Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With Pulmonary Fibrosis.
Phase: EARLY_PHASE1
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Hal Chapman

Harold A. Chapman 
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NIH 
Clinical Research Protocol 
 
Fibroblast Specific Inhibition of LOXL2 and TGFbeta1 Signaling in Patients With 
Pulmonary Fibrosis. 
 
Protocol Number: 
17-23008 
Version Date: 
01/30/2018 
Investigational Product: 
Epigallocatechin-3-gallate (EGCG) 
IND Number: 
144120 
NCT Number: 
NCT03928847 
Development Phase: 
Pilot Study 
Sponsor: 
Harold A. Chapman 
513 Parnassus Ave, HSE 201 
San Francisco, CA 94143 
Funding Organization: 
NIH and private foundation 
Principal Investigators: 
Harold A. Chapman  
Telephone: 415-514-1210 
Fax: 415-502-4995 
 
E-mail: hal.chapman@ucsf.edu 
 
Harold R. Collard 
Telephone: 415-353-1043 
Email: hal.collard@ucsfledu 
Coordinating Center: 
UCSF 
 
Approval: 
 
 
 
 
03/20/20 
PI or Sponsor Signature (Name and Title)  
 
 
 
Date 
 
 

Harold A. Chapman 
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TABLE OF CONTENTS 
 
1 
BACKGROUND ............................................................................................................ 4 
1.1 
Overview of Non-Clinical Studies........................................................................... 8 
1.2 
Overview of Clinical Studies .................................................................................. 9 
2 
STUDY RATIONALE ................................................................................................... 9 
2.1 
Risk / Benefit Assessment ....................................................................................... 9 
3 
STUDY OBJECTIVES .................................................................................................. 10 
3.1 
Primary Objective ................................................................................................... 10 
3.2 
Secondary Objectives ............................................................................................. 10 
4 
STUDY DESIGN ............................................................................................................ 10 
4.1 
Study Overview ...................................................................................................... 10 
5 
CRITERIA FOR EVALUATION
 
ERROR! BOOKMARK NOT DEFINED. 
5.1 
Primary Efficacy Endpoint ...................................................................................... 10 
5.2 
Secondary Efficacy Endpoints ................................................................................ 10 
5.3 
Safety Evaluations .................................................................................................. 10 
5.4 
Other Evaluations (include only if applicable) ......................................................... 11 
6 
SUBJECT SELECTION ................................................................................................ 11 
6.1 
Study Population .................................................................................................... 11 
6.2 
Inclusion Criteria .................................................................................................... 11 
6.3 
Exclusion Criteria ................................................................................................... 11 
7 
CONCURRENT MEDICATIONS ................................................................................ 11 
7.1 
Allowed .................................................................................................................. 11 
7.2 
Prohibited
 
Error! Bookmark not defined. 
8 
STUDY TREATMENTS................................................................................................ 11 
8.1 
Method of Assigning Subjects to Treatment Groups ................................................ 11 
8.2 
Blinding ................................................................................................................. 12 
8.3 
Test and Control Formulation ................................................................................. 12 
8.4 
Supply of Study Medication at the Site ................................................................... 13 
8.5 
Study Medication Accountability ............................................................................ 13 
8.6 
Measures of Treatment Compliance ........................................................................ 13 
9 
STUDY PROCEDURES AND GUIDELINES .............................................................. 13 
9.1 
Clinical Assessments .............................................................................................. 13 
9.2 
Clinical Laboratory Measurements (include sections as appropriate) ....................... 14 
9.3 
Pharmacokinetic Measurements .............................................................................. 15 
9.4 
Research Laboratory Measurements (include sections as appropriate) ..................... 15 
10 EVALUATIONS BY VISIT........................................................................................... 15 
10.1 Visit 1 (Day/Week/Month #)................................................................................... 15 
10.2 Visit 2 (Day/Week/Month # include visit window).................................................. 15 
10.3 Visit 3 (Day/Week/Month # include visit window)
 
Error! Bookmark not defined. 
10.4 Visit 4 (Day/Week/Month # include visit window)
 
Error! Bookmark not defined. 
10.5 Visit 5 (Follow-up or Day/Week/Month # include visit window)
 
Error! Bookmark not defined. 
10.6 Early Withdrawal Visit
 
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11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION ...................... 16 
11.1 Adverse Events ....................................................................................................... 16 

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11.2 Serious Adverse Experiences (SAE) ....................................................................... 17 
11.3 Protocol Defined Important Medical Findings Requiring Real Time Reporting
 
