Clinical trial NCT02272634
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Sponsor: Yungjin Pharm. Co., Ltd.
Start date: 2015-06-04; Completion date: 2017-11-08
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, double dummy, 3-treatment, parallel study, with low and high YPL 001 doses (low dose and high dose twice daily \[BID\]) and a placebo control in moderate to severe Chronic Obstructive Pulmonary Disease (COPD) patients.

Detailed description:
Treatments are described as follows:

Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 80 mg matching placebo tablet) will be administered approximately every 12 hours under fasting conditions for 55 consecutive days. Only the morning dose will be administered on Day 56.

Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be administered approximately every 12 hours under fasting conditions for 55 consecutive days. Only the morning dose will be administered on Day 56.

Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo tablets) will be administered approximately every 12 hours under fasting conditions for 55 consecutive days. Only the morning dose will be administered on Day 56. In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be administered QD every morning prior to study drugs administration. Albuterol will be administered on an as needed basis. Each dose of Treatments A, B and C will be administered orally with approximately 240 mL of water.

Arms: arm 1: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 80 mg matching placebo tablet) are administered approximately every 12 hours under fasting conditions for 55 consecutive days. arm 2: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) are administered approximately every 12 hours under fasting conditions for 55 consecutive days. arm 3: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo tablets) will be administered approximately every 12 hours under fasting conditions for 55 consecutive days.
Interventions: intervention 1: YPL-001 80 mg intervention 2: YPL-001 160 mg intervention 3: Placebo
Intervention descriptions: intervention 1: twice daily \[BID\] intervention 2: twice daily \[BID\] intervention 3: twice daily \[BID\]

Protocol documents:
Prot_000.pdf: 
 
16. 
Appendices 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _7_08Jun2016 
 
1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
08-Jun-2016 
by Caroline Engel 
Final Protocol, Amendment 7 
This protocol amendment is generated to allow patients on low dose of 
aspirin for prophylactic treatment, since acetylsalicylic acid is a reversible 
non-competive inhibitor. However a washout of 7 days prior the main PK 
days and the bronchoscopy procedures will be required. Therefore the 
following sections were updated accordingly with the new text added in 
bold: 
1. Section 13.3.3 Exclusion Criteria – Exclusion criterion #19 was 
updated as follow: 
Use of any drugs or substances known to be significant inhibitors 
(strong or moderate) of UDP-glucuronosyltransferase (UGT) (such as 
17-beta-estradiol glucuronide, flavonoids [citrus fruit], silybin [herb 
supplement milk thistle]) and/or sulfotransferases (SULT) (refer to 
Appendix 1), within 12 hours prior to Day 1 of the Run-in Period. The 
use of low dose of acetylsalicylic acid (e.g., aspirin) will be 
allowed during the study, but prohibited 7 days prior to the 
bronchoscopy performed prior to dosing of Day 1 until the last 
PK blood sample collected on Day 1, and 7 days prior to Day 54 
(± 1 
day) 
dosing 
until 
completion 
of 
the 
bronchoscopy 
procedures on Day 56. Additional sources may be consulted by the 
PI or medical monitor to confirm lack of PK/PD interaction with study 
drug. 
2. Section 13.3.5.1.1 Prohibited Therapy – bullet #8 was updated as 
follow: 
Drugs or substances known to be significant inhibitors (strong or 
moderate) of UGT and/or SULT, within 12 hours prior to Day 1 of the 
Run-in Period and through collection of the final PK sample. The use 
of low dose of acetylsalicylic acid (e.g., aspirin) will be allowed 
during the study, but prohibited 7 days prior to the bronchoscopy 
performed prior to dosing of Day 1 until the last PK blood sample 
collected on Day 1, and 7 days prior to Day 54 (± 1 day) dosing 
until completion of the bronchoscopy procedures on Day 56. 
3. Minor editorial corrections were made where applicable. 
28-Apr-2016 
by Caroline Engel 
 
 
 
 
 
Final Protocol, Amendment 6 
This protocol amendment is generated to change the Sponsor 
representative, CEO and President, to Su-Jun Park. Therefore Section 2 
Sponsor – Signatories was updated accordingly. 
And to add the following Investigator and clinical site: 
Faisal Fakih, MD 
Florida Pulmonary Research Institute, LLC 
1788 W. Fairbanks Avenue,Suite B 
Winter Park, Florida, 32789 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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DATE/NAME 
DESCRIPTION 
28-Apr-2016 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
United States 
Tel.:  +1 407 740-8078 
Therefore, Section 3 Investigators Signatures was updated accordingly. 
Section 4 Additional Key Contacts for the Study was also updated to add 
the corresponding certified clinical laboratory.  
In addition, the following changes were made to facilitate the clinical 
conduct at each investigative site: 
1. To allow patients to recover from the bronchoscopy procedure before 
going through a 12 hours’ period of PK blood draws and collect quality 
samples, a recovery period was added between these procedures; 
Procedures scheduled on Day -1 will now be performed within 3 days 
prior to Day 1 (now defined as Check-in procedures). In addition, the 
PK sampling previously scheduled on Day 56 will be conducted on 
Day 54 (± 1 day) before the bronchoscopy now scheduled on Day 56, 
instead of Day 55. Therefore, the following sections were updated 
acccordingly: 
• 
Section 5 Synopsis - Summary of Study Design, Dosage, Dosage 
Form, Route, and Dose Regimen, and Exploratory Outcome 
Measures. 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.2.4 Treatment Period (Days 1 to 56)  
• 
Section 13.2.4.1 Meal Schedule 
• 
Section 13.3.5.2 Prohibitions 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 14.3.1 Pulmonary Function (Spirometry) 
• 
Section 14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea 
Index (BDI/TDI) 
• 
Section 15.1.2 Patients to Analyze 
• 
Section 15.1.6.1.1 Plasma 
• 
Section 15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
2. To provide flexibility in the schedule of events, electrocardiograms, 
vital sign and pulse oximetry will be measured within 4 hours of 
bronchoscopy procedures, instead of 2 hours. Therefore, Section 6 
Study Events Flow Chart, Section 14.1.3 Vital Signs, Section 14.1.4 
Pulse Oximetry, and Section 14.1.5 Electrocardiogram Monitoring 
were updated accordingly. 
3. Exclusion criterion #9 was updated to clarify that patients withclinically 
significant cardiac arrhythmia; prostatic hyperplasia; bladder-neck 
obstruction; urinary retention; and narrow-angle glaucoma that, in the 
opinion of the PI, would contraindicate the administration of tiotropium, 
will be excluded. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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DATE/NAME 
DESCRIPTION 
28-Apr-2016 
by Caroline Engel 
4. To allow flexibility, subjects with a positive alcohol screen or subjects 
reporting consumption of alcohol within 48 hours prior to testing, an 
alcohol test may be rescheduled or repeated, at the discretion of the PI 
if there is sufficient time remaining to perform the visit procedures 
within the time window specified for this visit (e.g., ± 2 days of Day 15 
visit). Therefore exclusion criterion # 13 was split into two exclusion 
criteria; criteria #13 (alcohol screen) and #14 (drug screen), which 
were updated accordingly. 
5. Exclusion criterion #15 was updated to exclude subject with a positive 
results for hepatitis C antibodies only if they present with clinically 
significant liver impairment and/or a viral ribonucleic acid (RNA) titer of 
> 6.9 ± 0.8log molecules/mL. Section 14.1.6.3 Serology was updated 
accordingly. Section 17 Reference was updated to include reference 
#3 as a justification to the titer value selected. 
6. The Child-Pugh scale should only be used to classify patients with a 
diagnosis of hepatic impairment. Thus, exclusion criteria #11 was 
clarified to exclude patients with diagnosed hepatic impairment and a 
Child-Pugh class A score or higher. Patients without hepatic 
impairment with normal laboratory results for bilirubin, albumin, 
prothrombin time/international normalized ratio (which automatically 
would fall in a Class A Score of 5) will not be assigned a Child-Pugh 
score and will thus be allowed to enrol. In addition, to assess the 
extent of hepatic impairment according to exclusion criterion # 11, a 
blood sample for prothrombin time/international normalized ratio will be 
collected at screening. Thus, a new section (14.1.6.9 Additional Tests) 
was added, and Section 6 Study Events Flow Chart, Section 8 
Abbreviations, and Table 5: Blood Volume during Study were updated 
accordingly. 
7. Prescribed vitamin supplement will be allowed, therefore the following 
sections were updated accordingly: 
• 
Section 13.3.5.1.1 Prohibited Therapy 
• 
Section 13.3.5.1.2 Permitted Therapy 
8. Minor editorial and typographical corrections were made where 
applicable. 
05-Nov-2015 
by Caroline Engel 
 
 
 
 
 
 
 
Final Protocol, Amendment 5 
This protocol amendment is generated to add the following Investigator 
and clinical site: 
Samir Arora, MD 
Aventiv Research Inc. 
99 North Brice Road, Suite 260 
Columbus, Ohio 43213 
United States 
Tel: + 1 614 501-6164 
Therefore, Section 3 Investigators Signature was updated accordingly. 
Section 4 Additional Key Contacts for the Study was also updated to add 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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DATE/NAME 
DESCRIPTION 
05-Nov-2015 
by Caroline Engel 
the correcponding certified clinical laboratory.  
All 3 sites clinical sites will be using the Western Institutional Review 
Board. Section 4 Additional Key Contacts for the Study was updated 
accordingly. 
Minor editorial corrections were made where applicable. 
16-Sep-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 4 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below: 
1. Brigham and Women's Hospital Investigator signature and contact 
information was removed throughout the protocol since the center will 
not be participating during this study. The following sections were 
updated accordingly: 
• Section 3 Investigators Signatures 
• Section 4 Additional Key Contacts for the Study 
2. The age limits were changed from 40 - 80 years of age, inclusively, to 
30 - 85 years of age, inclusively. The following sections were updated 
accordingly: 
• Section 5 Synopsis - Study Population 
• Section 13.3.2 Inclusion Criteria – Inclusion criterion #1 
3. To provide scheduling flexibility to the patients, a ±2-day window was 
added to the return visits on Days 15, 29, and 43. The following 
sections were updated accordingly: 
• Section 5 Synopsis - Summary of Study Design and Exploratory 
Outcome Measures 
• Section 6 Study Events Flow Chart 
• Section 13.1 Overall Study Design and Plan 
• Section 13.4.1.2 Drug Administration During Treatment Period 
• Section 15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
4. Breathalyzer was added as an alternative method to the urine dipstick 
for the alcohol screen. The following sections were updated 
accordingly: 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.3.3 Exclusion Criteria – Exclusion criterion #13 
• 
Section 14.1.6.7 Urine/Breathalyzer Alcohol Screen was added 
• 
Section 14.1.6.8 (previously 14.1.6.7) was renamed Urine Drug 
Screen (previously Urine Drug/Alcohol Screen). 
5. Only patients suffering from severe sleep apnea, as assessed by the 
Berlin Questionnaire, will be excluded from the study; The following 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
16-Sep-2015 
by Caroline Engel 
sections were updated accordingly:  
• 
Section 6 Study Events Flow Chart 
• 
Section 13.3.3 Exclusion Criteria - exclusion criterion #8. 
• 
Section 14.1.8 Berlin Questionnaire was added. 
6. The body mass index upper limit was increased from 32.0 kg/m2 to 
40.0 kg/m2 inclusively. Therefore inclusion criterion #5 of 
Section 13.3.2 Inclusion Criteria was revised accordingly. 
7. Drug screen false positive will be allowed if they are due to the use of 
prescription medication following approval from the PI and the medical 
monitor, the exclusion criterion #13 of Section 13.3.3 Exclusion Criteria 
was revised accordingly. 
8. Smoking restriction prior to the bronchoscopy procedures was 
removed. Therefore, Section 14.3.2 Bronchoscopy and 
Bronchoalveolar Lavage (BAL) Biomarkers was updated accordingly. 
9. Only strong and moderate inhibitors of UDP-glucuronosyltransferase 
and/or sulfotransferases are prohibited, therefore to prevent confusion 
with the list of substrats that was provided in Appendix 1, Appendix 1 
was remove and the only 3 inhibitors listed in that table was 
enumarated in exclusion criterion #18. The list of substrate in appendix 
2 (now rename Appendix 1) was also remove. This change will prevent 
possible confusion with the lists provided in the appendices. Exclusion 
criterion #18 of Section 13.3.3 Exclusion Criteria was revised 
accordingly. 
10. To be consistent with Section 6 Study Events Flow Chart, pulse 
oximetry was added to the order of procecedures listed in Section 14.1 
Safety Assessments. 
11. Typographic and editorial corrections were made where applicable. 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 3 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. The changes to the protocol are presented 
with new text in bold font and deleted text in strikethrough font. 
Serious Adverse Event Contact Information 
Drug Safety Solution’s Medical Monitor will be contacted in case of serious 
adverse events. Hence the information under Sponsor Contact for Serious 
Adverse Events (Medical Monitor) in Section 4 Additional Key Contacts for 
the Study was corrected as follows: 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, Seoul, 134-721, Republic of 
Korea   
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
Dr. Kathy Smith 
Drug Safety Solution  
Tel.: +1 919 264-5626 
E-mail:  ksmith@drugsafety.biz 
Section 14.1.8.4 Serious Adverse Events and Section 13.4.3.2 Procedures 
for Breaking the Blind Prior to Study Completion was also corrected 
accordingly. 
Certified Clinical Laboratory: 
Brigham and Women's Hospital and UAB Lung Health Center clinical 
laboratories contact information were added to Section 4 Additional Key 
Contacts for the Study. 
Clinical Indication: 
As indicated in the objectives of the study, the study will examine the 
pharmacodynamic (PD) effect of YPL-001 in patients with chronic 
obstructive pulmonary disease (COPD) only. Therefore, to prevent 
potential confusion and to capture the intended indication of the study 
specifically “asthma” was removed from the Clinical Indication in Section 5 
synopsis and Section 10.1 Purpose of the Study. 
Study Population: 
As indicated throughout the protocol, patients will be will be adult males 
and females with moderate to severe COPD (conform to the severity 
classification for Global Initiative for Chronic Obstructive Lung Disease 
[GOLD] Stage 2-3). Hence to be consistent with the GOLD Stage 
standards, the first sentence under Study Population from Section 5, 
Synopsis was corrected as follow: 
“Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant 
bronchitic component and a history of frequent (>2/year) COPD 
exacerbations, between 40 and 80 years of age (inclusive).” 
Randomization and Drug Dispensing 
Instruction for randomization and drug dispensing are provided in a 
separate document. To be consistent with this document, which states that 
two sets of randomization code envelopes will be provided to site 
pharmacist/study coordinators and patients will received appropriately 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
labeled kits and/or any unused wallets from previously provided kits 
(when applicable) for YPL-001 home dosing in addition to the containers 
for tiotropium/albuterol home dosing, the following section were modified 
accordingly: 
• 
Section 5 Synopsis under Summary of Study Design and Study 
Products 
• 
Section 6 Study Event Flow Chart, Day 1 Study Drug Administration at 
CRU - Footnotes “k” and “p” 
• 
Section 6 Study Event Flow Chart, Days 2 to 55 Study Drug 
Administration at Home – Footnotes “j” and “o” 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 13.4.3.1 Maintenance of Randomization 
• 
Section 13.4.3.2 Procedures for Breaking the Blind Prior to Study 
Completion 
In addition, and “X” was also added in the “Randomization” row under Day 
1 predose in Section 6 Study Events Flow Chart. 
Fasting Conditions 
As indicated throughout the protocol, subjects will be required to fast for at 
least 8 hours before and 4 hours after YPL-001/placebo morning 
administration on Days 1 and 56. For clarity, footnote “q” was added to 
Day 1 Study Drug Administration at CRU and footnote “k” was added to 
Day 56 Study Drug Administration at CRU in Section 6 Study Events Flow 
Chart. 
Analytes to be Measured 
As indicated throughout the protocol, blood samples will be collected for 
the analyses of verproside and picroside II in plasma. Hence, the row 
identified as “Blood for Verproside Phamacokinetics” on Day 56 of Section 
6 Study Events Flow Chart, was corrected to read: “Blood for Verproside & 
Picroside II PK”. 
End-of-Treatment – Early Termination Procedures 
All procedures listed under End-of-Treatment/Early Termination column in 
Section 6 Study Events Flow Chart are also scheduled to be performed on 
Day 55 before the bronchoscopy procedures. Therefore, as it is not 
required to repeat these procedures for two consecutive days, 
End-of-Treatment procedures were removed on Day 56, however early 
termination (ET) procedures were listed under the new ET column. Hence, 
the following sections were corrected accordingly.  
• 
Section 6 Study Events Flow Chart  
• 
Section 13.2.4.2 End-of-Treatment or Early Termination (Day 56), 
(renamed Section 13.2.4.2 Early Termination). 
• 
Section 13.3.2 Inclusion Criteria – Criterion #16 
• 
Section 13.3.4 Removal of Patients from the Study 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 13.3.5.1.1 Prohibited Therapy 
• 
Section 13.3.5.1.2 Permitted Therapy 
• 
Section 14.1.8.2 Monitoring 
• 
Section 14.5 Blood Volume for Study Assessments (Table 5:  Blood 
Volume during Study) 
In addition, the following sentence was added to Section 13.2.4.2 End-of-
Treatment or Early Termination (Day 56), (renamed Section 13.2.4.2 Early 
Termination):   
“Patients who want to terminate from the study and are not currently on-
site will be contacted and asked to return to the CRU to perform the early 
termination procedures” 
Investigator’s Brochure Version 
In Section 9.1 YPL-001, the Investigator’s Brochure version was updated 
to reflect the reference section and the most recent version of the 
Investigator’s Brochure. 
Method of Blood Collection 
Throughout the protocol, the option of using an angiocatheter was added. 
Hence, the following sections were corrected accordingly: 
• 
Section 11 Risk/Benefit 
• 
Section 14.3.3 Blood Biomarkers 
• 
Section 14.4.1 Blood Sampling and Processing 
• 
Section 14.5 Blood Volume for Study Assessments 
Recording of Meal 
To be consistent with clinical sites standard procedures, the last sentence 
of Section 13.2.4.1 Meal Schedule was corrected as follow: 
“Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs.’ 
Coffee, Tea and Alcohol Prohibition 
As indicated in Section 13.3.5.2 Prohibitions, coffee tea, and red wine will 
be restricted for 7 days prior to Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample. Beer will be restricted 
for 14 days prior to Day 1 of the Treatment Period through collection of 
Day 56 last PK sample. Any other product containing xanthines or caffeine 
will be restricted 24 hours prior to each CRU visit and prior to dosing on 
Days 1 and 56 of the Treatment Period through collection of Days 1 and 
56 last PK sample. Any other alcohol product will be restricted 48 hours 
prior to each CRU visit, 48 hours prior to dosing on Days 1 and 56 last PK 
sample. Hence, the xanthines/caffeine prohibition  and the alcohol 
prohibition were corrected as follows for clarification: 
“Xanthines/caffeine (other than coffee and tea):  24 hours prior to each 
CRU visit and prior to dosing on Days 1 and 56 of the Treatment Period 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
through collection of Days 1 and 56 last PK sample.” 
“Alcohol (other than red wine and beer):  48 hours prior to each CRU 
visit, 48 hours prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
e-Diary 
Home dosing will be recorded using a yes/no answer in the e-diary. 
Therefore the last sentence of the second to last paragraph of 
Section 13.4.1.2 Drug Administration During Treatment Period was 
corrected as follows: 
“Patients will be given instructions on recording of dosing times how to 
record their drug administration in their e-diary on home-dosing days.’ 
In addition, estimation of sputum quantity was added to the list of major 
symptoms of COPD exacerbation recorded daily by the patients on their e-
diary, “color” and “consistency” was moved as example of sputum quality, 
and a statement indicating that the e-diary device will be return in case of 
early termination was also added. Hence, the following sections were 
corrected accordingly: 
• 
Section 5 Synopsis under Secondary Outcome Measures 
• 
Section 5 Synopsis under Summary of Study Design 
• 
Section 6 Study Events Flow Chart – Day 1, Footnote “j” 
• 
Section 6 Study Events Flow Chart – Days 2-55, Footnote “i” 
• 
Section 6 Study Events Flow Chart – Day 56, Footnotes “g” and “h” 
• 
Section 12.2 Study Endpoints 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
• 
Section 13.2.4 Treatment Period (Days 1 to 56) 
• 
Section 14.2.1 Electronic Diary 
• 
Section 14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease 
Exacerbation 
Treatment Compliance 
Drug administration at home will be monitored by HGE Technologies Inc. 
via the e-diary. Therefore, the last sentence of Section 13.4.4. Treatment 
Compliance was corrected as follow: 
“Self-administration by patients at home will be monitored by the CRU via 
the e-diary and attempted phone calls will be performed to remind patients 
to take their medication, if they did not record their self-administration on 
the e-diary.” 
Oxygen Saturation 
For consistency throughout the protocol, “oxygen levels, saturation (%)” 
was replaced with “oxygen saturation (%).” 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 11 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Treatment 
As indicated in Section 13.3.2 Inclusion Criteria and Section 13.3.5.1.2 
Permitted Therapy, tiotropium will be withheld 24 hours prior to pulmonary 
function (spirometry) measurements. Hence, the 2nd paragraph of Section 
14.3.1 Pulmonary Function (Spirometry), was corrected to read: 
“Short acting β2-agonist and anticholinergic bronchodilators (e.g., 
albuterol, ipratropium bromide) and long 
acting β2-agonist and 
anticholinergic bronchodilators (e.g., salmeterol, tiotropium) agents will be 
withheld approximately 4 and 12 24 hours, respectively, before each 
pre-bronchodilator spirometry.” 
Spirometer Across Clinical Site 
The 3rd paragraph of Section 14.3.1 Pulmonary Function (Spirometry) was 
corrected as follow: 
“Every effort will be made to perform all assessments for a given patient 
on the same instrument throughout the study and all sites should be using 
the same brand and model of spirometer for this study.” 
Bronchoalveolar Lavage (BAL) Collection 
It is planned that a maximum of 180 mL BAL will be performed during each 
planned bronchoscopy procedures. Therefore, to prevent confusion, the 
second sentence of Section 14.3.2.3, Bronchoalveolar Lavage (BAL) was 
corrected to read: 
“A total of 180 mL BAL, using 6 x 30 mL aliquots of normal saline 
warmed to room temperature, will be performed in using each 
subsegment of the right middle or lower lobe, as deemed appropriate by 
the Investigator, using 6 x 30 mL aliquots of normal saline warmed to room 
temperature.” 
Blood 
Volume 
for 
Clinical 
Safety 
Laboratory 
Tests, 
Pharmacodynamic (PD) Markers and Pharmacokinetic (PK) Samples: 
Blood collection volume for PD markers, as indicated in Section 14.3.3 
Blood Biomarkers and Section 14.5 Blood Volume for Study Assessments, 
only accounts for 1 tube. However, 3 tubes will be required to assess CRP 
(4 mL tube), fibrinogen (3.5 mL tube) and the rest of the PD biomarkers (6 
mL tube). The blood volume per time point will be approximately 13.5 mL 
instead of 4.5 mL. 
As indicated above, End-of-Treatment listed on Day 56 were removed as 
the same tests are scheduled on Day 55 before the bronchoscopy 
procedures. Hence one sample was removed for a total of 3 on-study 
hematology and serum chemistry tests to be performed throughout the 
study. 
In addition, 4 mL of blood will be sufficient for the determination of 
verproside and picroside II concentration in plasma at each time point. 
Therefore the total blood volume was corrected to 310.5 mL for males and 
317.5 mL for females. Section 14.3.3 Blood Biomarkers, Section 14.4.1 
Blood Sampling and Processing, and Section 14.5 Blood Volume for Study 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
12


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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 12 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
Assessments were corrected accordingly. 
Minor typographic and editorial corrections were made where applicable. 
16-Feb-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 2 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. 
Number of Subjects: 
The sample size was revised to 60 subjects as it is sufficient to meet the 
objectives of the study. In case of dropouts, discontinued patients may be 
replaced at the discretion of the Sponsor as indicated throughout the 
protocol. Therefore the following sections were corrected accordingly to 
indicate that at least 60 subjects are planned to be enrolled and 
randomized with 20 patients to receive one of the 3 treatments: 
• 
Section 5 Synopsis (the 1st sentence of the 2nd paragraph under 
Summary of Study Design and the 1st and 2nd sentences under 
Number of Patients). 
• 
The 1st sentence of the 2nd paragraph of Section 13.1 Overall Study 
Design and Plan. 
• 
The 1st and 3rd sentences of Section 13.3.1 Number of Patients. 
• 
The last sentence of Section 15.1.1 Sample Size Calculation. 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) and 
COPD Assessment Test (CAT): 
BDI/TDI and CAT questionnaires will not be used as a diagnostic tool to 
assess the patient’s potential to meet all inclusion criteria and none of the 
exclusion criteria. Therefore these questionnaires are not required at 
screening. In addition, it is not required to perform them for 2 consecutive 
days to meet the study objectives and therefore, Day 55 assessments 
were removed.  
Section 6 Study Events Flow Chart was corrected accordingly. 
The first sentence in Section 14.3.4.1 Baseline Dyspnea Index/Transition 
Dyspnea Index (BDI/TDI) was also corrected to be consistent with Section 
6. 
Early Termination Procedures: 
Weight, and oxygen levels, saturation (%), and heart rate assessed using 
a pulse oximeter were added to the procedures performed at the end of 
the Treatment Period on Day 56 or prior to early termination from the study 
to monitor subject’s safety appropriately. 
A 
pulmonary function 
(spirometry) test was also added prior to early termination for safety 
monitoring. 
Section 6 Study Events Flow Chart was corrected accordingly. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
13


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 13 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
16-Feb-2015 
by Caroline Engel 
 
 
Recording Concomitant Medication: 
Concomitant medication will be recorded at each study visit by the clinical 
staff in to the electronic data capture system. Therefore, concomitant 
medications was removed from the list of events that will be recorded by 
the patients via their e-diary throughout the protocol. The following 
sections were corrected accordingly: 
• 
Footnotes in Section 6 Study Events Flow Chart. 
• 
The first sentence of the 4th paragraph of Section 13.2.3 Run-In 
Period (Days 1 to 14 [± 2 days]). 
• 
The 2nd sentence of the 2nd paragraph of Section 13.2.4 Treatment 
Period (Days 1 to 56). 
• 
The 2nd sentence of the first paragraph of Section 14.2.1 Electronic 
Diary. 
Subject Numbering: 
The first paragraph of Section 13.4.2 Method of Assigning Patients to 
Treatment Groups was modified to clarify that the screening number and 
randomization number are two separate identification number given to 
each subject at different stages of the study. 
Adverse Events Reporting 
Footnotes were added to clarify the rating severity definitions in 
Section 14.1.8.3 Reporting. 
Minor editorial and typographical corrections were made where applicable. 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 1 
This protocol amendment is generated to update the study population with 
regards to smoking frequency, to update the handling procedures for BAL 
samples, and to clarify other study procedures as listed below. 
Study Population: 
Section 13.3.2 - Inclusion Criteria, bullet 11 was updated to indicate that 
the study population will consist only of current and ex-smokers with a 
history of >10 pack years. As such, the indications for ‘packs/year’ were 
replaced with ‘pack years’ and the allowance for current smokers with <10 
pack/years was removed. 
Wording was added to indicate an approximately equal number of current  
and ex-smokers will be enrolled, and that each treatment group will consist 
of an approximately equal number of smokers and ex-smokers. In 
addition, the stratification criteria for the randomization was updated to 
consist of either current or ex-smokers. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Population and Number of 
Patients) 
• 
Section 13.1 - Overall Study Design and Plan (second paragraph) 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
14


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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 14 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 13.3.1 – Number of Patients. 
• 
Section 13.4.2 - Method of Assigning Patients to Treatment Groups. 
BAL Sample Handling: 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) was updated to indicate 
that sample handling, processing and storage procedures will be provided 
in a separate document.  
Follow-up Procedures: 
The wording in regards to follow-up procedures to be conducted on 
14 days (± 2 day), after the last study drug administration, was updated to 
indicated a phone-call and not a visit, as indicated correctly in Section 6 – 
Study Event Flow Chart. Study event were updated accordingly. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Duration of Participation for Patients, and 
Exploratory 
Outcome 
Measures 
[under 
Blood 
Assessments, 
Pulmonary Assessment, and Quality of Life Assessments])  
• 
Section 13.3.5.2 – Prohibitions (under Alcohol) 
• 
Section 14.1.8.2 – Monitoring (first paragraph). 
Study Duration: 
The total duration of the study indicated in Section 5 – Synopsis (under 
Duration of Participation for Patients) was corrected to 12 weeks to 
correspond with the actual study duration as indicated throughout the 
protocol.  
Inflammatory Markers in Blood Samples: 
The list of cell types to be evaluated as part of the inflammatory markers in 
the blood was updated to include monocytes instead of macrophages, as 
macrophages are not expected to be present in blood. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, fourth exploratory 
objective, 
and 
under 
Exploratory 
Outcome 
Measures 
[under 
Pharmacodynamic Assesments, Blood Assessments, first bullet]) 
• 
Section 12.1 - Study Objectives (fourth exploratory objective) 
• 
Section 12.2 - Study Endpoints (third exploratory endpoint) 
• 
Section 14.3.3 - Blood Biomarkers (first bullet) 
• 
Section 15.1.5.1 - Biomarkers (third bullet)  
Neutrophil Evaluation in BAL Samples 
Neutrophils were added to the list of cell types to be evaluated as a 
percentage of the total cell count in BAL samples. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, second exploratory 
objective 
and 
under 
Exploratory 
Outcome 
Measures 
[under 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
15


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 15 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
Pharmacodynamic 
Assessments, 
Bronchoalveolar 
Lavage 
Assessments, second bullet]) 
• 
Section 12.1 - Study Objectives (second exploratory objective) 
• 
Section 12.2 - Study Endpoints (second exploratory endpoint)  
• 
Section 14.3.2.4 - Biomarkers (second bullet) 
• 
Section 15.1.5.1 – Biomarkers (second bullet) 
Location of Study Drug Administration: 
Wording was added in Section 6 – Study Events Flow Chart for Day 56, to 
clarify that the study drug will be administered at the CRU. 
 
Meal Schedule: 
The indication for fasting requirement in Section 13.2.4.1 – Meal Schedule, 
was corrected to indicate patients will fast overnight for at least 12 hours 
before bronchoscopy and BAL collection on Days -1 and 55 instead of 
Days -1 and 56, as correctly indicated in Section 6 – Study Events Flow 
Chart. 
ECG Monitoring:  
Following an update in Celerion’s standard operating procedure, Section 
14.1.5 – Electrocardiogram Monitoring was updated to include at least 
5 minutes of rest prior to each ECG measurement (instead of at least 
1 minute as previously indicated). 
Hematology: 
The tests included in the hematology panel Section 14.1.6.1 – Hematology 
were updated to indicate that the red blood cell (RBC) count will include a 
reticulocytes count, and that the white blood cell (WBC) count with 
differential will include monocytes but will not include reticulocytes. 
Bronchoscopy and BAL: 
Due to the sensitivity of YPL-001 components to UV light, a warning was 
added to protect all samples from exposure to UV light, as indicated for the 
PK blood samples. 
The following sections were affected: 
• 
Section 14.3.2.2 - Bronchial Brushings 
• 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) 
PK Population: 
The indication for measurable concentration of verproside and picroside II 
in urine was removed from the definition of PK population in Section 15.1.2 
- Patients to Analyze, as there is no urine PK sampling planned for this 
study. 
Minor typographic and editorial corrections were made where applicable.  
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 16 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
DATE/NAME 
DESCRIPTION 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
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YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
22


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 20 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious 
Adverse Events (Medical Monitor) 
Dr. Kathy Smith 
Drug Safety Solution 
Tel.: +1 919 264-5626 
E-mail:  ksmith@drugsafety.biz  
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratories 
For Temple University School of Medicine: 
Yuri Persidsky, MD, Ph.D. 
Chairperson, 
Department 
of 
Pathology 
and 
Laboratory Medicine 
Professor, Pathology and Laboratory Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
 
UAB Lung Health Center: 
UAB Hospital Laboratories 
619 19th Street South 
Birmingham, Alabama, 35249 
United States  
 
 
Aventiv Research Inc.: 
Quest Laboratories 
6700 Steger Drive,  
Cincinnati, Ohio, 45237 
United States  
 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 21 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
Certified Clinical Laboratories 
(continued) 
Florida Pulmonary Research Institute, LLC: 
Quest Diagnostics 
4225 E Fowler Avenue 
Tampa, Florida, 33617 
United States  
Lab Director: Luis A. Diaz-Rosario, MD (FASCCP, 
FCAP), MT (FASCP) 
E-mail: luis.a.diaz-rosario@questdiagnostics.com 
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
 
Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Board Main 
Office Location 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 22 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such chronic 
obstructive pulmonary disease (COPD) 
Study Type: 
Phase 2a, proof of concept 
Study Objectives: 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, monocytes, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
25


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 23 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
Summary of Study 
Design: 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups 
(20 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) in the morning within 
3 days prior to Day 1 (define hereafter as Check-in) of the Treatment Period 
to confirm their eligibility and assess their health conditions. If they still meet 
all of the inclusion criteria and none of the exclusion criteria, they will 
undergo Check-in scheduled study procedures. Patients will return to the 
CRU on the morning of Day 1 to be randomized and receive one of the 
3 treatments and undergo all scheduled study procedures. Patients will 
return on the morning of Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), 
54 (± 1 day), and 56 of the Treatment Period for study drug administration 
and procedures. Prior to each release from the CRU, patients will receive a 
properly labeled YPL-001 kit (and/or any unused wallets from previously 
provided kits [when applicable]) and tiotropium/albuterol container with 
sufficient doses which will be self-administered by patients at home until the 
next morning visit at the CRU. Patients will continue recording their daily 
symptoms via the e-diary throughout the Treatment Period. Patients will 
return the e-diary device on Day 56 (or prior to early termination) to CRU 
staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
26


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 24 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
will be administered in accordance with the study center standard of care. 
Study Population: 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component, between 30 and 85 years of age (inclusive). An approximately 
equal number of current and ex-smokers will be enrolled. 
Number of 
Patients: 
The study is planned to enroll at least 60 patients. Patients will be divided in 
3 treatment groups with 20 patients to receive one of the 3 treatments (i.e., 
low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo 
control) as per the randomization schedule. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Duration of 
Participation for 
Patients: 
The planned length of participation in the study for each patient is 
approximately 12 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up procedures on Day 70 [± 2 days]). 
Duration of Study 
Conduct: 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products: 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
YPL-001 or placebo will be dispensed in accordance with the Randomization 
and Drug Dispensing Instructions provided in a separate document. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen: 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 
80 
mg matching 
placebo 
tablet) 
will 
be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days.. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B, and C will be administered orally with 
approximately 240 mL of water. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 25 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
Stopping Rules: 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 26 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
Safety and 
Tolerability 
Analysis 
(continued): 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures: 
PEF, major (e.g., estimated sputum quality [e.g., color, consistency], and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, 
discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (Duke 
Activity Status Index [DASI]) self-reported daily by the patients using an 
e-diary. 
Symptom 
Monitoring 
Analysis: 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, and throughout the study for 
PD assessments of biomarkers. Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Page 27 
AA98497_Final_Prot_Amendment _7_08Jun2016 
 
Exploratory 
Outcome 
Measures 
(continued): 
IC] will be performed at screening, and throughout the study. 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, and throughout the study. 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 54 (± 1 day) to determine 
verproside and picroside II concentrations in plasma. Predose samples will 
also be collected in the morning of Days 15 (± 2 days), 29 (± 2 days), 
43 (± 2 days) and 54 (± 1 day) for Ctrough determination. Other components of 
YPL-001 and its metabolites may also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis: 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis: 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-001 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
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AA98497_Final_Prot_Amendment_7_08Jun2016 
 
6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
Up to  
-3 c 
1 
Hours → 
 
 
C-I 
Predose 0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-rayf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Berlin Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsh 
X 
 
 
Xg 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAi 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usej 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityk 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationl 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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AA98497_Final_Prot_Amendment_7_08Jun2016 
 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
Up to  
-3 c 
1 
Hours → 
 
 
C-I 
Predose 0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 3.5 4 5 6 8 10 
12 
Study Drug Administration at CRUm,n 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)o 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersp 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xq 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitsr 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
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AA98497_Final_Prot_Amendment_7_08Jun2016 
 
a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. Scheduled procedures may be performed within 3 days prior to Day 1 dosing. 
d. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
e. To be performed prior to the bronchoscopy procedures. 
f. 
To be performed at screening or within 3 months (inclusive) of screening. 
g. ECGs, vital sign and pulse oximetry will be measured within 4 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
h. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
i. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
j. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
k. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
l. 
Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
m. Prior to release from the CRU, patients will receive a properly labeled kit with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
n. On Day 1, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
o. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
p. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
q. To be performed prior to dosing. 
r. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
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AA98497_Final_Prot_Amendment_7_08Jun2016 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 
2-14 
15 (± 2) 
16-28 
29 (± 2) 
30-42 
43 (± 2) 
44-53 
Hours → 
 
AM 
PM 
 
AM 
PM 
 
AM 
PM 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Vital Signsd 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Hem, Chem, and UAe 
 
 
 
 
Xc 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Urine Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Urine or Breathalyzer Alcohol Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
Diary Usef 
X 
PEF, COPD exacerbation, dyspnea and activityg 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationh 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
Study Drug Administration at Homei 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)j 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
BDI/TDI & CAT 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
Return Visitsk 
 
X 
 
 
X 
 
 
X 
 
 
Refer to the footnotes on the next page 
 
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AA98497_Final_Prot_Amendment_7_08Jun2016 
 
a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
e. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
f. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
g. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
h. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
i. 
Prior to release from the CRU on Days 15 (± 2 days), 29 (± 2 days), and 43 (± 2 days) patients will receive a properly labeled kit and/or any 
unused wallets from previously provided kits (when applicable) with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
j. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
k. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
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AA98497_Final_Prot_Amendment_7_08Jun2016 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
ETb FUc 
Days → 
54 (± 1 day) 
55 
56 
Hours → Predose 
0 
0.167 0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
Vital Signsg 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Xf 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
Hem, Chem, and UAh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
PEF, COPD exacerbation, dyspnea 
and activityj 
X 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Study Drug Administration at CRUk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Study Drug Administration at Homel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
X 
 
Bronchoscopy and BAL Biomarkerso 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Blood Biomarkers 
Xp 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsq 
X 
 
X 
X 
 
Refer to the footnotes on the next page 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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a. For details on Procedures, refer to Section 14. 
b. To be performed prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. To be performed or completed prior to bronchoscopy procedures. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 4 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
i. 
Patients will return the e-diary device on Day 56 (or prior to early termination) to CRU staff.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
k. On Day 54 (± 1 day), patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning 
administration.  
l. 
Prior to release from the CRU on Day 54 (± 1 day) patients will receive a properly labeled kit and/or any unused wallets from previously 
provided kits (when applicable) with sufficient study drug for their assigned treatment which will be self-administered by patients at home until 
the next morning visit at the CRU. Patients must return the used and unused wallets at the next morning visit. Home dosing will be monitored 
via attempted phone calls where patients will be reminded to take their medication, if they did not record their self-administration on the 
e-diary, and queried about the occurrence of AEs. 
m. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
n. To be completed prior to bronchoscopy procedures. 
o. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
p. To be performed at predose on Day 54 (± 1 day) or upon early termination. 
q. Patients will be admitted to the CRU at the time indicated by the CRU. 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition Dyspnea Index 
Test, CAT = COPD Assessment Test, Chem = Serum chemistry, C-I = Check-in, COPD = chronic obstructive pulmonary disease, CRU = Clinical research unit, 
ConMeds = Concomitant medication, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = electronic diary, ET =  Early termination, 
FSH = Follicle-stimulating 
hormone, 
Hem = Hematology, 
HIV = Human 
immunodeficiency 
virus, 
IL= 
interleukin, 
PEF = Peak 
expiratory 
flow, 
PK = Pharmacokinetics, PM = Evening, Preg = Serum pregnancy, PT/INR = Prothrombin time/international normalized ratio, Screen = Screening, UA = Urinalysis. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Celerion Project No. : AA98497 
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Page 35 
AA98497_Final_Prot_Amendment_7_08Jun2016 
 
7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY .......................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ................................................................................................. 17 
3. 
INVESTIGATORS SIGNATURES .......................................................................................... 18 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY .............................................................. 20 
5. 
SYNOPSIS ............................................................................................................................. 22 
6. 
STUDY EVENTS FLOW CHART ........................................................................................... 28 
7. 
TABLE OF CONTENTS ......................................................................................................... 35 
8. 
ABBREVIATIONS .................................................................................................................. 38 
9. 
INTRODUCTION AND BACKGROUND ................................................................................ 42 
9.1 
YPL-001 ....................................................................................................................... 42 
9.1.1 
Preclinical Trials .............................................................................................. 42 
9.1.1.1 
Pharmacology ................................................................................. 42 
9.1.1.2 
Pharmacokinetics ............................................................................ 43 
9.1.1.3 
Toxicology ....................................................................................... 44 
9.1.2 
Clinical Experience ......................................................................................... 45 
9.1.2.1 
SAD study ....................................................................................... 46 
9.1.2.2 
MAD Study ...................................................................................... 47 
10. RATIONALE ........................................................................................................................... 49 
10.1 Purpose of the Study ................................................................................................... 49 
10.2 Dose Selection ............................................................................................................. 49 
11. RISK/BENEFIT ....................................................................................................................... 51 
12. STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 52 
12.1 Study Objectives .......................................................................................................... 52 
12.2 Study Endpoints ........................................................................................................... 52 
13. INVESTIGATIONAL PLAN ..................................................................................................... 54 
13.1 Overall Study Design and Plan .................................................................................... 54 
13.2 Study Conduct ............................................................................................................. 55 
13.2.1 Screening ........................................................................................................ 55 
13.2.2 Patient Confinement ....................................................................................... 55 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ......................................................... 55 
13.2.4 Treatment Period (Days 1 to 56) .................................................................... 56 
13.2.4.1 Meal Schedule ................................................................................ 56 
13.2.4.2 Early Termination ............................................................................ 57 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................... 57 
13.2.6 Scheduled End of Study ................................................................................. 57 
13.3 Selection of Study Population ...................................................................................... 57 
13.3.1 Number of Patients ......................................................................................... 57 
13.3.2 Inclusion Criteria ............................................................................................. 57 
13.3.3 Exclusion Criteria ............................................................................................ 59 
13.3.4 Removal of Patients from the Study ............................................................... 61 
13.3.5 Study Restrictions ........................................................................................... 62 
13.3.5.1 Concomitant Therapy ...................................................................... 62 
13.3.5.1.1 
Prohibited Therapy ..................................................... 62 
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13.3.5.1.2 
Permitted Therapy ...................................................... 63 
13.3.5.2 Prohibitions...................................................................................... 63 
13.3.5.3 Activity ............................................................................................. 64 
13.4 Treatments ................................................................................................................... 64 
13.4.1 Treatments administered ................................................................................ 64 
13.4.1.1 Drug Administration During Run-in Period ...................................... 64 
13.4.1.2 Drug Administration During Treatment Period ................................ 64 
13.4.1.3 Stopping Rules ................................................................................ 65 
13.4.2 Method of Assigning Patients to Treatment Groups ....................................... 66 
13.4.3 Blinding ........................................................................................................... 66 
13.4.3.1 Maintenance of Randomization ...................................................... 66 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 66 
13.4.3.3 Revealing of Randomization ........................................................... 67 
13.4.4 Treatment Compliance ................................................................................... 67 
14. STUDY PROCEDURES ......................................................................................................... 68 
14.1 Safety Assessments .................................................................................................... 68 
14.1.1 Body Height and Weight ................................................................................. 68 
14.1.2 Physical Examination ...................................................................................... 68 
14.1.3 Vital Signs ....................................................................................................... 68 
14.1.4 Pulse Oximetry................................................................................................ 69 
14.1.5 Electrocardiogram Monitoring ......................................................................... 69 
14.1.6 Clinical Laboratory Tests ................................................................................ 70 
14.1.6.1 Hematology ..................................................................................... 70 
14.1.6.2 Serum Chemistry ............................................................................ 70 
14.1.6.3 Serology .......................................................................................... 70 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............. 70 
14.1.6.5 Follicle-Stimulating Hormone .......................................................... 71 
14.1.6.6 Urinalysis ......................................................................................... 71 
14.1.6.7 Urine/Breathalyzer Alcohol Screen ................................................. 71 
14.1.6.8 Urine Drug Screen .......................................................................... 71 
14.1.6.9 Additional Tests ............................................................................... 71 
14.1.7 Chest X-Ray .................................................................................................... 71 
14.1.8 Berlin Questionnaire ....................................................................................... 71 
14.1.9 Adverse Events ............................................................................................... 72 
14.1.9.1 Adverse Event Definition ................................................................. 72 
14.1.9.2 Monitoring........................................................................................ 72 
14.1.9.3 Reporting ......................................................................................... 72 
14.1.9.4 Serious Adverse Events .................................................................. 74 
14.2 Symptom Assessments ............................................................................................... 74 
14.2.1 Electronic Diary ............................................................................................... 74 
14.2.2 Peak Expiratory Flow ...................................................................................... 75 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ............ 75 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) ....................................................... 75 
14.2.5 Activity (Duke Activity Status Index) ............................................................... 75 
14.3 Pharmacodynamic Assessments ................................................................................. 75 
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14.3.1 Pulmonary Function (Spirometry) ................................................................... 75 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers .................... 76 
14.3.2.1 Bronchoscopy ................................................................................. 76 
14.3.2.2 Bronchial Brushings ........................................................................ 77 
14.3.2.3 Bronchoalveolar Lavage (BAL) ....................................................... 77 
14.3.2.4 Biomarkers ...................................................................................... 77 
14.3.3 Blood Biomarkers ........................................................................................... 78 
14.3.4 Quality of Life Questionnaires ......................................................................... 78 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ......................................................................................... 78 
14.3.4.2 COPD Assessment Test (CAT)....................................................... 78 
14.4 Pharmacokinetic Assessments .................................................................................... 79 
14.4.1 Blood Sampling and Processing ..................................................................... 79 
14.5 Blood Volume for Study Assessments......................................................................... 80 
15. DATA ANALYSIS ................................................................................................................... 81 
15.1 Statistical Analysis ....................................................................................................... 81 
15.1.1 Sample Size Calculation ................................................................................. 81 
15.1.2 Patients to Analyze ......................................................................................... 81 
15.1.3 Safety Analysis ............................................................................................... 82 
15.1.4 Symptom Monitoring Analysis ........................................................................ 83 
15.1.5 Pharmacodynamic Analysis ............................................................................ 83 
15.1.5.1 Biomarkers ...................................................................................... 83 
15.1.5.2 Quality of Life .................................................................................. 84 
15.1.6 Pharmacokinetic Analysis ............................................................................... 84 
15.1.6.1 Pharmacokinetic Parameters .......................................................... 84 
15.1.6.1.1 
Plasma ....................................................................... 84 
15.1.6.1.2 
Bronchoalveolar Lavage ............................................ 85 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ......................... 86 
15.1.7 Assessment of Efficacy ................................................................................... 86 
16. STUDY ADMINISTRATION ................................................................................................... 87 
16.1 Ethics ........................................................................................................................... 87 
16.1.1 Institutional Review Board .............................................................................. 87 
16.1.2 Ethical Conduct of the Study .......................................................................... 87 
16.1.3 Patient Information and Consent .................................................................... 87 
16.2 Termination of the Study .............................................................................................. 87 
16.3 Data Quality Assurance ............................................................................................... 87 
16.4 Direct Access to Source Data/Documents .................................................................. 88 
16.5 Drug Supplies, Packaging and Labeling ...................................................................... 88 
16.6 Data Handling and Record Keeping ............................................................................ 88 
16.7 Protocol Amendments ................................................................................................. 88 
16.8 Finance and Insurance ................................................................................................ 89 
16.9 Publication Policy ......................................................................................................... 89 
17. REFERENCES ....................................................................................................................... 90 
18. APPENDICES ........................................................................................................................ 91 
18.1 Appendix 1 - SULT Drug Interaction Table .................................................................. 91 
 
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8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
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CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
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INR 
International normalized ratio 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
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OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
RNA 
Ribonucleic acid 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
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9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
GCP, and applicable regulatory requirements. The patient population will be comprised 
of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of June 3, 2014. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Bronchoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
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verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
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picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
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and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
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9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 
0.67 hours under fasting conditions. Verproside appeared to be cleared rapidly from 
plasma, with mean t1/2 values under 1 hour; plasma verproside concentrations were 
below the lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 
below summaries the PK parameters of verproside following single-dose administrations 
of YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
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9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t½ values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t½ values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
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Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
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10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such COPD to demonstrate safety and 
evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
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Table 4: Traditional Chinese Medicine Use versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
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11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an angiocatheter is utilized and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
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12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., estimated sputum quality [e.g., color, consistency] and quantity) and 
minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body 
temperature above 100°F) symptoms of COPD exacerbation;  
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• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and 
eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
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13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups (20 patients 
per group). Patients will participate only once. An approximately equal number of current 
and ex-smokers will be enrolled in the study. 
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU in the morning, –for Check-in of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Check-in scheduled 
study procedures. Patients will return to the CRU on the morning of Day 1 to be 
randomized and receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15 (± 2 days), 29 (± 2 days), 43 
(± 2 days), 54 (± 1 day), and 56 of the Treatment Period for study drug administration 
and procedures. Prior to each release from the CRU, patients will receive a properly 
labeled kit and/or any unused wallets from previously provided kits (when applicable) 
with sufficient doses which will be self-administered by patients at home until the next 
morning visit at the CRU. Patients will continue recording their daily symptoms via the e-
diary throughout the Treatment Period. Patients will return the e-diary device on Day 56 
(or prior to early termination) to CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
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will be discontinued. Rescue medication will be used for any patient with an 
exacerbation of COPD and will be administered in accordance with the study center 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses and their daily respiratory symptoms. Prior to each morning 
dose, patients will record at home their daily PEF, major (e.g., estimated sputum quality 
[e.g., color, consistency] and quantity) and minor (e.g., cough, wheeze, sore throat, 
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nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 55 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses and their daily 
respiratory symptoms on their e-diary. Prior to each morning dose, patients will record at 
home their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and 
body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before the bronchoscopy 
and BAL collection at the Check-in of the Treatment Period and on Day 56. On Days 1 
and 54 (± 1 day), patients will be required to fast overnight for at least 8 hours before 
and for at least 4 hours after the morning dose. On all other days, patients will be asked 
to fast for at least 2 hours before and 2 hours after each morning dose. Patients will also 
be asked to fast for at least 2 hours before and after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 54 (± 1 day), patients will fast from all food and drink except water 
between meals and snacks. Foods and beverages containing alcohol, xanthines, 
caffeine, vegetables from the mustard green family, mustard, tea (especially speedwell 
tea), or grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, 
menus should be similar in content. The same menu and meal (except for snacks) 
schedule will be administered uniformly for all patients confined within the same CRU, 
across all treatment groups. Meals are not required to be completed by patients. 
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13.2.4.2 Early Termination  
Early termination evaluations will be performed on patients prior to early termination. 
Patients who want to terminate from the study and are not currently on-site will be 
contacted and asked to return to the CRU to perform the early termination procedures. 
The early termination procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll at least 60 patients. An approximately equal number of 
current and ex-smokers will be enrolled. Patients will be divided in 3 treatment groups 
with 20 patients to receive one of the 3 treatments (i.e., low and high YPL-001 doses 
[80 mg and 160 mg BID] and a placebo control) as per the randomization schedule. 
Each treatment group will consist of an approximately equal number of current and 
ex-smokers. 
13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 30 to 85 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
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4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-40.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24 hours 
prior to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled 
CRU visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack years. Ten pack years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Patients, who undergo smoking cessation therapy, must be completed 
3 months prior to screening visit and smoking status should not change between the 
patient’s screening visit and patient’s last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
13. A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method 
(e.g., condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
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IND No.: 114903 
 
 
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14. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
15. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the last scheduled study procedures on Day 56 or upon early 
termination. Patients will be advised to use a condom with spermicide for 90 days 
following the last administration of the study drug, and to not donate sperm during 
this same period of time. In the event that the sexual partner is surgically sterile, use 
of a condom with spermicide is not necessary. No restrictions are required for 
vasectomized males provided their vasectomy has been performed 120 days or 
more prior to study start. Males who have been vasectomized less than 120 days 
prior to study start must follow the same restrictions as non-vasectomized males. 
16. Understands study procedures and provides written informed consent for the trial. 
17. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
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IND No.: 114903 
 
 
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8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), severe sleep apnea (assessed using the Berlin Questionnaire [refer to 
Section 14.1.8]), cardiovascular, endocrine, neurological, hepatic, gastrointestinal, 
renal, hematological, urological, immunological or ophthalmic diseases that the 
Investigator believes are clinically significant e.g., unstable and could impact patient 
safety by participation in the study. 
9. History or presence of clinically significant cardiac arrhythmia, prostatic hyperplasia, 
bladder-neck obstruction, urinary retention, or narrow-angle glaucoma that, in the 
opinion of the PI, would contraindicate the administration of tiotropium. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Diagnosed with hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive alcohol (using urine dipstick or breathalyzer) test results at screening or at 
each CRU visit. If alcohol test is positive or subject reports consumption of alcohol 
within 48 hours prior to testing, alcohol test maybe rescheduled or repeated, at the 
discretion of the PI and if study visit time window allows.  
14. Urine drug testing at screening or at each CRU visit, unless the positive drug screen 
is due to prescription drug use and is approved by the PI and the medical monitor. 
15. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C infection with clinically significant liver impairement and/or a 
viral ribonucleic acid (RNA) titer of > 6.9 ± 0.8log molecules/mL.3  
16. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
17. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
18. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
19. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) (such as 17-beta-estradiol 
glucuronide, flavonoids [citrus fruit], silybin [herb supplement milk thistle]) and/or 
sulfotransferases (SULT) (refer to Appendix 1), within 12 hours prior to Day 1 of the 
Run-in Period. The use of low dose of acetylsalicylic acid (e.g., aspirin) will be 
allowed during the study, but prohibited 7 days prior to the bronchoscopy performed 
prior to dosing of Day 1 until the last PK blood sample collected on Day 1, and 
7 days prior to Day 54 (± 1 day) dosing until completion of the bronchoscopy 
procedures on Day 56. Additional sources may be consulted by the PI or medical 
monitor to confirm lack of PK/PD interaction with study drug. 
20. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
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21. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
22. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
23. Females who are pregnant or lactating.  
24. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
25. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion (early 
termination evaluations) as the situation allows (see Section 13.2.4.2). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
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13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the last scheduled study 
procedures on Day 56 or upon early termination). Intake of these medications during the 
Run-in Period constitutes a non-eligibility criterion and the patients will not be 
randomized into the study. If any of these medications are taken during the Treatment 
Period, the need for this patient to be withdrawn from the study will be carefully 
evaluated by the Investigator and the Sponsor on the basis of the potential impact on 
efficacy or safety evaluation and in the patient's best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. The use of low dose of acetylsalicylic acid (e.g., 
aspirin) will be allowed during the study, but prohibited 7 days prior to the 
bronchoscopy performed prior to dosing of Day 1 until the last PK blood sample 
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IND No.: 114903 
 
 
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collected on Day 1, and 7 days prior to Day 54 (± 1 day) dosing until completion of 
the bronchoscopy procedures on Day 56. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements (except for prescribed vitamin supplement) and herbal products 
(especially Speedwell) will be prohibited 7 days prior Day 1 of the Treatment Period 
and through collection of the final PK sample. 
13.3.5.1.2 Permitted Therapy 
Throughout the study period (from Day 1 of the Run-in Period to the completion of the 
last scheduled study procedures on Day 56 or upon early termination) patients will be 
permitted to take the following medications in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 24 hours 
before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. Prescribed vitamin supplement (except for Vitamin C). 
5. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine (other than coffee and tea):  24 hours prior to each CRU visit and 
prior to dosing on Days 1 and 54 (± 1 day) of the Treatment Period through collection 
of Days 1 and 54 (± 1 day) last PK sample. 
• 
Alcohol (other than red wine and beer):  48 hours prior to each CRU visit and 
48 hours prior to dosing on Days 1 and 54 (± 1 day) of the Treatment Period through 
collection of Days 1 and 54 (± 1 day) last PK sample. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 54 (± 1 day) last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 
54 (± 1 day) of the Treatment Period through collection of Days 1 and 54 (± 1 day) 
last PK sample. 
• 
Tea (especially Speedwell tea), coffee, and red wine:  7 days prior to Days 1 and 
54 (± 1 day) of the Treatment Period through collection of Days 1 and 54 (± 1 day) 
last PK sample. 
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IND No.: 114903 
 
 
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• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 54 (± 1 day) last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
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IND No.: 114903 
 
 
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In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
YPL-001 or placebo will be dispensed in accordance with the Randomization and Drug 
Dispensing Instructions provided in a separate document. 
Prior to release from the CRU on Days 1, 15 (± 2 days), and 29 (± 2 days), of the 
Treatment Period, patients will receive a properly labeled new kit, which contains 
4 wallets of 2 blister cards, with the appropriate doses which will be self-administered by 
patients at home. Any unused wallets from previously provided kits will also be 
dispensed to patients on Days 15 (± 2 days) and 29 (± 2 days). Prior to release from the 
CRU on Days 43 (± 2 days), and 54 (± 1 day), patients will received unused wallets from 
previously provided kits with the appropriate doses which will be self-administered by 
patients at home. Patients will also receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. Patients will record their 
self-administered doses in their e-diary, and whether the dose was administered with 
food, and must return the YPL-001 used and unused wallets and the tiotropium and 
albuterol container (empty or not) at the next schedule visit at the next morning visit. 
Home dosing will be monitored via attempted phone calls where patients will be 
reminded to take their medication, if they did not record their self-administration on the 
e-diary, and queried about the occurrence of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
given instructions on how to record their drug administration in their e-diary on 
home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
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IND No.: 114903 
 
 
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a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique screening identification number upon screening. 
Patients who complete the study screening assessments, complete the Run-in Period, 
and meet all the eligibility criteria will be assigned a unique randomization identification 
number, different from the screening number, and receive the corresponding product, 
according to a randomization scheme generated at Celerion. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
The randomization will not be made available to the Sponsor, patients, or members of 
the staff responsible for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
The site Pharmacist/Study Coordinator will receive two sets of randomization code 
envelopes, one set for “Current Smokers” and another for “Ex-Smokers”. Each individual 
envelope is marked on the outside with one of the randomization numbers and contains 
the treatment for that patient. These envelopes must be kept in a secure locked location. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the medical monitor or designee prior to breaking the blind. If breaking 
the blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
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IND No.: 114903 
 
 
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In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
1. All data are entered in the database, edits checks are performed, queries 
closed, CRFs signed by the Investigator, and the database is officially locked. 
2. All PK/PD samples have been analyzed and quality checked by the 
responsible analytical associate. 
13.4.4 Treatment Compliance 
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
Self-administration by patients at home will be monitored via the e-diary and attempted 
phone calls will be performed to remind patients to take their medication, if they did not 
record their self-administration on the e-diary. 
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IND No.: 114903 
 
 
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14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs and pulse oximetry 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
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IND No.: 114903 
 
 
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When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When performed prior to the bronchoscopy, 
blood pressure and heart rate will be measured within 4 hours prior to the bronchoscopy. 
When scheduled postdose, vital signs readings will be performed within approximately 
10 minutes of the scheduled time point. When performing the bronchoscopy, vital signs 
(body temperature, respiratory rate, blood pressure, and heart rate) will be monitored 
continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen saturation (%), and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen saturation [%], and heart rate) 
as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. When performed prior to the bronchoscopy, pulse 
oximetry monitoring will be measured within 4 hours prior to the bronchoscopy. 
Readings may be taken at other times, if deemed necessary by the Investigator. When 
performing the bronchoscopy, oxygen saturation will be monitored continuously until the 
end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performed prior to the bronchoscopy, ECG will be measured within 
4 hours prior to the bronchoscopy. When performing the bronchoscopy, ECG will be 
monitored continuously until the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
5 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
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14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count (including a 
reticulocytes count) 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, and 
monocytes) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
• 
HCV viral RNA titer 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
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14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine/Breathalyzer Alcohol Screen 
Alcohol levels will be tested using urine dipsticks or breathalyzers. 
14.1.6.8 Urine Drug Screen 
• 
Cannabinoids  
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.6.9 Additional Tests 
• 
Prothrombin time/international normalized ratio (PT/INR) 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Berlin Questionnaire 
The Berlin Questionnaire is a validated screening questionnaire used to quickly identify 
the risk (low to high) of sleep disordered breathing. The questionnaire consists of three 
categories and risk is based on the responses to individual items and overall scores in 
the symptom categories. Assessments will be performed according to the Study Events 
Flow Chart (Section 6). The questionnaire will be provided as a separate document and 
a copy of the questionnaire to be used will be kept in the study binder.  
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14.1.9 Adverse Events 
14.1.9.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.4 
14.1.9.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, after the last 
scheduled study procedures on Day 56 (or upon early withdrawal), and at the follow-up 
phone call. The inquiry will be made in a non-specific manner using open-ended 
questions so as not to bias the response (e.g., How have you been feeling since your 
last visit?). 
All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.9.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 5 and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
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The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade; ADL = Activities of Daily Living 
*Instrumental ADL refer 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. 
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14.1.9.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Medical Monitor via fax or e-mail within one working day of 
becoming aware of the event, whether or not the serious events are deemed 
drug-related. All serious event reporting will adhere to 21 CFR 312.32 for Investigational 
New Drugs (IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20124. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
If an SAE occurs to a patient on this study, the Medical Monitor is to be contacted (see 
Section 4). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses, whether the dose was 
administered with food, and daily respiratory symptoms throughout the Run-in and 
Treatment Periods. Patients will return the e-diary device on Day 56 (or prior to early 
termination) to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., 
estimated sputum quality [e.g., color, consistency] and quantity) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity 
(DASI). 
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14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., estimated sputum quality [e.g., color, 
consistency] and quantity) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation via the e-diary before each dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) 
and 
long 
acting 
β2-agonist 
and 
anticholinergic 
bronchodilators 
(e.g., salmeterol, tiotropium) agents will be withheld approximately 4 and 24 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study. 
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At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol (100 μg/inhalation) for a total dose of 
400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes 
after albuterol administration, the baseline post-bronchodilator spirometry will be 
performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Check-in measurement): Predose 
FEV1 is defined as the time point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
FEV1 measurement at predose at Check-in of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose at Check-in, up to 3 measures will be 
performed.  
Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be fasted for 12 hours before the bronchoscopy procedures. If required, 
blood pressure medications can be taken with small sip of water based on preapproval 
of local Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.6,7 
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Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal cannula will be 
administered during bronchoscopy and oxygen saturation will be maintained at ≥95%. 
Conscious sedation will be achieved with incremental doses of 1–4 mg midazolam and 
50-100 μg fentanyl. Local upper and lower airway topical anesthesia will be achieved 
with 1% or 2% lidocaine. The dose of lidocaine administered during the procedure will 
not exceed a total of 450 mg. The bronchoscope will usually be inserted preferably 
through the nares into trachea. The bronchoscope will be wedged into 2 subsegments of 
the right middle or lower lobe, as deemed appropriate by the Investigator. Emergency 
treatments for cardiopulmonary arrest and pneumothorax will be immediately available in 
the bronchoscopy room. The patient will remain in the recovery suite for observation for 
a minimum of 2 hours after the procedure.  
14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A total of 180 mL BAL, 
using 6 x 30 mL aliquots of normal saline warmed to room temperature, will be 
performed using each subsegment of the right middle or lower lobe, as deemed 
appropriate by the Investigator. BAL fluid will be aspirated following each 30 mL 
instillation. The lavage material, which averages 25% return in COPD patients, typically 
yields 1-10 x 106 macrophages. The centrifuged cell pellet and supernatant will be kept 
cooled until processed or stored as indicated in the laboratory manual to be provided as 
a separate document. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and eosinophils 
as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
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as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture or an angiocatheter at the time 
points delineated in the Study Events Flow Chart (Section 6) for PD assessments of 
biomarkers. Biomarker assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 3 tubes.  A manual for blood sampling, collection, processing, 
and sample shipment will be provided in a separate document. 
14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Check-in of the Treatment Period) will be assessed with the BDI. 
This instrument has 3 domains (functional impairment, magnitude of task, and 
magnitude of effort) with the values added for a combined focal score. Functional 
impairment determines the impact of breathlessness on the ability to carry out activities; 
magnitude of task determines the type of task that causes breathlessness, magnitude of 
effort establishes the level of effort that results in breathlessness. The BDI scores range 
from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline 
focal score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.8,9 
A copy of the questionnaire to be used will be kept in the study binder. 
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14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture or an angiocatheter at the time points 
delineated in the Study Events Flow Chart (Section 6).  
Blood will be drawn into 4 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
 
 
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14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time 
Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology, PT/INR), FSH (for 
postmenopausal female patients only), 
and serum pregnancy (for female 
patients only). 
1 
~ 17 mL** or 
21 mL*** 
~ 17 mL** or 21 mL*** 
On-study serum chemistry and serum 
pregnancy (for female patients only) 
when scheduled at the same time 
3 
~ 8.5 mL 
~ 25.5 mL 
Additional on-study serum pregnancy 
(for female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
3 
~ 4 mL 
~ 12 mL 
Blood samples for PD biomarkers 
(except CRP and fibrinogen) 
8 
~ 6 mL 
~ 48 mL 
Blood samples for PD biomarker - 
CRP 
8 
~ 4 mL 
~ 32 mL 
Blood samples for PD biomarker - 
Fibrinogen 
8 
~ 3.5 mL 
~ 28 mL 
Blood samples for PK of verproside 
and picroside II 
37 
~ 4 mL 
~ 148 mL 
Total Blood Volume for males† → 
~ 310.5 mL** or 
314.5 mL*** 
Total Blood Volume for females† → 
~ 317.5 mL **or 
321.5 mL*** 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** For patients enrolled at UAB Lung Health Center, Florida Pulmonary Research Institute, LLC, 
or Temple University School of Medicine.  
***For patients enrolled at Aventiv Research Inc. only. 
†   If an angiocatheter is used, up to 5 mL of blood will be used to flush the catheter prior to each 
collection of PK and/or PD blood samples. Hence the total blood volume collected may 
increase by approximately 205 mL. 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma concentration of verproside and 
picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Day 1 and/or Day 54 
(± 1 day). 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 
post-baseline PD measurement. 
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• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
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Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes, 
neutrophils, and eosinophils as a percentage of total cells; total cell count [cells/mL] 
of neutrophils, macrophages, lymphocytes and eosinophils as absolute inflammatory 
cell numbers; and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9): raw and % change from baseline levels; 
and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and lymphocytes] 
and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
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15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
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† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
The following PK parameters will be computed following Day 54 (± 1 day) morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc 
Percent fluctuation will be calculated as follows: 
𝐶𝐶max _𝑠𝑠𝑠𝑠−𝐶𝐶min _𝑠𝑠𝑠𝑠
𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎
 𝑥𝑥 100 
Swing 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
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15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), and 54 (± 1 day) following multiple oral 
dose administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
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16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP 
(E6 Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
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check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets, and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 
5 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
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16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
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17. REFERENCES 
 
                                               
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 Gretch D, et al. Assessment of Hepatitis C Virus RNA Levels by Quantitative Competitive RNA 
Polymerase Chain Reaction: High-Titer Viremia Correlates with Advanced Stage of Disease. J 
Infect Dis. 1994;169(6):1219-1225. 
4 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
5 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
6 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
7 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
8 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
9 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
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18. APPENDICES 
18.1 Appendix 1 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
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Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
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1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
28-Apr-2016 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 6 
This protocol amendment is generated to change the Sponsor 
representative, CEO and President, to Su-Jun Park. Therefore Section 2 
Sponsor – Signatories was updated accordingly. 
And to add the following Investigator and clinical site: 
Faisal Fakih, MD 
Florida Pulmonary Research Institute, LLC 
1788 W. Fairbanks Avenue,Suite B 
Winter Park, Florida, 32789 
United States 
Tel.:  +1 407 740-8078 
Therefore, Section 3 Investigators Signatures was updated accordingly. 
Section 4 Additional Key Contacts for the Study was also updated to add 
the corresponding certified clinical laboratory.  
In addition, the following changes were made to facilitate the clinical 
conduct at each investigative site: 
1. To allow patients to recover from the bronchoscopy procedure before 
going through a 12 hours’ period of PK blood draws and collect quality 
samples, a recovery period was added between these procedures; 
Procedures scheduled on Day -1 will now be performed within 3 days 
prior to Day 1 (now defined as Check-in procedures). In addition, the 
PK sampling previously scheduled on Day 56 will be conducted on 
Day 54 (± 1 day) before the bronchoscopy now scheduled on Day 56, 
instead of Day 55. Therefore, the following sections were updated 
acccordingly: 
• 
Section 5 Synopsis - Summary of Study Design, Dosage, Dosage 
Form, Route, and Dose Regimen, and Exploratory Outcome 
Measures. 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.2.4 Treatment Period (Days 1 to 56)  
• 
Section 13.2.4.1 Meal Schedule 
• 
Section 13.3.5.2 Prohibitions 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 14.3.1 Pulmonary Function (Spirometry) 
• 
Section 14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea 
Index (BDI/TDI) 
• 
Section 15.1.2 Patients to Analyze 
• 
Section 15.1.6.1.1 Plasma 
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DATE/NAME 
DESCRIPTION 
28-Apr-2016 
by Caroline Engel 
• 
Section 15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
2. To provide flexibility in the schedule of events, electrocardiograms, 
vital sign and pulse oximetry will be measured within 4 hours of 
bronchoscopy procedures, instead of 2 hours. Therefore, Section 6 
Study Events Flow Chart, Section 14.1.3 Vital Signs, Section 14.1.4 
Pulse Oximetry, and Section 14.1.5 Electrocardiogram Monitoring 
were updated accordingly. 
3. Exclusion criterion #9 was updated to clarify that patients withclinically 
significant cardiac arrhythmia; prostatic hyperplasia; bladder-neck 
obstruction; urinary retention; and narrow-angle glaucoma that, in the 
opinion of the PI, would contraindicate the administration of tiotropium, 
will be excluded. 
4. To allow flexibility, subjects with a positive alcohol screen or subjects 
reporting consumption of alcohol within 48 hours prior to testing, an 
alcohol test may be rescheduled or repeated, at the discretion of the PI 
if there is sufficient time remaining to perform the visit procedures 
within the time window specified for this visit (e.g., ± 2 days of Day 15 
visit). Therefore exclusion criterion # 13 was split into two exclusion 
criteria; criteria #13 (alcohol screen) and #14 (drug screen), which 
were updated accordingly. 
5. Exclusion criterion #15 was updated to exclude subject with a positive 
results for hepatitis C antibodies only if they present with clinically 
significant liver impairment and/or a viral ribonucleic acid (RNA) titer of 
> 6.9 ± 0.8log molecules/mL. Section 14.1.6.3 Serology was updated 
accordingly. Section 17 Reference was updated to include reference 
#3 as a justification to the titer value selected. 
6. The Child-Pugh scale should only be used to classify patients with a 
diagnosis of hepatic impairment. Thus, exclusion criteria #11 was 
clarified to exclude patients with diagnosed hepatic impairment and a 
Child-Pugh class A score or higher. Patients without hepatic 
impairment with normal laboratory results for bilirubin, albumin, 
prothrombin time/international normalized ratio (which automatically 
would fall in a Class A Score of 5) will not be assigned a Child-Pugh 
score and will thus be allowed to enrol. In addition, to assess the 
extent of hepatic impairment according to exclusion criterion # 11, a 
blood sample for prothrombin time/international normalized ratio will be 
collected at screening. Thus, a new section (14.1.6.9 Additional Tests) 
was added, and Section 6 Study Events Flow Chart, Section 8 
Abbreviations, and Table 5: Blood Volume during Study were updated 
accordingly. 
7. Prescribed vitamin supplement will be allowed, therefore the following 
sections were updated accordingly: 
• 
Section 13.3.5.1.1 Prohibited Therapy 
• 
Section 13.3.5.1.2 Permitted Therapy 
8. Minor editorial and typographical corrections were made where 
applicable. 
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DATE/NAME 
DESCRIPTION 
05-Nov-2015 
by Caroline Engel 
 
Final Protocol, Amendment 5 
This protocol amendment is generated to add the following Investigator 
and clinical site: 
Samir Arora, MD 
Aventiv Research Inc. 
99 North Brice Road, Suite 260 
Columbus, Ohio 43213 
United States 
Tel: + 1 614 501-6164 
Therefore, Section 3 Investigators Signature was updated accordingly. 
Section 4 Additional Key Contacts for the Study was also updated to add 
the correcponding certified clinical laboratory.  
All 3 sites clinical sites will be using the Western Institutional Review 
Board. Section 4 Additional Key Contacts for the Study was updated 
accordingly. 
Minor editorial corrections were made where applicable. 
16-Sep-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 4 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below: 
1. Brigham and Women's Hospital Investigator signature and contact 
information was removed throughout the protocol since the center will 
not be participating during this study. The following sections were 
updated accordingly: 
• Section 3 Investigators Signatures 
• Section 4 Additional Key Contacts for the Study 
2. The age limits were changed from 40 - 80 years of age, inclusively, to 
30 - 85 years of age, inclusively. The following sections were updated 
accordingly: 
• Section 5 Synopsis - Study Population 
• Section 13.3.2 Inclusion Criteria – Inclusion criterion #1 
3. To provide scheduling flexibility to the patients, a ±2-day window was 
added to the return visits on Days 15, 29, and 43. The following 
sections were updated accordingly: 
• Section 5 Synopsis - Summary of Study Design and Exploratory 
Outcome Measures 
• Section 6 Study Events Flow Chart 
• Section 13.1 Overall Study Design and Plan 
• Section 13.4.1.2 Drug Administration During Treatment Period 
• Section 15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
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4. Breathalyzer was added as an alternative method to the urine dipstick 
for the alcohol screen. The following sections were updated 
accordingly: 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.3.3 Exclusion Criteria – Exclusion criterion #13 
• 
Section 14.1.6.7 Urine/Breathalyzer Alcohol Screen was added 
• 
Section 14.1.6.8 (previously 14.1.6.7) was renamed Urine Drug 
Screen (previously Urine Drug/Alcohol Screen). 
5. Only patients suffering from severe sleep apnea, as assessed by the 
Berlin Questionnaire, will be excluded from the study; The following 
sections were updated accordingly:  
• 
Section 6 Study Events Flow Chart 
• 
Section 13.3.3 Exclusion Criteria - exclusion criterion #8. 
• 
Section 14.1.8 Berlin Questionnaire was added. 
6. The body mass index upper limit was increased from 32.0 kg/m2 to 
40.0 kg/m2 inclusively. Therefore inclusion criterion #5 of 
Section 13.3.2 Inclusion Criteria was revised accordingly. 
7. Drug screen false positive will be allowed if they are due to the use of 
prescription medication following approval from the PI and the medical 
monitor, the exclusion criterion #13 of Section 13.3.3 Exclusion Criteria 
was revised accordingly. 
8. Smoking restriction prior to the bronchoscopy procedures was 
removed. Therefore, Section 14.3.2 Bronchoscopy and 
Bronchoalveolar Lavage (BAL) Biomarkers was updated accordingly. 
9. Only strong and moderate inhibitors of UDP-glucuronosyltransferase 
and/or sulfotransferases are prohibited, therefore to prevent confusion 
with the list of substrats that was provided in Appendix 1, Appendix 1 
was remove and the only 3 inhibitors listed in that table was 
enumarated in exclusion criterion #18. The list of substrate in appendix 
2 (now rename Appendix 1) was also remove. This change will prevent 
possible confusion with the lists provided in the appendices. Exclusion 
criterion #18 of Section 13.3.3 Exclusion Criteria was revised 
accordingly. 
10. To be consistent with Section 6 Study Events Flow Chart, pulse 
oximetry was added to the order of procecedures listed in Section 14.1 
Safety Assessments. 
11. Typographic and editorial corrections were made where applicable. 
 
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23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 3 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. The changes to the protocol are presented 
with new text in bold font and deleted text in strikethrough font. 
Serious Adverse Event Contact Information 
Drug Safety Solution’s Medical Monitor will be contacted in case of serious 
adverse events. Hence the information under Sponsor Contact for Serious 
Adverse Events (Medical Monitor) in Section 4 Additional Key Contacts for 
the Study was corrected as follows: 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, Seoul, 134-721, Republic of 
Korea   
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
Dr. Kathy Smith 
Drug Safety Solution  
Tel.: +1 919 264-5626 
E-mail:  ksmith@drugsafety.biz 
Section 14.1.8.4 Serious Adverse Events and Section 13.4.3.2 Procedures 
for Breaking the Blind Prior to Study Completion was also corrected 
accordingly. 
Certified Clinical Laboratory: 
Brigham and Women's Hospital and UAB Lung Health Center clinical 
laboratories contact information were added to Section 4 Additional Key 
Contacts for the Study. 
Clinical Indication: 
As indicated in the objectives of the study, the study will examine the 
pharmacodynamic (PD) effect of YPL-001 in patients with chronic 
obstructive pulmonary disease (COPD) only. Therefore, to prevent 
potential confusion and to capture the intended indication of the study 
specifically “asthma” was removed from the Clinical Indication in Section 5 
synopsis and Section 10.1 Purpose of the Study. 
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23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Population: 
As indicated throughout the protocol, patients will be will be adult males 
and females with moderate to severe COPD (conform to the severity 
classification for Global Initiative for Chronic Obstructive Lung Disease 
[GOLD] Stage 2-3). Hence to be consistent with the GOLD Stage 
standards, the first sentence under Study Population from Section 5, 
Synopsis was corrected as follow: 
“Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant 
bronchitic component and a history of frequent (>2/year) COPD 
exacerbations, between 40 and 80 years of age (inclusive).” 
Randomization and Drug Dispensing 
Instruction for randomization and drug dispensing are provided in a 
separate document. To be consistent with this document, which states that 
two sets of randomization code envelopes will be provided to site 
pharmacist/study coordinators and patients will received appropriately 
labeled kits and/or any unused wallets from previously provided kits 
(when applicable) for YPL-001 home dosing in addition to the containers 
for tiotropium/albuterol home dosing, the following section were modified 
accordingly: 
• 
Section 5 Synopsis under Summary of Study Design and Study 
Products 
• 
Section 6 Study Event Flow Chart, Day 1 Study Drug Administration at 
CRU - Footnotes “k” and “p” 
• 
Section 6 Study Event Flow Chart, Days 2 to 55 Study Drug 
Administration at Home – Footnotes “j” and “o” 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 13.4.3.1 Maintenance of Randomization 
• 
Section 13.4.3.2 Procedures for Breaking the Blind Prior to Study 
Completion 
In addition, and “X” was also added in the “Randomization” row under Day 
1 predose in Section 6 Study Events Flow Chart. 
Fasting Conditions 
As indicated throughout the protocol, subjects will be required to fast for at 
least 8 hours before and 4 hours after YPL-001/placebo morning 
administration on Days 1 and 56. For clarity, footnote “q” was added to 
Day 1 Study Drug Administration at CRU and footnote “k” was added to 
Day 56 Study Drug Administration at CRU in Section 6 Study Events Flow 
Chart. 
Analytes to be Measured 
As indicated throughout the protocol, blood samples will be collected for 
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by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
the analyses of verproside and picroside II in plasma. Hence, the row 
identified as “Blood for Verproside Phamacokinetics” on Day 56 of Section 
6 Study Events Flow Chart, was corrected to read: “Blood for Verproside & 
Picroside II PK”. 
End-of-Treatment – Early Termination Procedures 
All procedures listed under End-of-Treatment/Early Termination column in 
Section 6 Study Events Flow Chart are also scheduled to be performed on 
Day 55 before the bronchoscopy procedures. Therefore, as it is not 
required to repeat these procedures for two consecutive days, 
End-of-Treatment procedures were removed on Day 56, however early 
termination (ET) procedures were listed under the new ET column. Hence, 
the following sections were corrected accordingly.  
• 
Section 6 Study Events Flow Chart  
• 
Section 13.2.4.2 End-of-Treatment or Early Termination (Day 56), 
(renamed Section 13.2.4.2 Early Termination). 
• 
Section 13.3.2 Inclusion Criteria – Criterion #16 
• 
Section 13.3.4 Removal of Patients from the Study 
• 
Section 13.3.5.1.1 Prohibited Therapy 
• 
Section 13.3.5.1.2 Permitted Therapy 
• 
Section 14.1.8.2 Monitoring 
• 
Section 14.5 Blood Volume for Study Assessments (Table 5:  Blood 
Volume during Study) 
In addition, the following sentence was added to Section 13.2.4.2 End-of-
Treatment or Early Termination (Day 56), (renamed Section 13.2.4.2 Early 
Termination):   
“Patients who want to terminate from the study and are not currently on-
site will be contacted and asked to return to the CRU to perform the early 
termination procedures” 
Investigator’s Brochure Version 
In Section 9.1 YPL-001, the Investigator’s Brochure version was updated 
to reflect the reference section and the most recent version of the 
Investigator’s Brochure. 
Method of Blood Collection 
Throughout the protocol, the option of using an angiocatheter was added. 
Hence, the following sections were corrected accordingly: 
• 
Section 11 Risk/Benefit 
• 
Section 14.3.3 Blood Biomarkers 
• 
Section 14.4.1 Blood Sampling and Processing 
• 
Section 14.5 Blood Volume for Study Assessments 
Recording of Meal 
To be consistent with clinical sites standard procedures, the last sentence 
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by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
of Section 13.2.4.1 Meal Schedule was corrected as follow: 
“Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs.’ 
Coffee, Tea and Alcohol Prohibition 
As indicated in Section 13.3.5.2 Prohibitions, coffee tea, and red wine will 
be restricted for 7 days prior to Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample. Beer will be restricted 
for 14 days prior to Day 1 of the Treatment Period through collection of 
Day 56 last PK sample. Any other product containing xanthines or caffeine 
will be restricted 24 hours prior to each CRU visit and prior to dosing on 
Days 1 and 56 of the Treatment Period through collection of Days 1 and 
56 last PK sample. Any other alcohol product will be restricted 48 hours 
prior to each CRU visit, 48 hours prior to dosing on Days 1 and 56 last PK 
sample. Hence, the xanthines/caffeine prohibition  and the alcohol 
prohibition were corrected as follows for clarification: 
“Xanthines/caffeine (other than coffee and tea):  24 hours prior to each 
CRU visit and prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
“Alcohol (other than red wine and beer):  48 hours prior to each CRU 
visit, 48 hours prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
e-Diary 
Home dosing will be recorded using a yes/no answer in the e-diary. 
Therefore the last sentence of the second to last paragraph of 
Section 13.4.1.2 Drug Administration During Treatment Period was 
corrected as follows: 
“Patients will be given instructions on recording of dosing times how to 
record their drug administration in their e-diary on home-dosing days.’ 
In addition, estimation of sputum quantity was added to the list of major 
symptoms of COPD exacerbation recorded daily by the patients on their e-
diary, “color” and “consistency” was moved as example of sputum quality, 
and a statement indicating that the e-diary device will be return in case of 
early termination was also added. Hence, the following sections were 
corrected accordingly: 
• 
Section 5 Synopsis under Secondary Outcome Measures 
• 
Section 5 Synopsis under Summary of Study Design 
• 
Section 6 Study Events Flow Chart – Day 1, Footnote “j” 
• 
Section 6 Study Events Flow Chart – Days 2-55, Footnote “i” 
• 
Section 6 Study Events Flow Chart – Day 56, Footnotes “g” and “h” 
• 
Section 12.2 Study Endpoints 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
• 
Section 13.2.4 Treatment Period (Days 1 to 56) 
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23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 14.2.1 Electronic Diary 
• 
Section 14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease 
Exacerbation 
Treatment Compliance 
Drug administration at home will be monitored by HGE Technologies Inc. 
via the e-diary. Therefore, the last sentence of Section 13.4.4. Treatment 
Compliance was corrected as follow: 
“Self-administration by patients at home will be monitored by the CRU via 
the e-diary and attempted phone calls will be performed to remind patients 
to take their medication, if they did not record their self-administration on 
the e-diary.” 
Oxygen Saturation 
For consistency throughout the protocol, “oxygen levels, saturation (%)” 
was replaced with “oxygen saturation (%).” 
Tiotropium Treatment 
As indicated in Section 13.3.2 Inclusion Criteria and Section 13.3.5.1.2 
Permitted Therapy, tiotropium will be withheld 24 hours prior to pulmonary 
function (spirometry) measurements. Hence, the 2nd paragraph of Section 
14.3.1 Pulmonary Function (Spirometry), was corrected to read: 
“Short acting β2-agonist and anticholinergic bronchodilators (e.g., 
albuterol, ipratropium bromide) and long 
acting β2-agonist and 
anticholinergic bronchodilators (e.g., salmeterol, tiotropium) agents will be 
withheld approximately 4 and 12 24 hours, respectively, before each 
pre-bronchodilator spirometry.” 
Spirometer Across Clinical Site 
The 3rd paragraph of Section 14.3.1 Pulmonary Function (Spirometry) was 
corrected as follow: 
“Every effort will be made to perform all assessments for a given patient 
on the same instrument throughout the study and all sites should be using 
the same brand and model of spirometer for this study.” 
Bronchoalveolar Lavage (BAL) Collection 
It is planned that a maximum of 180 mL BAL will be performed during each 
planned bronchoscopy procedures. Therefore, to prevent confusion, the 
second sentence of Section 14.3.2.3, Bronchoalveolar Lavage (BAL) was 
corrected to read: 
“A total of 180 mL BAL, using 6 x 30 mL aliquots of normal saline 
warmed to room temperature, will be performed in using each 
subsegment of the right middle or lower lobe, as deemed appropriate by 
the Investigator, using 6 x 30 mL aliquots of normal saline warmed to room 
temperature.” 
Blood 
Volume 
for 
Clinical 
Safety 
Laboratory 
Tests, 
Pharmacodynamic (PD) Markers and Pharmacokinetic (PK) Samples: 
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DATE/NAME 
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23-Apr-2015 
by Caroline Engel 
Blood collection volume for PD markers, as indicated in Section 14.3.3 
Blood Biomarkers and Section 14.5 Blood Volume for Study Assessments, 
only accounts for 1 tube. However, 3 tubes will be required to assess CRP 
(4 mL tube), fibrinogen (3.5 mL tube) and the rest of the PD biomarkers (6 
mL tube). The blood volume per time point will be approximately 13.5 mL 
instead of 4.5 mL. 
As indicated above, End-of-Treatment listed on Day 56 were removed as 
the same tests are scheduled on Day 55 before the bronchoscopy 
procedures. Hence one sample was removed for a total of 3 on-study 
hematology and serum chemistry tests to be performed throughout the 
study. 
In addition, 4 mL of blood will be sufficient for the determination of 
verproside and picroside II concentration in plasma at each time point. 
Therefore the total blood volume was corrected to 310.5 mL for males and 
317.5 mL for females. Section 14.3.3 Blood Biomarkers, Section 14.4.1 
Blood Sampling and Processing, and Section 14.5 Blood Volume for Study 
Assessments were corrected accordingly. 
Minor typographic and editorial corrections were made where applicable. 
16-Feb-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 2 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. 
Number of Subjects: 
The sample size was revised to 60 subjects as it is sufficient to meet the 
objectives of the study. In case of dropouts, discontinued patients may be 
replaced at the discretion of the Sponsor as indicated throughout the 
protocol. Therefore the following sections were corrected accordingly to 
indicate that at least 60 subjects are planned to be enrolled and 
randomized with 20 patients to receive one of the 3 treatments: 
• 
Section 5 Synopsis (the 1st sentence of the 2nd paragraph under 
Summary of Study Design and the 1st and 2nd sentences under 
Number of Patients). 
• 
The 1st sentence of the 2nd paragraph of Section 13.1 Overall Study 
Design and Plan. 
• 
The 1st and 3rd sentences of Section 13.3.1 Number of Patients. 
• 
The last sentence of Section 15.1.1 Sample Size Calculation. 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) and 
COPD Assessment Test (CAT): 
BDI/TDI and CAT questionnaires will not be used as a diagnostic tool to 
assess the patient’s potential to meet all inclusion criteria and none of the 
exclusion criteria. Therefore these questionnaires are not required at 
screening. In addition, it is not required to perform them for 2 consecutive 
days to meet the study objectives and therefore, Day 55 assessments 
were removed.  
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DATE/NAME 
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16-Feb-2015 
by Caroline Engel 
 
 
Section 6 Study Events Flow Chart was corrected accordingly. 
The first sentence in Section 14.3.4.1 Baseline Dyspnea Index/Transition 
Dyspnea Index (BDI/TDI) was also corrected to be consistent with Section 
6. 
Early Termination Procedures: 
Weight, and oxygen levels, saturation (%), and heart rate assessed using 
a pulse oximeter were added to the procedures performed at the end of 
the Treatment Period on Day 56 or prior to early termination from the study 
to monitor subject’s safety appropriately. 
A 
pulmonary function 
(spirometry) test was also added prior to early termination for safety 
monitoring. 
Section 6 Study Events Flow Chart was corrected accordingly. 
Recording Concomitant Medication: 
Concomitant medication will be recorded at each study visit by the clinical 
staff in to the electronic data capture system. Therefore, concomitant 
medications was removed from the list of events that will be recorded by 
the patients via their e-diary throughout the protocol. The following 
sections were corrected accordingly: 
• 
Footnotes in Section 6 Study Events Flow Chart. 
• 
The first sentence of the 4th paragraph of Section 13.2.3 Run-In 
Period (Days 1 to 14 [± 2 days]). 
• 
The 2nd sentence of the 2nd paragraph of Section 13.2.4 Treatment 
Period (Days 1 to 56). 
• 
The 2nd sentence of the first paragraph of Section 14.2.1 Electronic 
Diary. 
Subject Numbering: 
The first paragraph of Section 13.4.2 Method of Assigning Patients to 
Treatment Groups was modified to clarify that the screening number and 
randomization number are two separate identification number given to 
each subject at different stages of the study. 
Adverse Events Reporting 
Footnotes were added to clarify the rating severity definitions in 
Section 14.1.8.3 Reporting. 
Minor editorial and typographical corrections were made where applicable. 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
Final Protocol, Amendment 1 
This protocol amendment is generated to update the study population with 
regards to smoking frequency, to update the handling procedures for BAL 
samples, and to clarify other study procedures as listed below. 
Study Population: 
Section 13.3.2 - Inclusion Criteria, bullet 11 was updated to indicate that 
the study population will consist only of current and ex-smokers with a 
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DATE/NAME 
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by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
history of >10 pack years. As such, the indications for ‘packs/year’ were 
replaced with ‘pack years’ and the allowance for current smokers with <10 
pack/years was removed. 
Wording was added to indicate an approximately equal number of current  
and ex-smokers will be enrolled, and that each treatment group will consist 
of an approximately equal number of smokers and ex-smokers. In 
addition, the stratification criteria for the randomization was updated to 
consist of either current or ex-smokers. 
 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Population and Number of 
Patients) 
• 
Section 13.1 - Overall Study Design and Plan (second paragraph) 
• 
Section 13.3.1 – Number of Patients. 
• 
Section 13.4.2 - Method of Assigning Patients to Treatment Groups. 
BAL Sample Handling: 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) was updated to indicate 
that sample handling, processing and storage procedures will be provided 
in a separate document.  
Follow-up Procedures: 
The wording in regards to follow-up procedures to be conducted on 
14 days (± 2 day), after the last study drug administration, was updated to 
indicated a phone-call and not a visit, as indicated correctly in Section 6 – 
Study Event Flow Chart. Study event were updated accordingly. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Duration of Participation for Patients, and 
Exploratory 
Outcome 
Measures 
[under 
Blood 
Assessments, 
Pulmonary Assessment, and Quality of Life Assessments])  
• 
Section 13.3.5.2 – Prohibitions (under Alcohol) 
• 
Section 14.1.8.2 – Monitoring (first paragraph). 
Study Duration: 
The total duration of the study indicated in Section 5 – Synopsis (under 
Duration of Participation for Patients) was corrected to 12 weeks to 
correspond with the actual study duration as indicated throughout the 
protocol.  
Inflammatory Markers in Blood Samples: 
The list of cell types to be evaluated as part of the inflammatory markers in 
the blood was updated to include monocytes instead of macrophages, as 
macrophages are not expected to be present in blood. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, fourth exploratory 
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objective, 
and 
under 
Exploratory 
Outcome 
Measures 
[under 
Pharmacodynamic Assesments, Blood Assessments, first bullet]) 
• 
Section 12.1 - Study Objectives (fourth exploratory objective) 
• 
Section 12.2 - Study Endpoints (third exploratory endpoint) 
• 
Section 14.3.3 - Blood Biomarkers (first bullet) 
• 
Section 15.1.5.1 - Biomarkers (third bullet)  
Neutrophil Evaluation in BAL Samples 
Neutrophils were added to the list of cell types to be evaluated as a 
percentage of the total cell count in BAL samples. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, second exploratory 
objective 
and 
under 
Exploratory 
Outcome 
Measures 
[under 
Pharmacodynamic 
Assessments, 
Bronchoalveolar 
Lavage 
Assessments, second bullet]) 
• 
Section 12.1 - Study Objectives (second exploratory objective) 
• 
Section 12.2 - Study Endpoints (second exploratory endpoint)  
• 
Section 14.3.2.4 - Biomarkers (second bullet) 
• 
Section 15.1.5.1 – Biomarkers (second bullet) 
Location of Study Drug Administration: 
Wording was added in Section 6 – Study Events Flow Chart for Day 56, to 
clarify that the study drug will be administered at the CRU. 
 
