for validation of our IHC assay results. LC/tandem MS is suitable for small-scale sample 
analysis in a basic research laboratory. In this study, we propose to use LC/tandem MS 
methodology to confirm the findings from IHC analysis.  
 
Blood and urine will be collected on Visit 1 for measuring bioactive catechin concentrations (EC, 
EGC, and EGCG) for pharmacokinetics study using a well-developed method (38).  In our study, 
blood and urine samples will be collected in six subjects on day 1 of a 4 week cycle, prior to the 
first dose, and then at 1.5, 3.5, and 8.5 hours (+/- 5 minutes) after the first dose of Polyphenon E. 
Clearance of Polyphenon E will be compared among cirrhotic liver of participants in this study 

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and results from this population will be compared with non-cirrhotic historical control participants 
(38). 
 
To evaluate the relationships of γ-OHPdG levels in the liver with that found in the urine and blood 
samples of these participants, urine samples will be collected at Screen 2 from participants who 
are subjected to a liver biopsy. Blood samples will be collected for all study participants at Visit 
1, Visit 2, and Visit 3. As a non-invasive method is a prerequisite for the clinic application of γ-
OHPdG as a prognostic biomarker, we will make an effort to develop a non-invasive method for 
measuring γ-OHPdG in urine and blood. The hypothesis is that the urinary γ-OHPdG reflects its 
hepatic levels.  An LC-MS/MS and/or ELISA based method will be developed and the correlation 
coefficient between urinary, blood, and liver γ-OHPdG levels will be established. 
 
Compliance will be verified by using the urine samples collected at Visits 2 and 3.  These samples 
will be analyzed for green tea catechins, specifically EGCG, EGC and EC by the HPLC-EC 
method described in literature which was further developed in Dr. Chung’s lab. 
 
Studies have shown that γ-OHPdG adduct formation causes GC to TA and GC to AT mutations 
(12,13). In our preclinical HCC animal model, from whole exome next-generation sequencing, we 
found GC to TA mutation as the dominant alteration, accounting for 92% and 86% mutations, 
respectively. The high GC to TA mutation frequency suggests that γ-OHPdG plays a role in the 
mutagenesis that leads to HCC development. DNA sequencing of human liver biopsy samples will 
allow us to assess changes in the mutation spectrum in liver biopsies before and after Polyphenon 
E treatment. This information is critical to our ability to assess the role of γ-OHPdG DNA adduct 
formation in the development of liver cancer in our currently proposed biomarker driven study.  β-
Catenin and p53 are the two most frequently mutated genes in HCC. If we are able to shown 
Polyphenon E treatment decreases the accumulation of γ-OHPdG, and also decreases the mutations 
frequency in p53, and β-catenin (CTNNB1) gene, the data will support the mechanistic role of  γ-
OHPdG in hepatocarcinogenesis, and Polyphenon E as an intervention for HCC prevention. The 
data from this pilot study will support a larger study evaluating Polyphenon E as a preventive 
treatment for HCC. 
 
9.2 
Comparable Methods 
 
In this study, we use IHC, a semi-quantitative method to measure the levels of γ-OHPdG in body 
tissues, and LC/tandem MS methodology, a quantitative method, to confirm these of γ-OHPdG 
levels. There are no other methods used to measure γ-OHPdG levels.  Only one such comparison 
was reported (34) and we will compare the results from this study to those previously reported. 
We found that approximately 30% of cirrhotic participants expressed high levels of γ-OHPdG in 
their liver biopsies. We will be able to compare this previous observation with the data obtained 
in this current study.  
 
The methods used for pharmacokinetic study and gene target sequencing are well-established 
procedures. No better methods exist for obtaining the data needed for this study.  
 
The novelty of the study lies in our evaluation of the change of γ-OHPdG levels in participants 
treated with Polyphenon E using standard established methods.  

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Research Urine – γ-OHPdG 
x 
 
 
 
Research Urine - Compliance 
 
 
x 
x 
Research Blood PKs** collected on Visit 1 
(pretreatment, 1.5, 3.5, and 8.5 hours (+/- 5 minutes) post 
treatment) 
 
x 
 
 
Research Urine PKs** (self-collected at pretreatment, 
1.5, 3.5, and 8.5 hours (+/- 15 minutes) post treatment)  
 
x 
 
 
* Liver biopsy is required for participants who have no archival liver biopsy tissue adequate for γ-OHPdG testing 
collected and stored within 12 months prior to consent. Participants with archival liver biopsy tissue adequate for 
γ-OHPdG testing, and collected and stored within 12 months prior to consent, may optionally have the liver biopsy 
at Screen 2. If the participant has archival liver biopsy tissue collected within the last 12 months prior to consent, 
the archival tissue can be tested (or sent for testing) for γ-OHPdG at either Screen 1 or Screen 2. Archival tissue 
will be sent to Dr. Chung’s laboratory as a formalin-fixed, paraffin-embedded block. 
** Research Urine and Research Blood PKs are performed on the first six participants at Georgetown University 
who agree to provide extra blood and urine. 
 
Liver Biopsies: Screen 2 and Visit 3 
Liver biopsy is required at Screen 2 for participants who have no archival liver biopsy tissue 
adequate for γ-OHPdG testing collected and stored within 12 months prior to consent. 
Participants with archival liver biopsy tissue adequate for γ-OHPdG testing, and collected and 
stored within 12 months prior to consent, may optionally have the liver biopsy at Screen 2. All 
participants will have a liver biopsy at Visit 3, regardless of archival tissue availability.  
 
Biopsies will be performed as per standard of care at the sites to generate one to two cores 
(diameter about 2 mm, with a throw length of approximately 2 cm), which will provide adequate 
tissue for study. Each set of core biopsies will be divided and processed as below for later analysis:  
1) Formalin-fixed, paraffin-embedded (FFPR) block 
a. Place the 1/4th core in the middle of the bottom Telfa paper, put the top piece of 
Telfa paper back to cover the biopsy specimen.  
b. Close the cassette and put it into 10% neutral buffered formalin and fix for 12 hours. 
c. Store the specimen in 70% ethanol and make paraffin block. 
d. Each mold will be labeled with the specimen ID number.  
e. The formalin fixed core will be shipped at 4°C (25% of the specimen, 1/4 core 
biopsy). 
2) Flash-frozen 
a. Transfer the remaining ¾ core into a separate 4mL cryovial or 100mL biopsy cup 
with DSMO-salt solution. 
b. Screw the cap of specimen, place study label to the tubes, and then place each 
sample in liquid nitrogen. 
c. Once cryogenic molds are frozen, transfer them to dry ice and store samples at -
80°C. 
 
Archival Liver Biopsy Tissue: Screen 1 or Screen 2 
If the participant has archival liver biopsy tissue collected within the last 12 months prior to 
consent, the archival tissue can be tested (or sent for testing) for γ-OHPdG at either Screen 1 or 
Screen 2. Archival tissue will be sent to Dr. Chung’s laboratory as a formalin-fixed, paraffin-
embedded block. If archival tissue is used in lieu of a Screen 2 liver biopsy (fresh tissue), then 
the pre-study p53 and β-catenin analyses will be performed on the formalin-fixed, paraffin-

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embedded archival tissue block (instead of using frozen fresh tissue).  
 
Research Urine: Screen 2, Visit 2, and Visit 3 
At Screen 2, Research Urine for measuring γ-OHPdG should be collected prior to the Screen 2 
Liver Biopsy for participants. At Visit 2 and Visit 3, compliance to treatment will be assessed 
using urine samples. 
 
For Screen 2 urine collection (γ-OHPdG): 
1) Instruct the participant to: 
a. Wash hands with soap and warm water. 
b. Hold the 100 mL Urine Specimen Cup labeled “Urine” as the specimen type, a few 
from the urethra and urinate, collection the first-void urine until the cup is half full. 
c. Void the rest of the urine into the toilet. 
d. Tightly screw the cap onto the cup and place in the biohazard transport bag 
e. Clean-up any spills on the cup using the provided towelette. 
2) Place the pre-generated label noting the participants study ID to the urine cup. 
3) For MedStar Georgetown: transfer urine specimen to the Dr. Chung’s laboratory for 
processing along with the processing labels and collection form. 
4) For non-MedStar Georgetown University sites: freeze and store samples immediately at -
80°C or colder. 
 
For Visit 2, and Visit 3 urine collection (compliance): 
1) Two urine collection cups will be provided in the kit, only the 100ml urine cup labeled 
“Parent Tube” will be given to the participant. Place the pre-generated label noting the 
participants study ID to the urine cup. 
2) Instruct the participant to: 
a. Wash hands with soap and warm water. 
b. Hold the 100 mL Urine Specimen Cup labeled “Urine” as the specimen type, a few 
from the urethra and urinate, collection the first-void urine until the cup is half full. 
c. Void the rest of the urine into the toilet. 
d. Tightly screw the cap onto the cup and place in the biohazard transport bag 
e. Clean-up any spills on the cup using the provided towelette. 
3) Transfer 30ml of urine sample to 30ml vial labeled “daughter tube” and mix with powder 
within 20 minutes of sample collection or as soon as possible. Place the pre-generated label 
noting the participants study ID to the urine cup. 
4) For MedStar Georgetown: transfer urine specimen to the Dr. Chung’s laboratory for 
processing. Along with the processing labels and collection form.  
5) For non-MedStar Georgetown University sites: freeze and store samples immediately at -
80°C or colder. 
 
Research Blood: Visit 1, Visit 2, and Visit 3 
Research Blood is taken at Visit 1, Visit 2, and Visit 3. The Research Blood on Visit 1 will be 
taken prior to the first dose of study agent. 
 
2 x 6mL NaHep (Green Top) Tubes - γ-OHPdG research blood 
1) Collect blood until vacuum is exhausted. 
2) After blood collection, gently invert tubes 8-10 times until blood is completely mixed 

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3) Place pre-generated label containing participants ID to each tube 
4) Place tubes in an upright position immediately on wet ice to then transfer over to lab for 
processing 
5) Within 2 hours of collection, centrifuge tubes at 2200-2500 RPM for 15 minutes at 4°C  
6) Remove plasma (supernatant) carefully and do not disturb the thin layer of white cells 
between the plasma and the red blood cells. Save tube for buffy coat processing.  
7) Distribute the plasma into 2ml screw topped cryogenic vials. Place 1mL (minimal 0.5mL, 
maximal 1.5mL) of plasma in each aliquot. 6 aliquots will be collected (3 cryovials of 
plasma from each parent tube). 
8) Buffy coat will be isolated and transferred into 2mL cryogenic vial, then flash frozen and stored at 
-80°C. 
9) Place pre-generated label containing participants ID to each cryovial, ensuring that 
daughter specimen labels match the parent specimen labels used on the tubes. 
10) Plasma aliquots need to be frozen in -80°C immediately 
 
2 x 6mL EDTA (Purple Top) Tubes - γ-OHPdG Whole Blood for LC-MS/MS and ELISA 
1) Collect blood until vacuum is exhausted.   
2) After blood collection, gently invert tubes 8-10 times until blood is completely mixed. 
3) Place pre-generated label containing participants ID to each tube. 
4) Store at ambient temperature until shipping. 
 