Error! Bookmark not defined. 
11.4 Medical Monitoring ................................................................................................ 18 
11.5 Safety Management Plan ........................................................................................ 4 
12 DISCONTINUATION AND REPLACEMENT OF SUBJECTS ................................. 18 
12.1 Withdrawal of Subjects ........................................................................................... 18 
12.3 Replacement of Subjects ......................................................................................... 18 
13 PROTOCOL VIOLATIONS ......................................................................................... 19 
14 DATA SAFETY MONITORING (OPTIONAL SECTION – INCLUDE WHEN 
APPROPRIATE) .................................................................................................................. 19 
15 STATISTICAL METHODS AND CONSIDERATIONS ............................................. 20 
15.1 Data Sets Analyzed ................................................................................................. 20 
15.2 Demographic and Baseline Characteristics .............................................................. 20 
15.3 Analysis of Primary Endpoint ................................................................................. 20 
15.4 Analysis of Secondary Endpoints ............................................................................ 20 
15.5 Interim Analysis ..................................................................................................... 20 
15.6 Sample Size and Randomization ............................................................................. 20 
16 DATA COLLECTION, RETENTION AND MONITORING ..................................... 20 
16.1 Data Collection Instruments .................................................................................... 20 
16.2 Data Management Procedures ................................................................................. 21 
16.3 Data Quality Control and Reporting ........................................................................ 21 
16.4 Archival of Data ..................................................................................................... 21 
16.5 Availability and Retention of Investigational Records ............................................. 21 
16.6 Monitoring ............................................................................................................. 21 
16.7 Subject Confidentiality ........................................................................................... 21 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ................. 21 
17.1 Protocol Amendments............................................................................................. 22 
17.2 Institutional Review Boards and Independent Ethics Committees ............................ 22 
17.3 Informed Consent Form .......................................................................................... 23 
17.4 Publications ............................................................................................................ 23 
17.5 Investigator Responsibilities ................................................................................... 23 
 

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LIST OF ABBREVIATIONS 
Add all other abbreviations referenced in the protocol and delete any not referenced in 
the protocol. 
AE 
adverse event 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
FEF25%-75% 
forced expiratory flow 
FEV1 
forced expiratory volume over one second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IV 
intravenous 
PI 
Principal Investigator 
PK 
pharmacokinetic 
SAE 
serious adverse experience 

Harold A. Chapman 
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PROTOCOL SYNOPSIS 
TITLE 
Fibroblast specific inhibition of LOXL2 and TGFbeta1 signaling in 
patients with pulmonary fibrosis. 
SPONSOR 
Harold A. Chapman 
FUNDING 
ORGANIZATION 
NIH 
NUMBER OF SITES 
2 
RATIONALE 
The marked anti-fibrotic effects in mice of combined LOXL2 and 
TGFbeta receptor kinase inhibition specifically in fibroblasts with an 
agent such as EGCG that is low cost and already experienced by many 
people compels an attempt at translation to humans with progressive 
fibrotic disease. We have recently verified that EGCG (100 mg/kg) 
given orally to mice completely blocks fibrosis and lung LOXL2 
activity induced by bleomycin. In this aim we want to determine if we 
can block LOXL2, and TGFbeta1 signaling, in lungs of humans with 
fibrosis given oral EGCG. 
STUDY DESIGN 
This is an interventional study with two parts intended to test 
inhibition of a signaling pathway in vivo in ILD patients.  
Part 1: We will initially establish doses of oral EGCG that achieve 
plasma levels known to be safe in non-diseased human volunteers and 
likely to target fibroblast TGFbetaRI kinase by measuring EGCG 
levels at baseline, 0.5, 2, and 4 hours after administration. 
Part 2: Patients presenting to the UCSF ILD clinic and scheduled for 
lung biopsy because of uncertain imaging will be approached and 
consented patients will be randomized to EGCG-treated or untreated 
control groups. EGCG-treated group will take EGCG daily for a 
minimum of 2 week prior to surgery. Disposable fragments of 
biopsies will be either powdered for biochemical assays including 
pSmad3 and Snail 1or immunoprecipitated to correlate LOXL2 
protein and LOXL2 enzyme activity, or dissociated for single cell 
analysis. Urine collected before and after EGCG exposure will be 
used to determine whether terminal collagen cross-link breakdown 
products, termed pyridinoline/deoxypyridinoline (PYD/DPD), are a 
reliable biomarker of drug response. 
PRIMARY 
OBJECTIVE 
Execute a proof-of-principle pilot study testing the hypothesis that 
oral EGCG will block LOXL2/TGFbeta receptor kinase activities and 
pro-fibrotic signaling in fibrotic lungs. 
SECONDARY 
OBJECTIVES 
If it becomes apparent that the pilot study will validate our central 
hypothesis then initiating the administrative procedure and incurring 
the administrative cost of preparing an IND application for a phase II 
trial with the FDA could proceed in parallel. 
NUMBER OF 
SUBJECTS 
35 (Part 1: 15 non-diseased patients; Part 2: 20 interstitial lung disease 
patients) 
SUBJECT 
Inclusion Criteria: 

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SELECTION 
CRITERIA 
Part 1: Age 40-70 yrs old; no history of chronic lung disease 
Part 2: Diagnosis of interstitial lung disease (ILD); high-resolution CT 
imaging indicative of lung fibrosis of uncertain classification; referral 
for diagnostic surgical biopsy at UCSF.   
 