Meal Schedule: 
The indication for fasting requirement in Section 13.2.4.1 – Meal Schedule, 
was corrected to indicate patients will fast overnight for at least 12 hours 
before bronchoscopy and BAL collection on Days -1 and 55 instead of 
Days -1 and 56, as correctly indicated in Section 6 – Study Events Flow 
Chart. 
ECG Monitoring:  
Following an update in Celerion’s standard operating procedure, Section 
14.1.5 – Electrocardiogram Monitoring was updated to include at least 
5 minutes of rest prior to each ECG measurement (instead of at least 
1 minute as previously indicated). 
Hematology: 
The tests included in the hematology panel Section 14.1.6.1 – Hematology 
were updated to indicate that the red blood cell (RBC) count will include a 
reticulocytes count, and that the white blood cell (WBC) count with 
differential will include monocytes but will not include reticulocytes. 
Bronchoscopy and BAL: 
Due to the sensitivity of YPL-001 components to UV light, a warning was 
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IND No.: 114903 
 
 
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DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
added to protect all samples from exposure to UV light, as indicated for the 
PK blood samples. 
The following sections were affected: 
• 
Section 14.3.2.2 - Bronchial Brushings 
• 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) 
PK Population: 
The indication for measurable concentration of verproside and picroside II 
in urine was removed from the definition of PK population in Section 15.1.2 
- Patients to Analyze, as there is no urine PK sampling planned for this 
study. 
Minor typographic and editorial corrections were made where applicable. 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
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Proof of Concept 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _6_28Apr2016 
 
3. INVESTIGATORS SIGNATURES 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
I agree with the content of this protocol and the confidential nature of the documentation 
made as part of this study. I also acknowledge that the Sponsor of the study has the 
right to discontinue the study at any time. I have read the protocol and understand it and 
will work according to it and according to the principles of Good Clinical Practices, 
applicable laws and regulations, and the Declaration of Helsinki. 
 
 
Gerard J Criner, MD 
Temple University School of Medicine 
745 Parkinson Pavilion 
3401 North Broad Street 
Philadelphia, Pennsylvania, 19140  
United States 
Tel.:  +1 215 707-8113 
 
 
 
 
 
 
 
Investigator (Signature) 
 
Date 
 
 
 
Mark T. Dransfield, M.D. 
Associate Professor, Medical Director, UAB Lung Health Center 
The Kirklin Clinic of UAB Hospital 
2000 6th Avenue South,  
Birmingham, Alabama, 35233 
United States 
Tel.:  + 1 205 934-9999 
 
 
 
 
 
 
 
Investigator (Signature) 
 
Date 
 
 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious 
Adverse Events (Medical Monitor) 
Dr. Kathy Smith 
Drug Safety Solution 
Tel.: +1 919 264-5626 
E-mail:  ksmith@drugsafety.biz  
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratories 
For Temple University School of Medicine: 
Yuri Persidsky, MD, Ph.D. 
Chairperson, 
Department 
of 
Pathology 
and 
Laboratory Medicine 
Professor, Pathology and Laboratory Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
 
UAB Lung Health Center: 
UAB Hospital Laboratories 
619 19th Street South 
Birmingham, Alabama, 35249 
United States  
 
 
Aventiv Research Inc.: 
Quest Laboratories 
6700 Steger Drive,  
Cincinnati, Ohio, 45237 
United States  
 
 
 
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IND No.: 114903 
 
 
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Certified Clinical Laboratories 
(continued) 
Florida Pulmonary Research Institute, LLC: 
Quest Diagnostics 
4225 E Fowler Avenue 
Tampa, Florida, 33617 
United States  
Lab Director: Luis A. Diaz-Rosario, MD (FASCCP, 
FCAP), MT (FASCP) 
E-mail: luis.a.diaz-rosario@questdiagnostics.com 
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
 
Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Board Main 
Office Location 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
  
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IND No.: 114903 
 
 
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5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such chronic 
obstructive pulmonary disease (COPD) 
Study Type: 
Phase 2a, proof of concept 
Study Objectives: 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, monocytes, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
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Summary of Study 
Design: 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups 
(20 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) in the morning within 
3 days prior to Day 1 (define hereafter as Check-in) of the Treatment Period 
to confirm their eligibility and assess their health conditions. If they still meet 
all of the inclusion criteria and none of the exclusion criteria, they will 
undergo Check-in scheduled study procedures. Patients will return to the 
CRU on the morning of Day 1 to be randomized and receive one of the 
3 treatments and undergo all scheduled study procedures. Patients will 
return on the morning of Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), 
54 (± 1 day), and 56 of the Treatment Period for study drug administration 
and procedures. Prior to each release from the CRU, patients will receive a 
properly labeled YPL-001 kit (and/or any unused wallets from previously 
provided kits [when applicable]) and tiotropium/albuterol container with 
sufficient doses which will be self-administered by patients at home until the 
next morning visit at the CRU. Patients will continue recording their daily 
symptoms via the e-diary throughout the Treatment Period. Patients will 
return the e-diary device on Day 56 (or prior to early termination) to CRU 
staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
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will be administered in accordance with the study center standard of care. 
Study Population: 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component, between 30 and 85 years of age (inclusive). An approximately 
equal number of current and ex-smokers will be enrolled. 
Number of 
Patients: 
The study is planned to enroll at least 60 patients. Patients will be divided in 
3 treatment groups with 20 patients to receive one of the 3 treatments (i.e., 
low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo 
control) as per the randomization schedule. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Duration of 
Participation for 
Patients: 
The planned length of participation in the study for each patient is 
approximately 12 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up procedures on Day 70 [± 2 days]). 
Duration of Study 
Conduct: 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products: 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
YPL-001 or placebo will be dispensed in accordance with the Randomization 
and Drug Dispensing Instructions provided in a separate document. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen: 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 
80 
mg matching 
placebo 
tablet) 
will 
be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days.. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B, and C will be administered orally with 
approximately 240 mL of water. 
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IND No.: 114903 
 
 
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Stopping Rules: 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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Safety and 
Tolerability 
Analysis 
(continued): 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures: 
PEF, major (e.g., estimated sputum quality [e.g., color, consistency], and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, 
discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (Duke 
Activity Status Index [DASI]) self-reported daily by the patients using an 
e-diary. 
Symptom 
Monitoring 
Analysis: 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, and throughout the study for 
PD assessments of biomarkers. Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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Exploratory 
Outcome 
Measures 
(continued): 
IC] will be performed at screening, and throughout the study. 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, and throughout the study. 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 54 (± 1 day) to determine 
verproside and picroside II concentrations in plasma. Predose samples will 
also be collected in the morning of Days 15 (± 2 days), 29 (± 2 days), 
43 (± 2 days) and 54 (± 1 day) for Ctrough determination. Other components of 
YPL-001 and its metabolites may also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis: 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis: 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-001 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
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IND No.: 114903 
 
 
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6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
Up to  
-3 c 
1 
Hours → 
 
 
C-I 
Predose 0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-rayf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Berlin Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsh 
X 
 
 
Xg 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAi 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usej 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityk 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationl 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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IND No.: 114903 
 
 
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Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
Up to  
-3 c 
1 
Hours → 
 
 
C-I 
Predose 0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 3.5 4 5 6 8 10 
12 
Study Drug Administration at CRUm,n 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)o 
X 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersp 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
 
 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xq 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitsr 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
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a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. Scheduled procedures may be performed within 3 days prior to Day 1 dosing. 
d. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
e. To be performed prior to the bronchoscopy procedures. 
f. 
To be performed at screening or within 3 months (inclusive) of screening. 
g. ECGs, vital sign and pulse oximetry will be measured within 4 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
h. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
i. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
j. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
k. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
l. 
Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
m. Prior to release from the CRU, patients will receive a properly labeled kit with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
n. On Day 1, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
o. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
p. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
q. To be performed prior to dosing. 
r. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
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STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 
2-14 
15 (± 2) 
16-28 
29 (± 2) 
30-42 
43 (± 2) 
44-53 
Hours → 
 
AM 
PM 
 
AM 
PM 
 
AM 
PM 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Vital Signsd 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Hem, Chem, and UAe 
 
 
 
 
Xc 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Urine Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Urine or Breathalyzer Alcohol Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
Diary Usef 
X 
PEF, COPD exacerbation, dyspnea and activityg 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationh 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
Study Drug Administration at Homei 
X 
 
X 
X 
 
X 
X 
 
X 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)j 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
BDI/TDI & CAT 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
Return Visitsk 
 
X 
 
 
X 
 
 
X 
 
 
Refer to the footnotes on the next page 
 
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a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
e. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
f. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
g. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
h. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
i. 
Prior to release from the CRU on Days 15 (± 2 days), 29 (± 2 days), and 43 (± 2 days) patients will receive a properly labeled kit and/or any 
unused wallets from previously provided kits (when applicable) with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
j. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
k. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
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STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
ETb FUc 
Days → 
54 (± 1 day) 
55 
56 
Hours → Predose 
0 
0.167 0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
Vital Signsg 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
 
Xf 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
Hem, Chem, and UAh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xe 
X 
 
PEF, COPD exacerbation, dyspnea 
and activityj 
X 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
Study Drug Administration at CRUk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Study Drug Administration at Homel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)m 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
X 
 
Bronchoscopy and BAL Biomarkerso 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Blood Biomarkers 
Xp 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsq 
X 
 
X 
X 
 
Refer to the footnotes on the next page 
 
 
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a. For details on Procedures, refer to Section 14. 
b. To be performed prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. To be performed or completed prior to bronchoscopy procedures. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 4 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
i. 
Patients will return the e-diary device on Day 56 (or prior to early termination) to CRU staff.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
k. On Day 54 (± 1 day), patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning 
administration.  
l. 
Prior to release from the CRU on Day 54 (± 1 day) patients will receive a properly labeled kit and/or any unused wallets from previously 
provided kits (when applicable) with sufficient study drug for their assigned treatment which will be self-administered by patients at home until 
the next morning visit at the CRU. Patients must return the used and unused wallets at the next morning visit. Home dosing will be monitored 
via attempted phone calls where patients will be reminded to take their medication, if they did not record their self-administration on the 
e-diary, and queried about the occurrence of AEs. 
m. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
n. To be completed prior to bronchoscopy procedures. 
o. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
p. To be performed at predose on Day 54 (± 1 day) or upon early termination. 
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q. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition 
Dyspnea Index Test, CAT = COPD Assessment Test, Chem = Serum chemistry, C-I = Check-in, COPD = chronic obstructive pulmonary disease, 
CRU = Clinical research unit, ConMeds = Concomitant medication, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = 
electronic diary, ET =  Early termination, FSH = Follicle-stimulating hormone, Hem = Hematology, HIV = Human immunodeficiency virus, IL= 
interleukin, 
PEF = Peak 
expiratory 
flow, 
PK = Pharmacokinetics, 
PM = Evening, 
Preg = Serum 
pregnancy, 
PT/INR = Prothrombin 
time/international normalized ratio, Screen = Screening, UA = Urinalysis. 
 
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7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY .......................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ................................................................................................. 16 
3. 
INVESTIGATORS SIGNATURES .......................................................................................... 17 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY .............................................................. 19 
5. 
SYNOPSIS ............................................................................................................................. 21 
6. 
STUDY EVENTS FLOW CHART ........................................................................................... 27 
7. 
TABLE OF CONTENTS ......................................................................................................... 35 
8. 
ABBREVIATIONS .................................................................................................................. 38 
9. 
INTRODUCTION AND BACKGROUND ................................................................................ 42 
9.1 
YPL-001 ....................................................................................................................... 42 
9.1.1 
Preclinical Trials .............................................................................................. 42 
9.1.1.1 
Pharmacology ................................................................................. 42 
9.1.1.2 
Pharmacokinetics ............................................................................ 43 
9.1.1.3 
Toxicology ....................................................................................... 44 
9.1.2 
Clinical Experience ......................................................................................... 45 
9.1.2.1 
SAD study ....................................................................................... 46 
9.1.2.2 
MAD Study ...................................................................................... 47 
10. RATIONALE ........................................................................................................................... 49 
10.1 Purpose of the Study ................................................................................................... 49 
10.2 Dose Selection ............................................................................................................. 49 
11. RISK/BENEFIT ....................................................................................................................... 51 
12. STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 52 
12.1 Study Objectives .......................................................................................................... 52 
12.2 Study Endpoints ........................................................................................................... 52 
13. INVESTIGATIONAL PLAN ..................................................................................................... 54 
13.1 Overall Study Design and Plan .................................................................................... 54 
13.2 Study Conduct ............................................................................................................. 55 
13.2.1 Screening ........................................................................................................ 55 
13.2.2 Patient Confinement ....................................................................................... 55 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ......................................................... 55 
13.2.4 Treatment Period (Days 1 to 56) .................................................................... 56 
13.2.4.1 Meal Schedule ................................................................................ 56 
13.2.4.2 Early Termination ............................................................................ 57 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................... 57 
13.2.6 Scheduled End of Study ................................................................................. 57 
13.3 Selection of Study Population ...................................................................................... 57 
13.3.1 Number of Patients ......................................................................................... 57 
13.3.2 Inclusion Criteria ............................................................................................. 57 
13.3.3 Exclusion Criteria ............................................................................................ 59 
13.3.4 Removal of Patients from the Study ............................................................... 61 
13.3.5 Study Restrictions ........................................................................................... 62 
13.3.5.1 Concomitant Therapy ...................................................................... 62 
13.3.5.1.1 
Prohibited Therapy ..................................................... 62 
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13.3.5.1.2 
Permitted Therapy ...................................................... 63 
13.3.5.2 Prohibitions...................................................................................... 63 
13.3.5.3 Activity ............................................................................................. 63 
13.4 Treatments ................................................................................................................... 64 
13.4.1 Treatments administered ................................................................................ 64 
13.4.1.1 Drug Administration During Run-in Period ...................................... 64 
13.4.1.2 Drug Administration During Treatment Period ................................ 64 
13.4.1.3 Stopping Rules ................................................................................ 65 
13.4.2 Method of Assigning Patients to Treatment Groups ....................................... 66 
13.4.3 Blinding ........................................................................................................... 66 
13.4.3.1 Maintenance of Randomization ...................................................... 66 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 66 
13.4.3.3 Revealing of Randomization ........................................................... 67 
13.4.4 Treatment Compliance ................................................................................... 67 
14. STUDY PROCEDURES ......................................................................................................... 68 
14.1 Safety Assessments .................................................................................................... 68 
14.1.1 Body Height and Weight ................................................................................. 68 
14.1.2 Physical Examination ...................................................................................... 68 
14.1.3 Vital Signs ....................................................................................................... 68 
14.1.4 Pulse Oximetry................................................................................................ 69 
14.1.5 Electrocardiogram Monitoring ......................................................................... 69 
14.1.6 Clinical Laboratory Tests ................................................................................ 70 
14.1.6.1 Hematology ..................................................................................... 70 
14.1.6.2 Serum Chemistry ............................................................................ 70 
14.1.6.3 Serology .......................................................................................... 70 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............. 70 
14.1.6.5 Follicle-Stimulating Hormone .......................................................... 71 
14.1.6.6 Urinalysis ......................................................................................... 71 
14.1.6.7 Urine/Breathalyzer Alcohol Screen ................................................. 71 
14.1.6.8 Urine Drug Screen .......................................................................... 71 
14.1.6.9 Additional Tests ............................................................................... 71 
14.1.7 Chest X-Ray .................................................................................................... 71 
14.1.8 Berlin Questionnaire ....................................................................................... 71 
14.1.9 Adverse Events ............................................................................................... 72 
14.1.9.1 Adverse Event Definition ................................................................. 72 
14.1.9.2 Monitoring........................................................................................ 72 
14.1.9.3 Reporting ......................................................................................... 72 
14.1.9.4 Serious Adverse Events .................................................................. 74 
14.2 Symptom Assessments ............................................................................................... 74 
14.2.1 Electronic Diary ............................................................................................... 74 
14.2.2 Peak Expiratory Flow ...................................................................................... 75 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ............ 75 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) ....................................................... 75 
14.2.5 Activity (Duke Activity Status Index) ............................................................... 75 
14.3 Pharmacodynamic Assessments ................................................................................. 75 
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14.3.1 Pulmonary Function (Spirometry) ................................................................... 75 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers .................... 76 
14.3.2.1 Bronchoscopy ................................................................................. 76 
14.3.2.2 Bronchial Brushings ........................................................................ 77 
14.3.2.3 Bronchoalveolar Lavage (BAL) ....................................................... 77 
14.3.2.4 Biomarkers ...................................................................................... 77 
14.3.3 Blood Biomarkers ........................................................................................... 78 
14.3.4 Quality of Life Questionnaires ......................................................................... 78 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ......................................................................................... 78 
14.3.4.2 COPD Assessment Test (CAT)....................................................... 78 
14.4 Pharmacokinetic Assessments .................................................................................... 79 
14.4.1 Blood Sampling and Processing ..................................................................... 79 
14.5 Blood Volume for Study Assessments......................................................................... 80 
15. DATA ANALYSIS ................................................................................................................... 81 
15.1 Statistical Analysis ....................................................................................................... 81 
15.1.1 Sample Size Calculation ................................................................................. 81 
15.1.2 Patients to Analyze ......................................................................................... 81 
15.1.3 Safety Analysis ............................................................................................... 82 
15.1.4 Symptom Monitoring Analysis ........................................................................ 83 
15.1.5 Pharmacodynamic Analysis ............................................................................ 83 
15.1.5.1 Biomarkers ...................................................................................... 83 
15.1.5.2 Quality of Life .................................................................................. 84 
15.1.6 Pharmacokinetic Analysis ............................................................................... 84 
15.1.6.1 Pharmacokinetic Parameters .......................................................... 84 
15.1.6.1.1 
Plasma ....................................................................... 84 
15.1.6.1.2 
Bronchoalveolar Lavage ............................................ 85 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ......................... 86 
15.1.7 Assessment of Efficacy ................................................................................... 86 
16. STUDY ADMINISTRATION ................................................................................................... 87 
16.1 Ethics ........................................................................................................................... 87 
16.1.1 Institutional Review Board .............................................................................. 87 
16.1.2 Ethical Conduct of the Study .......................................................................... 87 
16.1.3 Patient Information and Consent .................................................................... 87 
16.2 Termination of the Study .............................................................................................. 87 
16.3 Data Quality Assurance ............................................................................................... 87 
16.4 Direct Access to Source Data/Documents .................................................................. 88 
16.5 Drug Supplies, Packaging and Labeling ...................................................................... 88 
16.6 Data Handling and Record Keeping ............................................................................ 88 
16.7 Protocol Amendments ................................................................................................. 88 
16.8 Finance and Insurance ................................................................................................ 89 
16.9 Publication Policy ......................................................................................................... 89 
17. REFERENCES ....................................................................................................................... 90 
18. APPENDICES ........................................................................................................................ 91 
18.1 Appendix 1 - SULT Drug Interaction Table .................................................................. 91 
 
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8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
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CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
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INR 
International normalized ratio 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
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OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
RNA 
Ribonucleic acid 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
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9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
GCP, and applicable regulatory requirements. The patient population will be comprised 
of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of June 3, 2014. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Bronchoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
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verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
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picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
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and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
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9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 
0.67 hours under fasting conditions. Verproside appeared to be cleared rapidly from 
plasma, with mean t1/2 values under 1 hour; plasma verproside concentrations were 
below the lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 
below summaries the PK parameters of verproside following single-dose administrations 
of YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
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9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t½ values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t½ values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
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Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
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10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such COPD to demonstrate safety and 
evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
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Table 4: Traditional Chinese Medicine Use versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
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11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an angiocatheter is utilized and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
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12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., estimated sputum quality [e.g., color, consistency] and quantity) and 
minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body 
temperature above 100°F) symptoms of COPD exacerbation;  
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• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and 
eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
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13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups (20 patients 
per group). Patients will participate only once. An approximately equal number of current 
and ex-smokers will be enrolled in the study. 
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU in the morning, –for Check-in of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Check-in scheduled 
study procedures. Patients will return to the CRU on the morning of Day 1 to be 
randomized and receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15 (± 2 days), 29 (± 2 days), 43 
(± 2 days), 54 (± 1 day), and 56 of the Treatment Period for study drug administration 
and procedures. Prior to each release from the CRU, patients will receive a properly 
labeled kit and/or any unused wallets from previously provided kits (when applicable) 
with sufficient doses which will be self-administered by patients at home until the next 
morning visit at the CRU. Patients will continue recording their daily symptoms via the e-
diary throughout the Treatment Period. Patients will return the e-diary device on Day 56 
(or prior to early termination) to CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
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will be discontinued. Rescue medication will be used for any patient with an 
exacerbation of COPD and will be administered in accordance with the study center 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses and their daily respiratory symptoms. Prior to each morning 
dose, patients will record at home their daily PEF, major (e.g., estimated sputum quality 
[e.g., color, consistency] and quantity) and minor (e.g., cough, wheeze, sore throat, 
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nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 55 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses and their daily 
respiratory symptoms on their e-diary. Prior to each morning dose, patients will record at 
home their daily PEF, major (e.g., estimated sputum quality [e.g., color, consistency] and 
quantity) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and 
body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before the bronchoscopy 
and BAL collection at the Check-in of the Treatment Period and on Day 56. On Days 1 
and 54 (± 1 day), patients will be required to fast overnight for at least 8 hours before 
and for at least 4 hours after the morning dose. On all other days, patients will be asked 
to fast for at least 2 hours before and 2 hours after each morning dose. Patients will also 
be asked to fast for at least 2 hours before and after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 54 (± 1 day), patients will fast from all food and drink except water 
between meals and snacks. Foods and beverages containing alcohol, xanthines, 
caffeine, vegetables from the mustard green family, mustard, tea (especially speedwell 
tea), or grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, 
menus should be similar in content. The same menu and meal (except for snacks) 
schedule will be administered uniformly for all patients confined within the same CRU, 
across all treatment groups. Meals are not required to be completed by patients. 
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13.2.4.2 Early Termination  
Early termination evaluations will be performed on patients prior to early termination. 
Patients who want to terminate from the study and are not currently on-site will be 
contacted and asked to return to the CRU to perform the early termination procedures. 
The early termination procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll at least 60 patients. An approximately equal number of 
current and ex-smokers will be enrolled. Patients will be divided in 3 treatment groups 
with 20 patients to receive one of the 3 treatments (i.e., low and high YPL-001 doses 
[80 mg and 160 mg BID] and a placebo control) as per the randomization schedule. 
Each treatment group will consist of an approximately equal number of current and 
ex-smokers. 
13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 30 to 85 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
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4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-40.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24 hours 
prior to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled 
CRU visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack years. Ten pack years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Patients, who undergo smoking cessation therapy, must be completed 
3 months prior to screening visit and smoking status should not change between the 
patient’s screening visit and patient’s last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
13. A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method 
(e.g., condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
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14. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
15. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the last scheduled study procedures on Day 56 or upon early 
termination. Patients will be advised to use a condom with spermicide for 90 days 
following the last administration of the study drug, and to not donate sperm during 
this same period of time. In the event that the sexual partner is surgically sterile, use 
of a condom with spermicide is not necessary. No restrictions are required for 
vasectomized males provided their vasectomy has been performed 120 days or 
more prior to study start. Males who have been vasectomized less than 120 days 
prior to study start must follow the same restrictions as non-vasectomized males. 
16. Understands study procedures and provides written informed consent for the trial. 
17. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
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8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), severe sleep apnea (assessed using the Berlin Questionnaire [refer to 
Section 14.1.8]), cardiovascular, endocrine, neurological, hepatic, gastrointestinal, 
renal, hematological, urological, immunological or ophthalmic diseases that the 
Investigator believes are clinically significant e.g., unstable and could impact patient 
safety by participation in the study. 
9. History or presence of clinically significant cardiac arrhythmia, prostatic hyperplasia, 
bladder-neck obstruction, urinary retention, or narrow-angle glaucoma that, in the 
opinion of the PI, would contraindicate the administration of tiotropium. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Diagnosed with hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive alcohol (using urine dipstick or breathalyzer) test results at screening or at 
each CRU visit. If alcohol test is positive or subject reports consumption of alcohol 
within 48 hours prior to testing, alcohol test maybe rescheduled or repeated, at the 
discretion of the PI and if study visit time window allows.  
14. Urine drug testing at screening or at each CRU visit, unless the positive drug screen 
is due to prescription drug use and is approved by the PI and the medical monitor. 
15. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C infection with clinically significant liver impairement and/or a 
viral ribonucleic acid (RNA) titer of > 6.9 ± 0.8log molecules/mL.3  
16. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
17. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
18. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
19. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) (such as 17-beta-estradiol 
glucuronide, flavonoids [citrus fruit], silybin [herb supplement milk thistle]) and/or 
sulfotransferases (SULT) (refer to Appendix 1), within 12 hours prior to Day 1 of the 
Run-in Period. Additional sources may be consulted by the PI or medical monitor to 
confirm lack of PK/PD interaction with study drug. 
20. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
21. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
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22. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
23. Females who are pregnant or lactating.  
24. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
25. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion (early 
termination evaluations) as the situation allows (see Section 13.2.4.2). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
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13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the last scheduled study 
procedures on Day 56 or upon early termination). Intake of these medications during the 
Run-in Period constitutes a non-eligibility criterion and the patients will not be 
randomized into the study. If any of these medications are taken during the Treatment 
Period, the need for this patient to be withdrawn from the study will be carefully 
evaluated by the Investigator and the Sponsor on the basis of the potential impact on 
efficacy or safety evaluation and in the patient's best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements (except for prescribed vitamin supplement) and herbal products 
(especially Speedwell) will be prohibited 7 days prior Day 1 of the Treatment Period 
and through collection of the final PK sample. 
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13.3.5.1.2 Permitted Therapy 
Throughout the study period (from Day 1 of the Run-in Period to the completion of the 
last scheduled study procedures on Day 56 or upon early termination) patients will be 
permitted to take the following medications in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 24 hours 
before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. Prescribed vitamin supplement (except for Vitamin C). 
5. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine (other than coffee and tea):  24 hours prior to each CRU visit and 
prior to dosing on Days 1 and 54 (± 1 day) of the Treatment Period through collection 
of Days 1 and 54 (± 1 day) last PK sample. 
• 
Alcohol (other than red wine and beer):  48 hours prior to each CRU visit and 
48 hours prior to dosing on Days 1 and 54 (± 1 day) of the Treatment Period through 
collection of Days 1 and 54 (± 1 day) last PK sample. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 54 (± 1 day) last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 
54 (± 1 day) of the Treatment Period through collection of Days 1 and 54 (± 1 day) 
last PK sample. 
• 
Tea (especially Speedwell tea), coffee, and red wine:  7 days prior to Days 1 and 
54 (± 1 day) of the Treatment Period through collection of Days 1 and 54 (± 1 day) 
last PK sample. 
• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 54 (± 1 day) last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
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muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
YPL-001 or placebo will be dispensed in accordance with the Randomization and Drug 
Dispensing Instructions provided in a separate document. 
Prior to release from the CRU on Days 1, 15 (± 2 days), and 29 (± 2 days), of the 
Treatment Period, patients will receive a properly labeled new kit, which contains 
4 wallets of 2 blister cards, with the appropriate doses which will be self-administered by 
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patients at home. Any unused wallets from previously provided kits will also be 
dispensed to patients on Days 15 (± 2 days) and 29 (± 2 days). Prior to release from the 
CRU on Days 43 (± 2 days), and 54 (± 1 day), patients will received unused wallets from 
previously provided kits with the appropriate doses which will be self-administered by 
patients at home. Patients will also receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. Patients will record their 
self-administered doses in their e-diary, and whether the dose was administered with 
food, and must return the YPL-001 used and unused wallets and the tiotropium and 
albuterol container (empty or not) at the next schedule visit at the next morning visit. 
Home dosing will be monitored via attempted phone calls where patients will be 
reminded to take their medication, if they did not record their self-administration on the 
e-diary, and queried about the occurrence of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
given instructions on how to record their drug administration in their e-diary on 
home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
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13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique screening identification number upon screening. 
Patients who complete the study screening assessments, complete the Run-in Period, 
and meet all the eligibility criteria will be assigned a unique randomization identification 
number, different from the screening number, and receive the corresponding product, 
according to a randomization scheme generated at Celerion. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
The randomization will not be made available to the Sponsor, patients, or members of 
the staff responsible for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
The site Pharmacist/Study Coordinator will receive two sets of randomization code 
envelopes, one set for “Current Smokers” and another for “Ex-Smokers”. Each individual 
envelope is marked on the outside with one of the randomization numbers and contains 
the treatment for that patient. These envelopes must be kept in a secure locked location. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the medical monitor or designee prior to breaking the blind. If breaking 
the blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
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13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
1. All data are entered in the database, edits checks are performed, queries 
closed, CRFs signed by the Investigator, and the database is officially locked. 
2. All PK/PD samples have been analyzed and quality checked by the 
responsible analytical associate. 
13.4.4 Treatment Compliance 
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
Self-administration by patients at home will be monitored via the e-diary and attempted 
phone calls will be performed to remind patients to take their medication, if they did not 
record their self-administration on the e-diary. 
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14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs and pulse oximetry 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
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When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When performed prior to the bronchoscopy, 
blood pressure and heart rate will be measured within 4 hours prior to the bronchoscopy. 
When scheduled postdose, vital signs readings will be performed within approximately 
10 minutes of the scheduled time point. When performing the bronchoscopy, vital signs 
(body temperature, respiratory rate, blood pressure, and heart rate) will be monitored 
continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen saturation (%), and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen saturation [%], and heart rate) 
as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. When performed prior to the bronchoscopy, pulse 
oximetry monitoring will be measured within 4 hours prior to the bronchoscopy. 
Readings may be taken at other times, if deemed necessary by the Investigator. When 
performing the bronchoscopy, oxygen saturation will be monitored continuously until the 
end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performed prior to the bronchoscopy, ECG will be measured within 
4 hours prior to the bronchoscopy. When performing the bronchoscopy, ECG will be 
monitored continuously until the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
5 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
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14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count (including a 
reticulocytes count) 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, and 
monocytes) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
• 
HCV viral RNA titer 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
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14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine/Breathalyzer Alcohol Screen 
Alcohol levels will be tested using urine dipsticks or breathalyzers. 
14.1.6.8 Urine Drug Screen 
• 
Cannabinoids  
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.6.9 Additional Tests 
• 
Prothrombin time/international normalized ratio (PT/INR) 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Berlin Questionnaire 
The Berlin Questionnaire is a validated screening questionnaire used to quickly identify 
the risk (low to high) of sleep disordered breathing. The questionnaire consists of three 
categories and risk is based on the responses to individual items and overall scores in 
the symptom categories. Assessments will be performed according to the Study Events 
Flow Chart (Section 6). The questionnaire will be provided as a separate document and 
a copy of the questionnaire to be used will be kept in the study binder.  
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14.1.9 Adverse Events 
14.1.9.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.4 
14.1.9.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, after the last 
scheduled study procedures on Day 56 (or upon early withdrawal), and at the follow-up 
phone call. The inquiry will be made in a non-specific manner using open-ended 
questions so as not to bias the response (e.g., How have you been feeling since your 
last visit?). 
All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.9.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 5 and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
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The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade; ADL = Activities of Daily Living 
*Instrumental ADL refer 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. 
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14.1.9.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Medical Monitor via fax or e-mail within one working day of 
becoming aware of the event, whether or not the serious events are deemed 
drug-related. All serious event reporting will adhere to 21 CFR 312.32 for Investigational 
New Drugs (IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20124. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
If an SAE occurs to a patient on this study, the Medical Monitor is to be contacted (see 
Section 4). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses, whether the dose was 
administered with food, and daily respiratory symptoms throughout the Run-in and 
Treatment Periods. Patients will return the e-diary device on Day 56 (or prior to early 
termination) to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., 
estimated sputum quality [e.g., color, consistency] and quantity) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity 
(DASI). 
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14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., estimated sputum quality [e.g., color, 
consistency] and quantity) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation via the e-diary before each dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) 
and 
long 
acting 
β2-agonist 
and 
anticholinergic 
bronchodilators 
(e.g., salmeterol, tiotropium) agents will be withheld approximately 4 and 24 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study. 
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At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol (100 μg/inhalation) for a total dose of 
400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes 
after albuterol administration, the baseline post-bronchodilator spirometry will be 
performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Check-in measurement): Predose 
FEV1 is defined as the time point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
FEV1 measurement at predose at Check-in of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose at Check-in, up to 3 measures will be 
performed.  
Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be fasted for 12 hours before the bronchoscopy procedures. If required, 
blood pressure medications can be taken with small sip of water based on preapproval 
of local Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.6,7 
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Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal cannula will be 
administered during bronchoscopy and oxygen saturation will be maintained at ≥95%. 
Conscious sedation will be achieved with incremental doses of 1–4 mg midazolam and 
50-100 μg fentanyl. Local upper and lower airway topical anesthesia will be achieved 
with 1% or 2% lidocaine. The dose of lidocaine administered during the procedure will 
not exceed a total of 450 mg. The bronchoscope will usually be inserted preferably 
through the nares into trachea. The bronchoscope will be wedged into 2 subsegments of 
the right middle or lower lobe, as deemed appropriate by the Investigator. Emergency 
treatments for cardiopulmonary arrest and pneumothorax will be immediately available in 
the bronchoscopy room. The patient will remain in the recovery suite for observation for 
a minimum of 2 hours after the procedure.  
14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A total of 180 mL BAL, 
using 6 x 30 mL aliquots of normal saline warmed to room temperature, will be 
performed using each subsegment of the right middle or lower lobe, as deemed 
appropriate by the Investigator. BAL fluid will be aspirated following each 30 mL 
instillation. The lavage material, which averages 25% return in COPD patients, typically 
yields 1-10 x 106 macrophages. The centrifuged cell pellet and supernatant will be kept 
cooled until processed or stored as indicated in the laboratory manual to be provided as 
a separate document. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and eosinophils 
as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
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as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture or an angiocatheter at the time 
points delineated in the Study Events Flow Chart (Section 6) for PD assessments of 
biomarkers. Biomarker assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 3 tubes.  A manual for blood sampling, collection, processing, 
and sample shipment will be provided in a separate document. 
14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Check-in of the Treatment Period) will be assessed with the BDI. 
This instrument has 3 domains (functional impairment, magnitude of task, and 
magnitude of effort) with the values added for a combined focal score. Functional 
impairment determines the impact of breathlessness on the ability to carry out activities; 
magnitude of task determines the type of task that causes breathlessness, magnitude of 
effort establishes the level of effort that results in breathlessness. The BDI scores range 
from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline 
focal score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.8,9 
A copy of the questionnaire to be used will be kept in the study binder. 
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14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture or an angiocatheter at the time points 
delineated in the Study Events Flow Chart (Section 6).  
Blood will be drawn into 4 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
 
 
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14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time 
Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology, PT/INR), FSH (for 
postmenopausal female patients only), 
and serum pregnancy (for female 
patients only). 
1 
~ 17 mL** or 
21 mL*** 
~ 17 mL** or 21 mL*** 
On-study serum chemistry and serum 
pregnancy (for female patients only) 
when scheduled at the same time 
3 
~ 8.5 mL 
~ 25.5 mL 
Additional on-study serum pregnancy 
(for female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
3 
~ 4 mL 
~ 12 mL 
Blood samples for PD biomarkers 
(except CRP and fibrinogen) 
8 
~ 6 mL 
~ 48 mL 
Blood samples for PD biomarker - 
CRP 
8 
~ 4 mL 
~ 32 mL 
Blood samples for PD biomarker - 
Fibrinogen 
8 
~ 3.5 mL 
~ 28 mL 
Blood samples for PK of verproside 
and picroside II 
37 
~ 4 mL 
~ 148 mL 
Total Blood Volume for males† → 
~ 310.5 mL** or 
314.5 mL*** 
Total Blood Volume for females† → 
~ 317.5 mL **or 
321.5 mL*** 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** For patients enrolled at UAB Lung Health Center, Florida Pulmonary Research Institute, LLC, 
or Temple University School of Medicine.  
***For patients enrolled at Aventiv Research Inc. only. 
†   If an angiocatheter is used, up to 5 mL of blood will be used to flush the catheter prior to each 
collection of PK and/or PD blood samples. Hence the total blood volume collected may 
increase by approximately 205 mL. 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma concentration of verproside and 
picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Day 1 and/or Day 54 
(± 1 day). 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 
post-baseline PD measurement. 
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• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
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Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes, 
neutrophils, and eosinophils as a percentage of total cells; total cell count [cells/mL] 
of neutrophils, macrophages, lymphocytes and eosinophils as absolute inflammatory 
cell numbers; and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9): raw and % change from baseline levels; 
and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and lymphocytes] 
and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
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15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
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† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
The following PK parameters will be computed following Day 54 (± 1 day) morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc 
Percent fluctuation will be calculated as follows: 
𝐶𝐶max _𝑠𝑠𝑠𝑠−𝐶𝐶min _𝑠𝑠𝑠𝑠
𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎
 𝑥𝑥 100 
Swing 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
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15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), and 54 (± 1 day) following multiple oral 
dose administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
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16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP 
(E6 Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
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check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets, and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 
5 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
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16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
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17. REFERENCES 
 
                                               
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 Gretch D, et al. Assessment of Hepatitis C Virus RNA Levels by Quantitative Competitive RNA 
Polymerase Chain Reaction: High-Titer Viremia Correlates with Advanced Stage of Disease. J 
Infect Dis. 1994;169(6):1219-1225. 
4 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
5 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
6 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
7 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
8 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
9 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
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18. APPENDICES 
18.1 Appendix 1 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
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Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
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1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
05-Nov-2015 
by Caroline Engel 
Final Protocol, Amendment 5 
This protocol amendment is generated to add the following Investigator 
and clinical site: 
Samir Arora, MD 
Aventiv Research Inc. 
99 North Brice Road, Suite 260 
Columbus, Ohio 43213 
United States 
Tel: + 1 614 501-6164 
Therefore, Section 3 Investigators Signature was updated accordingly. 
Section 4 Additional Key Contacts for the Study was also updated to add 
the correcponding certified clinical laboratory.  
All 3 sites clinical sites will be using the Western Institutional Review 
Board. Section 4 Additional Key Contacts for the Study was updated 
accordingly. 
Minor editorial corrections were made where applicable. 
16-Sep-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 4 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below: 
1. Brigham and Women's Hospital Investigator signature and contact 
information was removed throughout the protocol since the center will 
not be participating during this study. The following sections were 
updated accordingly: 
• 
Section 3 Investigators Signatures 
• 
Section 4 Additional Key Contacts for the Study 
2. The age limits were changed from 40 - 80 years of age, inclusively, to 
30 - 85 years of age, inclusively. The following sections were updated 
accordingly: 
• 
Section 5 Synopsis - Study Population 
• 
Section 13.3.2 Inclusion Criteria – Inclusion criterion #1 
3. To provide scheduling flexibility to the patients, a ±2-day window was 
added to the return visits on Days 15, 29, and 43. The following 
sections were updated accordingly: 
• 
Section 5 Synopsis - Summary of Study Design and Exploratory 
Outcome Measures 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.1 Overall Study Design and Plan 
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DATE/NAME 
DESCRIPTION 
16-Sep-2015 
by Caroline Engel 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 15.1.6.2 Statistical Methods for Pharmacokinetic 
Analyses 
4. Breathalyzer was added as an alternative method to the urine dipstick 
for the alcohol screen. The following sections were updated 
accordingly: 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.3.3 Exclusion Criteria – Exclusion criterion #13 
• 
Section 14.1.6.7 Urine/Breathalyzer Alcohol Screen was added 
• 
Section 14.1.6.8 (previously 14.1.6.7) was renamed Urine Drug 
Screen (previously Urine Drug/Alcohol Screen). 
5. Only patients suffering from severe sleep apnea, as assessed by the 
Berlin Questionnaire, will be excluded from the study; The following 
sections were updated accordingly:  
• 
Section 6 Study Events Flow Chart 
• 
Section 13.3.3 Exclusion Criteria - exclusion criterion #8. 
• 
Section 14.1.8 Berlin Questionnaire was added. 
6. The body mass index upper limit was increased from 32.0 kg/m2 to 
40.0 
kg/m2 
inclusively. 
Therefore 
inclusion 
criterion 
#5 
of 
Section 13.3.2 Inclusion Criteria was revised accordingly. 
7. Drug screen false positive will be allowed if they are due to the use of 
prescription medication following approval from the PI and the 
medical monitor, the exclusion criterion #13 of Section 13.3.3 
Exclusion Criteria was revised accordingly. 
8. Smoking restriction prior to the bronchoscopy procedures was 
removed. 
Therefore, 
Section 
14.3.2 
Bronchoscopy 
and 
Bronchoalveolar Lavage (BAL) Biomarkers was updated accordingly. 
9. Only strong and moderate inhibitors of UDP-glucuronosyltransferase 
and/or sulfotransferases are prohibited, therefore to prevent 
confusion with the list of substrats that was provided in Appendix 1, 
Appendix 1 was remove and the only 3 inhibitors listed in that table 
was enumarated in exclusion criterion #18. The list of substrate in 
appendix 2 (now rename Appendix 1) was also remove. This change 
will prevent possible confusion with the lists provided in the 
appendices. Exclusion criterion #18 of Section 13.3.3 Exclusion 
Criteria was revised accordingly. 
10. To be consistent with Section 6 Study Events Flow Chart, pulse 
oximetry was added to the order of procecedures listed in 
Section 14.1 Safety Assessments. 
11. Typographic and editorial corrections were made where applicable. 
 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 3 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. The changes to the protocol are presented 
with new text in bold font and deleted text in strikethrough font. 
Serious Adverse Event Contact Information 
Drug Safety Solution’s Medical Monitor will be contacted in case of 
serious adverse events. Hence the information under Sponsor Contact for 
Serious Adverse Events (Medical Monitor) in Section 4 Additional Key 
Contacts for the Study was corrected as follows: 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, Seoul, 134-721, Republic of 
Korea   
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
Dr. Kathy Smith 
Drug Safety Solution  
Tel.: +1 919 264-5626 
E-mail:  ksmith@drugsafety.biz 
Section 14.1.8.4 Serious Adverse Events and Section 13.4.3.2 
Procedures for Breaking the Blind Prior to Study Completion was also 
corrected accordingly. 
Certified Clinical Laboratory: 
Brigham and Women's Hospital and UAB Lung Health Center clinical 
laboratories contact information were added to Section 4 Additional Key 
Contacts for the Study. 
Clinical Indication: 
As indicated in the objectives of the study, the study will examine the 
pharmacodynamic (PD) effect of YPL-001 in patients with chronic 
obstructive pulmonary disease (COPD) only. Therefore, to prevent 
potential confusion and to capture the intended indication of the study 
specifically “asthma” was removed from the Clinical Indication in Section 
5 synopsis and Section 10.1 Purpose of the Study. 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Population: 
As indicated throughout the protocol, patients will be will be adult males 
and females with moderate to severe COPD (conform to the severity 
classification for Global Initiative for Chronic Obstructive Lung Disease 
[GOLD] Stage 2-3). Hence to be consistent with the GOLD Stage 
standards, the first sentence under Study Population from Section 5, 
Synopsis was corrected as follow: 
“Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant 
bronchitic component and a history of frequent (>2/year) COPD 
exacerbations, between 40 and 80 years of age (inclusive).” 
Randomization and Drug Dispensing 
Instruction for randomization and drug dispensing are provided in a 
separate document. To be consistent with this document, which states 
that two sets of randomization code envelopes will be provided to site 
pharmacist/study coordinators and patients will received appropriately 
labeled kits and/or any unused wallets from previously provided kits 
(when applicable) for YPL-001 home dosing in addition to the containers 
for tiotropium/albuterol home dosing, the following section were modified 
accordingly: 
• 
Section 5 Synopsis under Summary of Study Design and Study 
Products 
• 
Section 6 Study Event Flow Chart, Day 1 Study Drug Administration 
at CRU - Footnotes “k” and “p” 
• 
Section 6 Study Event Flow Chart, Days 2 to 55 Study Drug 
Administration at Home – Footnotes “j” and “o” 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 13.4.3.1 Maintenance of Randomization 
• 
Section 13.4.3.2 Procedures for Breaking the Blind Prior to Study 
Completion 
In addition, and “X” was also added in the “Randomization” row under 
Day 1 predose in Section 6 Study Events Flow Chart. 
Fasting Conditions 
As indicated throughout the protocol, subjects will be required to fast for 
at least 8 hours before and 4 hours after YPL-001/placebo morning 
administration on Days 1 and 56. For clarity, footnote “q” was added to 
Day 1 Study Drug Administration at CRU and footnote “k” was added to 
Day 56 Study Drug Administration at CRU in Section 6 Study Events 
Flow Chart. 
 
 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Analytes to be Measured 
As indicated throughout the protocol, blood samples will be collected for 
the analyses of verproside and picroside II in plasma. Hence, the row 
identified as “Blood for Verproside Phamacokinetics” on Day 56 of 
Section 6 Study Events Flow Chart, was corrected to read: “Blood for 
Verproside & Picroside II PK”. 
End-of-Treatment – Early Termination Procedures 
All procedures listed under End-of-Treatment/Early Termination column in 
Section 6 Study Events Flow Chart are also scheduled to be performed 
on Day 55 before the bronchoscopy procedures. Therefore, as it is not 
required to repeat these procedures for two consecutive days, 
End-of-Treatment procedures were removed on Day 56, however early 
termination (ET) procedures were listed under the new ET column. 
Hence, the following sections were corrected accordingly.  
• 
Section 6 Study Events Flow Chart  
• 
Section 13.2.4.2 End-of-Treatment or Early Termination (Day 56), 
(renamed Section 13.2.4.2 Early Termination). 
• 
Section 13.3.2 Inclusion Criteria – Criterion #16 
• 
Section 13.3.4 Removal of Patients from the Study 
• 
Section 13.3.5.1.1 Prohibited Therapy 
• 
Section 13.3.5.1.2 Permitted Therapy 
• 
Section 14.1.8.2 Monitoring 
• 
Section 14.5 Blood Volume for Study Assessments (Table 5:  Blood 
Volume during Study) 
In addition, the following sentence was added to Section 13.2.4.2 End-of-
Treatment or Early Termination (Day 56), (renamed Section 13.2.4.2 
Early Termination):   
“Patients who want to terminate from the study and are not currently on-
site will be contacted and asked to return to the CRU to perform the early 
termination procedures” 
Investigator’s Brochure Version 
In Section 9.1 YPL-001, the Investigator’s Brochure version was updated 
to reflect the reference section and the most recent version of the 
Investigator’s Brochure. 
Method of Blood Collection 
Throughout the protocol, the option of using an angiocatheter was added. 
Hence, the following sections were corrected accordingly: 
• 
Section 11 Risk/Benefit 
• 
Section 14.3.3 Blood Biomarkers 
• 
Section 14.4.1 Blood Sampling and Processing 
• 
Section 14.5 Blood Volume for Study Assessments 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recording of Meal 
To be consistent with clinical sites standard procedures, the last sentence 
of Section 13.2.4.1 Meal Schedule was corrected as follow: 
“Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs.’ 
Coffee, Tea and Alcohol Prohibition 
As indicated in Section 13.3.5.2 Prohibitions, coffee tea, and red wine will 
be restricted for 7 days prior to Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample. Beer will be 
restricted for 14 days prior to Day 1 of the Treatment Period through 
collection of Day 56 last PK sample. Any other product containing 
xanthines or caffeine will be restricted 24 hours prior to each CRU visit 
and prior to dosing on Days 1 and 56 of the Treatment Period through 
collection of Days 1 and 56 last PK sample. Any other alcohol product will 
be restricted 48 hours prior to each CRU visit, 48 hours prior to dosing on 
Days 1 and 56 last PK sample. Hence, the xanthines/caffeine prohibition  
and the alcohol prohibition were corrected as follows for clarification: 
“Xanthines/caffeine (other than coffee and tea):  24 hours prior to each 
CRU visit and prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
“Alcohol (other than red wine and beer):  48 hours prior to each CRU 
visit, 48 hours prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
e-Diary 
Home dosing will be recorded using a yes/no answer in the e-diary. 
Therefore the last sentence of the second to last paragraph of 
Section 13.4.1.2 Drug Administration During Treatment Period was 
corrected as follows: 
“Patients will be given instructions on recording of dosing times how to 
record their drug administration in their e-diary on home-dosing days.’ 
In addition, estimation of sputum quantity was added to the list of major 
symptoms of COPD exacerbation recorded daily by the patients on their 
e-diary, “color” and “consistency” was moved as example of sputum 
quality, and a statement indicating that the e-diary device will be return in 
case of early termination was also added. Hence, the following sections 
were corrected accordingly: 
• 
Section 5 Synopsis under Secondary Outcome Measures 
• 
Section 5 Synopsis under Summary of Study Design 
• 
Section 6 Study Events Flow Chart – Day 1, Footnote “j” 
• 
Section 6 Study Events Flow Chart – Days 2-55, Footnote “i” 
• 
Section 6 Study Events Flow Chart – Day 56, Footnotes “g” and “h” 
• 
Section 12.2 Study Endpoints 
• 
Section 13.1 Overall Study Design and Plan 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
• 
Section 13.2.4 Treatment Period (Days 1 to 56) 
• 
Section 14.2.1 Electronic Diary 
• 
Section 14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease 
Exacerbation 
Treatment Compliance 
Drug administration at home will be monitored by HGE Technologies Inc. 
via the e-diary. Therefore, the last sentence of Section 13.4.4. Treatment 
Compliance was corrected as follow: 
“Self-administration by patients at home will be monitored by the CRU via 
the e-diary and attempted phone calls will be performed to remind 
patients to take their medication, if they did not record their 
self-administration on the e-diary.” 
Oxygen Saturation 
For consistency throughout the protocol, “oxygen levels, saturation (%)” 
was replaced with “oxygen saturation (%).” 
Tiotropium Treatment 
As indicated in Section 13.3.2 Inclusion Criteria and Section 13.3.5.1.2 
Permitted Therapy, tiotropium will be withheld 24 hours prior to 
pulmonary function (spirometry) measurements. Hence, the 2nd 
paragraph of Section 14.3.1 Pulmonary Function (Spirometry), was 
corrected to read: 
“Short acting β2-agonist and anticholinergic bronchodilators (e.g., 
albuterol, ipratropium bromide) and long acting β2-agonist and 
anticholinergic bronchodilators (e.g., salmeterol, tiotropium) agents will be 
withheld approximately 4 and 12 24 hours, respectively, before each 
pre-bronchodilator spirometry.” 
Spirometer Across Clinical Site 
The 3rd paragraph of Section 14.3.1 Pulmonary Function (Spirometry) 
was corrected as follow: 
“Every effort will be made to perform all assessments for a given patient 
on the same instrument throughout the study and all sites should be 
using the same brand and model of spirometer for this study.” 
Bronchoalveolar Lavage (BAL) Collection 
It is planned that a maximum of 180 mL BAL will be performed during 
each planned bronchoscopy procedures. Therefore, to prevent confusion, 
the second sentence of Section 14.3.2.3, Bronchoalveolar Lavage (BAL) 
was corrected to read: 
“A total of 180 mL BAL, using 6 x 30 mL aliquots of normal saline 
warmed to room temperature, will be performed in using each 
subsegment of the right middle or lower lobe, as deemed appropriate by 
the Investigator, using 6 x 30 mL aliquots of normal saline warmed to 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
room temperature.” 
Blood 
Volume 
for 
Clinical 
Safety 
Laboratory 
Tests, 
Pharmacodynamic 
(PD) 
Markers 
and 
Pharmacokinetic 
(PK) 
Samples: 
Blood collection volume for PD markers, as indicated in Section 14.3.3 
Blood Biomarkers and Section 14.5 Blood Volume for Study 
Assessments, only accounts for 1 tube. However, 3 tubes will be required 
to assess CRP (4 mL tube), fibrinogen (3.5 mL tube) and the rest of the 
PD biomarkers (6 mL tube). The blood volume per time point will be 
approximately 13.5 mL instead of 4.5 mL. 
As indicated above, End-of-Treatment listed on Day 56 were removed as 
the same tests are scheduled on Day 55 before the bronchoscopy 
procedures. Hence one sample was removed for a total of 3 on-study 
hematology and serum chemistry tests to be performed throughout the 
study. 
In addition, 4 mL of blood will be sufficient for the determination of 
verproside and picroside II concentration in plasma at each time point. 
Therefore the total blood volume was corrected to 310.5 mL for males 
and 317.5 mL for females. Section 14.3.3 Blood Biomarkers, 
Section 14.4.1 Blood Sampling and Processing, and Section 14.5 Blood 
Volume for Study Assessments were corrected accordingly. 
Minor typographic and editorial corrections were made where applicable. 
16-Feb-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 2 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. 
Number of Subjects: 
The sample size was revised to 60 subjects as it is sufficient to meet the 
objectives of the study. In case of dropouts, discontinued patients may be 
replaced at the discretion of the Sponsor as indicated throughout the 
protocol. Therefore the following sections were corrected accordingly to 
indicate that at least 60 subjects are planned to be enrolled and 
randomized with 20 patients to receive one of the 3 treatments: 
• 
Section 5 Synopsis (the 1st sentence of the 2nd paragraph under 
Summary of Study Design and the 1st and 2nd sentences under 
Number of Patients). 
• 
The 1st sentence of the 2nd paragraph of Section 13.1 Overall Study 
Design and Plan. 
• 
The 1st and 3rd sentences of Section 13.3.1 Number of Patients. 
• 
The last sentence of Section 15.1.1 Sample Size Calculation. 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) and 
COPD Assessment Test (CAT): 
BDI/TDI and CAT questionnaires will not be used as a diagnostic tool to 
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DATE/NAME 
DESCRIPTION 
16-Feb-2015 
by Caroline Engel 
assess the patient’s potential to meet all inclusion criteria and none of the 
exclusion criteria. Therefore these questionnaires are not required at 
screening. In addition, it is not required to perform them for 2 consecutive 
days to meet the study objectives and therefore, Day 55 assessments 
were removed.  
Section 6 Study Events Flow Chart was corrected accordingly. 
The first sentence in Section 14.3.4.1 Baseline Dyspnea Index/Transition 
Dyspnea Index (BDI/TDI) was also corrected to be consistent with 
Section 6. 
Early Termination Procedures: 
Weight, and oxygen levels, saturation (%), and heart rate assessed using 
a pulse oximeter were added to the procedures performed at the end of 
the Treatment Period on Day 56 or prior to early termination from the 
study to monitor subject’s safety appropriately. A pulmonary function 
(spirometry) test was also added prior to early termination for safety 
monitoring. 
Section 6 Study Events Flow Chart was corrected accordingly. 
Recording Concomitant Medication: 
Concomitant medication will be recorded at each study visit by the clinical 
staff in to the electronic data capture system. Therefore, concomitant 
medications was removed from the list of events that will be recorded by 
the patients via their e-diary throughout the protocol. The following 
sections were corrected accordingly: 
• 
Footnotes in Section 6 Study Events Flow Chart. 
• 
The first sentence of the 4th paragraph of Section 13.2.3 Run-In 
Period (Days 1 to 14 [± 2 days]). 
• 
The 2nd sentence of the 2nd paragraph of Section 13.2.4 Treatment 
Period (Days 1 to 56). 
• 
The 2nd sentence of the first paragraph of Section 14.2.1 Electronic 
Diary. 
Subject Numbering: 
The first paragraph of Section 13.4.2 Method of Assigning Patients to 
Treatment Groups was modified to clarify that the screening number and 
randomization number are two separate identification number given to 
each subject at different stages of the study. 
Adverse Events Reporting 
Footnotes were added to clarify the rating severity definitions in 
Section 14.1.8.3 Reporting. 
Minor editorial and typographical corrections were made where 
applicable. 
 
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DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 1 
This protocol amendment is generated to update the study population 
with regards to smoking frequency, to update the handling procedures for 
BAL samples, and to clarify other study procedures as listed below. 
Study Population: 
Section 13.3.2 - Inclusion Criteria, bullet 11 was updated to indicate that 
the study population will consist only of current and ex-smokers with a 
history of >10 pack years. As such, the indications for ‘packs/year’ were 
replaced with ‘pack years’ and the allowance for current smokers with 
<10 pack/years was removed. 
Wording was added to indicate an approximately equal number of current  
and ex-smokers will be enrolled, and that each treatment group will 
consist of an approximately equal number of smokers and ex-smokers. In 
addition, the stratification criteria for the randomization was updated to 
consist of either current or ex-smokers. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Population and Number of 
Patients) 
• 
Section 13.1 - Overall Study Design and Plan (second paragraph) 
• 
Section 13.3.1 – Number of Patients. 
• 
Section 13.4.2 - Method of Assigning Patients to Treatment Groups. 
BAL Sample Handling: 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) was updated to indicate 
that sample handling, processing and storage procedures will be provided 
in a separate document.  
Follow-up Procedures: 
The wording in regards to follow-up procedures to be conducted on 
14 days (± 2 day), after the last study drug administration, was updated to 
indicated a phone-call and not a visit, as indicated correctly in Section 6 – 
Study Event Flow Chart. Study event were updated accordingly. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Duration of Participation for Patients, 
and Exploratory Outcome Measures [under Blood Assessments, 
Pulmonary Assessment, and Quality of Life Assessments])  
• 
Section 13.3.5.2 – Prohibitions (under Alcohol) 
• 
Section 14.1.8.2 – Monitoring (first paragraph). 
Study Duration: 
The total duration of the study indicated in Section 5 – Synopsis (under 
Duration of Participation for Patients) was corrected to 12 weeks to 
correspond with the actual study duration as indicated throughout the 
protocol.  
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DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inflammatory Markers in Blood Samples: 
The list of cell types to be evaluated as part of the inflammatory markers 
in the blood was updated to include monocytes instead of macrophages, 
as macrophages are not expected to be present in blood. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, fourth exploratory 
objective, and under Exploratory Outcome Measures [under 
Pharmacodynamic Assesments, Blood Assessments, first bullet]) 
• 
Section 12.1 - Study Objectives (fourth exploratory objective) 
• 
Section 12.2 - Study Endpoints (third exploratory endpoint) 
• 
Section 14.3.3 - Blood Biomarkers (first bullet) 
• 
Section 15.1.5.1 - Biomarkers (third bullet)  
Neutrophil Evaluation in BAL Samples 
Neutrophils were added to the list of cell types to be evaluated as a 
percentage of the total cell count in BAL samples. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, second exploratory 
objective and under Exploratory Outcome Measures [under 
Pharmacodynamic 
Assessments, 
Bronchoalveolar 
Lavage 
Assessments, second bullet]) 
• 
Section 12.1 - Study Objectives (second exploratory objective) 
• 
Section 12.2 - Study Endpoints (second exploratory endpoint)  
• 
Section 14.3.2.4 - Biomarkers (second bullet) 
• 
Section 15.1.5.1 – Biomarkers (second bullet) 
Location of Study Drug Administration: 
Wording was added in Section 6 – Study Events Flow Chart for Day 56, 
to clarify that the study drug will be administered at the CRU. 
Meal Schedule: 
The indication for fasting requirement in Section 13.2.4.1 – Meal 
Schedule, was corrected to indicate patients will fast overnight for at least 
12 hours before bronchoscopy and BAL collection on Days -1 and 55 
instead of Days -1 and 56, as correctly indicated in Section 6 – Study 
Events Flow Chart. 
ECG Monitoring:  
Following an update in Celerion’s standard operating procedure, Section 
14.1.5 – Electrocardiogram Monitoring was updated to include at least 
5 minutes of rest prior to each ECG measurement (instead of at least 
1 minute as previously indicated). 
 
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DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
 
Hematology: 
The tests included in the hematology panel Section 14.1.6.1 – 
Hematology were updated to indicate that the red blood cell (RBC) count 
will include a reticulocytes count, and that the white blood cell (WBC) 
count with differential will include monocytes but will not include 
reticulocytes. 
Bronchoscopy and BAL: 
Due to the sensitivity of YPL-001 components to UV light, a warning was 
added to protect all samples from exposure to UV light, as indicated for 
the PK blood samples. 
The following sections were affected: 
• 
Section 14.3.2.2 - Bronchial Brushings 
• 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) 
PK Population: 
The indication for measurable concentration of verproside and picroside II 
in urine was removed from the definition of PK population in 
Section 15.1.2 - Patients to Analyze, as there is no urine PK sampling 
planned for this study. 
Minor typographic and editorial corrections were made where applicable. 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
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IND No.: 114903 
 
 
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4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Events (Medical Monitor) 
Dr. Kathy Smith 
Drug Safety Solution Tel.: +1 919 264-
5626E-mail:  ksmith@drugsafety.biz  
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratory 
For Temple University School of Medicine: 
Yuri Persidsky, MD, Ph.D. 
Chairperson, Department of Pathology and 
Laboratory Medicine 
Professor, 
Pathology 
and 
Laboratory 
Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
UAB Lung Health Center: 
UAB Hospital Laboratories 
619 19th Street South 
Birmingham, Alabama, 35249 
United States  
 
Aventiv Research Inc: 
Quest Laboratories 
6700 Steger Drive,  
Cincinnati, Ohio, 45237 
United States  
 
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
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Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Board Main Office 
Location 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
  
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5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such chronic 
obstructive pulmonary disease (COPD) 
Study Type: 
Phase 2a, proof of concept 
Study Objectives: 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, monocytes, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
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Summary of Study 
Design: 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups 
(20 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) on the morning of 
Day -1 of the Treatment Period to confirm their eligibility and assess their 
health conditions. If they still meet all of the inclusion criteria and none of the 
exclusion criteria, they will undergo Day -1 scheduled study procedures. 
Patients will return to the CRU the next day (Day 1) to be randomized and 
receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15 (± 2 days), 
29 (± 2 days), 43 (± 2 days), 55, and 56 of the Treatment Period for study 
drug administration and procedures. Prior to each release from the CRU, 
patients will receive a properly labeled YPL-001 kit (and/or any unused 
wallets 
from 
previously 
provided 
kits 
[when 
applicable]) 
and 
tiotropium/albuterol 
container 
with 
sufficient 
doses 
which 
will 
be 
self-administered by patients at home until the next morning visit at the CRU. 
Patients will continue recording their daily symptoms via the e-diary 
throughout the Treatment Period. Patients will return the e-diary device on 
Day 56 (or prior to early termination) to CRU staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
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will be administered in accordance with the study center standard of care. 
Study Population: 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component, between 30 and 85 years of age (inclusive). An approximately 
equal number of current and ex-smokers will be enrolled. 
Number of 
Patients: 
The study is planned to enroll at least 60 patients. Patients will be divided in 
3 treatment groups with 20 patients to receive one of the 3 treatments (i.e., 
low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo 
control) as per the randomization schedule. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Duration of 
Participation for 
Patients: 
The planned length of participation in the study for each patient is 
approximately 12 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up procedures on Day 70 [± 2 days]). 
Duration of Study 
Conduct: 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products: 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
YPL-001 or placebo will be dispensed in accordance with the Randomization 
and Drug Dispensing Instructions provided in a separate document. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen: 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 80 mg matching placebo tablet) will be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be 
administered on Day 56. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B, and C will be administered orally with 
approximately 240 mL of water. 
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Stopping Rules: 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
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Safety and 
Tolerability 
Analysis 
(continued): 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures: 
PEF, major (e.g., estimated sputum quality (e.g., color, consistency), and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, 
discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (Duke 
Activity Status Index [DASI]) self-reported daily by the patients using an 
e-diary. 
Symptom 
Monitoring 
Analysis: 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, and throughout the study for 
PD assessments of biomarkers. Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
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Exploratory 
Outcome 
Measures 
(continued): 
IC] will be performed at screening, and throughout the study. 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, and throughout the study. 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 56 to determine verproside and 
picroside II concentrations in plasma. Predose samples will also be collected 
in the morning of Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days) and 56 for 
Ctrough determination. Other components of YPL-001 and its metabolites may 
also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis: 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis: 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-001 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
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6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Berlin Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg 
X 
 
 
Xf 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAh 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityj 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationp 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk,q 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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AA98497_Final_Prot_Amendment_5_05Nov2015 
 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)l 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xn 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitso 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
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AA98497_Final_Prot_Amendment_5_05Nov2015 
 
a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
d. To be performed prior to the bronchoscopy procedures. 
e. To be performed at screening or within 3 months (inclusive) of screening. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
i. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
k. Prior to release from the CRU, patients will receive a properly labeled kit with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
l. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
m. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
n. To be performed prior to dosing. 
o. Patients will be admitted to the CRU at the time indicated by the CRU. 
p. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
q. On Day 1, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
 
 
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STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 2-14 
15 (± 2) 16-28 29 (± 2) 30-42 
43 (± 2) 
44-54 
55 
Hours → 
 
AM PM 
 
AM PM 
 
AM 
PM 
 
AM 
PM 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Xe 
 
Vital Signsf 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xe 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
Xe 
 
Hem, Chem, and UAg 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine or Breathalyzer Alcohol Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useh 
X 
PEF, COPD exacerbation, dyspnea 
and activityi 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationo 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Administration at Homej 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)k 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xn 
 
Bronchoscopy and BAL Biomarkersl 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
BDI/TDI & CAT 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Refer to the footnotes on the next page 
 
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AA98497_Final_Prot_Amendment_5_05Nov2015 
 
a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. To be performed or completed prior to bronchoscopy procedures and/or dosing. 
e. ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
f. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
g. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
h. Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
i. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
j. 
Prior to release from the CRU on Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), and 55 patients will receive a properly labeled kit and/or 
any unused wallets from previously provided kits (when applicable) with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
k. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
l. 
Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
m. Patients will be admitted to the CRU at the time indicated by the CRU. 
n. To be completed prior to bronchoscopy procedures and dosing. 
o. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
 
 
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STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
ETb FUc 
Days → 
56 
Hours → Predose 0 
0.167 
0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signse 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hem, Chem, and UAf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UrineDrug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PEF, COPD exacerbation, dyspnea and 
activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood Biomarkers 
Xi 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsj 
X 
X 
 
Refer to the footnotes on the next page 
 
 
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a. For details on Procedures, refer to Section 14. 
b. To be performed prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
f. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
g. Patients will return the e-diary device on Day 56 (or prior to early termination) to CRU staff.  
h. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
i. 
To be performed at predose on Day 56 or upon early termination. 
j. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
k. On Day 56, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition 
Dyspnea Index Test, CAT = COPD Assessment Test, Chem = Serum chemistry, COPD = chronic obstructive pulmonary disease, CRU = Clinical 
research unit, ConMeds = Concomitant medication, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = electronic diary, 
ET =  Early termination, FSH = Follicle-stimulating hormone, Hem = Hematology, HIV = Human immunodeficiency virus, IL= interleukin, 
PEF = Peak expiratory flow, PK = Pharmacokinetics, PM = Evening, Preg = Serum pregnancy, Screen = Screening, UA = Urinalysis. 
 
