Study Regarding the Clinical Efficacy of Synatura® in Patients With Chronic Bronchitis Type COPD
Phase: PHASE4
Conditions: Bronchitis, COPD
Sponsor: Ahn-Gook Pharmaceuticals Co.,Ltd

IRB of The Catholic University of Korea/Catholic Medical Center 
Form 1_v4_141125 Revised 
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Clinical Study Protocol 
1. Title and Phase of Study  
Title: Study regarding the clinical efficacy of Synatura® in patients with chronic bronchitis type COPD 
Phase: Interventional, single center, single group, open-label study 
2. Name and Address of Study Site  
Site Name: The Catholic University of Korea Seoul St. Mary’s Hospital  
Address: 222, Banpo-daero, Seocho-gu, Seoul, Republic of Korea 
3. Name and Title of Principal Investigator, Subinvestigator and co-investigator 
Role 
Name 
Affiliation 
Title 
Contact  
(Mobile) 
Principal  
Investigator 
Chin Kook Rhee 
Pulmonology  
and Allergy 
Associate Professor 
82-10-2285-9601 
 
4. Name and Title of Clinical Research Pharmacist  
Not applicable: the study drug (Synatura®) is currently approved by Korean Ministry of  Food and Drug 
Safety (MFDS) and prescribed for patients with chronic bronchitis, and this is an open-label study with 
no placebo.  
5. Name and Address of Sponsor  
Ahngook Pharm(613, Siheung-daero, Yeongdeungpo-gu, Seoul, Republic of Korea) 
6. Background and objectives of Study  
Synatura® is a drug commonly used to suppress cough and sputum in patients with acute upper 
respiratory tract infection and chronic inflammatory bronchitis. According to the Phase III studies 
conducted in Korea, the safety and efficacy of Synatura® on antitussive and expectorant effects were 
confirmed in patients with acute upper respiratory infection and chronic inflammatory bronchitis. 
However, no studies have been conducted for the effects of Synatura® in patients with COPD. COPD is 
divided into emphysema type and chronic bronchitis type, while typical clinical symptoms of chronic 
bronchitis are cough and sputum. Therefore, Synatura®, which is effective for chronic bronchitis, is 
expected to be effective in patients with chronic bronchitis accompanied by COPD.  
 Primary Objective:  
Establish clinical efficacy of Synatura® in patients with chronic bronchitis-type chronic obstructive 
pulmonary disease  

IRB of The Catholic University of Korea/Catholic Medical Center 
Form 1_v4_141125 Revised 
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① Primary endpoint:  
Establish the effect of Synatura® on patient’s symptoms in patients with chronic bronchitis-type 
chronic obstructive pulmonary disease – Reduction of COPD assessment test (CAT) score and 
Bronchitis severity score (BSS)  
 Secondary Objective:  
① Secondary endpoints:  
Establish the effect of Synatura® on patient’s pulmonary functions in patients with chronic 
bronchitis-type chronic obstructive pulmonary disease 
Establish the effect of Synatura® on systemic inflammation in patients with chronic bronchitis-type 
chronic obstructive pulmonary disease  
7. Investigational Product Information 
1) Active Ingredient: Coptis Rhizome butanol dried extract (4.5-7→1) 87.5 mg ·  
               Ivy leaf 30% ethanol extract (5-7.5→1) 262.5 mg in 100 mL 
2) Indication: Cough and sputum due to the following illness: acute upper respiratory tract infection  
and chronic inflammatory bronchitis  
3) Side Effects: Nausea, vomiting, dizziness, etc. Please follow Precautions on the package insert  
for details. 
4) Handling and Storage: After registering the study code, Synatura® will be prescribed as a  
“drug from the inside pharmacy” and dispensed to patients. 
8. Indication 
Chronic bronchitis-type chronic obstructive pulmonary disease 
9. Inclusion Criteria, Exclusion Criteria, Sample Size and Rationale  
Inclusion Criteria: 
1) Post bronchodilator FEV1/FVC < 0.7 
2) Smoking history of 10 pack-years 
3) 40 to <75 years of age 
4) Patients with symptoms of chronic bronchitis (in case they have symptoms of cough or sputum over 3 
months)  
Exclusion Criteria: 
1) Patients with acute exacerbation 
2) Patients with pneumonia 
3) Patients with active tuberculosis 

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Form 1_v4_141125 Revised 
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4) Pregnant women 
5) Breast-feeding women 
6) Patients with fructose intolerance  
 
Sample size: 30 subjects  
 
Rationale: 
The primary outcome of this study is CAT reduction after taking Synatura®. 
The margin of error was set at 3 points. Also, the standard deviation of the CAT score is reported to be 
7.7 from the previous study (Int J Chron Obstruct Pulmon Dis. 2015;10:1623-1631). Assuming Alpha to 
be 0.05, beta 0.2, 25.307 subjects will be calculated. Assuming a drop rate of 0.15, 29.773 subjects will 
be required.  
10. Study Period  
From approval date of the study to 31 December 2018  
11. Clinical Study Methods (including Dose, Treatment Method, Treatment Period and 
Concomitant Medications)  
1) Overview 
The clinical study on the effect of Synatura® will be conducted in COPD patients with symptoms of 
chronic bronchitis. The enrolled patients will be prescribed Synatura® following measurement of 
pre-dose pulmonary functions, quality of life and systemic inflammatory state. Pulmonary functions, 
quality of life and systemic inflammatory state will be repeatedly measured after taking Synatura® for 3 
months, and the changes from pre-dose measurements will be observed. 
2) Group: Single group  
3) Study drug: Synatura® 15 mL TID for 3 months 
Patients will be administered the above drug, and changes from pre-dose measurements will be observed. 
① Changes from pre-dose measurement in pulmonary functions will be observed (FVC, FEV1, post 
bronchodilator FVC, FEV1). 
② Changes from pre-dose scores in quality of life will be observed (COPD assessment test - CAT). 
③ Changes from pre-dose measurement in systemic inflammatory state will be observed (CRP, 
fibrinogen, IL-6, TNF-a). 
 