Exclusion Criteria: 
Both Part 1 and 2: any co-morbidity affecting hepatic function, such 
as HCV infection, cirrhosis, or using drugs with significant hepatic 
toxicities (total bilirubin >1.5× the upper limit of normal (ULN); 
aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
>3× ULN; alkaline phosphatase >2.5× ULN). 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
Epigallocatechin-3-gallate (EGCG) 
Part 1: 450 mg, 600 mg, or 750 mg once orally 
Part 2: 600 mg once daily orally for at least 2 weeks (dose to be 
determined in Part 1). 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
N/A 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Part 1: up to 8 hours 
Part 2: up to 4 weeks 
 
The total duration of the study is expected to be 2 years. 
CONCOMMITANT 
MEDICATIONS 
Allowed:  Standard therapy for ILD 
 
Prohibited:  Drugs with significant hepatic toxicities 
EFFICACY 
EVALUATIONS 
N/A 
PRIMARY ENDPOINT 
Part 1: EGCG blood levels 
Part 2: LOXL2 activity and TGFbeta1 signaling markers Snail1, 
pSmad3, and single cell analysis in lung biopsy tissue; urinary 
collagen crosslinks (PYD/DPD) 
SECONDARY 
ENDPOINTS 
Tolerability 
OTHER 
EVALUATIONS 
N/A 
SAFETY 
EVALUATIONS 
Standard adverse event reporting. 
PLANNED INTERIM 
ANALYSES  
N/A 

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STATISTICS 
Primary Analysis Plan 
Part 1: 
 
Part 2: LOXL2 protein levels and activity in lung tissue specimens 
will be compared to levels and activity in control lung tissue available 
from the UCSF ILD tissue bank using non-parametric analytical 
methods as appropriate. Post-treatment reductions in urinary 
PYD/DPD levels will be compared using parametric methods as 
appropriate. 
Rationale for Number 
of Subjects 
Part 1: Based on variability in prior dosing studies of EGCG in human 
volunteers, 5 volunteers per dose is at the minimum end to assess 
reliability of sufficient blood levels of EGCG, detected by LC/MS, in 
doses of 450 to 750 mg once orally. 
 
Part 2: For urine biomarker analyses, we are not sure of the needed 
population size but because each patient serves as their own control 
we believe 20 subjects should reveal whether there is any change in 
urinary PYD/DPD levels after at least 2 weeks of EGCG. 
 

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1 
BACKGROUND 
TGFβ1 is strongly implicated in the relentless accumulation of cross-linked, fibrillar 
collagens that characterize fibrotic diseases, especially IPF. Although attractive as a 
target, the critical roles of TGFβ1 in suppressing inflammation and epithelial proliferation 
give pause to the idea of global inhibition of TGFβ1 signaling. Indeed systemic inhibition 
of TGFβ1 can lead to the development of squamous skin tumors and autoreactive 
immunity. In addition, chronic administration of small molecule inhibitors of TGFβ1 
receptor kinases have led to enhanced skin and colonic inflammation and abnormalities in 
cardiac valves. In an attempt to develop a more circumscribed inhibitor of TGFβ1 
signaling centered on suppression of collagen accumulation we undertook a high-
throughput, image-based phenotypic screen (HTS) of small molecules that block TGFβ1-
induced epithelial-mesenchymal transition (EMT) of A549 cells in vitro, and suppress 
fibrosis in vivo, but not immediately inhibit TβRI kinase itself. We identified 
trihydroxyphenolic compounds such as epigallocatechin-3-gallate (EGCG) as potent 
(IC50 ~ 50 nM) blockers of TGFβ1 responses, Snail1 expression (a critical driver of 
mesenchymal expansion), and collagen deposition in vivo in the single dose bleomycin 
model of pulmonary fibrosis. Remarkably, the functional effects of trihydroxyphenolics 
required the presence of active lysyl oxidase-like 2 (LOXL2) thereby limiting effects to 
fibroblasts, the major LOXL2 producers (apart from tumor cells). Mechanistic studies 
revealed that the trihydroxyphenolics induce auto-oxidation of a LOXL2/3-specific lysine 
(K731) in a time-dependent reaction that irreversibly inhibits LOXL2 and converts the 
trihydroxyphenolic to a novel metabolite directly inhibiting TGFβ1 receptor kinase 
(TβRI). Combined inhibition of LOXL2 and TβRI activities by trihydroxyphenolics 
results in potent blockade of pathological collagen accumulation in vivo. Positive data 
generated from this human pilot study would compell a phase 2 clinical trial of a non-
patentable, inexpensive agent such as EGCG as a therapeutic for IPF. 
1.1 
Overview of Non-Clinical Studies 
The marked anti-fibrotic effects in mice of combined LOXL2 and TβR kinase inhibition 
specifically in fibroblasts with an agent such as EGCG that is low cost and already 
experienced by many people compels an attempt at translation to humans with progressive 
fibrotic disease. We have recently verified that EGCG (100 mg/kg) given orally to mice 
completely blocks lung LOXL2 induced by bleomycin. We want to determine if we can 
block LOXL2, and TGFβ1 signaling, in lungs of humans with fibrosis given oral EGCG. 
 
We have obtained 10 samples of explanted IPF lung tissue banked in the UCSF 
Biorepository and 10 samples from IPF patients with FVC < 50% obtained through the 
NIH-funded LTRC, along with tissue from 9 mostly normal lungs not used for 
transplantation. Extracts of these samples were processed and analyzed for LOXL2 
protein and enzyme activity. Overall, LOXL2 activity was significantly increased in the 
IPF population compared with normal, consistent with several prior reports that LOXL2 
mRNA and protein are increased in IPF. These findings imply that inhibition of LOXL2 in 
vivo ini ILD subjects is feasible and can be measured. 
 