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7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY ...................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ............................................................................................. 14 
3. 
INVESTIGATORS SIGNATURES ...................................................................................... 15 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY ............................................................ 17 
5. 
SYNOPSIS ........................................................................................................................ 19 
6. 
STUDY EVENTS FLOW CHART ....................................................................................... 25 
7. 
TABLE OF CONTENTS ..................................................................................................... 32 
8. 
ABBREVIATIONS.............................................................................................................. 35 
9. 
INTRODUCTION AND BACKGROUND ............................................................................. 40 
9.1 
YPL-001 .................................................................................................................. 40 
9.1.1 
Preclinical Trials .......................................................................................... 40 
9.1.1.1 
Pharmacology .............................................................................. 40 
9.1.1.2 
Pharmacokinetics ......................................................................... 41 
9.1.1.3 
Toxicology ................................................................................... 42 
9.1.2 
Clinical Experience...................................................................................... 43 
9.1.2.1 
SAD study .................................................................................... 44 
9.1.2.2 
MAD Study .................................................................................. 45 
10. RATIONALE ...................................................................................................................... 47 
10.1 Purpose of the Study ............................................................................................... 47 
10.2 Dose Selection ........................................................................................................ 47 
11. RISK/BENEFIT .................................................................................................................. 49 
12. STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 50 
12.1 Study Objectives ..................................................................................................... 50 
12.2 Study Endpoints ...................................................................................................... 50 
13. INVESTIGATIONAL PLAN ................................................................................................ 52 
13.1 Overall Study Design and Plan ................................................................................ 52 
13.2 Study Conduct ......................................................................................................... 53 
13.2.1 Screening ................................................................................................... 53 
13.2.2 Patient Confinement .................................................................................... 53 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ....................................................... 53 
13.2.4 Treatment Period (Days 1 to 56) ................................................................. 54 
13.2.4.1 Meal Schedule ............................................................................. 54 
13.2.4.2 Early Termination ......................................................................... 55 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................ 55 
13.2.6 Scheduled End of Study .............................................................................. 55 
13.3 Selection of Study Population .................................................................................. 55 
13.3.1 Number of Patients ..................................................................................... 55 
13.3.2 Inclusion Criteria ......................................................................................... 55 
13.3.3 Exclusion Criteria ........................................................................................ 57 
13.3.4 Removal of Patients from the Study ............................................................ 59 
13.3.5 Study Restrictions ....................................................................................... 60 
13.3.5.1 Concomitant Therapy ................................................................... 60 
13.3.5.1.1 
Prohibited Therapy ................................................... 60 
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13.3.5.1.2 
Permitted Therapy ................................................... 61 
13.3.5.2 Prohibitions .................................................................................. 61 
13.3.5.3 Activity ......................................................................................... 61 
13.4 Treatments .............................................................................................................. 62 
13.4.1 Treatments administered ............................................................................. 62 
13.4.1.1 Drug Administration During Run-in Period .................................... 62 
13.4.1.2 Drug Administration During Treatment Period............................... 62 
13.4.1.3 Stopping Rules ............................................................................ 63 
13.4.2 Method of Assigning Patients to Treatment Groups ..................................... 64 
13.4.3 Blinding ....................................................................................................... 64 
13.4.3.1 Maintenance of Randomization .................................................... 64 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 64 
13.4.3.3 Revealing of Randomization ......................................................... 65 
13.4.4 Treatment Compliance ................................................................................ 65 
14. STUDY PROCEDURES .................................................................................................... 66 
14.1 Safety Assessments ................................................................................................ 66 
14.1.1 Body Height and Weight .............................................................................. 66 
14.1.2 Physical Examination .................................................................................. 66 
14.1.3 Vital Signs ................................................................................................... 66 
14.1.4 Pulse Oximetry............................................................................................ 67 
14.1.5 Electrocardiogram Monitoring ...................................................................... 67 
14.1.6 Clinical Laboratory Tests ............................................................................. 68 
14.1.6.1 Hematology.................................................................................. 68 
14.1.6.2 Serum Chemistry ......................................................................... 68 
14.1.6.3 Serology ...................................................................................... 68 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............ 68 
14.1.6.5 Follicle-Stimulating Hormone ........................................................ 69 
14.1.6.6 Urinalysis ..................................................................................... 69 
14.1.6.7 Urine/Breathalyzer Alcohol Screen ............................................... 69 
14.1.6.8 Urine Drug Screen ....................................................................... 69 
14.1.7 Chest X-Ray ............................................................................................... 69 
14.1.8 Berlin Questionnaire .................................................................................... 69 
14.1.9 Adverse Events ........................................................................................... 69 
14.1.9.1 Adverse Event Definition .............................................................. 69 
14.1.9.2 Monitoring .................................................................................... 70 
14.1.9.3 Reporting ..................................................................................... 70 
14.1.9.4 Serious Adverse Events ............................................................... 71 
14.2 Symptom Assessments ........................................................................................... 72 
14.2.1 Electronic Diary ........................................................................................... 72 
14.2.2 Peak Expiratory Flow .................................................................................. 72 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ........... 73 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) .................................................... 73 
14.2.5 Activity (Duke Activity Status Index) ............................................................ 73 
14.3 Pharmacodynamic Assessments ............................................................................. 73 
14.3.1 Pulmonary Function (Spirometry) ................................................................ 73 
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14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers.................... 74 
14.3.2.1 Bronchoscopy .............................................................................. 74 
14.3.2.2 Bronchial Brushings ..................................................................... 75 
14.3.2.3 Bronchoalveolar Lavage (BAL) ..................................................... 75 
14.3.2.4 Biomarkers .................................................................................. 75 
14.3.3 Blood Biomarkers ........................................................................................ 76 
14.3.4 Quality of Life Questionnaires ..................................................................... 76 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ..................................................................................... 76 
14.3.4.2 COPD Assessment Test (CAT) .................................................... 76 
14.4 Pharmacokinetic Assessments ................................................................................ 76 
14.4.1 Blood Sampling and Processing .................................................................. 77 
14.5 Blood Volume for Study Assessments ..................................................................... 77 
15. DATA ANALYSIS .............................................................................................................. 78 
15.1 Statistical Analysis ................................................................................................... 78 
15.1.1 Sample Size Calculation ............................................................................. 78 
15.1.2 Patients to Analyze ..................................................................................... 78 
15.1.3 Safety Analysis ........................................................................................... 79 
15.1.4 Symptom Monitoring Analysis ..................................................................... 79 
15.1.5 Pharmacodynamic Analysis ........................................................................ 80 
15.1.5.1 Biomarkers .................................................................................. 80 
15.1.5.2 Quality of Life ............................................................................... 80 
15.1.6 Pharmacokinetic Analysis ........................................................................... 81 
15.1.6.1 Pharmacokinetic Parameters ....................................................... 81 
15.1.6.1.1 
Plasma .................................................................... 81 
15.1.6.1.2 
Bronchoalveolar Lavage ........................................... 82 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ........................ 83 
15.1.7 Assessment of Efficacy ............................................................................... 83 
16. STUDY ADMINISTRATION ............................................................................................... 84 
16.1 Ethics ...................................................................................................................... 84 
16.1.1 Institutional Review Board ........................................................................... 84 
16.1.2 Ethical Conduct of the Study ....................................................................... 84 
16.1.3 Patient Information and Consent ................................................................. 84 
16.2 Termination of the Study .......................................................................................... 84 
16.3 Data Quality Assurance ........................................................................................... 84 
16.4 Direct Access to Source Data/Documents ................................................................ 85 
16.5 Drug Supplies, Packaging and Labeling ................................................................... 85 
16.6 Data Handling and Record Keeping ......................................................................... 85 
16.7 Protocol Amendments ............................................................................................. 85 
16.8 Finance and Insurance ............................................................................................ 86 
16.9 Publication Policy .................................................................................................... 86 
17. REFERENCES .................................................................................................................. 87 
18. APPENDICES ................................................................................................................... 88 
18.1 Appendix 1 - SULT Drug Interaction Table ............................................................... 88 
 
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8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
Coag 
Coagulation 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
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CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
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IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
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ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
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US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
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9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
GCP, and applicable regulatory requirements. The patient population will be comprised 
of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of June 3, 2014. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Bronchoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
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CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
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were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
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values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
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9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 
0.67 hours under fasting conditions. Verproside appeared to be cleared rapidly from 
plasma, with mean t1/2 values under 1 hour; plasma verproside concentrations were 
below the lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 
below summaries the PK parameters of verproside following single-dose administrations 
of YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
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9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t½ values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t½ values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
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Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
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10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such COPD to demonstrate safety and 
evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
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Table 4: Traditional Chinese Medicine Use Versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
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11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an angiocatheter is utilized and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
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12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., estimated sputum quality (e.g., color, consistency) and quantity,) 
and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and 
body temperature above 100°F) symptoms of COPD exacerbation;  
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• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and 
eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
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13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups (20 patients 
per group). Patients will participate only once. An approximately equal number of current 
and ex-smokers will be enrolled in the study. 
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU on the morning of Day -1 of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Day -1 scheduled 
study procedures. Patients will return to the CRU the next day (Day 1) to be randomized 
and receive one of the 3 treatments and undergo all scheduled study procedures. 
Patients will return on the morning of Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), 
55, and 56 of the Treatment Period for study drug administration and procedures. Prior 
to each release from the CRU, patients will receive a properly labeled kit and/or any 
unused wallets from previously provided kits (when applicable) with sufficient doses 
which will be self-administered by patients at home until the next morning visit at the 
CRU. Patients will continue recording their daily symptoms via the e-diary throughout the 
Treatment Period. Patients will return the e-diary device on Day 56 (or prior to early 
termination) to CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
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will be discontinued. Rescue medication will be used for any patient with an 
exacerbation of COPD and will be administered in accordance with the study center 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses and their daily respiratory symptoms. Prior to each morning 
dose, patients will record at home their daily PEF, major (e.g., estimated sputum quality 
(e.g., color, consistency) and quantity,) and minor (e.g., cough, wheeze, sore throat, 
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nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 56 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses and their daily 
respiratory symptoms on their e-diary. Prior to each morning dose, patients will record at 
home their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) 
and quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, 
and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea 
(Modified Borg Dyspnea Scale), and activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before bronchoscopy and 
BAL collection on Days -1 and 55. On Days 1 and 56, patients will be required to fast 
overnight for at least 8 hours before and for at least 4 hours after the morning dose. On 
all other days, patients will be asked to fast for at least 2 hours before and 2 hours after 
each morning dose. Patients will also be asked to fast for at least 2 hours before and 
after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 56, patients will fast from all food and drink except water between meals 
and snacks. Foods and beverages containing alcohol, xanthines, caffeine, vegetables 
from the mustard green family, mustard, tea (especially speedwell tea), or 
grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, menus should 
be similar in content. The same menu and meal (except for snacks) schedule will be 
administered uniformly for all patients confined within the same CRU, across all 
treatment groups. Meals are not required to be completed by patients. 
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13.2.4.2 Early Termination  
Early termination evaluations will be performed on patients prior to early termination. 
Patients who want to terminate from the study and are not currently on-site will be 
contacted and asked to return to the CRU to perform the early termination procedures. 
The early termination procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll at least 60 patients. An approximately equal number of 
current and ex-smokers will be enrolled. Patients will be divided in 3 treatment groups 
with 20 patients to receive one of the 3 treatments (i.e., low and high YPL-001 doses 
[80 mg and 160 mg BID] and a placebo control) as per the randomization schedule. 
Each treatment group will consist of an approximately equal number of current and 
ex-smokers. 
13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 30 to 85 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
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4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-40.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24 hours 
prior to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled 
CRU visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack years. Ten pack years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Patients, who undergo smoking cessation therapy, must be completed 
3 months prior to screening visit and smoking status should not change between the 
patient’s screening visit and patient’s last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
13. A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method 
(e.g., condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
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IND No.: 114903 
 
 
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14. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
15. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the last scheduled study procedures on Day 56 or upon early 
termination. Patients will be advised to use a condom with spermicide for 90 days 
following the last administration of the study drug, and to not donate sperm during 
this same period of time. In the event that the sexual partner is surgically sterile, use 
of a condom with spermicide is not necessary. No restrictions are required for 
vasectomized males provided their vasectomy has been performed 120 days or 
more prior to study start. Males who have been vasectomized less than 120 days 
prior to study start must follow the same restrictions as non-vasectomized males. 
16. Understands study procedures and provides written informed consent for the trial. 
17. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
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8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), severe sleep apnea (assessed using the Berlin Questionnaire [refer to 
Section 14.1.8]), cardiovascular, endocrine, neurological, hepatic, gastrointestinal, 
renal, hematological, urological, immunological or ophthalmic diseases that the 
Investigator believes are clinically significant e.g., unstable and could impact patient 
safety by participation in the study. 
9. History or presence of: 
• 
significant cardiac arrhythmia; 
• 
prostatic hyperplasia; 
• 
bladder-neck obstruction; 
• 
urinary retention; 
• 
narrow-angle glaucoma. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Evidence of hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive alcohol (using urine dipstick or breathalyzer) and/or urine drug testing at 
screening or at each CRU visit, unless the positive drug screen is due to prescription 
drug use and is approved by the PI and the medical monitor. 
14. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies (HCV). 
15. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
16. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
17. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
18. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) (such as 17-beta-estradiol 
glucuronide, flavonoids [citrus fruit], silybin [herb supplement milk thistle]) and/or 
sulfotransferases (SULT) (refer to Appendix 1), within 12 hours prior to Day 1 of the 
Run-in Period. Additional sources may be consulted by the PI or medical monitor to 
confirm lack of PK/PD interaction with study drug. 
19. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
20. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
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21. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
22. Females who are pregnant or lactating.  
23. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
24. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion (early 
termination evaluations) as the situation allows (see Section 13.2.4.2). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
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IND No.: 114903 
 
 
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13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the last scheduled study 
procedures on Day 56 or upon early termination). Intake of these medications during the 
Run-in Period constitutes a non-eligibility criterion and the patients will not be 
randomized into the study. If any of these medications are taken during the Treatment 
Period, the need for this patient to be withdrawn from the study will be carefully 
evaluated by the Investigator and the Sponsor on the basis of the potential impact on 
efficacy or safety evaluation and in the patient's best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements and herbal products (especially Speedwell) will be prohibited 
7 days prior Day 1 of the Treatment Period and through collection of the final PK 
sample. 
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IND No.: 114903 
 
 
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13.3.5.1.2 Permitted Therapy 
Throughout the study Period (from Day 1 of the Run-in Period to the completion of the 
last scheduled study procedures on Day 56 or upon early termination) patients will be 
permitted to take the following medications in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 24 hours 
before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine (other than coffee and tea):  24 hours prior to each CRU visit and 
prior to dosing on Days 1 and 56 of the Treatment Period through collection of Days 
1 and 56 last PK sample. 
• 
Alcohol (other than red wine and beer):  48 hours prior to each CRU visit, 48 hours 
prior to dosing on Days 1 and 56 of the Treatment Period through collection of 
Days 1 and 56 last PK sample. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 56 last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 56 of 
the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Tea (especially Speedwell tea), coffee, and red wine:  7 days prior to Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 56 last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. Only the 
morning dose will be administered on Day 56. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be administered on 
Day 56. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose will be 
administered on Day 56. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
YPL-001 or placebo will be dispensed in accordance with the Randomization and Drug 
Dispensing Instructions provided in a separate document. 
Prior to release from the CRU on Days 1, 15 (± 2 days), and 29 (± 2 days), of the 
Treatment Period, patients will receive a properly labeled new kit, which contains 
4 wallets of 2 blister cards, with the appropriate doses which will be self-administered by 
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IND No.: 114903 
 
 
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patients at home. Any unused wallets from previously provided kits will also be 
dispensed to patients on Days 15 (± 2 days) and 29 (± 2 days). Prior to release from the 
CRU on Days 43 (± 2 days), and 55, patients will received unused wallets from 
previously provided kits with the appropriate doses which will be self-administered by 
patients at home. Patients will also receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. Patients will record their 
self-administered doses in their e-diary, and whether the dose was administered with 
food, and must return the YPL-001 used and unused wallets and the tiotropium and 
albuterol container (empty or not) at the next schedule visit at the next morning visit. 
Home dosing will be monitored via attempted phone calls where patients will be 
reminded to take their medication, if they did not record their self-administration on the e-
diary, and queried about the occurrence of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
given instructions on how to record their drug administration in their e-diary on 
home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
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13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique screening identification number upon screening. 
Patients who complete the study screening assessments, complete the Run-in Period, 
and meet all the eligibility criteria will be assigned a unique randomization identification 
number, different from the screening number, and receive the corresponding product, 
according to a randomization scheme generated at Celerion. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
The randomization will not be made available to the Sponsor, patients, or members of 
the staff responsible for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
The site Pharmacist/Study Coordinator will receive two sets of randomization code 
envelopes, one set for “Current Smokers” and another for “Ex-Smokers”. Each individual 
envelope is marked on the outside with one of the randomization numbers and contains 
the treatment for that patient. These envelopes must be kept in a secure locked location. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the medical monitor or designee prior to breaking the blind. If breaking 
the blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
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13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
1. All data are entered in the database, edits checks are performed, queries 
closed, CRFs signed by the Investigator, and the database is officially locked. 
2. All PK/PD samples have been analyzed and quality checked by the 
responsible analytical associate. 
13.4.4 Treatment Compliance 
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
Self-administration by patients at home will be monitored via the e-diary and attempted 
phone calls will be performed to remind patients to take their medication, if they did not 
record their self-administration on the e-diary. 
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IND No.: 114903 
 
 
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14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs and pulse oximetry 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
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IND No.: 114903 
 
 
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When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When scheduled postdose, vital signs readings 
will be performed within approximately 10 minutes of the scheduled time point. When 
performing the bronchoscopy, vital signs (body temperature, respiratory rate, blood 
pressure, and heart rate) will be monitored continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen saturation (%), and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen saturation [%], and heart rate) 
as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. Readings may be taken at other times, if deemed 
necessary by the Investigator. When performing the bronchoscopy, oxygen saturation 
will be monitored continuously until the end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performing the bronchoscopy, ECG will be monitored continuously until 
the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
5 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
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14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count (including a 
reticulocytes count) 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, and 
monocytes) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
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14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine/Breathalyzer Alcohol Screen 
Alcohol levels will be tested using urine dipsticks or breathalyzers. 
14.1.6.8 Urine Drug Screen 
• 
Cannabinoids  
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Berlin Questionnaire 
The Berlin Questionnaire is a validated screening questionnaire used to quickly identify 
the risk (low to high) of sleep disordered breathing. The questionnaire consists of three 
categories and risk is based on the responses to individual items and overall scores in 
the symptom categories. Assessments will be performed according to the Study Events 
Flow Chart (Section 6). The questionnaire will be provided as a separate document and 
a copy of the questionnaire to be used will be kept in the study binder.  
14.1.9 Adverse Events 
14.1.9.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
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An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.3 
14.1.9.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, after the last 
scheduled study procedures on Day 56 (or upon early withdrawal), and at the follow-up 
phone call. The inquiry will be made in a non-specific manner using open-ended 
questions so as not to bias the response (e.g., How have you been feeling since your 
last visit?). 
All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.9.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 4 and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
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Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade; ADL = Activities of Daily Living 
*Instrumental ADL refer 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. 
14.1.9.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Medical Monitor via fax or e-mail within one working day of 
becoming aware of the event, whether or not the serious events are deemed 
drug-related. All serious event reporting will adhere to 21 CFR 312.32 for Investigational 
New Drugs (IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20123. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
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If an SAE occurs to a patient on this study, the Medical Monitor is to be contacted (see 
Section 4). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses, whether the dose was 
administered with food, and daily respiratory symptoms throughout the Run-in and 
Treatment Periods. Patients will return the e-diary device on Day 56 (or prior to early 
termination) to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., 
estimated sputum quality (e.g., color, consistency) and quantity,) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity 
(DASI). 
14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
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14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., estimated sputum quality (e.g., color, 
consistency) and quantity,) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation via the e-diary before each dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) 
and 
long 
acting 
β2-agonist 
and 
anticholinergic 
bronchodilators 
(e.g., salmeterol, tiotropium) agents will be withheld approximately 4 and 24 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study. 
At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol (100 μg/inhalation) for a total dose of 
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400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes 
after albuterol administration, the baseline post-bronchodilator spirometry will be 
performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Day -1 measurement): Predose 
FEV1 is defined as the time point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
FEV1 measurement at predose on Day -1 of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose on Day -1, up to 3 measures will be 
performed.  
Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be fasted for 12 hours before the bronchoscopy procedures. If required, 
blood pressure medications can be taken with small sip of water based on preapproval 
of local Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.5,6 
Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal cannula will be 
administered during bronchoscopy and oxygen saturation will be maintained at ≥95%. 
Conscious sedation will be achieved with incremental doses of 1–4 mg midazolam and 
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50-100 μg fentanyl. Local upper and lower airway topical anesthesia will be achieved 
with 1% or 2% lidocaine. The dose of lidocaine administered during the procedure will 
not exceed a total of 450 mg. The bronchoscope will usually be inserted preferably 
through the nares into trachea. The bronchoscope will be wedged into 2 subsegments of 
the right middle or lower lobe, as deemed appropriate by the Investigator. Emergency 
treatments for cardiopulmonary arrest and pneumothorax will be immediately available in 
the bronchoscopy room. The patient will remain in the recovery suite for observation for 
a minimum of 2 hours after the procedure.  
14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A total of 180 mL BAL, 
using 6 x 30 mL aliquots of normal saline warmed to room temperature, will be 
performed using each subsegment of the right middle or lower lobe, as deemed 
appropriate by the Investigator. BAL fluid will be aspirated following each 30 mL 
instillation. The lavage material, which averages 25% return in COPD patients, typically 
yields 1-10 x 106 macrophages. The centrifuged cell pellet and supernatant will be kept 
cooled until processed or stored as indicated in the laboratory manual to be provided as 
a separate document. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and eosinophils 
as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
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14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture or an angiocatheter at the time 
points delineated in the Study Events Flow Chart (Section 6) for PD assessments of 
biomarkers. Biomarker assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 3 tubes.  A manual for blood sampling, collection, processing, 
and sample shipment will be provided in a separate document. 
14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Day -1 of the Treatment Period) will be assessed with the BDI. 
This instrument has 3 domains (functional impairment, magnitude of task, and 
magnitude of effort) with the values added for a combined focal score. Functional 
impairment determines the impact of breathlessness on the ability to carry out activities; 
magnitude of task determines the type of task that causes breathlessness, magnitude of 
effort establishes the level of effort that results in breathlessness. The BDI scores range 
from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline 
focal score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.7,8 
A copy of the questionnaire to be used will be kept in the study binder. 
14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
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14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture or an angiocatheter at the time points 
delineated in the Study Events Flow Chart (Section 6).  
Blood will be drawn into 4 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time 
Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology), FSH (for 
postmenopausal female patients only) 
and serum pregnancy (for female 
patients only). 
1 
~ 17 mL 
~ 17 mL 
On-study serum chemistry and serum 
pregnancy (for female patients only) 
when scheduled at the same time 
3 
~ 8.5 mL 
~ 25.5 mL 
Additional on-study serum pregnancy 
(for female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
3 
~ 4 mL 
~ 12 mL 
Blood samples for PD biomarkers 
(except CRP and fibrinogen) 
8 
~ 6 mL 
~ 48 mL 
Blood samples for PD biomarker - 
CRP 
8 
~ 4 
~ 32 
Blood samples for PD biomarker - 
Fibrinogen 
8 
~ 3.5 
~ 28 
Blood samples for PK of verproside 
and picroside II 
37 
~ 4 mL 
~ 148 mL 
Total Blood Volume for males → 
~ 310.5 mL** 
Total Blood Volume for females → 
~ 317.5 mL** 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** If an angiocatheter is used, up to 5 mL of blood will be used to flush the catheter prior to each 
collection of PK and/or PD blood samples. Hence the total blood volume collected may 
increase by approximately 205 mL. 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma concentration of verproside and 
picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Days 1 and/or 56. 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 post-
baseline PD measurement. 
• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
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the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
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received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes, 
neutrophils, and eosinophils as a percentage of total cells; total cell count [cells/mL] 
of neutrophils, macrophages, lymphocytes and eosinophils as absolute inflammatory 
cell numbers; and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9): raw and % change from baseline levels; 
and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and lymphocytes] 
and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
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15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
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The following PK parameters will be computed following Day 56 morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc 
Percent fluctuation will be calculated as follows: 
𝐶𝐶max _𝑠𝑠𝑠𝑠−𝐶𝐶min _𝑠𝑠𝑠𝑠
𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎
 𝑥𝑥 100 
Swing 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
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15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), and 56 following multiple oral dose 
administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
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16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP 
(E6 Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
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check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets, and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 5 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
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16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
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17. REFERENCES 
 
                                               
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
4 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
5 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
6 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
7 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
8 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
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18. APPENDICES 
18.1 Appendix 1 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
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Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
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1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
16-Sep-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 4 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below: 
1. Brigham and Women's Hospital Investigator signature and contact 
information was removed throughout the protocol since the center will 
not be participating during this study. The following sections were 
updated accordingly: 
• 
Section 3 Investigators Signatures 
• 
Section 4 Additional Key Contacts for the Study 
2. The age limits were changed from 40 - 80 years of age, inclusively, to 
30 - 85 years of age, inclusively. The following sections were updated 
accordingly: 
• 
Section 5 Synopsis - Study Population 
• 
Section 13.3.2 Inclusion Criteria – Inclusion criterion #1 
3. To provide scheduling flexibility to the patients, a ±2-day window was 
added to the return visits on Days 15, 29, and 43. The following 
sections were updated accordingly: 
• 
Section 5 Synopsis - Summary of Study Design and Exploratory 
Outcome Measures 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 15.1.6.2 Statistical Methods for Pharmacokinetic 
Analyses 
4. Breathalyzer was added as an alternative method to the urine dipstick 
for the alcohol screen. The following sections were updated 
accordingly: 
• 
Section 6 Study Events Flow Chart 
• 
Section 13.3.3 Exclusion Criteria – Exclusion criterion #13 
• 
Section 14.1.6.7 Urine/Breathalyzer Alcohol Screen was added 
• 
Section 14.1.6.8 (previously 14.1.6.7) was renamed Urine Drug 
Screen (previously Urine Drug/Alcohol Screen). 
5. Only patients suffering from severe sleep apnea, as assessed by the 
Berlin Questionnaire, will be excluded from the study; The following 
sections were updated accordingly:  
• 
Section 6 Study Events Flow Chart 
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DATE/NAME 
DESCRIPTION 
16-Sep-2015 
by Caroline Engel 
• 
Section 13.3.3 Exclusion Criteria - exclusion criterion #8. 
• 
Section 14.1.8 Berlin Questionnaire was added. 
6. The body mass index upper limit was increased from 32.0 kg/m2 to 
40.0 
kg/m2 
inclusively. 
Therefore 
inclusion 
criterion 
#5 
of 
Section 13.3.2 Inclusion Criteria was revised accordingly. 
7. Drug screen false positive will be allowed if they are due to the use of 
prescription medication following approval from the PI and the 
medical monitor, the exclusion criterion #13 of Section 13.3.3 
Exclusion Criteria was revised accordingly. 
8. Smoking restriction prior to the bronchoscopy procedures was 
removed. 
Therefore, 
Section 
14.3.2 
Bronchoscopy 
and 
Bronchoalveolar Lavage (BAL) Biomarkers was updated accordingly. 
9. Only strong and moderate inhibitors of UDP-glucuronosyltransferase 
and/or sulfotransferases are prohibited, therefore to prevent 
confusion with the list of substrats that was provided in Appendix 1, 
Appendix 1 was remove and the only 3 inhibitors listed in that table 
was enumarated in exclusion criterion #18. The list of substrate in 
appendix 2 (now rename Appendix 1) was also remove. This change 
will prevent possible confusion with the lists provided in the 
appendices. Exclusion criterion #18 of Section 13.3.3 Exclusion 
Criteria was revised accordingly. 
10. To be consistent with Section 6 Study Events Flow Chart, pulse 
oximetry was added to the order of procecedures listed in 
Section 14.1 Safety Assessments. 
11. Typographic and editorial corrections were made where applicable. 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 3 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. The changes to the protocol are presented 
with new text in bold font and deleted text in strikethrough font. 
Serious Adverse Event Contact Information 
Drug Safety Solution’s Medical Monitor will be contacted in case of 
serious adverse events. Hence the information under Sponsor Contact for 
Serious Adverse Events (Medical Monitor) in Section 4 Additional Key 
Contacts for the Study was corrected as follows: 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, Seoul, 134-721, Republic of 
Korea   
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
Dr. Kathy Smith 
Drug Safety Solution  
Tel.: +1 919 264-5626 
E-mail:  ksmith@drugsafety.biz 
Section 14.1.8.4 Serious Adverse Events and Section 13.4.3.2 
Procedures for Breaking the Blind Prior to Study Completion was also 
corrected accordingly. 
Certified Clinical Laboratory: 
Brigham and Women's Hospital and UAB Lung Health Center clinical 
laboratories contact information were added to Section 4 Additional Key 
Contacts for the Study. 
Clinical Indication: 
As indicated in the objectives of the study, the study will examine the 
pharmacodynamic (PD) effect of YPL-001 in patients with chronic 
obstructive pulmonary disease (COPD) only. Therefore, to prevent 
potential confusion and to capture the intended indication of the study 
specifically “asthma” was removed from the Clinical Indication in Section 
5 synopsis and Section 10.1 Purpose of the Study. 
Study Population: 
As indicated throughout the protocol, patients will be will be adult males 
and females with moderate to severe COPD (conform to the severity 
classification for Global Initiative for Chronic Obstructive Lung Disease 
[GOLD] Stage 2-3). Hence to be consistent with the GOLD Stage 
standards, the first sentence under Study Population from Section 5, 
Synopsis was corrected as follow: 
“Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant 
bronchitic component and a history of frequent (>2/year) COPD 
exacerbations, between 40 and 80 years of age (inclusive).” 
Randomization and Drug Dispensing 
Instruction for randomization and drug dispensing are provided in a 
separate document. To be consistent with this document, which states 
that two sets of randomization code envelopes will be provided to site 
pharmacist/study coordinators and patients will received appropriately 
labeled kits and/or any unused wallets from previously provided kits 
(when applicable) for YPL-001 home dosing in addition to the containers 
for tiotropium/albuterol home dosing, the following section were modified 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
accordingly: 
• 
Section 5 Synopsis under Summary of Study Design and Study 
Products 
• 
Section 6 Study Event Flow Chart, Day 1 Study Drug Administration 
at CRU - Footnotes “k” and “p” 
• 
Section 6 Study Event Flow Chart, Days 2 to 55 Study Drug 
Administration at Home – Footnotes “j” and “o” 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 13.4.3.1 Maintenance of Randomization 
• 
Section 13.4.3.2 Procedures for Breaking the Blind Prior to Study 
Completion 
In addition, and “X” was also added in the “Randomization” row under 
Day 1 predose in Section 6 Study Events Flow Chart. 
Fasting Conditions 
As indicated throughout the protocol, subjects will be required to fast for 
at least 8 hours before and 4 hours after YPL-001/placebo morning 
administration on Days 1 and 56. For clarity, footnote “q” was added to 
Day 1 Study Drug Administration at CRU and footnote “k” was added to 
Day 56 Study Drug Administration at CRU in Section 6 Study Events 
Flow Chart. 
Analytes to be Measured 
As indicated throughout the protocol, blood samples will be collected for 
the analyses of verproside and picroside II in plasma. Hence, the row 
identified as “Blood for Verproside Phamacokinetics” on Day 56 of 
Section 6 Study Events Flow Chart, was corrected to read: “Blood for 
Verproside & Picroside II PK”. 
End-of-Treatment – Early Termination Procedures 
All procedures listed under End-of-Treatment/Early Termination column in 
Section 6 Study Events Flow Chart are also scheduled to be performed 
on Day 55 before the bronchoscopy procedures. Therefore, as it is not 
required to repeat these procedures for two consecutive days, 
End-of-Treatment procedures were removed on Day 56, however early 
termination (ET) procedures were listed under the new ET column. 
Hence, the following sections were corrected accordingly.  
• 
Section 6 Study Events Flow Chart  
• 
Section 13.2.4.2 End-of-Treatment or Early Termination (Day 56), 
(renamed Section 13.2.4.2 Early Termination). 
• 
Section 13.3.2 Inclusion Criteria – Criterion #16 
• 
Section 13.3.4 Removal of Patients from the Study 
• 
Section 13.3.5.1.1 Prohibited Therapy 
• 
Section 13.3.5.1.2 Permitted Therapy 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 14.1.8.2 Monitoring 
• 
Section 14.5 Blood Volume for Study Assessments (Table 5:  Blood 
Volume during Study) 
In addition, the following sentence was added to Section 13.2.4.2 End-of-
Treatment or Early Termination (Day 56), (renamed Section 13.2.4.2 
Early Termination):   
“Patients who want to terminate from the study and are not currently on-
site will be contacted and asked to return to the CRU to perform the early 
termination procedures” 
Investigator’s Brochure Version 
In Section 9.1 YPL-001, the Investigator’s Brochure version was updated 
to reflect the reference section and the most recent version of the 
Investigator’s Brochure. 
Method of Blood Collection 
Throughout the protocol, the option of using an angiocatheter was added. 
Hence, the following sections were corrected accordingly: 
• 
Section 11 Risk/Benefit 
• 
Section 14.3.3 Blood Biomarkers 
• 
Section 14.4.1 Blood Sampling and Processing 
• 
Section 14.5 Blood Volume for Study Assessments 
Recording of Meal 
To be consistent with clinical sites standard procedures, the last sentence 
of Section 13.2.4.1 Meal Schedule was corrected as follow: 
“Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs.’ 
Coffee, Tea and Alcohol Prohibition 
As indicated in Section 13.3.5.2 Prohibitions, coffee tea, and red wine will 
be restricted for 7 days prior to Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample. Beer will be 
restricted for 14 days prior to Day 1 of the Treatment Period through 
collection of Day 56 last PK sample. Any other product containing 
xanthines or caffeine will be restricted 24 hours prior to each CRU visit 
and prior to dosing on Days 1 and 56 of the Treatment Period through 
collection of Days 1 and 56 last PK sample. Any other alcohol product will 
be restricted 48 hours prior to each CRU visit, 48 hours prior to dosing on 
Days 1 and 56 last PK sample. Hence, the xanthines/caffeine prohibition  
and the alcohol prohibition were corrected as follows for clarification: 
“Xanthines/caffeine (other than coffee and tea):  24 hours prior to each 
CRU visit and prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
“Alcohol (other than red wine and beer):  48 hours prior to each CRU 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
visit, 48 hours prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
 
e-Diary 
Home dosing will be recorded using a yes/no answer in the e-diary. 
Therefore the last sentence of the second to last paragraph of 
Section 13.4.1.2 Drug Administration During Treatment Period was 
corrected as follows: 
“Patients will be given instructions on recording of dosing times how to 
record their drug administration in their e-diary on home-dosing days.’ 
In addition, estimation of sputum quantity was added to the list of major 
symptoms of COPD exacerbation recorded daily by the patients on their 
e-diary, “color” and “consistency” was moved as example of sputum 
quality, and a statement indicating that the e-diary device will be return in 
case of early termination was also added. Hence, the following sections 
were corrected accordingly: 
• 
Section 5 Synopsis under Secondary Outcome Measures 
• 
Section 5 Synopsis under Summary of Study Design 
• 
Section 6 Study Events Flow Chart – Day 1, Footnote “j” 
• 
Section 6 Study Events Flow Chart – Days 2-55, Footnote “i” 
• 
Section 6 Study Events Flow Chart – Day 56, Footnotes “g” and “h” 
• 
Section 12.2 Study Endpoints 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
• 
Section 13.2.4 Treatment Period (Days 1 to 56) 
• 
Section 14.2.1 Electronic Diary 
• 
Section 14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease 
Exacerbation 
Treatment Compliance 
Drug administration at home will be monitored by HGE Technologies Inc. 
via the e-diary. Therefore, the last sentence of Section 13.4.4. Treatment 
Compliance was corrected as follow: 
“Self-administration by patients at home will be monitored by the CRU via 
the e-diary and attempted phone calls will be performed to remind 
patients to take their medication, if they did not record their 
self-administration on the e-diary.” 
Oxygen Saturation 
For consistency throughout the protocol, “oxygen levels, saturation (%)” 
was replaced with “oxygen saturation (%).” 
Tiotropium Treatment 
As indicated in Section 13.3.2 Inclusion Criteria and Section 13.3.5.1.2 
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DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
Permitted Therapy, tiotropium will be withheld 24 hours prior to 
pulmonary function (spirometry) measurements. Hence, the 2nd 
paragraph of Section 14.3.1 Pulmonary Function (Spirometry), was 
corrected to read: 
“Short acting β2-agonist and anticholinergic bronchodilators (e.g., 
albuterol, ipratropium bromide) and long acting β2-agonist and 
anticholinergic bronchodilators (e.g., salmeterol, tiotropium) agents will be 
withheld approximately 4 and 12 24 hours, respectively, before each 
pre-bronchodilator spirometry.” 
Spirometer Across Clinical Site 
The 3rd paragraph of Section 14.3.1 Pulmonary Function (Spirometry) 
was corrected as follow: 
“Every effort will be made to perform all assessments for a given patient 
on the same instrument throughout the study and all sites should be 
using the same brand and model of spirometer for this study.” 
Bronchoalveolar Lavage (BAL) Collection 
It is planned that a maximum of 180 mL BAL will be performed during 
each planned bronchoscopy procedures. Therefore, to prevent confusion, 
the second sentence of Section 14.3.2.3, Bronchoalveolar Lavage (BAL) 
was corrected to read: 
“A total of 180 mL BAL, using 6 x 30 mL aliquots of normal saline 
warmed to room temperature, will be performed in using each 
subsegment of the right middle or lower lobe, as deemed appropriate by 
the Investigator, using 6 x 30 mL aliquots of normal saline warmed to 
room temperature.” 
Blood 
Volume 
for 
Clinical 
Safety 
Laboratory 
Tests, 
Pharmacodynamic 
(PD) 
Markers 
and 
Pharmacokinetic 
(PK) 
Samples: 
Blood collection volume for PD markers, as indicated in Section 14.3.3 
Blood Biomarkers and Section 14.5 Blood Volume for Study 
Assessments, only accounts for 1 tube. However, 3 tubes will be required 
to assess CRP (4 mL tube), fibrinogen (3.5 mL tube) and the rest of the 
PD biomarkers (6 mL tube). The blood volume per time point will be 
approximately 13.5 mL instead of 4.5 mL. 
As indicated above, End-of-Treatment listed on Day 56 were removed as 
the same tests are scheduled on Day 55 before the bronchoscopy 
procedures. Hence one sample was removed for a total of 3 on-study 
hematology and serum chemistry tests to be performed throughout the 
study. 
In addition, 4 mL of blood will be sufficient for the determination of 
verproside and picroside II concentration in plasma at each time point. 
Therefore the total blood volume was corrected to 310.5 mL for males 
and 317.5 mL for females. Section 14.3.3 Blood Biomarkers, 
Section 14.4.1 Blood Sampling and Processing, and Section 14.5 Blood 
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DATE/NAME 
DESCRIPTION 
Volume for Study Assessments were corrected accordingly. 
Minor typographic and editorial corrections were made where applicable. 
16-Feb-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 2 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. 
Number of Subjects: 
The sample size was revised to 60 subjects as it is sufficient to meet the 
objectives of the study. In case of dropouts, discontinued patients may be 
replaced at the discretion of the Sponsor as indicated throughout the 
protocol. Therefore the following sections were corrected accordingly to 
indicate that at least 60 subjects are planned to be enrolled and 
randomized with 20 patients to receive one of the 3 treatments: 
• 
Section 5 Synopsis (the 1st sentence of the 2nd paragraph under 
Summary of Study Design and the 1st and 2nd sentences under 
Number of Patients). 
• 
The 1st sentence of the 2nd paragraph of Section 13.1 Overall Study 
Design and Plan. 
• 
The 1st and 3rd sentences of Section 13.3.1 Number of Patients. 
• 
The last sentence of Section 15.1.1 Sample Size Calculation. 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) and 
COPD Assessment Test (CAT): 
BDI/TDI and CAT questionnaires will not be used as a diagnostic tool to 
assess the patient’s potential to meet all inclusion criteria and none of the 
exclusion criteria. Therefore these questionnaires are not required at 
screening. In addition, it is not required to perform them for 2 consecutive 
days to meet the study objectives and therefore, Day 55 assessments 
were removed.  
Section 6 Study Events Flow Chart was corrected accordingly. 
The first sentence in Section 14.3.4.1 Baseline Dyspnea Index/Transition 
Dyspnea Index (BDI/TDI) was also corrected to be consistent with 
Section 6. 
Early Termination Procedures: 
Weight, and oxygen levels, saturation (%), and heart rate assessed using 
a pulse oximeter were added to the procedures performed at the end of 
the Treatment Period on Day 56 or prior to early termination from the 
study to monitor subject’s safety appropriately. A pulmonary function 
(spirometry) test was also added prior to early termination for safety 
monitoring. 
Section 6 Study Events Flow Chart was corrected accordingly. 
 
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DATE/NAME 
DESCRIPTION 
16-Feb-2015 
by Caroline Engel 
Recording Concomitant Medication: 
Concomitant medication will be recorded at each study visit by the clinical 
staff in to the electronic data capture system. Therefore, concomitant 
medications was removed from the list of events that will be recorded by 
the patients via their e-diary throughout the protocol. The following 
sections were corrected accordingly: 
• 
Footnotes in Section 6 Study Events Flow Chart. 
• 
The first sentence of the 4th paragraph of Section 13.2.3 Run-In 
Period (Days 1 to 14 [± 2 days]). 
• 
The 2nd sentence of the 2nd paragraph of Section 13.2.4 Treatment 
Period (Days 1 to 56). 
• 
The 2nd sentence of the first paragraph of Section 14.2.1 Electronic 
Diary. 
Subject Numbering: 
The first paragraph of Section 13.4.2 Method of Assigning Patients to 
Treatment Groups was modified to clarify that the screening number and 
randomization number are two separate identification number given to 
each subject at different stages of the study. 
Adverse Events Reporting 
Footnotes were added to clarify the rating severity definitions in 
Section 14.1.8.3 Reporting. 
Minor editorial and typographical corrections were made where 
applicable. 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 1 
This protocol amendment is generated to update the study population 
with regards to smoking frequency, to update the handling procedures for 
BAL samples, and to clarify other study procedures as listed below. 
Study Population: 
Section 13.3.2 - Inclusion Criteria, bullet 11 was updated to indicate that 
the study population will consist only of current and ex-smokers with a 
history of >10 pack years. As such, the indications for ‘packs/year’ were 
replaced with ‘pack years’ and the allowance for current smokers with 
<10 pack/years was removed. 
Wording was added to indicate an approximately equal number of current  
and ex-smokers will be enrolled, and that each treatment group will 
consist of an approximately equal number of smokers and ex-smokers. In 
addition, the stratification criteria for the randomization was updated to 
consist of either current or ex-smokers. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Population and Number of 
Patients) 
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DATE/NAME 
DESCRIPTION 
 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 13.1 - Overall Study Design and Plan (second paragraph) 
• 
Section 13.3.1 – Number of Patients. 
• 
Section 13.4.2 - Method of Assigning Patients to Treatment Groups. 
BAL Sample Handling: 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) was updated to indicate 
that sample handling, processing and storage procedures will be provided 
in a separate document.  
Follow-up Procedures: 
The wording in regards to follow-up procedures to be conducted on 
14 days (± 2 day), after the last study drug administration, was updated to 
indicated a phone-call and not a visit, as indicated correctly in Section 6 – 
Study Event Flow Chart. Study event were updated accordingly. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Duration of Participation for Patients, 
and Exploratory Outcome Measures [under Blood Assessments, 
Pulmonary Assessment, and Quality of Life Assessments])  
• 
Section 13.3.5.2 – Prohibitions (under Alcohol) 
• 
Section 14.1.8.2 – Monitoring (first paragraph). 
Study Duration: 
The total duration of the study indicated in Section 5 – Synopsis (under 
Duration of Participation for Patients) was corrected to 12 weeks to 
correspond with the actual study duration as indicated throughout the 
protocol.  
Inflammatory Markers in Blood Samples: 
The list of cell types to be evaluated as part of the inflammatory markers 
in the blood was updated to include monocytes instead of macrophages, 
as macrophages are not expected to be present in blood. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, fourth exploratory 
objective, and under Exploratory Outcome Measures [under 
Pharmacodynamic Assesments, Blood Assessments, first bullet]) 
• 
Section 12.1 - Study Objectives (fourth exploratory objective) 
• 
Section 12.2 - Study Endpoints (third exploratory endpoint) 
• 
Section 14.3.3 - Blood Biomarkers (first bullet) 
• 
Section 15.1.5.1 - Biomarkers (third bullet)  
Neutrophil Evaluation in BAL Samples 
Neutrophils were added to the list of cell types to be evaluated as a 
percentage of the total cell count in BAL samples. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, second exploratory 
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DATE/NAME 
DESCRIPTION 
 
20-Nov-2014 
by Ziv Machnes 
 
objective and under Exploratory Outcome Measures [under 
Pharmacodynamic 
Assessments, 
Bronchoalveolar 
Lavage 
Assessments, second bullet]) 
• 
Section 12.1 - Study Objectives (second exploratory objective) 
• 
Section 12.2 - Study Endpoints (second exploratory endpoint)  
• 
Section 14.3.2.4 - Biomarkers (second bullet) 
• 
Section 15.1.5.1 – Biomarkers (second bullet) 
Location of Study Drug Administration: 
Wording was added in Section 6 – Study Events Flow Chart for Day 56, 
to clarify that the study drug will be administered at the CRU. 
Meal Schedule: 
The indication for fasting requirement in Section 13.2.4.1 – Meal 
Schedule, was corrected to indicate patients will fast overnight for at least 
12 hours before bronchoscopy and BAL collection on Days -1 and 55 
instead of Days -1 and 56, as correctly indicated in Section 6 – Study 
Events Flow Chart. 
ECG Monitoring:  
Following an update in Celerion’s standard operating procedure, Section 
14.1.5 – Electrocardiogram Monitoring was updated to include at least 
5 minutes of rest prior to each ECG measurement (instead of at least 
1 minute as previously indicated). 
Hematology: 
The tests included in the hematology panel Section 14.1.6.1 – 
Hematology were updated to indicate that the red blood cell (RBC) count 
will include a reticulocytes count, and that the white blood cell (WBC) 
count with differential will include monocytes but will not include 
reticulocytes. 
Bronchoscopy and BAL: 
Due to the sensitivity of YPL-001 components to UV light, a warning was 
added to protect all samples from exposure to UV light, as indicated for 
the PK blood samples. 
The following sections were affected: 
• 
Section 14.3.2.2 - Bronchial Brushings 
• 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) 
PK Population: 
The indication for measurable concentration of verproside and picroside II 
in urine was removed from the definition of PK population in 
Section 15.1.2 - Patients to Analyze, as there is no urine PK sampling 
planned for this study. 
Minor typographic and editorial corrections were made where applicable. 
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DATE/NAME 
DESCRIPTION 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
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AA98497_Final_Prot_Amendment _4_16Sep2015 
 
4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Events (Medical Monitor) 
Dr. Kathy Smith 
Drug Safety Solution Tel.: +1 919 264-
5626E-mail:  ksmith@drugsafety.biz  
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratory 
For Temple University School of Medicine: 
Yuri Persidsky, MD, Ph.D. 
Chairperson, Department of Pathology and 
Laboratory Medicine 
Professor, 
Pathology 
and 
Laboratory 
Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
UAB Lung Health Center: 
UAB Hospital Laboratories 
619 19th Street South 
Birmingham, Alabama, 35249 
United States  
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
 
 
 
 
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Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Boards Main Office 
Location 
For Temple University School of Medicine: 
Student Faculty Center - Suite 304 
3340 North Broad Street 
Philadelphia, Pennsylvania, 19140 
United States 
Tel.: +1 215 707-3390 
Fax: +1 215 707-9100 
 
UAB Lung Health Center: 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
  
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5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such chronic 
obstructive pulmonary disease (COPD) 
Study Type: 
Phase 2a, proof of concept 
Study Objectives: 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, monocytes, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
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AA98497_Final_Prot_Amendment _4_16Sep2015 
 
Summary of Study 
Design: 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups 
(20 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) on the morning of 
Day -1 of the Treatment Period to confirm their eligibility and assess their 
health conditions. If they still meet all of the inclusion criteria and none of the 
exclusion criteria, they will undergo Day -1 scheduled study procedures. 
Patients will return to the CRU the next day (Day 1) to be randomized and 
receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15 (± 2 days), 
29 (± 2 days), 43 (± 2 days), 55, and 56 of the Treatment Period for study 
drug administration and procedures. Prior to each release from the CRU, 
patients will receive a properly labeled YPL-001 kit (and/or any unused 
wallets 
from 
previously 
provided 
kits 
[when 
applicable]) 
and 
tiotropium/albuterol 
container 
with 
sufficient 
doses 
which 
will 
be 
self-administered by patients at home until the next morning visit at the CRU. 
Patients will continue recording their daily symptoms via the e-diary 
throughout the Treatment Period. Patients will return the e-diary device on 
Day 56 (or prior to early termination) to CRU staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
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Page 20 
AA98497_Final_Prot_Amendment _4_16Sep2015 
 
will be administered in accordance with the study center standard of care. 
Study Population: 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component, between 30 and 85 years of age (inclusive). An approximately 
equal number of current and ex-smokers will be enrolled. 
Number of 
Patients: 
The study is planned to enroll at least 60 patients. Patients will be divided in 
3 treatment groups with 20 patients to receive one of the 3 treatments (i.e., 
low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo 
control) as per the randomization schedule. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Duration of 
Participation for 
Patients: 
The planned length of participation in the study for each patient is 
approximately 12 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up procedures on Day 70 [± 2 days]). 
Duration of Study 
Conduct: 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products: 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
YPL-001 or placebo will be dispensed in accordance with the Randomization 
and Drug Dispensing Instructions provided in a separate document. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen: 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 80 mg matching placebo tablet) will be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be 
administered on Day 56. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B, and C will be administered orally with 
approximately 240 mL of water. 
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AA98497_Final_Prot_Amendment _4_16Sep2015 
 
Stopping Rules: 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
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Celerion Project No. : AA98497 
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Page 22 
AA98497_Final_Prot_Amendment _4_16Sep2015 
 
Safety and 
Tolerability 
Analysis 
(continued): 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures: 
PEF, major (e.g., estimated sputum quality (e.g., color, consistency), and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, 
discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (Duke 
Activity Status Index [DASI]) self-reported daily by the patients using an 
e-diary. 
Symptom 
Monitoring 
Analysis: 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, and throughout the study for 
PD assessments of biomarkers. Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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IND No.: 114903 
 
 
Page 23 
AA98497_Final_Prot_Amendment _4_16Sep2015 
 
Exploratory 
Outcome 
Measures 
(continued): 
IC] will be performed at screening, and throughout the study. 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, and throughout the study. 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 56 to determine verproside and 
picroside II concentrations in plasma. Predose samples will also be collected 
in the morning of Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days) and 56 for 
Ctrough determination. Other components of YPL-001 and its metabolites may 
also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis: 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis: 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-001 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
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IND No.: 114903 
 
 
Page 24 
AA98497_Final_Prot_Amendment_4_16Sep2015 
 
6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Berlin Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg 
X 
 
 
Xf 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAh 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityj 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationp 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk,q 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 25 
AA98497_Final_Prot_Amendment_4_16Sep2015 
 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)l 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xn 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitso 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
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IND No.: 114903 
 
 
Page 26 
AA98497_Final_Prot_Amendment_4_16Sep2015 
 
a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
d. To be performed prior to the bronchoscopy procedures. 
e. To be performed at screening or within 3 months (inclusive) of screening. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
i. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
k. Prior to release from the CRU, patients will receive a properly labeled kit with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
l. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
m. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
n. To be performed prior to dosing. 
o. Patients will be admitted to the CRU at the time indicated by the CRU. 
p. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
q. On Day 1, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
 
 
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IND No.: 114903 
 
 
Page 27 
AA98497_Final_Prot_Amendment_4_16Sep2015 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 2-14 
15 (± 2) 16-28 29 (± 2) 30-42 
43 (± 2) 
44-54 
55 
Hours → 
 
AM PM 
 
AM PM 
 
AM 
PM 
 
AM 
PM 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Xe 
 
Vital Signsf 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xe 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
Xe 
 
Hem, Chem, and UAg 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine or Breathalyzer Alcohol Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useh 
X 
PEF, COPD exacerbation, dyspnea 
and activityi 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationo 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Administration at Homej 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)k 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xn 
 
Bronchoscopy and BAL Biomarkersl 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
BDI/TDI & CAT 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Refer to the footnotes on the next page 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 28 
AA98497_Final_Prot_Amendment_4_16Sep2015 
 
a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. To be performed or completed prior to bronchoscopy procedures and/or dosing. 
e. ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
f. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
g. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
h. Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
i. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
j. 
Prior to release from the CRU on Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), and 55 patients will receive a properly labeled kit and/or 
any unused wallets from previously provided kits (when applicable) with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
k. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
l. 
Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
m. Patients will be admitted to the CRU at the time indicated by the CRU. 
n. To be completed prior to bronchoscopy procedures and dosing. 
o. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
304


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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 29 
AA98497_Final_Prot_Amendment_4_16Sep2015 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
ETb FUc 
Days → 
56 
Hours → Predose 0 
0.167 
0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signse 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hem, Chem, and UAf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UrineDrug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine or Breathalyzer Alcohol Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PEF, COPD exacerbation, dyspnea and 
activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood Biomarkers 
Xi 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsj 
X 
X 
 
Refer to the footnotes on the next page 
 
 
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a. For details on Procedures, refer to Section 14. 
b. To be performed prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
f. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
g. Patients will return the e-diary device on Day 56 (or prior to early termination) to CRU staff.  
h. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
i. 
To be performed at predose on Day 56 or upon early termination. 
j. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
k. On Day 56, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition 
Dyspnea Index Test, CAT = COPD Assessment Test, Chem = Serum chemistry, COPD = chronic obstructive pulmonary disease, CRU = Clinical 
research unit, ConMeds = Concomitant medication, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = electronic diary, 
ET =  Early termination, FSH = Follicle-stimulating hormone, Hem = Hematology, HIV = Human immunodeficiency virus, IL= interleukin, 
PEF = Peak expiratory flow, PK = Pharmacokinetics, PM = Evening, Preg = Serum pregnancy, Screen = Screening, UA = Urinalysis. 
 
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7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY ...................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ............................................................................................. 14 
3. 
INVESTIGATORS SIGNATURES ...................................................................................... 15 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY ............................................................ 16 
5. 
SYNOPSIS ........................................................................................................................ 18 
6. 
STUDY EVENTS FLOW CHART ....................................................................................... 24 
7. 
TABLE OF CONTENTS ..................................................................................................... 31 
8. 
ABBREVIATIONS.............................................................................................................. 34 
9. 
INTRODUCTION AND BACKGROUND ............................................................................. 39 
9.1 
YPL-001 .................................................................................................................. 39 
9.1.1 
Preclinical Trials .......................................................................................... 39 
9.1.1.1 
Pharmacology .............................................................................. 39 
9.1.1.2 
Pharmacokinetics ......................................................................... 40 
9.1.1.3 
Toxicology ................................................................................... 41 
9.1.2 
Clinical Experience...................................................................................... 42 
9.1.2.1 
SAD study .................................................................................... 43 
9.1.2.2 
MAD Study .................................................................................. 44 
10. RATIONALE ...................................................................................................................... 46 
10.1 Purpose of the Study ............................................................................................... 46 
10.2 Dose Selection ........................................................................................................ 46 
11. RISK/BENEFIT .................................................................................................................. 48 
12. STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 49 
12.1 Study Objectives ..................................................................................................... 49 
12.2 Study Endpoints ...................................................................................................... 49 
13. INVESTIGATIONAL PLAN ................................................................................................ 51 
13.1 Overall Study Design and Plan ................................................................................ 51 
13.2 Study Conduct ......................................................................................................... 52 
13.2.1 Screening ................................................................................................... 52 
13.2.2 Patient Confinement .................................................................................... 52 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ....................................................... 52 
13.2.4 Treatment Period (Days 1 to 56) ................................................................. 53 
13.2.4.1 Meal Schedule ............................................................................. 53 
13.2.4.2 Early Termination ......................................................................... 54 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................ 54 
13.2.6 Scheduled End of Study .............................................................................. 54 
13.3 Selection of Study Population .................................................................................. 54 
13.3.1 Number of Patients ..................................................................................... 54 
13.3.2 Inclusion Criteria ......................................................................................... 54 
13.3.3 Exclusion Criteria ........................................................................................ 56 
13.3.4 Removal of Patients from the Study ............................................................ 58 
13.3.5 Study Restrictions ....................................................................................... 59 
13.3.5.1 Concomitant Therapy ................................................................... 59 
13.3.5.1.1 
Prohibited Therapy ................................................... 59 
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13.3.5.1.2 
Permitted Therapy ................................................... 60 
13.3.5.2 Prohibitions .................................................................................. 60 
13.3.5.3 Activity ......................................................................................... 60 
13.4 Treatments .............................................................................................................. 61 
13.4.1 Treatments administered ............................................................................. 61 
13.4.1.1 Drug Administration During Run-in Period .................................... 61 
13.4.1.2 Drug Administration During Treatment Period............................... 61 
13.4.1.3 Stopping Rules ............................................................................ 62 
13.4.2 Method of Assigning Patients to Treatment Groups ..................................... 63 
13.4.3 Blinding ....................................................................................................... 63 
13.4.3.1 Maintenance of Randomization .................................................... 63 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 63 
13.4.3.3 Revealing of Randomization ......................................................... 64 
13.4.4 Treatment Compliance ................................................................................ 64 
14. STUDY PROCEDURES .................................................................................................... 65 
14.1 Safety Assessments ................................................................................................ 65 
14.1.1 Body Height and Weight .............................................................................. 65 
14.1.2 Physical Examination .................................................................................. 65 
14.1.3 Vital Signs ................................................................................................... 65 
14.1.4 Pulse Oximetry............................................................................................ 66 
14.1.5 Electrocardiogram Monitoring ...................................................................... 66 
14.1.6 Clinical Laboratory Tests ............................................................................. 67 
14.1.6.1 Hematology.................................................................................. 67 
14.1.6.2 Serum Chemistry ......................................................................... 67 
14.1.6.3 Serology ...................................................................................... 67 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............ 67 
14.1.6.5 Follicle-Stimulating Hormone ........................................................ 68 
14.1.6.6 Urinalysis ..................................................................................... 68 
14.1.6.7 Urine/Breathalyzer Alcohol Screen ............................................... 68 
14.1.6.8 Urine Drug Screen ....................................................................... 68 
14.1.7 Chest X-Ray ............................................................................................... 68 
14.1.8 Berlin Questionnaire .................................................................................... 68 
14.1.9 Adverse Events ........................................................................................... 68 
14.1.9.1 Adverse Event Definition .............................................................. 68 
14.1.9.2 Monitoring .................................................................................... 69 
14.1.9.3 Reporting ..................................................................................... 69 
14.1.9.4 Serious Adverse Events ............................................................... 70 
14.2 Symptom Assessments ........................................................................................... 71 
14.2.1 Electronic Diary ........................................................................................... 71 
14.2.2 Peak Expiratory Flow .................................................................................. 71 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ........... 72 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) .................................................... 72 
14.2.5 Activity (Duke Activity Status Index) ............................................................ 72 
14.3 Pharmacodynamic Assessments ............................................................................. 72 
14.3.1 Pulmonary Function (Spirometry) ................................................................ 72 
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14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers.................... 73 
14.3.2.1 Bronchoscopy .............................................................................. 73 
14.3.2.2 Bronchial Brushings ..................................................................... 74 
14.3.2.3 Bronchoalveolar Lavage (BAL) ..................................................... 74 
14.3.2.4 Biomarkers .................................................................................. 74 
14.3.3 Blood Biomarkers ........................................................................................ 75 
14.3.4 Quality of Life Questionnaires ..................................................................... 75 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ..................................................................................... 75 
14.3.4.2 COPD Assessment Test (CAT) .................................................... 75 
14.4 Pharmacokinetic Assessments ................................................................................ 75 
14.4.1 Blood Sampling and Processing .................................................................. 76 
14.5 Blood Volume for Study Assessments ..................................................................... 76 
15. DATA ANALYSIS .............................................................................................................. 77 
15.1 Statistical Analysis ................................................................................................... 77 
15.1.1 Sample Size Calculation ............................................................................. 77 
15.1.2 Patients to Analyze ..................................................................................... 77 
15.1.3 Safety Analysis ........................................................................................... 78 
15.1.4 Symptom Monitoring Analysis ..................................................................... 78 
15.1.5 Pharmacodynamic Analysis ........................................................................ 79 
15.1.5.1 Biomarkers .................................................................................. 79 
15.1.5.2 Quality of Life ............................................................................... 79 
15.1.6 Pharmacokinetic Analysis ........................................................................... 80 
15.1.6.1 Pharmacokinetic Parameters ....................................................... 80 
15.1.6.1.1 
Plasma .................................................................... 80 
15.1.6.1.2 
Bronchoalveolar Lavage ........................................... 81 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ........................ 82 
15.1.7 Assessment of Efficacy ............................................................................... 82 
16. STUDY ADMINISTRATION ............................................................................................... 83 
16.1 Ethics ...................................................................................................................... 83 
16.1.1 Institutional Review Board ........................................................................... 83 
16.1.2 Ethical Conduct of the Study ....................................................................... 83 
16.1.3 Patient Information and Consent ................................................................. 83 
16.2 Termination of the Study .......................................................................................... 83 
16.3 Data Quality Assurance ........................................................................................... 83 
16.4 Direct Access to Source Data/Documents ................................................................ 84 
16.5 Drug Supplies, Packaging and Labeling ................................................................... 84 
16.6 Data Handling and Record Keeping ......................................................................... 84 
16.7 Protocol Amendments ............................................................................................. 84 
16.8 Finance and Insurance ............................................................................................ 85 
16.9 Publication Policy .................................................................................................... 85 
17. REFERENCES .................................................................................................................. 86 
18. APPENDIXES ................................................................................................................... 87 
18.1 Appendix 1 - SULT Drug Interaction Table ............................................................... 87 
 
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8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
Coag 
Coagulation 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
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CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
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IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
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ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
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US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
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9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
GCP, and applicable regulatory requirements. The patient population will be comprised 
of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of June 3, 2014. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Bronchoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
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CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
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were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
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values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
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9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 
0.67 hours under fasting conditions. Verproside appeared to be cleared rapidly from 
plasma, with mean t1/2 values under 1 hour; plasma verproside concentrations were 
below the lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 
below summaries the PK parameters of verproside following single-dose administrations 
of YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
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9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t½ values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t½ values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
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Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
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10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such COPD to demonstrate safety and 
evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
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Table 4: Traditional Chinese Medicine Use Versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
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11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an angiocatheter is utilized and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
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12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., estimated sputum quality (e.g., color, consistency) and quantity,) 
and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and 
body temperature above 100°F) symptoms of COPD exacerbation;  
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• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and 
eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
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13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups (20 patients 
per group). Patients will participate only once. An approximately equal number of current 
and ex-smokers will be enrolled in the study. 
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU on the morning of Day -1 of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Day -1 scheduled 
study procedures. Patients will return to the CRU the next day (Day 1) to be randomized 
and receive one of the 3 treatments and undergo all scheduled study procedures. 
Patients will return on the morning of Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), 
55, and 56 of the Treatment Period for study drug administration and procedures. Prior 
to each release from the CRU, patients will receive a properly labeled kit and/or any 
unused wallets from previously provided kits (when applicable) with sufficient doses 
which will be self-administered by patients at home until the next morning visit at the 
CRU. Patients will continue recording their daily symptoms via the e-diary throughout the 
Treatment Period. Patients will return the e-diary device on Day 56 (or prior to early 
termination) to CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
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will be discontinued. Rescue medication will be used for any patient with an 
exacerbation of COPD and will be administered in accordance with the study center 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses and their daily respiratory symptoms. Prior to each morning 
dose, patients will record at home their daily PEF, major (e.g., estimated sputum quality 
(e.g., color, consistency) and quantity,) and minor (e.g., cough, wheeze, sore throat, 
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nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 56 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses and their daily 
respiratory symptoms on their e-diary. Prior to each morning dose, patients will record at 
home their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) 
and quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, 
and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea 
(Modified Borg Dyspnea Scale), and activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before bronchoscopy and 
BAL collection on Days -1 and 55. On Days 1 and 56, patients will be required to fast 
overnight for at least 8 hours before and for at least 4 hours after the morning dose. On 
all other days, patients will be asked to fast for at least 2 hours before and 2 hours after 
each morning dose. Patients will also be asked to fast for at least 2 hours before and 
after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 56, patients will fast from all food and drink except water between meals 
and snacks. Foods and beverages containing alcohol, xanthines, caffeine, vegetables 
from the mustard green family, mustard, tea (especially speedwell tea), or 
grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, menus should 
be similar in content. The same menu and meal (except for snacks) schedule will be 
administered uniformly for all patients confined within the same CRU, across all 
treatment groups. Meals are not required to be completed by patients. 
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13.2.4.2 Early Termination  
Early termination evaluations will be performed on patients prior to early termination. 
Patients who want to terminate from the study and are not currently on-site will be 
contacted and asked to return to the CRU to perform the early termination procedures. 
The early termination procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll at least 60 patients. An approximately equal number of 
current and ex-smokers will be enrolled. Patients will be divided in 3 treatment groups 
with 20 patients to receive one of the 3 treatments (i.e., low and high YPL-001 doses 
[80 mg and 160 mg BID] and a placebo control) as per the randomization schedule. 
Each treatment group will consist of an approximately equal number of current and 
ex-smokers. 
13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 30 to 85 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
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4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-40.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24 hours 
prior to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled 
CRU visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack years. Ten pack years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Patients, who undergo smoking cessation therapy, must be completed 
3 months prior to screening visit and smoking status should not change between the 
patient’s screening visit and patient’s last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
13. A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method 
(e.g., condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
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14. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
15. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the last scheduled study procedures on Day 56 or upon early 
termination. Patients will be advised to use a condom with spermicide for 90 days 
following the last administration of the study drug, and to not donate sperm during 
this same period of time. In the event that the sexual partner is surgically sterile, use 
of a condom with spermicide is not necessary. No restrictions are required for 
vasectomized males provided their vasectomy has been performed 120 days or 
more prior to study start. Males who have been vasectomized less than 120 days 
prior to study start must follow the same restrictions as non-vasectomized males. 
16. Understands study procedures and provides written informed consent for the trial. 
17. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
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8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), severe sleep apnea (assessed using the Berlin Questionnaire [refer to 
Section 14.1.8]), cardiovascular, endocrine, neurological, hepatic, gastrointestinal, 
renal, hematological, urological, immunological or ophthalmic diseases that the 
Investigator believes are clinically significant e.g., unstable and could impact patient 
safety by participation in the study. 
9. History or presence of: 
• 
significant cardiac arrhythmia; 
• 
prostatic hyperplasia; 
• 
bladder-neck obstruction; 
• 
urinary retention; 
• 
narrow-angle glaucoma. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Evidence of hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive alcohol (using urine dipstick or breathalyzer) and/or urine drug testing at 
screening or at each CRU visit, unless the positive drug screen is due to prescription 
drug use and is approved by the PI and the medical monitor. 
14. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies (HCV). 
15. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
16. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
17. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
18. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) (such as 17-beta-estradiol 
glucuronide, flavonoids [citrus fruit], silybin [herb supplement milk thistle]) and/or 
sulfotransferases (SULT) (refer to Appendix 1), within 12 hours prior to Day 1 of the 
Run-in Period. Additional sources may be consulted by the PI or medical monitor to 
confirm lack of PK/PD interaction with study drug. 
19. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
20. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
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21. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
22. Females who are pregnant or lactating.  
23. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
24. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion (early 
termination evaluations) as the situation allows (see Section 13.2.4.2). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
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13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the last scheduled study 
procedures on Day 56 or upon early termination). Intake of these medications during the 
Run-in Period constitutes a non-eligibility criterion and the patients will not be 
randomized into the study. If any of these medications are taken during the Treatment 
Period, the need for this patient to be withdrawn from the study will be carefully 
evaluated by the Investigator and the Sponsor on the basis of the potential impact on 
efficacy or safety evaluation and in the patient's best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements and herbal products (especially Speedwell) will be prohibited 
7 days prior Day 1 of the Treatment Period and through collection of the final PK 
sample. 
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13.3.5.1.2 Permitted Therapy 
Throughout the study Period (from Day 1 of the Run-in Period to the completion of the 
last scheduled study procedures on Day 56 or upon early termination) patients will be 
permitted to take the following medications in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 24 hours 
before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine (other than coffee and tea):  24 hours prior to each CRU visit and 
prior to dosing on Days 1 and 56 of the Treatment Period through collection of Days 
1 and 56 last PK sample. 
• 
Alcohol (other than red wine and beer):  48 hours prior to each CRU visit, 48 hours 
prior to dosing on Days 1 and 56 of the Treatment Period through collection of 
Days 1 and 56 last PK sample. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 56 last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 56 of 
the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Tea (especially Speedwell tea), coffee, and red wine:  7 days prior to Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 56 last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
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13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. Only the 
morning dose will be administered on Day 56. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be administered on 
Day 56. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose will be 
administered on Day 56. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
YPL-001 or placebo will be dispensed in accordance with the Randomization and Drug 
Dispensing Instructions provided in a separate document. 
Prior to release from the CRU on Days 1, 15 (± 2 days), and 29 (± 2 days), of the 
Treatment Period, patients will receive a properly labeled new kit, which contains 
4 wallets of 2 blister cards, with the appropriate doses which will be self-administered by 
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patients at home. Any unused wallets from previously provided kits will also be 
dispensed to patients on Days 15 (± 2 days) and 29 (± 2 days). Prior to release from the 
CRU on Days 43 (± 2 days), and 55, patients will received unused wallets from 
previously provided kits with the appropriate doses which will be self-administered by 
patients at home. Patients will also receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. Patients will record their 
self-administered doses in their e-diary, and whether the dose was administered with 
food, and must return the YPL-001 used and unused wallets and the tiotropium and 
albuterol container (empty or not) at the next schedule visit at the next morning visit. 
Home dosing will be monitored via attempted phone calls where patients will be 
reminded to take their medication, if they did not record their self-administration on the e-
diary, and queried about the occurrence of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
given instructions on how to record their drug administration in their e-diary on 
home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
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13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique screening identification number upon screening. 
Patients who complete the study screening assessments, complete the Run-in Period, 
and meet all the eligibility criteria will be assigned a unique randomization identification 
number, different from the screening number, and receive the corresponding product, 
according to a randomization scheme generated at Celerion. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
The randomization will not be made available to the Sponsor, patients, or members of 
the staff responsible for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
The site Pharmacist/Study Coordinator will receive two sets of randomization code 
envelopes, one set for “Current Smokers” and another for “Ex-Smokers”. Each individual 
envelope is marked on the outside with one of the randomization numbers and contains 
the treatment for that patient. These envelopes must be kept in a secure locked location. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the medical monitor or designee prior to breaking the blind. If breaking 
the blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
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13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
1. All data are entered in the database, edits checks are performed, queries 
closed, CRFs signed by the Investigator, and the database is officially locked. 
2. All PK/PD samples have been analyzed and quality checked by the 
responsible analytical associate. 
13.4.4 Treatment Compliance 
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
Self-administration by patients at home will be monitored via the e-diary and attempted 
phone calls will be performed to remind patients to take their medication, if they did not 
record their self-administration on the e-diary. 
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14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs and pulse oximetry 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
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When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When scheduled postdose, vital signs readings 
will be performed within approximately 10 minutes of the scheduled time point. When 
performing the bronchoscopy, vital signs (body temperature, respiratory rate, blood 
pressure, and heart rate) will be monitored continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen saturation (%), and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen saturation [%], and heart rate) 
as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. Readings may be taken at other times, if deemed 
necessary by the Investigator. When performing the bronchoscopy, oxygen saturation 
will be monitored continuously until the end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performing the bronchoscopy, ECG will be monitored continuously until 
the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
5 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
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14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count (including a 
reticulocytes count) 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, and 
monocytes) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
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14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine/Breathalyzer Alcohol Screen 
Alcohol levels will be tested using urine dipsticks or breathalyzers. 
14.1.6.8 Urine Drug Screen 
• 
Cannabinoids  
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Berlin Questionnaire 
The Berlin Questionnaire is a validated screening questionnaire used to quickly identify 
the risk (low to high) of sleep disordered breathing. The questionnaire consists of three 
categories and risk is based on the responses to individual items and overall scores in 
the symptom categories. Assessments will be performed according to the Study Events 
Flow Chart (Section 6). The questionnaire will be provided as a separate document and 
a copy of the questionnaire to be used will be kept in the study binder.  
14.1.9 Adverse Events 
14.1.9.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
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An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.3 
14.1.9.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, after the last 
scheduled study procedures on Day 56 (or upon early withdrawal), and at the follow-up 
phone call. The inquiry will be made in a non-specific manner using open-ended 
questions so as not to bias the response (e.g., How have you been feeling since your 
last visit?). 
All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.9.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 4 and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
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Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade; ADL = Activities of Daily Living 
*Instrumental ADL refer 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. 
14.1.9.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Medical Monitor via fax or e-mail within one working day of 
becoming aware of the event, whether or not the serious events are deemed 
drug-related. All serious event reporting will adhere to 21 CFR 312.32 for Investigational 
New Drugs (IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20123. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
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If an SAE occurs to a patient on this study, the Medical Monitor is to be contacted (see 
Section 4). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses, whether the dose was 
administered with food, and daily respiratory symptoms throughout the Run-in and 
Treatment Periods. Patients will return the e-diary device on Day 56 (or prior to early 
termination) to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., 
estimated sputum quality (e.g., color, consistency) and quantity,) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity 
(DASI). 
14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
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14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., estimated sputum quality (e.g., color, 
consistency) and quantity,) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation via the e-diary before each dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) 
and 
long 
acting 
β2-agonist 
and 
anticholinergic 
bronchodilators 
(e.g., salmeterol, tiotropium) agents will be withheld approximately 4 and 24 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study. 
At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol (100 μg/inhalation) for a total dose of 
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400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes 
after albuterol administration, the baseline post-bronchodilator spirometry will be 
performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Day -1 measurement): Predose 
FEV1 is defined as the time point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
FEV1 measurement at predose on Day -1 of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose on Day -1, up to 3 measures will be 
performed.  
Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be fasted for 12 hours before the bronchoscopy procedures. If required, 
blood pressure medications can be taken with small sip of water based on preapproval 
of local Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.5,6 
Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal cannula will be 
administered during bronchoscopy and oxygen saturation will be maintained at ≥95%. 
Conscious sedation will be achieved with incremental doses of 1–4 mg midazolam and 
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50-100 μg fentanyl. Local upper and lower airway topical anesthesia will be achieved 
with 1% or 2% lidocaine. The dose of lidocaine administered during the procedure will 
not exceed a total of 450 mg. The bronchoscope will usually be inserted preferably 
through the nares into trachea. The bronchoscope will be wedged into 2 subsegments of 
the right middle or lower lobe, as deemed appropriate by the Investigator. Emergency 
treatments for cardiopulmonary arrest and pneumothorax will be immediately available in 
the bronchoscopy room. The patient will remain in the recovery suite for observation for 
a minimum of 2 hours after the procedure.  
14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A total of 180 mL BAL, 
using 6 x 30 mL aliquots of normal saline warmed to room temperature, will be 
performed using each subsegment of the right middle or lower lobe, as deemed 
appropriate by the Investigator. BAL fluid will be aspirated following each 30 mL 
instillation. The lavage material, which averages 25% return in COPD patients, typically 
yields 1-10 x 106 macrophages. The centrifuged cell pellet and supernatant will be kept 
cooled until processed or stored as indicated in the laboratory manual to be provided as 
a separate document. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and eosinophils 
as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
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14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture or an angiocatheter at the time 
points delineated in the Study Events Flow Chart (Section 6) for PD assessments of 
biomarkers. Biomarker assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 3 tubes.  A manual for blood sampling, collection, processing, 
and sample shipment will be provided in a separate document. 
14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Day -1 of the Treatment Period) will be assessed with the BDI. 
This instrument has 3 domains (functional impairment, magnitude of task, and 
magnitude of effort) with the values added for a combined focal score. Functional 
impairment determines the impact of breathlessness on the ability to carry out activities; 
magnitude of task determines the type of task that causes breathlessness, magnitude of 
effort establishes the level of effort that results in breathlessness. The BDI scores range 
from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline 
focal score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.7,8 
A copy of the questionnaire to be used will be kept in the study binder. 
14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
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14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture or an angiocatheter at the time points 
delineated in the Study Events Flow Chart (Section 6).  
Blood will be drawn into 4 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time 
Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology), FSH (for 
postmenopausal female patients only) 
and serum pregnancy (for female 
patients only). 
1 
~ 17 mL 
~ 17 mL 
On-study serum chemistry and serum 
pregnancy (for female patients only) 
when scheduled at the same time 
3 
~ 8.5 mL 
~ 25.5 mL 
Additional on-study serum pregnancy 
(for female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
3 
~ 4 mL 
~ 12 mL 
Blood samples for PD biomarkers 
(except CRP and fibrinogen) 
8 
~ 6 mL 
~ 48 mL 
Blood samples for PD biomarker - 
CRP 
8 
~ 4 
~ 32 
Blood samples for PD biomarker - 
Fibrinogen 
8 
~ 3.5 
~ 28 
Blood samples for PK of verproside 
and picroside II 
37 
~ 4 mL 
~ 148 mL 
Total Blood Volume for males → 
~ 310.5 mL** 
Total Blood Volume for females → 
~ 317.5 mL** 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** If an angiocatheter is used, up to 5 mL of blood will be used to flush the catheter prior to each 
collection of PK and/or PD blood samples. Hence the total blood volume collected may 
increase by approximately 205 mL. 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma concentration of verproside and 
picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Days 1 and/or 56. 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 post-
baseline PD measurement. 
• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
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the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
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received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes, 
neutrophils, and eosinophils as a percentage of total cells; total cell count [cells/mL] 
of neutrophils, macrophages, lymphocytes and eosinophils as absolute inflammatory 
cell numbers; and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9): raw and % change from baseline levels; 
and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and lymphocytes] 
and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
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15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
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The following PK parameters will be computed following Day 56 morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc 
Percent fluctuation will be calculated as follows: 
𝐶𝐶max _𝑠𝑠𝑠𝑠−𝐶𝐶min _𝑠𝑠𝑠𝑠
𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎
 𝑥𝑥 100 
Swing 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
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15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15 (± 2 days), 29 (± 2 days), 43 (± 2 days), and 56 following multiple oral dose 
administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
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16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP 
(E6 Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
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check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets, and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 5 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
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16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
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17. REFERENCES 
 
                                               
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
4 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
5 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
6 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
7 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
8 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
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18. APPENDIXES 
18.1 Appendix 1 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
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Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
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IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _3_23Apr2015 
 
1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 3 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. The changes to the protocol are presented 
with new text in bold font and deleted text in strikethrough font. 
Serious Adverse Event Contact Information 
Drug Safety Solution’s Medical Monitor will be contacted in case of 
serious adverse events. Hence the information under Sponsor Contact for 
Serious Adverse Events (Medical Monitor) in Section 4 Additional Key 
Contacts for the Study was corrected as follows: 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, Seoul, 134-721, Republic of 
Korea   
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
Dr. Kathy Smith 
Drug Safety Solution  
Tel.: +1 919 264-5626 
E-mail:  ksmith@drugsafety.biz 
Section 14.1.8.4 Serious Adverse Events and Section 13.4.3.2 
Procedures for Breaking the Blind Prior to Study Completion was also 
corrected accordingly. 
Certified Clinical Laboratory: 
Brigham and Women's Hospital and UAB Lung Health Center clinical 
laboratories contact information were added to Section 4 Additional Key 
Contacts for the Study. 
Clinical Indication: 
As indicated in the objectives of the study, the study will examine the 
pharmacodynamic (PD) effect of YPL-001 in patients with chronic 
obstructive pulmonary disease (COPD) only. Therefore, to prevent 
potential confusion and to capture the intended indication of the study 
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IND No.: 114903 
 
 
Page 3 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
specifically “asthma” was removed from the Clinical Indication in Section 
5 synopsis and Section 10.1 Purpose of the Study. 
Study Population: 
As indicated throughout the protocol, patients will be will be adult males 
and females with moderate to severe COPD (conform to the severity 
classification for Global Initiative for Chronic Obstructive Lung Disease 
[GOLD] Stage 2-3). Hence to be consistent with the GOLD Stage 
standards, the first sentence under Study Population from Section 5, 
Synopsis was corrected as follow: 
“Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant 
bronchitic component and a history of frequent (>2/year) COPD 
exacerbations, between 40 and 80 years of age (inclusive).” 
Randomization and Drug Dispensing 
Instruction for randomization and drug dispensing are provided in a 
separate document. To be consistent with this document, which states 
that two sets of randomization code envelopes will be provided to site 
pharmacist/study coordinators and patients will received appropriately 
labeled kits and/or any unused wallets from previously provided kits 
(when applicable) for YPL-001 home dosing in addition to the containers 
for tiotropium/albuterol home dosing, the following section were modified 
accordingly: 
• 
Section 5 Synopsis under Summary of Study Design and Study 
Products 
• 
Section 6 Study Event Flow Chart, Day 1 Study Drug Administration 
at CRU - Footnotes “k” and “p” 
• 
Section 6 Study Event Flow Chart, Days 2 to 55 Study Drug 
Administration at Home – Footnotes “j” and “o” 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.4.1.2 Drug Administration During Treatment Period 
• 
Section 13.4.3.1 Maintenance of Randomization 
• 
Section 13.4.3.2 Procedures for Breaking the Blind Prior to Study 
Completion 
In addition, and “X” was also added in the “Randomization” row under 
Day 1 predose in Section 6 Study Events Flow Chart. 
Fasting Conditions 
As indicated throughout the protocol, subjects will be required to fast for 
at least 8 hours before and 4 hours after YPL-001/placebo morning 
administration on Days 1 and 56. For clarity, footnote “q” was added to 
Day 1 Study Drug Administration at CRU and footnote “k” was added to 
Day 56 Study Drug Administration at CRU in Section 6 Study Events 
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IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Flow Chart. 
Analytes to be Measured 
As indicated throughout the protocol, blood samples will be collected for 
the analyses of verproside and picroside II in plasma. Hence, the row 
identified as “Blood for Verproside Phamacokinetics” on Day 56 of 
Section 6 Study Events Flow Chart, was corrected to read: “Blood for 
Verproside & Picroside II PK”. 
End-of-Treatment – Early Termination Procedures 
All procedures listed under End-of-Treatment/Early Termination column in 
Section 6 Study Events Flow Chart are also scheduled to be performed 
on Day 55 before the bronchoscopy procedures. Therefore, as it is not 
required to repeat these procedures for two consecutive days, 
End-of-Treatment procedures were removed on Day 56, however early 
termination (ET) procedures were listed under the new ET column. 
Hence, the following sections were corrected accordingly.  
• 
Section 6 Study Events Flow Chart  
• 
Section 13.2.4.2 End-of-Treatment or Early Termination (Day 56), 
(renamed Section 13.2.4.2 Early Termination). 
• 
Section 13.3.2 Inclusion Criteria – Criterion #16 
• 
Section 13.3.4 Removal of Patients from the Study 
• 
Section 13.3.5.1.1 Prohibited Therapy 
• 
Section 13.3.5.1.2 Permitted Therapy 
• 
Section 14.1.8.2 Monitoring 
• 
Section 14.5 Blood Volume for Study Assessments (Table 5:  Blood 
Volume during Study) 
In addition, the following sentence was added to Section 13.2.4.2 End-of-
Treatment or Early Termination (Day 56), (renamed Section 13.2.4.2 
Early Termination):   
“Patients who want to terminate from the study and are not currently on-
site will be contacted and asked to return to the CRU to perform the early 
termination procedures” 
Investigator’s Brochure Version 
In Section 9.1 YPL-001, the Investigator’s Brochure version was updated 
to reflect the reference section and the most recent version of the 
Investigator’s Brochure. 
Method of Blood Collection 
Throughout the protocol, the option of using an angiocatheter was added. 
Hence, the following sections were corrected accordingly: 
• 
Section 11 Risk/Benefit 
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IND No.: 114903 
 
 
Page 5 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 14.3.3 Blood Biomarkers 
• 
Section 14.4.1 Blood Sampling and Processing 
• 
Section 14.5 Blood Volume for Study Assessments 
Recording of Meal 
To be consistent with clinical sites standard procedures, the last sentence 
of Section 13.2.4.1 Meal Schedule was corrected as follow: 
“Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs.’ 
Coffee, Tea and Alcohol Prohibition 
As indicated in Section 13.3.5.2 Prohibitions, coffee tea, and red wine will 
be restricted for 7 days prior to Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample. Beer will be 
restricted for 14 days prior to Day 1 of the Treatment Period through 
collection of Day 56 last PK sample. Any other product containing 
xanthines or caffeine will be restricted 24 hours prior to each CRU visit 
and prior to dosing on Days 1 and 56 of the Treatment Period through 
collection of Days 1 and 56 last PK sample. Any other alcohol product will 
be restricted 48 hours prior to each CRU visit, 48 hours prior to dosing on 
Days 1 and 56 last PK sample. Hence, the xanthines/caffeine prohibition  
and the alcohol prohibition were corrected as follows for clarification: 
“Xanthines/caffeine (other than coffee and tea):  24 hours prior to each 
CRU visit and prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
“Alcohol (other than red wine and beer):  48 hours prior to each CRU 
visit, 48 hours prior to dosing on Days 1 and 56 of the Treatment Period 
through collection of Days 1 and 56 last PK sample.” 
e-Diary 
Home dosing will be recorded using a yes/no answer in the e-diary. 
Therefore the last sentence of the second to last paragraph of 
Section 13.4.1.2 Drug Administration During Treatment Period was 
corrected as follows: 
“Patients will be given instructions on recording of dosing times how to 
record their drug administration in their e-diary on home-dosing days.’ 
In addition, estimation of sputum quantity was added to the list of major 
symptoms of COPD exacerbation recorded daily by the patients on their 
e-diary, “color” and “consistency” was moved as example of sputum 
quality, and a statement indicating that the e-diary device will be return in 
case of early termination was also added. Hence, the following sections 
were corrected accordingly: 
• 
Section 5 Synopsis under Secondary Outcome Measures 
• 
Section 5 Synopsis under Summary of Study Design 
• 
Section 6 Study Events Flow Chart – Day 1, Footnote “j” 
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AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 6 Study Events Flow Chart – Days 2-55, Footnote “i” 
• 
Section 6 Study Events Flow Chart – Day 56, Footnotes “g” and “h” 
• 
Section 12.2 Study Endpoints 
• 
Section 13.1 Overall Study Design and Plan 
• 
Section 13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
• 
Section 13.2.4 Treatment Period (Days 1 to 56) 
• 
Section 14.2.1 Electronic Diary 
• 
Section 14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease 
Exacerbation 
Treatment Compliance 
Drug administration at home will be monitored by HGE Technologies Inc. 
via the e-diary. Therefore, the last sentence of Section 13.4.4. Treatment 
Compliance was corrected as follow: 
“Self-administration by patients at home will be monitored by the CRU via 
the e-diary and attempted phone calls will be performed to remind 
patients to take their medication, if they did not record their 
self-administration on the e-diary.” 
Oxygen Saturation 
For consistency throughout the protocol, “oxygen levels, saturation (%)” 
was replaced with “oxygen saturation (%).” 
Tiotropium Treatment 
As indicated in Section 13.3.2 Inclusion Criteria and Section 13.3.5.1.2 
Permitted Therapy, tiotropium will be withheld 24 hours prior to 
pulmonary function (spirometry) measurements. Hence, the 2nd 
paragraph of Section 14.3.1 Pulmonary Function (Spirometry), was 
corrected to read: 
“Short acting β2-agonist and anticholinergic bronchodilators (e.g., 
albuterol, ipratropium bromide) and long acting β2-agonist and 
anticholinergic bronchodilators (e.g., salmeterol, tiotropium) agents will be 
withheld approximately 4 and 12 24 hours, respectively, before each 
pre-bronchodilator spirometry.” 
Spirometer Across Clinical Site 
The 3rd paragraph of Section 14.3.1 Pulmonary Function (Spirometry) 
was corrected as follow: 
“Every effort will be made to perform all assessments for a given patient 
on the same instrument throughout the study and all sites should be 
using the same brand and model of spirometer for this study.” 
Bronchoalveolar Lavage (BAL) Collection 
It is planned that a maximum of 180 mL BAL will be performed during 
each planned bronchoscopy procedures. Therefore, to prevent confusion, 
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Page 7 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
23-Apr-2015 
by Caroline Engel 
the second sentence of Section 14.3.2.3, Bronchoalveolar Lavage (BAL) 
was corrected to read: 
“A total of 180 mL BAL, using 6 x 30 mL aliquots of normal saline 
warmed to room temperature, will be performed in using each 
subsegment of the right middle or lower lobe, as deemed appropriate by 
the Investigator, using 6 x 30 mL aliquots of normal saline warmed to 
room temperature.” 
Blood 
Volume 
for 
Clinical 
Safety 
Laboratory 
Tests, 
Pharmacodynamic 
(PD) 
Markers 
and 
Pharmacokinetic 
(PK) 
Samples: 
Blood collection volume for PD markers, as indicated in Section 14.3.3 
Blood Biomarkers and Section 14.5 Blood Volume for Study 
Assessments, only accounts for 1 tube. However, 3 tubes will be required 
to assess CRP (4 mL tube), fibrinogen (3.5 mL tube) and the rest of the 
PD biomarkers (6 mL tube). The blood volume per time point will be 
approximately 13.5 mL instead of 4.5 mL. 
As indicated above, End-of-Treatment listed on Day 56 were removed as 
the same tests are scheduled on Day 55 before the bronchoscopy 
procedures. Hence one sample was removed for a total of 3 on-study 
hematology and serum chemistry tests to be performed throughout the 
study. 
In addition, 4 mL of blood will be sufficient for the determination of 
verproside and picroside II concentration in plasma at each time point. 
Therefore the total blood volume was corrected to 310.5 mL for males 
and 317.5 mL for females. Section 14.3.3 Blood Biomarkers, 
Section 14.4.1 Blood Sampling and Processing, and Section 14.5 Blood 
Volume for Study Assessments were corrected accordingly. 
Minor typographic and editorial corrections were made where applicable. 
16-Feb-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 2 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. 
Number of Subjects: 
The sample size was revised to 60 subjects as it is sufficient to meet the 
objectives of the study. In case of dropouts, discontinued patients may be 
replaced at the discretion of the Sponsor as indicated throughout the 
protocol. Therefore the following sections were corrected accordingly to 
indicate that at least 60 subjects are planned to be enrolled and 
randomized with 20 patients to receive one of the 3 treatments: 
• 
Section 5 Synopsis (the 1st sentence of the 2nd paragraph under 
Summary of Study Design and the 1st and 2nd sentences under 
Number of Patients). 
• 
The 1st sentence of the 2nd paragraph of Section 13.1 Overall Study 
Design and Plan. 
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IND No.: 114903 
 
 
Page 8 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
16-Feb-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
The 1st and 3rd sentences of Section 13.3.1 Number of Patients. 
• 
The last sentence of Section 15.1.1 Sample Size Calculation. 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) and 
COPD Assessment Test (CAT): 
BDI/TDI and CAT questionnaires will not be used as a diagnostic tool to 
assess the patient’s potential to meet all inclusion criteria and none of the 
exclusion criteria. Therefore these questionnaires are not required at 
screening. In addition, it is not required to perform them for 2 consecutive 
days to meet the study objectives and therefore, Day 55 assessments 
were removed.  
Section 6 Study Events Flow Chart was corrected accordingly. 
The first sentence in Section 14.3.4.1 Baseline Dyspnea Index/Transition 
Dyspnea Index (BDI/TDI) was also corrected to be consistent with 
Section 6. 
Early Termination Procedures: 
Weight, and oxygen levels, saturation (%), and heart rate assessed using 
a pulse oximeter were added to the procedures performed at the end of 
the Treatment Period on Day 56 or prior to early termination from the 
study to monitor subject’s safety appropriately. A pulmonary function 
(spirometry) test was also added prior to early termination for safety 
monitoring. 
Section 6 Study Events Flow Chart was corrected accordingly. 
Recording Concomitant Medication: 
Concomitant medication will be recorded at each study visit by the clinical 
staff in to the electronic data capture system. Therefore, concomitant 
medications was removed from the list of events that will be recorded by 
the patients via their e-diary throughout the protocol. The following 
sections were corrected accordingly: 
• 
Footnotes in Section 6 Study Events Flow Chart. 
• 
The first sentence of the 4th paragraph of Section 13.2.3 Run-In 
Period (Days 1 to 14 [± 2 days]). 
• 
The 2nd sentence of the 2nd paragraph of Section 13.2.4 Treatment 
Period (Days 1 to 56). 
• 
The 2nd sentence of the first paragraph of Section 14.2.1 Electronic 
Diary. 
Subject Numbering: 
The first paragraph of Section 13.4.2 Method of Assigning Patients to 
Treatment Groups was modified to clarify that the screening number and 
randomization number are two separate identification number given to 
each subject at different stages of the study. 
 