Research Blood PKs: Visit 1 (week 1 day 1) only 
Six participants at Georgetown University will participate in a PK evaluation. The day before the 
pharmacokinetic study (Visit 1), Georgetown University study participants are instructed to fast 
after midnight except for drinking water. On the pharmacokinetic study day, Georgetown 
University study subjects skip breakfast and take no over the counter medications, vitamins, or 
health food products. Georgetown University study participants come to the clinic in the early 
morning (6–8 a.m.) and are provided with food for breakfast. Immediately after or during 
breakfast, study subjects swallow their Polyphenon E capsules with a glass of water. Study subjects 
are allowed unlimited water intake throughout the study day. Other drinks are not allowed. They 
will fast until they take their first dose of Polyphenon E. Blood will be collected: 
• Prior to the first dose 
• 1.5 hours (+/- 5 minutes) after first dose 
• 3.5 hours (+/- 5 minutes) after first dose.  Food for lunch is provided to the study subjects 
after this blood draw.   
• 8.5 hours (+/- 5 minutes) after first dose 
For each blood draw: 
1) Draw 4 mL of whole blood in each of two green-top tubes containing sodium heparin (for 
a total of 8 mL of whole blood).  
2) Collect blood until vacuum is exhausted for each tube. 
3) After blood collection, gently invert tubes 8-10 times until blood is completely mixed. 
4) Record the time of the dose administration and the time of the blood draw. 
5) Place pre-generated label containing participants ID to each tube 
6) After collection, place tube in an upright position immediately on wet ice. 
7) Within 2 hours of collection, centrifuge tubes at 2000-2500 RPM for 15 minutes at 4°C. 

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8) Distribute the plasma into 2mL screw topped cryogenic vials. Place 1ml (minimal 0.5ml, 
maximal 1.5ml) of plasma in each aliquot. 4 aliquots will be collected (2 cyrovials of 
plasma from each parent tube). Note: Do not transfer red cells to the vial. 
9) Add 20 ul of ascorbic-EDTA solution [0.4 m NaH2PO4 buffer containing 20% ascorbic 
acid and 0.1% EDTA (pH 3.6)], screw the top  and gently mix.  
10)  Place pre-generated label containing participants ID to each cryovial, ensuring that 
daughter specimen labels match the parent specimen labels used on the tubes. 
11) Freeze and store samples at −80°C until analysis or shipment.   
 
Research Urine PKs: Visit 1 (week 1 day 1) only 
Six participants at Georgetown University will participate in a PK evaluation. They will fast until 
they take their first dose of Polyphenon E. They will take their first dose of Polyphenon E with 
food, and urine (30 ml) will be collected: 
• Prior to the first dose 
• 1.5 hours (+/- 15 minutes) after first dose 
• 3.5 hours (+/- 15 minutes) after first dose 
• 8.5 hours (+/- 15 minutes) after first dose 
 
For urine collection (PK): 
1) Two urine collection cups will be provided in the kit, only the 100ml urine cup labeled 
“Parent Tube” will be given to the participant. Place the pre-generated label noting the 
participants study ID to the urine cup. 
2) Instruct the participant to: 
a. Wash hands with soap and warm water. 
b. Hold the 100 mL Urine Specimen Cup labeled “Urine” as the specimen type, a few 
from the urethra and urinate, collection the first-void urine until the cup is half full. 
c. Void the rest of the urine into the toilet. 
d. Tightly screw the cap onto the cup and place in the biohazard transport bag 
e. Clean-up any spills on the cup using the provided towelette. 
3) Transfer 30ml of urine sample to 30ml vial labeled “daughter tube” and mix with powder 
within 20 minutes of sample collection or as soon as possible. Place the pre-generated label 
noting the participants study ID to the urine cup. 
4) For MedStar Georgetown: transfer urine specimen to the Dr. Chung’s laboratory for 
processing. Along with the processing labels and collection form.  
5) For non-MedStar Georgetown University sites: freeze and store samples immediately at -
80°C or colder. 
 
10.3 
Shipping Instructions 
 
All samples will be shipped in compliance with the International Air Transport Association 
Dangerous Goods Regulations. All shipments should be batch shipped once a week, Monday 
through Friday, after communication with the receiving site. 
 
Whole blood and FFPE biopsy specimens (including archival biopsy samples) will be shipped at 
refrigerated temperature (4°C).  All other specimens (the remaining two biopsy samples, Research 

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Plasma, Research Blood PKs, and Research Urine PKs) will be packed in sufficient dry ice to last 
during transport for 3 days, and shipped or transported from the study site to: 
 
Dr. Fung-Lung Chung 
3970 Reservoir Road, NW 
Georgetown University Medical Center 
New Research Building E215 
Washington, DC 20057 
Tel: 202-687-3021 
Fax: 202-687-1068 
Email: flc6@georgetown.edu 
 
10.4 
Tissue Banking 
 
The biopsy samples will be labeled appropriately with the study protocol number, subject number, 
the date of collection, study time point, and location of collection (GUH or UPR) and stored at Dr. 
Chung’s laboratory in a -80o Freezer.  FFPE biopsy specimens will be stored at room temperature.   
 
Biological 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 
 

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All AEs that occur after the informed consent is signed and baseline assessments are completed  
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. 
• AE verbatim term 
• NCI Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0) AE term 
(MedDRA lowest level term) 
• CTCAE (MedDRA) System Organ Class (SOC) 
• Event onset date and event ended date 
• Treatment assignment code (TAC) at time of AE onset 
• Severity grade 
• Attribution to study agent (relatedness) 
• Whether or not the event was reported as a SAE 
• Whether or not the subject dropped due to the event 
• 
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 

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*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  
 
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. 

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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: 
• Date and time of the SAE 
• Date and time of the SAE report 
• Name of reporter 
• Call back phone number 
• Affiliation/Institution conducting the study 
• DCP protocol number 
• Title of protocol 
• 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.    
• DCP’s Regulatory Contractor CCS Associates, Inc. (CCSA; phone: 650-691-4400) at 
safety@ccsainc.com 
• DCP Medical Monitor, Dr. Luz Rodriguez (rodrigul@mail.nih.gov) 
• 
Northwestern Cancer Prevention Consortium (ncpc@northwestern.edu) 
• 
The Protocol PI, Dr. Ruth He (arh29@georgetown.edu)  
 
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 IRB/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. The length of time for follow-
up of an SAE is 6 months.  
 
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.  The Consortia 2012 Data Management Plan, submitted as part of a 

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contract agreement with the NCI (HHSN261201200035I), was approved.  
 
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 CRF (e-CRF) screens in the Robert H. Lurie Comprehensive Cancer Center of 
Northwestern University (Lurie Cancer Center) Clinical Trials Management System (CTMS). 
Accrual-site staff will enter data into the e-CRFs for transmission to DCP according to DCP 
standards and procedures. 
 
12.3 
Source Documents 
 
All source documents will be collected and stored in the Clinical Research Office of the site where 
the participant was accrued.  Any data recorded directly on CRFs that constitute no prior written 
or electronic record of data, will be specifically identified as source data.    
 
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.  This study will be subject to Northwestern 
Data Monitoring Committee review according to the Master DSMP.  Any future changes will be 
forwarded for review.  
 
As part of our Master DSMP, this study will be reviewed semi-annually by a Data Monitoring 
Committee.  This semi-annual report includes a list of all reported adverse events, serious adverse 
events, dose limiting toxicities, and protocol deviations.   
 
Adverse events are reviewed monthly by the NCI DCP medical monitor through the submission 
of the Minimum Data Set.   
 
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 

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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) 
 
N/A 
 
13. 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Description  
 
We propose a single-arm, multicenter MTD seeking, escalation study. To meet our primary goal, 2-
48 participants with cirrhotic livers expressing high levels (score 3 and above) of γ-OHPdG (γ-
OHPdG-high) in their baseline biopsy are required for the Polyphenon E intervention portion of the 
study.  
 
In our unpublished data, 68 participants with cirrhosis, 38% (90% confidence interval, range 0.28, 
0.49) of cirrhotic liver biopsies demonstrated high γ-OHPdG levels (IHC score ≥ 3). Therefore, a 
minimum of 4 and maximum of 171 participants with liver cirrhosis will be screened in our current 
study. A minimum of 2 and a maximum of 48 participants whose cirrhotic liver biopsies show a γ-
OHPdG score ≥ 3 will be registered for treatment.  If a maximum tolerated dose is established, a total 
of 24 participants will receive the maximum tolerated dose. The maximum tolerated dose is defined 
as the highest dose where no more than 1 of 6 participants experience an event meeting the Discontinue 
Therapy Criteria (DTC) during the first four weeks of treatment and the next higher dose is such that 
2 or more participants had experienced an event meeting the DTC during the first four weeks of 
treatment. 
 
Trial enrollment was stopped early, with 13 patients enrolled in Cohorts 1- 4 during dose escalation, 
of whom 10 participants had both pre- and post-treatment biopsies for biomarker assessment (Table 
6). No participants were enrolled in the dose expansion cohort.  
 
Table 6: Trial Enrollment 
Cohort 
Started Trt Pre & Post Bx 
DTC 
Cohort 1 (400mg QD) 
3 
3 
0 
Cohort 2 (400 mg BID) 
3 
3 
0 
Cohort 3 (600 mg BID) 
3 
2 
0 
Cohort 4 (800 mg BID) 
4 
2 
1 
 
13.2 
Randomization/Stratification  
 

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There is no randomization in this study. 
 
13.3 
Accrual and Feasibility 
 
The following strategies will be applied to ensure complete enrollment within the first twelve 
months of study initiation: 
 
MedStar Georgetown Transplant Institute is a network of multidisciplinary teams that provides 
medical care to participants with chronic liver disease. This network includes GUH, Washington 
Hospital Center (WHC), Franklin Square Medical Center, and MedStar Georgetown Transplant 
Institutes in Fairfax and Frederick.  The network serves about 2,200 participants with chronic liver 
disease each year. Drs. Smith, Dr. Rangnekar, and Dr. Thomas have weekly clinics in MedStar 
GUH, WHC, and Georgetown Transplant Institute in Fairfax. When they identify potential 
candidates at any of the sites (pre-screen), these participants will be screened for the study at 
MedStar GUH (screen 1 and 2) and registered if indeed eligible. The distance between MedStar 
Georgetown Transplant Institute in Fairfax and MedStar GUH is 17 miles (a 25 minute drive by 
car), and the distance between MedStar WHC and GUH is 5 miles (a 15 minute drive by car); these 
distances allow participants relatively easy travel from MedStar Georgetown Transplant Institute 
in Fairfax or WHC to GUH for medical care.   
 