Harold A. Chapman 
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Urine collected from two cohorts of IPF patients and controls at two sites: UT San 
Antonio Medical Center and UCSF were tested in the PYD/DPD EIA assay along with 
PYD/DPD standards and levels normalized to creatinine according to manufacturer’s 
instructions. There are significant (Mann-Whitney) increases in urinary PYD/DPD in both 
IPF patient cohorts. In mice, the increase in PYD/DPD after bleomycin is blocked by a 
trihydroxyphenolic (corilagin). 
1.2 
Overview of Clinical Studies 
N/A 
2 
STUDY RATIONALE 
The marked anti-fibrotic effects in mice of combined LOXL2 and TbetaR kinase 
inhibition specifically in fibroblasts with an agent such as EGCG that is low cost and 
already experienced by many people compels an attempt at translation to humans with 
progressive fibrotic disease. We have recently verified that EGCG (100 mg/kg) given 
orally to mice completely blocks fibrosis and lung LOXL2 activity induced by bleomycin. 
In this aim we want to determine if we can block LOXL2, and TGFbeta1 signaling, in 
lungs of humans with fibrosis given oral EGCG. 
2.1 
Risk / Benefit Assessment 
Potential Risks 
a. By participating in the study patients are at risk for loss of confidentiality. 
b. The risk of donation of 60 ml blood is minimal though transient pain, bleeding, and 
bruising at the site are possible. There is no risk of collection of voided urine samples. 
c. There is potential risk for adverse effects from oral ingestion of EGCG. EGCG is 
currently listed as the main active compound in over 90 trials registered on 
clinicaltrials.gov. None of these relate to fibrosis. In at least two completed trials EGCG 
800 mg per day was given between recruitment and surgery for both breast and prostate 
cancer and no serious adverse events were noted. In a meta analysis of green tea extract 
containing ~800-1200 mg EGCG per day in 34 trials over 10 yrs mild liver transaminitis 
was noted in 4 trials and overall the incidence of liver toxicity was estimated to be rare. 
No serious adverse events were noted. Several trials for “chemoprevention” employing 
800 EGCG per day and lasting 6 months to a year in patients at risk for cardiovascular 
disease or cancer noted no adverse effects. Overall, it appears mild liver transaminitis may 
occur but this is rare. 
 
There is no direct benefit at present for any of the subjects individually. There is the 
potential for improved therapy of pulmonary fibrosis progression if EGCG has the 
predicted biological impact and for a new noninvasive biomarker to track drug responses 
that may benefit future subjects with IPF. 
 
IPF is the leading cause of death from pulmonary fibrosis in the US and the cause of death 
is largely due to the untreatable and progressive nature of the illness. Experiments 
proposed in this application are intended to support the development of a new therapeutic 
approach to IPF based on inhibition of LOXL2 and TGFβ1 signaling specifically in 
fibroblasts. This project is particularly important because the knowledge gained could 

Harold A. Chapman 
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support a phase II clinical trial in IPF, raising the possibility of improved management of 
this relentless disease. 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to execute a proof-of-principle pilot study in ILD patients with 
fibrosis testing the hypothesis that oral EGCG will block LOXL2/TbetaR kinase activities 
and pro-fibrotic signaling in fibrotic lungs. 
3.2 
Secondary Objectives 
If it becomes apparent that the pilot study will validate our central hypothesis then 
initiating the administrative procedure and incurring the administrative cost of preparing 
an IND application for a phase II trial with the FDA could proceed in parallel. 
4 
STUDY DESIGN 
4.1 
Study Overview 
This is an interventional, multi-site study with two parts intended to test inhibition of a 
signaling pathway in vivo in ILD patients.  
 
Part 1: We will initially establish doses of oral EGCG that achieve plasma levels known to 
be safe in non-diseased human volunteers and likely to target fibroblast TGFbetaRI kinase 
by measuring EGCG levels as baseline, 0.5, 2, and 4 hours after administration. 
 
Part 2: Patients presenting to the UCSF ILD clinic and scheduled for lung biopsy because 
of uncertain imaging will be approached and consented patients will be randomized to 
EGCG-treated or untreated control groups. EGCG-treated group will take EGCG daily for 
a minimum of 2 week prior to surgery. Disposable fragments of biopsies will be either 
powdered for biochemical assays including pSmad3 and Snail 1 or immunoprecipitated to 
correlate LOXL2 protein and LOXL2 enzyme activity, or dissociated for single cell 
analysis. Urine collected before and after egcg exposure will be used to determine whether 
terminal collagen cross-link breakdown products, termed pyridinoline/deoxypyridinoline 
(PYD/DPD), are a reliable biomarker of drug response. 
4.2 
Primary Efficacy Endpoint 
Part 1: EGCG blood levels 
Part 2: LOXL2 activity and TGFbeta1 signaling markers Snail1, pSmad3, and single cell 
analysis in lung biopsy tissue; urinary collagen crosslinks (PYD/DPD). 
4.3 
Secondary Efficacy Endpoints 
N/A 
4.4 
Safety Evaluations 
Standard adverse event reporting. 