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IND No.: 114903 
 
 
Page 9 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
16-Feb-2015 
by Caroline Engel 
Adverse Events Reporting 
Footnotes were added to clarify the rating severity definitions in 
Section 14.1.8.3 Reporting. 
Minor editorial and typographical corrections were made where 
applicable. 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 1 
This protocol amendment is generated to update the study population 
with regards to smoking frequency, to update the handling procedures for 
BAL samples, and to clarify other study procedures as listed below. 
Study Population: 
Section 13.3.2 - Inclusion Criteria, bullet 11 was updated to indicate that 
the study population will consist only of current and ex-smokers with a 
history of >10 pack years. As such, the indications for ‘packs/year’ were 
replaced with ‘pack years’ and the allowance for current smokers with 
<10 pack/years was removed. 
Wording was added to indicate an approximately equal number of current  
and ex-smokers will be enrolled, and that each treatment group will 
consist of an approximately equal number of smokers and ex-smokers. In 
addition, the stratification criteria for the randomization was updated to 
consist of either current or ex-smokers. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Population and Number of 
Patients) 
• 
Section 13.1 - Overall Study Design and Plan (second paragraph) 
• 
Section 13.3.1 – Number of Patients. 
• 
Section 13.4.2 - Method of Assigning Patients to Treatment Groups. 
BAL Sample Handling: 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) was updated to indicate 
that sample handling, processing and storage procedures will be provided 
in a separate document.  
Follow-up Procedures: 
The wording in regards to follow-up procedures to be conducted on 
14 days (± 2 day), after the last study drug administration, was updated to 
indicated a phone-call and not a visit, as indicated correctly in Section 6 – 
Study Event Flow Chart. Study event were updated accordingly. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Duration of Participation for Patients, 
and Exploratory Outcome Measures [under Blood Assessments, 
Pulmonary Assessment, and Quality of Life Assessments])  
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IND No.: 114903 
 
 
Page 10 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
• 
Section 13.3.5.2 – Prohibitions (under Alcohol) 
• 
Section 14.1.8.2 – Monitoring (first paragraph). 
Study Duration: 
The total duration of the study indicated in Section 5 – Synopsis (under 
Duration of Participation for Patients) was corrected to 12 weeks to 
correspond with the actual study duration as indicated throughout the 
protocol.  
Inflammatory Markers in Blood Samples: 
The list of cell types to be evaluated as part of the inflammatory markers 
in the blood was updated to include monocytes instead of macrophages, 
as macrophages are not expected to be present in blood. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, fourth exploratory 
objective, and under Exploratory Outcome Measures [under 
Pharmacodynamic Assesments, Blood Assessments, first bullet]) 
• 
Section 12.1 - Study Objectives (fourth exploratory objective) 
• 
Section 12.2 - Study Endpoints (third exploratory endpoint) 
• 
Section 14.3.3 - Blood Biomarkers (first bullet) 
• 
Section 15.1.5.1 - Biomarkers (third bullet)  
Neutrophil Evaluation in BAL Samples 
Neutrophils were added to the list of cell types to be evaluated as a 
percentage of the total cell count in BAL samples. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, second exploratory 
objective and under Exploratory Outcome Measures [under 
Pharmacodynamic 
Assessments, 
Bronchoalveolar 
Lavage 
Assessments, second bullet]) 
• 
Section 12.1 - Study Objectives (second exploratory objective) 
• 
Section 12.2 - Study Endpoints (second exploratory endpoint)  
• 
Section 14.3.2.4 - Biomarkers (second bullet) 
• 
Section 15.1.5.1 – Biomarkers (second bullet) 
Location of Study Drug Administration: 
Wording was added in Section 6 – Study Events Flow Chart for Day 56, 
to clarify that the study drug will be administered at the CRU. 
Meal Schedule: 
The indication for fasting requirement in Section 13.2.4.1 – Meal 
Schedule, was corrected to indicate patients will fast overnight for at least 
12 hours before bronchoscopy and BAL collection on Days -1 and 55 
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IND No.: 114903 
 
 
Page 11 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
instead of Days -1 and 56, as correctly indicated in Section 6 – Study 
Events Flow Chart. 
ECG Monitoring:  
Following an update in Celerion’s standard operating procedure, Section 
14.1.5 – Electrocardiogram Monitoring was updated to include at least 
5 minutes of rest prior to each ECG measurement (instead of at least 
1 minute as previously indicated). 
Hematology: 
The tests included in the hematology panel Section 14.1.6.1 – 
Hematology were updated to indicate that the red blood cell (RBC) count 
will include a reticulocytes count, and that the white blood cell (WBC) 
count with differential will include monocytes but will not include 
reticulocytes. 
Bronchoscopy and BAL: 
Due to the sensitivity of YPL-001 components to UV light, a warning was 
added to protect all samples from exposure to UV light, as indicated for 
the PK blood samples. 
The following sections were affected: 
• 
Section 14.3.2.2 - Bronchial Brushings 
• 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) 
PK Population: 
The indication for measurable concentration of verproside and picroside II 
in urine was removed from the definition of PK population in 
Section 15.1.2 - Patients to Analyze, as there is no urine PK sampling 
planned for this study. 
Minor typographic and editorial corrections were made where applicable. 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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AA98497_Final_Prot_Amendment _3_23Apr2015 
 
4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Events (Medical Monitor) 
Dr. Kathy Smith 
Drug Safety Solution Tel.: +1 919 264-
5626E-mail:  ksmith@drugsafety.biz  
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratory 
For Temple University School of Medicine: 
Yuri Persidsky, MD, Ph.D. 
Chairperson, Department of Pathology and 
Laboratory Medicine 
Professor, 
Pathology 
and 
Laboratory 
Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
Brigham and Women's Hospital: 
75 Francis Street 
Boston, Massachusetts, 02115 
United States  
 
UAB Lung Health Center: 
UAB Hospital Laboratories 
619 19th Street South 
Birmingham, Alabama, 35249 
United States  
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
 
 
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Page 16 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Boards Main Office 
Location 
For Temple University School of Medicine: 
Student Faculty Center - Suite 304 
3340 North Broad Street 
Philadelphia, Pennsylvania, 19140 
United States 
Tel.: +1 215 707-3390 
Fax: +1 215 707-9100 
 
Brigham and Women's Hospital:  
Partners Human Reseach Committee 
116 Huntington Avenue, 10th Floor 
Boston, Massachusetts, 02116 
United States 
Tel.: +1 617 424-4100  
Fax: +1 617 424-4199 
 
UAB Lung Health Center: 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
  
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 17 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such chronic 
obstructive pulmonary disease (COPD) 
Study Type: 
Phase 2a, proof of concept 
Study Objectives: 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, monocytes, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 18 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
Summary of Study 
Design: 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups 
(20 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) on the morning of 
Day -1 of the Treatment Period to confirm their eligibility and assess their 
health conditions. If they still meet all of the inclusion criteria and none of the 
exclusion criteria, they will undergo Day -1 scheduled study procedures. 
Patients will return to the CRU the next day (Day 1) to be randomized and 
receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15, 29, 43, 55, and 
56 of the Treatment Period for study drug administration and procedures. 
Prior to each release from the CRU, patients will receive a properly labeled 
YPL-001 kit (and/or any unused wallets from previously provided kits [when 
applicable]) and tiotropium/albuterol container with sufficient doses which will 
be self-administered by patients at home until the next morning visit at the 
CRU. Patients will continue recording their daily symptoms via the e-diary 
throughout the Treatment Period. Patients will return the e-diary device on 
Day 56 (or prior to early termination) to CRU staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
will be administered in accordance with the study center standard of care. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
381


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 19 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
Study Population: 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component, between 40 and 80 years of age (inclusive). An approximately 
equal number of current and ex-smokers will be enrolled. 
Number of 
Patients: 
The study is planned to enroll at least 60 patients. Patients will be divided in 
3 treatment groups with 20 patients to receive one of the 3 treatments (i.e., 
low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo 
control) as per the randomization schedule. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Duration of 
Participation for 
Patients: 
The planned length of participation in the study for each patient is 
approximately 12 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up procedures on Day 70 [± 2 days]). 
Duration of Study 
Conduct: 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products: 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
YPL-001 or placebo will be dispensed in accordance with the Randomization 
and Drug Dispensing Instructions provided in a separate document. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen: 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 80 mg matching placebo tablet) will be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be 
administered on Day 56. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B, and C will be administered orally with 
approximately 240 mL of water. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
382


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 20 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
Stopping Rules: 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
383


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 21 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
Safety and 
Tolerability 
Analysis 
(continued): 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures: 
PEF, major (e.g., estimated sputum quality (e.g., color, consistency), and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, 
discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (Duke 
Activity Status Index [DASI]) self-reported daily by the patients using an 
e-diary. 
Symptom 
Monitoring 
Analysis: 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, and throughout the study for 
PD assessments of biomarkers. Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
384


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 22 
AA98497_Final_Prot_Amendment _3_23Apr2015 
 
Exploratory 
Outcome 
Measures 
(continued): 
IC] will be performed at screening, and throughout the study. 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, and throughout the study. 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 56 to determine verproside and 
picroside II concentrations in plasma. Predose samples will also be collected 
in the morning of Days 15, 29, 43 and 56 for Ctrough determination. Other 
components of YPL-001 and its metabolites may also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis: 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis: 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-001 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
385


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 23 
AA98497_Final_Prot_Amendment_3_23Apr2015 
 
6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg 
X 
 
 
Xf 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAh 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityj 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationp 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk,q 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)l 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
386


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 24 
AA98497_Final_Prot_Amendment_3_23Apr2015 
 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xn 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitso 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
387


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 25 
AA98497_Final_Prot_Amendment_3_23Apr2015 
 
a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
d. To be performed prior to the bronchoscopy procedures. 
e. To be performed at screening or within 3 months (inclusive) of screening. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
i. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
k. Prior to release from the CRU, patients will receive a properly labeled kit with sufficient study drug for their assigned treatment which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients must return the used and unused wallets at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they did not 
record their self-administration on the e-diary, and queried about the occurrence of AEs. 
l. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
m. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
n. To be performed prior to dosing. 
o. Patients will be admitted to the CRU at the time indicated by the CRU. 
p. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
q. On Day 1, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 26 
AA98497_Final_Prot_Amendment_3_23Apr2015 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 2-14 
15 
16-28 
29 
30-42 
43 
44-54 
55 
Hours → 
 
AM PM 
 
AM PM 
 
AM 
PM 
 
AM 
PM 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Xe 
 
Vital Signsf 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xe 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
Xe 
 
Hem, Chem, and UAg 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine Alcohol & Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useh 
X 
PEF, COPD exacerbation, dyspnea 
and activityi 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administrationo 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Administration at Homej 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)k 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xn 
 
Bronchoscopy and BAL Biomarkersl 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
BDI/TDI & CAT 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Refer to the footnotes on the next page 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
389


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
Page 27 
AA98497_Final_Prot_Amendment_3_23Apr2015 
 
a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. To be performed or completed prior to bronchoscopy procedures and/or dosing. 
e. ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
f. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
g. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
h. Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
i. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
j. 
Prior to release from the CRU on Days 15, 29, 43, and 55 patients will receive a properly labeled kit and/or any unused wallets from previously 
provided kits (when applicable) with sufficient study drug for their assigned treatment which will be self-administered by patients at home until 
the next morning visit at the CRU. Patients must return the used and unused wallets at the next morning visit. Home dosing will be monitored 
via attempted phone calls where patients will be reminded to take their medication, if they did not record their self-administration on the e-
diary, and queried about the occurrence of AEs. 
k. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
l. 
Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
m. Patients will be admitted to the CRU at the time indicated by the CRU. 
n. To be completed prior to bronchoscopy procedures and dosing. 
o. Patients will receive a properly labeled container with the appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit. 
 
 
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STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
ETb FUc 
Days → 
56 
Hours → Predose 0 
0.167 
0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signse 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hem, Chem, and UAf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PEF, COPD exacerbation, dyspnea and 
activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Blood Biomarkers 
Xi 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsj 
X 
X 
 
Refer to the footnotes on the next page 
 
 
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a. For details on Procedures, refer to Section 14. 
b. To be performed prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
f. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
g. Patients will return the e-diary device on Day 56 (or prior to early termination) to CRU staff.  
h. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) and 
quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
i. 
To be performed at predose on Day 56 or upon early termination. 
j. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
k. On Day 56, patients will be required to fast overnight for at least 8 hours before and 4 hours after YPL-001/placebo morning administration. 
 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition 
Dyspnea Index Test, CAT = COPD Assessment Test, Chem = Serum chemistry, COPD = chronic obstructive pulmonary disease, CRU = Clinical 
research unit, ConMeds = Concomitant medication, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = electronic diary, 
ET =  Early termination, FSH = Follicle-stimulating hormone, Hem = Hematology, HIV = Human immunodeficiency virus, IL= interleukin, 
PEF = Peak expiratory flow, PK = Pharmacokinetics, PM = Evening, Preg = Serum pregnancy, Screen = Screening, UA = Urinalysis. 
 
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7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY ...................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ............................................................................................. 12 
3. 
INVESTIGATORS SIGNATURES ...................................................................................... 13 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY ............................................................ 15 
5. 
SYNOPSIS ........................................................................................................................ 17 
6. 
STUDY EVENTS FLOW CHART ....................................................................................... 23 
7. 
TABLE OF CONTENTS ..................................................................................................... 30 
8. 
ABBREVIATIONS.............................................................................................................. 33 
9. 
INTRODUCTION AND BACKGROUND ............................................................................. 38 
9.1 
YPL-001 .................................................................................................................. 38 
9.1.1 
Preclinical Trials .......................................................................................... 38 
9.1.1.1 
Pharmacology .............................................................................. 38 
9.1.1.2 
Pharmacokinetics ......................................................................... 39 
9.1.1.3 
Toxicology ................................................................................... 40 
9.1.2 
Clinical Experience...................................................................................... 41 
9.1.2.1 
SAD study .................................................................................... 42 
9.1.2.2 
MAD Study .................................................................................. 43 
10. RATIONALE ...................................................................................................................... 45 
10.1 Purpose of the Study ............................................................................................... 45 
10.2 Dose Selection ........................................................................................................ 45 
11. RISK/BENEFIT .................................................................................................................. 47 
12. STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 48 
12.1 Study Objectives ..................................................................................................... 48 
12.2 Study Endpoints ...................................................................................................... 48 
13. INVESTIGATIONAL PLAN ................................................................................................ 50 
13.1 Overall Study Design and Plan ................................................................................ 50 
13.2 Study Conduct ......................................................................................................... 51 
13.2.1 Screening ................................................................................................... 51 
13.2.2 Patient Confinement .................................................................................... 51 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ....................................................... 51 
13.2.4 Treatment Period (Days 1 to 56) ................................................................. 52 
13.2.4.1 Meal Schedule ............................................................................. 52 
13.2.4.2 Early Termination ......................................................................... 53 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................ 53 
13.2.6 Scheduled End of Study .............................................................................. 53 
13.3 Selection of Study Population .................................................................................. 53 
13.3.1 Number of Patients ..................................................................................... 53 
13.3.2 Inclusion Criteria ......................................................................................... 53 
13.3.3 Exclusion Criteria ........................................................................................ 55 
13.3.4 Removal of Patients from the Study ............................................................ 57 
13.3.5 Study Restrictions ....................................................................................... 57 
13.3.5.1 Concomitant Therapy ................................................................... 57 
13.3.5.1.1 
Prohibited Therapy ................................................... 57 
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13.3.5.1.2 
Permitted Therapy ................................................... 58 
13.3.5.2 Prohibitions .................................................................................. 59 
13.3.5.3 Activity ......................................................................................... 59 
13.4 Treatments .............................................................................................................. 59 
13.4.1 Treatments administered ............................................................................. 59 
13.4.1.1 Drug Administration During Run-in Period .................................... 59 
13.4.1.2 Drug Administration During Treatment Period............................... 60 
13.4.1.3 Stopping Rules ............................................................................ 61 
13.4.2 Method of Assigning Patients to Treatment Groups ..................................... 61 
13.4.3 Blinding ....................................................................................................... 61 
13.4.3.1 Maintenance of Randomization .................................................... 62 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 62 
13.4.3.3 Revealing of Randomization ......................................................... 62 
13.4.4 Treatment Compliance ................................................................................ 62 
14. STUDY PROCEDURES .................................................................................................... 64 
14.1 Safety Assessments ................................................................................................ 64 
14.1.1 Body Height and Weight .............................................................................. 64 
14.1.2 Physical Examination .................................................................................. 64 
14.1.3 Vital Signs ................................................................................................... 64 
14.1.4 Pulse Oximetry............................................................................................ 65 
14.1.5 Electrocardiogram Monitoring ...................................................................... 65 
14.1.6 Clinical Laboratory Tests ............................................................................. 65 
14.1.6.1 Hematology.................................................................................. 66 
14.1.6.2 Serum Chemistry ......................................................................... 66 
14.1.6.3 Serology ...................................................................................... 66 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............ 66 
14.1.6.5 Follicle-Stimulating Hormone ........................................................ 66 
14.1.6.6 Urinalysis ..................................................................................... 67 
14.1.6.7 Urine Drug/Alcohol Screen ........................................................... 67 
14.1.7 Chest X-Ray ............................................................................................... 67 
14.1.8 Adverse Events ........................................................................................... 67 
14.1.8.1 Adverse Event Definition .............................................................. 67 
14.1.8.2 Monitoring .................................................................................... 67 
14.1.8.3 Reporting ..................................................................................... 68 
14.1.8.4 Serious Adverse Events ............................................................... 69 
14.2 Symptom Assessments ........................................................................................... 70 
14.2.1 Electronic Diary ........................................................................................... 70 
14.2.2 Peak Expiratory Flow .................................................................................. 70 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ........... 70 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) .................................................... 70 
14.2.5 Activity (Duke Activity Status Index) ............................................................ 71 
14.3 Pharmacodynamic Assessments ............................................................................. 71 
14.3.1 Pulmonary Function (Spirometry) ................................................................ 71 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers.................... 72 
14.3.2.1 Bronchoscopy .............................................................................. 72 
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14.3.2.2 Bronchial Brushings ..................................................................... 73 
14.3.2.3 Bronchoalveolar Lavage (BAL) ..................................................... 73 
14.3.2.4 Biomarkers .................................................................................. 73 
14.3.3 Blood Biomarkers ........................................................................................ 73 
14.3.4 Quality of Life Questionnaires ..................................................................... 74 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ..................................................................................... 74 
14.3.4.2 COPD Assessment Test (CAT) .................................................... 74 
14.4 Pharmacokinetic Assessments ................................................................................ 74 
14.4.1 Blood Sampling and Processing .................................................................. 74 
14.5 Blood Volume for Study Assessments ..................................................................... 75 
15. DATA ANALYSIS .............................................................................................................. 76 
15.1 Statistical Analysis ................................................................................................... 76 
15.1.1 Sample Size Calculation ............................................................................. 76 
15.1.2 Patients to Analyze ..................................................................................... 76 
15.1.3 Safety Analysis ........................................................................................... 77 
15.1.4 Symptom Monitoring Analysis ..................................................................... 77 
15.1.5 Pharmacodynamic Analysis ........................................................................ 78 
15.1.5.1 Biomarkers .................................................................................. 78 
15.1.5.2 Quality of Life ............................................................................... 78 
15.1.6 Pharmacokinetic Analysis ........................................................................... 79 
15.1.6.1 Pharmacokinetic Parameters ....................................................... 79 
15.1.6.1.1 
Plasma .................................................................... 79 
15.1.6.1.2 
Bronchoalveolar Lavage ........................................... 80 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ........................ 81 
15.1.7 Assessment of Efficacy ............................................................................... 81 
16. STUDY ADMINISTRATION ............................................................................................... 82 
16.1 Ethics ...................................................................................................................... 82 
16.1.1 Institutional Review Board ........................................................................... 82 
16.1.2 Ethical Conduct of the Study ....................................................................... 82 
16.1.3 Patient Information and Consent ................................................................. 82 
16.2 Termination of the Study .......................................................................................... 82 
16.3 Data Quality Assurance ........................................................................................... 82 
16.4 Direct Access to Source Data/Documents ................................................................ 83 
16.5 Drug Supplies, Packaging and Labeling ................................................................... 83 
16.6 Data Handling and Record Keeping ......................................................................... 83 
16.7 Protocol Amendments ............................................................................................. 83 
16.8 Finance and Insurance ............................................................................................ 84 
16.9 Publication Policy .................................................................................................... 84 
17. REFERENCES .................................................................................................................. 85 
18. APPENDIXES ................................................................................................................... 86 
18.1 Appendix 1 - UGT Drug Interaction Table ................................................................ 86 
18.2 Appendix 2 - SULT Drug Interaction Table ............................................................... 87 
 
 
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8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
Coag 
Coagulation 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
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CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
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IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimeter of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
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ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
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US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
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9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
GCP, and applicable regulatory requirements. The patient population will be comprised 
of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of June 3, 2014. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Bronchoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
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CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
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were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
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values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
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9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 
0.67 hours under fasting conditions. Verproside appeared to be cleared rapidly from 
plasma, with mean t1/2 values under 1 hour; plasma verproside concentrations were 
below the lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 
below summaries the PK parameters of verproside following single-dose administrations 
of YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
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9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t½ values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t½ values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
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Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
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10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such COPD to demonstrate safety and 
evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
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Table 4: Traditional Chinese Medicine Use Versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
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11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an angiocatheter is utilized and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
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12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., estimated sputum quality (e.g., color, consistency) and quantity,) 
and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and 
body temperature above 100°F) symptoms of COPD exacerbation;  
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• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and 
eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
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13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups (20 patients 
per group). Patients will participate only once. An approximately equal number of current 
and ex-smokers will be enrolled in the study. 
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU on the morning of Day -1 of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Day -1 scheduled 
study procedures. Patients will return to the CRU the next day (Day 1) to be randomized 
and receive one of the 3 treatments and undergo all scheduled study procedures. 
Patients will return on the morning of Days 15, 29, 43, 55, and 56 of the Treatment 
Period for study drug administration and procedures. Prior to each release from the 
CRU, patients will receive a properly labeled kit and/or any unused wallets from 
previously provided kits (when applicable) with sufficient doses which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients 
will continue recording their daily symptoms via the e-diary throughout the Treatment 
Period. Patients will return the e-diary device on Day 56 (or prior to early termination) to 
CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
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IND No.: 114903 
 
 
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will be discontinued. Rescue medication will be used for any patient with an 
exacerbation of COPD and will be administered in accordance with the study center 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses and their daily respiratory symptoms. Prior to each morning 
dose, patients will record at home their daily PEF, major (e.g., estimated sputum quality 
(e.g., color, consistency) and quantity,) and minor (e.g., cough, wheeze, sore throat, 
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nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 56 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses and their daily 
respiratory symptoms on their e-diary. Prior to each morning dose, patients will record at 
home their daily PEF, major (e.g., estimated sputum quality (e.g., color, consistency) 
and quantity,) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, 
and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea 
(Modified Borg Dyspnea Scale), and activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before bronchoscopy and 
BAL collection on Days -1 and 55. On Days 1 and 56, patients will be required to fast 
overnight for at least 8 hours before and for at least 4 hours after the morning dose. On 
all other days, patients will be asked to fast for at least 2 hours before and 2 hours after 
each morning dose. Patients will also be asked to fast for at least 2 hours before and 
after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 56, patients will fast from all food and drink except water between meals 
and snacks. Foods and beverages containing alcohol, xanthines, caffeine, vegetables 
from the mustard green family, mustard, tea (especially speedwell tea), or 
grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, menus should 
be similar in content. The same menu and meal (except for snacks) schedule will be 
administered uniformly for all patients confined within the same CRU, across all 
treatment groups. Meals are not required to be completed by patients. 
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13.2.4.2 Early Termination  
Early termination evaluations will be performed on patients prior to early termination. 
Patients who want to terminate from the study and are not currently on-site will be 
contacted and asked to return to the CRU to perform the early termination procedures. 
The early termination procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll at least 60 patients. An approximately equal number of 
current and ex-smokers will be enrolled. Patients will be divided in 3 treatment groups 
with 20 patients to receive one of the 3 treatments (i.e., low and high YPL-001 doses 
[80 mg and 160 mg BID] and a placebo control) as per the randomization schedule. 
Each treatment group will consist of an approximately equal number of current and 
ex-smokers. 
13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 40 to 80 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
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• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-32.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24 hours 
prior to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled 
CRU visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack years. Ten pack years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Patients, who undergo smoking cessation therapy, must be completed 
3 months prior to screening visit and smoking status should not change between the 
patient’s screening visit and patient’s last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
13. A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method 
(e.g., condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
14. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
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d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
15. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the last scheduled study procedures on Day 56 or upon early 
termination. Patients will be advised to use a condom with spermicide for 90 days 
following the last administration of the study drug, and to not donate sperm during 
this same period of time. In the event that the sexual partner is surgically sterile, use 
of a condom with spermicide is not necessary. No restrictions are required for 
vasectomized males provided their vasectomy has been performed 120 days or 
more prior to study start. Males who have been vasectomized less than 120 days 
prior to study start must follow the same restrictions as non-vasectomized males. 
16. Understands study procedures and provides written informed consent for the trial. 
17. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), 
sleep 
apnea, 
cardiovascular, 
endocrine, 
neurological, 
hepatic, 
gastrointestinal, renal, hematological, urological, immunological or ophthalmic 
diseases that the Investigator believes are clinically significant e.g., unstable and 
could impact patient safety by participation in the study. 
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9. History or presence of: 
• 
significant cardiac arrhythmia; 
• 
prostatic hyperplasia; 
• 
bladder-neck obstruction; 
• 
urinary retention; 
• 
narrow-angle glaucoma. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Evidence of hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive urine drug/alcohol testing at screening or at each CRU visit. 
14. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies (HCV). 
15. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
16. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
17. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
18. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) and/or sulfotransferases (SULT), 
within 12 hours prior to Day 1 of the Run-in Period (refer to Appendix 1 and 
Appendix 2). 
19. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
20. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
21. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
22. Females who are pregnant or lactating.  
23. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
24. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
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13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion (early 
termination evaluations) as the situation allows (see Section 13.2.4.2). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the last scheduled study 
procedures on Day 56 or upon early termination). Intake of these medications during the 
Run-in Period constitutes a non-eligibility criterion and the patients will not be 
randomized into the study. If any of these medications are taken during the Treatment 
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Period, the need for this patient to be withdrawn from the study will be carefully 
evaluated by the Investigator and the Sponsor on the basis of the potential impact on 
efficacy or safety evaluation and in the patient's best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements and herbal products (especially Speedwell) will be prohibited 
7 days prior Day 1 of the Treatment Period and through collection of the final PK 
sample. 
13.3.5.1.2 Permitted Therapy 
Throughout the study Period (from Day 1 of the Run-in Period to the completion of the 
last scheduled study procedures on Day 56 or upon early termination) patients will be 
permitted to take the following medications in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 24 hours 
before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
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Page 59 
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13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine (other than coffee and tea):  24 hours prior to each CRU visit and 
prior to dosing on Days 1 and 56 of the Treatment Period through collection of Days 
1 and 56 last PK sample. 
• 
Alcohol (other than red wine and beer):  48 hours prior to each CRU visit, 48 hours 
prior to dosing on Days 1 and 56 of the Treatment Period through collection of 
Days 1 and 56 last PK sample. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 56 last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 56 of 
the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Tea (especially Speedwell tea), coffee, and red wine:  7 days prior to Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 56 last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
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13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. Only the 
morning dose will be administered on Day 56. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be administered on 
Day 56. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose will be 
administered on Day 56. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
YPL-001 or placebo will be dispensed in accordance with the Randomization and Drug 
Dispensing Instructions provided in a separate document. 
Prior to release from the CRU on Days 1, 15, and 29, of the Treatment Period, patients 
will receive a properly labeled new kit, which contains 4 wallets of 2 blister cards, with 
the appropriate doses which will be self-administered by patients at home. Any unused 
wallets from previously provided kits will also be dispensed to patients on Days 15 and 
29. Prior to release from the CRU on Days 43, and 55, patients will received unused 
wallets from previously provided kits with the appropriate doses which will be 
self-administered by patients at home. Patients will also receive a properly labeled 
container with the appropriate doses of tiotropium and albuterol for home dosing. 
Patients will record their self-administered doses in their e-diary, and whether the dose 
was administered with food, and must return the YPL-001 used and unused wallets and 
the tiotropium and albuterol container (empty or not) at the next schedule visit at the next 
morning visit. Home dosing will be monitored via attempted phone calls where patients 
will be reminded to take their medication, if they did not record their self-administration 
on the e-diary, and queried about the occurrence of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
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given instructions on how to record their drug administration in their e-diary on 
home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique screening identification number upon screening. 
Patients who complete the study screening assessments, complete the Run-in Period, 
and meet all the eligibility criteria will be assigned a unique randomization identification 
number, different from the screening number, and receive the corresponding product, 
according to a randomization scheme generated at Celerion. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
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13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
The randomization will not be made available to the Sponsor, patients, or members of 
the staff responsible for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
The site Pharmacist/Study Coordinator will receive two sets of randomization code 
envelopes, one set for “Current Smokers” and another for “Ex-Smokers”. Each individual 
envelope is marked on the outside with one of the randomization numbers and contains 
the treatment for that patient. These envelopes must be kept in a secure locked location. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the medical monitor or designee prior to breaking the blind. If breaking 
the blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
1. All data are entered in the database, edits checks are performed, queries 
closed, CRFs signed by the Investigator, and the database is officially locked. 
2. All PK/PD samples have been analyzed and quality checked by the 
responsible analytical associate. 
13.4.4 Treatment Compliance 
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
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Self-administration by patients at home will be monitored via the e-diary and attempted 
phone calls will be performed to remind patients to take their medication, if they did not 
record their self-administration on the e-diary. 
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14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
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When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When scheduled postdose, vital signs readings 
will be performed within approximately 10 minutes of the scheduled time point. When 
performing the bronchoscopy, vital signs (body temperature, respiratory rate, blood 
pressure, and heart rate) will be monitored continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen saturation (%), and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen saturation [%], and heart rate) 
as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. Readings may be taken at other times, if deemed 
necessary by the Investigator. When performing the bronchoscopy, oxygen saturation 
will be monitored continuously until the end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performing the bronchoscopy, ECG will be monitored continuously until 
the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
5 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
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14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count (including a 
reticulocytes count) 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, and 
monocytes) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
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14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine Drug/Alcohol Screen 
• 
Cannabinoids  
• 
Alcohol 
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Adverse Events 
14.1.8.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.3 
14.1.8.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, after the last 
scheduled study procedures on Day 56 (or upon early withdrawal), and at the follow-up 
phone call. The inquiry will be made in a non-specific manner using open-ended 
questions so as not to bias the response (e.g., How have you been feeling since your 
last visit?). 
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All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.8.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 4 and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
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The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade; ADL = Activities of Daily Living 
*Instrumental ADL refer 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. 
14.1.8.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Medical Monitor via fax or e-mail within one working day of 
becoming aware of the event, whether or not the serious events are deemed 
drug-related. All serious event reporting will adhere to 21 CFR 312.32 for Investigational 
New Drugs (IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20123. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
If an SAE occurs to a patient on this study, the Medical Monitor is to be contacted (see 
Section 4). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
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dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed; or is not consistent with the risk information described in the general 
investigational plan or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses, whether the dose was 
administered with food, and daily respiratory symptoms throughout the Run-in and 
Treatment Periods. Patients will return the e-diary device on Day 56 (or prior to early 
termination) to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., 
estimated sputum quality (e.g., color, consistency) and quantity,) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity 
(DASI). 
14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., estimated sputum quality (e.g., color, 
consistency) and quantity,) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation via the e-diary before each dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
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14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) 
and 
long 
acting 
β2-agonist 
and 
anticholinergic 
bronchodilators 
(e.g., salmeterol, tiotropium) agents will be withheld approximately 4 and 24 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study. 
At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol (100 μg/inhalation) for a total dose of 400 
μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes after 
albuterol administration, the baseline post-bronchodilator spirometry will be performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Day -1 measurement): Predose 
FEV1 is defined as the time point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
FEV1 measurement at predose on Day -1 of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
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2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose on Day -1, up to 3 measures will be 
performed.  
Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be asked to refrain from smoking approximately 48 hours before the 
bronchoscopy procedures and will be fasted for 12 hours before. If required, blood 
pressure medications can be taken with small sip of water based on preapproval of local 
Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.5,6 
Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal cannula will be 
administered during bronchoscopy and oxygen saturation will be maintained at ≥95%. 
Conscious sedation will be achieved with incremental doses of 1–4 mg midazolam and 
50-100 μg fentanyl. Local upper and lower airway topical anesthesia will be achieved 
with 1% or 2% lidocaine. The dose of lidocaine administered during the procedure will 
not exceed a total of 450 mg. The bronchoscope will usually be inserted preferably 
through the nares into trachea. The bronchoscope will be wedged into 2 subsegments of 
the right middle or lower lobe, as deemed appropriate by the Investigator. Emergency 
treatments for cardiopulmonary arrest and pneumothorax will be immediately available in 
the bronchoscopy room. The patient will remain in the recovery suite for observation for 
a minimum of 2 hours after the procedure.  
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14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A total of 180 mL BAL, 
using 6 x 30 mL aliquots of normal saline warmed to room temperature, will be 
performed using each subsegment of the right middle or lower lobe, as deemed 
appropriate by the Investigator. BAL fluid will be aspirated following each 30 mL 
instillation. The lavage material, which averages 25% return in COPD patients, typically 
yields 1-10 x 106 macrophages. The centrifuged cell pellet and supernatant will be kept 
cooled until processed or stored as indicated in the laboratory manual to be provided as 
a separate document. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and eosinophils 
as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture or an angiocatheter at the time 
points delineated in the Study Events Flow Chart (Section 6) for PD assessments of 
biomarkers. Biomarker assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 3 tubes.  A manual for blood sampling, collection, processing, 
and sample shipment will be provided in a separate document. 
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14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Day -1 of the Treatment Period) will be assessed with the BDI. 
This instrument has 3 domains (functional impairment, magnitude of task, and 
magnitude of effort) with the values added for a combined focal score. Functional 
impairment determines the impact of breathlessness on the ability to carry out activities; 
magnitude of task determines the type of task that causes breathlessness, magnitude of 
effort establishes the level of effort that results in breathlessness. The BDI scores range 
from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline 
focal score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.7,8 
A copy of the questionnaire to be used will be kept in the study binder. 
14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture or an angiocatheter at the time points 
delineated in the Study Events Flow Chart (Section 6).  
Blood will be drawn into 4 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
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14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time 
Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests 
(including hematology, serum 
chemistry, serology), FSH (for 
postmenopausal female patients only) 
and serum pregnancy (for female 
patients only). 
1 
~ 17 mL 
~ 17 mL 
On-study serum chemistry and serum 
pregnancy (for female patients only) 
when scheduled at the same time 
3 
~ 8.5 mL 
~ 25.5 mL 
Additional on-study serum pregnancy 
(for female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
3 
~ 4 mL 
~ 12 mL 
Blood samples for PD biomarkers 
(except CRP and fibrinogen) 
8 
~ 6 mL 
~ 48 mL 
Blood samples for PD biomarker - 
CRP 
8 
~ 4 
~ 32 
Blood samples for PD biomarker - 
Fibrinogen 
8 
~ 3.5 
~ 28 
Blood samples for PK of verproside 
and picroside II 
37 
~ 4 mL 
~ 148 mL 
Total Blood Volume for males → 
~ 310.5 mL** 
Total Blood Volume for females → 
~ 317.5 mL** 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
** If an angiocatheter is used, up to 5 mL of blood will be used to flush the catheter prior to each 
collection of PK and/or PD blood samples. Hence the total blood volume collected may 
increase by approximately 205 mL. 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma concentration of verproside and 
picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Days 1 and/or 56. 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 post-
baseline PD measurement. 
• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
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the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
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received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes, 
neutrophils, and eosinophils as a percentage of total cells; total cell count [cells/mL] 
of neutrophils, macrophages, lymphocytes and eosinophils as absolute inflammatory 
cell numbers; and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9): raw and % change from baseline levels; 
and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and lymphocytes] 
and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
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15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
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The following PK parameters will be computed following Day 56 morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc 
Percent fluctuation will be calculated as follows: 
𝐶𝐶max _𝑠𝑠𝑠𝑠−𝐶𝐶min _𝑠𝑠𝑠𝑠
𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎
 𝑥𝑥 100 
Swing 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
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15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15, 29, 43, and 56 following multiple oral dose administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
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16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP (E6 
Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
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check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets, and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 5 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
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16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
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17. REFERENCES 
 
                                               
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
4 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
5 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
6 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
7 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
8 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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18. APPENDIXES 
18.1 
Appendix 1 - UGT Drug Interaction Table 
The following list provides medications that are substrates or inhibitors of UGT. Adapted 
from Williams JA, et al. Drug-drug interactions for UDP-glucuronosyltransferase 
substrates:  a pharmacokinetic explanation for typically observed low exposure 
(AUCi/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201-8. Epub 2004 Aug 10. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Amitriptyline 
Carvedilol 
Clofibric acid 
Codeine 
Cyclobenzaprine 
Diclofenac 
DMXAA 
Fenofibrate 
Flavopiridol 
Furosemide 
Gemfibrozil 
Glipizide 
Irbesartan 
Lamotrigine 
Levothyroxine 
Metoclopramide 
Metronidazole 
Morphine 
Naloxone 
Naproxen 
Olanzapine 
Oxazepam 
Paracetamol 
Propofol 
Raloxifene 
Tramadol 
Valdecoxib 
Valproic acid 
Zidovudine 
17-beta-estradiol glucuronide 
Flavonoids (citrus fruit) 
Silybin (herb supplement milk thistle) 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
 
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18.2 Appendix 2 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Acetaminophen 
 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
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450


 
 
 
 
Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
451


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
16-Feb-2015 
by Caroline Engel 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 2 
This protocol amendment is generated to clarify and adjust study 
procedures as listed below. 
Number of Subjects: 
The sample size was revised to 60 subjects as it is sufficient to meet the 
objectives of the study. In case of dropouts, discontinued patients may be 
replaced at the discretion of the Sponsor as indicated throughout the 
protocol. Therefore the following sections were corrected accordingly to 
indicate that at least 60 subjects are planned to be enrolled and 
randomized with 20 patients to receive one of the 3 treatments: 
• 
Section 5 Synopsis (the 1st sentence of the 2nd paragraph under 
Summary of Study Design and the 1st and 2nd sentences under 
Number of Patients). 
• 
The 1st sentence of the 2nd paragraph of Section 13.1 Overall Study 
Design and Plan. 
• 
The 1st and 3rd sentences of Section 13.3.1 Number of Patients. 
• 
The last sentence of Section 15.1.1 Sample Size Calculation. 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) and 
COPD Assessment Test (CAT): 
BDI/TDI and CAT questionnaires will not be used as a diagnostic tool to 
assess the patient’s potential to meet all inclusion criteria and none of the 
exclusion criteria. Therefore these questionnaires are not required at 
screening. In addition, it is not required to perform them for 2 consecutive 
days to meet the study objectives and therefore, Day 55 assessments 
were removed.  
Section 6 Study Events Flow Chart was corrected accordingly. 
The first sentence in Section 14.3.4.1 Baseline Dyspnea Index/Transition 
Dyspnea Index (BDI/TDI) was also corrected to be consistent with 
Section 6. 
Early Termination Procedures: 
Weight, and oxygen levels, saturation (%), and heart rate assessed using 
a pulse oximeter were added to the procedures performed at the end of 
the Treatment Period on Day 56 or prior to early termination from the 
study to monitor subject’s safety appropriately. A pulmonary function 
(spirometry) test was also added prior to early termination for safety 
monitoring. 
Section 6 Study Events Flow Chart was corrected accordingly. 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
DATE/NAME 
DESCRIPTION 
16-Feb-2015 
by Caroline Engel 
Recording Concomitant Medication: 
Concomitant medication will be recorded at each study visit by the clinical 
staff in to the electronic data capture system. Therefore, concomitant 
medications was removed from the list of events that will be recorded by 
the patients via their e-diary throughout the protocol. The following 
sections were corrected accordingly: 
• 
Footnotes in Section 6 Study Events Flow Chart. 
• 
The first sentence of the 4th paragraph of Section 13.2.3 Run-In 
Period (Days 1 to 14 [± 2 days]). 
• 
The 2nd sentence of the 2nd paragraph of Section 13.2.4 Treatment 
Period (Days 1 to 56). 
• 
The 2nd sentence of the first paragraph of Section 14.2.1 Electronic 
Diary. 
Subject Numbering: 
The first paragraph of Section 13.4.2 Method of Assigning Patients to 
Treatment Groups was modified to clarify that the screening number and 
randomization number are two separate identification number given to 
each subject at different stages of the study. 
Adverse Events Reporting 
Footnotes were added to clarify the rating severity definitions in 
Section 14.1.8.3 Reporting. 
Minor editorial and typographical corrections were made where 
applicable. 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Final Protocol, Amendment 1 
This protocol amendment is generated to update the study population 
with regards to smoking frequency, to update the handling procedures for 
BAL samples, and to clarify other study procedures as listed below. 
Study Population: 
Section 13.3.2 - Inclusion Criteria, bullet 11 was updated to indicate that 
the study population will consist only of current and ex-smokers with a 
history of >10 pack years. As such, the indications for ‘packs/year’ were 
replaced with ‘pack years’ and the allowance for current smokers with 
<10 pack/years was removed. 
Wording was added to indicate an approximately equal number of current  
and ex-smokers will be enrolled, and that each treatment group will 
consist of an approximetly equal number of smokers and ex-smokers. In 
addition, the stratification criteria for the randomization was updated to 
consist of either current or ex-smokers. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Population and Number of 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients) 
• 
Section 13.1 - Overall Study Design and Plan (second paragraph) 
• 
Section 13.3.1 – Number of Patients. 
• 
Section 13.4.2 - Method of Assigning Patients to Treatment Groups. 
BAL Sample Handling: 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) was updated to indicate 
that sample handling, processing and storage procedures will be provided 
in a separate document.  
Follow-up Procedures: 
The wording in regards to follow-up procedures to be conducted on 
14 days (± 2 day), after the last study drug administration, was updated to 
indicated a phone-call and not a visit, as indicated correctly in Section 6 – 
Study Event Flow Chart. Study event were updated accordingly. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Duration of Participation for Patients, 
and Exploratory Outcome Measures [under Blood Assessments, 
Pulmonary Assessment, and Quality of Life Assessments])  
• 
Section 13.3.5.2 – Prohibitions (under Alcohol) 
• 
Section 14.1.8.2 – Monitoring (first paragraph). 
Study Duration: 
The total duration of the study indicated in Section 5 – Synopsis (under 
Duration of Participation for Patients) was corrected to 12 weeks to 
correspond with the actual study duration as indicated throughout the 
protocol.  
Inflammatory Markers in Blood Samples: 
The list of cell types to be evaluated as part of the inflammatory markers 
in the blood was updated to include monocytes instead of macrophages, 
as macrophages are not expected to be present in blood. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, fourth exploratory 
objective, and under Exploratory Outcome Measures [under 
Pharmacodynamic Assesments, Blood Assessments, first bullet]) 
• 
Section 12.1 - Study Objectives (fourth exploratory objective) 
• 
Section 12.2 - Study Endpoints (third exploratory endpoint) 
• 
Section 14.3.3 - Blood Biomarkers (first bullet) 
• 
Section 15.1.5.1 - Biomarkers (third bullet)  
 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophil Evaluation in BAL Samples 
Neutrophils were added to the list of cell types to be evaluated as a 
percentage of the total cell count in BAL samples. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, second exploratory 
objective 
and 
under Exploratory Outcome Measures [under 
Pharmacodynamic 
Assessments, 
Bronchoalveolar 
Lavage 
Assessments, second bullet]) 
• 
Section 12.1 - Study Objectives (second exploratory objective) 
• 
Section 12.2 - Study Endpoints (second exploratory endpoint)  
• 
Section 14.3.2.4 - Biomarkers (second bullet) 
• 
Section 15.1.5.1 – Biomarkers (second bullet) 
Location of Study Drug Administration: 
Wording was added in Section 6 – Study Events Flow Chart for Day 56, 
to clarify that the study drug will be administered at the CRU. 
Meal Schedule: 
The indication for fasting requirement in Section 13.2.4.1 – Meal 
Schedule, was corrected to indicate patients will fast overnight for at least 
12 hours before bronchoscopy and BAL collection on Days -1 and 55 
instead of Days -1 and 56, as correctly indicated in Section 6 – Study 
Events Flow Chart. 
ECG Monitoring:  
Following an update in Celerion’s standard operating procedure, Section 
14.1.5 – Electrocardiogram Monitoring was updated to include at least 
5 minutes of rest prior to each ECG measurement (instead of at least 
1 minute as previously indicated). 
Hematology: 
The tests included in the hematology panel Section 14.1.6.1 – 
Hematology were updated to indicate that the red blood cell (RBC) count 
will include a reticulocytes count, and that the white blood cell (WBC) 
count with differential will include monocytes but will not include 
reticulocytes. 
Bronchoscopy and BAL: 
Due to the sensitivity of YPL-001 components to UV light, a warning was 
added to protect all samples from exposure to UV light, as indicated for 
the PK blood samples. 
The following sections were affected: 
• 
Section 14.3.2.2 - Bronchial Brushings 
• 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
 
PK Population: 
The indication for measurable concentration of verproside and picroside II 
in urine was removed from the definition of PK population in 
Section 15.1.2 - Patients to Analyze, as there is no urine PK sampling 
planned for this study. 
Minor typographic and editorial corrections were made where applicable. 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Events 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, 
Seoul, 134-721, Republic of Korea   
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratory 
Yuri Persidsky, MD, Ph.D. 
Chairperson, Department of Pathology and 
Laboratory Medicine 
Professor, 
Pathology 
and 
Laboratory 
Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Boards Main Office 
Location 
For Temple University School of Medicine: 
Student Faculty Center - Suite 304 
3340 North Broad Street 
Philadelphia, Pennsylvania, 19140 
United States 
Tel.: +1 215 707-3390 
Fax: +1 215 707-9100 
 
Brigham and Women's Hospital:  
Partners Human Reseach Committee 
116 Huntington Avenue, 10th Floor 
Boston, Massachusetts, 02116 
United States 
Tel.: +1 617 424-4100  
Fax: +1 617 424-4199 
 
UAB Lung Health Center: 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
  
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such as asthma 
and chronic obstructive pulmonary disease (COPD) 
Study Type 
Phase 2a, proof of concept 
Study Objectives 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, monocytes, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Summary of Study 
Design 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups 
(20 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) on the morning of 
Day -1 of the Treatment Period to confirm their eligibility and assess their 
health conditions. If they still meet all of the inclusion criteria and none of the 
exclusion criteria, they will undergo Day -1 scheduled study procedures. 
Patients will return to the CRU the next day (Day 1) to be randomized and 
receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15, 29, 43, 55, and 
56 of the Treatment Period for study drug administration and procedures. 
Prior to each release from the CRU, patients will receive a properly labeled 
container with sufficient doses which will be self-administered by patients at 
home until the next morning visit at the CRU. Patients will continue recording 
their daily symptoms via the e-diary throughout the Treatment Period. 
Patients will return the e-diary device on Day 56 to CRU staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
will be administered in accordance with the study center standard of care. 
 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Study Population 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component and a history of frequent (>2/year) COPD exacerbations, 
between 40 and 80 years of age (inclusive). An approximately equal number 
of current and ex-smokers will be enrolled. 
Number of 
Patients 
The study is planned to enroll at least 60 patients. Patients will be divided in 
3 treatment groups with 20 patients to receive one of the 3 treatments (i.e., 
low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo 
control) as per the randomization schedule. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Duration of 
Participation for 
Patients 
The planned length of participation in the study for each patient is 
approximately 12 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up procedures on Day 70 [± 2 days]). 
Duration of Study 
Conduct 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
An unblinded pharmacist will be responsible for providing YPL-001 or 
placebo to the blinded study personnel for administration. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 
80 
mg matching 
placebo 
tablet) 
will 
be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be 
administered on Day 56. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B, and C will be administered orally with 
approximately 240 mL of water. 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
 
Page 15 
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465


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Safety and 
Tolerability 
Analysis 
(continued) 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures 
PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature 
above 100°F) symptoms of COPD exacerbation, dyspnea (Modified Borg 
Dyspnea Scale), and activity (Duke Activity Status Index [DASI]) self-
reported daily by the patients using an e-diary. 
Symptom 
Monitoring 
Analysis 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline, will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, and throughout the study for 
PD assessments of biomarkers. Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
IC] will be performed at screening, and throughout the study. 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Exploratory 
Outcome 
Measures 
(continued) 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, and throughout the study. 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 56 to determine verproside and 
picroside II concentrations in plasma. Predose samples will also be collected 
in the morning of Days 15, 29, 43 and 56 for Ctrough determination. Other 
components of YPL-001 and its metabolites may also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-001 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
 
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467


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 
3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg 
X 
 
 
Xf 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAh 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityj 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)l 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 18 
AA98497_Final_Prot_Amendment_2_12Jan2015 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
468


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 
3.5 4 5 6 8 10 
12 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xn 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitso 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
 
Page 19 
AA98497_Final_Prot_Amendment_2_12Jan2015 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
469


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
d. To be performed prior to the bronchoscopy procedures. 
e. To be performed at screening or within 3 months (inclusive) of screening. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
i. 
Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
k. Prior to release from the CRU, patients will receive a properly labeled container with sufficient study drug for their assigned treatment which 
will be self-administered by patients at home until the next morning visit at the CRU. Patients must return the container (empty or not) at the 
next morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence of AEs. 
l. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
m. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
n. To be performed prior to dosing. 
o. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
 
Page 20 
AA98497_Final_Prot_Amendment_2_12Jan2015 
 
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470


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 2-14 
15 
16-28 
29 
30-42 
43 
44-54 
55 
Hours → 
 
AM PM 
 
AM PM 
 
AM 
PM 
 
AM 
PM 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Xe 
 
Vital Signsf 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xe 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
Xe 
 
Hem, Chem, and UAg 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine Alcohol & Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useh 
X 
PEF, COPD exacerbation, dyspnea 
and activityi 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Administration at Homej 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)k 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xn 
 
Bronchoscopy and BAL Biomarkersl 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
BDI/TDI & CAT 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitsm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Refer to the footnotes on the next page 
 
 
Page 21 
AA98497_Final_Prot_Amendment_2_12Jan2015 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
471


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. To be performed or completed prior to bronchoscopy procedures and/or dosing. 
e. ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
f. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
g. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
h. Patients will be provided with an e-diary device to record their self-administered doses, whether the dose was administered with food, and 
daily respiratory symptoms.  
i. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
j. 
Prior to release from the CRU, patients will receive a properly labeled container with sufficient study drug for their assigned treatment which 
will be self-administered by patients at home until the next morning visit at the CRU. Patients must return the container (empty or not) at the 
next morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence of AEs. 
k. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
l. 
Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
m. Patients will be admitted to the CRU at the time indicated by the CRU. 
n. To be completed prior to bronchoscopy procedures and dosing, or upon early termination. 
 
 
 
Page 22 
AA98497_Final_Prot_Amendment_2_12Jan2015 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
472


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
EOT 
or 
ETb 
FUc 
Days → 
56 
Hours → Predose 0 
0.167 
0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signse 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hem, Chem, and UAf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEF, COPD exacerbation, dyspnea and 
activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
Xi 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside Pharmacokinetics 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsj 
X 
X 
 
Refer to the footnotes on the next page 
 
 
 
Page 23 
AA98497_Final_Prot_Amendment_2_12Jan2015 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
473


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
a. For details on Procedures, refer to Section 14. 
b. To be performed at the end of the Treatment Period on Day 56 or prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
f. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, Patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
g. Patients will return the e-diary device on Day 56 to CRU staff.  
h. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
i. 
To be performed at predose on Day 56 or upon early termination. 
j. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition 
Dyspnea Index Test, CAT = COPD Assessment Test, Chem = Serum chemistry, COPD = chronic obstructive pulmonary disease, CRU = Clinical 
research unit, ConMeds = Concomitant medication, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = electronic diary, 
EOT/ET = End-of-Treatment or early termination, FSH = Follicle-stimulating hormone, Hem = Hematology, HIV = Human immunodeficiency virus, 
IL= interleukin, PEF = Peak expiratory flow, PK = Pharmacokinetics, PM = Evening, Preg = Serum pregnancy, Screen = Screening, 
UA = Urinalysis. 
 
 
Page 24 
AA98497_Final_Prot_Amendment_2_12Jan2015 
 
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474


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY .......................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ................................................................................................... 7 
3. 
INVESTIGATORS SIGNATURES ............................................................................................ 8 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY .............................................................. 10 
5. 
SYNOPSIS ............................................................................................................................. 12 
6. 
STUDY EVENTS FLOW CHART ........................................................................................... 18 
7. 
TABLE OF CONTENTS ......................................................................................................... 25 
8. 
ABBREVIATIONS .................................................................................................................. 28 
9. 
INTRODUCTION AND BACKGROUND ................................................................................ 33 
9.1 
YPL-001 ....................................................................................................................... 33 
9.1.1 
Preclinical Trials .............................................................................................. 33 
9.1.1.1 
Pharmacology ................................................................................. 33 
9.1.1.2 
Pharmacokinetics ............................................................................ 34 
9.1.1.3 
Toxicology ....................................................................................... 35 
9.1.2 
Clinical Experience ......................................................................................... 36 
9.1.2.1 
SAD study ....................................................................................... 37 
9.1.2.2 
MAD Study ...................................................................................... 38 
10. RATIONALE ........................................................................................................................... 40 
10.1 Purpose of the Study ................................................................................................... 40 
10.2 Dose Selection ............................................................................................................. 40 
11. RISK/BENEFIT ....................................................................................................................... 42 
12. STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 43 
12.1 Study Objectives .......................................................................................................... 43 
12.2 Study Endpoints ........................................................................................................... 43 
13. INVESTIGATIONAL PLAN ..................................................................................................... 45 
13.1 Overall Study Design and Plan .................................................................................... 45 
13.2 Study Conduct ............................................................................................................. 46 
13.2.1 Screening ........................................................................................................ 46 
13.2.2 Patient Confinement ....................................................................................... 46 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ......................................................... 46 
13.2.4 Treatment Period (Days 1 to 56) .................................................................... 47 
13.2.4.1 Meal Schedule ................................................................................ 47 
13.2.4.2 End-of-Treatment or Early Termination (Day 56) ........................... 48 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................... 48 
13.2.6 Scheduled End of Study ................................................................................. 48 
13.3 Selection of Study Population ...................................................................................... 48 
13.3.1 Number of Patients ......................................................................................... 48 
13.3.2 Inclusion Criteria ............................................................................................. 49 
13.3.3 Exclusion Criteria ............................................................................................ 50 
13.3.4 Removal of Patients from the Study ............................................................... 52 
13.3.5 Study Restrictions ........................................................................................... 53 
13.3.5.1 Concomitant Therapy ...................................................................... 53 
13.3.5.1.1 
Prohibited Therapy ..................................................... 53 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
13.3.5.1.2 
Permitted Therapy ...................................................... 54 
13.3.5.2 Prohibitions...................................................................................... 54 
13.3.5.3 Activity ............................................................................................. 54 
13.4 Treatments ................................................................................................................... 55 
13.4.1 Treatments administered ................................................................................ 55 
13.4.1.1 Drug Administration During Run-in Period ...................................... 55 
13.4.1.2 Drug Administration During Treatment Period ................................ 55 
13.4.1.3 Stopping Rules ................................................................................ 56 
13.4.2 Method of Assigning Patients to Treatment Groups ....................................... 56 
13.4.3 Blinding ........................................................................................................... 57 
13.4.3.1 Maintenance of Randomization ...................................................... 57 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 57 
13.4.3.3 Revealing of Randomization ........................................................... 57 
13.4.4 Treatment Compliance ................................................................................... 58 
14. STUDY PROCEDURES ......................................................................................................... 59 
14.1 Safety Assessments .................................................................................................... 59 
14.1.1 Body Height and Weight ................................................................................. 59 
14.1.2 Physical Examination ...................................................................................... 59 
14.1.3 Vital Signs ....................................................................................................... 59 
14.1.4 Pulse Oximetry................................................................................................ 60 
14.1.5 Electrocardiogram Monitoring ......................................................................... 60 
14.1.6 Clinical Laboratory Tests ................................................................................ 60 
14.1.6.1 Hematology ..................................................................................... 61 
14.1.6.2 Serum Chemistry ............................................................................ 61 
14.1.6.3 Serology .......................................................................................... 61 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............. 61 
14.1.6.5 Follicle-Stimulating Hormone .......................................................... 61 
14.1.6.6 Urinalysis ......................................................................................... 62 
14.1.6.7 Urine Drug/Alcohol Screen.............................................................. 62 
14.1.7 Chest X-Ray .................................................................................................... 62 
14.1.8 Adverse Events ............................................................................................... 62 
14.1.8.1 Adverse Event Definition ................................................................. 62 
14.1.8.2 Monitoring........................................................................................ 62 
14.1.8.3 Reporting ......................................................................................... 63 
14.1.8.4 Serious Adverse Events .................................................................. 64 
14.2 Symptom Assessments ............................................................................................... 65 
14.2.1 Electronic Diary ............................................................................................... 65 
14.2.2 Peak Expiratory Flow ...................................................................................... 65 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ............ 65 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) ....................................................... 65 
14.2.5 Activity (Duke Activity Status Index) ............................................................... 66 
14.3 Pharmacodynamic Assessments ................................................................................. 66 
14.3.1 Pulmonary Function (Spirometry) ................................................................... 66 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers .................... 67 
14.3.2.1 Bronchoscopy ................................................................................. 67 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
14.3.2.2 Bronchial Brushings ........................................................................ 68 
14.3.2.3 Bronchoalveolar Lavage (BAL) ....................................................... 68 
14.3.2.4 Biomarkers ...................................................................................... 68 
14.3.3 Blood Biomarkers ........................................................................................... 68 
14.3.4 Quality of Life Questionnaires ......................................................................... 69 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ......................................................................................... 69 
14.3.4.2 COPD Assessment Test (CAT)....................................................... 69 
14.4 Pharmacokinetic Assessments .................................................................................... 69 
14.4.1 Blood Sampling and Processing ..................................................................... 69 
14.5 Blood Volume for Study Assessments......................................................................... 70 
15. DATA ANALYSIS ................................................................................................................... 71 
15.1 Statistical Analysis ....................................................................................................... 71 
15.1.1 Sample Size Calculation ................................................................................. 71 
15.1.2 Patients to Analyze ......................................................................................... 71 
15.1.3 Safety Analysis ............................................................................................... 72 
15.1.4 Symptom Monitoring Analysis ........................................................................ 72 
15.1.5 Pharmacodynamic Analysis ............................................................................ 73 
15.1.5.1 Biomarkers ...................................................................................... 73 
15.1.5.2 Quality of Life .................................................................................. 73 
15.1.6 Pharmacokinetic Analysis ............................................................................... 74 
15.1.6.1 Pharmacokinetic Parameters .......................................................... 74 
15.1.6.1.1 
Plasma ....................................................................... 74 
15.1.6.1.2 
Bronchoalveolar Lavage ............................................ 75 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ......................... 76 
15.1.7 Assessment of Efficacy ................................................................................... 76 
16. STUDY ADMINISTRATION ................................................................................................... 77 
16.1 Ethics ........................................................................................................................... 77 
16.1.1 Institutional Review Board .............................................................................. 77 
16.1.2 Ethical Conduct of the Study .......................................................................... 77 
16.1.3 Patient Information and Consent .................................................................... 77 
16.2 Termination of the Study .............................................................................................. 77 
16.3 Data Quality Assurance ............................................................................................... 77 
16.4 Direct Access to Source Data/Documents .................................................................. 78 
16.5 Drug Supplies, Packaging and Labeling ...................................................................... 78 
16.6 Data Handling and Record Keeping ............................................................................ 78 
16.7 Protocol Amendments ................................................................................................. 78 
16.8 Finance and Insurance ................................................................................................ 79 
16.9 Publication Policy ......................................................................................................... 79 
17. REFERENCES ....................................................................................................................... 80 
18. APPENDIXES ........................................................................................................................ 81 
18.1 Appendix 1 - UGT Drug Interaction Table ................................................................... 81 
18.2 Appendix 2 - SULT Drug Interaction Table .................................................................. 82 
 
 
 
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IND No.: 114903 
 
8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
Coag 
Coagulation 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
 
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Proof of Concept 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
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CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
 
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IND No.: 114903 
 
IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimetre of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
 
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IND No.: 114903 
 
ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 
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Proof of Concept 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
Good Clinical Practice (GCP), and applicable regulatory requirements. The patient 
population will be comprised of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of March 1, 2013. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Bronchoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
 
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CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
 
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were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
 
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IND No.: 114903 
 
values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
 
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IND No.: 114903 
 
9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 
0.67 hours under fasting conditions. Verproside appeared to be cleared rapidly from 
plasma, with mean t1/2 values under 1 hour; plasma verproside concentrations were 
below the lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 
below summaries the PK parameters of verproside following single-dose administrations 
of YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
 
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t1/2 values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t1/2 values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
 
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as asthma and COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such as asthma and COPD to 
demonstrate safety and evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
Table 4: Traditional Chinese Medicine Use Versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an indwelling cannula is utilized (as a last resort solution when venipuncture 
becomes difficult for a patient) and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
 
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., sputum quality, color, consistency) and minor (e.g., cough, wheeze, 
sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation;  
 
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IND No.: 114903 
 
• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and 
eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
 
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
At least 60 patients will be enrolled and randomized into 3 treatment groups (20 patients 
per group). Patients will participate only once. An approximately equal number of current 
and ex-smokers will be enrolled in the study. 
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU on the morning of Day -1 of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Day -1 scheduled 
study procedures. Patients will return to the CRU the next day (Day 1) to be randomized 
and receive one of the 3 treatments and undergo all scheduled study procedures. 
Patients will return on the morning of Days 15, 29, 43, 55, and 56 of the Treatment 
Period for study drug administration and procedures. Prior to each release from the 
CRU, patients will receive a properly labeled container with sufficient doses which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients 
will continue recording their daily symptoms via the e-diary throughout the Treatment 
Period. Patients will return the e-diary device on Day 56 to CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
will be discontinued. Rescue medication will be used for any patient with an 
exacerbation of COPD and will be administered in accordance with the study center 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses and their daily respiratory symptoms. Prior to each morning 
dose, patients will record at home their daily PEF, major (e.g., sputum quality, color, 
consistency) and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, 
and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea 
(Modified Borg Dyspnea Scale), and activity (DASI). 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 56 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses and their daily 
respiratory symptoms on their e-diary. Prior to each morning dose, patients will record at 
home their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., 
cough, wheeze, sore throat, nasal congestion, discharge, and body temperature above 
100°F) symptoms of COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and 
activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before bronchoscopy and 
BAL collection on Days -1 and 55. On Days 1 and 56, patients will be required to fast 
overnight for at least 8 hours before and for at least 4 hours after the morning dose. On 
all other days, patients will be asked to fast for at least 2 hours before and 2 hours after 
each morning dose. Patients will also be asked to fast for at least 2 hours before and 
after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 56, patients will fast from all food and drink except water between meals 
and snacks. Foods and beverages containing alcohol, xanthines, caffeine, vegetables 
from the mustard green family, mustard, tea (especially speedwell tea), or 
grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, menus should 
be similar in content. The same menu and meal (except for snacks) schedule will be 
administered uniformly for all patients confined within the same CRU, across all 
treatment groups. Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
13.2.4.2 End-of-Treatment or Early Termination (Day 56) 
End-of-treatment evaluation will be performed on all patients before leaving the CRU or 
prior to early termination. 
The end-of-treatment procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll at least 60 patients. An approximately equal number of 
current and ex-smokers will be enrolled. Patients will be divided in 3 treatment groups 
with 20 patients to receive one of the 3 treatments (i.e., low and high YPL-001 doses 
[80 mg and 160 mg BID] and a placebo control) as per the randomization schedule. 
Each treatment group will consist of an approximately equal number of current and ex-
smokers. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 40 to 80 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-32.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24 hours 
prior to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled 
CRU visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack years. Ten pack years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Patients, who undergo smoking cessation therapy, must be completed 
3 months prior to screening visit and smoking status should not change between the 
patient’s screening visit and patient’s last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
 
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IND No.: 114903 
 
c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method 
(e.g., condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
13. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
14. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the end-of-treatment evaluations. Patients will be advised to use a 
condom with spermicide for 90 days following the last administration of the study 
drug, and to not donate sperm during this same period of time. In the event that the 
sexual partner is surgically sterile, use of a condom with spermicide is not necessary. 
No restrictions are required for vasectomized males provided their vasectomy has 
been performed 120 days or more prior to study start. Males who have been 
vasectomized less than 120 days prior to study start must follow the same 
restrictions as non-vasectomized males. 
15. Understands study procedures and provides written informed consent for the trial. 
16. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
 
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IND No.: 114903 
 
6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), 
sleep 
apnea, 
cardiovascular, 
endocrine, 
neurological, 
hepatic, 
gastrointestinal, renal, hematological, urological, immunological or ophthalmic 
diseases that the Investigator believes are clinically significant e.g., unstable and 
could impact patient safety by participation in the study. 
9. History or presence of: 
• 
significant cardiac arrhythmia; 
• 
prostatic hyperplasia; 
• 
bladder-neck obstruction; 
• 
urinary retention; 
• 
narrow-angle glaucoma. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Evidence of hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive urine drug/alcohol testing at screening or at each CRU visit. 
14. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies (HCV). 
15. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
16. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
17. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
18. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) and/or sulfotransferases (SULT), 
within 12 hours prior to Day 1 of the Run-in Period (refer to Appendix 1 and 
Appendix 2). 
19. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
 
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IND No.: 114903 
 
20. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
21. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
22. Females who are pregnant or lactating.  
23. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
24. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion 
(end-of-treatment evaluations) as the situation allows (see Section 13.2.5). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
 
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IND No.: 114903 
 
13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the end-of-treatment 
procedures). Intake of these medications during the Run-in Period constitutes a 
non-eligibility criterion and the patients will not be randomized into the study. If any of 
these medications are taken during the Treatment Period, the need for this patient to be 
withdrawn from the study will be carefully evaluated by the Investigator and the Sponsor 
on the basis of the potential impact on efficacy or safety evaluation and in the patient's 
best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements and herbal products (especially Speedwell) will be prohibited 
7 days prior Day 1 of the Treatment Period and through collection of the final PK 
sample. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
13.3.5.1.2 Permitted Therapy 
Throughout the study Period (from Day 1 of the Run-in Period to the completion of the 
end-of-treatment procedures) patients will be permitted to take the following medications 
in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 
24 hours before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine:  24 hours prior to each CRU visit and prior to dosing on Days 1 
and 56 of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Alcohol:  48 hours prior to each CRU visit, 48 hours prior to dosing on Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 56 last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 56 of 
the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Tea (especially Speedwell tea), Coffee and Red Wine:  7 days prior to Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 56 last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. Only the 
morning dose will be administered on Day 56. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be administered on 
Day 56. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose will be 
administered on Day 56. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for 
each patient, as per the randomization scheme. 
Prior to release from the CRU on Days 1, 15, 29, 43, and 55 of the Treatment Period, 
patients will receive a properly labeled container with the appropriate doses which will be 
self-administered by patients at home. Patients will record their self-administered doses 
 
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in their e-diary, and whether the dose was administered with food, and must return the 
container (empty or not) at the next morning visit. Home dosing will be monitored via 
attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence 
of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
given instructions on recording of dosing times in their e-diary on home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique screening identification number upon screening. 
Patients who complete the study screening assessments, complete the Run-in Period, 
and meet all the eligibility criteria will be assigned a unique randomization identification 
number, different from the screening number, and receive the corresponding product, 
according to a randomization scheme generated at Celerion. Each treatment group will 
consist of an approximately equal number of current and ex-smokers. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
 
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IND No.: 114903 
 
If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
The randomization is available only to the clinic pharmacy staff preparing the drug who 
are not involved in any other aspect of the study including administration of the drug. It 
will not be made available to the Sponsor, patients, or members of the staff responsible 
for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
One set of the sealed envelopes containing the randomization code will be available to 
the Investigator at the start of the trial. 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the study monitor or designee prior to breaking the blind. If breaking the 
blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
1. All data are entered in the database, edits checks are performed, queries 
closed, CRFs signed by the Investigator, and the database is officially locked. 
2. All PK/PD samples have been analyzed and quality checked by the 
responsible analytical associate. 
 
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IND No.: 114903 
 
13.4.4 Treatment Compliance  
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
Self-administration by patients at home will be monitored by the CRU via the e-diary and 
attempted phone calls will be performed to remind patients to take their medication, if 
they did not record their self-administration on the e-diary. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
 
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When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When scheduled postdose, vital signs readings 
will be performed within approximately 10 minutes of the scheduled time point. When 
performing the bronchoscopy, vital signs (body temperature, respiratory rate, blood 
pressure, and heart rate) will be monitored continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen levels, saturation [%], and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen levels, saturation [%], and 
heart rate) as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. Readings may be taken at other times, if deemed 
necessary by the Investigator. When performing the bronchoscopy, oxygen saturation 
will be monitored continuously until the end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performing the bronchoscopy, ECG will be monitored continuously until 
the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
5 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count (including a 
reticulocytes count) 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, and 
monocytes) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
 
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14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine Drug/Alcohol Screen 
• 
Cannabinoids  
• 
Alcohol 
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Adverse Events 
14.1.8.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.3 
14.1.8.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, at the end-of treatment 
(or upon early withdrawal), and at the follow-up phone call. The inquiry will be made in a 
non-specific manner using open-ended questions so as not to bias the response 
(e.g., How have you been feeling since your last visit?). 
 
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All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.8.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 4 and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
 
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The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
A semi-colon indicates ‘or’ within the description of the grade; ADL = Activities of Daily Living 
*Instrumental ADL refer 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. 
14.1.8.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Sponsor via fax or e-mail within one working day of becoming 
aware of the event, whether or not the serious events are deemed drug-related. All 
serious event reporting will adhere to 21 CFR 312.32 for Investigational New Drugs 
(IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20123. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
If an SAE occurs to a patient on this study, the Sponsor’s Medical Expert is to be 
contacted (see Section 3). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
 
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dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; 
or is not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses, whether the dose was 
administered with food, and daily respiratory symptoms throughout the Run-in and 
Treatment Periods. Patients will return the e-diary device on Day 56 to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum 
quality, color, consistency) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., sputum quality, color, consistency) and 
minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body 
temperature above 100°F) symptoms of COPD exacerbation via the e-diary before each 
dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
 
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14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) 
and 
long 
acting 
β2-agonist 
and 
anticholinergic 
bronchodilators 
(e.g., salmeterol, tiotropium) agents will be withheld approximately 4 and 12 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study and all sites should be using the same brand and model 
of spirometer for this study. 
At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol, (100 μg/inhalation), for a total dose of 
400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes 
after albuterol administration, the baseline post-bronchodilator spirometry will be 
performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Day -1 measurement): Predose 
FEV1 is defined as the time-point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
FEV1 measurement at predose on Day -1 of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
 
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2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose on Day -1, up to 3 measures will be 
performed.  
Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be asked to refrain from smoking approximately 48 hours before the 
bronchoscopy procedures and will be fasted for 12 hours before. If required, blood 
pressure medications can be taken with small sip of water based on preapproval of local 
Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.5,6 
Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal canula will be administered 
during bronchoscopy and oxygen saturation will be maintained at ≥95%. Conscious 
sedation will be achieved with incremental doses of 1–4 mg midazolam and 50-100 μg 
fentanyl. Local upper and lower airway topical anesthesia will be achieved with 1% or 
2% lidocaine. The dose of lidocaine administered during the procedure will not exceed a 
total of 450 mg. The bronchoscope will usually be inserted preferably through the nares 
into trachea. The bronchoscope will be wedged into 2 subsegments of the right middle or 
lower lobe, as deemed appropriate by the Investigator. Emergency treatments for 
cardiopulmonary arrest and pneumothorax will be immediately available in the 
bronchoscopy room. The patient will remain in the recovery suite for observation for a 
minimum of 2 hours after the procedure.  
 
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14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A 180 mL BAL will be 
performed in each subsegment of the right middle or lower lobe, as deemed appropriate 
by the Investigator, using 6 x 30 mL aliquots of normal saline warmed to room 
temperature. BAL fluid will be aspirated following each 30 mL instillation. The lavage 
material, which averages 25% return in COPD patients, typically yields 1-10 x 106 
macrophages. The centrifuged cell pellet and supernatant will be kept cooled until 
processed or stored as indicated in the laboratory manual to be provided as a separate 
document. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and eosinophils 
as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture at the time points delineated in 
the Study Events Flow Chart (Section 6) for PD assessments of biomarkers. Biomarker 
assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 4.5 mL pre-chilled evacuated tubes containing K2EDTA and 
 
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stored in an ice bath until processing. 
14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Day -1 of the Treatment Period) will be assessed with the BDI. 
This instrument has 3 domains (functional impairment, magnitude of task, and 
magnitude of effort) with the values added for a combined focal score. Functional 
impairment determines the impact of breathlessness on the ability to carry out activities; 
magnitude of task determines the type of task that causes breathlessness, magnitude of 
effort establishes the level of effort that results in breathlessness. The BDI scores range 
from 0 (very severe impairment) to 4 (no impairment) for each domain with the baseline 
focal score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.7,8 
A copy of the questionnaire to be used will be kept in the study binder. 
14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture at the time points delineated in the 
Study Events Flow Chart (Section 6).  
Blood will be drawn into 5 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
 
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14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests (including 
hematology, serum chemistry, serology), 
FSH (for postmenopausal female patients 
only) and serum pregnancy (for female 
patients only). 
1 
~ 17 mL 
~ 17 mL 
On-study serum chemistry and serum 
pregnancy (for female patients only) when 
scheduled at the same time 
4 
~ 8.5 mL 
~ 34 mL 
Additional on-study serum pregnancy (for 
female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
4 
~ 4 mL 
~ 16 mL 
Blood samples for PD biomarkers 
8 
~ 4.5 mL 
~ 36 mL 
Blood samples for PK of verproside and 
picroside II 
37 
~ 5 mL 
~ 185 mL 
Total Blood Volume for males → 
~ 288 mL 
Total Blood Volume for females → 
~ 295 mL 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma concentration of verproside and 
picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Days 1 and/or 56. 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 post-
baseline PD measurement. 
• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
 
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the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline, will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes, 
neutrophils, and eosinophils as a percentage of total cells; total cell count [cells/mL] 
of neutrophils, macrophages, lymphocytes and eosinophils as absolute inflammatory 
cell numbers; and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9): raw and % change from baseline levels; 
and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and lymphocytes] 
and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
The following PK parameters will be computed following Day 56 morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss: 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc: 
Percent fluctuation will be calculated as follows: 
𝐶𝐶max _𝑠𝑠𝑠𝑠−𝐶𝐶min _𝑠𝑠𝑠𝑠
𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎
 𝑥𝑥 100 
Swing: 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
 
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15, 29, 43, and 56 following multiple oral dose administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP (E6 
Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
 
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets,  and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 5 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
17. REFERENCES 
 
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
4 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
5 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
6 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
7 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
8 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
18. APPENDIXES 
18.1 
Appendix 1 - UGT Drug Interaction Table 
The following list provides medications that are substrates or inhibitors of UGT. Adapted 
from Williams JA, et al. Drug-drug interactions for UDP-glucuronosyltransferase 
substrates:  a pharmacokinetic explanation for typically observed low exposure 
(AUCi/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201-8. Epub 2004 Aug 10. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Amitriptyline 
Carvedilol 
Clofibric acid 
Codeine 
Cyclobenzaprine 
Diclofenac 
DMXAA 
Fenofibrate 
Flavopiridol 
Furosemide 
Gemfibrozil 
Glipizide 
Irbesartan 
Lamotrigine 
Levothyroxine 
Metoclopramide 
Metronidazole 
Morphine 
Naloxone 
Naproxen 
Olanzapine 
Oxazepam 
Paracetamol 
Propofol 
Raloxifene 
Tramadol 
Valdecoxib 
Valproic acid 
Zidovudine 
17-beta-estradiol glucuronide 
Flavonoids (citrus fruit) 
Silybin (herb supplement milk thistle) 
 
 
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Proof of Concept 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No.: 114903 
 
18.2 Appendix 2 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Acetaminophen 
 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
 
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Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
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1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
20-Nov-2014 
by Ziv Machnes 
Final Protocol, Amendment 1 
This protocol amendment is generated to update the study population 
with regards to smoking frequency, to update the handling procedures for 
BAL samples, and to clarify other study procedures as listed below. 
Study Population: 
Section 13.3.2 - Inclusion Criteria, bullet 11 was updated to indicate that 
the study population will consist only of current and ex-smokers with a 
history of >10 pack years. As such, the indications for ‘packs/year’ were 
replaced with ‘pack years’ and the allowance for current smokers with 
<10 pack/years was removed. 
Wording was added to indicate an approximately equal number of current  
and ex-smokers will be enrolled, and that each treatment group will 
consist of an approximetly equal number of smokers and ex-smokers. In 
addition, the stratification criteria for the randomization was updated to 
consist of either current or ex-smokers. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Population and Number of 
Patients) 
• 
Section 13.1 - Overall Study Design and Plan (second paragraph) 
• 
Section 13.3.1 – Number of Patients. 
• 
Section 13.4.2 - Method of Assigning Patients to Treatment Groups. 
BAL Sample Handling: 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) was updated to indicate 
that sample handling, processing and storage procedures will be provided 
in a separate document.  
Follow-up Procedures: 
The wording in regards to follow-up procedures to be conducted on 
14 days (± 2 day), after the last study drug administration, was updated to 
indicated a phone-call and not a visit, as indicated correctly in Section 6 – 
Study Event Flow Chart. Study event were updated accordingly. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Duration of Participation for Patients, 
and Exploratory Outcome Measures [under Blood Assessments, 
Pulmonary Assessment, and Quality of Life Assessments])  
• 
Section 13.3.5.2 – Prohibitions (under Alcohol) 
• 
Section 14.1.8.2 – Monitoring (first paragraph). 
 
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IND No. 114903 
 
 
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Study Duration: 
The total duration of the study indicated in Section 5 – Synopsis (under 
Duration of Participation for Patients) was corrected to 12 weeks to 
correspond with the actual study duration as indicated throughout the 
protocol.  
Inflammatory Markers in Blood Samples: 
The list of cell types to be evaluated as part of the inflammatory markers 
in the blood was updated to include monocytes instead of macrophages, 
as macrophages are not expected to be present in blood. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, fourth exploratory 
objective, and under Exploratory Outcome Measures [under 
Pharmacodynamic Assesments, Blood Assessments, first bullet]) 
• 
Section 12.1 - Study Objectives (fourth exploratory objective) 
• 
Section 12.2 - Study Endpoints (third exploratory endpoint) 
• 
Section 14.3.3 - Blood Biomarkers (first bullet) 
• 
Section 15.1.5.1 - Biomarkers (third bullet)  
Neutrophil Evaluation in BAL Samples 
Neutrophils were added to the list of cell types to be evaluated as a 
percentage of the total cell count in BAL samples. 
The following sections were affected: 
• 
Section 5 – Synopsis (under Study Objectives, second exploratory 
objective and under Exploratory Outcome Measures [under 
Pharmacodynamic 
Assessments, 
Bronchoalveolar 
Lavage 
Assessments, second bullet]) 
• 
Section 12.1 - Study Objectives (second exploratory objective) 
• 
Section 12.2 - Study Endpoints (second exploratory endpoint)  
• 
Section 14.3.2.4 - Biomarkers (second bullet) 
• 
Section 15.1.5.1 – Biomarkers (second bullet) 
Location of Study Drug Administration: 
Wording was added in Section 6 – Study Events Flow Chart for Day 56, 
to clarify that the study drug will be administered at the CRU. 
Meal Schedule: 
The indication for fasting requirement in Section 13.2.4.1 – Meal 
Schedule, was corrected to indicate patients will fast overnight for at least 
12 hours before bronchoscopy and BAL collection on Days -1 and 55 
instead of Days -1 and 56, as correctly indicated in Section 6 – Study 
Events Flow Chart. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
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ECG Monitoring:  
Following an update in Celerion’s standard operating procedure, Section 
14.1.5 – Electrocardiogram Monitoring was updated to include at least 
5 minutes of rest prior to each ECG measurement (instead of at least 
1 minute as previously indicated). 
Hematology: 
The tests included in the hematology panel Section 14.1.6.1 – 
Hematology were updated to indicate that the red blood cell (RBC) count 
will include a reticulocytes count, and that the white blood cell (WBC) 
count with differential will include monocytes but will not include 
reticulocytes. 
Bronchoscopy and BAL: 
Due to the sensitivity of YPL-001 components to UV light, a warning was 
added to protect all samples from exposure to UV light, as indicated for 
the PK blood samples. 
The following sections were affected: 
• 
Section 14.3.2.2 - Bronchial Brushings 
• 
Section 14.3.2.3 - Bronchoalveolar Lavage (BAL) 
PK Population: 
The indication for measurable concentration of verproside and picroside II 
in urine was removed from the definition of PK population in 
Section 15.1.2 - Patients to Analyze, as there is no urine PK sampling 
planned for this study. 
 
Minor typographic and editorial corrections were made where applicable. 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
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4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Events 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, 
Seoul, 134-721, Republic of Korea   
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratory 
Yuri Persidsky, MD, Ph.D. 
Chairperson, Department of Pathology and 
Laboratory Medicine 
Professor, 
Pathology 
and 
Laboratory 
Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
540


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 9 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Boards Main Office 
Location 
For Temple University School of Medicine: 
Student Faculty Center - Suite 304 
3340 North Broad Street 
Philadelphia, Pennsylvania, 19140 
United States 
Tel.: +1 215 707-3390 
Fax: +1 215 707-9100 
 
Brigham and Women's Hospital:  
Partners Human Reseach Committee 
116 Huntington Avenue, 10th Floor 
Boston, Massachusetts, 02116 
United States 
Tel.: +1 617 424-4100  
Fax: +1 617 424-4199 
 
UAB Lung Health Center: 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
  
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
541


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 10 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such as asthma 
and chronic obstructive pulmonary disease (COPD) 
Study Type 
Phase 2a, proof of concept 
Study Objectives 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, monocytes, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
542


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 11 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
Summary of Study 
Design 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
Sixty-nine (69) patients will be enrolled and randomized into 3 treatment 
groups (23 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) on the morning of 
Day -1 of the Treatment Period to confirm their eligibility and assess their 
health conditions. If they still meet all of the inclusion criteria and none of the 
exclusion criteria, they will undergo Day -1 scheduled study procedures. 
Patients will return to the CRU the next day (Day 1) to be randomized and 
receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15, 29, 43, 55, and 
56 of the Treatment Period for study drug administration and procedures. 
Prior to each release from the CRU, patients will receive a properly labeled 
container with sufficient doses which will be self-administered by patients at 
home until the next morning visit at the CRU. Patients will continue recording 
their daily symptoms via the e-diary throughout the Treatment Period. 
Patients will return the e-diary device on Day 56 to CRU staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
will be administered in accordance with the study center standard of care. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
543


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 12 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
Study Population 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component and a history of frequent (>2/year) COPD exacerbations, 
between 40 and 80 years of age (inclusive). An approximately equal number 
of current and ex-smokers will be enrolled. 
Number of 
Patients 
The study is planned to enroll 69 patients to ensure completing the study 
with 60 patients. Patients will be divided in 3 treatment groups with 
23 patients to receive one of the 3 treatments (i.e., low and high YPL-001 
doses [80 mg and 160 mg BID] and a placebo control) as per the 
randomization schedule. Each treatment group will consist of an 
approximately equal number of current and ex-smokers. 
Duration of 
Participation for 
Patients 
The planned length of participation in the study for each patient is 
approximately 12 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up procedures on Day 70 [± 2 day]). 
Duration of Study 
Conduct 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
An unblinded pharmacist will be responsible for providing YPL-001 or 
placebo to the blinded study personnel for administration. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 80 mg matching placebo tablet) will be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be 
administered on Day 56. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B and C will be administered orally with 
approximately 240 mL of water. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
544


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 13 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
545


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 14 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
Safety and 
Tolerability 
Analysis 
(continued) 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures 
PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature 
above 100°F) symptoms of COPD exacerbation, dyspnea (Modified Borg 
Dyspnea Scale), and activity (Duke Activity Status Index [DASI]) self-
reported daily by the patients using an e-diary. 
Symptom 
Monitoring 
Analysis 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline, will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, and throughout the study for 
PD assessments of biomarkers. Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
IC) will be performed at screening, and throughout the study. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
546


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 15 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
Exploratory 
Outcome 
Measures 
(continued) 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, and throughout the study. 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 56 to determine verproside and 
picroside II concentrations in plasma. Predose samples will also be collected 
in the morning of Days 15, 29, 43 and 56 for Ctrough determination. Other 
components of YPL-001 and its metabolites may also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-001 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
547


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 16 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg 
X 
 
 
Xf 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAh 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityj 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)l 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
548


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 17 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 
3 3.5 4 5 6 8 10 
12 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xn 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitso 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
549


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 18 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
d. To be performed prior to the bronchoscopy procedures. 
e. To be performed at screening or within 3 months (inclusive) of screening. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
i. 
Patients will be provided with an e-diary device to record their self-administered doses and whether the dose was administered with food, 
concomitant medications and daily respiratory symptoms.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
k. Prior to release from the CRU, patients will receive a properly labeled container with sufficient study drug for their assigned treatment which 
will be self-administered by patients at home until the next morning visit at the CRU. Patients must return the container (empty or not) at the 
next morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence of AEs. 
l. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
m. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
n. To be performed prior to dosing. 
o. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
550


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Page 19 
AA98497_Final_Prot_Amendment_1_20Nov2014 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 2-14 
15 
16-28 
29 
30-42 
43 
44-54 
55 
Hours → 
 
AM PM 
 
AM PM 
 
AM 
PM 
 
AM 
PM 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Xe 
 
Vital Signsf 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xe 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
Xe 
 
Hem, Chem, and UAg 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine Alcohol & Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useh 
X 
PEF, COPD exacerbation, dyspnea 
and activityi 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Administration at Homej 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)k 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Bronchoscopy and BAL Biomarkersl 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
BDI/TDI & CAT 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
Xd 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitsm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Refer to the footnotes on the next page 
 
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a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. To be performed or completed prior to bronchoscopy procedures and/or dosing. 
e. ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
f. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
g. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
h. Patients will be provided with an e-diary device to record their self-administered doses and whether the dose was administered with food, 
concomitant medications and daily respiratory symptoms.  
i. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
j. 
Prior to release from the CRU, patients will receive a properly labeled container with sufficient study drug for their assigned treatment which 
will be self-administered by patients at home until the next morning visit at the CRU. Patients must return the container (empty or not) at the 
next morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence of AEs. 
k. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
l. 
Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
m. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
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STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
EOT 
or 
ETb 
FUc 
Days → 
56 
Hours → Predose 0 
0.167 
0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signse 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEF, COPD exacerbation, dyspnea and 
activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
Xi 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside Pharmacokinetics 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsj 
X 
X 
 
Refer to the footnotes on the next page 
 
 
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a. For details on Procedures, refer to Section 14. 
b. To be performed at the end of the Treatment Period on Day 56 or prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
f. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, Patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
g. Patients will return the e-diary device on Day 56 to CRU staff.  
h. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
i. 
To be performed at predose on Day 56 or upon early termination. 
j. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition 
Dyspnea Index Test, CAT = COPD Assessment Test, Chem = Serum chemistry, COPD = chronic obstructive pulmonary disease, CRU = Clinical 
research unit, ConMeds = Concomitant medication monitoring, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = electronic 
diary, EOT/ET = End-of-Treatment or early termination, FSH = Follicle-stimulating hormone, Hem = Hematology, HIV = Human immunodeficiency 
virus, IL= interleukin, PEF = Peak expiratory flow, PK = Pharmacokinetics, PM = Evening, Preg = Serum pregnancy, Screen = Screening, 
UA = Urinalysis. 
 
