Browse EPPT > 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

The following datasets contain the data available for EPPT NWU2016-08-02. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Files	Description
Data Dictionary (PDF - 1014.7 KB)	1. The Enhanced Person dataset contains enhanced Person
Data Dictionary (PDF - 129.7 KB)	2. The Adverse Events dataset contains adverse Events

Raw Datasets

These 40 datasets contain the raw form data received, excluding PII.

Show these datasets

Files	Description
Data Dictionary (PDF - 125.3 KB)	1. The Adverse Events dataset contains adverse Events That Occurred
Data Dictionary (PDF - 116.6 KB)	2. The AFP/-L3 dataset contains blood Lab Tests
Data Dictionary (PDF - 104.9 KB)	3. The Agent Interruption dataset contains agen Interruptions That Occurred
Data Dictionary (PDF - 103.6 KB)	4. The Agent Return And Compliance dataset contains agent Return Information
Data Dictionary (PDF - 124.7 KB)	5. The Baseline Alcohol dataset contains alcohol Use Details At Baseline
Data Dictionary (PDF - 103.1 KB)	6. The Baseline Symptoms dataset contains adverse Symptoms At Baseline
Data Dictionary (PDF - 147.7 KB)	7. The Baseline Tobacco dataset contains tobacco Use Details At Baseline
Data Dictionary (PDF - 108.1 KB)	8. The Batch Shipment Specimen Inventory dataset contains batch Shipment Specimen Inventory Information
Data Dictionary (PDF - 104.6 KB)	9. The Blood and Urinary g-OHPdG dataset contains blood And Urinary g-OHPdG Results
Data Dictionary (PDF - 132.2 KB)	10. The Blood Comprehensive Metabolic Panel dataset contains comprehensive Metabolic Panel Blood Chemistry Lab Tests
Data Dictionary (PDF - 108.8 KB)	11. The Child Pugh Score dataset contains child Pugh Score Results
Data Dictionary (PDF - 106.9 KB)	12. The Compliance Urine dataset contains compliance Urine Results
Data Dictionary (PDF - 118.6 KB)	13. The Concomitant Medications dataset contains concomitant Medications Taken
Data Dictionary (PDF - 101.0 KB)	14. The Eligibility dataset contains eligibility Information
Data Dictionary (PDF - 103.2 KB)	15. The Enrollment dataset contains enrollment Information
Data Dictionary (PDF - 108.5 KB)	16. The FIB-4 Score dataset contains FIB-4 Score Results
Data Dictionary (PDF - 100.8 KB)	17. The Fibroscan Results dataset contains fibroscan Results
Data Dictionary (PDF - 107.5 KB)	18. The Follow Up Alcohol dataset contains follow Up Alcohol Use Details
Data Dictionary (PDF - 136.9 KB)	19. The Follow Up Tobacco dataset contains tobacco Use Details
Data Dictionary (PDF - 105.6 KB)	20. The HCC Imaging dataset contains HCC Imaging
Data Dictionary (PDF - 123.8 KB)	21. The Hematology dataset contains hematology
Data Dictionary (PDF - 106.1 KB)	22. The Immunohistochemistry dataset contains immunohistochemistry
Data Dictionary (PDF - 118.6 KB)	23. The Informed Consent Form dataset contains informed Consent Details
Data Dictionary (PDF - 104.3 KB)	24. The Liver dataset contains participant Liver
Data Dictionary (PDF - 117.9 KB)	25. The Liver Biopsy dataset contains liver Biopsy Results
Data Dictionary (PDF - 97.4 KB)	26. The Liver Biopsy Date dataset contains liver Biopsy Date
Data Dictionary (PDF - 149.1 KB)	27. The Liver Function Tests and Coagulation dataset contains liver Function Tests and Coagulation Results
Data Dictionary (PDF - 115.1 KB)	28. The Medical/Surgical History dataset contains medical/Surgical History
Data Dictionary (PDF - 114.4 KB)	29. The Off Study dataset contains off Study
Data Dictionary (PDF - 118.1 KB)	30. The Physical Exam dataset contains physical Exam Details
Data Dictionary (PDF - 108.9 KB)	31. The Polyphenon E/EGCG dataset contains polyphenon E/EGCG Results
Data Dictionary (PDF - 107.6 KB)	32. The Polyphenon E/EGCG Pharmacokinetic Data dataset contains polyphenon E/EGCG Pharmacokinetic Data Information
Data Dictionary (PDF - 120.5 KB)	33. The Pre-Enrollment dataset contains pre-Enrollment Information
Data Dictionary (PDF - 100.0 KB)	34. The Pregnancy Test dataset contains pregnancy Test Results
Data Dictionary (PDF - 124.9 KB)	35. The Research Blood Specimen Collection dataset contains research Blood Specimen Collection Results
Data Dictionary (PDF - 103.1 KB)	36. The Research Urine Specimen Collection dataset contains research Urine Specimen Collection Results
Data Dictionary (PDF - 105.0 KB)	37. The Stability dataset contains participant Stability
Data Dictionary (PDF - 99.4 KB)	38. The Treatment Assignment Codes/Descriptions dataset contains treatment Assignment Details
Data Dictionary (PDF - 111.4 KB)	39. The Unblinding dataset contains study Unblinding Details
Data Dictionary (PDF - 111.4 KB)	40. The Vitals dataset contains participant Vitals

