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12/03/03

Green Tea Clinical Trial

1.0 PROTOCOL SYNOPSIS The objective of this clinical trial is to evaluate a novel botanical chemopreventive agent – Polyphenon E, on dysplastic bronchial epithelium and correlate its effect on histopathology and nuclear morphometry as well as several biomarkers. A total of 2574former heavy smokers ( 30 pack-years) without evidence of overt lung cancer will be recruited over a three-year period. Image analysis of sputum cells obtained by combined high frequency chest wall oscillation and 3% hypertonic saline induction will be used to identify individuals harboring bronchial intraepithelial neoplasia (IEN). Quantitative fluorescence bronchoscopic method will be used to localize the site and measure the size of potential IEN lesions for biopsy for pathological confirmation. One-hundred and twenty subjects with one or more sites of IEN lesions with a nuclear morphometry index of >1.36 as well as a surface diameter > 1.2 mm (larger than the size of a biopsy forceps) on fluorescence bronchoscopy will be invited to take part in the chemoprevention trial with Polyphenon E (a decaffeinated green tea preparation made by Tokyo Food Techo Company, Japan). The study will consist of two parts. Part I will be an open study in twenty subjects for two months to (a) validate the biomarkers and Polyphenon E blood level measurements; (b) determine if current and former smokers respond differently to green tea; and (c) determine if inhaled budesonide (Pulmicort) in a dose of 400 mcg twice a day can enhance the effect of green tea. The green tea powder will be encapsulated and administered as 4 capsules twice a day. Each green tea capsule is standardized to contain 200 mg of tea catechins. This is equivalent to 5 cups of Japanese – style green tea orally twice a day. In Part II of the study, one hundred and ten subjects will be randomized to receive Polyphenon E 4 capsules twice a day or its placebo for 6 months. Fluorescence bronchoscopy will be repeated at the end of the month 1 and 2 (Part I) or six months (Part II) intervention. All pre-treatment IEN lesions and any new lesions appearing at the end of one or six month of study medication will be precisely biopsied under fluorescence bronchoscopy guidance. In Part I of the study, changes in oncogene/tumor suppression gene expression as well as Phase I & II enzyme regulation as measured by Affymetrix chip analysis of RNA from bronchial brush cells will be used to assess how Polyphenon with or without Pulmicort modulates different pathways of the carcinogenesis process. In Part II of the study, changes in the combined histopathology and nuclear morphometry grades on a lesion-by-lesion and subject-by-subject basis will be used as the primary endpoint for the intervention. In the Phase II randomized placebo control study, subjects with reversal of the IEN lesions will be off treatment. Those with stable or progressive disease after 6 months of treatment will be offered the option to enter into an open label study of Polyphenon E for 6 months if they were randomized to the placebo arm. All subjects in the Polyphenon E/Placebo arms will have a third bronchoscopy at month 12. The usefulness of other biomarkers (nuclear morphometry of sputum and BAL cells, methylation markers in sputa, and BAL cells will be evaluated. To understand how green tea works, markers of cell cycle regulation, angiogenesis and apoptosis such as Ki-67, Bcl-2, TUNEL, p53, p16, and VEGF will be assayed by immunohistochemistry in bronchial biopsies before and after one or six months of treatment. Changes in oncogene/tumor suppression gene expression as well as Phase I & II enzyme regulation will be measured by Affymetrix chip analysis of RNA from bronchial brush cells to assess how Polyphenon modulates different pathways of the carcinogenesis process. To explore the use of non-biopsy imaging methods to assess the efficacy of the chemopreventive agent, a library of in-vivo confocal micro-endoscopy images and volumetric measurements of small lung nodules on spiral CT will be established to correlate with the clinical outcome and other biomarker information before and after treatment. The results will provide new information on the efficacy and safety of a common beverage for chemoprevention of lung cancer. It will also provide new information on the use of novel biomarkers as surrogate endpoints for assessing the effect of chemoprevention. Study Agent: Polyphenon E (Decaffeinated green tea preparation) or its placebo. It will be supplied by Tokyo Food Techno Co., Ltd. (Japan).

Study Duration (Months): 52 months (estimated clinical = 48 months; estimated biomarker studies and data analysis, an additional 4 months) Total Number of Participants: Initial Screening – 2574
Chemoprevention Treatment – 140


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