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7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY ...................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ............................................................................................... 5 
3. 
INVESTIGATORS SIGNATURES ........................................................................................ 6 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY .............................................................. 8 
5. 
SYNOPSIS ........................................................................................................................ 10 
6. 
STUDY EVENTS FLOW CHART ....................................................................................... 16 
7. 
TABLE OF CONTENTS ..................................................................................................... 23 
8. 
ABBREVIATIONS.............................................................................................................. 26 
9. 
INTRODUCTION AND BACKGROUND ............................................................................. 31 
9.1 
YPL-001 .................................................................................................................. 31 
9.1.1 
Preclinical Trials .......................................................................................... 31 
9.1.1.1 
Pharmacology .............................................................................. 31 
9.1.1.2 
Pharmacokinetics ......................................................................... 32 
9.1.1.3 
Toxicology ................................................................................... 33 
9.1.2 
Clinical Experience...................................................................................... 34 
9.1.2.1 
SAD study .................................................................................... 35 
9.1.2.2 
MAD Study .................................................................................. 36 
10. RATIONALE ...................................................................................................................... 38 
10.1 Purpose of the Study ............................................................................................... 38 
10.2 Dose Selection ........................................................................................................ 38 
11. RISK/BENEFIT .................................................................................................................. 40 
12. STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 41 
12.1 Study Objectives ..................................................................................................... 41 
12.2 Study Endpoints ...................................................................................................... 41 
13. INVESTIGATIONAL PLAN ................................................................................................ 43 
13.1 Overall Study Design and Plan ................................................................................ 43 
13.2 Study Conduct ......................................................................................................... 44 
13.2.1 Screening ................................................................................................... 44 
13.2.2 Patient Confinement .................................................................................... 44 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ....................................................... 44 
13.2.4 Treatment Period (Days 1 to 56) ................................................................. 45 
13.2.4.1 Meal Schedule ............................................................................. 45 
13.2.4.2 End-of-Treatment or Early Termination (Day 56) .......................... 46 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................ 46 
13.2.6 Scheduled End of Study .............................................................................. 46 
13.3 Selection of Study Population .................................................................................. 46 
13.3.1 Number of Patients ..................................................................................... 46 
13.3.2 Inclusion Criteria ......................................................................................... 47 
13.3.3 Exclusion Criteria ........................................................................................ 48 
13.3.4 Removal of Patients from the Study ............................................................ 50 
13.3.5 Study Restrictions ....................................................................................... 51 
13.3.5.1 Concomitant Therapy ................................................................... 51 
13.3.5.1.1 
Prohibited Therapy ................................................... 51 
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13.3.5.1.2 
Permitted Therapy ................................................... 52 
13.3.5.2 Prohibitions .................................................................................. 52 
13.3.5.3 Activity ......................................................................................... 52 
13.4 Treatments .............................................................................................................. 53 
13.4.1 Treatments administered ............................................................................. 53 
13.4.1.1 Drug Administration During Run-in Period .................................... 53 
13.4.1.2 Drug Administration During Treatment Period............................... 53 
13.4.1.3 Stopping Rules ............................................................................ 54 
13.4.2 Method of Assigning Patients to Treatment Groups ..................................... 54 
13.4.3 Blinding ....................................................................................................... 55 
13.4.3.1 Maintenance of Randomization .................................................... 55 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 55 
13.4.3.3 Revealing of Randomization ......................................................... 55 
13.4.4 Treatment Compliance ................................................................................ 56 
14. STUDY PROCEDURES .................................................................................................... 57 
14.1 Safety Assessments ................................................................................................ 57 
14.1.1 Body Height and Weight .............................................................................. 57 
14.1.2 Physical Examination .................................................................................. 57 
14.1.3 Vital Signs ................................................................................................... 57 
14.1.4 Pulse Oximetry............................................................................................ 58 
14.1.5 Electrocardiogram Monitoring ...................................................................... 58 
14.1.6 Clinical Laboratory Tests ............................................................................. 58 
14.1.6.1 Hematology.................................................................................. 59 
14.1.6.2 Serum Chemistry ......................................................................... 59 
14.1.6.3 Serology ...................................................................................... 59 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............ 59 
14.1.6.5 Follicle-Stimulating Hormone ........................................................ 59 
14.1.6.6 Urinalysis ..................................................................................... 60 
14.1.6.7 Urine Drug/Alcohol Screen ........................................................... 60 
14.1.7 Chest X-Ray ............................................................................................... 60 
14.1.8 Adverse Events ........................................................................................... 60 
14.1.8.1 Adverse Event Definition .............................................................. 60 
14.1.8.2 Monitoring .................................................................................... 60 
14.1.8.3 Reporting ..................................................................................... 61 
14.1.8.4 Serious Adverse Events ............................................................... 62 
14.2 Symptom Assessments ........................................................................................... 63 
14.2.1 Electronic Diary ........................................................................................... 63 
14.2.2 Peak Expiratory Flow .................................................................................. 63 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ........... 63 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) .................................................... 63 
14.2.5 Activity (Duke Activity Status Index) ............................................................ 63 
14.3 Pharmacodynamic Assessments ............................................................................. 64 
14.3.1 Pulmonary Function (Spirometry) ................................................................ 64 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers.................... 65 
14.3.2.1 Bronchoscopy .............................................................................. 65 
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14.3.2.2 Bronchial Brushings ..................................................................... 65 
14.3.2.3 Bronchoalveolar Lavage (BAL) ..................................................... 66 
14.3.2.4 Biomarkers .................................................................................. 66 
14.3.3 Blood Biomarkers ........................................................................................ 66 
14.3.4 Quality of Life Questionnaires ..................................................................... 66 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ..................................................................................... 66 
14.3.4.2 COPD Assessment Test (CAT) .................................................... 67 
14.4 Pharmacokinetic Assessments ................................................................................ 67 
14.4.1 Blood Sampling and Processing .................................................................. 67 
14.5 Blood Volume for Study Assessments ..................................................................... 68 
15. DATA ANALYSIS .............................................................................................................. 69 
15.1 Statistical Analysis ................................................................................................... 69 
15.1.1 Sample Size Calculation ............................................................................. 69 
15.1.2 Patients to Analyze ..................................................................................... 69 
15.1.3 Safety Analysis ........................................................................................... 70 
15.1.4 Symptom Monitoring Analysis ..................................................................... 71 
15.1.5 Pharmacodynamic Analysis ........................................................................ 71 
15.1.5.1 Biomarkers .................................................................................. 71 
15.1.5.2 Quality of Life ............................................................................... 71 
15.1.6 Pharmacokinetic Analysis ........................................................................... 72 
15.1.6.1 Pharmacokinetic Parameters ....................................................... 72 
15.1.6.1.1 
Plasma .................................................................... 72 
15.1.6.1.2 
Bronchoalveolar Lavage ........................................... 73 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ........................ 74 
15.1.7 Assessment of Efficacy ............................................................................... 74 
16. STUDY ADMINISTRATION ............................................................................................... 75 
16.1 Ethics ...................................................................................................................... 75 
16.1.1 Institutional Review Board ........................................................................... 75 
16.1.2 Ethical Conduct of the Study ....................................................................... 75 
16.1.3 Patient Information and Consent ................................................................. 75 
16.2 Termination of the Study .......................................................................................... 75 
16.3 Data Quality Assurance ........................................................................................... 75 
16.4 Direct Access to Source Data/Documents ................................................................ 76 
16.5 Drug Supplies, Packaging and Labeling ................................................................... 76 
16.6 Data Handling and Record Keeping ......................................................................... 76 
16.7 Protocol Amendments ............................................................................................. 76 
16.8 Finance and Insurance ............................................................................................ 77 
16.9 Publication Policy .................................................................................................... 77 
17. REFERENCES .................................................................................................................. 78 
18. APPENDIXES ................................................................................................................... 79 
18.1 Appendix 1 - UGT Drug Interaction Table ................................................................ 79 
18.2 Appendix 2 - SULT Drug Interaction Table ............................................................... 80 
 
 
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8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Bronchoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
Coag 
Coagulation 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
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CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
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IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimetre of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
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ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
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US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
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9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
Good Clinical Practice (GCP), and applicable regulatory requirements. The patient 
population will be comprised of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of March 1, 2013. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Bronchoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
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CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
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were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
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values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
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9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 
0.67 hours under fasting conditions. Verproside appeared to be cleared rapidly from 
plasma, with mean t1/2 values under 1 hour; plasma verproside concentrations were 
below the lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 
below summaries the PK parameters of verproside following single-dose administrations 
of YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
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9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t1/2 values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t1/2 values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
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Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax_ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax_ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
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10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as asthma and COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such as asthma and COPD to 
demonstrate safety and evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
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Table 4: Traditional Chinese Medicine Use Versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
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11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an indwelling cannula is utilized (as a last resort solution when venipuncture 
becomes difficult for a patient) and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
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12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., sputum quality, color, consistency) and minor (e.g., cough, wheeze, 
sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation;  
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• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and 
eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
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13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
Sixty-nine (69) patients will be enrolled and randomized into 3 treatment groups 
(23 patients per group) to ensure completing the study with 60 patients. Patients will 
participate only once. An approximately equal number of current and ex-smokers will be 
enrolled in the study. 
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU on the morning of Day -1 of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Day -1 scheduled 
study procedures. Patients will return to the CRU the next day (Day 1) to be randomized 
and receive one of the 3 treatments and undergo all scheduled study procedures. 
Patients will return on the morning of Days 15, 29, 43, 55, and 56 of the Treatment 
Period for study drug administration and procedures. Prior to each release from the 
CRU, patients will receive a properly labeled container with sufficient doses which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients 
will continue recording their daily symptoms via the e-diary throughout the Treatment 
Period. Patients will return the e-diary device on Day 56 to CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
will be discontinued. Rescue medication will be used for any patient with an 
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exacerbation of COPD and will be administered in accordance with the study center 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses, concomitant medications use, and their daily respiratory 
symptoms. Prior to each morning dose, patients will record at home their daily PEF, 
major (e.g., sputum quality, color, consistency) and minor (e.g., cough, wheeze, sore 
throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of 
COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
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13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 56 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses, concomitant 
medications use, and their daily respiratory symptoms on their e-diary. Prior to each 
morning dose, patients will record at home their daily PEF, major (e.g., sputum quality, 
color, consistency) and minor (e.g., cough, wheeze, sore throat, nasal congestion, 
discharge, and body temperature above 100°F) symptoms of COPD exacerbation, 
dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before bronchoscopy and 
BAL collection on Days -1 and 55. On Days 1 and 56, patients will be required to fast 
overnight for at least 8 hours before and for at least 4 hours after the morning dose. On 
all other days, patients will be asked to fast for at least 2 hours before and 2 hours after 
each morning dose. Patients will also be asked to fast for at least 2 hours before and 
after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 56, patients will fast from all food and drink except water between meals 
and snacks. Foods and beverages containing alcohol, xanthines, caffeine, vegetables 
from the mustard green family, mustard, tea (especially speedwell tea), or 
grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, menus should 
be similar in content. The same menu and meal (except for snacks) schedule will be 
administered uniformly for all patients confined within the same CRU, across all 
treatment groups. Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs. 
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13.2.4.2 End-of-Treatment or Early Termination (Day 56) 
End-of-treatment evaluation will be performed on all patients before leaving the CRU or 
prior to early termination. 
The end-of-treatment procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll 69 patients to ensure completion of 60 patients. An 
approximately equal number of current and ex-smokers will be enrolled. Patients will be 
divided in 3 treatment groups with 23 patients to receive one of the 3 treatments 
(i.e., low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo control) as 
per the randomization schedule. Each treatment group will consist of an approximately 
equal number of current and ex-smokers. 
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IND No. 114903 
 
 
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13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 40 to 80 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-32.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24h prior 
to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled CRU 
visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack years. Ten pack years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Patients, who undergo smoking cessation therapy, must be completed 
3 months prior to screening visit and smoking status should not change between the 
patient’s screening visit and patient’s last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
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c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method 
(e.g., condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
13. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
14. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the end-of-treatment evaluations. Patients will be advised to use a 
condom with spermicide for 90 days following the last administration of the study 
drug, and to not donate sperm during this same period of time. In the event that the 
sexual partner is surgically sterile, use of a condom with spermicide is not necessary. 
No restrictions are required for vasectomized males provided their vasectomy has 
been performed 120 days or more prior to study start. Males who have been 
vasectomized less than 120 days prior to study start must follow the same 
restrictions as non-vasectomized males. 
15. Understands study procedures and provides written informed consent for the trial. 
16. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
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6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), 
sleep 
apnea, 
cardiovascular, 
endocrine, 
neurological, 
hepatic, 
gastrointestinal, renal, hematological, urological, immunological or ophthalmic 
diseases that the Investigator believes are clinically significant e.g., unstable and 
could impact patient safety by participation in the study. 
9. History or presence of: 
• 
significant cardiac arrhythmia; 
• 
prostatic hyperplasia; 
• 
bladder-neck obstruction; 
• 
urinary retention; 
• 
narrow-angle glaucoma. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Evidence of hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive urine drug/alcohol testing at screening or at each CRU visit. 
14. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies (HCV). 
15. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
16. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
17. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
18. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) and/or sulfotransferases (SULT), 
within 12 hours prior to Day 1 of the Run-in Period (refer to Appendix 1 and 
Appendix 2). 
19. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
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20. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
21. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
22. Females who are pregnant or lactating.  
23. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
24. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion 
(end-of-treatment evaluations) as the situation allows (see Section 13.2.5). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
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13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the end-of-treatment 
procedures). Intake of these medications during the Run-in Period constitutes a 
non-eligibility criterion and the patients will not be randomized into the study. If any of 
these medications are taken during the Treatment Period, the need for this patient to be 
withdrawn from the study will be carefully evaluated by the Investigator and the Sponsor 
on the basis of the potential impact on efficacy or safety evaluation and in the patient's 
best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements and herbal products (especially Speedwell) will be prohibited 
7 days prior Day 1 of the Treatment Period and through collection of the final PK 
sample. 
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13.3.5.1.2 Permitted Therapy 
Throughout the study Period (from Day 1 of the Run-in Period to the completion of the 
end-of-treatment procedures) patients will be permitted to take the following medications 
in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 
24 hours before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine:  24 hours prior to each CRU visit and prior to dosing on Days 1 
and 56 of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Alcohol:  48 hours prior to each CRU visit, 48 hours prior to dosing on Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 56 last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 56 of 
the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Tea (especially Speedwell tea), Coffee and Red Wine:  7 days prior to Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 56 last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
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13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. Only the 
morning dose will be administered on Day 56. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be administered on 
Day 56. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose will be 
administered on Day 56. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for 
each patient, as per the randomization scheme. 
Prior to release from the CRU on Days 1, 15, 29, 43, and 55 of the Treatment Period, 
patients will receive a properly labeled container with the appropriate doses which will be 
self-administered by patients at home. Patients will record their self-administered doses 
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in their e-diary, and whether the dose was administered with food, and must return the 
container (empty or not) at the next morning visit. Home dosing will be monitored via 
attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence 
of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
given instructions on recording of dosing times in their e-diary on home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique identification number upon screening. Patients 
who complete the study screening assessments, complete the Run-in Period, and meet 
all the eligibility criteria will receive the corresponding product, according to a 
randomization scheme generated at Celerion. Each treatment group will consist of an 
approximately equal number of current and ex-smokers. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
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If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
The randomization is available only to the clinic pharmacy staff preparing the drug who 
are not involved in any other aspect of the study including administration of the drug. It 
will not be made available to the Sponsor, patients, or members of the staff responsible 
for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
One set of the sealed envelopes containing the randomization code will be available to 
the Investigator at the start of the trial 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the study monitor or designee prior to breaking the blind. If breaking the 
blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
All data are entered in the database, edits checks are performed, queries closed, 
CRFs signed by the Investigator, and the database is officially locked. 
All PK/PD samples have been analyzed and quality checked by the responsible 
analytical associate. 
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13.4.4 Treatment Compliance  
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
Self-administration by patients at home will be monitored by the CRU via the e-diary and 
attempted phone calls will be performed to remind patients to take their medication, if 
they did not record their self-administration on the e-diary. 
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14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
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When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When scheduled postdose, vital signs readings 
will be performed within approximately 10 minutes of the scheduled time point. When 
performing the bronchoscopy, vital signs (body temperature, respiratory rate, blood 
pressure, and heart rate) will be monitored continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen levels, saturation [%], and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen levels, saturation [%], and 
heart rate) as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. Readings may be taken at other times, if deemed 
necessary by the Investigator. When performing the bronchoscopy, oxygen saturation 
will be monitored continuously until the end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performing the bronchoscopy, ECG will be monitored continuously until 
the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
5 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
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14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count (including a 
reticulocytes count) 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, and 
monocytes) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
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14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine Drug/Alcohol Screen 
• 
Cannabinoids  
• 
Alcohol 
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Adverse Events 
14.1.8.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.3 
14.1.8.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, at the end-of treatment 
(or upon early withdrawal), and at the follow-up phone call. The inquiry will be made in a 
non-specific manner using open-ended questions so as not to bias the response 
(e.g., How have you been feeling since your last visit?). 
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All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.8.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 4 and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
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The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
14.1.8.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Sponsor via fax or e-mail within one working day of becoming 
aware of the event, whether or not the serious events are deemed drug-related. All 
serious event reporting will adhere to 21 CFR 312.32 for Investigational New Drugs 
(IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20123. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
If an SAE occurs to a patient on this study, the Sponsor’s Medical Expert is to be 
contacted (see Section 3). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
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does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; 
or is not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses and whether the dose was 
administered with food, concomitant medications and daily respiratory symptoms 
throughout the Run-in and Treatment Periods. Patients will return the e-diary device on 
Day 56 to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum 
quality, color, consistency) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., sputum quality, color, consistency) and 
minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body 
temperature above 100°F) symptoms of COPD exacerbation via the e-diary before each 
dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
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based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) 
and 
long 
acting 
β2-agonist 
and 
anticholinergic 
bronchodilators 
(e.g., salmeterol, tiotropium) agents will be withheld approximately 4 and 12 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study and all sites should be using the same brand and model 
of spirometer for this study. 
At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol, (100 μg/inhalation), for a total dose of 
400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes 
after albuterol administration, the baseline post-bronchodilator spirometry will be 
performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Day -1 measurement): Predose 
FEV1 is defined as the time-point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
FEV1 measurement at predose on Day -1 of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose on Day -1, up to 3 measures will be 
performed.  
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Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be asked to refrain from smoking approximately 48 hours before the 
bronchoscopy procedures and will be fasted for 12 hours before. If required, blood 
pressure medications can be taken with small sip of water based on preapproval of local 
Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.5,6 
Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal canula will be administered 
during bronchoscopy and oxygen saturation will be maintained at ≥95%. Conscious 
sedation will be achieved with incremental doses of 1–4 mg midazolam and 50-100 μg 
fentanyl. Local upper and lower airway topical anesthesia will be achieved with 1% or 
2% lidocaine. The dose of lidocaine administered during the procedure will not exceed a 
total of 450 mg. The bronchoscope will usually be inserted preferably through the nares 
into trachea. The bronchoscope will be wedged into 2 subsegments of the right middle or 
lower lobe, as deemed appropriate by the Investigator. Emergency treatments for 
cardiopulmonary arrest and pneumothorax will be immediately available in the 
bronchoscopy room. The patient will remain in the recovery suite for observation for a 
minimum of 2 hours after the procedure.  
14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
Samples must be protected from UV light during collection, processing, and storage.  
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14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A 180 mL BAL will be 
performed in each subsegment of the right middle or lower lobe, as deemed appropriate 
by the Investigator, using 6 x 30 mL aliquots of normal saline warmed to room 
temperature. BAL fluid will be aspirated following each 30 mL instillation. The lavage 
material, which averages 25% return in COPD patients, typically yields 1-10 x 106 
macrophages. The centrifuged cell pellet and supernatant will be kept cooled until 
processed or stored as indicated in the laboratory manual to be provided as a separate 
document. 
Samples must be protected from UV light during collection, processing, and storage.  
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, and eosinophils 
as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture at the time points delineated in 
the Study Events Flow Chart (Section 6) for PD assessments of biomarkers. Biomarker 
assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, monocytes, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 4.5 mL pre-chilled evacuated tubes containing K2EDTA and 
stored in an ice bath until processing. 
14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Day 1 of the Treatment Period) will be assessed with the BDI. This 
instrument has 3 domains (functional impairment, magnitude of task and magnitude of 
effort) with the values added for a combined focal score. Functional impairment 
determines the impact of breathlessness on the ability to carry out activities; magnitude 
of task determines the type of task that causes breathlessness, magnitude of effort 
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establishes the level of effort that results in breathlessness. The BDI scores range from 
0 (very severe impairment) to 4 (no impairment) for each domain with the baseline focal 
score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.7,8 
A copy of the questionnaire to be used will be kept in the study binder. 
14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture at the time points delineated in the 
Study Events Flow Chart (Section 6).  
Blood will be drawn into 5 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
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14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests (including 
hematology, serum chemistry, serology), 
FSH (for postmenopausal female patients 
only) and serum pregnancy (for female 
patients only). 
1 
~ 17 mL 
~ 17 mL 
On-study serum chemistry and serum 
pregnancy (for female patients only) when 
scheduled at the same time 
4 
~ 8.5 mL 
~ 34 mL 
Additional on-study serum pregnancy (for 
female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
4 
~ 4 mL 
~ 16 mL 
Blood samples for PD biomarkers 
8 
~ 4.5 mL 
~ 36 mL 
Blood samples for PK of verproside and 
picroside II 
37 
~ 5 mL 
~ 185 mL 
Total Blood Volume for males → 
~ 288 mL 
Total Blood Volume for females → 
~ 295 mL 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. An additional 9 patients will be enrolled to account for a 15% 
drop-out rate. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma concentration of verproside and 
picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Days 1 and/or 56. 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 post-
baseline PD measurement. 
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• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
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15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline, will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes, 
neutrophils, and eosinophils as a percentage of total cells; total cell count [cells/mL] 
of neutrophils, macrophages, lymphocytes and eosinophils as absolute inflammatory 
cell numbers; and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9): raw and % change from baseline levels; 
and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and lymphocytes] 
and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
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15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
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The following PK parameters will be computed following Day 56 morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss: 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc: 
Percent fluctuation will be calculated as follows: 
𝐶𝐶max _𝑠𝑠𝑠𝑠−𝐶𝐶min _𝑠𝑠𝑠𝑠
𝐶𝐶𝑎𝑎𝑎𝑎𝑎𝑎
 𝑥𝑥 100 
Swing: 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
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15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15, 29, 43, and 56 following multiple oral dose administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
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16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP (E6 
Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges, etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
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check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets,  and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 5 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
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16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
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17. REFERENCES 
 
                                               
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
4 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
5 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
6 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
7 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
8 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
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18. APPENDIXES 
18.1 
Appendix 1 - UGT Drug Interaction Table 
The following list provides medications that are substrates or inhibitors of UGT. Adapted 
from Williams JA, et al. Drug-drug interactions for UDP-glucuronosyltransferase 
substrates:  a pharmacokinetic explanation for typically observed low exposure 
(AUCi/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201-8. Epub 2004 Aug 10. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Amitriptyline 
Carvedilol 
Clofibric acid 
Codeine 
Cyclobenzaprine 
Diclofenac 
DMXAA 
Fenofibrate 
Flavopiridol 
Furosemide 
Gemfibrozil 
Glipizide 
Irbesartan 
Lamotrigine 
Levothyroxine 
Metoclopramide 
Metronidazole 
Morphine 
Naloxone 
Naproxen 
Olanzapine 
Oxazepam 
Paracetamol 
Propofol 
Raloxifene 
Tramadol 
Valdecoxib 
Valproic acid 
Zidovudine 
17-beta-estradiol glucuronide 
Flavonoids (citrus fruit) 
Silybin (herb supplement milk thistle) 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
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18.2 Appendix 2 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Acetaminophen 
 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
612


 
 
 
 
Celerion Project No.: AA98497 
 
Sponsor Project No.: YPL-001-YJP-130403 
 
IND No.:  114903 
 
 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to 
Assess Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker 
Variations after Administration of either YPL-001, or Placebo in Patients with 
Moderate-to-Severe Chronic Obstructive Pulmonary Disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GCP Statement 
This study is to be performed in full compliance with the protocol, Good Clinical Practices (GCP), 
and applicable regulatory requirements. All required study documentation will be archived as 
required by regulatory authorities. 
Confidentiality Statement 
This document is confidential. It contains proprietary information of Yungjin Pharm, CO., LTD. 
Any viewing or disclosure of such information that is not authorized in writing by Yungjin Pharm, 
CO., LTD. is strictly prohibited. Such information may be used solely for the purpose of reviewing 
or performing this study. 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
1. 
PROTOCOL REVISION HISTORY 
DATE/NAME 
DESCRIPTION 
18-Sep-2014 
by Caroline Engel 
Final Protocol  
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
4. ADDITIONAL KEY CONTACTS FOR THE STUDY 
Sponsor Contact for Serious Adverse 
Events 
Primary Contact: 
 
Yongnam Lee, Ph.D. 
Principal Scientist,  
Yungjin Pharm. CO., LTD. 
#451-20 Cheonho-3 dong, Gangdong-gu, 
Seoul, 134-721, Republic of Korea   
Tel.: +82-(31) 546-6980 ext. 220 
Fax: +82-(31) 546-6983 
E-mail: nami0209@yungjin.co.kr 
Mobile: +82-(10) 6311-4228 
 
Secondary Contact: 
 
Kangrae Ha, B.Sc. 
E-mail: hakr@yungjin.co.kr  
 
 
Celerion Protocol Author 
Caroline Engel, B.Sc. 
Senior Scientist 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec, H4M 2N8 
Canada 
Tel.: +1 514 744-8738 
Fax: +1 514 744-8700 
E-mail: caroline.engel@celerion.com 
 
Certified Clinical Laboratory 
Yuri Persidsky, MD, Ph.D. 
Chairperson, Department of Pathology and 
Laboratory Medicine 
Professor, 
Pathology 
and 
Laboratory 
Medicine 
3401 N. Broad Street 
Philadelphia, Pennsylvania, 19140 
United States  
E-mail: Yuri.Persidsky@tuhs.temple.edu 
 
Bioanalytical Laboratory 
Celerion 
621 Rose Street  
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-0428 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
 
Pharmacokinetic and Statistical 
Analyses 
Celerion 
100 Alexis-Nihon Boulevard 
Suite 360 
Montreal, Quebec  H4M 2N8 
Canada 
Tel.: +1 514 744-9090 
Fax: +1 514 744-8700 
 
AND/OR 
 
Celerion  
621 Rose Street 
Lincoln, Nebraska  68502 
United States  
Tel.: +1 402 476-2811 
Fax: +1 402 476-7598 
 
Institutional Review Boards Main Office 
Location 
For Temple University School of Medicine: 
Student Faculty Center - Suite 304 
3340 North Broad Street 
Philadelphia, Pennsylvania, 19140 
United States 
Tel.: +1 215 707-3390 
Fax: +1 215 707-9100 
 
Brigham and Women's Hospital:  
Partners Human Reseach Committee 
116 Huntington Avenue, 10th Floor 
Boston, Massachusetts, 02116 
United States 
Tel.: +1 617 424-4100  
Fax: +1 617 424-4199 
 
UAB Lung Health Center: 
Western Institutional Review Board 
1019 39th Avenue SE, Suite 120 
Puyallup, Washington, 98374-2115 
United States 
Tel.: +1 360 252-2500 
 
  
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
5. SYNOPSIS 
Compound: 
YPL-001 
Clinical Indication: 
Treatment of inflammatory diseases of the respiratory tract such as asthma 
and chronic obstructive pulmonary disease (COPD) 
Study Type 
Phase 2a, proof of concept 
Study Objectives 
The primary objective of the study is to assess the safety and tolerability of 
two multiple oral YPL-001 dose levels versus placebo in moderate to severe 
COPD patients. 
The secondary objective of the study is to assess the number and 
magnitude of daily respiratory symptoms of two multiple oral YPL-001 dose 
levels versus placebo in moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in 
moderate to severe COPD patients: 
1. 
To assess bronchoalveolar lavage (BAL) epithelial brushings for 
YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes and eosinophils as a percentage of total cells; neutrophil, 
macrophage, 
lymphocyte 
and 
eosinophil 
counts 
as 
absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for tumor necrosis factors alpha (TNF-α), 
interleukin (IL)-1β, IL-4, IL-5, IL-6, IL-8, IL-13, myeloperoxidase (MPO), 
neutrophil elastase, monocyte chemotactic protein (MCP)-1, and matrix 
metalloproteinase (MMP)-9 in YPL-001 groups versus placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell 
counts as absolute and percentage for neutrophils, macrophages, 
eosinophils and lymphocytes) and concentrations of C-reactive protein 
(CRP), fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and 
MMP-9 in YPL-001 groups versus placebo group. 
5. 
To compare spirometric functions (forced expiratory volume in one 
second [FEV1], forced vital capacity [FVC], FEV1/FVC, and inspiratory 
capacity [IC]) in YPL-001 groups versus placebo group. 
6. 
To compare patient reported outcomes (Baseline Dyspnea Index 
[BDI]/Transition Dyspnea Index [TDI], COPD Assessment Test [CAT]) 
in YPL-001 groups versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL 
and verproside and picroside II pharmacokinetics (PK) in plasma 
following multiple oral doses administration of two YPL-001 dose levels. 
 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Summary of Study 
Design 
 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 
doses (80 mg and 160 mg twice daily [BID]) and a placebo control in 
moderate to severe COPD patients.  
Sixty-nine (69) patients will be enrolled and randomized into 3 treatment 
groups (23 patients per group). Patients will participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of 
respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of peak 
expiratory flow (PEF), major and minor symptoms of COPD exacerbation, 
dyspnea, and activity in their electronic diary (e-diary). Spirometry 
measurement, bronchoalveolar lavage (BAL), and blood samples will be 
collected for the pharmacodynamic (PD) assessment of YPL-001 and 
placebo treatments. Serial blood samples will also be collected for PK 
assessment of verproside (the principal active ingredient of YPL-001) and 
picroside II. Other components of YPL-001 and its metabolites may also be 
analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted 
respiratory drugs if already receiving them and enter a 14 ± 2 days Run-in 
Period during which patients will be given albuterol taken on an as required 
basis and daily tiotropium 18 μg (one capsule inhaled daily in the morning) to 
be administered at home. On Day 1 of the Run-in Period, each patient will be 
issued and trained on the use of the e-diary. They will record their daily 
symptoms throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) on the morning of 
Day -1 of the Treatment Period to confirm their eligibility and assess their 
health conditions. If they still meet all of the inclusion criteria and none of the 
exclusion criteria, they will undergo Day -1 scheduled study procedures. 
Patients will return to the CRU the next day (Day 1) to be randomized and 
receive one of the 3 treatments and undergo all scheduled study 
procedures. Patients will return on the morning of Days 15, 29, 43, 55, and 
56 of the Treatment Period for study drug administration and procedures. 
Prior to each release from the CRU, patients will receive a properly labeled 
container with sufficient doses which will be self-administered by patients at 
home until the next morning visit at the CRU. Patients will continue recording 
their daily symptoms via the e-diary throughout the Treatment Period. 
Patients will return the e-diary device on Day 56 to CRU staff. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days (± 2 days) after the last study drug administration to 
determine if any adverse event (AE) has occurred since the last dose of 
study drug. Patients who terminate the study early will be contacted or asked 
to return to the CRU for monitoring if the Investigator deems necessary.  
Patients will be instructed to call the Investigator if breathing worsens or if 
they need to take more than 8 puffs per day of albuterol for more than 
2 consecutive days. If the Investigator determines that the patient is too 
unstable to continue in the study, he/she will be discontinued. Rescue 
medication will be used for any patient with an exacerbation of COPD and 
will be administered in accordance with the study center standard of care. 
 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Study Population 
Patients will be adult males and females with moderate to severe COPD 
(conform to the severity classification for Global Initiative for Chronic 
Obstructive Lung Disease [GOLD] Stage 2-3) with a predominant bronchitic 
component and a history of frequent (>2/year) COPD exacerbations, 
between 40 and 80 years of age (inclusive). 
Number of 
Patients 
The study is planned to enroll 69 patients to ensure completing the study 
with 60 patients. Patients will be divided in 3 treatment groups with 
23 patients to receive one of the 3 treatments (i.e., low and high YPL-001 
doses [80 mg and 160 mg BID] and a placebo control) as per the 
randomization schedule.  
Duration of 
Participation for 
Patients 
The planned length of participation in the study for each patient is 
approximately 10 weeks (from Day 1 of the Run-in Period through 
completion of the follow-up clinical procedures on Day 70 [± 2 day]). 
Duration of Study 
Conduct 
The study is planned to take place over approximately 12 to 24 months (from 
screening of the first patient through completion of all study procedures for 
the last patient). 
This time period may change in the event that the study is terminated early, 
additional time is required to review safety, or a decision is made to 
complete an unscheduled analysis for a group. 
Study Products 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
An unblinded pharmacist will be responsible for providing YPL-001 or 
placebo to the blinded study personnel for administration. 
Dosage, Dosage 
Form, Route, and 
Dose Regimen 
 
Treatments are described as follows: 
Treatment A: 
Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 
80 
mg matching 
placebo 
tablet) 
will 
be 
administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment B: 
Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will 
be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose 
will be administered on Day 56. 
Treatment C: 
Multiple oral matching placebo (2 x  1 YPL-001 80 mg 
matching 
placebo 
tablets) 
will 
be 
administered 
approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be 
administered on Day 56. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will 
also be administered QD every morning prior to study drugs administration. 
Albuterol will be administered on an as needed basis. 
Each dose of Treatments A, B and C will be administered orally with 
approximately 240 mL of water. 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor 
and the Investigator following the review of all pertinent safety and 
tolerability. Together they will make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at 
any dose level meets any of the following criteria and the patient was 
determined to have received YPL-001 after unblinding: 
a. Has a drug–related, unexpected serious adverse event (SAE).  
b. Experiences drug-related grade ≥ 3 toxicity.  
4. The study will be terminated if ≥ 3 patients at any dose level meet any of 
the following criteria and the patients were determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
Primary Outcome 
Measures 
Safety and tolerability will be monitored through physical examinations, vital 
signs, pulse oximetry, ECGs, clinical laboratory tests, and AEs. 
Safety and 
Tolerability 
Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The following analyses will be performed. Safety analyses will be based on 
treatment actually received by patients. Descriptive statistics will be 
calculated for quantitative safety data and frequency counts will be compiled 
for classification of qualitative safety data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current Medical Dictionary for Regulatory 
Activities (MedDRA®) available at Celerion (e.g., 17.0 or higher) and data will 
be summarized by System organ class (SOC) and preferred term. The 
number of treatment-emergent AEs (TEAEs) will be reported. In addition, the 
number and percent of patients reporting each TEAE will be summarized 
separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, 
treatment, severity, outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final 
report and significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs, and Pulse 
Oximetry Measurements: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry 
measurements and their change from baseline, if applicable, will be 
summarized by treatment and time point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical 
laboratory results.  
A normal-abnormal shift table will be presented for ECGs. 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Safety and 
Tolerability 
Analysis 
(continued) 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most 
current World Health Organization (WHO) drug dictionary available at 
Celerion (e.g., 01-MAR-2014 or later). 
Secondary 
Outcome 
Measures 
PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature 
above 100°F) symptoms of COPD exacerbation, dyspnea (Modified Borg 
Dyspnea Scale), and activity (Duke Activity Status Index [DASI]) self-
reported daily by the patients using an e-diary. 
Symptom 
Monitoring 
Analysis 
Symptom free days and overall symptom burden will be evaluated and 
compared across treatment groups. Secondary outcome analysis will be 
based on treatment actually received by patients. Descriptive statistics will 
be calculated for quantitative data and frequency counts will be compiled for 
classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change 
from baseline, will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Exploratory 
Outcome 
Measures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study for PD assessments of biomarkers. Biomarker assessments include: 
1. epithelial brushings for YPL-001 component levels; 
2. total cell count (cells/mL) of macrophages, lymphocytes, and 
eosinophils as a percentage of total cells 
3. total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
4. concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
Blood Assessments: 
Blood samples will be collected at screening, throughout the study, and at 
the follow-up visit (Day 70 [± 2 days]), for PD assessments of biomarkers. 
Biomarker assessments include: 
1. inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, macrophages, eosinophils and 
lymphocytes)  
2. concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Exploratory 
Outcome 
Measures 
(continued) 
Pulmonary Assessment: 
Pulmonary function measurements (spirometry [FEV1, FVC, FEV1/FVC, and 
IC) will be performed at screening, throughout the study and at the follow-up 
visit (Day 70 [± 2 days]). 
Quality of Life Assessments: 
Patient reported outcomes (e-diary, BDI/TDI, CAT) will be performed at 
baseline, throughout the study and at the follow-up visit (Day 70 [± 2 days]). 
Pharmacokinetic Assessments: 
Bronchoalveolar Lavage Assessments: 
BAL samples will be collected at baseline and again at the completion of the 
study to determine verproside and picroside II concentrations in BAL. Other 
components of YPL-001 and its metabolites may also be analyzed. 
Plasma Assessments: 
Serial blood samples will be collected prior to the initial dosing and through 
12 hours following dosing on Days 1 and 56 to determine verproside and 
picroside II concentrations in plasma. Predose samples will also be collected 
in the morning of Days 15, 29, 43 and 56 for Ctrough determination. Other 
components of YPL-001 and its metabolites may also be analyzed. 
The sampling schedule and/or collection intervals may be modified based on 
the results as the study progress. 
Pharmacodynamic 
Analysis 
Blood, Plasma, and Pulmonary biomarkers: 
When applicable, the raw data and % change from baseline or placebo, as 
appropriate, for PD markers (BAL biomarkers, blood biomarkers, and 
pulmonary biomarker) will be summarized by time point and treatment using 
descriptive 
statistics 
(arithmetic 
means, 
standard 
deviations 
[SD], 
coefficients of variation [CV], sample size [N], minimum, maximum, and 
median). Figures will be created to display mean and individual level or 
activity as a function of time. 
Quality of Life:  
The quality of life parameters will be listed and presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
Pharmacokinetic 
Parameters and 
Analysis 
Noncompartmental PK parameters, including AUC0-t, AUC0-inf, AUCτ, kel, 
Cmax, Cmax_ss, Cmin_ss, Ctrough, tmax, tmax_ss, CL/F, CLss/F, Vz/F, Vz_ss/F, and t1/2, 
as appropriate, will be calculated from plasma concentrations of verproside 
and picroside II from patients who received YPL-001 only.  
Additional PK parameters may be calculated if deemed appropriate. Plasma 
PK parameters may also be calculated for other components of YPL-001 
and its metabolites. 
PK parameters will be summarized by treatment using descriptive statistics. 
Relative exposure of verproside and picroside II will be assessed between 
the two YPL-01 dose levels, and steady-state will be assessed by visual 
inspection in the active treatment groups. 
Verproside and picroside II concentration in BAL samples from patients who 
received YPL-001 only will be listed. 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
6. STUDY EVENTS FLOW CHART 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 
3.5 4 5 6 8 10 
12 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationc 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-raye 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signsg 
X 
 
 
Xf 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Pulse Oximetry 
X 
 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAh 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test (♀ only) 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum FSH (postmenopausal ♀ only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV/Hepatitis Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Monitoring 
 
X 
ConMeds Monitoring 
X 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Usei 
 
X 
PEF, COPD exacerbation, dyspnea 
and activityj 
 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration at CRUk 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)l 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Study Proceduresa 
Screenb 
Run-in 
Period 
Treatment Period 
Days → 
1 
2-14 
(±2)  
-1 
1 
Hours → 
 
 
 
Predose 
0 0.167 0.25 
0.5 
0.75 
1 1.5 2 2.5 3 
3.5 4 5 6 8 10 
12 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bronchoscopy and BAL Biomarkersm 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
X 
 
 
Xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X X X X X 
Xn 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitso 
X 
X 
 
X 
X 
Refer to the footnotes on the next page 
 
 
 
Page 15 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
a. For details on Procedures, refer to Section 14. 
b. Within 14 days of Day 1 (inclusive) of the Run-in Period. 
c. A full physical examination will be performed at screening. Symptom-driven physical examinations will be performed at other scheduled times, 
and may be performed at other times at the Investigator’s discretion. 
d. To be performed prior to the bronchoscopy procedures. 
e. To be performed at screening or within 3 months (inclusive) of screening. 
f. 
ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
g. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
h. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
i. 
Patients will be provided with an e-diary device to record their self-administered doses and whether the dose was administered with food, 
concomitant medications and daily respiratory symptoms.  
j. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
k. Prior to release from the CRU, patients will receive a properly labeled container with sufficient study drug for their assigned treatment which 
will be self-administered by patients at home until the next morning visit at the CRU. Patients must return the container (empty or not) at the 
next morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence of AEs. 
l. 
Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
m. Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
n. To be performed prior to dosing. 
o. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
Days → 2-14 
15 
16-28 
29 
30-42 
43 
44-54 
55 
Hours → 
 
AM PM 
 
AM PM 
 
AM 
PM 
 
AM 
PM 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationb 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Weight 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
12-Lead Electrocardiogram 
 
 
 
 
Xc 
 
 
 
 
 
Xe 
 
Vital Signsf 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xe 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
Xe 
 
Hem, Chem, and UAg 
 
 
 
 
Xc 
 
 
 
 
 
Xd 
 
Serum Pregnancy Test (♀ only) 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Urine Alcohol & Drug Screen 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Inquiries 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
AE Monitoring 
X 
ConMeds Monitoring 
X 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useh 
X 
PEF, COPD exacerbation, dyspnea 
and activityi 
X 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
Study Drug Administration at CRU 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Study Drug Administration at Homej 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
Pulmonary Function (Spirometry)k 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xd 
 
Bronchoscopy and BAL Biomarkersl 
 
 
 
 
 
 
 
 
 
 
Xc 
 
Blood Biomarkers 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
BDI/TDI & CAT 
 
Xd 
 
 
Xd 
 
 
Xd 
 
 
Xd 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside & Picroside II PK 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Visit & Return Visitsm 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
Refer to the footnotes on the next page 
 
 
Page 17 
AA98497_Final Prot_18Sep2014 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
a. For details on Procedures, refer to Section 14. 
b. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
c. To be performed or completed prior to dosing. 
d. To be performed or completed prior to bronchoscopy procedures and/or dosing. 
e. ECGs, vital sign and pulse oximetry will be measured within 2 hours of bronchoscopy procedures. During the bronchoscopy procedures and 
BAL sample collection, patients will be continuously monitored for ECGs, vital signs (blood pressure, heart rate, respiration rate, and body 
temperature), and oxygen saturation. 
f. 
Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
g. Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, patients 
may not have fasted for 8 hours before the serum chemistry sample is taken.  
h. Patients will be provided with an e-diary device to record their self-administered doses and whether the dose was administered with food, 
concomitant medications and daily respiratory symptoms.  
i. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
j. 
Prior to release from the CRU, patients will receive a properly labeled container with sufficient study drug for their assigned treatment which 
will be self-administered by patients at home until the next morning visit at the CRU. Patients must return the container (empty or not) at the 
next morning visit. Home dosing will be monitored via attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence of AEs. 
k. Pulmonary function will be performed prior to and 20 to 30 minutes after inhalation of approximately 400 μg albuterol. 
l. 
Bronchoscopy and BAL sample collection will be performed following a 12-hour fast. 
m. Patients will be admitted to the CRU at the time indicated by the CRU. 
 
 
 
Page 18 
AA98497_Final Prot_18Sep2014 
 
 
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630


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
STUDY EVENTS FLOW CHART (CONTINUED) 
Study Proceduresa 
Treatment Period  
EOT 
or 
ETb 
FUc 
Days → 
56 
Hours → Predose 0 
0.167 
0.25 0.5 
0.75 
1 
1.5 
2 
2.5 
3 
3.5 
4 
5 
6 
8 
10 
12 
Safety Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationd 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-Lead Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Vital Signse 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Pulse Oximetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hem, Chem, and UAf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serum Pregnancy Test (females only) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Alcohol & Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE Inquiries 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
AE Monitoring 
X 
X 
Concomitant Medication Monitoring 
X 
 
Symptoms Monitoring 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diary Useg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PEF, COPD exacerbation, dyspnea and 
activityh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tiotropium Administration 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacodynamic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Biomarkers 
Xi 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BDI/TDI & CAT 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Verproside Pharmacokinetics 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Other Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return Visitsj 
X 
X 
 
Refer to the footnotes on the next page 
 
 
 
Page 19 
AA98497_Final Prot_18Sep2014 
 
 
YPL-001-YJP-130403; AA98497; 16.1.1 Protocol and Protocol Amendments
631


Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
a. For details on Procedures, refer to Section 14. 
b. To be performed at the end of the Treatment Period on Day 56 or prior to early termination from the study. 
c. The CRU will attempt to contact patients using their standard procedures approximately 14 days (± 2 days) after the last study drug 
administration to determine if any AE has occurred since the last dose of study drug. Patients who terminate the study early will be contacted 
or asked to return to the CRU for monitoring if the Investigator deems necessary. 
d. Symptom-driven physical examinations will be performed at scheduled times, and may be performed at other times at the Investigator’s 
discretion. 
e. Vital signs include blood pressure, heart rate, respiration rate, and body temperature. 
f. 
Samples for serum chemistry will be obtained following a fast of approximately 8 hours, however, in case of dropouts or rechecks, Patients 
may not have fasted for 8 hours before the serum chemistry sample is taken. 
g. Patients will return the e-diary device on Day 56 to CRU staff.  
h. Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum quality, color, consistency) and minor (e.g., cough, 
wheeze, sore throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of COPD exacerbation, dyspnea (Modified 
Borg Dyspnea Scale), and activity (DASI). 
i. 
To be performed at predose on Day 56 or upon early termination. 
j. 
Patients will be admitted to the CRU at the time indicated by the CRU. 
 
Abbreviations:  ♀ = Female, AE = Adverse events, AM = Morning, BAL = bronchoalveolar lavage, BDI/TDI = Baseline Dyspnea Index/Transition 
Dyspnea Index Test, CAT = COPD Assessment Test, Chem = Serum chemistry, COPD = chronic obstructive pulmonary disease, CRU = Clinical 
research unit, ConMeds = Concomitant medication monitoring, DASI = Duke Activity Status Index, ECG = Electrocardiogram, e-diary = electronic 
diary, EOT/ET = End-of-Treatment or early termination, FSH = Follicle-stimulating hormone, Hem = Hematology, HIV = Human immunodeficiency 
virus, IL= interleukin, PEF = Peak expiratory flow, PK = Pharmacokinetics, PM = Evening, Preg = Serum pregnancy, Screen = Screening, 
UA = Urinalysis. 
 
 
Page 20 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
7. TABLE OF CONTENTS 
1. 
PROTOCOL REVISION HISTORY .......................................................................................... 2 
2. 
SPONSOR – SIGNATORIES ................................................................................................... 3 
3. 
INVESTIGATORS SIGNATURES ............................................................................................ 4 
4. 
ADDITIONAL KEY CONTACTS FOR THE STUDY ................................................................ 6 
5. 
SYNOPSIS ............................................................................................................................... 8 
6. 
STUDY EVENTS FLOW CHART ........................................................................................... 14 
7. 
TABLE OF CONTENTS ......................................................................................................... 21 
8. 
ABBREVIATIONS .................................................................................................................. 24 
9. 
INTRODUCTION AND BACKGROUND ................................................................................ 29 
9.1 
YPL-001 ....................................................................................................................... 29 
9.1.1 
Preclinical Trials .............................................................................................. 29 
9.1.1.1 
Pharmacology ................................................................................. 29 
9.1.1.2 
Pharmacokinetics ............................................................................ 30 
9.1.1.3 
Toxicology ....................................................................................... 31 
9.1.2 
Clinical Experience ......................................................................................... 32 
9.1.2.1 
SAD study ....................................................................................... 33 
9.1.2.2 
MAD Study ...................................................................................... 34 
10. RATIONALE ........................................................................................................................... 36 
10.1 Purpose of the Study ................................................................................................... 36 
10.2 Dose Selection ............................................................................................................. 36 
11. RISK/BENEFIT ....................................................................................................................... 38 
12. STUDY OBJECTIVES AND ENDPOINTS ............................................................................. 39 
12.1 Study Objectives .......................................................................................................... 39 
12.2 Study Endpoints ........................................................................................................... 39 
13. INVESTIGATIONAL PLAN ..................................................................................................... 41 
13.1 Overall Study Design and Plan .................................................................................... 41 
13.2 Study Conduct ............................................................................................................. 42 
13.2.1 Screening ........................................................................................................ 42 
13.2.2 Patient Confinement ....................................................................................... 42 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) ......................................................... 42 
13.2.4 Treatment Period (Days 1 to 56) .................................................................... 43 
13.2.4.1 Meal Schedule ................................................................................ 43 
13.2.4.2 End-of-Treatment or Early Termination (Day 56) ........................... 43 
13.2.5 Follow-up Call (14 ± 2 days) ........................................................................... 44 
13.2.6 Scheduled End of Study ................................................................................. 44 
13.3 Selection of Study Population ...................................................................................... 44 
13.3.1 Number of Patients ......................................................................................... 44 
13.3.2 Inclusion Criteria ............................................................................................. 44 
13.3.3 Exclusion Criteria ............................................................................................ 46 
13.3.4 Removal of Patients from the Study ............................................................... 48 
13.3.5 Study Restrictions ........................................................................................... 48 
13.3.5.1 Concomitant Therapy ...................................................................... 48 
13.3.5.2 Prohibitions...................................................................................... 50 
 
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13.3.5.3 Activity ............................................................................................. 50 
13.4 Treatments ................................................................................................................... 50 
13.4.1 Treatments administered ................................................................................ 50 
13.4.1.1 Drug Administration During Run-in Period ...................................... 50 
13.4.1.2 Drug Administration During Treatment Period ................................ 51 
13.4.1.3 Stopping Rules ................................................................................ 52 
13.4.2 Method of Assigning Patients to Treatment Groups ....................................... 52 
13.4.3 Blinding ........................................................................................................... 52 
13.4.3.1 Maintenance of Randomization ...................................................... 52 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion ........ 53 
13.4.3.3 Revealing of Randomization ........................................................... 53 
13.4.4 Treatment Compliance ................................................................................... 53 
14. STUDY PROCEDURES ......................................................................................................... 54 
14.1 Safety Assessments .................................................................................................... 54 
14.1.1 Body Height and Weight ................................................................................. 54 
14.1.2 Physical Examination ...................................................................................... 54 
14.1.3 Vital Signs ....................................................................................................... 54 
14.1.4 Pulse Oximetry................................................................................................ 55 
14.1.5 Electrocardiogram Monitoring ......................................................................... 55 
14.1.6 Clinical Laboratory Tests ................................................................................ 56 
14.1.6.1 Hematology ..................................................................................... 56 
14.1.6.2 Serum Chemistry ............................................................................ 56 
14.1.6.3 Serology .......................................................................................... 56 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test) ............. 56 
14.1.6.5 Follicle-Stimulating Hormone .......................................................... 57 
14.1.6.6 Urinalysis ......................................................................................... 57 
14.1.6.7 Urine Drug/Alcohol Screen.............................................................. 57 
14.1.7 Chest X-Ray .................................................................................................... 57 
14.1.8 Adverse Events ............................................................................................... 57 
14.1.8.1 Adverse Event Definition ................................................................. 57 
14.1.8.2 Monitoring........................................................................................ 57 
14.1.8.3 Reporting ......................................................................................... 58 
14.1.8.4 Serious Adverse Events .................................................................. 59 
14.2 Symptom Assessments ............................................................................................... 60 
14.2.1 Electronic Diary ............................................................................................... 60 
14.2.2 Peak Expiratory Flow ...................................................................................... 60 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation ............ 60 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) ....................................................... 60 
14.2.5 Activity (Duke Activity Status Index) ............................................................... 61 
14.3 Pharmacodynamic Assessments ................................................................................. 61 
14.3.1 Pulmonary Function (Spirometry) ................................................................... 61 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers .................... 62 
14.3.2.1 Bronchoscopy ................................................................................. 62 
14.3.2.2 Bronchial Brushings ........................................................................ 63 
14.3.2.3 Bronchoalveolar Lavage (BAL) ....................................................... 63 
 
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Sponsor Project No.: YPL-001-YJP-130403 
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14.3.2.4 Biomarkers ...................................................................................... 63 
14.3.3 Blood Biomarkers ........................................................................................... 63 
14.3.4 Quality of Life Questionnaires ......................................................................... 64 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index 
(BDI/TDI) ......................................................................................... 64 
14.3.4.2 COPD Assessment Test (CAT)....................................................... 64 
14.4 Pharmacokinetic Assessments .................................................................................... 64 
14.4.1 Blood Sampling and Processing ..................................................................... 64 
14.5 Blood Volume for Study Assessments......................................................................... 65 
15. DATA ANALYSIS ................................................................................................................... 66 
15.1 Statistical Analysis ....................................................................................................... 66 
15.1.1 Sample Size Calculation ................................................................................. 66 
15.1.2 Patients to Analyze ......................................................................................... 66 
15.1.3 Safety Analysis ............................................................................................... 67 
15.1.4 Symptom Monitoring Analysis ........................................................................ 68 
15.1.5 Pharmacodynamic Analysis ............................................................................ 68 
15.1.5.1 Biomarkers ...................................................................................... 68 
15.1.5.2 Quality of Life .................................................................................. 68 
15.1.6 Pharmacokinetic Analysis ............................................................................... 69 
15.1.6.1 Pharmacokinetic Parameters .......................................................... 69 
15.1.6.2 Statistical Methods for Pharmacokinetic Analyses ......................... 71 
15.1.7 Assessment of Efficacy ................................................................................... 71 
16. STUDY ADMINISTRATION ................................................................................................... 72 
16.1 Ethics ........................................................................................................................... 72 
16.1.1 Institutional Review Board .............................................................................. 72 
16.1.2 Ethical Conduct of the Study .......................................................................... 72 
16.1.3 Patient Information and Consent .................................................................... 72 
16.2 Termination of the Study .............................................................................................. 72 
16.3 Data Quality Assurance ............................................................................................... 72 
16.4 Direct Access to Source Data/Documents .................................................................. 73 
16.5 Drug Supplies, Packaging and Labeling ...................................................................... 73 
16.6 Data Handling and Record Keeping ............................................................................ 73 
16.7 Protocol Amendments ................................................................................................. 73 
16.8 Finance and Insurance ................................................................................................ 74 
16.9 Publication Policy ......................................................................................................... 74 
17. REFERENCES ....................................................................................................................... 75 
18. APPENDIXES ........................................................................................................................ 76 
18.1 Appendix 1 - UGT Drug Interaction Table ................................................................... 76 
18.2 Appendix 2 - SULT Drug Interaction Table .................................................................. 77 
 
 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
8. ABBREVIATIONS 
Only those uncommon abbreviations specific to this study are listed. Pharmacokinetic 
(PK) parameter abbreviations and definitions may be found in Section 15.1.6.1. 
AE 
Adverse event 
AHR 
Airway hyper-responsiveness 
ALD 
Approximate lethal dose 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
ANOVA 
Analysis of variance 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BAL 
Bronchoalveolar lavage 
BALF 
Broncheoalveolar lavage fluid 
BDI 
Baseline Dyspnea Index 
BID 
Twice daily 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
bpm 
Beat per minute 
BUN 
Blood urea nitrogen 
°C 
Degrees Celsius 
CAT 
COPD Assessment Test 
Chem 
Chemistry 
CFR 
Code of Federal Regulations 
CK 
Creatine kinase 
CNS 
Central nervous system 
CO2 
Carbon dioxide 
Coag 
Coagulation 
COPD 
Chronic obstructive pulmonary disease  
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CRU 
Clinical research unit 
 
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CS 
Clinically significant abnormality 
CSC 
Cigarette smoking condensate 
CXCL 
Chemokine (C-X-C motif) ligand 
CV 
Coefficient of variation 
DASI 
Duke Activity Status Index 
dL 
Deciliter 
DRF 
Dose range finding 
e-diary 
Electronic diary 
ECG 
 
Electrocardiogram 
eCRF 
Electronic case report form 
EDTA  
Ethylenediaminetetraacetic acid 
ERS 
European Respiratory Society 
F 
Female 
°F 
Degrees Fahrenheit 
FDA 
Unites States Foods and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSH 
Follicle-stimulating hormone 
FU 
Follow-up 
FVC 
Forced vital capacity 
g 
gram 
GCP 
Good Clinical Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
HBsAg 
hepatitis B surface antigen 
HCO3 
Bicarbonate 
HCV 
hepatitis C antibodies  
HED 
Human equivalent dose 
Hem 
Hematology 
HIV 
Human immunodeficiency virus 
hr 
Hour 
IC 
Inspiratory capacity 
ICH 
International Conference on Harmonization 
ICS 
Inhaled corticosteroid 
 
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IgE 
Immunoglobulin E 
IL 
Interleukin 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
K2EDTA 
Dipotassium ethylenediaminetetraacetic acid 
kg 
Kilogram 
kg/m2 
Kilogram per meter squared 
LABA 
long acting beta agonist 
LDH 
Lactate dehydrogenase 
LLOQ 
Lower limit of quantitation 
LOQ 
Limit of quantitation 
LPS 
Lipopolysaccharide 
LSM 
Least-squares means 
μg 
Microgram 
m2 
Square meter 
M 
Male 
MAD 
Multiple ascending dose 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCO 
Myeloperoxidase 
MCP 
Monocyte chemotactic protein 
MCV 
Mean Corpuscular Volume 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
MIP 
Monocyte inhibitory protein 
mL 
Milliliter 
mmHg 
Millimetre of mercury 
MMP 
Matrix metalloproteinase 
msec 
Millisecond 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NCS 
Not clinically significant 
 
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ng 
Nanogram 
No. 
Number 
NOAEL 
No observed adverse effect levels 
OTC 
Over-the-counter 
OVA 
Ovalbumin 
PD 
Pharmacodynamic(s) 
PEF 
Peak expiratory flow 
PK 
Pharmacokinetic(s) 
QA 
Quality Assurance 
QC 
Quality Control 
QT 
Interval between the Q and T waves on the electrocardiogram tracing 
QTcF 
Corrected QT interval with Fridericia’s formula 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
Resp 
Respiration 
ROS 
Reactive oxygen species 
SABA 
Short-acting β2-agonist 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAMA 
Short-acting anticholinergic agent 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
SULT 
Sulfotranferase 
TBIL 
Total bilirubin 
TDI 
Transition Dyspnea Index 
TEAE 
Treatment-emergent adverse event 
Th 
T helper 
TNF-α 
Tumor necrosis factors alpha 
UA 
Urinalysis 
UGT 
UDP-glucuronosyltransferase 
ULN 
Upper limit of normal 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
US 
United States 
WBC 
White blood cell 
WHO 
World Health Organization 
 
 
 
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Proof of Concept 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
9. INTRODUCTION AND BACKGROUND 
This study is being conducted as the third in a series of studies for the clinical 
development of YPL-001. The trial will be conducted in compliance with the protocol, 
Good Clinical Practice (GCP), and applicable regulatory requirements. The patient 
population will be comprised of moderate to severe (GOLD Stage 2-3) COPD patients. 
9.1 
YPL-001 
YPL-001 drug product is an oral dosage form of an herbal extract from the aerial parts of 
the 
plant 
Speedwell 
(Pseudolysimachion 
rotundum 
subsp. 
Subintegrum). 
Pseudolysimachion (Veronica) is a perennial herb which has been used as a traditional 
medicine in Korea and China for the treatment of inflammatory diseases of the 
respiratory tract such as asthma and COPD. 
As a botanical drug product, the drug substance is a mixture of chemical species 
(iridoids [including verproside] and other related compounds) and biological activity is 
considered to be from the mixture and not from an individual component. It is unknown if 
the total activity from individual components is additive or synergistic. Five active 
constituents, classified as iridoids, have been identified in the herbal extract: verproside, 
picroside II, catalpolside, isovanilloyl catalpol, and 6-O-veratroylcatalpol. Recent 
experimentation has revealed that the principal active ingredient in Pseudolysimachion is 
verproside, a dihydroxylated catalpol derivative.  
YPL-001, containing verproside and other active ingredients, is being developed as a 
potential oral treatment for long term inflammatory diseases of the respiratory tract such 
as asthma or bronchitic COPD. Current long term control medications include 
corticosteroids, cromolyn sodium, immunomodulators, long acting beta agonists, 
(LABAs), methylxanthines, and leukotriene modifiers. YPL-001 belongs most closely 
with the leukotriene modifier class of drug. 
A brief overview of available information regarding YPL-001 follows below. Details can 
be found in the YPL-001 Investigator’s Brochure of March 1, 2013. 1 
9.1.1 Preclinical Trials 
9.1.1.1 Pharmacology 
Five in vivo primary pharmacology studies have been completed.   
In ovalbumin-sensitized mice, an animal model for asthma, YPL-001 reduced elevated 
immunoglobulin E (IgE), IL-4, IL-5, IL-13, airway hyper-responsiveness, and mucus 
hyper-secretion. 
In the lipopolysaccharide (LPS)- and cigarette smoking condensate (CSC)-induced 
COPD mice model, verproside and roflumilast treatment inhibited the accumulation of 
neutrophils in Broncheoalveolar lavage fluid (BALF) as well as the increase of several 
proinflammatory cytokines and chemokines. Neutrophil infiltration induced by LPS and 
CSC treatments was associated with a significant increase in BALF levels of the 
chemoattractants, TNF-α, chemokine (C-X-C motif) ligand (CXCL)-1, and monocyte 
inhibitory protein (MIP)-2. These data also demonstrated that the effect of YPL-001 and 
verproside involves down-regulation of the influx of neutrophils and production of TNF-α, 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
CXCL-1, and MIP-2 molecules which play a major role in tissue remodeling. 
YPL-001 significantly suppressed the increase of inflammatory cell counts, particularly 
neutrophils in BALF and also effectively suppressed elevated levels of TNF-α, CXCL-1 
and MIP-2 with the reduction in airway inflammatory responses in CSC- and 
LPS-induced COPD mice. 
YPL-001 also effectively suppressed the increased inflammatory cell count, particularly 
neutrophils in BALF and also significantly inhibited elevated levels of TNF-α, IL-1β and 
IL-6 with the reduction in reactive oxygen species (ROS) production and elastase activity 
in cigarette smoke- and LPS-induced COPD mice. 
In the LPS- and cigarette smoke-induced COPD rats model, YPL-001 significantly 
inhibited the increase of inflammatory cell count, particularly neutrophils in BALF and 
also effectively suppressed elevated levels of TNF-α, IL-1β, IL-6, MIP-2 and CRP. 
YPL-001 effectively inhibited development of both T helper (Th)2 and Th1/Th17 type 
asthma in these murine models. These effects resulted from inhibition of cytokine and 
chemokine production by infiltrated inflammatory cells and antigen specific T cells in 
lymph nodes. YPL-001 did not inhibit development of COPD which was induced by 
E.coli extracellular vesicles. 
9.1.1.2 Pharmacokinetics 
After oral administration of YPL-001 at 12.5, 25, and 50 mg/kg doses (5.225, 10.45, and 
20.9 mg/kg as verproside) in rats, verproside was rapidly absorbed; verproside was 
detected at the first blood sampling time (5 min) and absorbed rapidly, with the tmax 
achieved at 0.46-0.61 hour for all three doses. The post-absorption phase of the mean 
plasma verproside concentration-time profiles showed a poly-exponential decay. 
The area under the plasma concentration-time curve (AUC) and the maximum plasma 
concentration (Cmax) of verproside were linearly increased as the oral dose of YPL-001 
increased. Alternately, the dose normalized (based on 12.5 mg/kg) AUCs and Cmax of 
verproside were comparable among different doses studied. The elimination half-lives 
(t1/2), 2.14 – 3.91 hours, and other PK parameters of verproside for all three doses were 
also comparable. These findings indicate that the PK parameters of verproside were 
independent of doses. 
The fraction of dose of verproside excreted unchanged in urine at 24 hours was less 
than 0.10%. Verproside was not detected in the 24 hours feces sample for all three 
doses studied. These results indicate that verproside is almost completely eliminated by 
the first pass metabolism due to O-methylation, glucuronidation, sulfation, and intestinal 
microflora-mediated metabolism. Verproside is metabolized to verproside glucuronides 
(M1 and M2), verproside sulfates (M3 and M4), O-methylverproside such as picroside II 
(M5) and isovanilloylcatalpol (M6), 3,4-dihydroxybenzoic acid (M11), 3-methyoxy-4-
hydroxybenzoic acid (M15) and 3-hydroxy-4-methoxybenzoic acid (M16), which are 
further metabolized to their glucuronides and sulfates including M5 glucuronide (M7), M5 
sulfate (M9), M6 glucuronide (M8), M6 sulfate (M10), M11 glucuronide (M12), M11 
sulfates (M13 and M14), M15 glucuronides (M17 and M18), M15 sulfate (M20), M16 
glucuronide (M19), and M16 sulfate (M21). The O-methylation of verproside to 
picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
were identified as the major metabolic pathway in bile and urine samples.  
Picroside II, a major metabolite of verproside, was detected in plasma samples but most 
plasma concentrations in 12.5 and 25 mg/kg YPL-001 treated groups were below the 
lower limit of quantification (LLOQ, 2.5 ng/mL) compared to 50 mg/kg YPL-001 treated 
group. The picroside II-to-verproside AUC ratios in the 50 mg/kg YPL-001 treated group 
were 13.9-65.1%, suggesting that picroside II may be one of the major YPL-001 
metabolites. Plasma concentrations of isovanilloylcatalpol, a metabolite of verproside 
and isomer of picroside II, were below LLOQ (2.5 ng/mL) after oral administration of all 
three YPL-001doses tested. 
Verproside, catalposide, and picroside II were not considerably bound to human plasma 
proteins; the binding values were 36.3-55.0% at verproside concentrations of 0.1, 1.0, 
and 10.0 µg/mL, 31.2-49.5% at catalposide concentrations of 0.5, 1, and 10 µg/mL, and 
34.0-41.2% at picroside II concentrations of 0.5, 1, and 10 µg/mL. 
9.1.1.3 Toxicology 
Two single dose toxicity studies with YPL-001 have been completed in rat and dog. In 
the rat study, polyuria was observed in the 5,000 mg/kg dosing group of each sex 
between 2-4 hours after YPL-001 administration. Discolored stool was observed 
dose-dependently in the all dosing groups of each sex at 1-3 days post administration. 
Soft stool, mucous stool and soiled perineal region were observed at 1 day after 
administration in the 2,500 and 5,000 mg/kg dosing group of each gender. There were 
no notable changes of body weight in any study group. There were no notable gross 
necropsy findings in any of the study groups. Based on the results above, when 
YLP-001 is administered orally to Sprague-Dawley rats, the approximate lethal dose 
(ALD) is higher than 5,000 mg/kg. In the dog study, There were no changes with respect 
to the toxicity of the test article in the clinical signs, body weight change and necropsy 
findings after a single dose. Vomiting and discoloration of stool was noted. The 
Maximum Tolerated Dose (MTD) was determined to be 2,000 mg/kg for males and 
1,000 mg/kg for females. 
Two dose range finding (DRF) studies with YPL-001 have been completed in rat and 
dog, followed by two pivotal, 4-week, GLP repeated-dose toxicology studies in the same 
species. In the rat DRF study, YPL-001 induced anemia and hemolysis at 667 mg/kg/d 
and at higher doses. In addition, enlargement of cecum was observed at 667 mg/kg/d 
and at higher doses. The NOEL for this study was 74 mg/kg/d in both genders. In the 
dog DRF study, decreases in red blood cell (RBC) values were present in males at the 
high dose level (1000 mg/kg/d). In females the TBIL values were elevated at the 
1000 mg/kg/d dose levels. Females had enlarged spleens at 125, 250 and 1000 mg/kg 
dose levels without dose relationship (trend was toward significance). The MTD for this 
study was 1000 mg/kg/d. 
Primary results from the pivotal, 4-week rat study included: 
There were no abnormal clinical signs observed in any group during dosing or the 
recovery periods and no mortality was reported. 
Hematology: Compared to controls, there were decreases in values of RBC, hematocrit, 
and hemoglobin at all dose levels of both genders in a dose-dependent fashion. The 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
values of hemoglobin distribution width, red cell distribution width (RDW) and 
reticulocyte at all dose levels of both genders were higher or significantly higher than 
those of vehicle control.  
Clinical Biochemistry: There were significant increases in the values of TBIL at all dose 
levels of both genders when compared with that of vehicle control. After the recovery 
period, there were no noticeable changes related to the test article. 
Organ Weights: Slight increase in absolute & relative weights of the spleen at 
540 mg/kg/d in males and notable increase in absolute & relative weights of the spleen 
at all dose levels of females were observed. Weights of left and right kidneys in female 
at 540 mg/kg/d were significantly higher than that of vehicle control. After the recovery 
period, the absolute weights of the spleen and both kidneys in both genders at 
540 mg/kg/d were significantly higher than that of vehicle control. 
Necropsy Findings: At necropsy, 6 cases of dark reddish discoloration of spleen were 
observed at 540 mg/kg/d in both genders, and 1 case of enlargement of cecum was 
observed at 540 mg/kg/d in female.  After the recovery period, one case of dark reddish 
discoloration of spleen was observed at 540 mg/kg/d in the female. The histopathology 
examination revealed increased hematopoiesis of spleen at the high dose in both 
genders.  
No Observed Adverse Effect Levels (NOAEL): The NOAEL for this study was 
180 mg/kg/d for both genders. 
Primary results from the pivotal, 4-week dog study included: 
YPL-001 colored stool with/without soft stool or diarrhea was persistently observed in 
both sexes at 1000 mg/kg/d during the dosing period. It was not observed during the 
recovery period. No mortality was reported. 
Hematology: There were no treatment-related changes. 
Clinical Biochemistry: The TBIL increased in a dose-dependent manner in both genders 
at 111, 333 and 1000 mg/kg/d, and it was not recovered completely after the 2-week 
recovery period. 
Organ Weights: There were no treatment-related changes. 
Necropsy Findings: Slight red discoloration of mucous membranes in the stomach or 
duodenum was observed in female treatment groups but not observed after the 2-week 
recovery period. 
NOAEL: The NOAEL for this study was 1000 mg/kg/d for both genders. 
9.1.2 Clinical Experience 
To date, 2 studies have been conducted in healthy subjects, a randomized, double-blind, 
placebo-controlled, sequential single ascending dose (SAD) clinical study (AA98496) 
and a randomized, double-blind, placebo-controlled, sequential multiple ascending dose 
(MAD) clinical study (AA98495).  
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
9.1.2.1 SAD study 
All 5 cohorts of 8 subjects (6 active and 2 placebo), with one cohort crossing over to 
assess food effect, were dosed and completed. All dosed levels (i.e., 40, 80, 160, 240, 
and 320 mg) were well tolerated with no SAEs reported during the conduct of the study. 
All 9 AEs reported in 7 subjects were mild in severity and the most frequent AE reported, 
regardless of causality, was headache. Of the 7 AEs experienced by subjects receiving 
the active drug, the Investigator considered 2 of these to be possibly related (nausea, 
and vomiting), 2 unlikely related, and 3 unrelated. Of the 2 AEs experienced by subjects 
receiving placebo, the Investigator considered 1 of these to be possibly related 
(headache), and 1 unrelated. 
Plasma samples were analyzed using a validated bioanalytical method. Verproside 
concentrations were lower than concentrations observed from the animal PK data. The 
limit of quantitation (LOQ) was approximately 20% of the Cmax after a single 160 mg 
dose and approximately 10% of the Cmax after a single 320 mg dose. Therefore, the 
half-life could not be well characterized since only a few PK concentrations were 
available for the estimation. 
Verproside appeared to be rapidly absorbed following oral administration and 
independent on dose, as suggested by median tmax values of approximately 0.5 to 0.67 
hours under fasting conditions. Verproside appeared to be cleared rapidly from plasma, 
with mean t1/2 values under 1 hour; plasma verproside concentrations were below the 
lower limit of quantification (BLQ) for all subjects by 6 hours postdose. Table 1 below 
summaries the PK parameters of verproside following single-dose administrations of 
YPL-001 at each dose level: 
Table 1 
Summary of PK Parameters 
Pharmacokinetic 
Parameters 
Dose Level 
Mean ± SD 
40 mg 
(N = 1)a 
80 mg  
(N = 6)b 
160 mg 
(fasting) 
(N = 6)c 
160 mg 
(fed) 
(N = 6)d 
240 mg  
(N = 6)e 
320 mg  
(N = 6)f 
Cmax (ng/mL) 
1.19 
1.14 ± 0.328 2.90 ± 1.76 
1.08 ± 
0.287 
4.78 ± 5.66 4.49 ± 1.44 
tmax (hr)g 
0.4969 
0.6682 
(0.5158, 
1.0025) 
0.5074 
(0.3331, 
0.6700) 
1.2538 
(0.9994, 
2.0008) 
0.5867 
(0.3486, 
1.5022) 
0.5057 
(0.3419, 
1.5014) 
AUC0-t  (ng·hr/mL) 0.7422 
0.7520 ± 
0.3818 
2.5616 ± 
1.7947 
1.2822 ± 
0.3599 
5.4567 ± 
5.0158 
5.3612 ± 
0.8664 
AUC0-inf  
(ng·hr/mL) 
. 
. 
3.8048 ± 
1.8238 
. 
8.2199 ± 
5.3327 
6.2162 ± 
0.7776 
t1/2 (hr) 
. 
. 
0.677 ± 
0.263 
. 
0.919 ± 
0.176 
0.713 ± 
0.100 
a Individual values are presented for the 40 mg dose level 
b N=5 for AUC0-t 
c N=3 for AUC0-inf and t1/2, 
d N=4 for AUC0-t 
e N=3 for AUC0-inf, and t1/2,  
f N=5 for AUC0-inf, and t1/2,  
g tmax  is presented as Median (Minimum, Maximum) 
· = Value missing or not reportable 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
9.1.2.2 MAD Study 
In total, 2 cohorts of 8 subjects and 1 cohort of 10 subjects received multiple YPL-001 
doses of 80, 160, or 240 mg BID. Each cohort was constituted of 2 subjects receiving 
placebo and the remaining subjects receiving the active drug. All dose levels were well 
tolerated. There were no deaths or SAEs in this study. One (1) subject was discontinued 
due to the AE of chest pain. Overall, TEAEs were experienced by 38% of subjects in this 
study. The Investigator considered 1 AE (chest pain) to be possibly related to study drug 
and the remaining AEs unlikely or unrelated. There were no treatment-related trends in 
physical examination, laboratory, vital sign, or ECG assessments in this study. 
Verproside appeared to be rapidly absorbed following multiple-dose oral administration, 
as suggested by median tmax values of approximately 0.5 - 0.9 hours and independent of 
dose. Following a multiple oral doses of YPL-001, verproside appeared to be cleared 
rapidly from plasma, with mean t½ values under 1.6 hours, and plasma verproside 
concentrations were BLQ for most subjects by 12 hours postdose. 
Picroside II appeared to be also rapidly absorbed following single- and multiple-dose oral 
administration, as suggested by median tmax values of approximately 0.6 to 0.9 hours 
and independent of dose. Following a single oral dose of YPL-001, picroside II appeared 
to be cleared rapidly from plasma, with mean t1/2 values under 1 hour, CL/F values of 
14000 – 18500 L/hour, and plasma picroside II concentrations BLQ by 10 - 12 hours 
postdose. Following multiple oral doses, mean t1/2 values were under 2.5 hours, and 
plasma picroside II concentrations were BLQ for most subjects by 12 hours postdose. 
For all 3 dose levels, minimal to modest accumulation of verproside and picroside II was 
observed following BID administration of YPL-001 for 2 weeks. The mean peak and total 
exposure of verproside and picroside II in plasma appeared to increase in a 
dose-dependent manner between 80 and 160 mg of YPL-001, but no increase in plasma 
bioavailability was observed between 160 and 240 mg dose levels. Table 2 and Table 3 
below summaries the PK parameters of verproside and picroside II, respectively, 
following multiple-dose administrations of YPL-001 at each dose level: 
Table 2 
Summary of Verproside PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
4709 ± 4080 
10860 ± 11424 
9658 ± 9246 
 
(N=6) 
(N=6) 
(N=5) 
AUC0-t (pg*hr/mL) 
4596 ± 4127 
10770 ± 11489 
9566 ± 9298 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
2414 ± 1281 
6737 ± 7342 
5458 ± 4387 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 0.528 (0.272, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
1.47 ± 0.425 
1.30 ± 0.406 
1.57 ± 0.236 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Table 3 
Summary of Picroside II PK Parameters 
Pharmacokinetic 
Parameters 
YPL-001 Dose Level 
Mean ± SD 
80 mg 
160 mg 
240 mg 
AUCτ (pg*hr/mL) 
2556 ± 599 
4287 ± 4369 
1985 ± 1024 
 
(N=2)† 
(N=4)† 
(N=5) 
AUC0-t (pg*hr/mL) 
1124 ± 1044 
3024 ± 3877 
1804 ± 949 
 
(N=6) 
(N=6) 
(N=5) 
Cmax ss (pg/mL) 
419 ± 240 
1116 ± 1391 
751 ± 490 
 
(N=6) 
(N=6) 
(N=5) 
tmax ss (hr)* 
0.756 (0.252, 2.00) 
0.759 (0.329, 1.50) 
0.748 (0.524, 0.751) 
 
(N=6) 
(N=6) 
(N=5) 
t½ (hr) 
2.23 ± 0.254 
1.84 ± 0.395 
2.08 ± 0.793 
 
(N=6) 
(N=6) 
(N=5) 
* = tmax_ss  is presented as median (minimum, maximum) 
. = Value missing or not reportable 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
10. RATIONALE 
10.1 Purpose of the Study 
This study will be the initial exploration of multiple-dose administration of YPL-001 in 
COPD patients. The assessments of the safety, tolerability, COPD symptoms, PD, and 
PK of verproside and picroside II following administration of multiple doses of YPL-001 
will guide decisions to further develop the drug and support the compound as a useful 
clinical candidate in the treatment of inflammatory diseases of the respiratory tract such 
as asthma and COPD and the data generated will support larger studies in patients with 
inflammatory diseases of the respiratory tract such as asthma and COPD to 
demonstrate safety and evidence of efficacy and clinical benefit. 
10.2 Dose Selection 
This will be the first COPD patient study of YPL-001. 
YPL-001 appeared well tolerated in a panel of standard animal toxicology studies. In the 
initial studies in humans, the initial dose of YPL-001 was justified conservatively 
according to the United States (US) Food and Drug Administration (FDA) guidance 
document “Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for 
Therapeutics in Adult Healthy Volunteers”.2  
Accordingly, the single and multiple dose escalation study (AA98496) initiated single 
doses at the 40 mg and 80 mg level, respectively. Dose escalations up to 320 mg and 
240 mg in the SAD and MAD studies, respectively, were reached. All cohorts have been 
completed and all doses administered were well tolerated in human subjects and no 
clear pattern of toxicity is apparent.  
Based on the review of safety, tolerability, and PK data from Cohorts 1 to 5 of the SAD 
study (AA98496) and Cohorts 1 to 3 of the MAD study, and the in vivo efficacy data in 
rat and mouse models, it is predicted that the therapeutic range should be between 
1.2 mg/kg and 4.8 mg/kg which is equivalent to 84 mg to 336 mg daily in a 70 kg patient. 
Therefore, a low YPL-001 dose of 80 mg BID and the high YPL-001 dose of 160 mg BID 
were selected for this proof-of-concept study. 
The total strength (23.75 mg) of identified compounds in YPL-001 as a whole in the 
40 mg starting dose administered in the first-time-in-human dose escalation study 
(AA98496) corresponded to approximately 35% of the dosages that have been used in 
the traditional medicine setting in China (68.65 mg). In this present proof-of-concept 
study the total strength (47.50 mg) of identified compounds in the initial starting dose of 
80 mg is still lower than the dosages that have been used in the traditional medicine 
setting in China, as shown in Table 4, corresponding to 70% of the traditional Chinese 
medicine. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
Table 4: Traditional Chinese Medicine Use Versus Proposed Clinical Starting 
Dose 
Identified Compounds in 
YPL-001 
1.40 g  
(Single Dose) 
Traditional Chinese 
Medicinea 
(mg) 
2.80 g/day  
(Divided Dose) 
Traditional Chinese 
Medicinea 
(mg) 
80 mg  
(Single Dose) 
for MAD Studyb 
(mg) 
Verproside 
47.94 
95.88 
30.64 
Veratric acid 
2.10 
4.20 
1.08 
Catalpolside  
3.77 
7.54 
4.08 
Picroside II  
3.43 
6.86 
3.36 
Isovanilloyl catalpol 
3.53 
7.06 
4.72 
6-O-veratroyl catalpol 
7.88 
15.76 
3.62 
Total 
68.65 
137.30 
47.50 
a Traditional medicine dosage from Chinese Medical Great Dictionary; Zhong Yao Da Ci Dian. 
b Proposed dosage of YPL-001 in MAD study 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
11. RISK/BENEFIT 
YPL-001 is being developed as a potential oral treatment for long term control of 
persistent asthma and COPD. YPL-001 belongs most closely with the leukotriene 
modifier class of drug and has the potential to inhibit the accumulation of neutrophils the 
increase of several proinflammatory cytokines and chemokines which play a major role 
in tissue remodeling. The development of a product to improve the treatment of asthma 
and COPD will be of benefit to the wider community/patients with respiratory disease. 
The safety monitoring practices employed by this protocol (i.e., physical examination, 
vital signs, pulse oximetry, 12-lead ECG, hematology, serum chemistry, urinalysis, AE 
monitoring, and AE questioning) are deemed adequate to protect the patients’ safety 
and should detect all expected TEAEs. The procedures employed in this study to assess 
efficacy are primarily non-invasive and present no undue risk to the patient. 
The approximate volume of blood planned for collection from each patient over the 
course of the study (see Section 14.5), presents no undue risk to the patients nor does 
the possibility of collection (for wasting to ensure clean sample) of additional blood in the 
event an indwelling cannula is utilized (as a last resort solution when venipuncture 
becomes difficult for a patient) and the possibility of additional blood collection for 
recheck of safety labs if deemed necessary by the Investigator. 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
12. STUDY OBJECTIVES AND ENDPOINTS 
12.1 Study Objectives 
The primary objective of the study is to assess the safety and tolerability of two multiple 
oral YPL-001 dose levels versus placebo in moderate to severe COPD patients. 
The secondary objective of the study is to assess the number and magnitude of daily 
respiratory symptoms of two multiple oral YPL-001 dose levels versus placebo in 
moderate to severe COPD patients. 
The exploratory objectives of the study are to evaluate the following in moderate to 
severe COPD patients: 
1. To assess BAL epithelial brushings for YPL-001 component levels. 
2. To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes and eosinophils as a percentage of total cells; neutrophil, 
macrophage, lymphocyte, and eosinophil counts as absolute inflammatory cell 
numbers in YPL-001 groups versus placebo group. 
3. To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus placebo 
group. 
4. To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, macrophages, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, 
IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus placebo group. 
5. To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in YPL-001 
groups versus placebo group. 
6. To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
12.2 Study Endpoints 
The primary endpoint is the number and severity of TEAEs following multiple oral doses 
of YPL-001 or placebo. 
The secondary endpoint is the number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily PEF;  
• 
major (e.g., sputum quality, color, consistency) and minor (e.g., cough, wheeze, 
sore throat, nasal congestion, discharge, and body temperature above 100°F) 
symptoms of COPD exacerbation;  
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
• 
dyspnea (using the Modified Borg Dyspnea Scale); and  
• 
activity (using the DASI). 
The exploratory endpoints are: 
1. YPL-001 component levels in epithelial brushings; 
2. BAL biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, and eosinophils as a 
percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and 
eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9. 
3. Blood biomarkers following multiple oral doses of YPL-001 or placebo, measuring: 
• 
inflammatory markers (total and differential cell counts as absolute and 
percentage for neutrophils, macrophages, eosinophils and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MCP-1, and MMP-9. 
4. Pulmonary function results (spirometry) following multiple oral doses of YPL-001 or 
placebo. 
5. Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. Concentrations and PK of verproside and picroside II in plasma following multiple 
oral doses of YPL-001. 
7. Concentrations of verproside and picroside II in BAL following multiple oral doses of 
YPL-001. 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
13. INVESTIGATIONAL PLAN 
13.1 Overall Study Design and Plan 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg BID) and a placebo control, in moderate to severe COPD patients.  
Sixty-nine (69) patients will be enrolled and randomized into 3 treatment groups 
(23 patients per group) to ensure completing the study with 60 patients. Patients will 
participate only once.  
Safety and tolerability will be assessed throughout the study. Assessment of respiratory 
symptoms and symptom burden in YPL-001 and placebo treatments will be performed 
daily through patient self-report of PEF, major and minor symptoms of COPD 
exacerbation, dyspnea, and activity in their e-diary. Spirometry measurement, BAL, and 
blood samples will be collected for the PD assessment of YPL-001 and placebo 
treatments. Serial blood samples will also be collected for PK assessment of verproside 
(the principal active ingredient of YPL-001) and picroside II. Other components of 
YPL-001 and its metabolites may also be analyzed in plasma.  
Following screening, eligible patients will discontinue non permitted respiratory drugs if 
already receiving them and enter a 14 ± 2 days Run-in Period during which patients will 
be given albuterol taken on an as required basis and daily tiotropium 18 μg (one capsule 
inhaled daily in the morning) to be administered at home. On Day 1 of the Run-in Period, 
each patient will be issued and trained on the use of the e-diary. They will record their 
daily symptoms throughout the Run-in Period. 
Patients will return to the CRU on the morning of Day -1 of the Treatment Period to 
confirm their eligibility and assess their health conditions. If they still meet all of the 
inclusion criteria and none of the exclusion criteria, they will undergo Day -1 scheduled 
study procedures. Patients will return to the CRU the next day (Day 1) to be randomized 
and receive one of the 3 treatments and undergo all scheduled study procedures. 
Patients will return on the morning of Days 15, 29, 43, 55, and 56 of the Treatment 
Period for study drug administration and procedures. Prior to each release from the 
CRU, patients will receive a properly labeled container with sufficient doses which will be 
self-administered by patients at home until the next morning visit at the CRU. Patients 
will continue recording their daily symptoms via the e-diary throughout the Treatment 
Period. Patients will return the e-diary device on Day 56 to CRU staff. 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
Patients will be instructed to call the Investigator if breathing worsens or if they need to 
take more than 8 puffs per day of albuterol for more than 2 consecutive days. If the 
Investigator determines that the patient is too unstable to continue in the study, he/she 
will be discontinued. Rescue medication will be used for any patient with an 
exacerbation of COPD and will be administered in accordance with the study center 
 