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4.5 
Other Evaluations (include only if applicable) 
 
5 
SUBJECT SELECTION 
5.1 
Study Population 
Two study populations will be recruited in this study: 
• Non-diseased volunteers. Healthy adults ages 40 to 70 will be recruited. 
• Subjects presenting to the UCSF ILD clinic and then scheduled for a diagnostic 
VATs biopsy. These subjects will have mild to moderate reductions in FVC and 
DLCO and high resolution chest CT imaging indicative of fibrosis but fibrosis that 
is judged unclassifiable, meaning possible IPF, hypersensitivity pneumonitis, 
CVD-associated ILD, or other non-IPF fibrotic disorders. Approximately 10-20 
diagnostic VATs biopsies are done each year at UCSF by one of our co-
investigators, Jasleen Kukreja. Subjects scheduled for biopsy will be asked their 
willingness to voluntarily participate in this study.   
5.2 
Inclusion Criteria 
Part 1: Age 40-70 yrs old; no history of chronic lung disease 
Part 2: Diagnosis of interstitial lung disease (ILD); high-resolution CT imaging indicative 
of lung fibrosis of uncertain classification; referral for diagnostic surgical biopsy at 
UCSF.   
 
5.3 
Exclusion Criteria 
Both Part 1 and 2: any co-morbidity affecting hepatic function, such as HCV 
infection, cirrhosis, or using drugs with significant hepatic toxicities (total bilirubin >1.5× 
the upper limit of normal (ULN); aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) >3× ULN; alkaline phosphatase >2.5× ULN). 
6 
CONCURRENT MEDICATIONS 
All subjects should be maintained on the same medications throughout the entire study 
period, as medically feasible, with no introduction of new chronic therapies. 
6.1 
Allowed Medications and Treatments 
Standard therapy for ILD is allowed except for treatments noted in the exclusion criteria 
described above and as noted in the prohibited medications section below.   
7 
STUDY TREATMENTS 
7.1 
Method of Assigning Subjects to Treatment Groups 
There is no randomization for this study. 

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7.2 
Blinding 
There is no blinding for this study. 
7.3 
Formulation of Test and Control Products 
 We plan to use >95% EGCG capsules purchased from Teavigo as a single lot. No control 
product. 
7.3.1 
Formulation of Test Product 
We plan to use >95% EGCG purchased from Teavigo. A composition of matter analysis 
by Covance of the lot used for encapsulation into 150 mg capsules is listed below. A 
single lot will be used for all dosing in this pilot study. 
 
Analysis of Teavigo EGCG capsule 150 mg by Convance 
 
Test Product 
Active Ingredient EGCG, mg/Serving Size 
160 
Other Ingredient, mg/ Serving Size 
52 
Total Sample Weight, mg/ Serving Size 
212 
 
7.3.2 
Formulation of Control Product 
N/A 
7.3.3 
Packaging and Labeling 
EGCG is supplied in cartons containing 70 capsules.  
Each carton of EGCG will be labeled with “Dietary Supplement”, the protocol number, a 
treatment number, the name of the sponsors, and directions for patient use and storage.   
7.4 
Supply of Study Drug at the Site 
The Sponsor (or designee) will purchase EGCG capsules from Teavigo. The initial 
shipment will be shipped after site activation (i.e., all required regulatory documentation 
has been received by the Sponsor and a contract has been executed). Subsequent 
shipments will be made after site request for resupply. 
7.4.1 
Dosage/Dosage Regimen 
Part 1: 450 mg, 600 mg, or 750 mg once orally 
Part 2: 600 mg once daily orally for at least 2 weeks (dose determined in Part 1).. 
7.4.2 
Dispensing 
Drs. Harold Chapman, Harold Collard, Jeffrey Golden have authority to dispense EGCG. 

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7.4.3 
Administration Instructions  
Part 1: 450 mg, 600 mg, or 750 mg once orally 
Part 2: 600 mg once daily orally for at least 2 weeks (dose determined in Part 1).. 
7.5 
Supply of Study Drug at the Site 
The Sponsor (or designee) will purchase EGCG capsules from Teavigo. The initial 
shipment will be shipped after site activation (i.e., all required regulatory documentation 
has been received by the Sponsor and a contract has been executed). Subsequent 
shipments will be made after site request for resupply. 
7.5.1 
Storage 
Dietary Supplement EGCG should be stored by the study site at controlled room temperature, 
15 to 30ºC (59 to 86ºF). If the temperature of storage in the clinic/pharmacy exceeds or falls 
below this range, this should be reported to the Sponsor or designee and captured as a 
deviation. Subjects will be instructed to store the medication in original packaging (foil pouch 
and protected from light) at room temperature according to the instructions outlined on the 
Drug Administration Instructions. 
7.6 
Study Drug Accountability 
An accurate and current accounting of the dispensing and return of study drug for each 
subject will be maintained on an ongoing basis by a member of the study site staff.  The 
number of study drug dispensed and returned by the subject will be recorded on the 
Investigational Drug Accountability Record.  The study monitor will verify these 
documents throughout the course of the study. 
7.7 
Measures of Treatment Compliance 
Subjects will be asked to keep a patient diary noting the day and date they take their 
EGCG supplement and any adverse events. They will be asked to bring their patient diary 
to 2 week visit along with all used and unused EGCG containers. 
8 
STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and 
dated by the subject or subject’s legal representative.  If appropriate, assent must also be 
obtained prior to conducting any study-related activities. 
8.1 
Clinical Assessments 
8.1.1 Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at 
Baseline/Screening and at Study Days or Visits 2, and at early termination when 