 

IRB of The Catholic University of Korea/Catholic Medical Center 
Form 1_v4_141125 Revised 
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Item 
At enrollment 
After 3 months 
Pulmonary functions 
O 
O 
CAT  
O 
O 
BSS  
O 
O 
CRP  
O 
O 
fibrinogen  
O 
O 
IL-6  
O 
O 
TNF-a  
O 
O 
4) Prohibited concomitant medications 
Xanthine derivatives (aminophylline, theophylline, choline theophyllinate, oxtriphylline), central nervous 
system stimulants (cocaine, amphetamine, codeine), antitussives and expectorants except for the study 
drug 
5) Cost for procedures 
In the case of pulmonary function test performed before and after treatment, it will be prescribed as a 
non-covered item and the actual cost of the test is paid the subject back. 
6) Transportation cost 
Patients participating in the study will be paid 50,000 KRW per visit. 
7) Cost for study drug 
Synatura® will be prescribed for 3 months, and patients will receive the drug at the pharmacy in the study 
site. The cost for study drug will be paid from the research fund as a non-covered drug. 
12. Observation Items/Clinical Test Items, Observation and Test Methods 
1) Pulmonary functions - pulmonary function test will be performed before and 3 months after taking 
Synatura®. 
2) Quality of life - CAT score and BSS will be performed before and 3 months after taking Synatura®. 
3) Systemic Inflammation - blood samples will be taken before and 3 months after taking Synatura®, 
then stored and measured by ELISA in the laboratory. 
13. Expected Side Effects and Precautions 
According to the results of previous phase III studies, nausea, vomiting and dizziness can occur after 
taking Synatura®. Most of them are mild side effects and severe side effects that require medical 
interventions are not expected to occur. Currently, Synatura® is approved by the Ministry of Food and 
Drug Safety in March 2011, and widely used in clinical practice. In the 4-year post-marketing survey 
conducted in 606 patients for re-examination in Korea, the incidence of adverse events was reported to be 
2.64% (16/606 patients, 16 cases) regardless of the causal relationship. No significant adverse events 
have been reported. 

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14. Discontinuation/Withdrawal Criteria  
If the patient no longer wants to participate in the study  
15. Evaluation Criteria, Evaluation Methods and Analysis Methods for Efficacy 
(Statistical Analysis Method)  
The paired t-test will be used to establish the statistical significance of changes pre-dose measurement. 
1) Changes from pre-dose measurement in pulmonary functions will be observed (FVC, FEV1, post 
bronchodilator FVC, FEV1). 
2) Changes from pre-dose scores in quality of life will be observed (COPD assessment test - CAT). 
3) Changes from pre-dose measurement in systemic inflammatory state will be observed (CRP, 
fibrinogen, IL-6, TNF-a). 
16. Evaluation Criteria, Evaluation Methods and Reporting Methods for Safety 
(including Side Effects)  
Side effects evaluation criteria and evaluation methods - in the investigator’s opinion, severity based on 
CTCAE 4.0, relationship to study drug and actions will be determined. 
Reporting adverse events 
Suspected unexpected serious adverse reactions will be reported to IRBs immediately. 
Suspected unexpected serious adverse reactions will be reported within following timeframe:  
① Causes death or be life-threatening: within 7 days 
② For other suspected unexpected serious adverse reactions: within 15 days. 
17. Agreement on Compensation for Victims  
1) For the safe characteristics of Synatura®, which will be administered in this study, it is considered that 
the risk to a victim is extremely low. 
2) Any serious adverse events or unexpected problems should be reported to IRBs immediately (within 
24 hours). 
3) In case of damage due to participation in the study, study staffs will be notified and patients will be 
received urgent emergency treatment by staffs from Department of Pulmonology and Allergy. 
It will also be reimbursed under the responsibility of the principal investigator for all medical problems 
that arise. 
4) Insured for compensation. 
18. Care and Treatment Criteria for subjects after the Study  
After the end of the study, patients may continue to take Synatura® or discontinue. After the end of the 

IRB of The Catholic University of Korea/Catholic Medical Center 
Form 1_v4_141125 Revised 
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study, continuation of taking Synatura® will be decided by the investigator based on the patient's 
symptoms (cough and sputum). 
19. Measures to Protect the Safety of Subjects  
1) Voluntary consent will be obtained from the subject based on sufficient explanation and understanding 
of the study. 
2) Personal identification number (resident registration number, case number, name) of the subject will 
not be collected. 
3) Extracted information will be safely stored for 5 years to prevent leakage, and discarded completely. 
4) After extracting the data, the patient ID will be used after substituting with an alternative key. Access 
to the file will be limited to the person in charge of the study conduct and analysis  
20. Other Necessary Details for safe and scientific implementation of Study 
In case of damage due to participation in the study, study staffs will be notified and patients will be 
received urgent emergency treatment by staffs from Department of Pulmonology and Allergy. 
Attachments: □ Informed Consent Form, □ Case Report Form □ Two references