Trial Summary

This is a single arm, multicenter phase I study of subjects with cirrhotic livers expressing high levels (score 3 and above) of gamma-hydroxypropanodeoxyguanosine (γ-OHPdG) in their baseline biopsy, who will receive Polyphenon E® for 24 weeks. This study is a dose escalation design. 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.

Enrollment Statistics

Underwent Pre-enrollment: 46

• Eligible: 14
  • 400mg QD: 3
    • Study Complete: 3
  • 400mg BID: 3
    • Protocol Defined Follow-up Completed: 2
    • Study Completed: 1
  • 600mg BID: 3
    • Participant Refused Follow-Up: 1
    • Study Complete: 2
  • 800mg BID: 4
    • Adverse Event: 2
    • Study Complete: 2
  • Not given treatment: 1
    • Lost to follow-up: 1
• Other: 20
  • Lost to follow-up: 2
  • Other, specify: 2
  • Participant Withdrawal: 6
  • Physician Decision: 2
  • Ineligible: 20

Total Study Population Demographics (13 Eligible People):

Eligibility Criteria

Inclusion Criteria

• 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
  • Transient elastography (FibroScan) with a result > 12.5 kPa
  Etiology of cirrhosis will not be considered in determining inclusion in the study.
• Participant is able and willing to comply with study procedures, and signed and dated informed consent is obtained.
• 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.
• 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.
• ECOG performance status ≤ 1 (Karnofsky ≥ 70%; see Appendix A).
• 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	Within normal institutional limits OR GFR within normal institutional limits as adjusted for age and sex.
  	Measured or calculated creatinine clearance
  	(GFR can also be used in place of creatinine or CrCl)
  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

• 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.
• Participant is able to undergo radiographic evaluation with ultrasound, CT or MRI.
• 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 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).

Exclusion Criteria

• 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.
• 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.
• Inability to swallow capsules.
• Participant has a known diagnosis of mental incapacitation that may affect their ability to consent and be compliant with the protocol.
• 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
• Participant has an underlying predisposition to GI or rectal bleeding are considered ineligible for study participation.
• 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.
• Participant is receiving any other investigational agents.
• Participants have taken supplements or foods that are labelled as containing green tea for 8 weeks before start of treatment.
• 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.
• 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.

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Results/Findings:

Liver γ-OHPdG levels were measured using IHC and LC/MS-MS. All prescreened and enrolled participants had IHC scores ranging from 5 to 6 at baseline, which remained in this range following Polyphenon E treatment. LC/MS-MS measures were available for eight participants, seven of whom had paired baseline and end-of-treatment data. Baseline γ-OHPdG ranged from 3 to 30 γ-OHPdG adducts per 109 deoxynucleotides. Six participants showed a decline in the liver γ-OHPdG adduct number after 6 months of Polyphenon E treatment (P value ¼ 0.2). The average liver γ-OHPdG decreased from 13 (n ¼ 3) to 6.3 (n ¼ 2) γ-OHPdG per 109 deoxynucleotides in DC 1 and from 13 to 5 γ-OHPdG per 109 deoxynucleotides in DC 3 (n ¼ 2); liver γ-OHPdG decreased from 7 to 5.5 γ-OHPdG per 109 deoxynucleotides in DC 4 (n ¼ 1). In DC 2 (n ¼ 2), γ-OHPdG increased from 17 to 36 per 109 deoxynucleotides for one participant and decreased from 10.5 to 8 per 109 deoxynucleotides for another participant. Plasma and urine PK data for EGC were available for the five participants enrolled at GUH. Baseline plasma EGC levels differed between participants. The pattern of change in serum plasma levels of EGC was similar across DCs 1, 2, and 3. After oral administration, plasma EGC levels increased toward a peak over 1.25 to 3.5 hours, declining rapidly with levels decreasing to close to baseline 8 hours after dosing. However, one participant in DC 4 showed increasing plasma EGC levels during the 8- hour PK analysis, with the highest levels detected 8 hours after dosing. Baseline urine EGC levels were 0 in four of five participants. After oral administration, urine EGC levels increased toward a peak from 1.25 to 3.5 hours and then declined rapidly. The levels were still higher than baseline at 8 hours after dosing.