Potential candidates from Franklin Square Medical Center and transplant clinic at Frederick will 
also be referred to GUH for this study. Among the 2,200 hepatology participants seen under the 
MedStar Network within one year, approximately 20% have compensated cirrhosis without liver 
cancer. Therefore we have a pool of 440 participants that meet the eligibility criteria for this study. 
Based on our small 50-patient survey, 90% of participants should be interested in participating in 
the study, despite having to undergo liver biopsy. Thus we have a pool of 400 participants per year 
from which to draw potential study candidates.  
 
At UPR, over 1000 participants are seen annually over the hepatology clinical enterprise. It is 
estimated that approximately 50% of these participants have underlying cirrhosis at different 
stages, including pre-transplant participants. Dr. Cruz estimates that 10% of cirrhotic individuals 
may be eligible for the study translating to approximately 50-100 participants providing adequate 
numbers for screening into the study. 
 
One study coordinator will be shared by Drs. Coleman Smith and the investigator’s at Georgetown 
for participant enrollment and follow-up in Washington DC. One or two specific days of the week 
can be assigned to each physician for seeing participants enrolled onto this study, so the study 
coordinator will be able to follow all participants enrolled in Washington DC. Monthly 
teleconferences will be arranged for Drs. Coleman Smith, Ruth He, and the study coordinators to 
discuss enrollment and study related issues. 
 
With these prescreening and rolling enrollment strategies, we believe that we will be able to 
screen 171 participants with liver cirrhosis in order to be able to find 48 participants whose 
cirrhotic liver biopsies show a γ-OHPdG score ≥ 3 by IHC (γ-OHPdG-high) to be enrolled into 
the pilot study within the first year.  

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Our strategies are to prescreen most participants by medical record review after the protocol is 
approved, obtain consent, and, if needed, obtain a baseline biopsy from most participants within 
the first few months of study initiation so that candidates for intervention enrollment for are 
identified quickly. From the pool of study candidates, we plan to enroll 6 participants per month 
if. With this plan, even if there are delays for any reason, we will be able to complete the study 
within two years.  
 
We plan to allow up to three weeks from the day of biopsy to obtain the liver γ-OHPdG score. The 
liver samples will be batched and tested twice per month. If the rate of cirrhotic liver biopsies with 
a γ-OHPdG score ≥ 3 is lower than expected, we will increase the number of subjects that are pre-
screened per month.  
 
13.4 
Primary Objective, Endpoint(s), Analysis Plan 
 
The primary objectives are to establish MTD, collect safety data of Polyphenon E/EGCG at MTD 
treatment in participants with cirrhosis and to determine the suppressing effects of /Polyphenon 
E/EGCG treatment on γ-hydroxy-1,N(2)-propanodeoxyguanosine (γ-OHPdG)levels in cirrhotic 
liver. 
 
To assess the safety of Polyphenon E treatment in participants with cirrhosis, we will list all the 
adverse events and provide summary statistics.  
 
To explore possible effects of Polyphenon E treatment on γ-OHPdG levels in cirrhotic liver 
samples of participants known to have high levels in liver biopsy samples.   
 
The primary study objective is to assess the effect of Polyphenon E treatment on γ-OHPdG 
expression. Based on our preliminary data, we expect a 30-40% decrease in γ-OHPdG expression 
in cirrhotic liver after six months of Polyphenon E treatment. Twenty-four subjects with high γ-
OHPdG levels in their liver biopsies will receive Polyphenon E.  This provides 80% or greater 
statistical power to confirm a 30% or bigger decrease in γ-OHPdG levels at a 0.05 alpha level with 
a two sided test, and coefficient of variation = 50%-100%. We will use a nonparametric Wilcoxon 
test to compare the post-pre differences to zero. We anticipate that high pre-therapy IHC scores = 
3, 4 and 5  vs. post-therapy scores mean = 2, —using a pre-therapy average of 4 to be conservative. 
Thus we will have two scores per person. The difference between Before and After = Before - 
After = B-A should be on average = 0 if treatment has no effect and on average about 1.33 and 
1.60 after treatment = reduction of 33% and 40% respectively, down from 4.   
 
Under usual assumptions of corr (B,A) = 0.5 and SD(B) = SD(A) we get mathematically SD(B-
A) = SD(B) = SD(A) = 2. SD=2 was selected so as to give CV=100% when mean = 2 and CV=50% 
when mean = 4.  
 
Numeric Results for Wilcoxon Test (Normal Distribution) 
 
Null Hypothesis: Mean0=Mean1     Alternative Hypothesis: Mean0≠Mean1 
 

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Unknown standard deviation. 
 
Power 
N 
Alpha 
Beta 
Mean0 
Mean1 
SD 
Effect 
Size 
0.84466 
24 
0.05 
0.15534 
0 
1.33 
2 
0.665 
0.94694 
24 
0.05 
0.05306 
0 
1.6 
2 
0.8 
 
Safety and adverse event data will be summarized using descriptive (frequency, %) statistics by 
dose cohort. The primary endpoint of MTD cannot be established because the study was closed 
early, and, based on the observed safety profile with a single DTC occurring in dose cohort 4 (1/4 
patients), future studies can consider dose level 3 as the starting dose. 
             
13.5 
Secondary Objectives, Endpoints, Analysis Plans 
 
Secondary endpoints: 
a) To collect Polyphenon E/EGCG pharmacokinetic data in participants with cirrhosis. 
 
b) To determine the effects of Polyphenon E/EGCG treatment on the suppression of γ-
hydroxy-1,N(2)-propanodeoxyguanosine (γ-OHPdG) levels in cirrhotic liver by LC-MS 
assay from baseline to post-treatment. 
 
c) To estimate the fraction of participants with liver cirrhosis that have high levels of γ-
OHPdG. 
 
We will test the γ-OHPdG levels at baseline and at the end of study in all subjects. Based on our 
preclinical models, we believe six months of intervention will decrease the γ-OHPdG levels. We 
will use two methods to measure the level of γ-OHPdG including IHC stain and Mass Spectrum 
analysis. The pathology slides prepared from the liver biopsy will be stained for antibody targeting 
γ-OHPdG. The level of γ-OHPdG will be scored from 0 to 6. IHC score of 0 to 2 is defined as γ-
OHPdG low, and IHC score of 3 to 6 is defined as defined as γ-OHPdG high. When γ-OHPdG is 
measured by mass spectrum, the absolute amount of γ-OHPdG will be measured. In this study, we 
hope to evaluate whether decrease in γ-OHPdG level will result in decrease in mutation frequency 
only in five subjects due to budget restriction. The data will help to test our hypothesis and support 
future studies.  If there is no restriction in budget, we would like to carry out the study in all 
subjects. 
 
For secondary outcome (b) LC-MS assay will be used to determine gamma-OHPdG changes from 
baseline to post-treatment. This will generate a continuous variable for values of gamma-OHPdG. 
Descriptive statistics (mean, range) will be used to summarize this continuous outcome by dose 
level.  A nonparametric trend test will be used to examine whether there is a trend for greater 
reduction in gamma-OHPdG as the dose level increases.  
 
 
For secondary outcome (c) we will use descriptive statistics to estimate the fraction of participants 
with liver cirrhosis that have high levels of γ-OHPdG. Participants will be screened for high levels 
of γ-OHPdG. Only participants with high levels of γ-OHPdG will be enrolled for intervention. The 

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fraction of participants with liver cirrhosis that have high levels of γ-OHPdG is calculated based 
on the number of subjects enrolled over the number of subjects screened based on the levels of γ-
OHPdG in their first liver biopsy. This important information may help to estimate the portion of 
cirrhotic participants with high risk for HCC development, and can be used to design a future large 
chemoprevention study using Polyphenon E or other green tea extract in HCC prevention. 
 
 
Due to the early stopping, secondary and exploratory endpoints will be summarized using 
descriptive statistics across dose cohorts. Changes in biomarkers across dose levels will be 
analyzed using a nonparametric trend test. 
 
Exploratory endpoint: 
For exploratory objective, we will assess the effects of Polyphenon E on the grade of cirrhosis, as 
measured by FibroScan. We will also develop an LC-MS and/or ELISA-based method for 
detecting urinary and blood γ-OHPdG. Additionally, we will measure the incidence of HCC across 
all dosage levels. 
 
Descriptive statistics (n; min; max; mean; median; SD for continuous variables; and n, frequency 
for categorical variables) will be used to summarize participant demographics. Participant safety 
data will be tabulated according to the symptom and grade. Estimates will be presented with their 
95% confidence intervals.  
 
Proposed Sample Size:  Final number of n=2 to 48 subjects. 
Proposed Sample Size:  A minimum of 4 and maximum of 171 eligible cirrhotic participants will 
be screened. Enrollment of subjects will stop according to the dose escalation 3 + 3 design, plus 
an expansion cohort of up to 24 subjects at the maximum tolerated dose if one is established, for a 
total of n = 2 to 48 subjects. 
 
13.6 
Reporting and Exclusions 
 
We expect that we will identify an MTD from the 3+3 dose escalation cohort, then move to dose 
expansion cohort. 
 
We expect that 2 to 48 subjects will have complete data on the primary endpoint. Main analysis 
will be based on the complete data. Additional descriptive analysis may be performed to see if 
dropouts show a systematic property. Thus, we expect the 15% of data missing values will be 
studied to determine possible patterns and dependence with other relevant variables. 
 
We will report the reasons for any missing outcomes to determine if they may be related to the 
unobserved outcome. We will write a cautionary note that results could be biased if there is a 
background change in γ-OHPdG over time that is unrelated to Polyphenon E treatment. 
 
13.7 
Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first dose.  
 

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13.8 
Evaluation of Response 
 
Intent to treat analysis: All samples from all subjects who receive drug will be evaluated and 
included in the primary analysis, which will be based on intent to treat principle.  
 
13.9 
Interim Analysis 
 
In dose escalation cohort, subjects enrolled in each dose level will be monitored for liver toxicities 
for four weeks prior to enrolling additional participants in the next dose level.  
 
Since all study subjects are planned to be enrolled within 12 months, interim analysis for efficacy 
will not be performed.  
 
13.10 Ancillary Studies 
 
The distribution of γ-OHPdG in participants with cirrhosis and stability of γ-OHPdG in cirrhotic 
participants have been studied, and data is provided in section 2.3.4 and 2.3.5 on page 13. 
 
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 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.  CVs or biosketches do not need to be updated for participating study staff after 
drug shipment authorization (DSA).  
   
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  Good Clinical Practice training for all study personnel listed on the 
FDA Form 1572 and Delegation of Tasks form for the Lead Organization and all Participating 
Organizations. 
 

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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 
appropriate IRB. 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 IRB prior to implementation 
 
14.4 
Informed Consent 
 
All potential study participants will be given a copy of the IRB-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. 
 
Prior to study initiation, the informed consent document must be reviewed and approved by NCI, 
DCP, the Consortium Lead Organization, 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, 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 

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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 
 
Study subjects will be provided with a compensation as follows: 
• $200 for each liver biopsy (at Screen 2 and at Visit 3) 
• $75 for each clinic visit, for transportation, parking, childcare, etc. (Screen 1, Screen 2, 
Visit 1, Visit 2, Visit 3, and Visit 4).   
• $25 for each weekly/bi-weekly blood draw between visits (max of 14).  Participants will 
be provided $25 for the blood draw even if it is performed at an outside clinic. 
The maximum total provided to each participant, depending on the requirements of their 
participation, is $1,200.   
 