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YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
standard of care. 
Discontinued patients may be replaced at the discretion of the Sponsor. 
13.2 Study Conduct 
Please see the Study Events Flow Chart for a summary of the schedule of study 
participation and procedures in Section 6. 
13.2.1 Screening 
Screening will begin within 14 days of Day 1 (inclusive) of the Run-in Period. Informed 
consent will be obtained at screening (see Section 16.1.3) and prior to any study 
procedures being performed. Patients will have to meet all eligibility criteria before being 
enrolled in the study (see Section 13.3). Patients will be informed of the study 
restrictions (see Section 13.3.5). 
The following will be recorded at screening: medical history and demographic data, 
including name, sex, age, race, ethnicity, body weight (kg), height (cm), BMI, and history 
of tobacco use (including number of pack-year and cigarette smoked per day).  
Screening procedures are listed in Section 6. 
13.2.2 Patient Confinement 
Patients will be admitted to the CRU on the morning of each scheduled visit at a time 
designated by the CRU as delineated in the Study Events Flow Chart (Section 6). 
Patients will remain in the clinic through completion of all scheduled study procedures. 
13.2.3 Run-In Period (Days 1 to 14 [± 2 days]) 
Eligible patients will be admitted to the CRU on the morning of Day 1 of the Run-in 
Period at a time designated by the CRU. Patients will discontinue all restricted 
concomitant medications as indicated in Section 13.3.5.1 and undergo the Run-in 
procedures as listed in Section 6.  
During the Run-in Period, patients will self-administer tiotropium (Spiriva® HandiHaler®) 
daily for 14 ± 2 days before Day 1 of the Treatment Period. Patients will be instructed to 
inhale 1 capsule of tiotropium (Spiriva® HandiHaler®) every morning. Patients will also 
receive albuterol for as needed use. Patient will keep this rescue albuterol throughout 
the Run-in Period.  
Prior to release from the CRU, patients will receive a properly labeled container with the 
appropriate doses of tiotropium and albuterol for home dosing. They must return the 
container (empty or not) at the next schedule visit, which is scheduled after 14 ± 2 days. 
Each patient will also be issued and trained on the use of the e-diary to record their 
self-administered doses, concomitant medications use, and their daily respiratory 
symptoms. Prior to each morning dose, patients will record at home their daily PEF, 
major (e.g., sputum quality, color, consistency) and minor (e.g., cough, wheeze, sore 
throat, nasal congestion, discharge, and body temperature above 100°F) symptoms of 
COPD exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
13.2.4 Treatment Period (Days 1 to 56) 
Patients who completed the Run-in Period and still meet all the inclusion criteria and 
none of the exclusion criteria will be randomized to receive one of the assigned 
treatments (80 mg or 160 mg YPL-001 BID, or placebo BID) on Day 1 through Day 56 
(see Section 13.4.1 and Section 13.4.2). 
Safety and tolerability will be monitored throughout the Treatment Period as listed in 
Section 6. Patients will continue to record their self-administered doses, concomitant 
medications use, and their daily respiratory symptoms on their e-diary. Prior to each 
morning dose, patients will record at home their daily PEF, major (e.g., sputum quality, 
color, consistency) and minor (e.g., cough, wheeze, sore throat, nasal congestion, 
discharge, and body temperature above 100°F) symptoms of COPD exacerbation, 
dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
BAL samples for YPL-001 concentrations and PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Spirometry and quality of life questionnaires for PD assessments will be collected at the 
time points delineated in the Study Events Flow Chart (Section 6). 
Blood samples for PD and PK assessment will be collected at the time points delineated 
in the Study Events Flow Chart (Section 6). 
13.2.4.1 Meal Schedule 
Patients will be required to fast overnight for at least 12 hours before bronchoscopy and 
BAL collection on Days -1 and 56. On Days 1 and 56, patients will be required to fast 
overnight for at least 8 hours before and for at least 4 hours after the morning dose. On 
all other days, patients will be asked to fast for at least 2 hours before and 2 hours after 
each morning dose. Patients will also be asked to fast for at least 2 hours before and 
after each evening dose. 
Patients will also be required to fast for at least 8 hours before the scheduled serum 
chemistry tests at the time points delineated in the Study Events Flow Chart (Section 6). 
During in-clinic dosing, water (except that administered with dosing) will not be permitted 
from 1 hour before until 1 hour after each dosing. Water will be allowed as desired at all 
other times. On all other days, patients will be informed to follow the same restrictions. 
On Days 1 and 56, patients will fast from all food and drink except water between meals 
and snacks. Foods and beverages containing alcohol, xanthines, caffeine, vegetables 
from the mustard green family, mustard, tea (especially speedwell tea), or 
grapefruit/Seville oranges will not be served in the CRU. Across all CRUs, menus should 
be similar in content. The same menu and meal (except for snacks) schedule will be 
administered uniformly for all patients confined within the same CRU, across all 
treatment groups. Meals are not required to be completed by patients and all meals and 
snacks eaten by patients will be recorded on the CRFs. 
13.2.4.2 End-of-Treatment or Early Termination (Day 56) 
End-of-treatment evaluation will be performed on all patients before leaving the CRU or 
prior to early termination. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
The end-of-treatment procedures are listed in Section 6. 
13.2.5 Follow-up Call (14 ± 2 days) 
The CRU will attempt to contact patients using their standard procedures approximately 
14 days (± 2 days) after the last study drug administration to determine if any AE has 
occurred since the last dose of study drug. Patients who terminate the study early will be 
contacted or asked to return to the CRU for monitoring if the Investigator deems 
necessary. 
13.2.6 Scheduled End of Study 
The end of the study is scheduled after completion of the evaluations in the 3 treatment 
groups or after dose-limiting clinical safety endpoints have been reached to preclude 
continuation of the study. The clinical conduct of the study is intended to last 
approximately 12 to 24 months. 
This time period may change in the event that the study is terminated early, additional 
time is required to review safety, or a decision is made to complete an unscheduled 
analysis for a group. 
13.3 Selection of Study Population 
13.3.1 Number of Patients 
The study is planned to enroll 69 patients to ensure completion of 60 patients. Patients 
will be divided in 3 treatment groups with 23 patients to receive one of the 3 treatments 
(i.e., low and high YPL-001 doses [80 mg and 160 mg BID] and a placebo control) as 
per the randomization schedule.  
13.3.2 Inclusion Criteria 
Patient candidates must fulfill all of the following inclusion criteria to be eligible for 
participation in the study: 
1. Adult males and/or females, 40 to 80 years of age (inclusive).  
2. History of COPD for at least 12 months prior to screening. 
3. Diagnosed with COPD as defined by the American Thoracic Society (ATS)/European 
Respiratory Society (ERS) guidelines with symptoms compatible with COPD for at 
least 12 months prior to screening. 
4. Classified as moderate to severe COPD based on the current severity classification 
GOLD Stage 2-3 disease in terms of post-bronchodilator spirometry at screening: 
• 
Post-bronchodilator FEV1/FVC ratio of <70% 
• 
Post-bronchodilator FEV1 ≥30 % and <80 % of predicted normal values 
5. Weigh at least 52 kg for males and 45 kg for females and within the normal range 
according to accepted normal values of the Body Mass Index (BMI) chart 
18.5-32.0 kg/m2 inclusive. 
6. In the judgment of the Investigator, the patient is medically stable with no change in 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
symptoms, medication, or with clinical laboratory results that in the Investigator’s 
opinion are compatible with the diagnosis of either COPD or a complication thereof 
and are judged acceptable for inclusion with predominantly bronchitic symptoms at 
screening. 
7. Must be on a stable medical regimen for COPD ≥ 30 days prior to screening.  
8. In the Investigator’s opinion patients should be able to withhold tiotropium 24h prior 
to Day 1 of the Run-in Period, if already receiving it and prior to each scheduled CRU 
visit. 
9. Must have oxygen saturation on room air > 93%. 
10. Hemoglobin must be equal to or above the lower limit of normal at screening and 
check-in. 
11. Current or ex-smoker with a history of >10 pack/years. Ten pack/years are defined 
as: 20 cigarettes a day for 10 years; 10 cigarettes a day for 20 years; or 40 cigarettes 
a day for 5 years (i.e., [number of cigarettes smoked per day × number of years 
smoked]/20). Current smokers with <10 pack/years can be included. Patients, who 
undergo smoking cessation therapy, must be completed 3 months prior to screening 
visit and smoking status should not change between the patients screening visit and 
patients last study visit.  
12. For a female of childbearing potential:  either be sexually inactive (abstinent) for 
14 days prior to the first dose and throughout the study or be using one of the 
following acceptable birth control methods: 
a. non-hormone releasing intrauterine device in place for at least 3 months prior to 
the first dose. 
b. surgical sterilization of the partner (vasectomy for 4 months minimum). 
c. physical barrier method (e.g., condom, diaphragm) with spermicide for at least 
14 days prior to the first dose and throughout the study. 
A female patient who claims to be sexually inactive, but becomes sexually active 
during the course of the study must agree to use a physical barrier method (e.g., 
condom, diaphragm) with spermicide from the time of the start of sexual activity 
through to the completion of the study. 
13. For a female of non-childbearing potential: must have undergone one of the following 
sterilization procedures at least 6 months prior to the first dose: 
a. hysteroscopic sterilization; 
b. bilateral tubal ligation or bilateral salpingectomy; 
c. hysterectomy; 
d. bilateral oophorectomy; 
or be postmenopausal with amenorrhea for at least 1 year prior to the first dose and 
follicle-stimulating hormone (FSH) serum levels consistent with postmenopausal 
status as per Investigator judgment. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
14. Non-vasectomized males must agree to be sexually abstinent or to use a condom 
with spermicide when engaging in sexual activity from the first dose through 
completion of the end-of-treatment evaluations. Patients will be advised to use a 
condom with spermicide for 90 days following the last administration of the study 
drug, and to not donate sperm during this same period of time. In the event that the 
sexual partner is surgically sterile, use of a condom with spermicide is not necessary. 
No restrictions are required for vasectomized males provided their vasectomy has 
been performed 120 days or more prior to study start. Males who have been 
vasectomized less than 120 days prior to study start must follow the same 
restrictions as non-vasectomized males. 
15. Understands study procedures and provides written informed consent for the trial. 
16. Be able to comply with the protocol, such as all the study restrictions, and the 
assessments therein. 
13.3.3 Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following 
criteria at screening or check-in, as appropriate.  
1. History of life-threatening COPD including respiratory arrest, intensive care unit 
admission and/or requiring intubation. 
2. History of more than 2 hospitalizations for COPD within 12 months prior to screening. 
3. Presentation of an acute exacerbation of COPD that will be associated with increase 
sputum volume or change in sputum color within 4 weeks before Day 1 of the Run-in 
Period. 
4. Evidence of cor pulmonale, or clinically significant pulmonary hypertension.  
5. Continuous use of more than 2L/day of oxygen. 
6. History or presence of other respiratory disorders, such as asthma, α-1 antitrypsin 
deficiency, active tuberculosis, lung cancer, bronchiectasis, sarcoidosis, lung fibrosis 
or other chronic pulmonary diseases. 
7. A chest X-ray at screening (or within 3 months prior to screening) showing 
abnormalities, which in the opinion of the Investigator are clinically significant and 
unrelated to COPD. 
8. A history of chronic disease including, but not limited to, unstable or uncontrolled 
hypertension (or been diagnosed with hypertension in the 6 months before 
screening), 
sleep 
apnea, 
cardiovascular, 
endocrine, 
neurological, 
hepatic, 
gastrointestinal, renal, hematological, urological, immunological or ophthalmic 
diseases that the Investigator believes are clinically significant e.g., unstable and 
could impact patient safety by participation in the study. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
9. History or presence of: 
• 
significant cardiac arrhythmia; 
• 
prostatic hyperplasia; 
• 
bladder-neck obstruction; 
• 
urinary retention; 
• 
narrow-angle glaucoma. 
10. Evidence of clinically relevant abnormal baseline hematology, serum chemistry, or 
urinalysis. Patients with an AST > 2 x ULN, ALT > 2 x ULN, bilirubin > 2 x ULN or 
creatinine > 2 x ULN (confirmation of results may be done once). 
11. Evidence of hepatic impairment with a Child-Pugh class A score or higher. 
12. Lung resection or lung reduction surgery within 12 months. 
13. Positive urine drug/alcohol testing at screening or at each CRU visit. 
14. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), or hepatitis C antibodies (HCV). 
15. History or presence of alcoholism or drug abuse within the 2 years prior to Day 1 of 
the Treatment Period. 
16. Hypersensitivity or idiosyncratic reaction to compounds related to YPL-001, including 
Speedwell tea and herbal remedies. 
17. Requires one (or more) routine therapies for COPD during the indicated restricted 
time period as listed in Section 13.3.5.1.1.  
18. Use of any drugs or substances known to be significant inhibitors (strong or 
moderate) of UDP-glucuronosyltransferase (UGT) and/or sulfotransferases (SULT), 
within 12 hours prior to Day 1 of the Run-in Period (refer to Appendix 1 and 
Appendix 2). 
19. Blood donation or significant blood loss within 56 days prior to Day 1 of the 
Treatment Period. 
20. Plasma donation within 7 days prior to Day 1 of the Treatment Period. 
21. Participation in another clinical trial within 30 days prior to Day 1 of the Run-in 
Period. 
22. Females who are pregnant or lactating.  
23. Surgery within the past 3 months prior to Day 1 of the Treatment Period determined 
by the Investigator to be clinically relevant. 
24. Active or history of any disease or condition that would, in the opinion of the 
Investigator and/or medical monitor, place the patient at an unacceptable risk to 
participate in this study. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
13.3.4 Removal of Patients from the Study 
Patient participation in this trial may be discontinued for any of the following reasons: 
1. Occurrence of any medical condition or circumstance that exposes the patient to 
substantial risk and/or does not allow the patient to adhere to the requirements of the 
protocol. 
2. Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, 
or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
3. The patient interrupts trial study drug administration for more than 7 consecutive 
days of dosing or missed a total of 17 doses (15%) throughout the Treatment Period. 
4. Patient's decision to withdraw. 
5. Requirement for prohibited concomitant medication. 
6. Patient failure to comply with protocol requirements or study related procedures. 
7. Termination of the study by the Investigator, Sponsor, FDA, Celerion, or other 
regulatory authorities. 
The clinical report will include reason(s) for patient withdrawals as well as details 
relevant to the patient withdrawal. If a patient is withdrawn from the trial prior to study 
completion, the patient will undergo all procedures scheduled for study completion 
(end-of-treatment evaluations) as the situation allows (see Section 13.2.5). Any patient 
withdrawn due to an AE (whether serious or non-serious) or clinically significant 
abnormal laboratory test values will be evaluated by the Investigator and will be treated 
and/or followed up until the symptoms or values return to normal or acceptable levels, as 
judged by the Investigator. 
Patients withdrawn may be replaced at the Sponsor’s discretion. 
13.3.5 Study Restrictions 
13.3.5.1 Concomitant Therapy 
All medications taken during the 30 days prior to the first dose will be recorded and 
reviewed by the Investigator. 
Any medication taken by patients during the course of the study will be recorded. 
Concomitant medication will be coded using the most current WHO drug dictionary 
available at Celerion (e.g., 01-MAR-2014 or later). If drug therapy other than that 
specified by the protocol is taken, a joint decision will be made by the Investigator and 
Sponsor to continue or discontinue the patient. 
13.3.5.1.1 Prohibited Therapy 
The following medications are not permitted within the time delineated below and during 
the study (from Day 1 of the Run-in Period to the completion of the end-of-treatment 
procedures). Intake of these medications during the Run-in Period constitutes a 
non-eligibility criterion and the patients will not be randomized into the study. If any of 
these medications are taken during the Treatment Period, the need for this patient to be 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
withdrawn from the study will be carefully evaluated by the Investigator and the Sponsor 
on the basis of the potential impact on efficacy or safety evaluation and in the patient's 
best interest: 
1. Any medications administered for the treatment of worsening of COPD within 
4 weeks prior to Day 1 of the Run-in Period: 
• 
nebulized, inhaled, oral, IV, IM corticosteroids; 
• 
oral or parenteral β2 agonists; 
• 
Antibiotics. 
2. Inhaled corticosteroids (ICS), LABA, and/or inhaled ICS/LABA fixed combinations 
within 12 hours prior to Day 1 of the Run-in Period; 
3. Inhaled long acting anticholinergic agents other than tiotropium within 2 weeks prior 
to Day 1 of the Run-in Period; 
4. Inhaled short-acting β2-agonists (SABA) other than albuterol (e.g., terbutaline, 
fenoterol) within 12 hours prior to Day 1 of the Run-in Period; 
5. Inhaled short-acting anticholinergic agents (SAMA) (e.g., ipratropium) within 
12 hours prior to Day 1 of the Run-in Period; 
6. PDE inhibitors (including roflumilast) within 2 weeks prior to Day 1 of the Run-in 
Period.  
7. Leukotriene modifiers and xanthines derivatives within 2 weeks prior to Day 1 of the 
Run-in Period. 
8. Drugs or substances known to be significant inhibitors (strong or moderate) of UGT 
and/or SULT, within 12 hours prior to Day 1 of the Run-in Period and through 
collection of the final PK sample. 
9. Acetaminophen will be prohibited 24 hours prior to Day 1 of the Treatment Period 
and through collection of the final PK sample. 
10. Vitamin supplements and herbal products (especially Speedwell) will be prohibited 
7 days prior Day 1 of the Treatment Period and through collection of the final PK 
sample. 
13.3.5.1.2 Permitted Therapy 
Throughout the study Period (from Day 1 of the Run-in Period to the completion of the 
end-of-treatment procedures) patients will be permitted to take the following medications 
in addition to the study drugs: 
1. Albuterol, as required (except approximately 4 hours before schedule pulmonary 
function test); 
2. Tiotropium (Spiriva® HandiHaler®) 18 μg once a day (except approximately 
24 hours before schedule pulmonary function test); 
3. Ibuprofen, as required, up to 1200 mg per day for intercurrent illness or AEs. 
Ibuprofen should not be taken for 2 hours before or after each dosing. 
4. In the case of a concomitant disease, appropriate treatment will be permitted if it 
does not interfere with the study evaluation parameters and does not qualify under 
the section "Prohibited Therapy” (see Section 13.3.5.1.1) 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
13.3.5.2 Prohibitions 
Consumption of foods and beverages containing the following substances will be 
prohibited as indicated: 
• 
Xanthines/caffeine:  24 hours prior to each CRU visit and prior to dosing on Days 1 
and 56 of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Alcohol:  48 hours prior to each CRU visit, 48 hours prior to dosing on Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample, and 
24 hours before the follow-up visit. 
• 
Vegetables from the mustard green family (e.g., kale, broccoli, watercress, collard 
greens, kohlrabi, Brussels sprouts), and mustard:  14 days prior to Day 1 of the 
Treatment Period through collection of Day 56 last PK sample. 
• 
Fruit Juice:  24 hours prior to each CRU visit and prior to dosing on Days 1 and 56 of 
the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Tea (especially Speedwell tea), Coffee and Red Wine:  7 days prior to Days 1 and 56 
of the Treatment Period through collection of Days 1 and 56 last PK sample. 
• 
Grapefruit/Seville orange and beer:  14 days prior to Day 1 of the Treatment Period 
through collection of Day 56 last PK sample. 
13.3.5.3 Activity 
Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Patients will be advised to refrain from strenuous physical activity which could cause 
muscle aches or injury, including contact sports at any time from screening until 
completion of the study. 
13.4 Treatments 
13.4.1 Treatments administered 
13.4.1.1 Drug Administration During Run-in Period 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol base) 
for oral inhalation. Albuterol may be administered via a nebulizer or a metered-dose 
inhaler. 
Multiple oral inhalation of tiotropium (Spiriva® HandiHaler®) 18 μg capsule will be 
administered QD every morning for 14 ± 2 days during the Run-in Period. Albuterol will 
be administered on an as needed basis. 
 
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IND No. 114903 
 
13.4.1.2 Drug Administration During Treatment Period 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A: Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 YPL-001 
80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days. Only the 
morning dose will be administered on Day 56. 
Treatment B: Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 
55 consecutive days. Only the morning dose will be administered on 
Day 56. 
Treatment C: Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching placebo 
tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days. Only the morning dose will be 
administered on Day 56. 
Each dose of Treatments A, B and C will be administered with approximately 240 mL of 
water. 
In all treatments, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also be 
administered QD every morning prior to study drugs administration. Albuterol will be 
administered on an as needed basis. 
The pharmacy at the CRU will provide each dose in individual unit dose containers for 
each patient, as per the randomization scheme. 
Prior to release from the CRU on Days 1, 15, 29, 43, and 55 of the Treatment Period, 
patients will receive a properly labeled container with the appropriate doses which will be 
self-administered by patients at home. Patients will record their self-administered doses 
in their e-diary, and whether the dose was administered with food, and must return the 
container (empty or not) at the next morning visit. Home dosing will be monitored via 
attempted phone calls where patients will be reminded to take their medication, if they 
did not record their self-administration on the e-diary, and queried about the occurrence 
of AEs. 
Patients will be instructed not to crush, split or chew the study drug. 
The exact clock time of dosing will be recorded on on-site dosing days. Patients will be 
given instructions on recording of dosing times in their e-diary on home-dosing days. 
Each dose will be administered under fasting conditions as described in 
Section 13.2.4.1. 
 
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Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
13.4.1.3 Stopping Rules 
A decision to stop or suspend the study will be made jointly by the Sponsor and the 
Investigator following the review of all pertinent safety and tolerability.  Together they will 
make one of the following determinations: 
1. To continue with the study as planned. 
2. To continue with the study and add additional safety evaluations. 
3. To continue with the study by adjusting to a lower dose if 2 patients at any dose level 
meets any of the following criteria and the patient was determined to have received 
YPL-001 after unblinding: 
a. Has a drug–related, unexpected SAE.  
b. Experiences drug-related grade ≥ 3 toxicity. 
4. The study will be terminated if ≥ 3 patients at any dose level meet any of the 
following criteria and the patients were determined to have received YPL-001 after 
unblinding: 
a. Has a drug–related, unexpected SAE. 
b. Experience drug related grade ≥ 3 toxicity. 
PK data will not be required for the dose-escalation decision.  
When applicable, a written statement fully documenting the reasons for study 
termination will be provided to the Institutional Review Board (IRB). 
13.4.2 Method of Assigning Patients to Treatment Groups 
Each patient will be assigned a unique identification number upon screening. Patients 
who complete the study screening assessments, complete the Run-in Period, and meet 
all the eligibility criteria will receive the corresponding product, according to a 
randomization scheme generated at Celerion. Patients will be randomized according to 
their daily consumption of smoked cigarettes per day. The 4 levels (strata) of cigarette 
smoked/day 
to 
be 
used 
in 
the 
randomization 
scheme 
are 
non-smokers 
(i.e., 0 cigarette/day), less than (<) 15 cigarettes/day, between 15 and 30 cigarettes/day, 
and more than (>) 30 cigarettes/day. 
Patients will receive one of the 3 treatments (Treatments A, B, or C) on one occasion. 
If replacement patients are used, the replacement patient number will be 100 more than 
the original (e.g., Patient No. 0101 will replace Patient No. 0001). 
13.4.3 Blinding 
This is a double-blind, double-dummy, randomized study. 
13.4.3.1 Maintenance of Randomization 
A computerized randomization scheme will be created by a Celerion unblinded 
statistician (who is not otherwise involved in the study) and shall be considered blinded 
(per the following).  
 
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The randomization is available only to the clinic pharmacy staff preparing the drug who 
are not involved in any other aspect of the study including administration of the drug. It 
will not be made available to the Sponsor, patients, or members of the staff responsible 
for the monitoring and evaluation of safety assessments. 
The bioanalytical department will also be blinded to the randomization scheme. 
13.4.3.2 Procedures for Breaking the Blind Prior to Study Completion 
One set of the sealed envelopes containing the randomization code will be available to 
the Investigator at the start of the trial 
Breaking of the blind is expressly forbidden except in the event of a medical emergency 
where the identity of the drug must be known in order to properly treat the patient. 
In the event of a medical emergency, it is requested that the Investigator make every 
effort to contact the study monitor or designee prior to breaking the blind. If breaking the 
blind is required because of a medical emergency, the treatment identity would be 
revealed by the qualified designee, for that patient only. In the event that the emergency 
is one, in which it appears that the other patients may be at imminent risk, the blind may 
be broken for all patients dosed at that dose level. The unblinding should be noted in the 
patient’s electronic case report form (eCRF). 
In all cases where the code is broken, the Investigator should record the date, reason for 
code breaking and his/her name for signature on the envelope. 
At the end of the study, the envelopes will be reviewed by the Sponsor. 
13.4.3.3 Revealing of Randomization 
In the absence of a medical emergency, the blinded randomization for this entire trial will 
not be revealed until the following conditions are fulfilled: 
All data are entered in the database, edits checks are performed, queries closed, 
CRFs signed by the Investigator, and the database is officially locked. 
All PK/PD samples have been analyzed and quality checked by the responsible 
analytical associate. 
13.4.4 Treatment Compliance  
During in-clinic dosing, a qualified designate will be responsible for monitoring the 
administration of timed oral doses. When appropriate, a mouth check will be performed 
by the qualified designate to ensure that the patients have swallowed the study 
medication. Once a patient has finished the water, the qualified designate will use a 
flashlight and a tongue depressor to check the side of the mouth, the sides of the upper 
and lower gums and the area under the tongue. Patients’ hands will also be verified to 
ensure that the medication was ingested. 
Self-administration by patients at home will be monitored by the CRU via the e-diary and 
attempted phone calls will be performed to remind patients to take their medication, if 
they did not record their self-administration on the e-diary. 
 
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Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
14. STUDY PROCEDURES 
14.1 Safety Assessments 
This study primarily assesses the safety and tolerability of YPL-001. Safety will be 
determined by evaluating physical examinations, vital signs, pulse oximetry, ECGs, 
clinical laboratory parameters, and AEs.  
If deemed necessary, additional safety measurements will be performed at the discretion 
of the Investigator. 
Study procedures should be completed as close to the prescribed/scheduled time as 
possible. The Quality of Life questionnaire should be performed prior to any other 
procedures. When the following procedures are scheduled at the same time, they will be 
performed in the following order: 
1. 
Vital signs 
2. 
ECG 
3. 
Pulmonary function measurement 
4. 
Bronchoscopy and BAL collection  
All other procedures can be performed without specific order. 
14.1.1 Body Height and Weight 
Body height (centimeters) and body weight (kilograms) will be measured as outlined in 
the Study Events Flow Chart (Section 6). 
14.1.2 Physical Examination 
All full physical examinations will include, at a minimum, assessment of the following 
systems: skin, head, ears, eyes, nose and throat, respiratory system, cardiovascular 
system, gastrointestinal system, neurological condition, blood and lymphatic systems, 
and the musculoskeletal system. 
A licensed physician will examine each patient as outlined in the Study Events Flow 
Chart (Section 6). 
Medical history will be recorded at screening.  
Physical examinations may be performed at various unscheduled time points if deemed 
necessary by the Investigator. 
14.1.3 Vital Signs 
Single measurements of body temperature, respiratory rate, blood pressure, and heart 
rate will be measured as outlined in the Study Events Flow Chart (Section 6). 
Vital signs may be taken at any other times, if deemed necessary. Blood pressure and 
heart rate measurements will be performed with patients in a seated position for at least 
1 minute, except when they are supine or semi-reclined because of study procedures 
and/or AEs (e.g., nausea, dizziness) or if deemed necessary by the Investigator. 
 
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IND No. 114903 
 
When performed prior to the morning dose, blood pressure and heart rate will be 
measured within 2 hours prior to dosing. When scheduled, postdose vital signs readings 
will be performed within approximately 10 minutes of the scheduled time point. When 
performing the bronchoscopy, vital signs (body temperature, respiratory rate, blood 
pressure, and heart rate) will be monitored continuously until the end of the procedure. 
14.1.4 Pulse Oximetry 
Oxygen levels, saturation [%], and heart rate will be assessed using a pulse oximeter. All 
readings will be performed with a pulse oximeter (oxygen levels, saturation [%], and 
heart rate) as outlined in the Study Events Flow Chart in Section 6. 
When performed prior to the morning dose, pulse oximetry monitoring will be measured 
within 2 hours prior to dosing. Readings may be taken at other times, if deemed 
necessary by the Investigator. When performing the bronchoscopy, oxygen saturation 
will be monitored continuously until the end of the procedure. 
Any clinically relevant oxygen saturation reading below 93% will be documented as an 
AE, as per Investigator discretion. 
14.1.5 Electrocardiogram Monitoring 
When performed prior to the morning dose, ECG will be measured within 2 hours prior to 
dosing. When performing the bronchoscopy, ECG will be monitored continuously until 
the end of the procedure. 
Single 12-lead ECGs will be performed as outlined in the Study Events Flow Chart 
(Section 6). Patients will be required to lie quietly in a supine position for at least 
1 minute prior to ECG measurements. Single 12-lead ECGs may be performed at 
various unscheduled time points, if deemed necessary by the Investigator. 
Single 12-lead ECGs will be interpreted and signed and dated by the Investigator. The 
ECGs will be classified as normal, having a non-clinically significant abnormality (NCS), 
or having a clinically significant abnormality (CS). In addition, ECG parameters of 
ventricular rate, PQ or PR interval, QRS duration, and QT interval (corrected according 
to Bazett’s formula [QTcB] and uncorrected) will be noted on the CRF. 
 
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Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
14.1.6 Clinical Laboratory Tests 
All tests listed below will be performed as outlined in the Study Events Flow Chart 
(Section 6). In addition, laboratory safety tests may be performed at various 
unscheduled time points, if deemed necessary by the Investigator. The clinical 
laboratory tests include the following: 
14.1.6.1 Hematology 
• 
Hemoglobin 
• 
Hematocrit 
• 
RBC count 
• 
Platelet count 
• 
Mean Corpuscular Hemoglobin 
(MCH) 
• 
Mean Corpuscular Volume (MCV) 
• 
Mean Corpuscular Hemoglobin 
Concentration (MCHC) 
• 
RDW 
• 
White blood cell (WBC) count with 
differential (including eosinophil, 
neutrophil, basophil, lymphocytes, 
leukocyte, reticulocyte) 
14.1.6.2 Serum Chemistry 
Serum chemistry tests will be performed after at least an 8-hour fast; however, in case of 
dropouts or rechecks, patients may not have fasted for 8 hours before the serum 
chemistry sample is taken. 
• 
BUN 
• 
Creatinine* 
• 
Bilirubin (total and direct) 
• 
Uric acid 
• 
Albumin 
• 
Alkaline phosphatase (ALP) 
• 
Creatine kinase (CK) 
• 
Lactate dehydrogenase (LDH) 
• 
Estimated glomerular filtration rate 
• 
Alpha-1 Antitrypsin** 
• 
AST 
• 
ALT 
• 
Amylase 
• 
Lipase 
• 
Glucose (fasting) 
• 
Carbon dioxide (CO2)/Bicarbonate (HCO3) 
• 
Sodium 
• 
Potassium 
• 
Chloride 
*  Creatinine clearance will be calculated using Cockcroft-Gault formula at screening. 
** To be performed at screening only. 
14.1.6.3 Serology 
• 
HIV 
• 
HBsAg 
• 
HCV 
14.1.6.4 Human Chorionic Gonadotropin (Serum Pregnancy Test)  
The test will be performed for females only. 
 
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IND No. 114903 
 
14.1.6.5 Follicle-Stimulating Hormone 
The test will be performed in postmenopausal females only. 
14.1.6.6 Urinalysis 
• 
pH 
• 
Specific gravity 
• 
Protein 
• 
Glucose 
• 
Ketones 
• 
Bilirubin 
• 
Blood 
• 
Nitrite 
• 
Urobilinogen 
• 
Leukocyte Esterase 
If urinalysis is positive for protein, blood, nitrite and/or leukocyte esterase, a microscopic 
examination will be performed. 
14.1.6.7 Urine Drug/Alcohol Screen 
• 
Cannabinoids  
• 
Alcohol 
• 
Cocaine 
• 
Amphetamines 
• 
Barbiturates 
• 
Benzodiazepines 
• 
Opiates 
14.1.7 Chest X-Ray 
A baseline chest x-ray will be performed at the screening visit. If the patient has had an 
x-ray within the last 3 months prior to the screening visit, and the CRU has access to the 
report and images, this can be used as the baseline chest x-ray and does not need to be 
repeated. 
14.1.8 Adverse Events 
14.1.8.1 Adverse Event Definition 
An AE means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 
A suspected adverse reaction means any AE for which there is a reasonable possibility 
that the drug caused the AE. Reasonable possibility means there is evidence to suggest 
a causal relationship between the drug and the AE.  
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product.3 
14.1.8.2 Monitoring 
The patients will be instructed to inform the Investigator or clinic staff of any AEs and 
intercurrent illnesses experienced during the trial. Additionally, a specific inquiry 
regarding AEs will be conducted prior to each dosing at the CRU, at the end-of treatment 
 
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(or upon early withdrawal), and at the follow-up visit. The inquiry will be made in a non-
specific manner using open-ended questions so as not to bias the response (e.g., How 
have you been feeling since your last visit?). 
All symptoms will be evaluated by the Investigator. 
Any patient who has a clinically significant AE (whether serious or non-serious) or 
clinically significant abnormal laboratory test value will be evaluated by the Investigator, 
or other monitoring physician, and will be treated and/or followed up until the symptoms 
or values return to normal or acceptable levels, as judged by the Investigator.  
Treatment of SAEs will be performed by a physician, either at the CRU or at a nearby 
hospital emergency room. Where appropriate, medical test(s) and/or examination(s) will 
be performed to document resolution of event(s). Outcome may be classified as 
resolved, improved, unchanged, worse, fatal or unknown (lost to follow-up). 
14.1.8.3 Reporting 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher). The Sponsor will inform the Celerion Global Project Manager which version is to 
be used prior to initiation of the study. 
The Investigator will review each event and assess its relationship to drug treatment 
(unrelated, unlikely, possible, probable, definite). The severity of each sign or symptom 
reported will be graded based on the NIH NCI CTCAE toxicity grading scale 5-point 
severity scale (Grade 1, 2, 3, 4 and 5) 4  and the date and time of onset, time relationship 
to drug dosing, duration, and outcome (resolved, improved, unchanged, worse, fatal, or 
unknown/lost to follow-up) of each event will be noted.  
The relationship of each AE will be assessed using the following definitions: 
Unrelated 
 Event occurring before dosing. 
 Event or intercurrent illness due wholly to factors other than drug 
treatment. 
Unlikely 
 Poor temporal relationship with drug treatment. 
 Event easily explained by patient’s clinical state or other factors. 
Possible 
 Reasonable temporal relationship with drug treatment. 
 Event could be explained by patient’s clinical state or other 
factors.  
Probable 
 Reasonable temporal relationship with drug treatment. 
 Likely to be known reaction to agent or chemical group, or 
predicted by known pharmacology. 
 Event cannot easily be explained by patient’s clinical state or 
other factors. 
 
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Definite 
 Distinct temporal relationship with drug treatment. 
 Known reaction to agent or chemical group, or predicted by 
known pharmacology. 
 Event cannot be explained by patient’s clinical state or other 
factors. 
 
The following definitions for rating severity will be used: 
Grade 1 
 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL*. 
Grade 3  
 
Severe or medically significant but not immediately life-threatening; 
hospitalization 
or 
prolongation 
of 
hospitalization 
indicated; 
disabling; limiting self care ADL**. 
Note: An experience may be severe but may not be serious, e.g., 
severe headache). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
14.1.8.4 Serious Adverse Events 
If any AEs are serious, as defined by the Food and Drug Administration (FDA) Code of 
Federal Regulations (CFR), Chapter 21, special procedures will be followed. All SAEs 
will be reported to the Sponsor via fax or e-mail within one working day of becoming 
aware of the event, whether or not the serious events are deemed drug-related. All 
serious event reporting will adhere to 21 CFR 312.32 for Investigational New Drugs 
(IND) and to the Guidance for Industry and Investigators: Safety Reporting 
Requirements for INDs and BA/BE, dated December 20123. The institutional review 
board (IRB) will be notified of the Alert Reports as per FDA regulations. 
If an SAE occurs to a patient on this study, the Sponsor’s Medical Expert is to be 
contacted (see Section 3). 
A SAE is any AE or suspected adverse reaction that in the view of either the Investigator 
or Sponsor, results in any 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 conduct normal life 
functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
 
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patient and may require medical or surgical intervention to prevent one of the outcomes 
listed in the above definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse.  
Life-threatening is defined as an AE or suspected adverse reaction that in the view of the 
investigator or sponsor, its occurrence places the patient at immediate risk of death. It 
does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
Unexpected is defined as an AE or suspected adverse reaction that is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; 
or is not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended. 
14.2 Symptom Assessments 
14.2.1 Electronic Diary 
On Day 1 of the Run-in Period, each patient will be issued and trained on the use of the 
e-diary. They will record their self-administered doses and whether the dose was 
administered with food, concomitant medications and daily respiratory symptoms 
throughout the Run-in and Treatment Periods. Patients will return the e-diary device on 
Day 56 to CRU staff. 
Prior to each dose, patients will record in the e-diary their daily PEF, major (e.g., sputum 
quality, color, consistency) and minor (e.g., cough, wheeze, sore throat, nasal 
congestion, discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation, dyspnea (Modified Borg Dyspnea Scale), and activity (DASI). 
14.2.2 Peak Expiratory Flow 
PEF assessments will be made daily prior to each dose from Day 1 of the Run-in Period 
to Day 56 of the Treatment Period. Three measurements will be made at each time point 
using a hand held PEF meter. Readings not performed in the CRU will be recorded in 
the patient e-diary. All PEF assessments should be performed before administration of a 
bronchodilator where possible. 
14.2.3 Symptoms of Chronic Obstructive Pulmonary Disease Exacerbation 
Patient will be asked to record the major (e.g., sputum quality, color, consistency) and 
minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body 
temperature above 100°F) symptoms of COPD exacerbation via the e-diary before each 
dosing. 
14.2.4 Dyspnea (Modified Borg Dyspnea Scale) 
Severity level of patient’s dyspnea will be assessed via the modified Borg dyspnea scale 
programmed within the e-diary. The modified Borg dyspnea scale is a self-administered 
categorical scale with a score from 0 to 10, where 0 (as a measure of dyspnea) 
 
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corresponds to the sensation of normal breathing (absence of dyspnea) and 10 
corresponds to the patient's maximum possible sensation of dyspnea. 
14.2.5 Activity (Duke Activity Status Index) 
Patient’s functional capacity and activity status will be assessed via the DASI 
programmed within the e-diary. DASI is a self-administered 12-item questionnaire that 
assesses daily activities such as personal care, ambulation, household tasks, sexual 
function and recreation with respective metabolic costs. Each item has a specific weight 
based on the metabolic cost. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. 
14.3 Pharmacodynamic Assessments 
14.3.1 Pulmonary Function (Spirometry) 
Spirometry measures will be taken at the time points delineated in the Study Events 
Flow Chart (Section 6) using a standard calibrated spirometer to determine the 
parameters detailed below.  
• 
FEV1; 
• 
FVC (forced vital capacity); 
• 
FEV1/FVC; 
• 
IC. 
Short acting β2-agonist and anticholinergic bronchodilators (e.g., albuterol, ipratropium 
bromide) and long acting β2-agonist and anticholinergic bronchodilators (e.g., 
salmeterol, tiotropium) agents will be withheld approximately 4 and 12 hours, 
respectively, before each pre-bronchodilator spirometry. 
Every effort will be made to perform all assessments for a given patient on the same 
instrument throughout the study and all sites should be using the same brand and model 
of spirometer for this study. 
At screening, baseline pre-bronchodilator spirometry will be performed (prior to albuterol 
administration) for a minimum of 3 times and a maximum of 8 times in order to obtain 
3 manoeuvers with FEV1 values within 150 mL of each other, using the manoeuver with 
the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol, (100 μg/inhalation), for a total dose of 
400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 30 minutes 
after albuterol administration, the baseline post-bronchodilator spirometry will be 
performed. 
Assessment of FEV1 stability will take place: 
1. Prior to Day 1 dosing of the Treatment Period (Day -1 measurement): Predose 
FEV1 is defined as the time-point prior to Day 1 dosing in the Treatment Period 
and will be performed pre- and post-bronchodilatator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best 
 
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FEV1 measurement at predose on Day -1 of the Treatment Period has declined 
by greater than 20% from the best FEV1 at screening, the visit may be 
rescheduled up to 3 times, at the discretion of the Investigator. 
2. Following Day 1 dosing: At all other spirometry time point, measurements will be 
performed once. If the value shows a difference of greater than 150 mL decline 
than the best FEV1 value collected predose on Day -1, up to 3 measures will be 
performed.  
Consideration should be given, if a patient experiences any change in post Day 1 
dose FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the Investigator to 
consider whether individual patients should continue to dose. The pulmonary 
function manoeuver(s) used to make this assessment must be valid and meet 
acceptable quality spirometry standards. 
The Investigator may also use his or her discretion as to the completion of dosing for any 
period in which an FEV1 decline and/or respiratory symptoms occur(s). 
14.3.2 Bronchoscopy and Bronchoalveolar Lavage (BAL) Biomarkers 
Patients will be asked to refrain from smoking approximately 48 hours before the 
bronchoscopy procedures and will be fasted for 12 hours before. If required, blood 
pressure medications can be taken with small sip of water based on preapproval of local 
Investigator. 
14.3.2.1 Bronchoscopy 
The bronchoscopy with bronchial brushings will be performed at the time points 
delineated in the Study Events Flow Chart (Section 6) by a licensed physician 
experienced in conducting the procedure according to guidelines published on the use of 
bronchoscopy for research on airway diseases such as COPD.5,6 
Albuterol will be administered 20 minutes prior to the beginning of the bronchoscopy. An 
intravenous line will also be established to administer conscious sedation, and to 
administer emergency medications if the need were to arise. During the procedure, 
oxygen saturation (SPO2), blood pressure, and heart rate and rhythm (continuous 
electrocardiogram) will be monitored. Oxygen 2-4 L via nasal canula will be administered 
during bronchoscopy and oxygen saturation will be maintained at ≥95%. Conscious 
sedation will be achieved with incremental doses of 1–4 mg midazolam and 50-100 μg 
fentanyl. Local upper and lower airway topical anesthesia will be achieved with 1% or 
2% lidocaine. The dose of lidocaine administered during the procedure will not exceed a 
total of 450 mg. The bronchoscope will usually be inserted preferably through the nares 
into trachea. The bronchoscope will be wedged into 2 subsegments of the right middle or 
lower lobe, as deemed appropriate by the Investigator. Emergency treatments for 
cardiopulmonary arrest and pneumothorax will be immediately available in the 
bronchoscopy room. The patient will remain in the recovery suite for observation for a 
minimum of 2 hours after the procedure.  
 
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14.3.2.2 Bronchial Brushings 
Prior to BAL, a cytology brush is inserted into the bronchoscope channel and brushings 
are collected twice from each of 4 quadrants of visible subsegments of the right middle 
or lower lobe, as deemed appropriate by the Investigator, under direct visualization. The 
cellular material is washed off in saline following each brushing. The brushing is 
performed a total of 8 times. The liquid is centrifuged and the cell pellet is stored 
at -70°C. 
14.3.2.3 Bronchoalveolar Lavage (BAL)  
BAL in the right middle or lower lobe, as deemed appropriate by the Investigator, will be 
performed at the time points delineated in the Study Events Flow Chart (Section 6) by a 
licensed physician experienced in conducting the procedure. A 180 mL BAL will be 
performed in each subsegment of the right middle or lower lobe, as deemed appropriate 
by the Investigator, using 6 x 30 mL aliquots of normal saline warmed to room 
temperature. BAL fluid will be aspirated following each 30 mL instillation. The lavage 
material, which averages 25% return in COPD patients, typically yields 1-10 x 106 
macrophages. The centrifuged cell pellet is divided into 2 aliquots. One (1) aliquot will be 
stored at -70°C and the other will be cooled and stored in an ice bath until processing. 
The supernatant is divided into 4-5 aliquots and stored in cryotubes in ice bath until 
processing. 
14.3.2.4 Biomarkers 
BAL samples will be analyzed for: 
• 
YPL-001 component levels in epithelial brushings; 
• 
total cell count (cells/mL) of macrophages, lymphocytes, and eosinophils as a 
percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, and eosinophils 
as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, 
MCP-1, and MMP-9. 
14.3.3 Blood Biomarkers 
Blood samples will be collected via direct venipuncture at the time points delineated in 
the Study Events Flow Chart (Section 6) for PD assessments of biomarkers. Biomarker 
assessments include: 
• 
inflammatory markers (total and differential cell counts as absolute and percentage 
for neutrophils, macrophages, eosinophils, and lymphocytes)  
• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, 
and MMP-9. 
Blood will be drawn into 4.5 mL pre-chilled evacuated tubes containing K2EDTA and 
stored in an ice bath until processing. 
 
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14.3.4 Quality of Life Questionnaires 
14.3.4.1 Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) 
Dyspnea at baseline (Day 1 of the Treatment Period) will be assessed with the BDI. This 
instrument has 3 domains (functional impairment, magnitude of task and magnitude of 
effort) with the values added for a combined focal score. Functional impairment 
determines the impact of breathlessness on the ability to carry out activities; magnitude 
of task determines the type of task that causes breathlessness, magnitude of effort 
establishes the level of effort that results in breathlessness. The BDI scores range from 
0 (very severe impairment) to 4 (no impairment) for each domain with the baseline focal 
score consisting of the sum of each domain (0 to 12).  
Dyspnea throughout the study will be performed at the time points delineated in the 
Study Events Flow Chart (Section 6). The change from baseline is measured by the TDI 
score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
The same Investigator or designee will interview specifically the patients during the 
study.  
A copy of the questionnaire to be used will be kept in the study binder.  
14.3.4.2 COPD Assessment Test (CAT) 
CAT is a short and simple questionnaire of 8 items completed by patients to be 
performed at the time points delineated in the Study Events Flow Chart (Section 6). 
Scores for each of the 8 items are summed to give a single, final score ranging from 0 
(no impact on daily activities) to 40 (very high impact on daily activity). This is a measure 
of the overall impact of a patient’s condition on their life. Scores for the individual items 
within the questionnaire will provide insight into the relative influence that the different 
components of COPD have on its overall impact on a patient’s life.7,8 
A copy of the questionnaire to be used will be kept in the study binder. 
14.4 Pharmacokinetic Assessments 
The sampling schedule and/or collection intervals delineated in the Study Events Flow 
Chart (Section 6) may be modified based on the results from previously dosed patients. 
14.4.1 Blood Sampling and Processing 
Samples must be protected from UV light during collection, processing, and storage.  
Samples will be collected via direct venipuncture at the time points delineated in the 
Study Events Flow Chart (Section 6).  
Blood will be drawn into 5 mL pre-chilled evacuated tubes containing K2EDTA. A manual 
for blood sampling, collection, processing, and sample shipment will be provided in a 
separate document.  
 
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14.5 Blood Volume for Study Assessments 
Table 5: Blood Volume during Study 
Sample Type 
Number of 
Time Points 
Volume per 
Time Point* 
Sample Volume Over 
Course of Study 
Screening laboratory safety tests (including 
hematology, serum chemistry, serology), 
FSH (for postmenopausal female patients 
only) and serum pregnancy (for female 
patients only). 
1 
~ 17 mL 
~ 17 mL 
On-study serum chemistry and serum 
pregnancy (for female patients only) when 
scheduled at the same time 
4 
~ 8.5 mL 
~ 34 mL 
Additional on-study serum pregnancy (for 
female patients only) 
2 
~ 3.5 mL 
~ 7 mL 
On-study hematology 
4 
~ 4 mL 
~ 16 mL 
Blood samples for PD biomarkers 
8 
~ 4.5 mL 
~ 36 mL 
Blood samples for PK of verproside and 
picroside II 
37 
~ 5 mL 
~ 185 mL 
Total Blood Volume for males → 
~ 288 mL 
Total Blood Volume for females → 
~ 295 mL 
* Represents the largest collection tube that may be used for this (a smaller tube may be used). 
 
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15. DATA ANALYSIS 
Data will be handled and processed according to Celerion Standard Operating 
Procedures, which are written based on the principles of GCPs. 
15.1 Statistical Analysis 
Detailed methodology for summary and statistical analyses of the data collected in this 
trial will be documented in a SAP. The SAP will be prepared by Celerion and agreed 
upon with the Sponsor. This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoints definition and/or its analysis 
will also be reflected in a protocol amendment. Additional statistical analyses other than 
those described in this section may be performed if deemed appropriate and included in 
the SAP.  
15.1.1 Sample Size Calculation 
According to the exploratory nature of this study no formal statistical hypotheses will be 
tested. However, a sample size of 60 evaluable patients is deemed to be sufficient to 
assess the safety and tolerability and to provide an indication of the potential effect of 
YPL-001 on COPD exacerbation symptoms, selected biomarkers and pulmonary 
function parameters. An additional 9 patients will be enrolled to account for a 15% 
drop-out rate. 
15.1.2 Patients to Analyze 
Safety population: the safety population data set will include all available data for 
patients who received at least one dose of the investigational product (i.e., YPL-001) or 
placebo. Safety data for all discontinued patients will be included in this set for the time 
points for which their data are available.   
Symptom monitoring population: the symptom monitoring population data set will 
include all available data for patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo. Symptom monitoring data for all 
discontinued patients will be included in this set for the time points for which their data 
are available. 
PK population:  
• 
The PK full data set will include all patients receiving at least one dose of YPL-001 
and having at least one measurable plasma and/or urine concentration of verproside 
and picroside II.   
• 
The PK per-protocol data set will include all patients receiving all scheduled doses of 
YPL-001 and having sufficient samples collected to determine PK parameters from 
plasma concentrations of verproside and picroside II on Days 1 and/or 56. 
PD population:  
• 
The PD full data set will include all patients who received at least one dose of the 
investigational product (i.e., YPL-001) or placebo and provide at least 1 post-
baseline PD measurement. 
 
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• 
The PD per-protocol data set will include all patients receiving all scheduled doses of 
the investigational product (i.e., YPL-001) or placebo and having measurable PD 
data. 
PK/PD population: All patients who receive at least one dose of YPL-001 and having 
any measurable concentration of verproside and picroside II and measurable PD data 
will be included in the PK/PD relationship assessment, as applicable. 
15.1.3 Safety Analysis 
The following analyses will be performed. Safety analyses will be based on treatment 
actually received by patients. Descriptive statistics will be calculated for quantitative 
safety data and frequency counts will be compiled for classification of qualitative safety 
data, when appropriate. 
Medical History: 
Medical history will be listed by patient. 
Adverse Events: 
AEs will be coded using the most current MedDRA® available at Celerion (e.g., 17.0 or 
higher) and data will be summarized by SOC and preferred term. The number of TEAEs 
will be reported. In addition, the number and percent of patients reporting each TEAE will 
be summarized separately for each treatment. 
A by-patient AE data listing, including verbatim term, preferred term, treatment, severity, 
outcome, and relationship to treatment, will be provided. 
Physical Examination: 
Changes in physical examinations will be described in the text of the final report and 
significant findings will be reported as AEs. 
Clinical Laboratory Tests, Electrocardiograms, Vital Signs and Pulse Oximetry: 
All clinical laboratory tests, 12-lead ECGs, vital signs, and pulse oximetry measurements 
and their change from baseline, if applicable, will be summarized by treatment and time 
point of collection. 
A shift table describing out-of-normal range shifts will be provided for clinical laboratory 
results.  
A normal-abnormal shift table will be presented for ECGs. 
Peak Expiratory Flow: 
PEF measurements and its change from baseline, will be summarized by treatment and 
time point of collection. 
Concomitant Medications: 
Concomitant medications will be listed by patient and coded using the most current 
WHO drug dictionary available at Celerion (e.g., 01-MAR-2014 or later). 
 
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15.1.4 Symptom Monitoring Analysis 
Symptom free days and overall symptom burden will be evaluated and compared across 
treatment groups. Secondary outcome analysis will be based on treatment actually 
received by patients. Descriptive statistics will be calculated for quantitative data and 
frequency counts will be compiled for classification of qualitative data, when appropriate. 
Peak Expiratory Flow and Symptoms of COPD Exacerbation: 
PEF measurements and symptoms of COPD exacerbation and their change from 
baseline, will be summarized by treatment and time point of collection. 
Dyspnea and Activity: 
The Modified Borg Dyspnea Scale and DASI scores will be listed and presented 
descriptively. 
Additional analysis may be performed if deemed appropriate. 
15.1.5 Pharmacodynamic Analysis 
15.1.5.1 Biomarkers 
When applicable, the following PD biomarkers will be summarized by treatment group 
using descriptive statistics (arithmetic means, SD, CV, N, minimum, maximum, and 
median). Figures will be created to display mean and individual level or activity as a 
function of time, as appropriate: 
• 
Pulmonary biomarker (i.e., Pulmonary Function measurements [Spirometry]): 
pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity; 
• 
BAL biomarkers (i.e., total cell count [cells/mL] of macrophages, lymphocytes and 
eosinophils as a percentage of total cells; total cell count [cells/mL] of neutrophils, 
macrophages, lymphocytes and eosinophils as absolute inflammatory cell numbers; 
and concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil 
elastase, MCP-1, and MMP-9): raw and % change from baseline levels; and 
• 
Blood biomarkers (i.e., inflammatory markers [total and differential cell counts as 
absolute 
and 
percentage 
for 
neutrophils, 
macrophages, 
eosinophils 
and 
lymphocytes] and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9): raw and % change from baseline levels.  
PK/PD relationship may be explored graphically using scatter plots and an appropriate 
regression model. 
15.1.5.2 Quality of Life 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires will be 
listed and presented descriptively. Additional analysis may be performed if deemed 
appropriate. 
 
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15.1.6 Pharmacokinetic Analysis 
15.1.6.1 Pharmacokinetic Parameters 
15.1.6.1.1 Plasma 
PK parameters will be computed from the individual plasma verproside and picroside II 
concentrations using a noncompartmental approach. Appropriate validated PK software 
(e.g., WinNonlin Professional) will be used. PK parameters for other components of 
YPL-001 and its metabolites may also be computed, as appropriate. 
The following PK parameters will be computed following Day 1 morning dose: 
AUC0-12 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to 12 hours. 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). This parameter will be reported 
only if plasma concentrations fall below the lower limit of quantitation 
before the last time point prior to the evening drug administration on 
Day 1 for at least one patient. Otherwise, only AUC0-12 will be reported. 
AUC0-inf 
Area under the drug concentration-time curve from time zero to infinity, 
AUC0-inf = AUC0-t + Ct/kel, where kel is the terminal elimination rate 
constant. † 
Cmax 
Maximum observed drug concentration. 
tmax 
Time of the maximum drug concentration (obtained without 
interpolation). 
kel 
Apparent terminal elimination rate constant, calculated by linear 
regression of the terminal linear portion of the log concentration vs. 
time curve. †  
t1/2 
Apparent elimination half-life, calculated as ln(2)/kel. † 
CL/F 
Oral clearance [Dose/AUC0-inf]. †  
VZ/F 
Apparent volume of distribution at the terminal phase, calculated as 
Dose/(kel * AUC0-inf).†  
† All kel and related PK parameters (AUC0-inf, t1/2, CL/F, and Vz/F) will be reported only if 
the half-life of verproside or picroside II can be appropriately estimated from a 12-hour 
sampling period following dosing. 
 
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The following PK parameters will be computed following Day 56 morning dose:  
AUCτ 
The area under the plasma concentration versus time curve over the 
final dosing interval, as calculated by the log-linear trapezoidal method 
(e.g., 0-12 hours). 
AUC0-t 
Area under the drug concentration-time curve, calculated using linear 
trapezoidal summation from time zero to time t, where t is the time of 
the last measurable concentration (Ct). 
Cmax_ss 
Maximum observed drug concentration at steady-state. 
Cmin,ss: 
Minimum observed/measured non-zero concentration at steady-state. 
Ctrough 
Concentration at the end of a dosing interval. 
Cavg 
Ratio of AUCτ to the dosing interval, τ. 
%Fluc: 
Percent fluctuation will be calculated as follows: 
𝐶max _𝑠𝑠−𝐶min _𝑠𝑠
𝐶𝑎𝑣𝑔
 𝑥 100 
Swing: 
Percent swing will be calculated as follows: 
Cmax _ss −Cmin _ss
Cmin_ss
 x 100 
tmax_ss 
Time to reach the maximum drug concentration (obtained without 
interpolation) at steady-state. 
CLss/F 
Total 
body 
clearance 
estimated 
at 
steady-state 
after 
oral 
administration, calculated as Dose/AUCτ. 
Vz_ss/F 
Apparent volume of distribution at steady-state, calculated as 
(CLss/F)/kel.* 
* All kel and related PK parameters (t1/2 or Vz_ss/F) will not be reported for cases that do 
not exhibit a terminal log-linear phase in the concentration versus time profile. 
If metabolite data are available, metabolite to parent ratios may be calculated for AUC0-t, 
AUCτ, and Cmax_ss. 
15.1.6.1.2 Bronchoalveolar Lavage 
Levels of YPL-001 components in epithelial brushing will be listed. 
 
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15.1.6.2 Statistical Methods for Pharmacokinetic Analyses 
PK parameters will be summarized by treatment group using descriptive statistics 
(arithmetic means, SD, CV, N, minimum, maximum, and median). In addition, 
geometric means will be calculated for AUCτ and Cmax_ss, as appropriate. Figures will 
be created to display mean and individual verproside and picroside II concentration-time 
curves. Additional PK analyses may be performed if deemed appropriate. 
No value for kel, t1/2, and Vz_ss/F, as appropriate, will be reported for cases that do not 
exhibit a terminal log-linear phase in the concentration versus time profile. 
An estimate of the relative systemic exposure of AUCτ and Cmax_ss will be performed by 
dose normalized ratio analysis expressing the geometric mean ratio and 90% CI of the 
geometric mean ratio. 
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15, 29, 43, and 56 following multiple oral dose administration of YPL-001. 
Additional analyses will be performed as deemed necessary upon review of the data. 
15.1.7 Assessment of Efficacy 
Efficacy will not be assessed in this study. 
 
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16. STUDY ADMINISTRATION 
16.1 Ethics 
16.1.1 Institutional Review Board  
This protocol will be reviewed by an IRB and the study will not start until the Board has 
approved the protocol or a modification thereof. The Board is constituted and operates in 
accordance with the principles and requirements described in the US Code of Federal 
Regulations (21 CFR Part 56). The board is ICH compliant. 
16.1.2 Ethical Conduct of the Study 
This research will be carried out in accordance with the protocol, US Code of Federal 
Regulations, GCP, 21 CFR Parts 50, 56, and 312, the ethical princliples set forth in the 
Declaration of Helsinki, and the ICH harmonized tripartite guideline regarding GCP (E6 
Consolidated Guidance, April 1996). 
16.1.3 Patient Information and Consent 
The purpose of the study, the procedures to be carried out and the potential hazards will 
be described to the patients in non-technical terms. Patients will be required to read, 
sign and date an informed consent form summarizing the discussion prior to screening, 
and will be assured that they may withdraw from the study at any time without 
jeopardizing their medical care. 
Patients will be given a copy of their informed consent form. 
16.2 Termination of the Study 
The Sponsor reserves the right to discontinue this study and the Investigator reserves 
the right to terminate their participation at any time.  
16.3 Data Quality Assurance 
Standard operating procedures are available for all activities performed at Celerion 
relevant to the quality of this study. Designated personnel of Celerion will be responsible 
for maintaining quality assurance (QA) and quality control (QC) to ensure that the trial is 
conducted, and that data are generated, documented and reported in compliance with 
the study protocol, GCP and Good Laboratory Practice requirements as well as 
applicable regulatory requirements. 
The Clinical Study Report will be audited by the QA department and the quality 
assurance audit certificate will be included in the study report. 
All clinical data will undergo a 100% quality control check prior to clinical database lock. 
Edit checks are then performed for appropriate databases as a validation routine using 
SAS® to check for missing data, data inconsistencies, data ranges etc. Corrections are 
made prior to statistical database lock. 
Patient compliance will be monitored throughout the study via procedures such as 
questioning at check-in to review inclusion and exclusion criteria, urine drug screen at 
 
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check-in, mouth check following dosing, and confinement for all conduct procedures with 
clinical research staff on site at all times. 
16.4 Direct Access to Source Data/Documents 
The Investigator must maintain, at all times, the primary records (i.e., source documents) 
of each patient’s data. Examples of source documents are laboratory reports, drug 
inventory, study drug label records, and eCRFs that are used as the source. 
Celerion will ensure that the sponsor, IRB and inspection by domestic and foreign 
regulatory authorities will have direct access to all trial-related sites, source 
data/documents, and reports for the purpose of monitoring and auditing (ICH[E6] 5.1.2 & 
6.10). In the event that other trial-related monitoring should be done by other parties, 
they will be required to sign a confidentiality agreement prior to any monitoring and 
auditing. 
16.5 
Drug Supplies, Packaging and Labeling 
The Sponsor will supply sufficient quantities of YPL-001 80 mg tablets,  and matching 
placebo tablets to allow completion of this study. The lot numbers and expiration dates 
(where available) of the drugs supplied will be recorded in the final report. 
Records will be made of the receipt and dispensing of the drugs supplied. At the 
conclusion of the study, any unused drugs (including placebo) will either be retained by 
the CRU, or returned to the Sponsor, depending on the specific requirements of the 
regulatory bodies to whom the study report will be submitted. If no supplies remain, this 
fact will be indicated in the Drug Accountability section of the final report. 
16.6 Data Handling and Record Keeping 
Celerion standard eCRFs will be used. Each eCRF is reviewed and signed off by the 
Investigator. 
All raw data generated in connection with this study, together with the original copy of 
the final report, will be retained at each CRU in a designated storage facility, until at least 
5 years after the last approval of a marketing application in an ICH region and until there 
are no pending or contemplated marketing applications in an ICH region or at least 5 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
the Sponsor. It is the responsibility of the Sponsor to inform the Investigator/Institution as 
to when these documents no longer need to be retained. 
16.7 Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study 
progresses will be discussed between Sponsor and the Investigator. All revisions and/or 
amendments to the protocol in writing must be approved by the Sponsor, the 
Investigator, and the IRB before implementation. 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
16.8 Finance and Insurance 
Finance and insurance will be addressed in a separate document. 
16.9 Publication Policy 
All unpublished information given to Celerion by the Sponsor shall not be published or 
disclosed to a third party without the prior written consent of the Sponsor.   
The data generated by this study are considered confidential information and the 
property of the Sponsor. This confidential information may be published only in 
collaboration with participating personnel from the Sponsor or upon Sponsor’s written 
consent to publish the article. 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
17. REFERENCES 
 
1 Yungjin Pharma Co., LTD.: YPL-001. Investigator’s Brochure. Final 2.0; 3 June 2014. 
2 FDA Guidance for Industry: Estimating the maximum safe starting dose in initial clinical trials for 
therapeutics 
in 
adult 
healthy 
volunteers. 
 
July 
2005. 
Available 
online:  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm
078932.pdf   
3 FDA Guidance for Industry and Investigators:  Safety Reporting Requirements for INDs and 
BA/BE 
Studies-Small 
Entity 
Compliance 
Guide. 
December 
2012. 
Available 
online: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UC
M332846.pdf 
4 National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0. NCI, NIH, 
DHHS. 
May 
29, 
2009. 
NIH 
publication 
# 
09-7473. 
Available 
online 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm The quick reference 
guide 
is 
available 
online 
at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
5 Busse WW, et al. Investigative bronchoprovocation and bronchoscopy in airway diseases. Am J 
Respir Crit Care Med. 2005;172(7):807-816 
6 Jarjour NN, Peters SP, Djukanović R, and Calhoun WJ. Investigative use of bronchoscopy in 
asthma. Am J Respir Crit Care Med. 1998;157(3 Pt 1):692-697. 
7 Jones PW, et al. Development and First Validation of the COPD Assessment Test. Eur Respir J. 
2009;34:648-654. 
8 The COPD Assessment Test healthcare professional user guide: expert guidance on frequently 
asked questions (issue 3: February 2012). Jones PW, Jenkins C, Bauerle O (on behalf of the 
CAT Development Steering Group). 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
18. APPENDIXES 
18.1 
Appendix 1 - UGT Drug Interaction Table 
The following list provides medications that are substrates or inhibitors of UGT. Adapted 
from Williams JA, et al. Drug-drug interactions for UDP-glucuronosyltransferase 
substrates:  a pharmacokinetic explanation for typically observed low exposure 
(AUCi/AUC) ratios. Drug Metab Dispos. 2004;32(11):1201-8. Epub 2004 Aug 10. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Amitriptyline 
Carvedilol 
Clofibric acid 
Codeine 
Cyclobenzaprine 
Diclofenac 
DMXAA 
Fenofibrate 
Flavopiridol 
Furosemide 
Gemfibrozil 
Glipizide 
Irbesartan 
Lamotrigine 
Levothyroxine 
Metoclopramide 
Metronidazole 
Morphine 
Naloxone 
Naproxen 
Olanzapine 
Oxazepam 
Paracetamol 
Propofol 
Raloxifene 
Tramadol 
Valdecoxib 
Valproic acid 
Zidovudine 
17-beta-estradiol glucuronide 
Flavonoids (citrus fruit) 
Silybin (herb supplement milk thistle) 
 
 
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Yungjin Pharm. CO., LTD. 
Proof of Concept 
YPL-001 
Celerion Project No. : AA98497 
Sponsor Project No.: YPL-001-YJP-130403 
IND No. 114903 
 
18.2 Appendix 2 - SULT Drug Interaction Table 
The following list provides medications that are substrates and inhibitors of 
sulfotransferase. Adapted from Zhang H, Cui D, Wang B, Han YH, et al. 
Pharmacokinetic drug interactions involving 17alpha-ethinylestradiol:  a new look at an 
old drug. Clin Pharmacokinet. 2007;46(2):133-57; Coughtrie MW, Johnston LE. 
Interactions between dietary chemicals and human sulfotransferases-molecular 
mechanisms and clinical significance. Drug Metab Dispos. 2001;29(4 Pt 2):522-528; 
King RS, Ghosh AA, and Wu J Inhibition of human phenol and estrogen sulfotransferase 
by certain non-steroidal anti-inflammatory agents. Curr Drug Metab. 2006;7(7):745–753; 
Nagai M, et al. Inhibitory effects of herbal extracts on the activity of human 
sulfotransferase 
isoform 
sulfotransferase 
1A3 
(SULT1A3). 
Biol 
Pharm 
Bull. 
2009;32(1):105-109; and Harris, R. M.; Waring, R. H. Sulfotransferase inhibition:  
potential impact of diet and environmental chemicals on steroid metabolism and drug. 
Current Drug Metabolism 2008;9(4):269-275. 
Substrates 
Inhibitors 
17-beta-estradiol glucuronide 
Vitamin C 
Acetaminophen 
 
17-beta-estradiol glucuronide 
Vitamin C 
Brown rice 
Beer 
Meclofenamate 
Nimesulide 
Salicylic acid 
Acetylsalicylic acid 
Naproxen  
Banaba extract 
Rafuma extract 
Grape seed extract 
Peanut seed coat extract 
Gingko extract 
Biloba leaf extract 
St. John’s wort 
Gymnema  
Milk thistle 
 
 
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SAP_001.pdf: 
Statistical Analysis Plan 
 
A Randomized, Double-Blind, Placebo Controlled, Multicenter Phase 2a Study to Assess 
Safety, Daily Respiratory Symptoms, Pharmacokinetics, and Biomarker Variations after 
Administration of either YPL-001, or Placebo in Patients with Moderate-to-Severe Chronic 
Obstructive Pulmonary Disease 
Celerion Protocol No:  AA98497 
Sponsor Project No:  YPL-001-YJP-130403 
Final Protocol Date:  18 September 2014 
Amendment One Date:  18 November 2014 
Amendment Two Date:  16 February 2015 
Amendment Three Date:  23 April 2015 
Amendment Four Date: 16 September 2015 
Amendment Five Date: 05 November 2015 
Amendment Six Date: 28 April 2016 
Amendment Seven Date: 08 June 2016 
Compound Name:  YPL-001 
Celerion Project AA98497 
Final Amendment 1 Version 
Date:   20 March 2017 
 
Yungjin Pharm. CO., LTD. 
13, Olympic-ro 35da-gil, Songpa-gu 
Seoul, 05510 
Republic of Korea 
Celerion 
621 Rose Street 
Lincoln, Nebraska 68502, USA 
 
 




Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 3 of 150 
Table of Contents 
1. 
INTRODUCTION .........................................................................................................5 
2. 
OBJECTIVES AND ENDPOINTS ...............................................................................5 
2.1 
Objectives ..........................................................................................................5 
2.2 
Endpoints ...........................................................................................................6 
3. 
STUDY DESIGN...........................................................................................................7 
4. 
ANALYSIS POPULATIONS .......................................................................................8 
4.1 
Analysis Populations ..........................................................................................8 
4.2 
Preliminary Data and Interim Analysis ..............................................................9 
5. 
TREATMENT DESCRIPTIONS ..................................................................................9 
5.1 
Study Treatments ...............................................................................................9 
5.2 
Other Treatments .............................................................................................10 
6. 
SYMPTOM MONITORING ANALYSIS ..................................................................10 
6.1 
Measurements, Collection Schedule, and Analysis .........................................10 
6.2 
Data Summarization and Presentation .............................................................11 
7. 
PHARMACODYNAMICS ANALYSIS .....................................................................11 
7.1 
Biomarkers and Quality of Life Assessments ..................................................11 
7.1.1 
Measurements, Collection Schedule, and Analysis ..........................11 
7.1.1.1 Biomarkers in Bronchoalveolar Lavage 
Samples ...........................................................................................11 
7.1.1.2 Biomarkers in Blood .......................................................................12 
7.1.1.3 Pulmonary Function Biomarkers ....................................................13 
7.1.1.4 Quality of Life Assessments ...........................................................14 
7.1.2 
Data Summarization and Presentation ..............................................14 
8. 
PHARMACOKINETIC ANALYSIS ..........................................................................15 
8.1 
Measurements and Collection Schedule ..........................................................15 
8.1.1 
Blood Sample Collection ..................................................................15 
8.1.1.1 Handling of Time Deviation ...........................................................15 
8.1.2 
Bronchoalveolar Sample Collection .................................................16 
8.2 
Bioanalytical Method .......................................................................................16 
8.3 
Investigational Product and PK Analyte Information ......................................16 
8.4 
Pharmacokinetic Concentrations .....................................................................17 
8.5 
Noncompartmental Pharmacokinetic Analysis and Parameter 
Calculation .......................................................................................................18 
8.5.1 
Plasma Pharmacokinetic Parameters ................................................18 
8.6 
Data Summarization and Presentation .............................................................22 
8.7 
Statistical Analysis of Pharmacokinetic Parameters ........................................24 
9. 
PHARMACOKINETIC/PHARMACODYNAMIC RELATIONSHIP ......................24 
10. 
SAFETY ......................................................................................................................24 
10.1 
Subject Discontinuation ...................................................................................25 
10.2 
Demographics ..................................................................................................25 
10.3 
Exposure to Study Drug ...................................................................................25 
10.4 
Adverse Events ................................................................................................25 
10.5 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Urinalysis) .........26 
10.6 
Vital Signs and Pulse Oximetry .......................................................................26 
10.7 
12-lead Electrocardiogram ...............................................................................26 


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YPL-001, Project Number YPL-001-YJP-130403 
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10.8 
Concomitant Medications ................................................................................27 
10.9 
Physical Examination.......................................................................................27 
10.10 Medical History ...............................................................................................27 
11. 
SUMMARY TABLES AND FIGURES .....................................................................27 
11.1 
In-text Summary Tables and Figures ...............................................................27 
11.2 
Section 14 Summary Tables and Figures.........................................................31 
11.3 
Section 16 Data Listings ..................................................................................43 
12. 
TABLE SHELLS .........................................................................................................48 
12.1 
In-text Table Shells ..........................................................................................49 
12.2 
Post-text Table Shells ......................................................................................67 
13. 
LISTING SHELLS ....................................................................................................111 
 
 
 


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YPL-001, Project Number YPL-001-YJP-130403 
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1. 
INTRODUCTION 
The following analysis plan provides the framework for the summarization of the data 
from this study. The Statistical Analysis Pan (SAP) may change due to unforeseen 
circumstances. Any changes made after the unblinding or locking of the database will 
be documented in the clinical study report (CSR). Please note that the header for this 
page will be the one used for the main body of the CSR.  
Any additional exploratory analyses not addressed within this SAP and/or driven by 
the data, or requested by Yungjin Pharm. CO., LTD., will be considered out of scope 
and must be approved, by Yungjin Pharm. CO., LTD., and must be described in the 
CSR.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
Primary Objective:  To assess the safety and tolerability of two multiple oral 
YPL-001 dose levels versus placebo in moderate to severe chronic obstructive 
pulmonary disease (COPD) patients. 
Secondary Objective:  To assess the number and magnitude of daily respiratory 
symptoms of two multiple oral YPL-001 dose levels versus placebo in moderate to 
severe COPD patients. 
Exploratory Objectives:  To evaluate the following in moderate to severe COPD 
patients: 
1. 
To assess BAL epithelial brushings for YPL-001 component levels. 
2. 
To compare BAL samples for total cell count (cells/mL) macrophages, 
lymphocytes, neutrophils, and eosinophils as a percentage of total cells; 
neutrophil, macrophage, lymphocyte, and eosinophil counts as absolute 
inflammatory cell numbers in YPL-001 groups versus placebo group. 
3. 
To compare BAL samples for TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, 
MPO, neutrophil elastase, MCP-1, and MMP-9 in YPL-001 groups versus 
placebo group. 
4. 
To compare blood inflammatory markers (total and differential cell counts as 
absolute and percentage for neutrophils, monocytes, eosinophils and 
lymphocytes) and concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, 
IL-5, IL-6, IL-8, IL-13, MCP-1, and MMP-9 in YPL-001 groups versus 
placebo group. 
5. 
To compare spirometric functions (FEV1, FVC, FEV1/FVC, and IC) in 
YPL-001 groups versus placebo group. 


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YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
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6. 
To compare patient reported outcomes (BDI/TDI, CAT) in YPL-001 groups 
versus placebo group. 
7. 
To assess verproside and picroside II concentration in plasma and BAL and 
verproside and picroside II PK in plasma following multiple oral doses 
administration of two YPL-001 dose levels. 
2.2 
Endpoints 
Primary Endpoint: The number and severity of treatment-emergent adverse events 
(TEAEs) following multiple oral doses of YPL-001 or placebo. 
Secondary Endpoint:  The number of symptom free days and overall symptom 
burden following multiple oral doses of YPL-001 or placebo, assessed by measuring: 
• 
daily peak expiratory flow (PEF);  
• 
major (e.g., estimated sputum quality (e.g., color, consistency) and quantity) 
and minor (e.g., cough, wheeze, sore throat, nasal congestion, discharge, and body 
temperature above 100°F) symptoms of COPD exacerbation;  
• 
dyspnea (using the Modified Borg Dyspnea Scale);  
• 
activity (using the Duke Activity Status Index [DASI]). 
Exploratory Endpoints:  
1. 
YPL-001 component levels in epithelial brushings; 
2. 
BAL biomarkers following multiple oral doses of YPL-001 or placebo, 
measuring: 
• 
total cell count (cells/mL) of macrophages, lymphocytes, neutrophils, 
and eosinophils as a percentage of total cells 
• 
total cell count (cells/mL) of neutrophils, macrophages, lymphocytes, 
and eosinophils as absolute inflammatory cell numbers 
• 
concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9. 
3. 
Blood biomarkers following multiple oral doses of YPL-001 or placebo, 
measuring: 
• 
inflammatory markers (total and differential cell counts as absolute 
and percentage for neutrophils, monocytes, eosinophils, and 
lymphocytes)  


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
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• 
concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, 
IL-8, IL-13, MCP-1, and MMP-9. 
4. 
Pulmonary function results (spirometry) following multiple oral doses of 
YPL-001 or placebo. 
5. 
Quality of life scores using the BDI/TDI, CAT questionnaires. 
6. 
Concentrations and PK of verproside and picroside II in plasma following 
multiple oral doses of YPL-001. 
7. 
Concentrations of verproside and picroside II in BAL following multiple oral 
doses of YPL-001. 
3. 
STUDY DESIGN 
This is a Phase 2a, proof-of-concept, multicenter, randomized, double-blind, 
double-dummy, 3-treatment, parallel study, with low and high YPL-001 doses (80 mg 
and 160 mg twice daily [BID]) and a placebo control, in moderate to severe COPD 
male and female patients.  
Sixty (60) patients will be enrolled and randomized into 3 treatment groups 
(20 patients per group). Patients will participate only once. An approximately equal 
number of current and ex-smokers will be enrolled in the study. 
Screening of patients will occur within 14 days of Day 1 (inclusive) of the Run-in 
Period. 
Following screening, eligible patients will discontinue non-permitted respiratory 
drugs and enter a 14 ± 2 days Run-in Period during which patients will be given 
albuterol taken on an as required basis and daily tiotropium 18 μg to be administered 
at home. They will record their daily symptoms in an electronic diary (e-diary) 
throughout the Run-in Period. 
Patients will return to the clinical research unit (CRU) in the morning of Day -3 to -1 
for Check-in of the Treatment Period to confirm their eligibility and undergo Check-
in scheduled study procedures. Patients will return to the CRU on the morning of Day 
1 to be randomized and receive one of the 3 treatments and undergo all scheduled 
study procedures. Patients will return on the morning of Days 15 (± 2 days), 29 (± 2 
days), 43 (± 2 days), 54 (± 1 day) , and 56 of the Treatment Period for study drug 
administration and procedures. Prior to each release from the CRU, patients will 
receive sufficient doses to be self-administered at home until the next morning visit at 
the CRU. Patients will continue recording their daily symptoms via the e-diary 
throughout the Treatment Period.  
YLP-001 and placebo will be administered approximately every 12 hours under 
fasting conditions.  


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
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Patients will remain ambulatory or seated upright for 1 hour following each study 
medication administration. 
Safety and tolerability will be assessed throughout the study through physical 
examinations, vital signs, pulse oximetry, electrocardiograms (ECGs), clinical 
laboratory tests, and adverse events (AEs). 
Assessment of respiratory symptoms and symptom burden in YPL-001 and placebo 
treatments will be performed daily through patient self-report of PEF, major and 
minor symptoms of COPD exacerbation, dyspnea, and activity. 
Spirometry measurement, quality of life assessments, BAL, and blood samples will 
be collected for the pharmacodynamic (PD) assessment of YPL-001 and placebo 
treatments.  
Serial blood samples will also be collected for PK assessment of verproside and 
picroside II in plasma and BAL. 
The CRU will attempt to contact patients using their standard procedures 
approximately 14 days after the last study drug administration to determine if any AE 
has occurred since the last dose of study drug. 
The planned length of participation in the study for each patient is approximately 
12 weeks (from Run-in through follow-up). 
4. 
ANALYSIS POPULATIONS 
4.1 
Analysis Populations 
Safety population:  All available data for patients who received at least one dose of 
the investigational product (i.e., YPL-001) or placebo. Safety data for all discontinued 
patients will be included in this set for the time points for which their data are 
available.  
Symptom monitoring population:  All available data for patients who received at 
least one dose of the investigational product (i.e., YPL-001) or placebo. Symptom 
monitoring data for all discontinued patients will be included in this set for the time 
points for which their data are available. 
PK population:  All patients receiving at least one dose of YPL-001 and having at 
least one measurable plasma concentration of verproside and picroside II.  
PK per-protocol population:  All protocol-compliant patients who received all 
scheduled doses of YPL-001 and have sufficient samples collected to determine PK 
parameters from plasma concentrations of verproside and picroside II on at least one 
of the two PK days (Days 1 and 54 (±1 day) or 56). 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
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PD population:  All patients who received at least one dose of YPL-001 or placebo 
and provide at least one post-baseline PD measurement. 
PD per-protocol population:  All protocol-compliant patients who received all 
scheduled doses ofYPL-001 or placebo and have measurable PD data. 
PK/PD population:  All patients who received at least one dose of YPL-001 and 
having any measurable concentration of verproside and picroside II and measurable 
PD data will be included in the PK/PD relationship assessment, as applicable. 
4.2 
Preliminary Data and Interim Analysis 
No formal interim analysis is planned for this study.  
5. 
TREATMENT DESCRIPTIONS 
5.1 
Study Treatments 
YPL-001 will be supplied as 80 mg tablets for oral administration. 
Placebo will be supplied as YPL-001 80 mg matching placebo tablets for oral 
administration. 
Treatments A, B, and C are described as follows: 
Treatment A:  Multiple oral YPL-001 80 mg doses (1 x 80 mg tablet + 1 x 1 
YPL-001 80 mg matching placebo tablet) will be administered approximately every 
12 hours under fasting conditions for 55 consecutive days.*  
Treatment B:  Multiple oral YPL-001 160 mg doses (2 x 80 mg tablets) will be 
administered approximately every 12 hours under fasting conditions for 55 
consecutive days.* 
Treatment C:  Multiple oral matching placebo (2 x 1 YPL-001 80 mg matching 
placebo tablets) will be administered approximately every 12 hours under fasting 
conditions for 55 consecutive days.* 
* Patients following up to Amendment version 5 of protocol also received a morning 
dose on Day 56 
In the tables, figures, and listings (TFLs) (PK, PD, and safety), treatments will be 
referred to as: 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55. 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55. 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55. 


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YPL-001, Project Number YPL-001-YJP-130403 
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Note: Patients following up to Amendment version 5 of the protocol also received a 
morning dose on Day 56. 
In the text of the CSR, treatments will be referred to as Treatments A, B and C or as 
80 mg YPL-001, 160 mg YPL-001, and placebo, respectively.  
The finished product will be referred to in the CSR as YPL-001 or placebo. The 
active ingredient will be referred to in the CSR as verproside and picroside II. 
5.2 
Other Treatments 
Tiotropium (Spiriva® HandiHaler®) will be supplied as 18 μg capsules for inhalation. 
Albuterol will be supplied as 100 µg albuterol base (1 actuation = 100 µg albuterol 
base) for oral inhalation. Albuterol may be administered via a nebulizer or a metered-
dose inhaler. 
During the Run-in Period, multiple oral inhalation of tiotropium (Spiriva® 
HandiHaler®) 18 μg capsule will be administered QD every morning for 14 ± 2 days. 
Albuterol will be administered on an as needed basis. 
In treatments A to C, one tiotropium (Spiriva® HandiHaler®) 18 μg capsule will also 
be administered QD every morning prior to study drugs administration. Albuterol will 
be administered on an as needed basis. 
6. 
SYMPTOM MONITORING ANALYSIS 
The following section is organized based on the secondary endpoints in Section 2.2. 
6.1 
Measurements, Collection Schedule, and Analysis 
When readings are not performed in the CRU, patients will record their daily 
symptoms in their e-diary prior to each dose from Day 1 of the Run-in Period through 
the Treatment Period. Patients will return the e-diary device on Day 56 (or prior to 
early termination) to CRU. 
The following symptoms will be monitored daily by all patients: 
Peak Expiratory Flow: Three (3) PEF measurements will be made at each time 
point. PEF measurements and their change from baseline will be summarized by 
treatment and time point of collection. Baseline is Day 1 predose measurement. 
Symptoms of COPD Exacerbation:  Major (estimated sputum quality [color and 
consistency] and quantity) and minor (cough, wheeze, sore throat, nasal congestion, 
nasal discharge, and body temperature above 100°F) symptoms of COPD 
exacerbation and their change from baseline will be listed and presented 
descriptively. Baseline is Day 1 predose measurement. 