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applicable.  Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured. 
8.1.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded at Screening. 
8.1.3 Medical History  
Relevant medical history, including history of current disease, other pertinent respiratory 
history, and information regarding underlying diseases will be recorded at Screening. 
8.1.4 Vital Signs 
Body temperature, blood pressure, pulse, height and weight, and respirations will be 
performed after resting for 5 minutes on Study Day 1 and Day 14. 
8.1.5 Other Clinical Procedures 
N/A  
8.1.6 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation 
to study drug will be recorded on the case report form (CRF). 
The study will be stopped if it meets the criteria below: 
• ≥ 2 participants experiencing a severe adverse event (SAE) 
• Any arrhythmias, abnormal liver function, or abnormality in physical (including 
neurologic examination) that in the opinion of the Principal Investigator or 
Medical Monitor constitutes an SAE or an AE and that warrants discontinuation in 
≥ 2 participants in the active group 
 
8.2 
Clinical Laboratory Measurements (include sections as appropriate) 
8.2.1 
Pregnancy Test 
A urine pregnancy test will be performed for subjects of childbearing potential prior to 
administration of the EGCG treatment. All potential subjects of childbearing potential will 
be also counselled to use appropriate contraception. We will exclude pregnant subjects 
from participation in the trial.   
8.2.2 
Liver Function Test 
Liver function testing will be obtained on Visit1 and Visit2 for all participating subjects. 
Any subjects have liver function test criteria above the limit will be excluded: total 
bilirubin >1.5× the upper limit of normal (ULN); aspartate aminotransferase (AST) or 
alanine aminotransferase (ALT) >3× ULN; alkaline phosphatase >2.5× ULN. 

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8.3 
Pharmacokinetic Measurements 
Part 1; EGCG levels as baseline, 0.5, 2, and 4 hours after administration  
8.4 
Research Laboratory Measurements (include sections as appropriate) 
8.4.1 
Cell Count and Differential 
N/A 
8.4.2 
Sputum Cytokine Measurements 
N/A. 
8.4.3 
Pharmacokinetic Measurements 
Part 1: Blood for determination of plasma concentrations of EGCG will be collected from healthy 
volunteers 0, 0.5, 2, and 4 hours after the start of a single dosing.  EGCG concentrations will be 
determined at Quintara Discovery using LC/MS method. 
8.4.4 
Fibrotic Marker Measurements  
Part 2: Disposable fragments of biopsies will be collected from IPF patients treated (at least 2 
weeks) with EGCG and analyzed in Chapman Lab. Tissues will be powdered for biochemical 
assays including pSmad3 and Snail 1 (Western blot using specific antibodies) or 
immunoprecipitated to correlate LOXL2 protein and LOXL2 enzyme activity (LOX enzyme 
activity kit from Abcam). Or fresh tissues will be dissociated for single cell analysis. 
8.4.5 
Urinary Collagen Crosslinks PYD/DPD Measurements 
Urine specimens will be collected from ILD patients treated (at least 2 weeks) with EGCG and 
analyzed in Chapman Lab. PYD/DPD collagen crosslinks will be measured and normalized using 
PYD EIA kit and creatinine kit from Quidel.  
 
9 
EVALUATIONS BY VISIT 
 
Part 1 (single visit in non diseased participants):  
 
Review the inclusion and exclusion criteria with the subject and obtain written informed 
consent and HIPAA authorization and assent. 
Assign the subject a unique number. 
Record demographics data. 
Perform and record vital signs. 
Collect baseline blood. 
Administer EGCG dose. 
Collect blood at 0.5, 2, and 4 hours post-EGCG administration 
 
Part 2 (two visits in ILD participants) 

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Visit 1 (during pre-surgical clinic visit) 
 
Review the inclusion and exclusion criteria with the subject and obtain written informed 
consent and HIPAA authorization and assent. 
Assign the subject a unique number. 
Record demographics data and concomitant medications. 
Record vital signs. 
Collect baseline blood and urine. 
Deliver EGCG (study medication) and instruct on administration and dosing. 
Provide subject diary. 
 