 

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DNA adducts. Chem Res Toxicol 22(3):511-517. 
30. Kanuri M, et al. (2002) Error prone translesion synthesis past gamma-hydroxypropano 
deoxyguanosine, the primary acrolein-derived adduct in mammalian cells. J Biol Chem 
277(21):18257-18265. 
31. Feng Z, Hu W, Hu Y, Tang MS (2006) Acrolein is a major cigarette-related lung cancer agent: 
preferential binding at p53 mutational hotspots and inhibition of DNA repair. Proc Natl Acad Sci 
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32. Liu RH (2004) Potential synergy of phytochemicals in cancer prevention: mechanism of 
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33. Lee JE, Chan AT (2011) Fruit, vegetables, and folate: cultivating the evidence for cancer 
prevention. Gastroenterology 141(1):16-20. 
34. Lippman SM, et al. (2009) Effect of selenium and vitamin E on risk of prostate cancer and 
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hepatocellular carcinoma. Hepatology 39(6):1663-1672. 
36. Maki A, et al. (2007) Predictive power of biomarkers of oxidative stress and inflammation in 
patients with hepatitis C virus-associated hepatocellular carcinoma. Ann Surg Oncol 14(3):1182-
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37. Marquardt JU, Andersen JB, Thorgeirsson SS (2015) Functional and genetic deconstruction of 
the cellular origin in liver cancer. Nat Rev Cancer 15(11):653-667. 
38. Yang JD, Roberts LR (2010) Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol 
Hepatol 7(8):448-458. 
39. Starley BQ, Calcagno CJ, Harrison SA (2010) Nonalcoholic fatty liver disease and 
hepatocellular carcinoma: a weighty connection. Hepatology 51(5):1820-1832. 
40. Lee HW, et al. (2014) Acrolein- and 4-Aminobiphenyl-DNA adducts in human bladder 
mucosa and tumor tissue and their mutagenicity in human urothelial cells. Oncotarget 5(11):3526-
3540. 
41. Ishikawa T, et al. (2004) DNA repair and cancer: lessons from mutant mouse models. Cancer 
Sci 95(2):112-117. 
42. Guichard C, et al. (2012) Integrated analysis of somatic mutations and focal copy-number 
changes identifies key genes and pathways in hepatocellular carcinoma. Nat Genet 44(6):694-698. 
43 Peraino C, Fry RJ, Staffeldt E (1973) Brief communication: Enhancement of spontaneous 
hepatic tumorigenesis in C3H mice by dietary phenobarbital. J Natl Cancer Inst 51(4):1349-1350. 
44 Verna L, Whysner J, Williams GM (1996) N-nitrosodiethylamine mechanistic data and risk 
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Ther 71(1-2):57-81. 
45. Thirunavukkarasu C, Sakthisekaran D (2001) Effect of selenium on N-nitrosodiethylamine-
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antioxidants. Cell Biochem Func 19(1):27-35. 
46. Fu Y, et al. (2014) In vivo detection of a novel endogenous etheno-DNA adduct derived from 
arachidonic acid and the effects of antioxidants on its formation. Free Radic Biol Med 73:12-20. 
47. Hasegawa R, et al. (1995) Preventive effects of green tea against liver oxidative DNA damage 
and hepatotoxicity in rats treated with 2-nitropropane. Food Chem Toxicol 33(11):961-970. 
48. Westerterp-Plantenga MS (2010) Green tea catechins, caffeine and body-weight regulation. 
Physiol Behav 100(1):42-46. 
49. Pan J, et al. (2012) Detection of acrolein-derived cyclic DNA adducts in human cells by 
monoclonal antibodies. Chem Res Toxicol 25(12):2788-2795. 
50. Chow HH1, Cai Y, Alberts DS, Hakim I, Dorr R, Shahi F, Crowell JA, Yang CS, Hara Y. 
Phase I pharmacokinetic study of tea polyphenols following single-dose administration of 
epigallocatechin gallate and polyphenon E. Cancer Epidemiol Biomarkers Prev. 2001 
Jan;10(1):53-8. 
51. Chow HH1, Hakim IA, Vining DR, Crowell JA, Ranger-Moore J, Chew WM, Celaya CA, 
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tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer 
Res. 2005 Jun 15;11(12):4627-33. 
52. Chow HH1, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts 
DS. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of 
epigallocatechin gallate and polyphenon E in healthy individuals Clin Cancer Res. 2003 Aug 
15;9(9):3312-9. 
53. Foster DR1, Sowinski KM, Chow HH, Overholser BR. Limited sampling strategies to estimate 
exposure to the green tea polyphenol, epigallocatechin gallate, in fasting and fed conditions. Ther 
Drug Monit. 2007 Dec;29(6):835-42. 
54. Moura FA, de Andrade KQ, dos Santos JC, Goulart MO.(2015) Lipoic Acid: its antioxidant 
and anti-inflammatory role and clinical applications. Curr Top Med Chem. 2015;15(5):458-83. 
55. Shanafelt TD1, Call TG, Zent CS, LaPlant B, Bowen DA, Roos M, Secreto CR, Ghosh AK, 
Kabat BF, Lee MJ, Yang CS, Jelinek DF, Erlichman C, Kay NE. Phase I trial of daily oral 
Polyphenon E in patients with asymptomatic Rai stage 0 to II chronic lymphocytic leukemia. J 
Clin Oncol. 2009 Aug 10;27(23):3808-14. doi: 10.1200/JCO.2008.21.1284. Epub 2009 May 26. 
56. Shanafelt TD1, Call TG, Zent CS, Leis JF, LaPlant B, Bowen DA, Roos M, Laumann K, Ghosh 
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Cancer. 2013 Jan 15;119(2):363-70. doi: 10.1002/cncr.27719. Epub 2012 Jul 3. 
57. Isomura T, Suzuki S, Origasa H, Hosono A, Suzuki M, Sawada T, Terao S, Muto Y, Koga 
T.Liver-related safety assessment of green tea extracts in humans: a systematic review of 
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58. Wang D, Wang Y, Wan X, Yang CS, Zhang J. (2015) Green tea polyphenol (-)-
epigallocatechin-3-gallate triggered hepatotoxicity in mice: responses of major antioxidant 
enzymes and the Nrf2 rescue pathway. Toxicol Appl Pharmacol. 2015 Feb 15;283(1):65-74. doi: 
10.1016/j.taap.2014.12.018. Epub 2015 Jan 10. 
59. Ali Pezeshki,  Sara Safi, Awat Feizi, Gholamreza Askari, and Fatemeh Karami. The Effect of 
Green Tea Extract Supplementation on Liver Enzymes in Patients with Nonalcoholic Fatty Liver 
Disease. Int J Prev Med. 2016; 7: 28. 
60. Ryuichiro Sakata,Toru Nakamura, Takuji Torimura, Takato Ueno,  Michio Sata Green tea with 
high-density catechins improves liver function and fat infiltration in non-alcoholic fatty liver 
disease (NAFLD) patients: A double-blind placebo-controlled study. Int J Mol Med. 2013 
Nov;32(5):989-94. doi: 10.3892/ijmm.2013.1503. Epub 2013 Sep 20. 
61. K. D. Crew, K. A. Ho, P. Brown, H. Greenlee1, T. B. Bevers, B. Arun, N. Sneige, C. Hudis3, 
H. L. McArthur, J. Chang, M. Rimawi, T. L. Cornelison, J. Cardelli, R. M. Santella1, A. Wang1, 
S. M. Lippman8, and D. L. Hershman. Effects of a green tea extract, Polyphenon E, on systemic 
biomarkers of growth factor signalling in women with hormone receptor-negative breast cancer. J 
Hum Nutr Diet. 2015 June ; 28(3): 272–282. doi:10.1111/jhn.12229. 
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Unpredictably Hepatotoxic: Phase I Single Group and Phase II Randomized Placebo-Controlled 
Studies. J Neurol Sci. 2015 November 15; 358(0): 46–52. doi:10.1016/j.jns.2015.08.006. 
64. Chow H-HS, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts 
DS. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of 
epigallocatechin gallate and polyphenon E in healthy individuals. Clin Cancer Res 2003;9:3312–
19. 
65. Chow H-H, Hakim IA, Vining DR, Crowell JA, Ranger-Moore J, Chew WM, Celaya CA, 
Rodney SR, Hara Y, Alberts DS. Effects of dosing condition on the oral bioavailability of green 
tea catechins after single-dose administration of Polyphenon E in healthy individuals. Clin Cancer 
Res 2005;11:4627–33. 
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Ranger-Moore J, Alberts DS. Effects of repeated green tea catechin administration on human 
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(Camellia sinensis). Ann Intern Med 2006;144:68–71. 
68. Javaid A, Bonkovsky HL. Hepatotoxicity due to extracts of Chinese green tea (Camellia 
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Giancaspro GI, Low Dog T. Safety of green tea extracts: A systematic review by the US 
Pharmacopeia. Drug Saf 2008;31:469–84. 
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2008:49:1017–1044. 
 
 

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Consent Form Version date: 03/06/2023 
Protocol Version and date: v4.13 03/06/2023 
 
Consent Form 
 
Study Title for Study Participants: Polyphenon E® to prevent liver cancer in 
people with liver cirrhosis. 
 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: 
NWU2016-08-02 A phase I single-arm, multicenter pilot study aimed at 
validating γ-OHPdG as a biomarker and testing the effects of Polyphenon E on 
its levels in patients with cirrhosis. 
 
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. 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 my Liver Cirrhosis?  
You are being asked to take part in this study because you have liver cirrhosis and are at increased 
risk for liver cancer. People who have liver cirrhosis and choose not to participate in a study are 
usually followed closely by their doctor to manage their cirrhosis and to find cancer if it occurs.  
 
What are my other choices if I do not take part in this study?  
If you decide not to take part in this study, you have other choices. For example: 
• you may choose to have the usual approach described above, 
• you may choose to take part in a different study, if one is available,  
• or you may choose to do nothing. 
 
Why is this study being done? 
We hope to determine how well cirrhotic participants tolerate different doses of green tea extract 
(Polyphenon E). We also hope to determine if green tea extract may decrease the level of a certain 
molecule called γ-OHPdG (“gamma”-OHPdG), and whether high levels of that molecule are 
associated with a higher risk of liver cancer. 
 
What are the study groups? 
If you chose to participate, your liver will be tested to see if it is making a molecule called γ-
OHPdG.  If your liver shows high levels of γ-OHPdG, you will receive the study drug 

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Polyphenon E.  Different doses of Polyphenon E will be given to several study participants.  
What dose you receive will depend on when you enroll in the study.   
 