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Dyspnea:  Severity level of patient’s dyspnea will be assessed via the Modified Borg 
Dyspnea Scale (0 to 10; where 0 corresponds the absence sensation of dyspnea and 10 
corresponds to maximum possible sensation of dyspnea). The Modified Borg 
Dyspnea Scale scores will be listed and presented descriptively. 
Activity:  Patient’s functional capacity and activity status will be assessed via the 
DASI 12-item questionnaire. The final score ranges between 0 and 58.2 points. The 
higher the score, the better the functional capacity. DASI scores will be listed and 
presented descriptively. 
Additional analysis may be performed if deemed appropriate. 
6.2 
Data Summarization and Presentation 
Symptom free days and overall symptom burden will be evaluated and compared 
across treatment groups. Secondary outcome analysis will be based on treatment 
actually received by patients. Quantitative data will be summarized by treatment 
group using descriptive statistics including sample size (N), arithmetic mean, standard 
deviation (SD), coefficient of variation (CV%), median, minimum, and maximum. 
Frequency counts will be compiled for classification of qualitative data, when 
appropriate. Descriptive statistics and frequency counts will be generated using SAS® 
Version 9.3 (or higher). 
7. 
PHARMACODYNAMICS ANALYSIS 
The following sub-sections are organized based on exploratory endpoints 1 to 5 in 
Section 2.2. 
7.1 
Biomarkers and Quality of Life Assessments 
7.1.1 Measurements, Collection Schedule, and Analysis 
7.1.1.1 Biomarkers in Bronchoalveolar Lavage Samples 
BAL samples for PD assessments of biomarkers will be collected at baseline at 
Check-in and on Day 55 or  56 of the Treatment Period. 
BAL (lavage material) will be performed in the right middle or lower lobe. BAL cell 
pellet and supernatant will be kept cooled until processed or stored as indicated in the 
laboratory manual to be provided as a separate document. 
Samples must be protected from UV light during collection, processing, and storage.  
Biomarkers assessments in BAL include: 
• 
White blood cell (WBC) count (cells/mL) and differential (including 
macrophages, lymphocytes, neutrophils, and eosinophils) will be expressed as 


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raw counts and % change from baseline and as a percent (%) of WBC for each 
differential.  
WBC and differential in BAL will be determined using a differential stain 
(blood smear; microscopic examination with manual differential WBC count) 
at the local Investigator sites. 
• 
Concentrations of TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, 
neutrophil elastase, MCP-1, and MMP-9 will be expressed as raw and % 
change from baseline levels. Baseline is defined as Check-in of the Treatment 
Period level and is patient specific. 
The concentrations of MPO, neutrophil elastase, MMP-9 will be determined 
using enzyme-linked immunosorbent assay (ELISA) assays and the rest of 
BAL inflammatory markers will be determined using Luminex® assays. All 
assays are validated with respect to accuracy, precision, linearity, sensitivity, 
and specificity at Temple University School of Medicine (Philadelphia, 
Pennsylvania, USA). 
7.1.1.2 Biomarkers in Blood 
Blood samples for PD assessments of biomarkers will be collected in pre-chilled 
evacuated tubes containing K2EDTA at screening, on Days 1 and 54 (± 1) or Day 56 
of the Treatment Period prior to dosing (predose) and at 1 hour postdose. In addition, 
predose samples will be collected on Days 15 (± 2), 29 (± 2), and 43 (± 2) of the 
Treatment Period. 
Biomarker assessments include: 
• 
WBC counts and differential (including monocytes, lymphocytes, neutrophils, 
and eosinophils) will be expressed as raw counts, % change from baseline, and as 
% of WBC for each differential. 
WBC and differential counts in blood will be determined using a differential stain 
(blood smear; microscopic examination with manual differential WBC count) at 
the local Investigator sites. 
• 
Concentrations of CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, 
IL-13, MCP-1, and MMP-9 will be expressed as raw and % change from baseline 
levels. Baseline is defined as the predose time point at Check-in of the Treatment 
Period level and is patient specific. 
The concentrations of MMP-9 will be determined using an ELISA assay and the 
rest of blood inflammatory markers will be determined using Luminex® assays. 
All assays are validated with respect to accuracy, precision, linearity, sensitivity, 


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and specificity at Temple University School of Medicine (Philadelphia, 
Pennsylvania, USA). 
7.1.1.3 Pulmonary Function Biomarkers 
Spirometry measures for assessment of the pulmonary function will be taken pre- and 
post-bronchodilator (albuterol) administration at Screening (baseline), at Check-in, on 
Days 15 (± 2), 29 (± 2), 43 (± 2), and 55 or 56 (predose) of the Treatment Period, and 
prior to early termination, if applicable. 
Pulmonary function measurements include the following parameters below: 
• 
FEV1; 
• 
FVC; 
• 
FEV1/FVC; 
• 
IC. 
Short and long acting β2-agonist and anticholinergic bronchodilators agents will be 
withheld approximately 4 and 24 hours, respectively, before each pre-bronchodilator 
spirometry. 
At screening, baseline pre-bronchodilator spirometry will be performed (prior to 
albuterol administration) for a minimum of 3 times and a maximum of 8 times in 
order to obtain 3 manoeuvers with FEV1 values within 150 mL of each other, using 
the manoeuver with the highest value of FEV1 and FVC as the basis for comparison.  
Patients shall receive 4 inhalations of albuterol, (100 μg/inhalation), for a total dose of 
400 μg via metered-dose inhaler using a spacer. Within approximately 20 to 
30 minutes after albuterol administration, the baseline post-bronchodilator spirometry 
will be performed. 
Assessment of FEV1 stability will take place: 
1. 
Prior to Day 1 dosing of the Treatment Period (Check-in measurement): 
Predose FEV1 is defined as the time-point prior to Day 1 dosing in the Treatment 
Period and will be performed pre- and post-bronchodilator administration. Predose 
FEV1 will be compared to the corresponding baseline measurement. If the best FEV1 
measurement at predose at Check-in of the Treatment Period has declined by greater 
than 20% from the best FEV1 at screening, the visit may be rescheduled up to 3 
times, at the discretion of the Investigator. 
2. 
Following Day 1 dosing: At all other spirometry time point, measurements 
will be performed once. If the value shows a difference of greater than 150 mL 


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decline than the best FEV1 value collected predose at Check-in, up to 3 measures will 
be performed.  
Consideration should be given, if a patient experiences any change in post Day 1 dose 
FEV1 from the Day 1 predose FEV1 value (measured following dosing with 
albuterol) equal to or greater than 20 % and should alert the PI to consider whether 
individual patients should continue to dose. 
Pre- and post-bronchodilator change in activity by time point will be calculated 
relative to the pre- and post-bronchodilator baseline activity. Baseline is defined as 
Screening and is patient specific. 
7.1.1.4 Quality of Life Assessments 
Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI): 
BDI/TDI has 3 domains (functional impairment, magnitude of task and magnitude of 
effort) with the values added for a combined focal score. 
Dyspnea will be assessed at Check-in of the Treatment Period (considered as the 
baseline) using the BDI score. The BDI scores range from 0 (very severe impairment) 
to 4 (no impairment) for each domain with the baseline focal score consisting of the 
sum of each domain (0 to 12). 
Dyspnea throughout the study will be assessed at predose on Days 15 (± 2), 29 (± 2), 
43 (± 2), and 54 (± 1) or Day 56 of the Treatment Period using the TDI score. The 
change from baseline (BDI score) is measured by the TDI score which ranges from -3 
(major deterioration) to +3 (major improvement) for each domain with the TDI focal 
score consisting in the sum of each domain (-9 to +9). 
COPD Assessment Test (CAT): 
Overall impact of a patient’s condition (i.e., COPD) on their life will be assessed. The 
CAT questionnaire will be completed by patients at Check-in of the Treatment 
Period, and at predose on Days 15 (± 2), 29 (± 2), 43 (± 2), 54 (± 1) or Day 56. CAT 
score range from 0 (no impact on daily activities) to 40 (very high impact on daily 
activity). 
7.1.2 Data Summarization and Presentation 
Descriptive statistics will be generated using SAS® Version 9.3 (or higher) for the 
actual values (raw) and relative values (% change from baseline or total) as specified 
above for each type of biomarker variable. When applicable, the PD biomarkers 
(BAL, blood, pulmonary function) will be summarized by treatment group and time 
point using descriptive statistics including sample size (N), arithmetic mean, standard 
deviation (SD), coefficient of variation (CV%), median, minimum, and maximum. 


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Figures will be created to display mean measure, level or activity value as a function 
of time on linear plots with and without SD, as appropriate. 
The quality of life parameters reported from the BDI/TDI and CAT questionnaires 
will be listed and presented descriptively using SAS® Version 9.3 (or higher) 
Additional analysis may be performed if deemed appropriate. 
8. 
PHARMACOKINETIC ANALYSIS 
This following section is organized based on the exploratory endpoints 6 and 7 in 
Section 2.2. 
8.1 
Measurements and Collection Schedule 
8.1.1 Blood Sample Collection 
PK blood samples for the determination of plasma verproside and picroside II 
concentrations will be collected in 4 mL pre-chilled evacuated tubes containing 
K2EDTA on Days 1 and 54 (± 1) or Day 56 of the Treatment Period prior to dosing 
(predose) and at 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 
hours postdose. In addition, predose samples will be collected on Days 15 (± 2), 29 
(± 2) and, 43 (± 2) of the Treatment Period. 
The sampling schedule and/or collection intervals may be modified based on the 
results as the study progresses. 
Samples must be protected from UV light during collection, processing, and storage. 
8.1.1.1 Handling of Time Deviation 
For verproside and picroside II PK blood samples, the actual sampling times will be 
assessed as available. 
All concentration data will be included in the calculation of the PK parameters and 
the individual concentration-time plots (based on actual sample times), as well as in 
the mean concentration-time plots (based on nominal sample times); however, if there 
are any significant deviations (i.e., the actual sample time is closer to the next 
nominal time point than the intended nominal time point), concentration data may be 
excluded from mean concentration-time plots (based on nominal sample times). 
However if there are any significant time deviations that are judged to compromise 
the integrity of the PK results, the PK data for those patients will be handled as 
described in Section 8.5.1. 


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8.1.2 Bronchoalveolar Sample Collection 
Epithelial brushings samples for the determination verproside and picroside II 
concentrations will be collected at baseline at Check-in and on Day 55 or 56 
The brushings (cellular material) will be collected from each of 4 quadrants of visible 
subsegments of the right middle or lower lobe. The brushings cell pellet will be stored 
at -70°C until processed or stored as indicated in the laboratory manual to be 
provided as a separate document. 
Samples must be protected from UV light during collection, processing, and storage.  
8.2 
Bioanalytical Method 
Plasma concentrations of verproside and picroside II will be determined using the 
bioanalytical method SOP (EDT) methods validated with respect to accuracy, 
precision, linearity, sensitivity, and specificity at Celerion, Lincoln, Nebraska, USA.  
The validated analytical range (lower limit of quantitation [LLOQ] – upper limit of 
quantitation [ULOQ]) for verproside and picroside II is 50.0 – 20 000 pg/mL.  
8.3 
Investigational Product and PK Analyte Information 
YPL-001 is a botanical drug substance containing a mixture of iridoids from the 
aerial parts of the plant Speedwell (Pseudolysimachion rotundum var. subintegrum). 
The principal pharmaceutically-active ingredient in YPL-001 is verproside, an 
iridoid. YPL-001 contains additional iridoids in lesser relative amounts.  
Molecular formulae and the molecular masses of the six constituents of YPL-001 are 
provided in Table 1. 
Table 1 
Principle Active Constituents in YPL-001 
Generic Name 
Molecular Formula 
Molecular Weight (g/mol) 
Verproside 
C22H26O13 
498.43 
Picroside II 
C23H28O13 
512.46 
Catalpolside 
C22H26O12 
482.43 
Isovanilloyl catalpol 
C23H28O13 
512.46 
6-O-veratroylcatalpol 
C24H28O13 
526.17 
Veratric acid 
C9H10O4 
182.17 
The structure of verproside and related congeners are provided in Figure 1. 


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Figure 1 Structure of Verproside and Related Active Compounds in YPL-001 
 
Note that only plasma and BAL verproside and picroside II concentrations are 
planned for analysis in this current study. However, other components of YPL-001 
and its metabolites may also be analyzed, if required. If metabolite data are available, 
metabolite to parent ratios may be calculated for AUC0-t, AUCτ, and Cmax_ss. 
Any dose dependent PK parameters such as clearance and volume of distribution will 
need adjustment for the content of verproside in the YPL-001 dose. Verproside 
content is 28.96 and 57.92 mg for the 80 and 160 mg YPL-001 dose levels, 
respectively. 
8.4 
Pharmacokinetic Concentrations 
Plasma and BAL concentrations of verproside and picroside II will be determined at 
the collection times and per the bioanalytic method described in Section 8.1 and 
Section 8.2, respectively. Plasma concentrations of verproside and picroside II will be 
used for the calculation of the plasma verproside and picroside II PK parameters. 
BAL concentrations of verproside and picroside II will be reported, but no PK 
parameters will be calculated. 


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8.5 
Noncompartmental Pharmacokinetic Analysis and Parameter Calculation 
8.5.1 Plasma Pharmacokinetic Parameters 
The appropriate noncompartmental PK parameters will be calculated from the plasma 
verproside and picroside II concentration-time data following administration of 
YLP-001 on Days 1 and 54 (± 1) or Day 56, as well as predose concentrations in 
morning of Days 15 (± 2), 29 (± 2), 43 (± 2), and 54 (± 1) or Day 56 using Phoenix® 
WinNonlin® Version 6.3 or higher. All PK parameters included in the protocol are 
listed in Table 2 below, and are defined as appropriate for study design. Other PK 
parameters may be calculated if deemed appropriate and requested by the sponsor and 
agreed upon by Celerion. 
Table 2 
Noncompartmental Pharmacokinetic Parameters to be Calculated 
Following a Single Dose of YLP-001 - Day 1 
Parameter 
Label to be 
Used in 
Post-Text 
Tables 
Definition 
Method of Determination 
AUC0-12 
AUC0-12 
Area under the drug 
concentration-time curve 
(AUC) from time zero to 
12 hours. 
Calculated using the Linear 
Trapezoidal with Linear 
Interpolation Method. 
May be extrapolated using the 
terminal elimination rate constant 
(kel), if last measurable 
concentration (Ct) occurs prior to 
12 hours postdose. 
AUC0-t 
AUC0-t 
AUC from time zero to time t, 
where t is the time of the Ct. 
This parameter will be reported 
only if plasma concentrations 
fall below the lower limit of 
quantitation before the last time 
point prior to the evening drug 
administration on Day 1 for at 
least one patient. Otherwise, 
only AUC0-12 will be reported. 
Calculated using the Linear 
Trapezoidal with Linear 
Interpolation Method. 
AUC0-inf 
AUCinf 
AUC from time 0 extrapolated 
to infinity. 
Calculated as:  AUC0-t + Ct/kel 
Cmax 
Cmax 
Maximum observed drug 
concentration. 
Taken directly from bioanalytical 
data. 


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Following a Single Dose of YLP-001 - Day 1 
Parameter 
Label to be 
Used in 
Post-Text 
Tables 
Definition 
Method of Determination 
tmax 
tmax 
Time of the maximum drug 
concentration (obtained 
without interpolation). 
Observed 
kel 
kel 
Apparent first-order terminal 
elimination rate constant, 
which represents the fraction of 
drug eliminated per unit time. 
Calculated from a semi-log plot of 
the plasma concentration versus 
time curve, calculated by linear 
least-squares regression analysis 
using the maximum number of 
points in the terminal log linear 
phase (e.g., three or more non-zero 
plasma concentrations). 
t½ 
t½ 
Apparent first-order 
elimination half-life. 
Calculated as:  ln(2)/kel 
CL/F 
CL/F 
Apparent total plasma 
clearance after extravascular 
administration (verproside 
only). 
Calculated as:  Dose/AUC0-inf 
VZ/F 
Vz/F 
Apparent volume of 
distribution during the terminal 
elimination phase after 
extravascular administration 
(verproside only). 
Calculated as: 
Dose/(kel × AUC0-inf) 
 


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Following Multiple Doses of YLP-001 - Day 54 (± 1) or Day 56 
Parameter 
Label to 
be Used 
in Tables 
Definition 
Method of Determination 
AUCτ 
AUCtau 
AUC over the final 12-hour 
dosing interval (τ) at steady 
state (e.g., 0-12 hours). 
Calculated using the Linear 
Trapezoidal with Linear 
Interpolation Method. 
May be extrapolated using the kel, if 
Ct occurs prior to 12 hours postdose. 
AUC0-t 
AUC0-t 
AUC from time zero to time t, 
where t is the time of the Ct. 
Calculated using the Linear 
Trapezoidal with Linear 
Interpolation Method. 
Cmax_ss 
Cmax_ss 
Maximum observed plasma 
concentration during a dosing 
interval at steady state. 
Taken directly from bioanalytical 
data. 
Cmin_ss 
Cmin,ss 
Minimum observed/measured 
non-zero concentration during a 
dosing interval at steady state. 
Taken directly from bioanalytical 
data. 
tmax_ss 
tmax_ss 
Time to reach Cmax_ss (obtained 
without interpolation). 
Observed 
Ctrough 
Ctrough 
Plasma concentration observed 
at the end of a dosing interval at 
steady state. Presented as 
predose in the morning Days 15 
(± 2), 29 (± 2), 43 (± 2), and 54 
(± 2) (following PM dosing on 
Days 14 (± 2), 28 (± 2), 42 (± 
2), and 54 (± 1) or 56, 
respectively). 
Taken directly from bioanalytical 
data. 
Cavg_ss 
Cavg_ss 
Average plasma concentration 
at steady state. 
Calculated as: 
AUCτ/τ 
%Fluc 
%Fluc 
Percent peak-to-trough 
fluctuation at steady-state. 
Calculated as:  
(Cmax_ss – Cmin_ss)/Cavg_ss × 100 
Swing 
Swing 
Percent swing at steady-state. 
Calculated as: 
(Cmax_ss – Cmin_ss)/Cmin_ss × 100 


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Following Multiple Doses of YLP-001 - Day 54 (± 1) or Day 56 
Parameter 
Label to 
be Used 
in Tables 
Definition 
Method of Determination 
kel 
kel 
Apparent first-order terminal 
elimination rate constant, which 
represents the fraction of drug 
eliminated per unit time. 
Calculated from a semi-log plot of 
the plasma concentration versus 
time curve, calculated by linear 
least-squares regression analysis 
using the maximum number of 
points in the terminal log linear 
phase (e.g., three or more non-zero 
plasma concentrations). 
t½ 
t½ 
Apparent first-order elimination 
half-life. 
Calculated as:  ln(2)/kel 
CLss/F 
CLss/F 
Total body clearance estimated 
at steady-state after oral 
administration (verproside 
only). 
Calculated as:  Dose/AUCτ 
RA,AUC 
RA,AUC 
Accumulation ratio 
Calculated as:   
AUCτ / AUC0-12 (on Day 1) 
If AUC0-12 on Day 1 or AUCτ on 
Day 54 (± 1) or 56 cannot be 
calculated for a patient, then no 
RA,AUC value will be presented for 
that patient. 
Vz_ss/F 
Vz,ss/F 
Apparent volume of distribution 
at steady state. 
Calculated as:  (CLss/F)/kel 
For the calculation of the PK parameters that depended on the dose (CL/F, VZ/F, 
CLss/F, and Vz_ss/F) verproside content is 28.96 and 57.92 mg for the 80 and 160 mg 
YPL-001 dose levels, respectively. 
Actual sample times will be used in the calculations. Patients for whom there are 
insufficient data to calculate the PK parameters (at least 3 consecutive measurable 
concentrations) will be included in the concentration tables only and excluded from 
the pharmacokinetic and statistical analyses. 
For the calculation of the PK parameters, plasma concentrations below the limit of 
quantitation (BLQ) prior to the first quantifiable concentration will be set to 0.00 and 
plasma concentrations BLQ after the first quantifiable concentration will be treated as 
missing.  
Plasma verproside and picroside II Ctrough concentrations will be presented. Although 
Ctrough concentrations are related to the PM dose given on Days 14 (± 2), 28 (± 2), 42 
(± 2), and 53 (± 2), they will be labeled and referred with in the TFLs as AM predose 
time point on Days 15 (± 2), 29 (± 2), 43 (± 2), and 54 (± 1) or Day 56. 


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For the calculation of summary statistics and PK parameters, BLQ plasma 
concentrations will generally be set to 0 prior to the first quantifiable concentration on 
each study day and to missing thereafter. Based on the reported mean t½ of plasma 
verproside and picroside II following the BID administration of 80 mg YLP-001 in a 
previous multiple ascending dose (MAD) study in healthy subjects, Ctrough that are 
BLQ may be expected in this study. Therefore, Ctrough BLQ concentrations measured 
at predose on Days 15 (± 2), 29 (± 2), 43 (± 2), and 54 (± 1) or Day 56 will be set to 0 
for the calculations of summary statistics and PK parameters. 
The kel will be determined using linear regressions composed of least 3 data points. 
The kel will not be assigned if 1) the terminal elimination phase is not apparent, 2) if 
tmax is one of the 3 last data points, or 3) if the R2 value is less than 0.8. For the 
analysis on Day 1, the kel will only be reported if the t½ of verproside or picroside II 
can be appropriately estimated from a 12-hour sampling period following dosing. In 
cases where the kel interval is not assigned, the values of AUC0-inf, t½, CL/F, Vz/F, 
AUCτ, CLss/F, Vz_ss/F, and RA,AUC, as applicable, are considered not calculable and 
will not be reported. Wherever the resulting t½ is more than half as long as the 
sampling interval, the kel values and associated parameters (AUC0-inf, t½, CL/F, Vz/F, 
AUCτ, CLss/F, Vz_ss/F, and RA,AUC as applicable) may not be presented as judged 
appropriate and in accordance wih Celerion SOPs. 
All available data will be included in the concentration and PK parameter tables to the 
extent possible. Patients will be excluded from the PK population if they significantly 
violate a protocol inclusion or exclusion criteria, deviate significantly from the 
protocol, or if data are unavailable or incomplete, which may influence the PK 
analysis. 
Except if otherwise specified, available concentration and PK data of each patient 
will be included in the summary statistics and statistical comparisons for PK 
parameters. 
Data from patients who experience emesis within 1.5 hours following YPL-001 
dosing ( i.e., a period of time equal to 2 times the estimated tmax of verproside and 
picroside II) during the PK sampling periods (i.e., after AM dosing on Days 1 or 54 
[± 1] or Day 56, as appropriate) may be excluded from the summary statistics for the 
given day and from the statistical comparison of PK parameters. 
Any patient or data excluded from the PK analysis, summary statistics or statistical 
analysis will be identified, along with their reason for exclusion, in the CSR. 
8.6 
Data Summarization and Presentation 
All plasma and BAL verproside and picroside II concentrations and plasma PK 
parameters descriptive statistics will be generated using SAS® Version 9.3 or higher. 


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Plasma and BAL concentrations of verproside and picroside II will be presented with 
the same level of precision as received from the bioanalytical laboratory. Summary 
statistics, including N, arithmetic mean, SD, CV%, median, minimum, and maximum 
will be calculated for all nominal concentration time points. The plasma and BAL 
concentrations of verproside and picroside II will be tabulated by treatment and listed 
by nominal sample time (Day/hour) and patient for all patients in the PK population. 
Patients included in the PK population but excluded from the PK per-protocol 
population will be included in the concentration table listings, but will be excluded 
from the summary statistics and noted as such in the tables. All BLQ values will be 
presented as “BLQ” in the concentration table listings and footnoted accordingly. For 
the calculation of summary statistics, BLQ concentrations will be treated as missing 
or 0 per defined in Section 8.5.1. 
The level of precision for each verproside and picroside II plasma PK parameter will 
be determined based on the output values, except for C parameters (i.e., Cmax, Cmax_ss, 
Cmin_ss, Cavg_ss, and Ctrough) which will be presented with the same precision as the 
concentrations. For instance, tmax, tlast, t½, %Fluc, and Swing and may be presented 
with 2-3 decimals and AUCs, kel, CL/F, Vz/F, CLss/F, and Vz_ss/F with 3-5 significant 
digits. Summary statistics, including N, arithmetic mean (mean), SD, CV%, median, 
minimum, maximum will be calculated for all verproside and picroside II PK 
parameters. In addition, geometric means (geo. mean) and geometric CV% (geo. 
CV%) will be presented for all C and AUC parameters. PK parameters will be 
tabulated by treatment and listed by patient and parameter for all patients in the PK 
population. Patients included in the PK population but excluded from the PK per-
protocol population will be included in the PK parameter table listings, but will be 
excluded from the summary statistics and noted as such in the tables.  
The level of precision for the summary statistics on plasma and BAL concentrations 
and plasma PK parameters will be the following: 
• N:  integer 
• Minimum/Maximum:  same precision as the individual values 
• Mean/Median/Geo. Mean:  1 more level of precision than the individual 
values 
• SD:  1 more level of precision than AM/median 
• CV% and Geo.CV%:  1 decimal place. 
Arithmetic mean and individual plasma verproside and picroside II concentrations 
versus time profiles on Days 1 and 54 (± 1) or Day 56 will be presented on the same 
plot and on linear and semi-log scales. Arithmetic mean and individual plasma 
verproside and picroside II Ctrough versus time profiles will be presented on a different 


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plot than for Days 1 and 54 (± 1) or Day 56 and on a linear scale. Linear mean plots 
will be presented with and without SD and semi-log mean plots without SD.  
Steady-state will be assessed by visual inspection of predose plasma Ctrough values on 
Days 15 (± 2), 29 (± 2), 43 (± 2), and 54 (± 1) or Day 56 following multiple oral dose 
administration of YPL-001. Ctrough values will be summarized by nominal day (i.e., 
15, 29, 43, and 54), and footnotes may be included as necessary to clarify actual 
sampling day windows. Additional summaries and plots by actual day may be 
presented if deemed appropriate (e.g., significant trends observed) and requested by 
the Sponsor. 
8.7 
Statistical Analysis of Pharmacokinetic Parameters 
An estimate of the relative systemic exposure after multiple dose administration of 
YLP-001 using plasma verproside and picroside II AUCτ, AUC0-t, and Cmax_ss on 
Day 54 (± 1) or Day 56 will be performed by dose-normalized (to 80 mg YLP-001) 
ratio analysis (i.e., parameter values for 160 mg versus parameter values for 80 mg; 
Treatment B Versus Treatment A), expressing the geometric mean ratio (GMR) and 
90% confidence interval (CI) of the GMR. 
The ANOVA analysis will be performed using the following SAS® code: 
PROC MIXED; 
CLASS TREATMENT SUBJECT; 
MODEL PK_PARAMETER = TREATMENT; 
ESTIMATE “B vs A” TREATMENT -1 1  / cl alpha=0.1 e;    
LSMEANS TREATMENT / cl; 
Note:  Parameters will be dose-normalized to 80 mg YLP-001, prior to analysis. 
Additional analyses may be performed as deemed necessary upon review of the data 
and/or upon Sponsor’s request. 
9. 
PHARMACOKINETIC/PHARMACODYNAMIC RELATIONSHIP 
There are no PK/PD analyses planned at this time. The PK/PD relationship(s) may be 
explored (e.g., graphically using scatter plots and an appropriate regression model), 
upon Sponsor’s request. 
10. 
SAFETY  
No inferential statistics are to be performed for safety analysis. 
The following are descriptions of the summary tables that will be created to assess 
safety. Table shells are also provided in Section 11. In the summary tables, N will be 
presented without decimal, minimum/maximum in same precision as in the database, 
mean/median in one more decimal than minimum/maximum, and SD in one more 
decimal than mean/median. 


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Where individual data points are missing because of dropouts or other reasons, the 
data will be summarized based on reduced denominators. 
When change from baseline is calculated, baseline is the last schedule assessment 
before dosing, also including rechecks and unscheduled assessments, whichever is 
later. Rechecks, unscheduled assessments and early termination measurements taken 
after first dosing will not be used in the summarization. 
10.1 
Subject Discontinuation 
Frequency counts will be tabulated by treatment and total for the number of subjects 
who were dosed, the number of subjects who completed, and the number of subjects 
who discontinued early, along with the reason for discontinuation. Individual 
patient’s treatment along with their study completion status and date will be provided 
in a listing.   
10.2 
Demographics 
Descriptive statistics (N, mean, SD, minimum, median, and maximum) will be 
calculated for continuous demographic variables (age, weight, height, and body mass 
index [BMI]) and frequency counts will be tabulated for categorical demographic 
variables (gender, race, and ethnicity) by treatment and total. 
10.3 
Exposure to Study Drug  
For each treatment, exposure to study drug will be summarized through frequency 
count (number of patients) and percentage by AM/PM of each study day for each 
scheduled dose. 
10.4 
Adverse Events 
Adverse events will be coded with MedDRA dictionary version 18.0. 
A treatment-emergent adverse event (TEAE) is defined as an AE that is starting or 
worsening at the time of or after study drug administration. All AEs collected by the 
clinics and recorded in the CRF are captured in the database and will be listed in by- 
patient data listings. Only TEAEs will be summarized in the report. Data will be 
summarized by SOC and preferred term. 
Summary tables will include the number and the percentage of patients reporting the 
TEAE and percentage of patients dosed, the number of TEAEs and the percentage of 
total TEAEs. These results will be summarized by treatment and total. The number of 
patients reporting each TEAE and number of TEAEs will also be summarized by 
treatment, severity, and relationship to treatment.  
A by-patient AE data listing, including verbatim term, preferred term, treatment, 
severity, outcome, and relationship to treatment, will be provided. 


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10.5 
Clinical Laboratory Tests (Serum Chemistry, Hematology, Urinalysis) 
Clinical laboratory assessments (serum chemistry, hematology, and urinalysis) will be 
performed at screening, Check-in, Day 29 (± 2), and Day 55 or Day 56  or early 
termination.   
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be 
reported for numeric clinical laboratory results and change-from-baseline values by 
treatment and time point of collection. Baseline value will be the Check-in value and 
is the last non-missing measurement prior to dosing. Postdose recheck values will not 
be used for calculation of descriptive statistics. Shift tables describing out-of-range 
shifts from baseline (in frequency counts) will be created. Out-of-normal-range and 
clinically significant laboratory values will be listed by patient. Early termination 
record will be excluded from the summary. All laboratory results will be listed in by-
patient data listings. Because clinical laboratory test results will come from multiple 
sites with different reference ranges, out-of-range tables and shift tables will still use 
original units for presentation. For mean and mean change summary tables, the results 
and ranges will be converted to SI units for presentation. In the lab listings, both 
original units and SI units will be presented. 
10.6 
Vital Signs and Pulse Oximetry 
Vital signs include systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature. They will be measured at screening, Check-in, predose and 1, 
2, 6 hours postdose of Day 1, Days 15 (± 2), 29 (± 2), 43 (± 2), and predose and 1, 2, 
6, 12 hours postdose of Day 55 or Day 56 or early termination. Pulse oximetry will be 
measured at screening, Check-in, and Day 55 or Day 56 or early termination. All vital 
signs and pulse oximetry results will be presented in a by-patient listing. 
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be 
provided for vital sign variables and change from baseline at each assessment time 
point by treatment. Baseline value will be the Day 1 predose value and is the last 
observation, including rechecks, obtained prior to dosing. For pulse oximetry, 
baseline value will be the Check-in  value and is the last observation, including 
rechecks, obtained prior to dosing. For the purposes of summary statistics 
calculations, recheck values will not be used in the determination of postdose values. 
Early termination record will be excluded from the summary. 
10.7 
12-lead Electrocardiogram 
Twelve-lead ECGs will be performed at screening, Check-in, Day 29 (± 2), and Day 
55 or Day 56 or early termination. All ECG results will be presented in a by-patient 
data listing.  
Descriptive statistics (N, mean, SD, median, minimum, and maximum) will be 
provided for ECG variables (HR, PR, QRS, QT, and QTcB [Bazett’s correction]) and 


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YPL-001, Project Number YPL-001-YJP-130403 
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change from baseline at each assessment time point by treatment. Baseline value will 
be the Check-in value and is the last observation, including rechecks, obtained prior 
to dosing. For the purposes of summary statistics calculations, recheck values will not 
be used in the determination of postdose values. ECG results will also be classified as 
normal, abnormal, not clinically significant (ANCS), and abnormal, clinically 
significant (ACS). A normal-abnormal shift table will be created to describe shifts 
from predose baseline for postdose time points. Early termination record will be 
excluded from the summary. 
10.8 
Concomitant Medications 
Concomitant medications will be coded with the WHO Drug Dictionary 01MAR2015 
version and presented in the data listings. 
10.9 
Physical Examination 
Physical examination will occur at screening, Check-in, Day 29, and Day 55 or Day 
56 early termination. Abnormal physical examination findings at screening will be 
reported as medical history. Any clinically significant changes compared to screening 
will be recorded as an AE.  
10.10 Medical History 
Medical history will be listed by patient. 
11. 
SUMMARY TABLES AND FIGURES 
Summary tables and figures are numbered following the International Conference on 
Harmonization (ICH) structure but may be renumbered as appropriate during the 
compilation of the tables and figures for the CSR. Please note that all Symptom 
Monitoring, PD, PK, PK/PD (if applicable), and Safety summary tables and figures 
will be generated using SAS® Version 9.3 or higher.  
The following are lists of TFLs numbers and titles that will be included within the 
CSR. 
11.1 
In-text Summary Tables and Figures 
The following is a list of table and figure titles that will be included in the text of the 
CSR. Tables and figures will be numbered appropriately during compilation of the 
CSR. 
Section 10: 
Table 10-1 
Disposition Summary by Treatment 
Section 11 (Symptom Monitoring, PD, PK, PK/PD (if applicable): 


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Note to programmer:  the following list of in-text tables and figures may be modified 
and numbering adjusted. 
Symptom Monitoring 
Table 11-1 
Summary and Change From Baseline of Main Peak Expiratory Flow 
(PEF) Recorded in the e-Diary Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
Table 11-2.1 Summary of Sputum Quantity for Symptoms of Chronic Obstructive 
Pulmonary Disease (COPD) Exacerbation Recorded in the e-Diary 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and 
Placebo in COPD Patients 
Table 11-2.2 Summary of Sputum Color for Symptoms of Chronic Obstructive 
Pulmonary Disease (COPD) Exacerbation Recorded in the e-Diary 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and 
Placebo in COPD Patients 
Table 11-2.3 Summary of Sputum Consistency for Symptoms of Chronic 
Obstructive Pulmonary Disease (COPD) Exacerbation Recorded in the 
e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients 
Table 11-3.1 Categorical Summary of Symptom Score for Symptoms of Chronic 
Obstructive Pulmonary Disease (COPD) Exacerbation Recorded in the 
e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 160 
mg and Placebo in COPD Patients  
Table 11-3.2 Summary and Change From Baseline of Symptom Severity Score for 
Symptoms of Chronic Obstructive Pulmonary Disease (COPD) 
Exacerbation Recorded in the e-Diary Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients 
Table 11-4 
Summary and Change From Baseline of Modified Borg Dyspnea Scale 
Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients 
Table 11-5 
Summary and Change From Baseline of Calculated Score from 
12-Item Questionnaire of Duke Activity Status Index (DASI) 
Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients 
Pharmacodynamics 
Table 11-6 
Summary of BAL WBC and Differential Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients –
Day 55 or Day 56 (% Change from Baseline) 
Table 11-7 
Summary of BAL Inflammatory Marker Concentration Changes 
Following Multiple Oral YPL 001 Doses of 80 mg and 160 mg and 


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Placebo in COPD Patients – Day 55 or Day 56  (% Change from 
Baseline) 
Table 11-8 
Summary and Change From Baseline of Pre-Bronchodilator 
Spirometric Functions Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients 
Table 11-9 
Change From Baseline of Combined Focal Score (-9 – +9) from 
Transition Dyspnea Index (TDI) Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
Table 11-10 
Summary and Change From Baseline of Total Score (0 – 40) from 
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test 
(CAT) Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg 
and Placebo in COPD Patients 
Figure 11-1 
Mean Blood Inflammatory Cell Counts Versus Time Following 
Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in 
COPD Patients 
Note:  This will be a multi-panel figure including plots for total inflammatory cells, 
monocyte, lymphocyte, neutrophil, and eosinophil (total of 5 pannels). 
Figure 11-2 
Mean Blood Inflammatory Marker Concentration Changes from 
Baseline Versus Time Concentrations Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients 
Note:  This will be a multi-panel figure spreading on 2 pages including plots for CRP, 
fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL-13, MCP-1, and MMP-9 (total of 
11 pannels). 
Figure 11-3 
Mean Spirometric Function Changes in Activity from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg 
and Placebo in COPD Patients 
Note:  This will be a multi-panel figure including plots for FEV1, FVC, FEV1/FVC, 
and IC pre- and post-bronchodilator change in activity (total of 4 pannels). 
Pharmacokinetics 
Table 11-11 
Summary of Plasma Verproside Pharmacokinetic Parameters 
Following Single Oral YPL-001 Doses of 80 mg and 160 mg in COPD 
Patients – Day 1 
Table 11-12 
Summary of Plasma Verproside Pharmacokinetic Parameters 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg in 
COPD Patients – Day 54 (± 1) or Day 56 
Table 11-13 
Statistical Comparisons of Dose-Normalized Plasma Verproside 
Pharmacokinetic Parameters Following Multiple Oral YPL-001 Doses 
of 160 mg Versus Multiple Oral YPL-001 Doses of 80 mg in COPD 
Patients – Day 54 (± 1) or Day 56 (Treatment B Versus Treatment A) 


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Table 11-14 
Epithelial Brushing Verproside Concentrations Following Multiple 
Oral YPL-001 Doses of 80 mg and 160 mg in COPD Patients – 
Baseline and Day 55 or Day 56 (Treatments A and B) 
Table 11-15 
Summary of Plasma Picroside II Pharmacokinetic Parameters 
Following Single Oral YPL-001 Doses of 80 mg and 160 mg in COPD 
Patients – Day 1 
Table 11-16 
Summary of Plasma Picroside II Pharmacokinetic Parameters 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg in 
COPD Patients – Day 54 (± 1) or Day 56 
Table 11-17 
Statistical Comparisons of Dose-Normalized Plasma Picroside II 
Pharmacokinetic Parameters Following Multiple Oral YPL-001 Doses 
of 160 mg Versus Multiple Oral YPL-001 Doses of 80 mg in COPD 
Patients – Day 54 (± 1) or Day 56 (Treatment B Versus Treatment A) 
Table 11-18 
Epithelial Brushing Picroside II Concentrations Following Multiple 
Oral YPL-001 Doses of 80 mg and 160 mg in COPD Patients – 
Baseline and Day 55 or Day 56 (Treatments A and B) 
Figure 11-4 
Arithmetic Mean Plasma Verproside Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 80 mg and 
160 mg in COPD Patients - Day 1 and 54 (± 1) or Day 56 (Linear 
Scale) 
Figure 11-5 
Arithmetic Mean Plasma Verproside Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 80 mg and 
160 mg in COPD Patients - Day 1 and 54 (± 1) or Day 56 (Semi-Log 
Scale) 
Figure 11-6 
Arithmetic Mean (SD) Plasma Verproside Trough (Predose) 
Concentrations Versus Time Following Multiple Oral YPL-001 Doses 
of 80 mg and 160 mg in COPD Patients (Linear Scale) 
Figure 11-7 
Arithmetic Mean Plasma Picroside II Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 80 mg and 
160 mg in COPD Patients - Day 1 and 54 (± 1) or Day 56 (Linear 
Scale) 
Figure 11-8 
Arithmetic Mean Plasma Picroside II Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 80 mg and 
160 mg in COPD Patients - Day 1 and 54 (± 1) or Day 56 (Semi-Log 
Scale) 
Figure 11-9 
Arithmetic Mean (SD) Plasma Picroside II Trough (Predose) 
Concentrations Versus Time Following Multiple Oral YPL-001 Doses 
of 80 mg and 160 mg in COPD Patients (Linear Scale) 
Section 12 (Safety): 
Table 12-1 
Incidence of Treatment-Emergent Adverse Events 


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11.2 
Section 14 Summary Tables and Figures 
The following is a list of table and figure titles that will be included in Section 14 of 
the CSR. 
14.1 
Demographic Data Summary Tables 
Table 14.1.1 Disposition of Patients  
Table 14.1.2 Demographic Summary 
Table 14.1.3 Summary of Exposure to Study Drug 
14.2 
Symptom Monitoring, Pharmacodynamic, Pharmacokinetic, and 
Pharmacokinetic/Pharmacodynamic (if applicable) Data Summary 
Tables and Figures 
Note to programmer:  the following list of tables and figures may be modified and 
numbering adjusted. 
Symptom Monitoring 
14.2.1 Symptom Monitoring Tables 
PEF 
Table 14.2.1.1 Summary and Change From Baseline of Main Peak Expiratory Flow 
(PEF) Recorded in the e-Diary Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Symptoms of COPD Exacerbation 
Table 14.2.1.2 Categorical Summary of Sputum Quantity, Color, and Consistency 
for Symptoms of Chronic Obstructive Pulmonary Disease (COPD) 
Exacerbation Recorded in the e-Diary Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Table 14.2.1.3 Categorical Summary of Cough, Wheeze, Sore Throat, Nasal 
Congestion, Nasal Discharge, and Body Temperature Above 100°F 
for Symptoms of Chronic Obstructive Pulmonary Disease (COPD) 
Exacerbation Recorded in the e-Diary Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Table 14.2.1.4 Categorical Summary of Symptom Score for Symptoms of Chronic 
Obstructive Pulmonary Disease (COPD) Exacerbation Recorded in 
the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) 
Table 14.2.1.5 Summary and Change From Baseline of Symptom Score for 
Symptoms of Chronic Obstructive Pulmonary Disease (COPD) 
Exacerbation Recorded in the e-Diary Following Multiple Oral 


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YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Dyspnea 
Table 14.2.1.6 Categorical Summary of Modified Borg Dyspnea Scale Recorded in 
the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) 
Table 14.2.1.7 Summary and Change From Baseline of Modified Borg Dyspnea 
Scale Recorded in the e-Diary Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Activity 
Table 14.2.1.8 Categorical Summary of 12-Item Questionnaire of Duke Activity 
Status Index (DASI) Recorded in the e-Diary Following Multiple 
Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients (Treatments A - C) 
Table 14.2.1.9 Summary and Change From Baseline of Calculated Score from 
12-Item Questionnaire of Duke Activity Status Index (DASI) 
Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients (Treatments A - 
C) 
Pharmacodynamics 
14.2.2 Pharmacodynamic Tables 
BAL Biomarkers 
Table 14.2.2.1 
Summary of BAL WBC Counts and Differential Following 
Multiple Oral YPL-001 Doses of 80 mg and 160 mg and 
Placebo in COPD Patients (Treatments A - C) (Raw, % Change 
from Baseline, and % of WBC) 
Table 14.2.2.2 
Summary of BAL Inflammatory Marker Concentrations 
Following Multiple Oral YPL 001 Doses of 80 mg and 160 mg 
and Placebo in COPD Patients (Treatments A - C) 
Table 14.2.2.3 
Summary of BAL Inflammatory Marker Concentration 
Changes Following Multiple Oral YPL 001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Raw and % Change from Baseline) 
Blood Biomarkers 
Table 14.2.2.4 
Summary of Blood WBC Counts and Differential Following 
Multiple Oral YPL-001 Doses of 80 mg and 160 mg and 
Placebo in COPD Patients (Treatments A - C) (Raw and % of 
WBC) 


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Table 14.2.2.5 
Summary of Blood Inflammatory Marker Concentrations 
Following Multiple Oral YPL 001 Doses of 80 mg and 160 mg 
and Placebo in COPD Patients (Treatments A - C) 
Table 14.2.2.6 
Summary of Blood Inflammatory Marker Concentration 
Changes Following Multiple Oral YPL 001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Raw and % Change from Baseline) 
Pulmonary Function Biomarkers 
Table 14.2.2.7 
Summary of Spirometric Functions Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients (Actual Results, Treatments A - C) 
Table 14.2.2.8 
Summary of Spirometric Functions Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients (Predicted Results, Treatments A - C) 
Table 14.2.2.9 
Summary of Spirometric Functions Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients (Percent Results, Treatments A - C) 
Quality of Life 
Table 14.2.2.10 
Categorical Summary of Baseline Dyspnea Index (BDI) at 
Check-in by Treatment Assignment of Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Table 14.2.2.11 
Categorical Summary of Transition Dyspnea Index (TDI) 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg 
and Placebo in COPD Patients (Treatments A - C) 
Table 14.2.2.12 
Change From Baseline of Combined Focal Score (-9 – +9) 
from Transition Dyspnea Index (TDI) Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients (Treatments A - C) 
Table 14.2.2.13 
Categorical Summary of Cough and Mucus Production from 
Chronic Obstructive Pulmonary Disease (COPD) Assessment 
Test (CAT) Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
Table 14.2.2.14 
Categorical Summary of Chest Tightness and Breathlessness 
from Chronic Obstructive Pulmonary Disease (COPD) 
Assessment Test (CAT) Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Table 14.2.2.15 
Categorical Summary of Level of Activities and Level of 
Confidence from Chronic Obstructive Pulmonary Disease 


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(COPD) Assessment Test (CAT) Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients (Treatments A - C) 
Table 14.2.2.16 
Categorical Summary of Level of Sleepiness and Level of 
Energy from Chronic Obstructive Pulmonary Disease (COPD) 
Assessment Test (CAT) Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) 
Table 14.2.2.17 
Summary and Change From Baseline of Individual Score (0 – 
5) and Total Score (0 – 40) from Chronic Obstructive 
Pulmonary Disease (COPD) Assessment Test (CAT) 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg 
and Placebo in COPD Patients (Treatments A - C) 
14.2.3 Pharmacodynamic Figures 
Note to programmer:  For all the following figures, the biomarker type will be 
included at the top of each graph. This will be used by the clinical pharmacologist to 
construct multi-panel in-text figures. 
BAL Biomarkers 
No figures are planned. 
Blood Biomarkers 
Note: where necessary, samples on Day 54 (± 1) or Day 56 will be presented as 
Day 54 with a footnote indicating this is Day 54 (± 1) or Day 56. 
Inflammatory Cells –% Change from Baselines Versus Time 
Figure 14.2.3.1 
Mean (SD) Blood WBC Counts Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.2 
Mean Blood WBC Counts Changes from Baseline Versus Time 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg 
and Placebo in COPD Patients (Treatments A - C) (Linear Scale) 
Figure 14.2.3.3 
Mean (SD) Blood Monocyte Counts Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.4 
Mean Blood Monocyte Counts Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 


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Figure 14.2.3.5 
Mean (SD) Blood Lymphocyte Counts Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.6 
Mean Blood Lymphocyte Counts Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.7 
Mean (SD) Blood Neutrophil Counts Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.8 
Mean Blood Neutrophil Counts Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.9 
Mean (SD) Blood Eosinophil Counts Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.10 Mean Blood Eosinophil Counts Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Biomarkers – % Change from Baseline Versus Time 
Figure 14.2.3.11 Mean (SD) Blood CRP Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.12 Mean Blood CRP Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.13 Mean (SD) Blood Fibrinogen Concentration Changes from 
Baseline Versus Time Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients (Treatments A - 
C) (Linear Scale) 
Figure 14.2.3.14 Mean Blood Fibrinogen Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 


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Figure 14.2.3.15 Mean (SD) Blood TNF-α Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.16 Mean Blood TNF-α Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.17 Mean (SD) Blood IL-1β Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.18 Mean Blood IL-1β Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.19 Mean (SD) Blood IL-4 Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.20 Mean Blood IL-4 Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.21 Mean (SD) Blood IL-5 Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.22 Mean Blood IL-5 Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.23 Mean (SD) Blood IL-6 Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.24 Mean Blood IL-6 Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 


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Figure 14.2.3.25 Mean (SD) Blood IL-8 Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.26 Mean Blood IL-8 Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.27 Mean (SD) Blood IL-13 Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.28 Mean Blood IL-13 Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.29 Mean (SD) Blood MCP-1 Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.30 Mean Blood MCP-1 Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Figure 14.2.3.31 Mean (SD) Blood MMP-9 Concentration Changes from Baseline 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.32 Mean Blood MMP-9 Concentration Changes from Baseline Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients (Treatments A - C) (Linear 
Scale) 
Pulmonary Function Measurement  
Note: where necessary, samples on Day 55 or 56 will be presented as Day 56 with a 
footnote indicating this is Day 55 or 56. 
% Change from Baseline Versus Time 
Figure 14.2.3.33 Mean (SD) FEV1 Pre- and Post-Bronchodilator Change in Activity 
from Baseline Versus Time Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) (Linear Scale) 


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Figure 14.2.3.34 Mean FEV1 Pre- and Post-Bronchodilator Change in Activity from 
Baseline Versus Time Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) (Linear Scale) 
Figure 14.2.3.35 Mean (SD) FVC Pre- and Post-Bronchodilator Change in Activity 
from Baseline Versus Time Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) (Linear Scale) 
Figure 14.2.3.36 Mean FVC Pre- and Post-Bronchodilator Change in Activity from 
Baseline Versus Time Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients (Treatments A - 
C) (Linear Scale) 
Figure 14.2.3.37 Mean (SD) FEV1/FVC Pre- and Post-Bronchodilator Change in 
from Baseline Activity Versus Time Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients (Treatments A - C) (Linear Scale) 
Figure 14.2.3.38 Mean FEV1/FVC Pre- and Post-Bronchodilator Change in Activity 
Versus Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
(Linear Scale) 
Figure 14.2.3.39 Mean (SD) IC Pre- and Post-Bronchodilator Change in Activity 
from Baseline Versus Time Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) (Linear Scale) 
Figure 14.2.3.40 Mean IC Pre- and Post-Bronchodilator Change in Activity from 
Baseline Versus Time Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients 
(Treatments A - C) (Linear Scale) 
Quality of Life 
No figures are planned. 
Pharmacokinetics 
14.2.4 Pharmacokinetic Tables 
14.2.4.1 Plasma Verproside Tables 
Table 14.2.4.1.1 Plasma Verproside Concentrations (pg/mL) Following 
Single and Multiple Oral YPL-001 Doses of 80 mg in 
COPD Patients - Days 1 to 54 (+/- 1) or Day 56 
(Treatment A) 
Table 14.2.4.1.2 Plasma Verproside Concentrations (pg/mL) Following 
Single and Multiple Oral YPL-001 Doses of 160 mg in 


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COPD Patients - Days 1 to 54 (+/- 1) or Day 56 
(Treatment B) 
Table 14.2.4.1.3 Plasma Verproside Pharmacokinetic Parameters Following 
a Single Oral YPL-001 Dose of 80 mg in COPD 
Patients - Day 1 (Treatment A) 
Table 14.2.4.1.4 Plasma Verproside Pharmacokinetic Parameters Following 
Multiple Oral YPL-001 Doses of 80 mg in COPD 
Patients - Day 54 54 (+/- 1) or Day 56 (Treatment A) 
Table 14.2.4.1.5 Plasma Verproside Pharmacokinetic Parameters Following 
a Single Oral YPL-001 Dose of 160 mg in COPD 
Patients - Day 1 (Treatment B) 
Table 14.2.4.1.6 Plasma Verproside Pharmacokinetic Parameters Following 
Multiple Oral YPL-001 Doses of 160 mg in COPD 
Patients - Day 54 (+/-1) or Day 56 (Treatment B) 
Table 14.2.4.1.7 Intervals (Hours) Used for Determination of Plasma 
Verproside kel Values Following Single and Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg - Days 1 to 54 (+/-1) 
or Day 56  (Treatments A and B) 
Table 14.2.4.1.8 Statistical Comparisons of Dose-Normalized Plasma 
Verproside Pharmacokinetic Parameters Following 
Multiple Oral YPL-001 Doses of 160 mg Versus Multiple 
Oral YPL-001 Doses of 80 mg in COPD Patients – Day 54 
(+/- 1) or Day 56 (Treatment B Versus Treatment A) 
14.2.4.2 Plasma Picroside II Tables 
Table 14.2.4.2.1 Plasma Picroside II Concentrations (pg/mL) Following 
Single and Multiple Oral YPL-001 Doses of 80 mg in 
COPD Patients - Days 1 to 54 (+/-1) or Day 56 
(Treatment A) 
Table 14.2.4.2.2 Plasma Picroside II Concentrations (pg/mL) Following 
Single and Multiple Oral YPL-001 Doses of160 mg in 
COPD Patients - Days 1 to 54 (+/-1) or Day 56 
(Treatment B) 
Table 14.2.4.2.3 Plasma Picroside II Pharmacokinetic Parameters Following 
a Single Oral YPL-001 Dose of 80 mg in COPD 
Patients - Day 1 (Treatment A) 
Table 14.2.4.2.4 Plasma Picroside II Pharmacokinetic Parameters Following 
Multiple Oral YPL-001 Doses of 80 mg in COPD 
Patients - Day 54 (+/-1) or Day 56 (Treatment A) 


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Table 14.2.4.2.5 Plasma Picroside II Pharmacokinetic Parameters Following 
a Single Oral YPL-001 Dose of 160 mg in COPD 
Patients - Day 1 (Treatment B) 
Table 14.2.4.2.6 Plasma Picroside II Pharmacokinetic Parameters Following 
Multiple Oral YPL-001 Doses of 160 mg in COPD 
Patients - Day 54 (+/-1) or Day 56 (Treatment B) 
Table 14.2.4.2.7 Intervals (Hours) Used for Determination of Plasma 
Picroside II kel Values Following Single and Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg - Days 1 to 54 (+/-1) 
or Day 56 (Treatments A and B) 
Table 14.2.4.2.8 Statistical Comparisons of Dose-Normalized Plasma 
Picroside II Pharmacokinetic Parameters Following 
Multiple Oral YPL-001 Doses of 160 mg Versus Multiple 
Oral YPL-001 Doses of 80 mg and in COPD Patients – 
Day 54 (+/-1) or Day 56 (Treatment B Versus 
Treatment A) 
14.2.4.3 Epithelial Brushing Verproside Table 
Table 14.2.4.3.1 Epithelial Brushing Verproside Concentrations (pg/mL) 
Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg in COPD Patients – Baseline and Day 55 or 56 
(Treatments A and B) 
14.2.4.4 Epithelial Brushing Picroside II Table 
Table 14.2.4.4.1 Epithelial Brushing Picroside II Concentrations (pg/mL) 
Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg in COPD Patients – Baseline and Day 55 or 56  
(Treatments A and B) 
14.2.5 Pharmacokinetic Figures 
14.2.5.1 Plasma Verproside Figures 
Figure 14.2.5.1.1 Mean (SD) Plasma Verproside Concentrations Versus 
Time Following Single and Multiple Oral YPL-001 Doses 
of 80 mg and 160 mg in COPD Patients – Day 1 and 54 
(+/- 1) or Day 56 (Treatments A and B) (Linear Scale) 
Figure 14.2.5.1.2 Mean Plasma Verproside Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 
80 mg and 160 mg in COPD Patients – Day 1 and 54 
(+/- 1) or Day 56  (Treatments A and B) (Linear Scale) 
Figure 14.2.5.1.3 Mean Plasma Verproside Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 
80 mg and 160 mg in COPD Patients – Day 1 and 54 
(+/- 1) or Day 56) (Treatments A and B) (Semi-Log Scale) 


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Figure 14.2.5.1.4 Mean (SD) Plasma Verproside Trough Concentrations 
Versus Time Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg in COPD Patients (Treatments A and 
B) (Linear Scale) 
Figure 14.2.5.1.5 Mean Plasma Verproside Trough Concentrations Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg in COPD Patients (Treatments A and B) 
(Linear Scale) 
14.2.5.2 Plasma Picroside II Figures 
Figure 14.2.5.2.1 Mean (SD) Plasma Picroside II Concentrations Versus 
Time Following Single and Multiple Oral YPL-001 Doses 
of 80 mg and 160 mg in COPD Patients – Day 1 and 54 
(+/- 1) or Day 56  (Treatments A and B) (Linear Scale) 
Figure 14.2.5.2.2 Mean Plasma Picroside II Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 
80 mg and 160 mg in COPD Patients – Day 1 and 54 
(+/- 1) or Day 56  (Treatments A and B) (Linear Scale) 
Figure 14.2.5.2.3 Mean Plasma Picroside II Concentrations Versus Time 
Following Single and Multiple Oral YPL-001 Doses of 
80 mg and 160 mg in COPD Patients – Day 1 and 54 
(+/- 1) or Day 56  (Treatments A and B) (Semi-Log Scale) 
Figure 14.2.5.2.4 Mean (SD) Plasma Picroside II Trough Concentrations 
Versus Time Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg in COPD Patients (Treatments A and 
B) (Linear Scale) 
Figure 14.2.5.2.5 Mean Plasma Picroside II Trough Concentrations Versus 
Time Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg in COPD Patients (Treatments A and B) 
(Linear Scale) 
14.3 
Safety Data Summary Tables  
14.3.1 
Displays of Adverse Events 
Table 14.3.1.1 Treatment-emergent Adverse Event Frequency by Treatment 
– Number of Patients Reporting the Event (% of Patients 
Dosed) 
Table 14.3.1.2 Treatment-emergent Adverse Event Frequency by Treatment 
– Number of Adverse Events (% of Total Adverse Events) 
Table 14.3.1.3 Treatment-emergent Adverse Event Frequency by Treatment, 
Severity, and Relationship to Drug – Number of Patients 
Reporting Events 


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Table 14.3.1.4 Treatment-emergent Adverse Event Frequency by Treatment, 
Severity, and Relationship to Drug – Number of Adverse 
Events 
14.3.2 
Listings of Deaths, other Serious and Significant Adverse Events 
Table 14.3.2.1 Serious Adverse Events <if no serious adverse event 
occurred, a statement ‘No serious adverse event was 
reported’> 
14.3.3. Narratives of Deaths, other Serious and Certain other 
Significant Adverse Events 
14.3.4. Abnormal Laboratory Value Listing (each patient) 
Table 14.3.4.1 Out-of-Range Values and Recheck Results – Serum 
Chemistry 
Table 14.3.4.2 Out-of-Range Values and Recheck Results – Hematology 
Table 14.3.4.3 Out-of-Range Values and Recheck Results – Urinalysis 
14.3.5. Displays of Other Laboratory, Vital Signs, Electrocardiogram, 
Physical Examination, and Other Safety Data 
Table 14.3.5.1 Clinical Laboratory Summary and Change from Check-in – 
Serum Chemistry 
Table 14.3.5.2 Clinical Laboratory Shift from Check-in – Serum Chemistry 
Table 14.3.5.3 Clinical Laboratory Summary and Change from Check-in – 
Hematology 
Table 14.3.5.4 Clinical Laboratory Shift from Check-in – Hematology 
Table 14.3.5.5 Clinical Laboratory Summary and Change from Check-in – 
Urinalysis 
Table 14.3.5.6 Clinical Laboratory Shift from Check-in – Urinalysis 
Table 14.3.5.7 Vital Sign Summary and Change From Day 1 Predose 
Table 14.3.5.8 Pulse Oximetry Summary and Change From Check-in 
Table 14.3.5.9 12-Lead Electrocardiogram Summary and Change From 
Check-in  
Table 14.3.5.10 12-Lead Electrocardiogram Shift From Check-in  
 
 


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11.3 
Section 16 Data Listings 
Note:  Hepatitis and HIV results that are provided by the clinical laboratory will not 
be presented in subject data listings and will not be included in any database transfer. 
Data listings are numbered following the ICH structure but may be renumbered as 
appropriate during the compilation of the tables and figures for the CSR. The 
following is a list of appendix numbers and titles that will be included as data listings. 
16.1. Study Information 
Appendix 16.1.10.1 
Clinical Laboratory Reference Ranges 
16.2. Subject Data Listings 
16.2.1. Subject Discontinuation 
Appendix 16.2.1 
Study Completion/Early Termination 
16.2.2. Protocol Deviations 
Appendix 16.2.2 
Protocol Deviations 
16.2.3. Patients Excluded From the Pharmacodymanic and 
Pharmacokinetic Analyses 
Appendix 16.2.3 
Patients Excluded from the Pharmacodynamic and 
Pharmacokinetic Analyses 
Note:  Appendices 16.2.2 and 16.2.3 are generated in Microsoft® Word® for 
inclusion in the CSR. 
16.2.4. Demographic Data 
Appendix 16.2.4.1 
Subject Information 
Appendix 16.2.4.2 
Demographics 
Appendix 16.2.4.3 
Physical Examination  
Appendix 16.2.4.4 
Chest X-Ray  
Appendix 16.2.4.5 
Medical History 
Appendix 16.2.4.6 
Substance Use 
16.2.5. Compliance and Drug Concentration Data 
Appendix 16.2.5.1 
Subject Eligibility 
Appendix 16.2.5.2 
Study Drug Administration 
Appendix 16.2.5.3 
Drug Accountability 
Appendix 16.2.5.4 
Tiotropium and Albuterol Administration 
Appendix 16.2.5.5.1 Bronchoscopy and BAL Biomarkers (I of II) 


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Appendix 16.2.5.5.2 Bronchoscopy and BAL Biomarkers (II of II) 
Appendix 16.2.5.6 
Blood Biomarker Samples 
Appendix 16.2.5.7 
Pharmacokinetic Sampling 
Appendix 16.2.5.8 
Prior and Concomitant Medications 
16.2.6. Individual Symptom Monitoring, Pharmacodynamic, 
Pharmacokinetic, and Response Data 
Note to programmer:  the following list of listings may be modified and 
numbering adjusted. 
16.2.6.1 Symptom Monitoring 
Appendix 16.2.6.1.1 Peak Expiratory Flow and Breathlessness (Modified 
Borg Dyspnea Scale) 
Appendix 16.2.6.1.2 Symptoms of COPD Exacerbation (I of II) 
Appendix 16.2.6.1.3 Symptoms of COPD Exacerbation (II of II) 
Appendix 16.2.6.1.4 Duke Activity Status Index (DASI) Scores 
16.2.6.2 Pharmacodynamics 
Appendix 16.2.6.2.1 BAL Inflammatory Cells Counts 
Appendix 16.2.6.2.2 BAL Inflammatory Marker Concentrations 
Appendix 16.2.6.2.3 Blood Inflammatory Cells 
Appendix 16.2.6.2.4 Blood Inflammatory Marker Concentrations 
Appendix 16.2.6.2.5 Individual Blood WBC Counts Changes from Baseline 
Versus Time Following Single and Multiple Oral 
YPL-001 Doses or Placebo in COPD Patients (Linear 
Scale) 
Appendix 16.2.6.2.6 Individual Blood Monocyte Counts Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.7 Individual Blood Lymphocyte Counts Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.8 Individual Blood Neutrophil Counts Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.9 Individual Blood Eosinophil Counts Changes from 
Baseline Versus Time Following Single and Multiple 


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Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.10 Blood Inflammatory Marker Concentrations 
Appendix 16.2.6.2.11 Individual Blood CRP Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.12 Individual Blood Fibrinogen Concentration Changes 
from Baseline Versus Time Following Single and 
Multiple Oral YPL-001 Doses or Placebo in COPD 
Patients (Linear Scale) 
Appendix 16.2.6.2.13 Individual Blood TNF-α Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.14 Individual Blood IL-1β Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.15 Individual Blood IL-4 Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.16 Individual Blood IL-5 Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.17 Individual Blood IL-6 Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.18 Individual Blood IL-8 Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.19 Individual Blood IL-13 Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.20 Individual Blood MCP-1 Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 


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Appendix 16.2.6.2.21 Individual Blood MMP-9 Concentration Changes from 
Baseline Versus Time Following Single and Multiple 
Oral YPL-001 Doses or Placebo in COPD Patients 
(Linear Scale) 
Appendix 16.2.6.2.22 Baseline Dyspnea Index 
Appendix 16.2.6.2.23 Transition Dyspnea Index 
Appendix 16.2.6.2.24 Pulmonary Function Test (Spirometry) 
Appendix 16.2.6.2.25 Change from Baseline in Pulmonary Function Test 
(Spirometry) 
Appendix 16.2.6.2.26 COPD Assessment Test 
16.2.6.3 Pharmacokinetics 
Appendix 16.2.6.3.1 Individual Plasma Verproside Concentrations Versus 
Time Following Single and Multiple Oral YPL-001 
Doses in COPD Patients (Linear and Semi-Log Scales) 
Appendix 16.2.6.3.2 Individual Trough Plasma Verproside Concentrations 
Versus Time Following Multiple Oral YPL-001 Doses 
in COPD Patients (Linear Scale) 
Appendix 16.2.6.3.3 Individual Plasma Concentrations Picroside II Versus 
Time Following Single and Multiple Oral YPL-001 
Doses in COPD Patients (Linear and Semi-Log Scales) 
Appendix 16.2.6.3.4 Individual Trough Plasma Picroside II Concentrations 
Versus Time Following Multiple Oral YPL-001 Doses 
in COPD Patients (Linear Scale) 
16.2.7. Individual Adverse Event Listings 
Appendix 16.2.7.1 
Adverse Events (I of III) 
Appendix 16.2.7.2 
Adverse Events (II of III) 
Appendix 16.2.7.2 
Adverse Events (III of III) 
Appendix 16.2.7.4 
Adverse Event Non-Drug Therapy 
Appendix 16.2.7.5 
Adverse Event Preferred Term Classification 
16.2.8. Individual Laboratory Measurements and Other Safety 
Observations 
Appendix 16.2.8.1 
Clinical Laboratory Report - Serum Chemistry 
Appendix 16.2.8.2 
Clinical Laboratory Report - Hematology  
Appendix 16.2.8.3 
Clinical Laboratory Report - Urinalysis  
Appendix 16.2.8.4 
Urine Alcohol and Drug Screen  
Appendix 16.2.8.5 
Pregnancy Test  
Appendix 16.2.8.6 
Serology 


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Appendix 16.2.8.7 
Vital Signs 
Appendix 16.2.8.8 
12-Lead Electrocardiogram 
Appendix 16.2.8.9 
Telephone Contact 


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12. 
TABLE SHELLS  
The following table shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the tables that will be presented and included in the final report. 


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12.1 
In-text Table Shells 
Note to programmer:  Formatting and content of PK and PD in-text tables may be 
modified based on provided data. 
Table 10-1 
Disposition Summary by Treatment 
 
Disposition 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Total 
Dosed 
XX (100%) 
XX (100%) 
XX (100%) 
XX (100%) 
Completed Study 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Dropped from Study 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
  Adverse Event 
X ( X%) 
X ( X%) 
X ( X%) 
X ( X%) 
  Protocol Deviation 
X ( X%) 
X ( X%) 
X ( X%) 
X ( X%) 
  Other 
X ( X%) 
X ( X%) 
X ( X%) 
X ( X%) 
  Etc. 
X ( X%) 
X ( X%) 
X ( X%) 
X ( X%) 
Percentage is based on number of patients dosed in a given dose. 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55  
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on 
Day 56. 
 
Source:  Table 14.1.1 and Appendix 16.2.1 
 
 
 


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Table 11-1 
Summary and Change From Baseline of Main Peak Expiratory 
Flow (PEF) Recorded in the e-Diary Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients 
 
 
Day 
Main Peak Expiratory Flow (L/min) 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
1 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
2 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
3 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
4 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
5 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
< > 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
Presented as arithmetic mean ± SD, baseline is Day 1. 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.1 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 51 of 150 
Table 11-2.1 Summary of Sputum Quantity for Symptoms of Chronic 
Obstructive Pulmonary Disease (COPD) Exacerbation Recorded 
in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients 
 
Day 
Sputum Quantity 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Less than 
 1 tbs 
1 tbs or 
 more 
Less than 
 1 tbs 
1 tbs or 
 more 
Less than 
 1 tbs 
1 tbs or 
more 
1 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
2 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
3 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
4 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
5 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
< > 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Less than 1 tbs includes none and less than 1 tbs. 
1 tbs or more includes 1 tbs or more and greater than ¼ cup. 
Percentage is based on number of patients in the binary arrangement. 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.2 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 52 of 150 
Table 11-2.2 Summary of Sputum Color for Symptoms of Chronic Obstructive 
Pulmonary Disease (COPD) Exacerbation Recorded in the e-Diary 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and 
Placebo in COPD Patients 
 
Day 
Sputum Color 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
White 
Not White 
White 
Not White 
White 
Not White 
1 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
2 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
3 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
4 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
5 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
< > 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Not white includes yellow, green, and brown colors. 
Percentage is based on number of patients in the binary arrangement. 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.2 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 53 of 150 
Table 11-2.3 Summary of Sputum Consistency for Symptoms of Chronic 
Obstructive Pulmonary Disease (COPD) Exacerbation Recorded 
in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients 
 
Day 
Sputum Consistency 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Watery 
Not Watery 
Watery 
Not Watery 
Watery Not Watery
1 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
XX  % 
(N=X) 
2 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
3 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
4 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
5 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
< > 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Not watery includes thin and thick consistency. 
Percentage is based on number of patients in the binary arrangement. 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.2 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 54 of 150 
Table 11-3.1 Categorical Summary of Symptom Score for Symptoms of Chronic Obstructive Pulmonary Disease 
(COPD) Exacerbation Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients 
 
Day 
Treatment 
N 
Symptom Score of COPD Symptoms 
0 
0.5 
1 
1.5 
2 
2.5 
3 
3.5 
1 
A 
XX 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
B 
XX 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
C 
XX 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
2 
A 
XX 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
B 
XX 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
 
C 
XX 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
< > 
< > 
XX 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
X (XX%) 
Symptom severity score: Normal (0-0.5), Mild (1-1.5), Moderate (2-2.5), Severe (3-3.5) 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.4 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 55 of 150 
Table 11-3.2 Summary and Change From Baseline of Symptom Severity Score 
for Symptoms of Chronic Obstructive Pulmonary Disease (COPD) 
Exacerbation Recorded in the e-Diary Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients 
 
Day 
Symptom Severity Score 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
1 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
2 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
3 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
4 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
5 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
< > 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
Presented as arithmetic mean scores ± SD, baseline is Day 1. 
Symptom severity score: Normal (0-0.5), Mild (1-1.5), Moderate (2-2.5), Severe (3-3.5) 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.5 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 56 of 150 
Table 11-4 
Summary and Change From Baseline of Modified Borg Dyspnea 
Scale Recorded in the e-Diary Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients 
 
Day 
Breathlessness Indicator 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
1 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
2 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
3 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
4 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
5 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
< > 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
Presented as arithmetic mean scores ± SD, baseline is Day 1. 
Breathlessness score: None (0), very mild (0.5), less mild (1), mild (2), more mild (3), less moderate (4), moderate 
(5), more moderate (6), less severe (7), severe (8), more severe (9), extreme (10) 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.7 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 57 of 150 
Table 11-5 
Summary and Change From Baseline of Calculated Score from 
12-Item Questionnaire of Duke Activity Status Index (DASI) 
Recorded in the e-Diary Following Multiple Oral YPL-001 Doses 
of 80 mg and 160 mg and Placebo in COPD Patients 
 
Day 
DASI Score 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
1 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
2 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
3 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
4 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
5 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
< > 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
Presented as arithmetic mean ± SD, baseline is Day 1. 
DASI score ranged from 0 to 58.2 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.1.9 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 58 of 150 
Table 11-6 
Summary of BAL WBC and Differential Following Multiple Oral 
YPL 001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients – Day 55 or Day 56 (% Change from Baseline) 
 
BAL Inflammatory 
Cell 
% Change from Baseline 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
WBC 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Macrophage 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Lymphocyte 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Neutrophil  
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Eosinophil  
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
XX  ± XX 
(N=X) 
Presented as arithmetic mean ± SD, baseline is at Check-in. 
WBC =  White blood cell 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.2.1 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 59 of 150 
Table 11-7 
Summary of BAL Inflammatory Marker Concentration Changes 
Following Multiple Oral YPL 001 Doses of 80 mg and 160 mg and 
Placebo in COPD Patients –Day 55 or Day 56 (% Change from 
Baseline) 
BAL Inflammatory 
Biomarkers 
% Change from Baseline 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
TNF-α 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
IL-1β 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
IL-4 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
IL-5 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
IL-6 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
IL-8 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
IL-13 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
MPO 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
Neutrophil Elastase 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
MCP-1 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
MMP-9 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
Presented as arithmetic mean ± SD, baseline is at Check-in. 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on 
Day 56. 
 
Source:  Table 14.2.2.3 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 60 of 150 
Table 11-8 
Summary and Change From Baseline of Pre-Bronchodilator 
Spirometric Functions Following Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients 
 
Parameter/Day 
Actual Value 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
Result 
Change from
Baseline 
FEV1 (L)/Screen XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
Check-in 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
15 (± 2) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
29 (± 2) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
43 (± 2) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
55 or 56 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
Presented as arithmetic mean ± SD, baseline is at Screening. 
FEV1 (L) = forced expiratory volume in one second, FVC (L) = forced vital capacity, IC (L) = inspiratory capacity 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.2.7 
 
Programmer note: Present FEV1, FVC, FEV1/FVC, and IC. 
If space is limiting, Day “55 or 56” may be presented as “56” with a footnote indicating 
“Day 55 or 56”. 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 61 of 150 
Table 11-9 
Change From Baseline of Combined Focal Score (-9 – +9) from 
Transition Dyspnea Index (TDI) Following Multiple Oral 
YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD 
Patients 
Day 
Combined Focal Score (-9 – +9) 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
15 (± 2) 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
29 (± 2) 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
43 (± 2) 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
54 (± 1) or 56 
XXX ± XXX 
XXX ± XXX 
XXX ± XXX 
(N=X) 
(N=X) 
(N=X) 
Presented as arithmetic mean ± SD 
TDI has 3 domains (functional impairment, magnitude of task, and magnitude of effort). 
The change from baseline is measured by the TDI score which ranges from -3 (major deterioration) to +3 
(major improvement) for each domain with the TDI focal score consisting in the sum of each domain (-9 to 
+9). 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on 
Day 56. 
 
Source:  Table 14.2.2.12 
 
 
Programmer note: If space is limiting, Day “54 (± 1) or 56” may be presented as Day “54” 
with a footnote indicating this is “Day 54 (± 1) or 56”. 
 


Yungjin Pharm. CO., LTD. 
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Statistical Analysis Plan  
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Table 11-10 Summary and Change From Baseline of Total Score (0 – 40) from 
Chronic Obstructive Pulmonary Disease (COPD) Assessment Test 
(CAT) Following Multiple Oral YPL-001 Doses of 80 mg and 
160 mg and Placebo in COPD Patients 
 
Day 
CAT Total Score 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
Result 
Change from 
Baseline 
Check-in 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
XXX ± XXX 
(N=X) 
NA 
15 (± 2) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
29 (± 2) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
43 (± 2) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
54 (± 1) or 
56 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
XXX ± XXX 
(N=X) 
Presented as arithmetic mean ± SD, baseline is at Check-in. 
CAT items are Cough, Mucus Production, Chest Tightness, Breathlessness, Activities, Confidence, Sleepiness, 
and Energy. Each has 0 to 5 scores so total has 0 to 40 scores (higher score indicates worse symptom). 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Source:  Table 14.2.2.17 
 
 
Programmer note: If space is limiting, Day “54 (± 1) or 56” may be presented as Day “54” 
with a footnote indicating this is “Day 54 (± 1) or 56”. 
 


Yungjin Pharm. CO., LTD. 
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Statistical Analysis Plan  
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Note that in-text Tables 11-12, -15, and -16 will be in a similar format as for 
Table 11-11: 
 
Table 11-11 Summary of Plasma Verproside Pharmacokinetic Parameters 
Following Single Oral YPL-001 Doses of 80 mg and 160 mg in 
COPD Patients – Day 1 
 
Verproside Pharmacokinetic 
Parameters 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
AUC0-12 (pg*hr/mL)a 
XXX (XXX) 
XXX (XXX) 
 
(N=X) 
(N=X) 
AUC0-t (pg*hr/mL)a 
XXX (XXX) 
XXX (XXX) 
 
(N=X) 
(N=X) 
AUC0-inf (pg*hr/mL)a 
XXX (XXX) 
XXX (XXX) 
 
(N=X) 
(N=X) 
Cmax (pg/mL)a 
XX (XX) 
XXX (XXX) 
 
(N=X) 
(N=X) 
tmax (hr)b 
XXX (XXX, XXX) 
XXX (XXX, XXX) 
 
(N=X) 
(N=X) 
tlast (hr)b 
XXX (XXX, XXX) 
XXX (XXX, XXX) 
 
(N=X) 
(N=X) 
kel (1/hr)c 
XXX ± XXX 
XXX ± XXX 
 
(N=X) 
(N=X) 
t½ (hr)c 
XXX ± XXX 
XXX ± XXX 
 
(N=X) 
(N=X) 
CL/F (L/hr)c 
XXX ± XXX 
XXX ± XXX 
 
(N=X) 
(N=X) 
Vz/F (L)c 
XXX ± XXX 
XXX ± XXX 
 
(N=X) 
(N=X) 
RA,AUC
c 
XXX ± XXX 
XXX ± XXX 
 
(N=X) 
(N=X) 
a: Presented as geo. mean (geo. CV%) 
b: Presented as median (minimum, maximum)  
c: Presented as arithmetic mean ± SD 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55  
Note:  Patients following up to Amendment version 5 of the protocol also received a 
morning dose on Day 56. 
 
Source:  Tables 14.2.4.1.3 and 14.2.4.1.5 
 
Note to Programmer: For verproside and picroside II tables on Day 54 (± 1) or 56 the PK 
parameters will be: AUCτ, AUC0-t, Cmax_ss, tmax_ss, Cmin_ss, tlast, Ctrough, Cavg_ss, %Fluc, Swing, 
kel, t½, CLss/F, Vz_ss/F, and RA,AUC.Note that in-text Table 11-17 will be in a similar format as 
for Table 11-13: 
 


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Statistical Analysis Plan  
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Page 64 of 150 
Table 11-13 Statistical Comparisons of Dose-Normalized Plasma Verproside 
Pharmacokinetic Parameters Following Multiple Oral YPL-001 
Doses of 160 mg Versus Multiple Oral YPL-001 Doses of 80 mg 
and in COPD Patients – Day 54 (± 1) or Day 56 (Treatment B 
Versus Treatment A) 
 
Verproside 
Pharmacokinetic 
Parameter 
Geometric LSM 
Geometric 
Mean Ratio 
(%) 
90% 
Confidence 
Intervals 
Treatment B 
(test, N=X) 
Treatment A 
(reference, N=X) 
AUCτ (pg*hr/mL) 
XX 
XX 
XX 
XX – XX 
AUC0-t (pg*hr/mL) 
XX 
XX 
XX 
XX – XX 
Cmax_ss (pg/mL) 
XX 
XX 
XX 
XX – XX 
Parameters were dose-normalized (to 80 mg YLP-001) and ln-transformed prior to analysis. 
Geometric least square means (LSMs) were calculated by exponentiating the LSM from the ANOVA. 
% Geometric Mean Ratio = 100 × (test/reference) 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
Source: Table 14.2.4.1.8 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 65 of 150 
Note that in-text Table 11-18 will be in a similar format as for Table 11-14: 
 
Table 11-14 Epithelial 
Brushing 
Verproside 
Concentrations 
Following 
Multiple Oral YPL-001 Doses of 80 mg and 160 mg in COPD 
Patients – Baseline and Day 55 or 56 (Treatments A and B) 
 
Time 
Verproside Concentration (pg/mL) 
Treatment A 
YPL-001 80 mg 
(N=X) 
Treatment B 
YPL-001 160 mg 
(N=X) 
Check-in (Baseline) 
XXX ±XXX 
XXX ± XXX 
Day 55 or 56 
XXX ± XXX 
XXX ± XXX 
Presented as arithmetic mean ± SD 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received 
a morning dose on Day 56. 
 
Source:  Table 14.2.4.3.1 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 66 of 150 
Table 12-1 
Incidence of Treatment-Emergent Adverse Events 
 
Adverse Events* 
Treatment A 
YPL-001 80 mg 
Treatment B 
YPL-001 160 mg 
Treatment C 
Placebo 
Total 
Number of Patients Dosed  
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
Number of Patients With 
Adverse Events 
XX (XX%) 
XX (XX%) 
XX (XX%) 
XX (XX%) 
System Organ Class 1 
X ( X%) 
X ( X%) 
X ( X%) 
X ( X%) 
     Preferred Term 1 
X ( X%) 
X ( X%) 
X ( X%) 
X ( X%) 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on 
Day 56. 
*Adverse events are coded using MedDRA® Version 18.0. 
 
Source: Table 14.3.1.1 
 
Programmer note: Present TEAEs ordered by decreasing frequency of SOC and then 
preferred term in the Total column.


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
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Page 67 of 150 
12.2 
Post-text Table Shells 
Note to programmer:  Formatting and content of post-text tables may be modified based on provided data. 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 68 of 150 
Page X of X 
                     Table 14.1.1  Disposition of Subjects 
  
 
                                          Treatment 
 
 
 
                                ----------------------------   
        Disposition                A         B         C       Total   
        -------------------------------------------------------------- 
        Dosed                   XX (XX%)  XX (XX%)  XX (XX%)  XX (XX%) 
        Completed Study         XX (XX%)  XX (XX%)  XX (XX%)  XX (XX%) 
        Dropped from Study      XX (XX%)  XX (XX%)  XX (XX%)  XX (XX%) 
           Reason 1             XX (XX%)  XX (XX%)  XX (XX%)  XX (XX%) 
           Reason 2             XX (XX%)  XX (XX%)  XX (XX%)  XX (XX%) 
           Reason 3             XX (XX%)  XX (XX%)  XX (XX%)  XX (XX%) 
           etc. 
 