Visit 2 (during surgical admission) 
Record any Adverse Experiences and/or Review subject diary for adverse experiences and 
dosing compliance. 
Record vital signs. 
Collect blood and urine pre-operatively. 
Collect Tissue Sample post -op 
 
10 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
10.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
patient administered  pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated 
with the administration of an investigational product, whether or not related to that 
investigational product.  An unexpected AE is one of a type not identified in nature, 
severity, or frequency in the current Investigator’s Brochure or of greater severity or 
frequency than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs 
during each subject visit and record the information in the site’s source documents.  
Adverse events will be recorded in the patient CRF.  Adverse events will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation to 
study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 should be used to assess and grade AE severity, including 
laboratory abnormalities judged to be clinically significant. The modified criteria can be 
found in the study manual.  If the experience is not covered in the modified criteria, the 
guidelines shown in Table 1 below should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 

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Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
AE Relationship to Study Drug 
The relationship of an AE to the study drug should be assessed using the following the 
guidelines in Table 2. 
Table 2.  AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of 
the drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; that is 
confirmed by stopping or reducing the dosage of the drug; and that is unlikely to be 
explained by the known characteristics of the subject’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; but 
that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
10.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the subject or require intervention to 
prevent one of the outcomes listed.  

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10.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) per 
UCSF CHR Guidelines.  The collection period for all SAEs will begin after informed 
consent is obtained and end after procedures for the final study visit have been completed. 
 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report 
SAEs to the IRB/IEC.   
10.3 Medical Monitoring 
Dr. Harold Collard, Jeffrey Golden or study personnel should be contacted directly at the 
below number to report medical concerns or questions regarding safety. 
Phone: 415-353-2593 
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
11.1 Early Discontinuation of Study Drug  
A subject may be discontinued from study treatment at any time if the subject, the 
investigator, or the Sponsor feels that it is not in the subject’s best interest to continue.  
The following is a list of possible reasons for study treatment discontinuation: 
Subject withdrawal of consent  
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment 
Protocol violation requiring discontinuation of study treatment 
Lost to follow-up 
 
If a subject is withdrawn from treatment due to an adverse event, the subject will be 
followed and treated by the Investigator until the abnormal parameter or symptom has 
resolved or stabilized.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or 
the Sponsor feels that it is not in the subject’s best interest to continue.   
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 

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the subject’s source documents.  Subjects who discontinue study treatment early (i.e., they 
withdraw prior to Visit 2) should have an early discontinuation visit.  
12.4 
Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced.   
Subjects who withdraw from the study will be replaced.   
 
12 PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to 
significant protocol requirements affecting the inclusion, exclusion, subject safety and 
primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
Failure to meet inclusion/exclusion criteria 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol 
Violation Form detailing the violation will be generated. This form will be signed by a 
Sponsor representative and the Investigator. A copy of the form will be filed in the site’s 
regulatory binder and in the Sponsor’s files. 
13 DATA SAFETY MONITORING (OPTIONAL SECTION – INCLUDE WHEN 
APPROPRIATE) 
The Independent Monitor for this study is Dr. John Fahy. Dr. Fahy is not associated with 
this research project and thus works independently of the PI. Dr. Fahy is not a part of the 
key personnel involved in this grant, and is qualified to review the patient safety data 
generated by this study because of his expertise in the area of pulmonary medicine and 
clinical trials. 
  
Study progress and safety will be reviewed monthly (and more frequently if needed). 
Progress reports, including patient recruitment, retention, and AEs/SAEs, will be provided 
to the monitor following each of the monthly reviews. An Annual Report will be compiled 
and will include a list and summary of AEs/SAEs. In addition, the Annual Report will 
address (1) whether AE/SAE rates are consistent with pre-study assumptions; (2) reason 
for dropouts from the study; (3) whether all participants met entry criteria; (4) whether 
continuation of the study is justified on the basis that additional data are needed to 
accomplish the stated aims of the study; and (5) conditions whereby the study might be 
terminated prematurely. The Annual Report will be sent to the monitor and will be 
forwarded to the IRB and NHLBI. The IRB will review progress of this study on an 
annual basis.  

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14 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will 
be written describing all analyses that will be performed.  The SAP will contain any 
modifications to the analysis plan described below.   
14.1 Data Sets Analyzed 
All eligible patients who receive at least one dose of the study dietary supplement (the 
Safety Population) will be included in the safety analysis. 
14.2 Demographic and Baseline Characteristics 
N/A   
14.3 Analysis of Primary Endpoint 
Post-treatment reductions in PYD/DPD levels, LOXL2 protein and activity will be 
assessed using non-parametric as appropriate. 
14.4 Analysis of Secondary Endpoints 
N/A 
14.5 Interim Analysis 
N/A 
14.6 
Sample Size and Randomization 
Based on variability in prior dosing studies of EGCG in human volunteers, 5 volunteers 
per dose is at the minimum end to assess reliability of sufficient blood levels of EGCG, 
detected by LC/MS, in doses of 450 to 750 mg once orally. 
 
For blood and urine biomarker analyses, we are not sure of the needed population size but 
because each patient serves as their own control we believe 20 subjects should reveal 
whether there is any change in urinary PYD/DPD levels after 2 weeks of EGCG. To 
prevent selection bias and produce comparable groups, patients will be randomized into 
EGCG-treated or untreated groups. 
 