Dose escalation part (the first five groups): In the first part of the study, several participants will 
receive Polyphenon E at a low dose.  If the study drug does not cause bothersome side effects, it 
will be given to the second group of study participants at a higher dose.  If the low dose causes 
bothersome side effects in one or more people in the first group, it will be given to additional 
study participants at the same dose to get a better idea of how often the study drug is bothersome.  
In this way, we hope to determine the safest/best tolerated dose of Polyphenon E.  Once this dose 
of Polyphenon E is found, then the next part of the study will begin. 
 
Dose expansion part (the sixth group): Twenty-four participants will receive the safest/best 
tolerated dose of the study drug to learn more about how the drug affects the liver.   
 
 
 
 
 
 
How long will I be in this study? 
You will receive the study drugs for 6 months. Even if you do not finish the study, your doctor 
will continue to watch you for side effects and follow your condition for 2 months. 
 
What extra tests and procedures will I have if I take part in this study? 
Most of the exams, tests, and procedures you will have are part of the usual approach for your 
condition. However, there are some extra tests that you will need to have if you take part in this 
study. 
 
Before you begin the study, you will need to have the following extra tests to find out if you can 
be in the study:  
Screen 1 Visit 
• FibroScan scan of your abdomen (if not already done within the past 3 months) as part 
of standard medical care; ultrasound, CT or MRI may be performed (if not already 
done within the past 3 months) as part of standard medical care 
• 
Blood tests to make sure you are healthy 
• 
Pregnancy test if you are female and able to have children 
 
Screen 2 Visit 
A biopsy (small pieces of liver tissue) is obtained by inserting a needle into the liver for a 
fraction of a second. This research biopsy is done in a similar way to biopsies are done for 
diagnosis. It is done in the hospital, and you will be sent home within two to three hours. This 
biopsy will be taken at the Screen 2 Visit.   
 
You agree to 
take part in 
the study 
Your liver is tested for 
γ-OHPdG, and you 
have high levels of γ-
OHPdG 
Polyphenon E for six 
months, once or twice 
daily by mouth 
Retest your 
liver for γ-
OHPdG 

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If you had a liver biopsy in the past year, let the study team know. If tissue from your liver 
biopsy in the past year was kept at the hospital, and can be used for the study, the Screen 2 
biopsy is optional for you.   
 
For participants who do not have tissue from a biopsy in the last year that was kept at the 
hospital, this biopsy is required in order for you to take part in this study. You will sign a 
separate consent form before the biopsy is taken. This will be a standard surgical consent form 
from the institution where the biopsy procedure takes place. 
 
We will test the biopsy sample for levels of a substance called γ-OHPdG, and you will only be 
treated on the study if your liver shows high levels of γ-OHPdG.   
 
A urine sample will also be collected to see the levels of γ-OHPdG in order to compare the levels 
found in your liver biopsy. 
 
The study coordinator will call you within around four weeks of Screen 1 and/or Screen 2 to let 
you know if you are eligible to continue in the study. 
    
If the liver biopsy shows that you have high levels of γ-OHPdG, and you choose to take part in the 
study, then you will need the following extra tests. They are not part of the usual approach for your 
liver cirrhosis. 
 
During the study: 
Visit 1 (Week 1 Day 1, the first day you start taking the study drug) 
• 
Physical examination and vital signs (for example, heart rate and blood pressure tests), 
and answering some questions about your medical history, other medications you are 
taking, and how the study drug is affecting you. 
• 
Answer questions about your tobacco and alcohol use 
o Researchers want to see if tobacco and alcohol use affects the side effects 
people might get while on this study, or if tobacco and alcohol use modifies the 
effects of the study agent 
• 
Blood tests to make sure you have good organ function. 
• Blood tests to (1) measure the levels of γ-OHPdG in your blood. 
• Optional (Georgetown University ONLY): Extra blood and urine tests used to study 
the way the body absorbs, distributes, and gets rid of a drug. This is referred to as a 
pharmacokinetics pharmacokinetics (PK) study. 
 
A PK study is when samples (such as blood and urine) are collected before and after 
taking a drug to see how your body absorbs, distributes, breaks down, and eliminates 
the drug.  
 
If you are one of the first six people who agree to provide extra blood and urine for the 
PK study: before you take your first dose of the study drug, two urine samples and four 
extra tubes of blood will be drawn to make sure you are healthy. You will then stay at 
the clinic for 9 hours after your first dose of the study drug to have three additional 
blood draws and three separate urine tests to see how your body processes the study 

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drug. The study coordinator will let you know if you are one of the first six people who 
can participate in this.   
 
Between Visits 1 and 2  
• Every week or every other week you will have one blood draw to make sure you are healthy 
and have good organ function. You may have it done at one of the scheduled visits, or have 
it done in LabCorp, or Quest lab, or your doctor’s office when you do not have a scheduled 
visit with your liver doctor.   
 
Visit 2 (Week 13, 12 weeks after you start taking the study drug) 
• Physical examination and vital signs, and answering some questions about your medical 
history, other medications you are taking, and how the study drug is affecting you. 
• Blood tests to make sure you are healthy and have good organ function. 
• Urine test to measure the amount of γ-OHPdG in your body 
• Blood tests to (1) measure levels of γ-OHPdG in your blood. 
 
Between Visits 2 and 3 
• Every week or every other week you will have one blood draw to make sure you have a 
good organ function. You may have it done at one of the scheduled visits, or have it done 
in LabCorp, or Quest lab, or your doctor’s office when you do not have a scheduled visit 
with your liver doctor.   
 
Visit 3 (Week 24, at the end of treatment with the study drug) 
• Physical examination and vital signs, and answering some questions about your medical 
history, other medications you are taking, and how the study drug is affecting you. 
• Answer questions about your tobacco and alcohol use 
o Researchers want to see if tobacco and alcohol use affects the side effects people 
might get while on this study, or if tobacco and alcohol use modifies the effects of 
the study agent 
• Blood tests to make sure you are healthy and have good organ function. 
• Urine test to measure the amount of γ-OHPdG in your body 
• Blood tests to (1) measure levels of γ-OHPdG in your blood. 
• Ultrasound, CT or MRI scan, and FibroScan of your abdomen. These tests may be done at 
the same visit, or at a separate visit within 3 weeks before or after your last day on the study 
drug.  
• Liver biopsy. The liver biopsy during Visit 3 is required for all participants on the study. 
 
Visit 4 (Week 28, 4 weeks after you stop taking the study drug) 
• Physical examination and vital signs, and answering some questions about your medical 
history, other medications you are taking, and how the study drug is affecting you. 
• Blood tests to make sure you are healthy and have good organ function. 
 
How should I take this medication? 
 

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The Polyphenon E/EGCG capsules are recommended to be taken with a cup of water after a light 
meal without milk or juice during the meal. Patient should not make up the missing dose the next 
day. Patient should not make up vomited doses. The missing dose or vomited dose should be 
reported in the medication diary. 
 
What possible risks can I expect from taking part in this study?  
 
If you choose to take part in this study, there is a risk that you may:  
1) Lose time at work or home and spend more time in the hospital or doctor’s office than 
usual. 
2) Be asked sensitive or private questions which you normally do not discuss, for example 
about your tobacco and alcohol use. 
3) There is a risk someone could get access to the personal information in your medical 
records or other information researchers have kept about you. Someone might be able 
to trace this information back 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. In some cases, this information could be used to 
make it harder for you to get or keep a job.  
 
The Polyphenon E used in this study may affect how different parts of your body work, such as 
your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you 
know if changes occur that may affect your health.  
 
Liver damage has been reported following use of green tea-containing extracts. In at least one case, 
liver failure occurred. There is no available information on the safety of administering Polyphenon 
E to participants with underlying cirrhosis/ liver disease, but the risk of that it may cause worsening 
liver damage or liver failure could be higher than the risk of administering Polyphenon E to 
participants with no underlying liver disease/ cirrhosis.  
 
We will be monitoring your liver tests closely during this study. 
 
It is not known if Polyphenon E/green tea extract consumption will directly benefit your liver 
disease. It is also not known whether six months of Polyphenon E will decrease the risk of liver 
cancer. The goal of the study is to test if Polyphenon E will decrease the biomarker that correlates 
with liver cancer development. 
 
You may or may not have side effects. Everyone taking part in this study will be watched carefully 
for any side effects. 
 
Here are important points about side effects: 
1) The study doctors do not know who will or will not have side effects. 
2) Some side effects may go away soon, some may last a long time, or some may never 
go away.  
3) Some side effects may interfere with your ability to have children. 
4) Some side effects may be serious and may even result in death.  
 

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Here are important points about how you and the study doctor can make side effects less of a 
problem: 
5) Tell the study doctor if you notice or feel anything different so they can see if you are 
having a side effect. 
6) The study doctor may be able to treat some side effects. 
 
The tables below show the most common side effects that we know about Polyphenon E, some of 
which may be serious. There might be other side effects that we do not yet know about. If important 
new side effects are found, the study doctor will discuss these with you. 
 
Possible Side Effects of Polyphenon E 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Polyphenon E, more than 20 may have: 
• Headache  
• Heartburn 
• Abnormal blood tests (related to how well liver is working) 
• Nausea  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving, from 4 to 20 may have: 
• Abnormal blood tests (related to how well liver, kidney, and pancreas are working)   
• Abnormal heartbeat 
• Abnormal laboratory test (increased protein in the urine, sugar present in the urine) 
• Abnormal menstrual period 
• Abdominal discomfort 
• Bleeding of the rectum 
• Bloating 
• Burping 
• Changes in taste 
• Chest pain 
• Constipation 
• Diarrhea 
• Difficulty sleeping  
• Discomfort from light  
• Dizziness 
• Flushing 
• Gas 
• Inflammation (swelling and redness) of the stomach lining   
• Itching 
• Low blood level of hemoglobin, a protein that carries oxygen in the body  
• Low level of blood bicarbonate  
• Nose bleed 
• Pain (pain in the belly, pain in the mouth, pain in the muscle, pain in the leg/arm) 
• Rash 
• Ringing in the ear 
• Swelling and redness of skin 
• Stuffy nose  

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OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving, from 4 to 20 may have: 
• Swelling of the eyelid 
• Temporary lowering of the number of white blood cell count, which can lead to infection 
• Tiredness 
• Vomiting 
• Weight increased 
 
RARE, SOME MAY BE SERIOUS 
In 100 people receiving Polyphenon E, 3 or fewer may have: 
• Loss of appetite 
• Widening of blood vessels (vasodilation) 
 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. 
The Polyphenon E used in this study could be very damaging to an unborn baby. Contraception 
must be used prior to study entry and throughout the study.  Check with the study doctor about 
what types of birth control, or pregnancy prevention, to use while in this study. 
 
Risk of the blood tests: Bruising, soreness, or rarely, infection may occur as a result of the needle 
sticks to obtain blood from your vein. 
 