 
  
  
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM   
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 69 of 150 
Page X of X 
                 Table 14.1.2  Demographic Summary 
                                         Treatment 
 
 
 
                              ------------------------------   
Trait                            A          B          C       Total     
------------------------------------------------------------------------ 
Gender           XXXXX         X (X %)    X (X %)    X (X %)    X (X %)    
                                                                           
Race             XXXXX         X (X %)    X (X %)    X (X %)    X (X %)    
                                                                                                                                                             
Ethnicity        XXXXXXX       X (X %)    X (X %)    X (X %)    X (X %)    
 
Age              N            XX.X       XX.X       XX.X       XX.X        
                 Mean         XX.X       XX.X       XX.X       XX.X        
                 SD           XX.X       XX.X       XX.X       XX.X        
                 Median       XX.X       XX.X       XX.X       XX.X        
                 Minimum      XX.X       XX.X       XX.X       XX.X        
                 Maximum      XX.X       XX.X       XX.X       XX.X        
                                                                           
Height (cm)      N            XX.X       XX.X       XX.X       XX.X        
                 Mean         XX.X       XX.X       XX.X       XX.X        
                 SD           XX.X       XX.X       XX.X       XX.X        
                 Median       XX.X       XX.X       XX.X       XX.X        
                 Minimum      XX.X       XX.X       XX.X       XX.X        
                 Maximum      XX.X       XX.X       XX.X       XX.X        
 
Weight (kg)      N            XX.X       XX.X       XX.X       XX.X        
                 Mean         XX.X       XX.X       XX.X       XX.X        
                 SD           XX.X       XX.X       XX.X       XX.X        
                 Median       XX.X       XX.X       XX.X       XX.X        
                 Minimum      XX.X       XX.X       XX.X       XX.X        
                 Maximum      XX.X       XX.X       XX.X       XX.X        
 
BMI (kg/m2)      N            XX.X       XX.X       XX.X       XX.X        
                 Mean         XX.X       XX.X       XX.X       XX.X        
                 SD           XX.X       XX.X       XX.X       XX.X        
                 Median       XX.X       XX.X       XX.X       XX.X        
                 Minimum      XX.X       XX.X       XX.X       XX.X        
                 Maximum      XX.X       XX.X       XX.X       XX.X        
BMI = Body Mass Index 
Weight at screening is used for summarization. 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM                                                         
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 70 of 150 
                                                                                                                                 Page 1 of X 
                        Table 14.1.3  Summary of Exposure to Study Drug 
 
                                               
                                                   Treatment  
 
 
                                        ------------------------------                                            
                                           A          B          C                          
                          Study Day     (N=XX)     (N=XX)     (N=XX)     
                          -------------------------------------------- 
                          1 AM          X ( %)      X ( %)    X ( %)        
                          1 PM          X ( %)      X ( %)    X ( %)        
                          2 AM          X ( %)      X ( %)    X ( %)        
                          2 PM          X ( %)      X ( %)    X ( %)        
                          3 AM          X ( %)      X ( %)    X ( %)        
                          3 PM          X ( %)      X ( %)    X ( %)        
                          4 AM          X ( %)      X ( %)    X ( %)        
                          4 PM          X ( %)      X ( %)    X ( %)        
                          5 AM          X ( %)      X ( %)    X ( %)        
                          5 PM          X ( %)      X ( %)    X ( %)        
                          6 AM          X ( %)      X ( %)    X ( %)        
                          6 PM          X ( %)      X ( %)    X ( %)        
                          7 AM          X ( %)      X ( %)    X ( %)        
                          7 PM          X ( %)      X ( %)    X ( %)        
                          8 AM          X ( %)      X ( %)    X ( %)        
                          8 PM          X ( %)      X ( %)    X ( %)        
                          9 AM          X ( %)      X ( %)    X ( %)        
                          9 PM          X ( %)      X ( %)    X ( %)        
                         10 AM          X ( %)      X ( %)    X ( %)        
                         10 PM          X ( %)      X ( %)    X ( %)        
                         < >            < >         < >       < >  
 
Number of subjects dosed by day with percentage is based on total number of subjects dosed in each treatment.  
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
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Page 71 of 150 
Symptom Monitoring 
Page X of X 
Table 14.2.1.1  Summary and Change From Baseline of Main Peak Expiratory Flow (PEF) Recorded in the e-Diary Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
                                             Treatment A                     Treatment B                      Treatment C    
                                   ------------------------------   ------------------------------   ------------------------------ 
                                    Result   Change From Baseline    Result   Change From Baseline    Result   Change From Baseline 
                  Summary          --------  --------------------   --------  --------------------   --------  --------------------        
Day               Statistic        (N = XX)        (N = XX)         (N = XX)        (N = XX)         (N = XX)        (N = XX) 
----------------------------------------------------------------------------------------------------------------------------------- 
1                 N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
2                 N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
Main peak expiratory flow (L/min) = Highest of the three peak flow recordings 
Baseline is Day 1 predose measurement. 
P-value (Within) came from Wilcoxon Signed Rank Test, P-value (Between) came from Wilcoxon Rank Sum Test: A vs C and B vs C 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 72 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.1.2  Categorical Summary of Sputum Quantity, Color, and Consistency for Symptoms of Chronic Obstructive Pulmonary Disease (COPD) 
Exacerbation Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - 
C) 
 
 
                            Sputum Quantity                                Sputum Color                       Sputum Consistency 
     Treat-  --------------------------------------------   ----------------------------------------   --------------------------------  
Day  ment    N      0        < 1 t      >= 1 t    > ¼ c     N   White     Yellow    Green    Brown     N    Watery     Thin     Thick  
--------------------------------------------------------------------------------------------------------------------------------------- 
1    A       XX  XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)   XX  X ( X%)   X ( X%)   X ( X%)  XX (XX%)  XX  XX (XX%)   X ( X%)   X ( X%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X ( X%)   XX  X (XX%)   X (XX%)   X ( X%)   X ( X%)  XX   X (XX%)   X ( X%)   X ( X%) 
     C       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   XX  X (XX%)   X (XX%)   X (XX%)   X (XX%)  XX   X ( X%)   X ( X%)   X ( X%) 
 
2    A       XX  XX (XX%)    X ( X%)    X ( X%)  XX (XX%)   XX  X (XX%)  XX (XX%)   X ( X%)   X ( X%)  XX   X ( X%)   X ( X%)   X ( X%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   XX  X (XX%)   X (XX%)   X (XX%)   X (XX%)  XX   X ( X%)   X ( X%)   X ( X%) 
     C       XX  XX (XX%)   XX (XX%)   XX (XX%)  XX (XX%)   XX  X (XX%)   X ( X%)   X ( X%)  XX (XX%)  XX   X ( X%)   X ( X%)   X ( X%) 
 
< > 
 
 
 
Sputum Quantity: 0 = None, < 1 t = Less than 1 tbs, >= 1 t = 1 tbs or more, > ¼ c = Greater than ¼ cup 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 73 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.1.3  Categorical Summary of Cough, Wheeze, Sore Throat, Nasal Congestion, Nasal Discharge, and Body Temperature Above 100°F for 
Symptoms of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
                                                                                 Nasal              Nasal         Body Temperature 
                   Cough                Wheeze           Sore Throat          Congestion          Discharge           Above 100°F 
     Treat- -------------------   ------------------  ------------------   ----------------   ------------------   -----------------  
Day  ment       N        Yes        N        Yes         N       Yes        N        Yes        N        Yes         N        Yes  
------------------------------------------------------------------------------------------------------------------------------------ 
1    A         XX     XX (XX%)     XX     XX (XX%)      XX     XX (XX%)    XX     XX (XX%)     XX     XX (XX%)      XX     XX (XX%) 
     B         XX      X (XX%)     XX      X (XX%)      XX      X (XX%)    XX      X (XX%)     XX      X (XX%)      XX      X (XX%) 
     C         XX      X (XX%)     XX      X (XX%)      XX      X (XX%)    XX      X (XX%)     XX      X (XX%)      XX      X (XX%) 
 
2    A         XX      X ( X%)     XX      X ( X%)      XX      X ( X%)    XX      X ( X%)     XX      X ( X%)      XX      X ( X%) 
     B         XX      X (XX%)     XX      X (XX%)      XX      X (XX%)    XX      X (XX%)     XX      X (XX%)      XX      X (XX%) 
     C         XX     XX (XX%)     XX     XX (XX%)      XX     XX (XX%)    XX     XX (XX%)     XX     XX (XX%)      XX     XX (XX%) 
 
< > 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 74 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.1.4  Categorical Summary of Symptom Score for Symptoms of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation Recorded in 
the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                       Symptom Score of COPD Symptoms 
     Treat-      --------------------------------------------------------------------------------  
Day  ment    N      0         0.5         1        1.5        2        2.5        3        3.5    
------------------------------------------------------------------------------------------------- 
1    A       XX  XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%)  XX (XX%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)   X (XX%)   X ( X%)   X ( X%) 
     C       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%) 
 
2    A       XX  XX (XX%)    X ( X%)    X ( X%)  XX (XX%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%) 
     C       XX  XX (XX%)   XX (XX%)   XX (XX%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%)  XX (XX%) 
 
< > 
 
 
 
Severity of symptom scores: Normal (0 - 0.5), Mild(1 - 1.5), Moderate(2 - 2.5), Severe(3 - 3.5) 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 75 of 150 
Page X of X 
Table 14.2.1.5  Summary and Change From Baseline of Symptom Score for Symptoms of Chronic Obstructive Pulmonary Disease (COPD) Exacerbation 
Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
                                             Treatment A                     Treatment B                      Treatment C    
                                   ------------------------------   ------------------------------   ------------------------------ 
                                    Result   Change From Baseline    Result   Change From Baseline    Result   Change From Baseline 
                  Summary          --------  --------------------   --------  --------------------   --------  --------------------        
Day               Statistic        (N = XX)        (N = XX)         (N = XX)        (N = XX)         (N = XX)        (N = XX) 
----------------------------------------------------------------------------------------------------------------------------------- 
1                 N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
2                 N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
 
Baseline is Day 1 predose measurement. 
Severity of symptom scores: Normal (0 - 0.5), Mild(1 - 1.5), Moderate(2 - 2.5), Severe(3 - 3.5) 
P-value (Within) came from Wilcoxon Signed Rank Test, P-value (Between) came from Wilcoxon Rank Sum Test: A vs C and B vs C 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 76 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.1.6  Categorical Summary of Modified Borg Dyspnea Scale Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg 
and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                                           Number Indicator of Breathlessness 
     Treat-      ------------------------------------------------------------------------------------------------------------------------  
Day  ment    N      0         0.5         1         2         3         4         5         6         7         8         9         10 
----------------------------------------------------------------------------------------------------------------------------------------- 
1    A       XX  XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%)   X ( X%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)   X (XX%)   X ( X%)   X ( X%)   X (XX%)   X ( X%)   X ( X%)   X ( X%) 
     C       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
 
2    A       XX  XX (XX%)    X ( X%)    X ( X%)  XX (XX%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
     C       XX  XX (XX%)   XX (XX%)   XX (XX%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%)  XX (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
 
< > 
 
 
 
0 = None, 0.5 = Very Mild, 1 = Less Mild, 2 = Mild, 3 = More Mild, 4 = Less Moderate, 5 = Moderate, 6 = More Moderate, 7 = Less Severe, 
8 = Severe, 9 = More Severe, 10 = Extreme 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 77 of 150 
Page X of X 
Table 14.2.1.7  Summary and Change From Baseline of Modified Borg Dyspnea Scale Recorded in the e-Diary Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
                                             Treatment A                     Treatment B                      Treatment C    
                                   ------------------------------   ------------------------------   ------------------------------ 
                                    Result   Change From Baseline    Result   Change From Baseline    Result   Change From Baseline 
                  Summary          --------  --------------------   --------  --------------------   --------  --------------------        
Day               Statistic        (N = XX)        (N = XX)         (N = XX)        (N = XX)         (N = XX)        (N = XX) 
----------------------------------------------------------------------------------------------------------------------------------- 
1                 N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
2                 N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
 
Baseline is Day 1 predose measurement. 
P-value (Within) came from Wilcoxon Signed Rank Test, P-value (Between) came from Wilcoxon Rank Sum Test: A vs C and B vs C 
Modified Borg Dyspnea Scale: 0 = None, 0.5 = Very Mild, 1 = Less Mild, 2 = Mild, 3 = More Mild, 4 = Less Moderate, 5 = Moderate,  
6 = More Moderate, 7 = Less Severe, 8 = Severe, 9 = More Severe, 10 = Extreme 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 78 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.1.8  Categorical Summary of 12-Item Questionnaire of Duke Activity Status Index (DASI) Recorded in the e-Diary Following Multiple 
Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                                             DASI 12-Item Questionnaire 
     Treat-      ------------------------------------------------------------------------------------------------------------------------  
Day  ment    N      1         2         3         4         5         6         7         8         9         10         11        12 
----------------------------------------------------------------------------------------------------------------------------------------- 
1    A       XX  XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%)   X ( X%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)   X (XX%)   X ( X%)   X ( X%)   X (XX%)   X ( X%)   X ( X%)   X ( X%) 
     C       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
 
2    A       XX  XX (XX%)    X ( X%)    X ( X%)  XX (XX%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
     B       XX   X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
     C       XX  XX (XX%)   XX (XX%)   XX (XX%)  XX (XX%)  XX (XX%)   X ( X%)   X ( X%)  XX (XX%)   X ( X%)   X ( X%)   X ( X%)   X ( X%) 
 
< > 
 
1. Able to take care of yourself that is eating, dressing, bathing, or using the toilet yet? 
2. Able to walk indoors, such as around the house? 
3. Able to walk a block or 2 on level ground? 
4. Able to climb a flight of stairs or walk up a hill without stopping? 
5. Able to run a short distance? 
6. Able to do light work around the house like dusting or washing dishes? 
7. Able to do moderate work around the house like vacuuming, sweeping floors or carrying in the groceries? 
8. Able to do heavy work around the house like scrubbing floors, or lifting or moving heavy furniture? 
9. Able to do yard work like raking leaves, weeding, or pushing a power mower yet? 
10. Are you having sexual relations? 
11. Able to participate in moderate recreational activities like golf, bowling, dancing, double tennis, or throwing a baseball or football 
yet? 
12. Are you able to participate in strenuous sports like swimming, singles tennis, football, basketball, or skiing? 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 79 of 150 
Page X of X 
Table 14.2.1.9  Summary and Change From Baseline of Calculated Score from 12-Item Questionnaire of Duke Activity Status Index (DASI) 
Recorded in the e-Diary Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
                                             Treatment A                     Treatment B                      Treatment C    
                                   ------------------------------   ------------------------------   ------------------------------ 
                                    Result   Change From Baseline    Result   Change From Baseline    Result   Change From Baseline 
                  Summary          --------  --------------------   --------  --------------------   --------  --------------------        
Day               Statistic        (N = XX)        (N = XX)         (N = XX)        (N = XX)         (N = XX)        (N = XX) 
----------------------------------------------------------------------------------------------------------------------------------- 
1                 N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
2                 N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
 
Baseline is Day 1 predose measurement. 
Score ranges between 0 and 58.2 points. 
P-value (Within) came from Wilcoxon Signed Rank Test, P-value (Between) came from Wilcoxon Rank Sum Test: A vs C and B vs C 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 80 of 150 
Pharmacodynamics 
Inflammatory Cell Counts in BAL and Blood 
 
Note: Tables 14.2.2.1 and 14.2.2.4 will be in a similar format: 
Page X of X 
 
Table 14.2.2.1  Summary of BAL WBC Counts Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments 
A - C) (Raw, % Change from Baseline, and % of WBC) 
 
                                                          Raw                  % Change from Baseline                 % of WBC 
                                              ---------------------------    ----------------------------    ---------------------------- 
                                                        Treatment                      Treatment                       Treatment 
                                              ---------------------------    ----------------------------    ---------------------------- 
Measurement     Time Point       Statistic         A          B         C         A          B          C         A          B          C 
----------------------------------------------------------------------------------------------------------------------------------------- 
WBC (units)     <Check-in>        N                X          X         X          X          X         X        NA         NA         NA 
                                  Mean         X.XXX      X.XXX     X.XXX      X.XXX      X.XXX     X.XXX        NA         NA         NA 
                                  SD          X.XXXX     X.XXXX    X.XXXX     X.XXXX     X.XXXX    X.XXXX        NA         NA         NA 
                                  CV%         X.XXXX     X.XXXX    X.XXXX     X.XXXX     X.XXXX    X.XXXX        NA         NA         NA 
                                  Median       X.XXX      X.XXX     X.XXX      X.XXX      X.XXX     X.XXX        NA         NA         NA 
                                  Minimum       X.XX       X.XX      X.XX       X.XX       X.XX      X.XX        NA         NA         NA 
                                  Maximum       X.XX       X.XX      X.XX       X.XX       X.XX      X.XX        NA         NA         NA 
 
<Cell type>   <Day 55 or 56>      N                X          X         X         X          X          X         X          X          X 
(units)                           Mean         X.XXX      X.XXX     X.XXX     X.XXX      X.XXX      X.XXX     X.XXX      X.XXX      X.XXX 
                                  SD          X.XXXX     X.XXXX    X.XXXX    X.XXXX     X.XXXX     X.XXXX    X.XXXX     X.XXXX     X.XXXX 
                                  CV%         X.XXXX     X.XXXX    X.XXXX    X.XXXX     X.XXXX     X.XXXX    X.XXXX     X.XXXX     X.XXXX 
                                  Median       X.XXX      X.XXX     X.XXX     X.XXX      X.XXX      X.XXX     X.XXX      X.XXX      X.XXX 
                                  Minimum       X.XX       X.XX      X.XX      X.XX       X.XX       X.XX      X.XX       X.XX       X.XX 
                                  Maximum       X.XX       X.XX      X.XX      X.XX       X.XX       X.XX      X.XX       X.XX       X.XX 
----------------------------------------------------------------------------------------------------------------------------------------- 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
NA = Not applicable 
. = Value missing or not reportable 
 
Programmers note: For the list of time point refer to Section 7.1.1.1 and 7.1.1.2 
Differential cells include macropaghes, lymphocytes, neutrophils, and eosinophils 
Program:  /CAXXXXX/XXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                      
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 81 of 150 
Inflammatory Markers in BAL and Blood 
 
Note: Tables 14.2.2.2 and 14.2.2.5 and will be in a similar format: 
Page X of X 
 
Table 14.2.2.5  Summary of Blood Inflammatory Marker Concentrations Following Multiple Oral YPL 001 Doses of 80 mg and 160 mg and Placebo in 
COPD Patients (Treatments A - C) 
 
                                                                                                Treatment                
                                                                                    --------------------------------- 
                   Measurement            Time Point               Statistic              A            B            C 
                    ------------------------------------------------------------------------------------------------- 
                   IL-X (units)  <Screen, Day X predose> (Baseline)> N                    X            X            X 
                                                                     Mean             X.XXX        X.XXX        X.XXX 
                                                                     SD              X.XXXX       X.XXXX       X.XXXX 
                                                                     CV%             X.XXXX       X.XXXX       X.XXXX 
                                                                     Median           X.XXX        X.XXX        X.XXX 
                                                                     Minimum           X.XX         X.XX         X.XX 
                                                                     Maximum           X.XX         X.XX         X.XX 
 
                   IL-X (units)   <Day X+/-X 1 Hr postdose           N                    X            X            X 
                                           or Predose>               Mean             X.XXX        X.XXX        X.XXX 
                                                                     SD              X.XXXX       X.XXXX       X.XXXX 
                                                                     CV%             X.XXXX       X.XXXX       X.XXXX 
                                                                     Median           X.XXX        X.XXX        X.XXX 
                                                                     Minimum           X.XX         X.XX         X.XX 
                                                                     Maximum           X.XX         X.XX         X.XX 
------------------------------------------------------------------------------------------------------------------------  
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
. = Value missing or not reportable 
 
Programmers note:  
Add separation (table break) between each marker type as well as the marker type name at the top of the table. 
For the list of time point for each table refer to Sections 7.1.1.1 and 7.1.1.2 
Biomarkers types include : BAL: TNF-α, IL 1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, MCP-1, and MMP-9 
Blood: CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL 13, MCP-1, and MMP-9 
Program:  /AAXXXXX/XXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                      
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 82 of 150 
Note: Tables 14.2.2.3 and 14.2.2.6 and will be in a similar format: 
Page X of X 
 
Table 14.2.2.6  Summary of Blood Inflammatory Marker Concentration Changes Following Multiple Oral YPL 001 Doses of 80 mg and 160 mg and 
Placebo in COPD Patients (Treatments A - C) (Raw and % Change from Baseline) 
 
                                                           Change From Baseline            % Change from Baseline          
                                                      --------------------------------   --------------------------------- 
                                                                Treatment                            Treatment 
                                                      ---------------------------------  --------------------------------- 
 Measurement          Time Point       Statistic         A            B              C      A            B              C  
 ------------------------------------------------------------------------------------------------------------------------- 
IL-X (units)    <Day X  1 Hr postdose  N                    X            X            X        X            X            X 
                    or predose>        Mean             X.XXX        X.XXX        X.XXX    X.XXX        X.XXX        X.XXX 
                                       SD              X.XXXX       X.XXXX       X.XXXX   X.XXXX       X.XXXX       X.XXXX 
                                       CV%             X.XXXX       X.XXXX       X.XXXX   X.XXXX       X.XXXX       X.XXXX 
                                       Median           X.XXX        X.XXX        X.XXX    X.XXX        X.XXX        X.XXX 
                                       Minimum           X.XX         X.XX         X.XX     X.XX         X.XX         X.XX 
                                       Maximum           X.XX         X.XX         X.XX     X.XX         X.XX         X.XX 
 
IL-X (units)     <Day X+/-X 1 Hr       N                    X            X            X        X            X            X 
             postdose or predose>      Mean             X.XXX        X.XXX        X.XXX    X.XXX        X.XXX        X.XXX 
                                       SD              X.XXXX       X.XXXX       X.XXXX   X.XXXX       X.XXXX       X.XXXX 
                                       CV%             X.XXXX       X.XXXX       X.XXXX   X.XXXX       X.XXXX       X.XXXX 
                                       Median           X.XXX        X.XXX        X.XXX    X.XXX        X.XXX        X.XXX 
                                       Minimum           X.XX         X.XX         X.XX     X.XX         X.XX         X.XX 
                                       Maximum           X.XX         X.XX         X.XX     X.XX         X.XX         X.XX 
---------------------------------------------------------------------------------------------------------------------------- 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
. = Value missing or not reportable 
 
Programmers note:  
Add separation (table break) between each marker type as well as the marker type name at the top of the table. 
For the list of time point for each table refer to Sections 7.1.1.1 and 7.1.1.2 
Biomarkers types include : BAL: TNF-α, IL 1β, IL-4, IL-5, IL-6, IL-8, IL-13, MPO, neutrophil elastase, MCP-1, and MMP-9 
Blood: CRP, fibrinogen, TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-8, IL 13, MCP-1, and MMP-9 
 
Program:  /AAXXXXX/XXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM           
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 83 of 150 
Pulmonary Function Biomarkers 
 
Note: Tables 14.2.2.7, 14.2.2.8, and 14.2.2.9 and will be in a similar format: 
Page X of X 
 
Table 14.2.2.7  Summary of Spirometric Functions Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients 
(Actual Results, Treatments A - C) 
 
                                             Treatment A                     Treatment B                      Treatment C    
Parameter (Unit)                    ------------------------------   ------------------------------   ------------------------------ 
(Pre/                               Result   Change From Baseline    Result   Change From Baseline    Result   Change From Baseline 
Post/             Summary          --------  --------------------   --------  --------------------   --------  --------------------        
Change)   Day     Statistic        (N = XX)        (N = XX)         (N = XX)        (N = XX)         (N = XX)        (N = XX) 
----------------------------------------------------------------------------------------------------------------------------------- 
FEV1 (L) 
Pre^      Screen  N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
Post^             N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
Change^           N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
Pre^   Check-in   N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 84 of 150 
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
Post^             N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
Change^           N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
Pre^  15+/-2      N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
Post^             N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
Change^           N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 85 of 150 
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
< >      < >      < > 
 
FEV1 = forced expiratory volume in one second, FVC = forced vital capacity, IC = inspiratory capacity 
^ Pre- and Post-Bronchodilator, Change = Post- minus Pre- 
Baseline is screening measurement. 
P-value (Within) came from Wilcoxon Signed Rank Test, P-value (Between) came from Wilcoxon Rank Sum Test: A vs C and B vs C 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Programmers note: 
Measurments to include are FEV1 (L), FVC (L), FEV1/FVC (%), and IC (L). 
Postdose time points are Day 15+/-2, 29+/-2, 43+/-2, and 55 or 56.  
If space is limiting, Day “55 or 56” may be presented as “56” with a footnote indicating “Day 55 or 56”. 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/XXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                      
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 86 of 150 
Quality of Life 
                                                                                                                       Page X of X 
 
Table 14.2.2.10  Categorical Summary of Baseline Dyspnea Index (BDI) at Check-in by Treatment Assignment of Multiple Oral YPL-001 Doses of 
80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                                                                                                   Impaired for Reasons   
Treat-                                                                                       Amount                Other than Shortness     
ment                              N      Grade 4    Grade 3   Grade 2   Grade 1    Grade 0   Uncertain   Unknown   of Breath   
--------------------------------------------------------------------------------------------------------------------------------------- 
A       Functional Impairment     XX     XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)  XX (XX%)   XX (XX%)   XX (XX%)      XX (XX%)  
        Magnitude of Task         XX      X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)    X (XX%)    X (XX%)       X (XX%)  
        Magnitude of Effort       XX      X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)    X (XX%)    X (XX%)       X (XX%)  
 
B       Functional Impairment     XX     XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)  XX (XX%)   XX (XX%)   XX (XX%)      XX (XX%)  
        Magnitude of Task         XX      X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)    X (XX%)    X (XX%)       X (XX%)  
        Magnitude of Effort       XX      X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)    X (XX%)    X (XX%)       X (XX%)  
 
C       Functional Impairment     XX     XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)  XX (XX%)   XX (XX%)   XX (XX%)      XX (XX%)  
        Magnitude of Task         XX      X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)    X (XX%)    X (XX%)       X (XX%)  
        Magnitude of Effort       XX      X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)    X (XX%)    X (XX%)       X (XX%)  
 
 
Functional Impairment: Grade 4 = No Impairment, Grade 3 = Slight Impairment, Grade 2 = Moderate Impairment, Grade 1 = Severe Impairment,  
                       Grade 0 = Very Severe Impairment  
Magnitude of Task:     Grade 4 = Extraordinary, Grade 3 = Major, Grade 2 = Moderate, Grade 1 = Light, Grade 0 = No Task 
Magnitude of Effort:   Grade 4 = Extraordinary, Grade 3 = Major, Grade 2 = Moderate, Grade 1 = Light, Grade 0 = No Effort 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 87 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.2.11  Categorical Summary of Transition Dyspnea Index (TDI) Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo 
in COPD Patients (Treatments A - C) 
 
                                                                                                                         Further Impairment    
                                                                                                                          for Reasons Other  
              Treat-  Change of Grade                                                                                        than Shortness     
Day           ment    From Check-in            N      -3         -2         -1         0        +1         +2         +3          of Breath   
------------------------------------------------------------------------------------------------------------------------------------------- 
15+/-2        A       Functional Impairment   XX   XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)  XX (XX%)   XX (XX%)   XX (XX%)        XX (XX%)  
                      Magnitude of Task       XX    X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)    X (XX%)    X (XX%)         X (XX%)  
                      Magnitude of Effort     XX    X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)    X (XX%)    X (XX%)         X (XX%)  
 
              B       Functional Impairment   XX   XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)  XX (XX%)   XX (XX%)   XX (XX%)        XX (XX%)  
                      Magnitude of Task       XX    X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)    X (XX%)    X (XX%)         X (XX%)  
                      Magnitude of Effort     XX    X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)    X (XX%)    X (XX%)         X (XX%)  
 
              C       Functional Impairment   XX   XX (XX%)   XX (XX%)   XX (XX%)   X ( X%)  XX (XX%)   XX (XX%)   XX (XX%)        XX (XX%)  
                      Magnitude of Task       XX    X (XX%)    X (XX%)    X (XX%)   X ( X%)   X (XX%)    X (XX%)    X (XX%)         X (XX%)  
                      Magnitude of Effort     XX    X (XX%)    X (XX%)    X (XX%)   X (XX%)   X (XX%)    X (XX%)    X (XX%)         X (XX%)  
 
 
-3 = Major Deterioration, -2 = Moderate Deterioration, -1 = Minor Deterioration, 0 = No Change, +1 = Minor Improvement, +2 = Moderate  
Improvement, +3 = Major Improvement 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Programmers note:  
Time points are Day 15+/-2, 29+/-2, 43+/-2, and 54+/-1 or 56.  
If space is limiting, Day “54+/-1 or 56” may be presented as Day “54” with a footnote indicating this is “Day 54+/-1 or 56”. 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 88 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.2.12  Change From Baseline of Combined Focal Score (-9 – +9) from Transition Dyspnea Index (TDI) Following Multiple Oral YPL-001 
Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
                                 Treatment A           Treatment B             Treatment C    
           Summary          --------------------   --------------------   --------------------        
Day        Statistic              (N = XX)               (N = XX)               (N = XX) 
---------------------------------------------------------------------------------------------- 
15+/-2     N                        XX                     XX                      XX   
           Mean                   -X.X                   -X.X                    -X.X   
           SD                    XX.XX                  XX.XX                   XX.XX   
           CV%                    XX.X                     XX.X                  XX.X 
           Median                 -X.X                   -X.X                    -X.X   
           Minimum                 -XX                    -XX                     -XX   
           Maximum                  XX                     XX                      XX   
           P-Value (Between)     X.XXX                  X.XXX                           
 
29+/-2     N                        XX                     XX                      XX   
           Mean                   -X.X                   -X.X                    -X.X   
           SD                    XX.XX                  XX.XX                   XX.XX   
           CV%                    XX.X                     XX.X                  XX.X 
           Median                 -X.X                   -X.X                    -X.X   
           Minimum                 -XX                    -XX                     -XX   
           Maximum                  XX                     XX                      XX   
           P-Value (Between)     X.XXX                  X.XXX                           
 
TDI has 3 domains (functional impairment, magnitude of task, and magnitude of effort). 
The change from baseline is measured by the TDI score which ranges from -3 (major deterioration) to +3 (major improvement) for each 
domain with the TDI focal score consisting in the sum of each domain (-9 to +9). 
P-value (Between) came from Wilcoxon Rank Sum Test: A vs C and B vs C 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Programmers note:  
Time points are Day 15+/-2, 29+/-2, 43+/-2, and 54+/-1 or 56. 
If space is limiting, Day “54+/-1 or 56” may be presented as Day “54” with a footnote indicating this is “Day 54+/-1 or 56”. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 89 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.2.13  Categorical Summary of Cough and Mucus Production from Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) 
Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                           Cough                                                   Mucus Production 
     Treat-  ------------------------------------------------------------   ------------------------------------------------------------      
Day  ment    N       0        1        2         3        4         5       N       0        1        2         3        4         5      
----------------------------------------------------------------------------------------------------------------------------------------     
CI^  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
15*  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
29*  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
54#  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
< > 
 
 
^ CI = Check-in 
* Nominal +/-2 days 
# Day 54+/1 or Day 56 
Cough: 0 = I never cough, 5 = I cough all the time 
Mucus Production: 0 = I have no phlegm (mucus) in my chest at all, 5 = My chest is completely full of phlegm (mucus) 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 90 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.2.14  Categorical Summary of Chest Tightness and Breathlessness from Chronic Obstructive Pulmonary Disease (COPD) Assessment Test 
(CAT) Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                     Chest Tightness                                                 Breathlessness 
     Treat-  ------------------------------------------------------------   ------------------------------------------------------------      
Day  ment    N       0        1        2         3        4         5       N       0        1        2         3        4         5      
----------------------------------------------------------------------------------------------------------------------------------------     
CI^  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
15*  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
29*  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
54#  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
< > 
 
 
^ CI = Check-in 
* Nominal +/-2 days 
# Day 54+/1 or Day 56 
Chest Tightness: 0 = My chest does not feel tight at all, 5 = My chest feels very tight 
Breathlessness: 0 = When I walk up a hill or one flight of stairs I am not breathless, 5 = When I walk up a hill or one flight of stairs 
                I am very breathless 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 91 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.2.15  Categorical Summary of Level of Activities and Level of Confidence from Chronic Obstructive Pulmonary Disease (COPD) 
Assessment Test (CAT) Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                  Level of Activities                                           Level of Confidence 
     Treat-  ------------------------------------------------------------   ------------------------------------------------------------      
Day  ment    N       0        1        2         3        4         5       N       0        1        2         3        4         5      
----------------------------------------------------------------------------------------------------------------------------------------     
CI^  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
15*  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
29*  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
54#  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
< > 
 
 
^ CI = Check=in 
* Nominal +/-2 days 
# Day 54+/1 or Day 56 
Level of Activities: 0 = I am not limited doing any activities at home, 5 = I am very limited doing activities at home 
Level of Confidence: 0 = I am confident leaving my home despite my lung condition, 5 = I am not at all confident leaving my home because 
                     of my lung condition 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 92 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.2.16  Categorical Summary of Level of Sleepiness and Level of Energy from Chronic Obstructive Pulmonary Disease (COPD) Assessment 
Test (CAT) Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - C) 
 
 
                                 Level of Sleepiness                                                Level of Energy 
     Treat-  ------------------------------------------------------------   ------------------------------------------------------------      
Day  ment    N       0        1        2         3        4         5       N       0        1        2         3        4         5      
----------------------------------------------------------------------------------------------------------------------------------------     
CI^  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
15*  A       XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)   XX   XX (XX%) XX (XX%) XX (XX%)   X ( X%) XX (XX%)   X ( X%)     
     B       XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)   XX    X (XX%)  X (XX%)  X (XX%)   X ( X%)  X (XX%)   X ( X%)     
     C       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)     
 
29*  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
54#  A       XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)   XX   XX (XX%)  X ( X%)  X ( X%)  XX (XX%)  X ( X%)  XX (XX%)      
     B       XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)   XX    X (XX%)  X (XX%)  X (XX%)   X (XX%)  X (XX%)   X (XX%)      
     C       XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)   XX   XX (XX%) XX (XX%) XX (XX%)  XX (XX%) XX (XX%)  XX (XX%)      
 
< > 
 
 
^ CI = Check-in 
* Nominal +/-2 days 
# Day 54+/1 or Day 56 
Level of Sleepiness: 0 = I sleep soundly, 5 = I don't sleep soundly because of my lung condition 
Level of Energy: 0 = I have lots of energy, 5 = I have no energy at all 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 93 of 150 
                                                                                                                       Page X of X 
 
Table 14.2.2.17  Summary and Change From Baseline of Individual Score (0 – 5) and Total Score (0 – 40) from Chronic Obstructive Pulmonary 
Disease (COPD) Assessment Test (CAT) Following Multiple Oral YPL-001 Doses of 80 mg and 160 mg and Placebo in COPD Patients (Treatments A - 
C) 
 
                                             Treatment A                     Treatment B                      Treatment C    
                                   ------------------------------   ------------------------------   ------------------------------ 
                                    Result   Change From Baseline    Result   Change From Baseline    Result   Change From Baseline 
CAT               Summary          --------  --------------------   --------  --------------------   --------  --------------------        
Item     Day      Statistic        (N = XX)        (N = XX)         (N = XX)        (N = XX)         (N = XX)        (N = XX) 
----------------------------------------------------------------------------------------------------------------------------------- 
Cough   Check-in  N                     XX                               XX                             XX          
                  Mean                XX.X                             XX.X                           XX.X          
                  SD                 XX.XX                            XX.XX                          XX.XX          
                  CV%                 XX.X                             XX.X                           XX.X          
                  Median              XX.X                             XX.X                           XX.X          
                  Minimum               XX                               XX                             XX          
                  Maximum               XX                               XX                             XX          
 
         15+/-2   N                     XX           XX                  XX                 XX          XX           XX   
                  Mean                XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  SD                 XX.XX        XX.XX               XX.XX              XX.XX       XX.XX        XX.XX   
                  CV%                 XX.X         XX.X                XX.X                 XX.X      XX.X         XX.X 
                  Median              XX.X         -X.X                XX.X               -X.X        XX.X         -X.X   
                  Minimum               XX          -XX                  XX                -XX          XX          -XX   
                  Maximum               XX           XX                  XX                 XX          XX           XX   
                  P-Value (Within)                X.XXX                                  X.XXX                    X.XXX   
                  P-Value (Between)               X.XXX                                  X.XXX                            
 
 
Baseline is Check-in measurement. 
P-value (Within) came from Wilcoxon Signed Rank Test, P-value (Between) came from Wilcoxon Rank Sum Test: A vs C and B vs C 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Programmers note: CAT items are Cough, Mucus Production, Chest Tightness, Breathlessness, Activities, Confidence, Sleepiness, Energy, and 
Total score. 
For the “Day 54+/1 or Day 56” time point (if space is limiting), this may be presented as Day “54” with a footnote indicating this is 
“Day 54+/1 or 56”. 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 94 of 150 
 
Pharmacokinetics 
 
Note: Tables 14.2.4.1.1 - 2, 14.2.4.2.1 – 2 (plasma), 14.2.4.3.1, and 14.2.4.4.1 (epithelial brushing) will be in a similar format: 
                                                                                                                                  
 
 
 
 
 Page X of X 
 
Table 14.2.4.1.1 Plasma Verproside Concentrations (pg/mL) Following Single and Multiple Oral YPL-001 Doses of 80 mg 
 in COPD Patients - Days 1 to 54 (+/- 1) or Day 56 (Treatment A) 
 
             ----------------------------- Sample Times (Day / hr) ------------------------------- 
Subject      -------------- Day X --------------      - Day X --    Day XX  Day XX ------Day XX--- 
 Number       XX      XX      XX      XX      XX      XX      XX    Predose  Predose  XX      XX 
-------------------------------------------------------------------------------------------------- 
   XXXX       BLQ     XX      XX      XX      XX      XX      XX      BLQ     XX      XX      XX 
   XXXX       BLQ     XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
   XXXX       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
---------------------------------------------------------------------------------------------------- 
      N       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
   Mean       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
     SD       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
    CV%       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
 Median       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
Maximum       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
Minimum       XX      XX      XX      XX      XX      XX      XX      XX      XX      XX      XX 
---------------------------------------------------------------------------------------------------- 
 
Footnotes to include, as appropriate: 
For the calculation of summary statistics and pharmacokinetic parameters, values on Days 1 and 54+/-2 that are below the lower limit of 
quantitation (BLQ) of 50.0 pg/mL are treated as 0.00 before the first quantifiable concentration on each study day and as missing elsewhere. 
In addition, predose BLQ values on Days 15+/-2 to 56 were set to 0.00. 
. = Value missing or not reportable 
 
Programmer Note: 
PK Time points are listed in Sections 8.1.1 and 8.1.2 of this SAP. 
Please see text in Section 8.6 for description of significant figures/decimals to be used for descriptive statistics. 
 
Program : /AAXXXXX/ECR/sas_prg/pksas/PROGRAMNAME.sas  DDMMMYYYY  HH:MM


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 95 of 150 
Note: Tables 14.2.4.1.3 - 6 (verproside) and 14.2.4.2.3 - 6 (picroside II) will be in a similar format: 
 
                                                                                                                                  
 
 
 
 
 Page X of X 
 
Table 14.2.4.1.3 
Plasma Verproside Pharmacokinetic Parameters Following a Single Oral YPL-001 Dose of 80 mg in COPD Patients - Day 1 
(Treatment A) 
 
 
                                       -------------------------------------- Parameters --------------------------------- 
                 Subject          Param      Param      Param      Param      Param      Param       Param       Param 
                  Number         (units)    (units)    (units)    (units)    (units)    (units)     (units)     (units) 
                 ---------------------------------------------------------------------------------------------------------- 
                      XX           XXX        XXX         XXX       XXX        XXX        XXX         XXX         XXX 
                      XX           XXX        XXX         XXX       XXX        XXX        XXX         XXX         XXX 
                      XX           XXX        XXX         XXX       XXX        XXX        XXX         XXX         XXX 
                 --------------------------------------------------------------------------------------------------------- 
                        N         XXXX       XXXX        XXXX      XXXX       XXXX       XXXX        XXXX        XXXX      
                     Mean         XXXX       XXXX        XXXX      XXXX       XXXX       XXXX        XXXX        XXXX 
                       SD         XXXX       XXXX        XXXX      XXXX       XXXX       XXXX        XXXX        XXXX 
                       CV%        XXXX       XXXX        XXXX      XXXX       XXXX       XXXX        XXXX        XXXX      
                   Median         XXXX       XXXX        XXXX      XXXX       XXXX       XXXX        XXXX        XXXX      
                  Minimum         XXXX       XXXX        XXXX      XXXX       XXXX       XXXX        XXXX        XXXX      
                  Maximum         XXXX       XXXX        XXXX      XXXX       XXXX       XXXX        XXXX        XXXX      
               Geom. Mean         XXXX         NC        XXXX        NC         NC       XXXX          NC          NC 
                 Geo. CV%         XXXX         NC        XXXX        NC         NC       XXXX          NC          NC 
               ------------------------------------------------------------------------------------------------------------ 
               NC = Not calculated. 
               . = Value missing or not reportable. 
 
Programmers note:  
Geo. Mean and Geo. CV% will be calculated for C and AUC parameters only. 
Please refer to Section 8.5.1 for list of pharmacokinetic parameters on each study day. Significant figures/decimals to be used for PK 
parameters will be specified by the PKist upon review of the data. Please refer to Section 8.6 for description of significant 
figures/decimals to be used for descriptive statistics. 
 
 
 
 
 
 
Program : /AAXXXXX/ECR/sas_prg/pksas/PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 96 of 150 
Note: Tables 14.2.4.1.7 and 14.2.4.2.7 and will be in a similar format: 
Page X of X 
 
Table 14.2.4.1.7 
Intervals (Hours) Used for Determination of Plasma Verproside kel Values Following Single and Multiple Oral YPL-001 
Doses of 80 mg and 160 mg - Days 1 to 54 (+/- 1) or Day 56(Treatments A and B) 
 
                                             Day 1 
                   
Treatment A                           Treatment B          
   Subject      -------------------------------   -------------------------------  
   Number              Interval        R2     N       Interval          R2      N   
---------------------------------------------------------------------------------  
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
---------------------------------------------------------------------------------- 
 
                      Day 54+/-1 or Day 56 
                   
Treatment A                           Treatment B          
   Subject      -------------------------------   -------------------------------  
   Number              Interval        R2     N       Interval          R2      N    
---------------------------------------------------------------------------------  
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
      XX             X.X - XX.X      X.XXX    X       X.X - XX.X      X.XXX    X   
---------------------------------------------------------------------------------- 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
R2 = Square of the correlation coefficient of the linear regression                             
 
N = Number of points used in kel calculation 
. = Value missing or not reportable 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 97 of 150 
Note: Tables 14.2.4.1.8 and 14.2.4.2.8 and will be in a similar format: 
 
Page 1 of X 
 
Table 14.2.4.1.8 
Statistical Comparisons of Dose-Normalized Plasma Verproside Pharmacokinetic 
Parameters Following Multiple Oral YPL-001 Doses of 160 mg Versus Multiple Oral 
YPL-001 Doses of 80 mg and in COPD Patients – Day 54 (+/- 1) or Day 56 (Treatment B 
Versus Treatment A) 
 
 
Geometric LSM 
 
 
Parameter 
Treatment B Treatment A 
Geometric 
Mean Ratio 
(%) 
90% CI 
Param1 (unit) 
X.XXX 
X.XXX 
XX.XX 
XXX.XX – XXX.XX 
Param2 (unit) 
X.XXX 
X.XXX 
XX.XX 
XXX.XX – XXX.XX 
Param3 (unit) 
X.XXX 
X.XXX 
XX.XX 
XXX.XX – XXX.XX 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Parameters were dose-normalized (to 80 mg YLP-001) and ln-transformed prior to analysis. 
Geometric least-squares means (LSMs) were calculated by exponentiating the LSM from the ANOVA. 
% Geometric Mean Ratio = 100 x (test/reference) 
CI = Confidence interval 
 
 
 
Program:  /AAXXXXX/sas_prg/pksas/PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 98 of 150 
Page X of X 
 
Table 14.3.1.1  Treatment-Emergent Adverse Event Frequency by Treatment - Number of Patients Reporting Events (% of Patients Dosed) 
 
 
                                                Treatment 
 
 
 
    
 
   
                                    -------------------------------   
  Adverse Event*                       A          B          C         Total                                                   
  ------------------------------------------------------------------------------- 
  Number of Patients Dosed          X (XXX %)  X (XXX %)  X (XXX %)   X (XXX %) 
  Number of Patients With AEs       X ( XX %)  X ( XX %)  X ( XX %)   X ( XX %) 
  Number of Patients Without AEs    X ( XX %)  X ( XX %)  X ( XX %)   X ( XX %) 
  -------------------------------------------------------------------------------                                   
  System Organ Class 1              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 2                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                                
  System Organ Class 2              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                                
  System Organ Class 3              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X ( XX %)  X ( XX %)  X ( XX %)   X ( XX %) 
                                                                                
  System Organ Class 4              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                                
  System Organ Class 5              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 2                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                      
  etc.                                                                                                                   
 
 
 
* Adverse events are classified according to MedDRA Version 18.0. 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program:  /AAXXXXX/ECR/SAS_PRG/STSAS/TAB  DDMMMYYYY  XX:XX                                                         
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 99 of 150 
Page X of X 
 
Table 14.3.1.2  Treatment-Emergent Adverse Event Frequency by Treatment - Number of Adverse Events (% of Total Adverse Events) 
 
 
                                                Treatment 
 
 
 
    
 
   
                                    -------------------------------   
  Adverse Event*                       A          B          C         Total                                                   
  ------------------------------------------------------------------------------- 
  Number of AEs                     X (XXX %)  X (XXX %)  X (XXX %)   X (XXX %) 
  -------------------------------------------------------------------------------                                   
  System Organ Class 1              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 2                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                                
  System Organ Class 2              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                                
  System Organ Class 3              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X ( XX %)  X ( XX %)  X ( XX %)   X ( XX %) 
                                                                                
  System Organ Class 4              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                                
  System Organ Class 5              X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 1                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
    Preferred term 2                X (  X %)  X (  X %)  X (  X %)   X ( XX %) 
                                                                      
  etc.                                                                                                                   
 
 
 
* Adverse events are classified according to MedDRA Version 18.0. 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program:  /AAXXXXX/ECR/SAS_PRG/STSAS/TAB  DDMMMYYYY  XX:XX                                                          
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 100 of 150 
Page X of X 
 
Table 14.3.1.3  Treatment-Emergent Adverse Event Frequency by Treatment, Severity, and Relationship to Drug - Number of Patients Reporting 
Events 
  
                                         Number of            Severity                        Relationship to Drug 
                           Treat-      Patients With   ----------------------  --------------------------------------------------- 
  Adverse Event*           ment        Adverse Events  Mild  Moderate  Severe  Unrelated  Unlikely  Possible  Probable   Definte     
  -------------------------------------------------------------------------------------------------------------------------------- 
  Anxiety                  C                 X          X       X        X         X         X         X         X          X    
                           A                 X          X       X        X         X         X         X         X          X    
  Chest discomfort         B                 X          X       X        X         X         X         X         X          X    
  Dry mouth                A                 X          X       X        X         X         X         X         X          X    
  Headache                 B                 X          X       X        X         X         X         X         X          X    
  Nausea                   B                 X          X       X        X         X         X         X         X          X    
  Nervousness              B                 X          X       X        X         X         X         X         X          X    
  Pharyngolaryngeal pain   C                 X          X       X        X         X         X         X         X          X      
  -------------------------------------------------------------------------------------------------------------------------------- 
  A                                          X          X       X        X         X         X         X         X          X    
  B                                          X          X       X        X         X         X         X         X          X    
  C                                          X          X       X        X         X         X         X         X          X    
  Total                                      X          X       X        X         X         X         X         X          X    
  -------------------------------------------------------------------------------------------------------------------------------- 
* Adverse events are classified according to MedDRA Version 18.0. 
  When a patient experienced the same AE at more than one level of severity,the patient was counted once under the highest severity level. 
  When a patient experienced the same AE at more than one level of drug relationship, the patient was counted once under the closest 
  relationship to study drug. 
  Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
  Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
  Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
  Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Programmers note: If Life-Threatening or Fatal severity is present, please add this. 
 
Program:  /AAXXXXX/ECR/SAS_PRG/STSAS/TAB  DDMMMYYYY  XX:XX      
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 101 of 150 
Page X of X 
 
Table 14.3.1.4  Treatment-Emergent Adverse Event Frequency by Treatment, Severity, and Relationship to Drug - Number of Adverse Events 
 
 
                                                             Severity                        Relationship to Drug 
                           Treat-        Number of     ----------------------  --------------------------------------------------- 
  Adverse Event*           ment        Adverse Events  Mild  Moderate  Severe  Unrelated  Unlikely  Possible  Probable   Definte     
  -------------------------------------------------------------------------------------------------------------------------------- 
  Anxiety                  C                 X          X       X        X         X         X         X         X          X    
                           A                 X          X       X        X         X         X         X         X          X    
  Chest discomfort         B                 X          X       X        X         X         X         X         X          X    
  Dry mouth                A                 X          X       X        X         X         X         X         X          X    
  Headache                 B                 X          X       X        X         X         X         X         X          X    
  Nausea                   B                 X          X       X        X         X         X         X         X          X    
  Nervousness              B                 X          X       X        X         X         X         X         X          X    
  Pharyngolaryngeal pain   C                 X          X       X        X         X         X         X         X          X      
  -------------------------------------------------------------------------------------------------------------------------------- 
  A                                          X          X       X        X         X         X         X         X          X    
  B                                          X          X       X        X         X         X         X         X          X    
  C                                          X          X       X        X         X         X         X         X          X    
  Total                                      X          X       X        X         X         X         X         X          X    
  -------------------------------------------------------------------------------------------------------------------------------- 
* Adverse events are classified according to MedDRA Version 18.0. 
  Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
  Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
  Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
  Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Programmers note: If Life-Threatening or Fatal severity is present, please add this. 
 
 
Program:  /AAXXXXX/ECR/SAS_PRG/STSAS/TAB  DDMMMYYYY  XX:XX                                                          
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 102 of 150 
Page X of X 
                
Table 14.3.2  Serious Adverse Event 
 
 
Subject  Treat-   Age/   Adverse Event       Date/Time        Date/Time                   Relation to  Action      Other  
Number   ment     Gender (Preferred Term*)   of Onset         of Resolved      Severity   Study Drug   Taken       Action   Outcome 
-------------------------------------------------------------------------------------------------------------------------------------- 
  X      A        XX/X    XXXXXXXXXXXXXXXX   DDMMMYYYY/HH:MM  DDMMMYYYY/HH:MM  Mild       Probable     XXXXXXXXX  XXXXXXXX  Recovered/  
                                                                                                                            Resolved 
 
                                                                                                                
 
 
 
Note: * Adverse events are classified according to MedDRA Version 18.0. 
 
 
 
 
 
 
 
 
 
NOTE: If no SAE occurred, in the middle of this table, a sentence, “No serious adverse event was reported.” will be added. 
 
 
 
 
 
 
 
 
 
 
Program : /AAXXXXX/ECR/sas_prg/stsas/tab/PROGRAMNAME.sas  DDMMMYYYY  HH:MM 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 103 of 150 
Note: Tables 14.3.4.2 - 14.3.4.3 will appear similar to Table 14.3.4.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page X of X 
 
Table 14.3.4.1  Out-of-Range Values and Recheck Results – Serum Chemistry 
 
  
                       Visit                    Collection                    Reference             Reference   
Subject  Age/   -------------------  Treat-  ----------------                 Range          Result Range          Result                                    
Number   Gender  Name     Date       ment    Date       Time   Parameter      (Unit)         Flag   (SI Unit)      (SI Unit) Comments    
------------------------------------------------------------------------------------------------------------------------------------------ 
  X      XX/X   Screening DDMMMYYYY    X     DDMMMYYYY  HH:MM  XXXXXXXXXXXXX  XX – XX (unit) XX HN  XX – XX (unit) XX        XXXXXXXXXXXXX     
                XXXX      DDMMMYYYY          DDMMMYYYY  HH:MM  XXXXXXXXXXXXX  XX – XX (unit) XX LY  XX – XX (unit) XX        XXXXXXXXXXXXX     
  
 
 
 
 
 
 
 
 
 
  
Abnormal Flag: H = Above Reference Range, L = Below Reference Range                                                                                         
Clinical Significance: N = Not Clinically Significant, Y = Clinically Significant                                                                         
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM                                                         
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 104 of 150 
Note: Tables 14.3.5.3 and 14.3.5.5 will appear similar to Table 14.3.5.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page X of X 
 
Table 14.3.5.1  Clinical Laboratory Summary and Change From Check-in – Serum Chemistry 
 
                                                                Treatment           Change From Check-in 
  
                                                      ---------------------------   ---------------------------- 
Laboratory Test    Range     Day       Statistic        A         B         C          A         B         C     
----------------------------------------------------------------------------------------------------------------                  
XXXXXXXXXXX (X)    X-X       Screen    N               X.XX      X.XX      X.XX         
                                       Mean            X.XX      X.XX      X.XX         
                                       SD              X.XX      X.XX      X.XX         
                                       Median          X.XX      X.XX      X.XX         
                                       Minimum         X.XX      X.XX      X.XX         
                                       Maximum         X.XX      X.XX      X.XX         
                                                                                        
                             Check-in  N               X.XX      X.XX      X.XX         
                                       Mean            X.XX      X.XX      X.XX         
                                       SD              X.XX      X.XX      X.XX         
                                       Median          X.XX      X.XX      X.XX         
                                       Minimum         X.XX      X.XX      X.XX         
                                       Maximum         X.XX      X.XX      X.XX         
                                                                                                                
                             29+/-2    N               X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Mean            X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       SD              X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Median          X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Minimum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Maximum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                                                                                                
                             54+/-2    N               X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Mean            X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       SD              X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Median          X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Minimum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                       Maximum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
 
Baseline is Check-in measurement. 
Early termination records are excluded from the summary.  
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM                                                         
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 105 of 150 
Note: Table 14.3.5.4 will appear similar to Table 14.3.5.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page X of X 
Table 14.3.5. 2  Clinical Laboratory Shift From Check-in – Serum Chemistry 
  
                                                                          Baseline L          Baseline N           Baseline H       
                                                                     -------------------  -------------------  ---------------------- 
                                                                           Postdose            Postdose             Postdose       
                                                                     -------------------  -------------------  ---------------------- 
                Laboratory Test          Treatment             Day     L      N      H      L      N      H      L      N      H   
                --------------------------------------------------------------------------------------------------------------------- 
                XXXXXXX XXXXXXXXXXXXXXXX A                     29+/-2 X      X      X      X      X      X      X      X      X      
                                                   
                                                               54+/-2  X      X      X      X      X      X      X      X      X      
                                                   
                                         B                     29+/-2  X      X      X      X      X      X      X      X      X      
                                                   
                                                               54+/-2  X      X      X      X      X      X      X      X      X      
                                                   
                                         C                     29+/-2 X      X      X      X      X      X      X      X      X      
                                                   
                                                       
 
L = Below Normal Range, N = Within Normal Range, H = Above Normal Range.  
Baseline is Check-in measurement. 
Early termination records are excluded from the summary.  
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM                                                         
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 106 of 150 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page X of X 
 
Table 14.3.5.6  Clinical Laboratory Shift From Check-in – Urinalysis 
  
                                                                             Baseline O      Baseline N       
                                                                         ---------------------------------- 
                                                                              Postdose        Postdose        
                                                                         ---------------------------------- 
                Laboratory Test          Treatment                 Day        O      N        O      N       
                ------------------------------------------------------------------------------------------- 
                XXXXXXX XXXXXXXXXXXXXXXX A                         29+/-2    X      X        X      X       
                                                   
                                                                   54+/-2     X      X        X      X      
                                                   
                                         B                         29+/-2     X      X        X      X      
                                                     
                                                                   54+/-2     X      X        X      X      
                                                   
                                         C                         29+/-2     X      X        X      X      
                                                     
                                                                   54+/-2     X      X        X      X      
                                                   
                                                   
                                                     
 
O = Outside of Normal Range, N = Within Normal Range.                                                                   
Baseline is Check-in measurement. 
Early termination records are excluded from the summary.  
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM                                                         
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 107 of 150 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page X of X 
 
Table 14.3.5.7  Vital Sign Summary and Change From Day 1 Predose 
 
                                                               Treatment            Change From Day 1 Predose    
                                                     ---------------------------   ----------------------------   
Measurement          Day       Hour^  Statistic        A         B         C          A         B         C        
---------------------------------------------------------------------------------------------------------------                                   
Systolic BP (mm Hg)  Screen           N               X.XX      X.XX      X.XX         
                                      Mean            X.XX      X.XX      X.XX         
                                      SD              X.XX      X.XX      X.XX         
                                      Median          X.XX      X.XX      X.XX         
                                      Minimum         X.XX      X.XX      X.XX         
                                      Maximum         X.XX      X.XX      X.XX         
                                                                                          
                     Check-in         N               X.XX      X.XX      X.XX         
                                      Mean            X.XX      X.XX      X.XX         
                                      SD              X.XX      X.XX      X.XX         
                                      Median          X.XX      X.XX      X.XX         
                                      Minimum         X.XX      X.XX      X.XX         
                                      Maximum         X.XX      X.XX      X.XX         
                                                                                                                  
                      1         0     N               X.XX      X.XX      X.XX            
                                      Mean            X.XX      X.XX      X.XX            
                                      SD              X.XX      X.XX      X.XX            
                                      Median          X.XX      X.XX      X.XX            
                                      Minimum         X.XX      X.XX      X.XX            
                                      Maximum         X.XX      X.XX      X.XX            
                                                                         
                                      N               X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                      1         1     Mean            X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                      SD              X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                      Median          X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                      Minimum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                      Maximum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
 
Hour 0 represents predose of that day. 
Baseline is the last predose timepoint. Early termination records are excluded from the summary. 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
<Programmer note: Day 1 at 2 and 6 hours postdose, Days 15+/-2, 29+/-2, 43+/-2, and Day 54+/-2 at 0 hour predose and at 1, 2, 6, and 12 
hours postdose, and end-of-treatment will also be presented.>                   
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 108 of 150 
Page X of X 
 
Table 14.3.5.8  Pulse Oximetry Summary and Change From Check-in 
 
                                                           Treatment           Change From Check-in    
                                                 ---------------------------   ---------------------------- 
Measurement             Day       Statistic        A         B         C          A         B         C     
-----------------------------------------------------------------------------------------------------------                            
Oxygen Saturation (%)   Screen    N               X.XX      X.XX      X.XX         
                                  Mean            X.XX      X.XX      X.XX         
                                  SD              X.XX      X.XX      X.XX         
                                  Median          X.XX      X.XX      X.XX         
                                  Minimum         X.XX      X.XX      X.XX         
                                  Maximum         X.XX      X.XX      X.XX         
                                                                                   
                        Check-in  N               X.XX      X.XX      X.XX         
                                  Mean            X.XX      X.XX      X.XX         
                                  SD              X.XX      X.XX      X.XX         
                                  Median          X.XX      X.XX      X.XX         
                                  Minimum         X.XX      X.XX      X.XX         
                                  Maximum         X.XX      X.XX      X.XX         
                                                                                                           
                        54+/-2    N               X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                  Mean            X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                  SD              X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                  Median          X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                  Minimum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                  Maximum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                                                                   
                         
                         
                         
Baseline is Check-in measurement. 
Early termination records are excluded from the summary.  
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 109 of 150 
Page X of X 
Table 14.3.5.9  12-Lead Electrocardiogram Summary and Change From Check-in 
 
                                                        Treatment           Change From Check-in 
   
                                              ---------------------------   ---------------------------- 
Measurement          Day       Statistic        A         B         C          A         B         C     
--------------------------------------------------------------------------------------------------------                           
Heart Rate (bpm)     Screen    N               X.XX      X.XX      X.XX         
                               Mean            X.XX      X.XX      X.XX         
                               SD              X.XX      X.XX      X.XX         
                               Median          X.XX      X.XX      X.XX         
                               Minimum         X.XX      X.XX      X.XX         
                               Maximum         X.XX      X.XX      X.XX         
                                                                                
                     Check-in  N               X.XX      X.XX      X.XX         
                               Mean            X.XX      X.XX      X.XX         
                               SD              X.XX      X.XX      X.XX         
                               Median          X.XX      X.XX      X.XX         
                               Minimum         X.XX      X.XX      X.XX         
                               Maximum         X.XX      X.XX      X.XX         
                                                                                                        
                     29+/-2    N               X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Mean            X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               SD              X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Median          X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Minimum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Maximum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                                                                                   
                     54+/-2    N               X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Mean            X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               SD              X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Median          X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Minimum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                               Maximum         X.XX      X.XX      X.XX       X.XX      X.XX      X.XX  
                      
 
Baseline is Check-in measurement. 
Early termination records are excluded from the summary.  
QTcB = QT corrected for heart rate using Bazett’s Correction 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
<Programmer note: ECG includes heart rate, PR, QRS, QT, and QTcB. >                                                                                      
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM                                                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Page X of X 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan  
20 March 2017 
 
Page 110 of 150 
Table 14.3.5.10  12-Lead Electrocardiogram Shift From Check-in 
 
                                    Predose=Normal                 Predose=ANCS                   Predose=ACS             
 -----------------------------   ---------------------------   ----------------------------- 
            Postdose                      Postdose                       Postdose           
                         ----------------------------    --------------------------    ---------------------------- 
 Treatment        Day    Normal       ANCS       ACS     Normal     ANCS      ACS      Normal      ANCS      ACS      
------------------------------------------------------------------------------------------------------------------- 
 A                29+/-2  X           X          X        X         X         X         X          X         X       
           
                  54+/-2  X           X          X        X         X         X         X          X         X       
           
 B                29+/-2  X           X          X        X         X         X         X          X         X       
             
                  54+/-2  X           X          X        X         X         X         X          X         X       
           
 C                29+/-2  X           X          X        X         X         X         X          X         X       
             
                  54+/-2  X           X          X        X         X         X         X          X         X       
           
 
 
 
ANCS = Abnormal, Not Clinically Significant, ACS = Abnormal, Clinically Significant 
Baseline is Check-in measurement. 
Early termination records are excluded from the summary.  
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program:  /AAXXXXX/ECR/sas prg/stsas/tab tab-programname.sas DDMMMYYYY  HH:MM                                                         


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 111 of 150 
13. 
LISTING SHELLS 
The following listing shells provide a framework for the display of data from this 
study. The shells may change due to unforeseen circumstances. These shells may not 
be reflective of every aspect of this study, but are intended to show the general layout 
of the listings that will be presented and included in the final report.  
Note to programmer:  Formatting and content of listings may be modified based on 
provided data. 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 112 of 150 
Page 1 of X 
                                   Appendix 16.1.10.1  Clinical Laboratory Reference Ranges 
 
        Site          Laboratory Group           Test Name                     Gender      Age Category  Reference Range  Unit      
        -------------------------------------------------------------------------------------------------------------------------- 
        XXXXX         Serum Chemistry            Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                                                                                                   
                      Hematology                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
                                                 Test Name                     <>          <>            XX – XX         units 
 
<similar for remaining Laboratory Groups and Test Names> 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis LIS_PROGRAMNAME.SAS  DDMMMYYYY  HH:MM                                                           
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 113 of 150 
                                                                                                                   Page 1 of X 
                                           Appendix 16.2.1  Study Completion/Early Termination 
  
 
 
                                       Visit                 
       Subject           Treat-   ------------------   Completed   Reason for                    Date of Completion         
       Number   Site     ment      Name    Date          Study?    Discontinuation   Specify     or Discontinuation 
       ------------------------------------------------------------------------------------------------------------ 
       XXXX     XXXX     X         XXXX   DDMMMYYYY       Yes                                    DDMMMYYYY 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 114 of 150 
                                                                                                                   Page 1 of X 
                                                 Appendix 16.2.4.1  Subject Information 
                         Informed/  Protocol  
                         Reconsent  Amendment/                                                         Randomization 
Subject  Site    Treat-  Consent    Reconsent     Subject                                 Enrolled   -------------------  Registration 
Number   Number  ment     Date      Version No.   Caption   Active?   Enrolled?  Dropped?   Date       Number    Date        Date 
--------------------------------------------------------------------------------------------------------------------------------- 
XXXX     XXXX    X       DDMMMYYYY/    XX/         XXX       XXX      XXX        XXX      DDMMMYYYY    XX     DDMMMYYYY   DDMMMYYYY 
                         DDMMMYYYY     XX 
 
 
 
  
 
 
 
 
 
 
Protocol amendment number indicates the version that the subject consented under. 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 115 of 150 
                                                                                                                   Page 1 of X 
                                                      Appendix 16.2.4.2  Demographics 
                                                                                                                                
                           Visit                                                                                                  
  Subject  Treat-  --------------------   Date Of     Age                            Primary     Height    Weight      BMI       
  Number   ment     Name       Date        Birth     (yrs)    Gender  Ethnicity      Race        (cm)      (kg)       (kg/m2)      
  ---------------------------------------------------------------------------------------------------------------------------- 
       X   A       Screening  DDMMMYYYY  DDMMMYYYY     XX     XXXX    XXXXXXXXXXX    XXXXXXXXX    XX.X     XXX.X       XX.XX     
       X   B       Screening  DDMMMYYYY  DDMMMYYYY     XX     XXXX    XXXXXXXXXXX    XXXXXXXXX    XX.X     XXX.X       XX.XX     
       X   C       Screening  DDMMMYYYY  DDMMMYYYY     XX     XXXX    XXXXXXXXXXX    XXXXXXXXX    XX.X     XXX.X       XX.XX     
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
  
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 116 of 150 
                                                                                                                   Page 1 of X 
                                        
 
 
Appendix 16.2.4.3  Physical Examination 
 
                                        Was Physical                                              
Subject  Treat-   Visit   Date of       Examination    If No,    Body                 Abnormal     Clinically 
Number   ment     Name    Examination   Performed?     Specify   System     Result    Fingings     Significant? 
---------------------------------------------------------------------------------------------------------------- 
  X      X         X      DDMMMYYYY     Yes                      XXXXXXXXX  Abnormal  XXXXXXXXXX   No 
                                                                  
 
        
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 117 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.4.4  Chest X-Ray 
  
                         Visit           
Subject   Treat-  ------------------     Date of      Abnormalities                  
Number    ment     Name       Date       Chest X-Ray  Found?          Specify                                     
----------------------------------------------------------------------------------- 
    X      X      XXXXXXX  DDMMMYYYY     DDMMMYYYY       Yes                                                                             
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 118 of 150 
  
   
 
                                                                                                                   Page 1 of X 
                                                  Appendix 16.2.4.5  Medical History 
  
                       Visit             Any Past and/or       Medical   Reported/                   Date 
Subject  Treat-   --------------------   Concomitant Disease   History   Preferred        ------------------------                 
Number   ment     Name        Date       or Past Surgeries?    Number     Term            Onset       End           Ongoing?                          
------------------------------------------------------------------------------------------------------------------------------    
    X     X       Screening  DDMMMYYYY     Yes                   XX      XXXXXXXXXXX/    DDMMMYYYY   DDMMMYYYY      YES                                      
                                                                         XXXXXXXXXXX  
   
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 119 of 150 
                                                                                                                   Page 1 of X 
                                                    Appendix 16.2.4.6  Substance Use 
  
                          Visit                      Amount of                                            Duration of                        
 Subject   Treat-  ------------------   Ever Used    Cigarettes       Frequency of  Start       End       Cigarette Use  Number of          
 Number    ment    Name      Date       Cigarettes?  (Unit)           Cigarettes    Date        Date      (Unit)         Pack-Year 
 --------------------------------------------------------------------------------------------------------------------------------- 
      X     X     Screening DDMMMYYYY    Current     XXXXXXXX (XX)    XXXXXXXX    DDMMMYYYY   DDMMMYYYY   XXXXXXXX (XX)  XX    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 120 of 150 
 
 
                                                                                                                   Page 1 of X 
                                                 Appendix 16.2.5.1  Subject Eligibility 
  
                                 
     Subject   Treat-  Visit            Did subject meet 
     Number    ment    Name        all eligibility criteria?     Crieterion Not Met     
     -------------------------------------------------------------------------------------- 
          X     X       X                    No                  EXCLUSION X            
  
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
                                                                      
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
                                                               
 
 


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Statistical Analysis Plan 
20 March 2017 
 
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                                                                                                                   Page 1 of X 
Appendix 16.2.5.2  Study Drug Administration 
 
                        Visit                            Dose 1                    Dose 2                   Kit Number   
Subject  Treat-    --------------   Took Study    --------------------      --------------------       -------------------- 
Number   ment      Name  Date       Treatment?      Date        Time          Date        Time         1       2       3         
--------------------------------------------------------------------------------------------------------------------------- 
   X      X        XXX  DDMMMYYYY     Yes         DDMMMYYYY     HH:MM       DDMMMYYYY     HH:MM        XXX     XXX     XXX      
 
                                                                                                                                           
  
                                                                                                      
 
  
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 122 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.5.3  Drug Accountability 
  
 
                      Visit                  Dispensed                       Returned             
Subject  Treat-  ---------------  ------------------------------  -------------------------------  Tablets    Tablets    
 Number   ment    Name  Date      Day     Date       Tablets       Day     Date      Tablets        Taken      Missed 
--------------------------------------------------------------------------------------------------------------------- 
    X       X     XXX  DDMMMYYYY   XXX   DDMMMYYYY      XX          XXX   DDMMMYYYY      XX 
       XX          XX 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 123 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.5.4  Tiotropium and Albuterol Administration 
  
 
                       Visit                     Last Tiotropium Dose                 Last Albuterol Dose                                               
Subject  Treat-   --------------   Take          --------------------   Take          --------------------                          
Number   ment     Name  Date       Tiotropium?   Date        Time       Albuterol?    Date        Time         
----------------------------------------------------------------------------------------------------------- 
    X     X       XXX  DDMMMYYYY      Yes        DDMMMYYYY   HH:MM         Yes        DDMMMYYYY   HH:MM                                                      
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 124 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.5.5.1  Bronchoscopy and BAL Biomarkers (I of II) 
  
                       Visit                                                                                      Bronchial 
Subject  Treat- --------------------    Bronchoscopy  Date        Time        BAL Sample   Date of     Time of    Brushings     Date          
Number   ment    Name       Date        Performed?    Performed   Performed   Collected?   Collection  Collection Performed?    Performed    
------------------------------------------------------------------------------------------------------------------------------------------- 
    X     X     XXXXXXXXX  DDMMMYYYY       Yes        DDMMMYYYY   HH:MM          Yes       DDMMMYYYY   HH:MM         Yes        DDMMMYYYY                    
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 125 of 150 
 
                                                                                                                   Page 1 of X 
Appendix 16.2.5.5.2  Bronchoscopy and BAL Biomarkers (II of II) 
  
                       Visit            
Subject  Treat- --------------------  Macrophages Neutrophages Eosinophages Lymphocytes  Macrophages Neutrophages Eosinophages Lymphocytes    
Number   ment    Name       Date      cells/mL)  (cells/mL)    (cells/mL)    (cells/mL)     (%)          (%)        (%)            (%) 
------------------------------------------------------------------------------------------------------------------------------------------- 
    X     X     XXXXXXXXX  DDMMMYYYY     XXX        XXX           XXX          XXX           XX           XX         XX             XX                       
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH: 
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 126 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.5.6  Blood Biomarker Samples 
  
 
                      Visit                                                                   Fibrinogen                                             
Subject Treat- --------------------   Biomarker Blood    Planned      Date of     PD Time of  Date/Time of Result   CRP Date/Time of  Result      
Number  ment    Name       Date       Sample Collected?  Time Point   Collection  Collection  Collection   (Unit)   Collection        (Unit)  
-------------------------------------------------------------------------------------------------------------------------------------------- 
    X    X     XXXXXXXXX  DDMMMYYYY        Yes              XX        DDMMMYYYY   HH:MM       DDMMMYYYY/   XXXX     DDMMMYYYY/        XXXX    
                                                                                              HH:MM        (XX)     HH:MM             (XX)                   
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 127 of 150 
 
                                                                                                                   Page 1 of X 
Appendix 16.2.5.7  Pharmacokinetic Sampling 
 
                       Visit       
Subject  Treat-   --------------    Planned      Sample      Date of       Time of                   
Number   ment     Name  Date        Time Point   Collected?  Collection    Collection                
------------------------------------------------------------------------------------- 
 X        X       XXX  DDMMMYYYY       XX          Yes       DDMMMYYYY     HH:MM                     
                                             
                                               
                                               
                                               
                                               
                                               
                                               
                                               
                                               
                                               
                                               
                                               
  
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 128 of 150 
                                                                                                                   Page 1 of X 
                                                Appendix 16.2.5.8  Prior and Concomitant Medications 
  
                                                                                                                            
Subject  Treat-    Medication                  AE      MH   Dose/                   Start       End 
Number   ment      (WHO* Term)    Indication   ID      ID   Unit    Freq.    Route   Date       Date      Ongoing? 
------------------------------------------------------------------------------------------------------------------- 
  X       X        ACETAMINOPHEN   <     >     XX      XX   XX mg   Once     Oral  DDMMMYYYY   DDMMMYYYY  No 
                  (ACETAMINOPHEN) 
                   
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Concomitant medications are coded with WHO Dictionary Version 01MAR2015. 
Freq. = Frequency, AE = Adverse Event, MH = Medical History, ID = Identification 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 129 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.1.1  Peak Expiratory Flow and Breathlessness (Modified Borg Dyspnea Scale) 
  
                         Assessment                    Peak Flow                      Breathlessness  
Subject  Treat-       ---------------    ---------------------------------------      (Modified Borg 
Number   ment    Day   Date     Time     First      Second      Third      Main       Dyspnea Scale) 
------------------------------------------------------------------------------------------------------------ 
    X     X      XX   DDMMMYYYY HH:MM     XX          XX          XX        XX        0.5, very mild                                        
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 130 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.1.2  Symptoms of COPD Exacerbation (I of II) 
  
                         Assessment                          Sputum                       
Subject  Treat-       ---------------    -----------------------------------------------    
Number   ment    Day   Date     Time     Quantity             Color          Consistency       
---------------------------------------------------------------------------------------- 
    X     X      XX   DDMMMYYYY HH:MM    less than 1 tbs.     White          Watery                                            
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 131 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.1.3  Symptoms of COPD Exacerbation (II of II) 
  
                         Assessment                                                                                      Symptm             
Subject  Treat-       ---------------                        Sore      Nasal        Nasal        Body Temperature   ---------------- 
Number   ment    Day   Date     Time      Cough    Wheeze    Throat    Congestion   Discharge    Above 100°F        Score   Severity  
------------------------------------------------------------------------------------------------------------------------------------ 
    X     X      XX   DDMMMYYYY HH:MM     Yes      Yes       Yes       Yes          Yes          Yes                3.5     Severe                    
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 132 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.1.4  Duke Activity Status Index (DASI) Scores 
  
                         Assessment                                 DASI 12-Item Questionnaire         
Subject  Treat-       ---------------   -----------------------------------------------------------------------------------  DASI 
Number   ment    Day   Date     Time      1      2      3      4      5      6      7      8      9      10     11     12    Score 
----------------------------------------------------------------------------------------------------------------------------------- 
    X     X      XX   DDMMMYYYY HH:MM    Yes    Yes    Yes    Yes    Yes    Yes    Yes    Yes    Yes     Yes    Yes    Yes   XX                 
 
 
 
 
 
 
1. Able to take care of yourself that is eating, dressing, bathing, or using the toilet yet? 
2. Able to walk indoors, such as around the house? 
3. Able to walk a block or 2 on level ground? 
4. Able to climb a flight of stairs or walk up a hill without stopping? 
5. Able to run a short distance? 
6. Able to do light work around the house like dusting or washing dishes? 
7. Able to do moderate work around the house like vacuuming, sweeping floors or carrying in the groceries? 
8. Able to do heavy work around the house like scrubbing floors, or lifting or moving heavy furniture? 
9. Able to do yard work like raking leaves, weeding, or pushing a power mower yet? 
10. Are you having sexual relations? 
11. Able to participate in moderate recreational activities like golf, bowling, dancing, double tennis, or throwing a baseball or football 
yet? 
12. Are you able to participate in strenuous sports like swimming, singles tennis, football, basketball, or skiing? 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 133 of 150 
All listings of PD measures in blood and BAL, Appendices 16.2.6.2.1 to 16.2.6.2.4, will have the following format:  
 
                                                                                                                   Page 1 of X 
                             Appendix 16.2.6.1.2.X < > 
                                                                    Parameter1  Parameter2   Parameter3  Parameter4  Parameter5 
        Subject  Treat-                         Collection          < Range>    < Range>     < Range>    < Range>    < Range>   
        Number   ment    Visit          Day        Date      Time    (Unit)      (Unit)       (Unit)      (Unit)      (Unit)    
------------------------------------------------------------------------------------------------------------------------------- 
        XXXXXX    X     Predose           1     DDMMMYYYY     XX:XX  XXXXX.XX       X.XX       X.XX        XXXX.XX     XXX.XX   
                        X.X hrs postdose  X     DDMMMYYYY     XX:XX   XXXX.XX      XX.XX       X.XX        XXXX.XX      XX.XX   
                        X hrs postdose    X     DDMMMYYYY     XX:XX   XXXX.XX       X.XX       X.XX        XXXX.XX      XX.XX   
                        X hrs postdose    X     DDMMMYYYY     XX:XX   XXXX.XX       X.XX       X.XX        XXXX.XX      XX.XX   
                       XX hrs postdose    X     DDMMMYYYY     XX:XX  XXXXX.XX       X.XX       X.XX        XXXX.XX      XX.XX   
                       XX hrs postdose    X     DDMMMYYYY     XX:XX   XXXX.XX       X.XX       X.XX        XXXX.XX      XX.XX   
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program:  /AAXXXXX/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM  
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 134 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.2.22  Baseline Dyspnea Index 
  
                       Visit           
Subject  Treat- --------------------   Date of      Functional   Magnitude   Magnitude     
Number   ment    Name       Date       Assessment   Impairment   of Task     of Effort                          
---------------------------------------------------------------------------------------- 
    X     X     Screening  DDMMMYYYY   DDMMMYYYY    XXXXXXXXXX   XXXXXXXXXX  XXXXXXXXXX                                                            
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 135 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.2.23  Transition Dyspnea Index 
  
                        Visit                                    Change in    Change in   Change in  
Subject  Treat-  --------------------  Planned      Date of      Functional   Magnitude   Magnitude     
Number   ment     Name       Date      Time Point   Assessment   Impairment   of Task     of Effort                          
----------------------------------------------------------------------------------------------------- 
    X     X      Screening  DDMMMYYYY     XX        DDMMMYYYY    XXXXXXXXXX   XXXXXXXXXX  XXXXXXXXXX                                                         
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 136 of 150 
 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.2.24  Pulmonary Function Test (Spirometry) 
  
                      Visit                                          Assessment    Pre/                           Result                         
Subject  Treat-  ---------------   Planned    Pulmonary Function  ---------------  Post/    Test      -------------------------------     
Number   ment     Name  Date       Time Point Test Performed?       Date     Time  Change^  Type      Actual  Predicted  Percent (%)     
------------------------------------------------------------------------------------------------------------------------------------- 
    X     X       XXX   DDMMMYYYY     XX            Yes           DDMMMYYYY HH:MM  Pre      FVC (L)     XX        XX         XX                              
                                                                                            FEV1(L)     XX        XX         XX 
                                                                                            FEV1/FVC    XX        XX         XX 
                                                                                            IC (L)      XX        XX         XX 
 
 
 
 
 
 
 
 
 
 
 
FEV1 = forced expiratory volume in one second, FVC = forced vital capacity, IC = inspiratory capacity, L = liter 
^ Pre- and Post-Bronchodilator, Change = Post- minus Pre- 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Programmers note: Please calculate Change and present this as the 3rd category. 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 137 of 150 
 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.2.25  Change from Baseline in Pulmonary Function Test (Spirometry) 
  
                      Visit                   Pre/                          Baseline                             Change from Baseline         
Subject  Treat-  ---------------   Planned    Post/   Test      -------------------------------   Test      ------------------------------ 
Number   ment     Name  Date       Time Point Change^ Type      Actual  Predicted  Percent (%)    Type      Actual  Predicted  Percent (%)  
------------------------------------------------------------------------------------------------------------------------------------------ 
    X     X       XXX   DDMMMYYYY     XX      Pre     FVC (L)     XX        XX         XX         FVC (L)     XX        XX         XX                        
                                                      FEV1(L)     XX        XX         XX         FEV1(L)     XX        XX         XX 
                                                      FEV1/FVC    XX        XX         XX         FEV1/FVC    XX        XX         XX 
                                                      IC (L)      XX        XX         XX         IC (L)      XX        XX         XX 
 
 
 
 
 
 
 
 
 
 
FEV1 = forced expiratory volume in one second, FVC = forced vital capacity, IC = inspiratory capacity 
^ Pre- and Post-Bronchodilator, Change = Post- minus Pre- 
Baseline is Check-in measurement. 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 138 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.6.2.26  COPD Assessment Test 
  
                                                     Rate        Rate       Rate      Rate        Rate       Rate       Rate                                 
                Visit     Planned             Rate   Mucus       Chest      Breath-   Level of    Level of   Level of   Level of  
Subject  Treat- Name/     Time    Date of     Cough  Production  Tightness  lessness  Activities  Confidence Sleepiness Energy    Total   
Number   ment   Date      Point   Assessment  (0-5)  (0-5)       (0-5)      (0-5)     (0-5)       (0-5)      (0-5)      (0-5)     Score                     
---------------------------------------------------------------------------------------------------------------------------------------- 
    X     X     XXXX/     XX      DDMMMYYYY   X      X           X          X         X           X           X            X      XX                         
                DDMMMYYYY 
 
 
 
 
 
 
 
 
 
Cough: 0 = I never cough, 5 = I cough all the time 
Mucus Production: 0 = I have no phlegm (mucus) in my chest at all, 5 = My chest is completely full of phlegm (mucus) 
Chest Tightness: 0 = My chest does not feel tight at all, 5 = My chest feels very tight 
Breathlessness: 0 = When I walk up a hill or one flight of stairs I am not breathless, 5 = When I walk up a hill or one flight of stairs I  
am very breathless 
Level of Activities: 0 = I am not limited doing any activities at home, 5 = I am very limited doing any activities at home 
Level of Confidence: 0 = I am confident leaving my home despite my lung condition, 5 = I am not at all confident leaving my home because of 
my lung condition 
Level of Sleepiness: 0 = I sleep soundly, 5 = I don't sleep soundly because of my lung condition 
Level of Energy: 0 = I have lots of energy, 5 = I have no energy at all 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 139 of 150 
                                                                                                                   Page 1 of X 
 
                                        Appendix 16.2.7.1  Adverse Events (I of III) 
 
 
                                                                Time From                                             
                                                                   Dose          Start            End         Duration  
Subject  Treat-    AE                                           ----------  --------------- ---------------  ------------ 
Number    ment   Number  TE?^  Adverse Event    Preferred Term*  (DD:HH:MM)   Date    Time    Date    Time   (DD:HH:MM)    Ongoing? 
----------------------------------------------------------------------------------------------------------------------------------- 
   X      X        X     Yes   XXXXXXXXXXXXX     XXXXXXXXXXXXX    XX:XX:XX  DDMMMYYYY HH:MM DDMMMYYYY HH:MM   XX:XX:XX      XXXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
^ = Abbreviation for treatment-emergent, * = Adverse events are classified according to MedDRA Version 18.0.                                                 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 140 of 150 
                                                                                                                   Page 1 of X 
                                       Appendix 16.2.7.2  Adverse Events (II of III) 
 
                                                                                               
                                     Start                             Relationship    Action Taken                         
Subject              Adverse    ---------------                            to            With           Other  
Number   Treatment   Event        Date    Time   Severity   Outcome     Study drug     Study Drug       Action 
----------------------------------------------------------------------------------------------------------------------                
  X         X        XXXXXXXXX DDMMMYYYY  XX:XX   Mild      Recovered/  XXXXXXXX       XXXXXXXXX       XXXXXXXX 
                                                            Resolved 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 141 of 150 
Page 1 of X 
 
                                       Appendix 16.2.7.3  Adverse Events (III of III) 
 
                                                                     
                                       Start                                 Serious Criteria *                                   
Subject                Adverse    ---------------                ---------------------------------------------    
Number    Treatment    Event        Date    Time   Serious         1       2       3        4      5       6  
--------------------------------------------------------------------------------------------------------------                
  X           X        XXXXXXXXX DDMMMYYYY  XX:XX    YES          XXX     XXX     XXX      XXX    XXX     XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Only subjects who reported adverse events during the study were included in the listing.   
* Serious Criteria: 1 = Death, 2 = Life Threatening, 3 = Initial or Prolonged Hospitalization 
                    4 = Persistent or Significant Disability or Incapacity, 5 = Congenital Anomaly or Birth Defect 
                    6 = Other Serious or Important Medical Events                                                                         
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 142 of 150 
                                                                                                                   Page 1 of X 
 
                                         Appendix 16.2.7.4  Adverse Event Non-Drug Therapy 
 
                                                 Start                    Therapy                
      Subject                  Adverse      --------------- ------------------------------------ 
      Number     Treatment     Event          Date    Time  Date      Time  Description          
      ------------------------------------------------------------------------------------------ 
          X          X         DRY LIPS     DDMMMYYYY XX:XX DDMMMYYYY XX:XX PETROLEUM JELLY      
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 143 of 150 
                                                                                                                   Page 1 of X 
                                                               
                              Appendix 16.2.7.5  Adverse Event Preferred Term Classification 
 
                                                                                                             Start      
 Subject               Adverse                                                                          ---------------- 
 Number    Treatment   Event                      Preferred Term*            System Organ Class           Date    Time  
 ----------------------------------------------------------------------------------------------------------------------- 
    X          X       XXXXXXX XXXXX XXXX XXXXXX  XXXXXXXXXX XXXXXXX         XXXXXXXXXXXXXXXXXXXXX      DDMMMYYYY  XX:XX 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* Adverse events are classified according to MedDRA Version 18.0.                                                  
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
   


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 144 of 150 
Note: Appendices 16.2.8.2 and 16.2.8.3 will have the following format. 
 
                                                                                                                   Page 1 of X 
                             Appendix 16.2.8.1  Clinical Laboratory Report - Serum Chemistry  
  
                                                                                                                                        
                       Visit                    Collection                    Reference             Reference   
Subject  Age/   -------------------  Treat-  ----------------                 Range          Result Range          Result                                    
Number   Gender  Name     Date       ment    Date       Time   Parameter      (Unit)         Flag   (SI Unit)      (SI Unit) Comments    
------------------------------------------------------------------------------------------------------------------------------------------ 
  X      XX/X   Screening DDMMMYYYY    X     DDMMMYYYY  HH:MM  XXXXXXXXXXXXX  XX – XX (unit) XX HN  XX – XX (unit) XX        XXXXXXXXXXXXX     
                XXXX      DDMMMYYYY          DDMMMYYYY  HH:MM  XXXXXXXXXXXXX  XX – XX (unit) XX LY  XX – XX (unit) XX        XXXXXXXXXXXXX     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abnormal Flag: H = Above Reference Range, L = Below Reference Range                                                                                         
Clinical Significance: N = Not Clinically Significant, Y = Clinically Significant                                                                         
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 145 of 150 
                                                          
                                                                                                                   Page 1 of X 
Appendix 16.2.8.4  Urine Alcohol and Drug Screen 
  
                      
                  Visit                  Was the              
Subject   -------------------   Treat-   Lab Sample     Planned       Date of 
Number     Name         Date     ment    Collected?     Time Point    Collection    Test          Result 
------------------------------------------------------------------------------------------------------------- 
   X      Screening  DDMMMYYYY    X       XXXXXXX          XX         DDMMMYYYY     XXXXXXX       NEGATIVE    
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 146 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.8.5  Pregnancy Test 
  
                      
                Visit                           
Subject   -------------------               Was the Pregnancy    Reason for    Test        Date of   
Number    Name         Date      Treatment    Test Done?         Not Done      Type      Collection      Result      
------------------------------------------------------------------------------------------------------------------- 
   X      Screening  DDMMMYYYY       X          XXX                XXXX        XXXXXX    DDMMMYYYY       NEGATIVE    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 147 of 150 
                                                                                                                   Page 1 of X 
Appendix 16.2.8.6  Serology 
  
                Visit                        
Subject   -------------------               Sample      Date of       Hepatitis B  Hepatitis C  HIV                               
Number    Name         Date      Treatment  Collected?  Collection    Result       Result       Result   
-------------------------------------------------------------------------------------------------------- 
   X      Screening  DDMMMYYYY       X        Yes       DDMMMYYYY     XXXXXX       XXXXXX       XXXXXX                                                  
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 148 of 150 
                                                                                                                   Page 1 of X 
                                                      Appendix 16.2.8.7  Vital Signs 
  
 
                                                                    Blood Pressure                            Oxygen 
                      Visit                                              (mmHg)       Heart  Respir- Temper-  Satur-              
Subject Treat- -------------------  Planned                       ------------------  Rate   ation   ature    ation    Weight         
Number  ment   Name       Date     Time Point   Date    Time Test Systolic/Diastolic (bpm)  (rpm)     (°C)     (% )    (kg)           
------------------------------------------------------------------------------------------------------------------------------     
   X     X     Screening DDMMMYYYY XXXXXXXX  DDMMMYYYY HH:MM XXXX     XXX/ XX           XX     XX     XX.X      XX     XXX.X                   
               XXXXX     DDMMMYYYY XXXXXXXX  DDMMMYYYY HH:MM                                                           XXX.X                  
                         DDMMMYYYY XXXXXXXX  DDMMMYYYY HH:MM          XXX/ XX           XX     XX                                 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
  
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                                


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 149 of 150 
                                                                                                                   Page 1 of X 
                                               Appendix 16.2.8.8  12-Lead Electrocardiogram 
  
 
                    Visit                        Assessment               Heart                                  If 
Subject Treat- ----------------     Planned   ---------------    ECG      Rate   PR    RR    QRS    QT    QTcB*  Abnormal,       
Number   ment   Name       Date     Time Point  Date     Time    Result  (bpm) (msec)(msec)(msec) (msec) (msec)  Specify 
-------------------------------------------------------------------------------------------------------------------------- 
   X      X    Screening  DDMMMYYYY  XXXXXX   DDMMMYYYY HH:MM    XXXXXX   XXX    XXX   XXX   XXX    XXX    XXX        
               XXXXX      DDMMMYYYY  XXXXXX   DDMMMYYYY HH:MM    XXXXXX   XXX    XXX   XXX   XXX    XXX    XXX   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* QTcB = QT corrected for heart rate using Bazett’s Correction 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM                                                               
 
 


Yungjin Pharm. CO., LTD. 
YPL-001, Project Number YPL-001-YJP-130403 
Celerion, Clinical Study Report No. AA98497 
 
Statistical Analysis Plan 
20 March 2017 
 
Page 150 of 150 
                                                                                                                   Page 1 of X 
 
                                         Appendix 16.2.8.9  Telephone Contact 
 
      Subject                Was Subject    Reason Subject     Date of                                           
      Number     Treatment   Contacted?     Not Contacted      Contact            
      -------------------------------------------------------------------- 
          X          X          Yes         XXXXXXXXXX         DDMMMYYYY        
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A:  Multiple oral doses of YPL-001 80 mg BID on Days 1 – 55 
Treatment B:  Multiple oral doses of YPL-001 160 mg BID on Days 1 – 55 
Treatment C:  Multiple oral doses of placebo BID on Days 1 – 55 
Note:  Patients following up to Amendment version 5 of the protocol also received a morning dose on Day 56. 
 
 
 
Program:  /AAXXXXX/ECR/sas_prg/stsas/lis_PROGRAMNAME.sas  DDMMMYYYY  HH:MM