15 DATA COLLECTION, RETENTION AND MONITORING 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents 
designed to record all observations and other pertinent data for each subject treated with 
the study drug.   
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the paper CRF when the information corresponding to that visit is 
available.  Subjects will not be identified by name in the study database or on any study 

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documents to be collected by the Sponsor (or designee), but will be identified by a site 
number, subject number and initials. 
If a correction is made on a CRF, the study staff member will line through the incorrect 
data, write in the correct data and initial and date the change. 
The Investigator is responsible for all information collected on subjects enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the Investigator.  A copy of the CRF will remain at the 
Investigator’s site at the completion of the study. 
15.2 Data Management Procedures 
All procedures for the handling and analysis of data will be conducted using good 
computing practices meeting FDA guidelines for the handling and analysis of data for 
clinical trials. 
15.3 Data Quality Control and Reporting 
After data have been entered into the study records, they will be double checked by study 
personnel for accuracy. All changes to the study database will be documented. 
15.4 Archival of Data 
The data is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained.   
15.5 Availability and Retention of Investigational Records 
A file for each subject must be maintained that includes the signed Informed Consent, 
HIPAA Authorization and Assent Form and copies of all source documentation related to 
that subject.  The Investigator must ensure the reliability and availability of source 
documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years.  There may be other 
circumstances for which the Sponsor is required to maintain study records and, therefore, 
the Sponsor should be contacted prior to removing study records for any reason. 
15.6 Monitoring 
N/A. 
15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and 
subject initials will identify all study subjects on CRFs and other documentation.   
16 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of 
Human Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and 
Obligations of Clinical Investigators (21 CFR 312). 

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To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other 
records will be identified by a coded number and initials only. The research results will be 
made available to the subject at request.  All study records will be kept in a locked file 
cabinet and code sheets linking a patient’s name to a patient identification number will be 
stored separately in another locked file cabinet.  Clinical information will not be released 
without written permission of the subject, except as necessary for monitoring by the FDA.  
The Investigator must also comply with all applicable privacy regulations (e.g., Health 
Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC). 
 
16.1 Protocol Amendments 
Protocol amendments cannot be implemented without prior written IRB/IEC approval 
except as necessary to eliminate immediate safety hazards to patients.  A protocol 
amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately, provided the IRBs are notified within five working days. 
16.2 Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each 
participating center prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB/IEC in accordance with the standard operating 
procedures and policies of the IRB/IEC, and the Investigator will keep the IRB/IEC 
informed as to the progress of the study.  The Investigator will obtain assurance of 
IRB/IEC compliance with regulations. 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, 
protocol amendments, Investigator’s Brochure, consent forms, information concerning 
patient recruitment, payment or compensation procedures, or other pertinent information) 
will be submitted to the IRB/IEC.  The IRB/IECs written unconditional approval of the 
study protocol and the informed consent form will be in the possession of the Investigator 
before the study is initiated.  The IRB/IECs unconditional approval statement will be 
transmitted by the Investigator to the Sponsor or designee prior to the shipment of study 
supplies to the site.  This approval must refer to the study by exact protocol title and 
number and should identify the documents reviewed and the date of review. 
Protocol and/or informed consent modifications or changes may not be initiated without 
prior written IRB/IEC approval except when necessary to eliminate immediate hazards to 
the patients or when the change(s) involves only logistical or administrative aspects of the 
study.  Such modifications will be submitted to the IRB/IEC and written verification that 
the modification was submitted and subsequently approved should be obtained.   
The IRB/IEC must be informed of revisions to other documents originally submitted for 
review; serious and/or unexpected adverse experiences occurring during the study in 
accordance with the standard operating procedures and policies of the IRB; new 
information that may affect adversely the safety of the patients of the conduct of the study; 
an annual update and/or request for re-approval; and when the study has been completed. 

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16.3 Informed Consent Form  
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH 
GCP, US Code of Federal Regulations for Protection of Human Subjects (21 CFR 
50.25[a,b], CFR 50.27, and CFR Part 56, Subpart A), the Health Insurance Portability and 
Accountability Act (HIPAA, if applicable), and local regulations. 
The Investigator will prepare the informed consent form, assent and HIPAA authorization 
and provide the documents to the Sponsor or designee for approval prior to submission to 
the IRB/IEC.  The consent form generated by the Investigator must be acceptable to the 
Sponsor and be approved by the IRB/IEC.  The written consent document will embody the 
elements of informed consent as described in the International Conference on 
Harmonisation and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for 
the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial.  Information should be given in both oral and written 
form and subjects (or their legal representatives) must be given ample opportunity to 
inquire about details of the study.  If appropriate and required by the local IRB/IEC, assent 
from the subject will also be obtained.  If a subject is unable to sign the informed consent 
form (ICF) and the HIPAA authorization, a legal representative may sign for the subject.   
A copy of the signed consent form (and assent) will be given to the subject or legal 
representative of the subject and the original will be maintained with the subject’s records. 
16.4 Publications  
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among the 
study Sponsor and participating institutions.  The publication or presentation of any study 
results shall comply with all applicable privacy laws, including, but not limited to, the 
Health Insurance Portability and Accountability Act of 1996.  
16.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after 
notifying the Sponsor (or designee), except when to protect the safety, rights or 
welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 

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6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to 
make those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research 
activity and all unanticipated problems involving risks to subjects or others (to 
include amendments and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators 
and all other pertinent requirements listed in § 21 CFR part 312.

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