Risks of liver biopsy: The primary risk of liver biopsy is bleeding from the site of needle entry into 
the liver, although this occurs in less than one per cent of participants. When it occurs, it usually 
stops on its own and does not lead to any other problems. Other rare complications include 
infection and the puncture of other organs, such as the kidney, lung or colon. A liver biopsy 
procedure that damages the gallbladder by mistake may lead to leakage of bile into the abdominal 
cavity, causing peritonitis. The risk of death from liver biopsy is extremely low, about 1 in 5,000. 
Common side effects of a biopsy are a small amount of bleeding at the time of the procedure, pain 
at the biopsy site, which can be treated with regular pain medications, and bruising. 
 
Risks of FibroScan: There are no known risks associated with a FibroScan examination. 
 
What possible benefits can I expect from taking part in this study? 
Participating in this study may or may not help your condition. This study may help us learn things 
that could help people in the future. 
 
Can I stop taking part in this study? 

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Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. Your study doctor will tell you 
how to stop taking the study drug and how to return the study drug you haven’t taken.  There are 
no consequences to stopping the study.  If you stop, you can decide whether or not to let the study 
doctor continue to provide your medical information to the organization running the study. 
 
For the tobacco and alcohol use questions, you can decide to not answer some or all of the 
questions. Your decision will not affect whether you can participate in the study, and it will not 
affect your relationship with your doctor or the study staff. 
 
The study doctor will tell you about any new information or changes in the study that could affect 
your health or your willingness to continue in the study. 
 
The study doctor may take you out of the study: 
a) If your health changes, for example, worsening liver function from cirrhosis, or 
development of liver cancer.  
b) If the study is no longer in your best interest. 
c) If new information becomes available, indicating there is a new treatment to prevent liver 
cancer, or green tea extract is harmful to your health. 
d) If you do not follow the study rules. 
e) If the study is stopped early for any reason by the sponsor, IRB 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. 
 
For questions about your rights while in this study, call the National Cancer Institute Central 
Institutional Review Board at 1-888-657-3711. 
 
What are the costs of taking part in this study? 
The Polyphenon E will be supplied at no charge while you take part in this study. The cost of 
study-specific biopsies and exams, blood tests, and any other procedures will be paid for by the 
study. 
 
Some costs associated with your care may be considered standard of 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 exactly what they will pay for.  
 
You will be provided $200 for each liver biopsy you have for this study (at Screen 2 and at Visit 
3)).  You will be provided $75 for each clinic visit (Screen 1, Screen 2, Visit 1, Visit 2, Visit 3, 
and Visit 4).  You will be provided $25 for each between-visit blood draw you need for this study 

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(up to 14).  Depending on what activities you participate in, the maximum total you may be 
provided is $1,200.   
 
What happens if I am injured or hurt because I took part in this study? 
If you feel you have been injured or hurt as a result of taking part in the study, it is important that 
you tell the study doctor immediately. You will get medical treatment if you are injured or hurt as 
a result of taking part in this study.  
 
The study sponsors will not offer to pay for medical treatment for injury. Your insurance company 
may not be willing to pay for study-related injury. If you have no insurance coverage, you would 
be responsible for any costs. Even though you are in a study, you keep all of your legal rights to 
receive payment for injury caused by medical errors. 
 
Who will see my medical information?  
 
Your privacy is very important to us and we will make every effort to protect it. 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. The study doctors have a privacy permit to help 
protect your records if there is a court case. 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/or information about your specimen, 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: 
1) The study sponsor and any drug company supporting the study 
2) 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. 
3) The Food and Drug Administration and the National Cancer Institute in the US. 
4) 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? 
The National Cancer Institute will obtain information from this clinical trial under data collection 
authority Title 42 U.S.C. 285. 
 
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 US 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? 

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You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries.  
 
If you are a patient of Medstar Georgetown University Hospital, contact the study doctor Dr. 
Coleman Smith at 202-444-3700.  If you need to contact study staff for emergencies or outside 
normal hours, you can call 202-444-2000 and ask for the hepatologist on call.  
 
If you are a patient of Medstar Washington Hospital Center, contact the study doctor Dr. Arul 
Thomas at 202-444-3700.  If you need to contact study staff for emergencies or outside normal 
hours, you can call 202-444-2000 and ask for the hepatologist on call.  
 
If you are a patient of the University of Puerto Rico, contact the study doctor Dr. Marcia Cruz, at 
787-772-8300.  If you need to contact study staff for emergencies or outside normal hours, you 
can call 787-772-8300.    
 
This section is about optional studies you can choose to take part in.  
This part of the consent form is about optional studies that you can choose to take part in. You will 
not get health benefits from any of these studies. The researchers leading this optional study hope 
the results will help other people with cancer in the future. 
 
The results will not be added to your medical records, and you or your study doctor may not know 
the results. You will not be billed for these optional studies.  
 
You can still take part in the main study even if you say ‘no’ to any or all of these studies. If you 
sign up for but cannot complete any of the studies for any reason, you can still take part in the 
main study. 
 
Circle your choice of “yes” or “no” for each of the following studies.  
 
Optional Sample Collections for Laboratory Studies and/or Biobanking for 
Possible Future Studies 
 
Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of 
this research is done using samples from your biopsies, blood, urine, 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 would like to ask your permission to store and use your leftover 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 and supported by The 
National Cancer Institute. 
 
The research that may be done is unknown at this time. Future research may include: 1) studies 

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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, here is what will happen next: 
1. If you are one of the first six people at Georgetown University who agree to provide extra 
blood and urine for the PK study: you will be asked to fast after midnight except for drinking 
water prior to coming into the clinic for Visit 1.  Before you take your first dose of the study 
drug, two urine samples and four extra tubes of blood will be drawn to make sure you are 
healthy. You will then stay at the clinic for 9 hours after your first dose of the study drug to 
have three additional blood draws and three separate urine tests to see how your body processes 
the study drug. The additional blood tests only will be obtained from the first six participants 
who wish to participate in these additional tests.   
2. You will need to have liver tissue tested for this study. If you have had a liver biopsy in the 
past year and tissue from that biopsy was stored at the hospital. , you can either: 
a) Give permission for the stored tissue to be used for the study, and also agree to have 
an additional liver biopsy at Screen 2, OR 
b) Give permission for the stored tissue to be used for the study, but decide NOT to 
have another liver biopsy at Screen 2, OR 
c) Don’t give permission for the stored tissue to be used for the study, but instead 
agree to have a liver biopsy at Screen 2 
3. Your leftover samples and some related information may be stored in the Biobank, along with 
samples and information from other people who take part. The samples will be stored at 
Georgetown University or the University of Puerto Rico until the end of the study, when they 
may be transferred to the National Institutes of Health. These are not additional samples that 
will be collected, but will consist of any material (tissue, urine, and blood samples) that remains 
after the tests described for this study have been conducted. 
4. Qualified researchers can submit a request to use the materials stored in the Biobank. A 
research committee will review each request. There will also be an ethics review to ensure that 
the request is necessary and proper. Researchers will not be given your name or any other 
information that could directly identify you. 
5. Neither you nor your study doctor will be notified if/when research is conducted using your 
samples.  
6. Some of your genetic and health information may be placed in central databases that may be 
public, along with information from many other people. Information that could directly 
identify you will not be included.  
 
WHAT ARE THE POSSIBLE RISKS?  
1. The most common risks related to drawing blood from your arm are brief pain and possibly 
a bruise. 
2. There is a risk that someone could get access to the personal information in your medical 
records or other information we have stored about you.  
3. There is a risk that someone could trace the information in a central database back to you. 
Even without your name or other identifiers, your genetic information is unique to you. 

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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.  
 
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: 
 
• Health insurance companies and group health plans may not request your genetic 
information that we get from this research.  
• 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 social security number) will be sent. Samples will be identified by a unique 
study code only. (Note to consent form authors: If investigators are receiving samples 
directly from sites without being coded, modify accordingly.) 
2. The list that links the unique code to your name will be kept separate from your sample 
and health information. Any Biobank and (insert name of clinical trials organization) staff 
with access to the list must sign an agreement to keep your identity confidential. 
3. Researchers to whom (insert name of clinical trials organization) sends your sample 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. 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.  The researchers, using the samples from you and others, 
might make discoveries that could help people in the future. 

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ARE THERE ANY COSTS OR PAYMENTS?  
There are no costs to you or your insurance. You will not be paid for taking part. 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?  
If you decide you no longer want your samples to be used, you can call the study doctor, 
_________________, (insert name of study doctor for main trial) at ________________________ 
(insert telephone number of study doctor for main trial) who will let the researchers know. Then, 
any sample that remains in the bank will no longer be used. 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 study doctor, 
________________, (insert name of study doctor for main trial), at _____________________ 
(insert telephone number of study doctor for main trial). 
 
Please circle your answer to show whether or not you would like to take part in each option: 
 
SAMPLES AND INFORMATION FOR FUTURE RESEARCH STUDIES: 
 
If you are one of the first six participants at Georgetown University who agrees to 
participate in the PK study:  
Participate in the PK study to study how the body absorbs, distributes, breaks down, 
and eliminates the study drug (three additional blood draw and urine test on Visit 1 
(week 1 day 1): 
 
 
YES 
 
NO 
 
N/A 
 
My samples and related information may be kept in the NCI Biobank for use in future 
health research. These are blood samples leftover from the main study. 
 
 
YES 
 
NO 
 
I agree that my study doctor, or their representative, may contact me or my physician to 
see if I wish to participate in other research in the future. 
 
 
YES 
 
NO 
 
The information from my tobacco and alcohol use questionnaires may be used in future 
health research. 
 
 
 
YES 
 
NO 
 
 
I provide permission to my study doctor, or their representatives, to contact me once the 
entire study has been completed for the purposes of sending study results when they 

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become available 
 
YES 
 
NO 
 
 
 
I have had a liver biopsy in the past year, and the tissue was stored at the hospital 
 
 
 
YES 
 
NO 
 
 
 
 
If YES:  
I agree that the liver biopsy tissue stored at the hospital can be used for this 
study 
 
YES 
 
NO 
 
N/A 
 
If NO: 
I agree to undergo an additional, optional liver biopsy at the Screen 2 Visit 
 
YES 
 
NO 
 
N/A 
 
This is the end of the section about optional studies. 
 
My Signature Agreeing to Take Part in the Main Study 
 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my 
questions have been answered. I will be given a signed copy of this form. I agree to take part in 
the main study. 
 
Participant’s signature ________________________________ 
 
Date of signature_____________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion  
___________________________________ 
 
Date of signature_____________________________________  

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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. 
 

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APPENDIX B 
 
 
Instructions for pills 
1. Store at room temperature 
2. Keep canisters out of reach of children 
3. If you can, take your pills at the same time. If you forget to take it at the same time, take it 
any time that you remember. 
4. If you prefer to take the pills at another time (for example, when you take your other 
medications) that is OK, as long as you remember to take it daily. 
5. Always take the pills after a light meal. 
6. If you start any new medications while you are on study, please call your study coordinator. 
She will check with the study doctor and if needed, with your personal physician so that 
possible interactions can be managed safely. 
7. Avoid fasting or taking vitamin C, fish oil , calcium, magnesium, or milk with the 
Polyphenon capsules. You should take your Polyphenon E/EGCG capsules with a cup of 
water after a light meal without milk or juice during the meal.  You should not make up the 
missing dose the next day.   You should not make up vomited doses. The missing dose or 
vomited dose should be reported in the medication diary. 
 
 
 
 
 
 
 

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APPENDIX C 
Participant Diary 
 
Participant ID__________________ 
 
DAY ___ 
 
DATE: ___/____/____ 
TIME: _____________ 
TIME: _____________ 
 
Please list any new 
symptoms, 
medications, or 
reasons for missed 
doses: 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
 
DAY ___ 
 
DATE: ___/____/____ 
TIME: _____________ 
TIME: _____________ 
 
Please list any new 
symptoms, 
medications, or 
reasons for missed 
doses: 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
 
DAY ___ 
 
DATE: ___/____/____ 
TIME: _____________ 
TIME: _____________ 
 
Please list any new 
symptoms, 
medications, or 
reasons for missed 
doses: 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
 
DAY ___ 
 
DATE: ___/____/____ 
TIME: _____________ 
TIME: _____________ 
 
Please list any new 
symptoms, 
medications, or 
reasons for missed 
doses: 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
 
DAY ___ 
 
DATE: ___/____/____ 
TIME: _____________ 
TIME: _____________ 
 
Please list any new 
symptoms, 
medications, or 
reasons for missed 
doses: 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
 
DAY ___ 
 
DATE: ___/____/____ 
TIME: _____________ 
TIME: _____________ 
 
Please list any new 
symptoms, 
medications, or 
reasons for missed 
doses: 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
 
DAY ___ 
 
DATE: ___/____/____ 
TIME: _____________ 
TIME: _____________ 
 
Please list any new 
symptoms, 
medications, or 
reasons for missed 
doses: 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
____________________ 
 
 
Study Coordinator Signature: ______________________________________________________     
Date: _______________ 

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If a participant meets any of these criteria, email NCPC and the protocol PI within 48 hours of learning about the event 
(ncpc@northwestern.edu and arh29@georgetown.edu).   
 
1. If direct bilirubin remains in the normal range during the trial and only transaminase elevations are observed: 
• When the baseline ALT or AST are normal at baseline and increase to ≥5x upper limit of normal (ULN) 
during the trial AND the patient does not have liver related symptoms (nausea, vomiting, right upper 
quadrant pain) then  
o Repeat liver profile (AST, ALT, Bilirubin (total, direct, and indirect)) and INR within 3 to 4 days. 
Monitor the patient as per “close observation” definition in the DILI guidance.  
 
• When the ALT or AST are elevated at baseline and increase to ≥3x baseline during the trial AND the 
patient does not have liver related symptoms (nausea, vomiting, right upper quadrant pain) then 
o Interrupt the study medication. Initiate potential DILI work-up for competing etiologies, repeat 
liver profile and INR within 48-72 hours, and place patient under “close observation” as defined 
in the DILI guidance. Study medication can be restarted only if a firm competing etiology is 
identified and liver tests return to baseline.  
 
•  When the ALT or AST increase to ≥3x baseline (irrespective of baseline levels) during the trial and are 
associated with symptoms of clinical hepatitis such as vomiting, nausea, right upper quadrant pain), then  
o Interrupt the study medication. Initiate potential DILI work-up for competing etiologies, repeat 
liver profile and INR within 48-72 hours, and place patient under “close observation” as defined 
in the DILI guidance. Study medication can be restarted only if a firm competing etiology is 
identified and liver tests return to baseline.  
 
2.  For patients with elevations in direct bilirubin > 1.5 x ULN, and if ALT or AST ≥3 x baseline but without 
liver related symptoms (vomiting, nausea, right upper quadrant pain) then 
o Interrupt the study medicine. Initiate potential DILI work-up for competing etiologies, repeat liver 
profile and INR within 48-72 hours, and closely observe the patient. For “close observation” of 
patients, refer to the DILI guidance1. Study medication can be restarted only if a firm competing 
etiology is identified and the liver tests return to baseline.  
 
3. With any elevation of direct bilirubin > ULN, regardless of ALT or AST levels, and in the presence of 
indicators of immunological reaction (i.e., rash or >5% eosinophilia), or appearance of nausea, vomiting, right 
upper quadrant pain (symptoms consistent with clinical hepatitis) then 
o Permanently discontinue study medication. Initiate potential DILI work-up for competing etiologies, 
repeat liver profile and INR within 48-72 hours, and place patient under “close observation” as defined 
in the DILI guidance.  
 
If a patient lives in a remote area, they can be tested locally and the results communicated to the 
investigator site promptly. 
 
Close observation: 
 
1. Interrupt the investigational agent administration  
2. Repeat liver biochemistries and additional testing within 24-72 hrs  
 
1 (refer to the “Guidance for Industry : Drug induced liver injury (DILI): Premarketing clinical evaluation” 
http://www.fda.gov/downloads/Drugs/.../Guidances/UCM174090.pdf) 

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3. Monitor patient twice or thrice a week until liver biochemistries (ALT, AST, alkaline phosphatase, 
bilirubin (total, direct, and indirect), and coagulation profile [INR]) resolve, stabilize or return to within 
baseline values 
4. Monitor liver biochemistries once a week if abnormalities stabilize and the patient is asymptomatic 
5. Obtain a detail history for symptoms assessment:  appearance or worsening of clinical symptoms of 
hepatitis (fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia). 
If a patient is symptomatic, the drug must be discontinued immediately and a potential DILI evaluation 
must be performed. 
6. Obtain a more detailed history of symptoms and prior or concomitant diseases; 
7. Obtain a history for concomitant medications, acetaminophen, dietary supplements, herbal remedies, 
other over the counter medications, recreational drug use, and special diets  
8. If possible quantify the alcohol consumption to assess for alcoholic hepatitis 
9. Obtain a history of exposure to environmental chemical agents. 
10.  If INR is also elevated, a trial of intravenous vitamin K administration may be considered, especially in 
cholestatic patients. 
 
Follow-Up Procedures for patient(s) who meet potential DILI evaluation criteria: 
1. Viral hepatitis serology including: 
a. Hepatitis A IgM antibody; 
b. Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); 
c. Hepatitis C RNA; 
d. Hepatitis E IgM antibody.  
e. Cytomegalovirus IgM antibody; 
f. Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain heterophile antibody or 
monospot testing); however IgM antibodies must be sent out asap  
g. Blood sample for pharmacokinetic (PK) analysis, obtained within 12 hours of last dose. Record 
the date/time of the PK blood sample draw and the date/time of the last dose of study treatment 
prior to blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the 
participant’s best approximation.  
h. Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH). 
i. Fractionate bilirubin, if total bilirubin >2xULN 
j. Assess for peripheral eosinophilia 
k. Assess for hypoxic/ischemic hepatopathy; and biliary tract disease 
 
The following are required for patients who meet the stopping criteria for both ALT and bilirubin OR 
experiences clinical symptoms of hepatitis: 
1. Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies 
and quantitative total immunoglobulin G (IgG or gamma globulins). 
2. If required evaluation of competing undiagnosed liver disease (hemochromatosis, Wilson’s disease, 
alpha-1 anti-trypsin deficiency) 
3. Serum acetaminophen levels OR serum acetaminophen adducts by HPLC assay (quantifies potential 
acetaminophen contribution to liver injury in participants with definite or likely acetaminophen use in 
the preceding week). 
4. Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease. 
5. A Liver Biopsy 
 
Treatment with investigational agent could be re-initiated if these abnormalities stabilize, return to pre-trial 
baseline, or normalize.  

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Investigational agent must be permanently discontinued and patient must be followed until the clinical and 
laboratory abnormalities stabilize or normalize if the following criteria are met: 
1) If close monitoring of a patient is not possible. or 
2)  Any elevation of direct bilirubin > ULN, regardless of ALT or AST levels, AND with indicators of 
immunological reaction (i.e., rash or >5% eosinophilia), or appearance of nausea, vomiting, right upper 
quadrant pain (symptoms consistent with clinical hepatitis)  
3) Any development of recurrent hepatotoxicity (as outlined in this table) upon rechallenge.  
4) Any hepatic decompensation as  
•  New onset ascites or worsening of ascites (requiring increase in drug therapy or requiring surgical 
intervention such as paracentesis). 
• Variceal bleeding documented by endoscopy 
• Spontaneous bacterial peritonitis documented by positive culture 
• Hepatic encephalopathy 
• Hepatorenal syndrome (Type 1 or 2) 
• Porto-pulmonary hypertension 
• Hepato-pulmonary hypertension 
• 
Any liver related event that leads to hospitalization or G4 event. 
 

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APPENDIX E 
Alcohol and Tobacco Use Assessment 
ALCOHOL ASSESSMENT – BASELINE 
 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 oz. 
glass of wine, or one and a half ounces of liquor. 
 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range 
or fraction of a number. 
 
1. In your entire life, have you had at least 12 drinks of any kind of alcoholic beverage?  
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. In the past 12 months, on average, how often did you drink any type of alcoholic beverage?  
________ (Enter the number of days you drank based on the timeframe checked below.  Enter 0 if you 
never drank and skip to Question 6.)  
 Week  
 Month 
 Year 
 Refused 
 Don’t know/Not sure 
 
3. In the past 12 months, on those days that you drank alcoholic beverages, on average, how many drinks 
did you have per day?  
________ (Enter the average number of drinks per day) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 12 months, on how many days did you have 5 or more drinks of any alcoholic beverage?  
_________ (Enter the number of days you had 5 or more drinks, or enter 0 if none.) 
 
 Refused 
 Don’t know/Not sure 
 
5. Was there ever a time or times in your life when you drank 5 or more drinks of any kind of alcoholic 
beverage almost every day?  
 Yes 
 No  
 Refused 
 Don’t know/Not sure 
 
 

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6. If you do not currently drink alcoholic beverages, but did in the past, how long has it been since you 
last drank regularly?  
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago  
 Don’t know/Not sure 
 Never drank regularly 
 
7. At the heaviest point, either now or in the past, on the days when you drank, about how many drinks 
did you drink a day on the average?  
__________ (Enter the number of drinks a day) 
  
 Refused 
 Don’t know/Not sure 
 
8. How many years have you been drinking (or did drink) regularly?  
______ years 
 
 Refused 
 Don’t know/Not sure  
 
9. At what age did you begin drinking regularly?  
______ years of age 
 
 Refused 
 Don’t know/Not sure  
 
10. What type(s) of alcohol do you drink? (Mark ALL that apply) 
 Wine 
 Liquor 
 Beer 
 Wine cooler 
 
 
Coordinator Signature _______________________________   Date __ __ / __ __ / __ __ __ __ 
 
(MM/DD/YYYY) 
 
 

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APPENDIX F 
Alcohol and Tobacco Use Assessment 
TOBACCO ASSESSMENT – BASELINE 
 
Instructions: 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range 
or fraction of a number. 
 
Section A. Basic Cigarette Use Information 
 
1. Have you smoked at least 100 cigarettes (5 packs = 100 cigarettes) in your entire life? 
Yes  
 
 No → Skip to Section B 
 Don’t know/Not sure → Skip to Section B 
 
2. How old were you when you first smoked a cigarette (even one or two puffs)? 
_______ Years old  
 
3. How old were you when you first began smoking cigarettes regularly?   
_______ Years old  
  Check here if you have never smoked cigarettes regularly. 
 
4. How many total years have you smoked (or did you smoke) cigarettes? Do not count any time you may 
have stayed off cigarettes. 
______ Years (If you smoked less than one year, write “1.”)  
 
5. On average when you have smoked, about how many cigarettes do you (or did you) smoke a day? (A 
pack usually has 20 cigarettes in it).  
_____ Number of cigarettes per day 
 
6. Do you NOW smoke cigarettes?  
 Everyday 
 Some days 
 Not at all → Skip to question 8 
 
7.  How soon after you wake up do you smoke your first cigarette?  
  Within 30 minutes 
  After 30 minutes 
 
8. How long has it been since you last smoked a cigarette (even one or two puffs)? 
First check which one of the following choices applies to you. Then, if applicable, write a number on the 
line for how many days, weeks, months, or years it has been since your last cigarette. 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette  ________ 
 Less than 1 month → Number of weeks since last cigarette  _________ 
 Less than 1 year → Number of months since last cigarette  __________ 
 More than 1 year → Number of years since last cigarette  ___________ 
 Don’t know/Don’t remember 
 

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Section B. Use of Other Forms of Tobacco 
9.  Have you ever used other forms of tobacco, not including cigarettes? 
      
 Yes  
 No → Skip to Section C 
 
10. How often do you/did you use other forms of tobacco?  
 Every day → Number of times per day  ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year 
 
11. Which of the following products have you ever used regularly? 
 Check all that apply  
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
 Other, Please specify:___________________________ 
 
12. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you 
last used other forms of tobacco regularly?  
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
Section C. Second-Hand Smoke Exposure 
13. Are you currently living with a smoker?   
Yes 
 
 No  
 
14. In the past 30 days, have you lived in a place where other people smoked cigarettes indoors?  
Yes 
 
 No  
 
 

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15. In the past 30 days, have you worked in a place where other people smoked cigarettes indoors? 
Yes 
 
 No  
 
16. Thinking of all your childhood and adult years, have you ever lived in a place where other people 
smoked cigarettes indoors? 
 Yes 
In total, for about how many years?_______ If less than 1, write “1.”   
 No  
 
17. Thinking of all the years you have worked, have you ever worked in a place where other people smoked 
cigarettes indoors?    
Yes 
→ In total, for about how many years?_______ If less than 1, write “1.”    
 No 
 
 
Coordinator Signature  _______________________________   Date  __ __ / __ __ / __ __ __ __ 
 
(MM/DD/YYYY) 
 
 
 

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APPENDIX G 
Alcohol and Tobacco Use Assessment 
ALCOHOL ASSESSMENT - FOLLOW-UP 
Instructions: 
For the following questions about drinking alcoholic beverages, a drink means a 12 oz. beer, a 5 oz. 
glass of wine, or one and a half ounces of liquor. 
 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range 
or fraction of a number. 
 
 
1. During the past 30 days, did you drink any alcoholic beverages?  
 Yes 
 No (End) 
 Refused (End) 
 Don’t know/Not sure 
 
2. During the past 30 days, how many days per week or per month did you drink any alcoholic beverages, 
on the average?  
________ (Enter number of days you drank based on the timeframe checked below.  Enter 0 if you did 
not drink.)  
 Week  
 Month 
 Refused 
 Don’t know/Not sure 
 
3. On the days when you drank, on average, about how many drinks did you have?  
________ (Enter the average number of drinks you had per day.) 
 
 Refused 
 Don’t know/Not sure 
 
4. In the past 30 days, on how many days did you have 5 or more drinks per day?  
_____________Number of times 
 
 None  
 Do not know/Not sure 
 
 
Coordinator Signature _______________________________   Date __ __ / __ __ / __ __ __ __ 
  
(MM/DD/YYYY) 
 
 
 

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APPENDIX H 
Alcohol and Tobacco Use Assessment 
TOBACCO ASSESSMENT - FOLLOW-UP 
Instructions: 
When a number is requested in the response, please enter a whole number (i.e. “4”) and not a range 
or fraction of a number. 
 
1. Do you NOW smoke cigarettes?  
 Everyday 
 Some days 
 Not at all → Skip to Question 3. 
 Never smoked → Skip to Question 4. 
 
2. On average, when you smoked, about how many cigarettes do you (or did you) smoke a day? (A pack 
usually has 20 cigarettes in it).    
_____ Number of cigarettes per day 
 
3. How long has it been since you last smoked a cigarette (even one or two puffs)?    
First check which one of the following choices applies to you. Then, if applicable, write a number on the 
line for how many days, weeks, months, or years it has been since your last cigarette. 
 I smoked a cigarette today (at least one puff) 
 1-7 days → Number of days since last cigarette ________ 
 Less than 1 month → Number of weeks since last cigarette _________ 
 Less than 1 year → Number of months since last cigarette __________ 
 More than 1 year → Number of years since last cigarette ___________ 
 Don’t know/Don’t remember 
 
4. Since your last visit, have you used other forms of tobacco, not including cigarettes?  
 Yes 
  No (End) 
 
5. How often do you/did you use other forms of tobacco?  
 Every day → Number of times per day ________ 
 Some days → Number of days _______ per 
 Week 
 Month 
Year 
 
 
 

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6. Since your last visit, which of the following products have you used?  Check all that apply 
 Cigarettes 
 E-cigarettes or other electronic nicotine delivery system 
 Traditional cigars, cigarillos or filtered cigars 
 Pipes 
 Waterpipe 
 Hookah 
 Clove cigarettes or kreteks 
 Bidis  
 Smokeless tobacco, like dip, chew, or snuff 
 Snus 
 Paan with tobacco, gutka, zarda, khaini 
Other, Specify___________________________________________________________ 
 
7. If you do not currently use other forms of tobacco, but did in the past, how long has it been since you last 
used other forms of tobacco regularly?  
 Within the past month (0 to 1 month ago) 
 Between 1 and 3 months (1 to 3 months ago) 
 Between 3 and 6 months (3 to 6 months ago) 
 Between 6 and 12 months (6 to 12 months ago) 
 Between 1 and 5 years (1 to 5 years ago) 
 Between 5 and 15 years (5 to 15 years ago) 
 More than 15 years ago 
 Don’t know/Not sure 
 Never used other forms of tobacco regularly 
 
The following instructions pertain to questions 8 - 10.  During each of the following time frames, please 
indicate whether you smoked cigarettes every day, some days, or not at all. 
 
8.  During study treatment 
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable  
 
9.  After the end of study treatment 
      
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 Not applicable (I have not completed the study treatment) 
 
 
 
 

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10.  Since your last visit to this clinic 
      
 Smoked every day 
 Smoked some days 
 Did not smoke at all 
 Don’t know/not sure 
 
 
Coordinator Signature _______________________________   Date __ __ / __ __ / __ __ __ (MM/DD/YYYY) 
 
 

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APPENDIX I 
Resources 
National and local resources to help with alcohol abuse and 
alcoholism 
NIAAA’s online guide Treatment for Alcohol Problems: Finding and Getting Help is written 
for individuals, and their family and friends, who are looking for options to address alcohol 
problems. It is intended as a resource to understand what treatment choices are available and 
what to consider when selecting among them. 
https://pubs.niaaa.nih.gov/publications/treatment/treatment.htm 
Other resources: 
National Institute on Alcohol Abuse and Alcoholism www.niaaa.nih.gov  
301–443–3860  
National Institute on Drug Abuse www.nida.nih.gov  
301–443–1124  
National Clearinghouse for Alcohol and Drug Information www.samhsa.gov  
1–800–729–6686  
Substance Abuse Treatment Facility Locator www.findtreatment.samhsa.gov  
1–800–662–HELP  
Alcoholics Anonymous (AA) www.aa.org  
212–870–3400 or check your local phone directory under “Alcoholism”  
Moderation Management www.moderation.org 
212–871–0974  
Secular Organizations for Sobriety www.sossobriety.org  
323–666–4295  
SMART Recovery www.smartrecovery.org  
440–951–5357  
Women for Sobriety www.womenforsobriety.org  
215–536–8026  
Al-Anon Family Groups www.al-anon.alateen.org  
1–888–425–2666 for meetings  
Adult Children of Alcoholics  www.adultchildren.org 
310–534–1815  
 

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National and local resources to help with quitting smoking 
NCI’s Smokefree.gov offers science-driven tools, information, and support that has helped 
smokers quit. You will find state and national resources, free materials, and quitting advice from 
NCI. 
Smokefree.gov was established by the Tobacco Control Research Branch 
(http://www.cancercontrol.cancer.gov/tcrb/) of NCI, a component of the National Institutes of 
Health, in collaboration with the Centers for Disease Control and Prevention and other 
organizations. 
Publications available from the Smokefree.gov Web site include the following: 
• 
Clearing the Air: Quit Smoking Today 
(http://smokefree.gov/sites/default/files/pdf/clearing-the-air-accessible.pdf) for smokers 
interested in quitting. 
• 
Clear Horizons (http://www.smokefree.gov/landing.aspx?rid=2) for smokers over age 50. 
• 
Forever Free™  (http://www.smokefree.gov/landing.aspx?rid=3) for smokers who have 
recently quit. 
• 
Forever Free for Baby and Me™, in English 
(http://www.smokefree.gov/landing.aspx?rid=4) and Spanish 
(http://www.smokefree.gov/landing.aspx?rid=5), for pregnant smokers who have recently 
quit. 
• 
Pathways to Freedom: Winning the Fight Against Tobacco 
(http://www.cdc.gov/tobacco/quit smoking/how to quit/pathways/index.htm) for 
African American smokers. 
NCI’s Smoking Quitline at 1–877–44U–QUIT (1–877–448–7848) offers a wide range of 
services, including individualized counseling, printed information, referrals to other resources, 
and recorded messages. Smoking cessation counselors are available to answer smoking-related 
questions in English or Spanish, Monday through Friday, 8:00 a.m. to 8:00 p.m., Eastern time. 
Smoking cessation counselors are also available through LiveHelp (https://livehelp.cancer.gov/), 
an online instant messaging service. LiveHelp is available Monday through Friday, 8:00 a.m. to 
11:00 p.m., Eastern time. 
Your state has a toll-free telephone quitline. Call 1–800–QUIT–NOW (1–800–784–8669) to get 
one-on-one help with quitting, support and coping strategies, and referrals to resources and local 
cessation programs. The toll-free number routes callers to state-run quitlines, which provide free 
cessation assistance and resource information to all tobacco users in the United States. This 
initiative was created by the Department of Health and Human Services (http://www.hhs.gov/). 
For more information about quitlines, speak to an expert (http://smokefree.gov/talk-to-an-expert) 
on the Smokefree.gov Web site.